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High resting heart rate (RHR) is associated with higher mortality in the general population and in cardiovascular disease. Less is known about the association of RHR with outcome in chronic obstructive pulmonary disease (COPD). In particular, the time-updated RHR (most recent value before the event) appears informative. This is the first study to investigate the association of time-updated RHR with mortality in COPD. We compared the baseline and time-updated RHR related to survival in 2218 COPD patients of the German COSYCONET cohort (COPD and Systemic Consequences—Comorbidities Network). Patients with a baseline RHR > 72 beats per minute (bmp) had a significantly (p = 0.049) higher all-cause mortality risk (adjusted hazard ratio (HR) of 1.37 (1.00–1.87) compared to baseline RHR ≤ 72 bpm. The time-updated RHR > 72 bpm was markedly superior (HR 1.79, 1.30–2.46, p = 0.001). Both, increased baseline and time-updated RHR, were independently associated with low FEV1, low TLCO, a history of diabetes, and medication with short-acting beta agonists (SABAs). In conclusion, increased time-updated RHR is associated with higher mortality in COPD independent of other predictors and superior to baseline RHR. Increased RHR is linked to lung function, comorbidities and medication. Whether RHR is an effective treatment target in COPD, needs to be proven in controlled trials.

Aims: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases are thought to be linked through various factors. We aimed to assess the relationship between airway obstruction, lung hyperinflation and diastolic filling in COPD. Methods: The study population was a subset of the COPD cohort COSYCONET. Echocardiographic parameters included the left atrial diameter (LA), early (E) and late (A) transmitral flow, mitral annulus velocity (e'), E wave deceleration time (E[dt]), and isovolumic relaxation time (IVRT). We quantified the effect of various predictors including forced expiratory volume in 1 s (FEV1) and intrathoracic gas volume (ITGV) on the echocardiographic parameters by multiple linear regression and integrated the relationships into a path analysis model. Results: A total of 615 COPD patients were included (mean FEV1 52.6% predicted). In addition to influences of age, BMI and blood pressure, ITGV was positively related to e'-septal and negatively to LA, FEV1 positively to E(dt) (p < 0.05 each). The effect of predictors was most pronounced for LA, e'-septal and E(dt), and less for E/A, IVRT and E/e'. Path analysis was used to take into account the additional relationships between the echocardiographic parameters themselves, demonstrating that their associations with the predictors were maintained and robust. Conclusions: Airway obstruction and lung hyperinflation were significantly associated with cardiac diastolic filling in patients with COPD, suggesting a decreased preload rather than an inherently impaired myocardial relaxation itself. This suggests that a reduction in obstruction and hyperinflation could help to improve cardiac filling.

Introduction The COPD classification proposed by the Global Initiative for Obstructive Lung Disease was recently revised, and the A to D grouping is now based on symptoms and exacerbations only. Potential associations with comorbidities have not been assessed so far. Thus the aim of the present study was to determine the relationship between the revised (2017) GOLD groups A-D and major comorbidities. Methods We used baseline data from the COPD cohort COSYCONET. Comorbidities were identified from patient self-reports and disease-specific medication: gastrointestinal disorders, asthma, sleep apnea, hyperuricemia, hyperlipidemia, diabetes, osteoporosis, mental disorders, heart failure, hypertension, coronary artery disease. The A-D groups were based on either the COPD Assessment Test or the modified Medical Research Council scale. Exacerbations were also categorized as per GOLD recommendations. Results Data from 2228 patients were analyzed. Using GOLD group A as a reference, group D was associated with nearly all comorbidities, followed by group B and C. When groups A-D were dichotomized as AC vs. BD (symptoms) and AB vs. CD (exacerbations), all comorbidities correlated with symptoms and/or exacerbations. This was true for both mMRC- and CAT-based categorizations. Conclusions These findings suggest that the recently modified GOLD categorization is clinically relevant beyond being purely an assessment of symptoms and exacerbations. As the A-D groups correlated with the risk of important comorbidities, with some differences in terms of the correlation with symptoms and exacerbations, the findings underline the importance of identifying comorbidities in COPD, particularly in non-responders to therapy who have high symptoms and/or exacerbation rates.

