Search

Background Garadacimab, a fully human IgG4 monoclonal antibody, inhibits the kallikrein-kinin pathway at a key initiator, activated coagulation factor XII (FXIIa), and may play a protective role in preventing the progression of COVID-19. This phase 2 study evaluated the efficacy and safety of garadacimab plus standard of care (SOC) versus placebo plus SOC in patients with severe COVID-19. Methods Patients hospitalised with COVID-19 were randomised (1:1) to a single intravenous dose of garadacimab (700 mg) plus SOC or placebo plus SOC. Co-primary endpoint was incidence of endotracheal intubation or death between randomisation and Day 28. All-cause mortality, safety and pharmacokinetic/pharmacodynamic parameters were assessed. Results No difference in incidence of tracheal intubation or death (p = 0.274) or all-cause mortality was observed (p = 0.382). Garadacimab was associated with a lower incidence of treatment-emergent adverse events (60.3% vs 67.8%) and fewer serious adverse events (34 vs 45 events) versus placebo. No garadacimab-related deaths or bleeding events were reported, including in the 45.9% (n = 28/61) of patients who received concomitant heparin. Prolonged activated partial thromboplastin time (aPTT), and increased coagulation factor XII (FXII) levels were observed with garadacimab versus placebo to Day 14, whilst FXIIa-mediated kallikrein activity (FXIIa-mKA) was suppressed to Day 28. Conclusion In patients with severe COVID-19, garadacimab did not confer a clinical benefit over placebo. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of garadacimab that was not associated with bleeding events even with concomitant anticoagulant use. The safety profile of garadacimab was consistent with