Background Adherence to COPD medication is often considered to be lower than in other chronic diseases. In view of the frequent comorbidities of COPD, the economic impact of nonadherence and the potential for adverse effects, a direct comparison between the adherence to respiratory and nonrespiratory medication in the same patients seems of particular interest. Objectives We aimed to investigate the intake of respiratory and nonrespiratory medication in the same patients with COPD and frequent comorbidities. Method Within the COPD cohort COSYCONET, we contacted 1042 patients, mailing them a list with all medication regarding all their diseases, asking for regular, irregular and non-intake. Results Valid responses were obtained in 707 patients covering a wide spectrum of drugs. Intake of LABA, LAMA or ICS was regular in 91.9% of patients, even higher for cardiovascular and antidiabetes medication but lower for hyperlipidemia and depression/anxiety medication. Regular intake of respiratory medication did not depend on GOLD groups A-D or grades 1-4, was highest in patients with concomitant cardiovascular disorders and was lowest for concomitant asthma. It was slightly larger for LAMA and LABA administered via combined compared to single inhalers, and lower when similar compounds were prescribed twice. Most differences did not reach statistical significance owing to the overall high adherence. Conclusion Our results indicate a high adherence to respiratory medication in participants of a COPD cohort, especially in those with cardiovascular comorbidities. Compared to the lower adherence reported in the literature for COPD patients, our observations still suggest some room for improvement, possibly through disease management programs.

Background: Bronchiectasis is known to be associated with COPD. We studied which degree of radiological alterations was associated with clinical signs of bronchiectasis in COPD. Methods: Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was analysed. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0-2), resulting in a total score of 0-12. We also included data from disease-specific questionnaires, medication, and lung function. Results: 1176 patients were included (mean age 67.3y, 61.1% males), among them 38 (3.2%) with patient-reported physicians’ diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). 429 patients had CT scans, with any signs of bronchiectasis in 46.6%, less than 50% bronchiectasis in ≤2 lobes in 18.6%, in 3-4 lobes in 10.0%, in 5-6 lobes in 15.9%, and more than 50% bronchiectasis in at least 1 lobe in 2.1%. Scores ≥4 were linked to elevated FRC/RV. Links to sputum production, composition (n=105) or inflammatory indices were borderline or absent. Triple therapy was associated with symptoms, but not radiological signs of bronchiectasis. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. AA1D was associated with radiological signs of bronchiectasis and only borderline with the clinical diagnosis. Conclusion: Clinical diagnosis and radiological signs of bronchiectasis showed only weak correlations in COPD patients. For a significant correspondence to symptoms and diagnosis, a threshold CT score implying radiological alterations in several lobes was needed, which was about one third of the maximum score.

Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of death, reducing life expectancy on average between 5 and 7 years. The survival time after diagnosis, however, varies considerably as a result of the heterogeneity of COPD. Therefore, markers that predict individual survival of COPD patients are of great value. We analyzed baseline molecular profiles and collected 54 months of follow-up data of the cohort study &ldquo, COPD and SYstemic consequences-COmorbidities NETwork&rdquo, (COSYCONET). Genome-wide microRNA signatures from whole blood collected at time of the inclusion in the study were generated for 533 COPD patients including patients that deceased during the 54-month follow-up period (n = 53) and patients that survived this period (n = 480). We identified two blood-born microRNAs (miR-150-5p and miR-320b) that were highly predictive for survival of COPD patients. The expression change was then confirmed by RT-qPCR in 245 individuals. Ninety percent of patients with highest expression of miR-150-5p survived the 54-month period in contrast to only 50% of patients with lowest expression intensity. Moreover, the abundance of the oncogenic miR-150-5p in blood of COPD patients was predictive for the development of cancer. Thus, molecular profiles measured at the time of a COPD diagnosis have a high predictive power for the survival of patients.

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients.

Chronic obstructive pulmonary disease (COPD) significantly increases the risk of developing cancer. Biomarker studies frequently follow a case-control set-up in which patients diagnosed with a disease are compared to controls. Longitudinal cohort studies such as the COPD-centered German COPD and SYstemic consequences-COmorbidities NETwork (COSYCONET) study provide the patient and biomaterial base for discovering predictive molecular markers. We asked whether microRNA (miRNA) profiles in blood collected from COPD patients prior to a tumor diagnosis could support an early diagnosis of tumor development independent of the tumor type. From 2741 participants of COSYCONET diagnosed with COPD, we selected 534 individuals including 33 patients who developed cancer during the follow-up period of 54 months and 501 patients who did not develop cancer, but had similar age, gender and smoking history. Genome-wide miRNA profiles were generated and evaluated using machine learning techniques. For patients developing cancer we identified nine miRNAs with significantly decreased abundance (two-tailed unpaired t-test adjusted for multiple testing P

High resting heart rate (RHR) is associated with higher mortality in general population and in cardiovascular disease. Less is known about the association of RHR with outcome in chronic obstructive pulmonary disease (COPD). This study investigated the influence of RHR on survival of 2741 COPD patients in the multicentre cohort study COSYCONET (German COPD and Systemic Consequences – Comorbidities Network). Patients with a baseline RHR >72 beats per minute (bbp) had a significantly (p=0.049) higher all-cause mortality risk (adjusted hazard ratio (HR) of 1.37 (1.00-1.87) compared to baseline RHR 72 bpm separates risk more precisely (HR 1.82, 1.22-2.50, p=0.0001) than baseline RHR. In conclusion, an increased RHR is independently associated with a higher mortality in patients with COPD. These results show that RHR, especially time-updated RHR, represents an independent predictor for mortality in COPD. Whether RHR is a treatment target needs to be proven in controlled trials.

Background Adherence to COPD medication is often considered to be lower than in other chronic diseases. In view of the frequent comorbidities of COPD, the economic impact of nonadherence and the potential for adverse effects, a direct comparison between the adherence to respiratory and nonrespiratory medication in the same patients seems of particular interest. Objectives We aimed to investigate the intake of respiratory and nonrespiratory medication in the same patients with COPD and frequent comorbidities. Method Within the COPD cohort COSYCONET, we contacted 1042 patients, mailing them a list with all medication regarding all their diseases, asking for regular, irregular and non-intake. Results Valid responses were obtained in 707 patients covering a wide spectrum of drugs. Intake of LABA, LAMA or ICS was regular in 91.9% of patients, even higher for cardiovascular and antidiabetes medication but lower for hyperlipidemia and depression/anxiety medication. Regular intake of respiratory medication did not depend on GOLD groups A-D or grades 1–4, was highest in patients with concomitant cardiovascular disorders and was lowest for concomitant asthma. It was slightly larger for LAMA and LABA administered via combined compared to single inhalers, and lower when similar compounds were prescribed twice. Most differences did not reach statistical significance owing to the overall high adherence. Conclusion Our results indicate a high adherence to respiratory medication in participants of a COPD cohort, especially in those with cardiovascular comorbidities. Compared to the lower adherence reported in the literature for COPD patients, our observations still suggest some room for improvement, possibly through disease management programs.

Background The German COPD cohort study COSYCONET (" CO PD and SY stemic consequences- CO morbidities NET work") investigates the interaction of lung disease, comorbidities and systemic inflammation. Recruitment took place from 2010 to 2013 in 31 study centers. In addition to the baseline visit, follow-up visits are scheduled at 6, 18, 36 and 54 months after baseline. The study also comprises a biobank, image bank, and includes health economic data. Here we describe the study design of COSYCONET and present baseline data of our COPD cohort. Methods Inclusion criteria were broad in order to cover a wide range of patterns of the disease. In each visit, patients undergo a large panel of assessments including e.g. clinical history, spirometry, body plethysmography, diffusing capacity, blood samples, 6-min walk-distance, electrocardiogram and echocardiography. Chest CTs are collected if available and CTs and MRIs are performed in a subcohort. Data are entered into eCRFs and subjected to several stages of quality control. Results Overall, 2741 subjects with a clinical diagnosis of COPD were included (59% male; mean age 65 ± 8.6 years (range 40–90)). Of these, 8/35/32/9% presented with GOLD stages I–IV; 16% were uncategorized, including the former GOLD-0 category. 24% were active smokers, 68% ex-smokers and 8% never-smokers. Data completeness was 96% for the baseline items. Conclusion The German COPD cohort comprises patients with advanced and less advanced COPD. This is particularly useful for studying the time course of COPD in relation to comorbidities. Baseline data indicate that COSYCONET offers the opportunity to investigate our research questions in a large-scale, high-quality dataset.

Background: Cardiovascular comorbidities are common in chronic obstructive pulmonary disease (COPD). We examined the association between airflow limitation, hyperinflation and the left ventricle (LV). Methods: Patients from the COPD cohort COSYCONET underwent evaluations including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), effective airway resistance (Reff), intrathoracic gas volume (ITGV), and echocardiographic LV end-diastolic volume (LVEDV), stroke volume (LVSV), end-systolic volume (LVESV), and end-diastolic and end-systolic LV wall stress. Data from Visit 1 (baseline) and Visit 3 (18 months later) were used. In addition to comparisons of both visits, multivariate regression analysis was conducted, followed by structural equation modelling (SEM) with latent variables “Lung” and “Left heart”. Results: A total of 641 participants were included in this analysis. From Visit 1 to Visit 3, there were significant declines in FEV1 and FEV1/FVC, and increases in Reff, ITGV and LV end-diastolic wall stress, and a borderline significant decrease in LV mass. There were significant correlations of: FEV1% predicted with LVEDV and LVSV; Reff with LVSV; and ITGV with LV mass and LV end-diastolic wall stress. The SEM fitted the data of both visits well (comparative fit index: 0.978, 0.962), with strong correlation between “Lung” and “Left heart”. Conclusions: We demonstrated a relationship between lung function impairment and LV wall stress in patients with COPD. This supports the hypothesis that LV impairment in COPD could be initiated or promoted, at least partly, by mechanical factors exerted by the lung disorder.

Background: Chronic obstructive pulmonary disease (COPD) is associated with a significant burden of comorbidity. Systemic inflammation has been proposed as a potential mechanism linking COPD and cardiovascular diseases. The aim of this study was to characterize blood levels of inflammatory biomarkers and to identify an inflammatory phenotype in COPD. Methods: Analysis of baseline data from the German COPD cohort COSYCONET. 2739 patients (GOLD 0-IV) were analyzed. A panel of inflammatory biomarkers was measured, including white blood cell count (WBC), C-reactive protein (CRP), interleukin (IL) -6 and -8, tumor necrosis factor (TNF), and fibrinogen. Comorbidities were assessed based on a self-report survey. Comprehensive comorbidity indices were defined. Results: WBC correlated with GOLD stage, 6MWD, and global and cardiovascular comorbidity indices. WBC inversely correlated with ITGV and TLCO. Mean WBC was significantly increased in several comorbidities, including hypertension (7.76 vs. 8.08/nl, p=0.0006), ischemic heart disease (7.84 vs. 8.47/nl, p Conclusion: WBC correlates with disease severity and is associated with relevant comorbidities. Other classical inflammatory biomarkers did not show a clear correlation with COPD severity of existing comorbidity.

Background: In large cohort studies comorbidities are commonly self-reported by the patients. Although this is a feasible way to collect information, it only represents conditions memorized. In order to improve the use of all available information, we developed a detailed procedure to compare self-reported comorbidities with medication and applied this to the data of the German COPD cohort COSYCONET. Methods: Approach I was based solely on ICD-10-codes for the diseases and the indications of medications. To deal with the non-specificity of medications, Approach II focused on disease-specific medication and ATC-codes. The relationship between comorbidities and medication was expressed by a four-level concordance score. Results: Approach I and II demonstrated that the patterns of concordance scores markedly differed between diseases. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. Approach II showed particularly large differences in its ability of matching with medications, due to large differences in the disease-specificity of drugs, e.g. for diabetes versus specific cardiovascular disorders. Conclusion: Both approaches provide defined strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specific information. Approach II is based on medications specific for a disease and can reach higher concordance. The strategies described are generally applicable in large studies to extract as much information as possible from the available data. Funded by BMBF COSYCONET and Mundipharma GmbH .

Objective In large cohort studies comorbidities are usually self- reported by the patients. This way to collect health information only represents conditions known, memorized and openly reported by the patients. Several studies addressed the relationship between self- reported comorbidities and medical records or pharmacy data, but none of them provided a structured, documented method of evaluation. We thus developed a detailed procedure to compare self- reported comorbidities with information on comorbidities derived from medication inspection. This was applied to the data of the German COPD cohort COSYCONET. Methods Approach I was based solely on ICD10-Codes for the diseases and the indications of medications. To overcome the limitations due to potential non-specificity of medications, Approach II was developed using more detailed information, such as ATC-Codes specific for one disease. The relationship between reported comorbidities and medication was expressed by a four-level concordance score. Results Approaches I and II demonstrated that the patterns of concordance scores markedly differed between comorbidities in the COSYCONET data. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. The more specific Approach II showed larger differences in the matching with medications, due to large differences in the disease-specificity of drugs. The highest concordance was achieved for diabetes and three combined cardiovascular disorders, while it was substantial for dyslipidemia and hyperuricemia, and low for asthma. Conclusion Both approaches represent feasible strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specificity. Approach II uses the information from medications specific for a single disease and therefore can reach higher concordance scores. The strategies described in a detailed and reproducible manner are generally applicable in large studies and might be useful to extract as much information as possible from the available data.

Phenotyping of chronic obstructive pulmonary disease (COPD) with computed tomography (CT) is used to distinguish between emphysema- and airway-dominated type. The phenotype is reflected in correlations with lung function measures. Among these, the relative value of body plethysmography has not been quantified. We addressed this question using CT scans retrospectively collected from clinical routine in a large COPD cohort. Three hundred and thirty five patients with baseline data of the German COPD cohort COPD and Systemic Consequences-Comorbidities Network were included. CT scans were primarily evaluated using a qualitative binary emphysema score. The binary score was positive for emphysema in 52.5% of patients, and there were significant differences between the positive/negative groups regarding forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), intrathoracic gas volume (ITGV), residual volume (RV), specific airway resistance (sRaw), transfer coefficient (KCO), transfer factor for carbon monoxide (TLCO), age, pack-years, and body mass index (BMI). Stepwise discriminant analyses revealed the combination of FEV1/FVC, RV, sRaw, and KCO to be significantly related to the binary emphysema score. The additional positive predictive value of body plethysmography, however, was only slightly higher than that of the conventional combination of spirometry and diffusing capacity, which if taken alone also achieved high predictive values, in contrast to body plethysmography. The additional information on the presence of CT-diagnosed emphysema as conferred by body plethysmography appeared to be minor compared to the well-known combination of spirometry and CO diffusing capacity.

The recent unfortunate rabies transmissions through solid organ transplants of an infected donor in Germany required the initiation of a vaccination program to protect health care workers (HCWs) with close contact to rabies-infected patients. A systematic follow-up of adverse effects was initiated. Rabies postexposure prophylaxis (PEP) was started in 269 HCWs at four German hospitals. Pre-exposure prophylaxis (PreEP) was administered to 74 HCWs caring for an already diagnosed rabies patient. At each vaccination date, HCWs were interviewed for symptoms possibly representing adverse effects. Adverse effects of PEP and PrePEP were compared. Out of 269 HCWs, 216 were included for the investigation of adverse effects. Of these 216 HCWs, 114 (53%) individuals developed at least one systemic adverse effect. Incidences of tiredness (30.6%), malaise (26.4%), headache (26.9%), dizziness (14.8%), and chills (13.0%) declined in the course of PEP (p < 0.05), whereas incidences of fever (7.4%), paraesthesias (7.9%), arthralgias (1.9%), myalgias (4.2%), nausea (9.3%), diarrheas (2.8%) and vomiting (1.4%) did not. In 11 (5.1%) HCWs PEP was discontinued mostly due to adverse reactions (four suffered strong headaches, two HCWs meningeal irritations, two chills, one paraesthesia, one malaise, and one a rush). Systemic effects of PEP or PreEP did not differ significantly. Despite relatively high incidences of moderate severe adverse reactions rabies PEP is safe. Strong headache, tiredness, dizziness, and paraesthesias are the most important postvaccinal symptoms. Vaccinees suffering from adverse effects of PEP must be strongly encouraged to complete PEP, as it is to date the only protection against fatal rabies.

Background. Natriuretic peptides such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) have become increasingly important in diagnosing left ventricular dysfunction (LVD), however, in patients with chronic kidney disease (CKD), their use is confounded by concomitant volume overload and reduced renal excretion. We hypothesized that a serum NT-proBNP cut-off value adjusted for patients with CKD could serve as a biochemical marker to detect LVD in patients on haemodialysis treatment regardless of chronic fluid overload.Methods. We assessed LV function using trans-thoracic echocardiography and indices of hydration status such as extracellular water (ECW) using bioelectrical impedance analysis (BIA) in 62 stable patients on maintenance haemodialysis. NT-proBNP cutoff values for LVD with different specificities and sensitivities were calculated by ROC curves.Results. We found a significant inverse correlation between LV ejection fraction (EF) and NT-proBNP levels (r = −0.77, P < 0.0001). In the multivariate regression analysis NT-proBNP was the only independent predictor of EF (r = 0.699, P < 0.0001). NT-proBNP levels were significantly higher (P < 0.0001) in patients with LVD (n = 15; 32 760 ± 6605 ng/L) compared to those without LVD (n = 47; 2835 ± 428 ng/L). An NT-proBNP cut-off value of 7168 ng/L resulted in 90% specificity and 79% sensitivity for the presence of LVD, i.e. an EF

Background: Chronic obstructive pulmonary disease (COPD) is often considered to be related to premature ageing but adequate, clinically feasible markers are lacking. We compared three molecular/biochemical markers and one set of phenomenological markers and determined their relationship to the disease state. Methods: Within the COSYCONET National COPD cohort, 127 patients from the study centre LMU Munich were investigated by comprehensive functional and clinical assessments, measurements of advanced glycation endproducts (AGE), the peptide LL-37 and telomere length (T/S ratio, qPCR) in blood, as well as scoring of facial wrinkling via coded photos. A binary CT emphysema score was available in 39 patients and predicted in 122 patients via a function based on functional parameters. Results: The percentages of COPD stages 0-IV were 5, 20, 35, 20, and 20%. Stages were not related to age or T/S ratio, but associated with lung function and the age excess (estimated–factual age) estimated from skin scoring. The predicted emphysema score also depended on age excess, lung function indices and BMI. Logistic regression analyses indicated that the association with age excess was robust. AGEs were mostly dependent on the comorbidity diabetes and LL-37 was affected by smoking. Conclusions: The results support the notion that COPD and emphysema are related to premature ageing. In particular biological excess age estimated from facial photos correlated with stages of COPD and (predicted) emphysema and was superior to blood markers of ageing. Supported by German Federal Ministry of Education and Research, Kompetenznetz Asthma/COPD, and by Friedrich-Baur-Stiftung, LMU Munchen.

OBJECTIVE To determine the frequency of potential drug-disease interaction in elderly patients in family practice. To assess which drugs and diagnoses are associated with a high risk related to drug-disease interaction and whether there are gender- or age-related differences. METHODS In routinely recorded electronic patient records, patients at least 65 years old with at least one diagnosis named in Beers list and one prescription were identified. Potential drug-disease interaction (PDDI) was presumed if within the same 3 months a "Beers" diagnosis and a potentially inappropriate prescription with respect to this diagnosis were documented for a patient. Multiple logistic regression analysis identified factors associated with a high risk of PDDI. RESULTS Of 24,619 patients (63.4% women) corresponding to our inclusion criteria, 10.4% were exposed to at least one PDDI. Almost no (0.0%) PDDI was associated with the most common Beers disorder hypertension (prevalence 49.2%). However, 23.4% of men suffering from bladder outflow obstruction (prevalence 17.6% in males) were exposed to at least one PDDI. PDDI was quite common in some rarer conditions, for example, indications for anticoagulation (prevalence 2.6%, 31.5% PDDI). PDDI was not influenced by gender, but associated with taking more than 4 drugs (OR 1.91 (1.83 - 2.00)), suffering from more than one Beers disorder (OR 1.24 (1.16 - 1.31)), and advanced age (OR 1.10 (1.05 - 1.15)). CONCLUSIONS High risk patient groups could be identified. Some disorders as well as some drugs are particularly prone to risky constellations; these should be reflected in systems assisting prescribing with regard to patient safety.

Background Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. Methods/Design The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. Discussion It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. Trial registration Clinical trials gov. number: NCT01117662

Background: In Germany, family physicians (FPs) are increasingly needed to participate in undergraduate medical education. Knowledge of FPs’ motivation to teach medical students in their practices is lacking. Purpose: To describe a novel questionnaire that assesses the motivation of FPs to teach undergraduates in their practices and to show the results of a subsequent survey using this instrument. Methods: The questionnaire was developed based on a review of the literature. Previously used empirical instruments assessing occupational values and motivation were included. A preliminary version was pretested in a pilot study. The resulting 68-item questionnaire was sent to 691 FPs involved in undergraduate medical education. Reliability was assessed and subgroups were analyzed with regard to differences in motivation. Results: A total of 523 physicians in n = 458 teaching practices participated (response rate 75.7%). ‘Helping others’ and ‘interest’ were revealed as the predominant motives. Responses showed a predominantly intrinsic motivation of the participating FPs. Their main incentives were an ambition to work as a medical preceptor, to generally improve undergraduate education and to share knowledge. Material compensation was of minor importance. Time restraints were indicated as a barrier by some FPs, but were not a general concern. Conclusion: German FPs involved in medical education have altruistic attitudes towards teaching medical students in their practices. Motivational features give an important insight for the recruitment of FP preceptors as well as for their training in instructional methods. peerReviewed

Background A better knowledge of methicillin-resistant Staphylococcus aureus (MRSA) persistence in hospitalised patients may impact on specific prevention strategies. We have investigated the persistence of MRSA-carriage in patients admitted and re-admitted to a university hospital. Patients and methods Between January 2002 and October 2005 all MRSA-positive patients admitted to the university hospital of Hannover Medical School were assessed at first admission and all subsequent re-admissions. Patients re-admitted at least once were analysed for the persistence or loss of MRSA. The association of possible factors influencing the persistence of MRSA colonisation or infection (age group, gender, decolonisation therapy during first hospital stay due to MRSA positivity and colonisation of different anatomical sites) was analysed using univariate, multivariate and time-dependent analyses. Results A total of 1,032 patients who had tested positive at least once for MRSA were admitted to our hospital during the study period, accounting for 2,038 admissions. Of these patients, 403 (39.1%) were admitted more than once (from two times to 21 times), and 238 (59.1%) of the re-admitted patients remained MRSA positive during all subsequent admissions. Fifty-five (13.6%) patients tested MRSA negative at their last admission, and 61 (15.1%) tested MRSA negative at at least two consecutive admissions. In 27 (6.7%) patients, the MRSA status differed more than once between subsequent admissions. Overall, the half-life time (HLT) of MRSA persistence was 549 days, with the duration of persistence dependent on the colonisation of different anatomical sites (HLT only wounds 117 days; HLT mouth, throat, bronchial secretions 627 days; HLT nose, wounds and other body sites 801 days; p

Introduction Endothelial activation leading to vascular barrier breakdown denotes a devastating event in sepsis. Angiopoietin (Ang)-2, a circulating antagonistic ligand of the endothelial specific Tie2 receptor, is rapidly released from Weibel-Palade and has been identified as a non-redundant gatekeeper of endothelial activation. We aimed to study: the time course of Ang-2 release during human experimental endotoxemia; the association of Ang-2 with soluble adhesion molecules and inflammatory cytokines; and the early time course of Ang-2 release during sepsis in critically ill patients.Methods In 22 healthy volunteers during a 24-hour period after a single intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) the following measurement were taken by immuno luminometric assay (ILMA), ELISA, and bead-based multiplex technology: circulating Ang-1, Ang-2, soluble Tie2 receptor, the inflammatory molecules TNF-alpha, IL-6, IL-8 and C-reactive protein, and the soluble endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin. A single oral dose of placebo or the p38 mitogen activated protein (MAP) kinase inhibitor drug, RWJ-67657, was administered 30 minutes before the endotoxin infusion. In addition, the course of circulating Ang-2 was analyzed in 21 septic patients at intensive care unit (ICU) admission and after 24 and 72 hours, respectively.Results During endotoxemia, circulating Ang-2 levels were significantly elevated, reaching peak levels 4.5 hours after LPS infusion. Ang-2 exhibited a kinetic profile similar to early proinflammatory cytokines TNF-alpha, IL-6, and IL-8. Ang-2 levels peaked prior to soluble endothelial-specific adhesion molecules. Finally, Ang-2 correlated with TNF-alpha levels (r = 0.61, P = 0.003), soluble E-selectin levels (r = 0.64, P Conclusions LPS is a triggering factor for Ang-2 release in men. Circulating Ang-2 appears in the systemic circulation during experimental human endotoxemia in a distinctive temporal sequence and correlates with TNF-alpha and E-selectin levels. In addition, not only higher baseline Ang-2 concentrations, but also a persistent increase in Ang-2 during the early course identifies septic patients with unfavorable outcome.

Background Supratentorial pneumocephalus after posterior fossa surgery in the semisitting position may lead to decreased alertness and other symptoms. We here aimed to prove the efficacy of normobaric hyperoxia on the absorption of postoperative pneumocephalus according to a standardized treatment protocol. Methods and Findings We enrolled 44 patients with postoperative supratentorial pneumocephalus (> 30 ml) after posterior fossa surgery in a semisitting position. After randomisation procedure, patients received either normobaric hyperoxia at FiO2 100% over an endotracheal tube for 3 hours (treatment arm) or room air (control arm). Routine cranial CT scans were performed immediately (CT1) and 24 hours (CT2) after completion of surgery and were rated without knowledge of the therapy arm. Two co-primary endpoints were assessed: (i) mean change of pneumocephalus volume, and (ii) air resorption rate in 24 hours. Secondary endpoints were subjective alertness (Stanford Sleepiness Scale) postoperatively and attention (Stroop test), which were evaluated preoperatively and 24 hours after surgery. The mean change in pneumocephalus volume was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.001). The air resorption rate was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.0015). Differences were more pronounced in patients aged 52 years and older. No difference between patients in treatment arm and control arm was observed for the Stroop test. The distribution of scores in the Stanford Sleepiness Scale differed in the treatment arm as compared to the control arm, and there was a difference in mean values (p = 0.015). Conclusions Administration of normobaric hyperoxia at FiO2 100% via an endotracheal tube for 3 hours is safe and efficacious in the treatment of pneumocephalus after posterior fossa surgery in the semisitting position. Largest benefit was found in elderly patients and particularly in older men. Trial Registration German Clinical Trials Register DRKS00006273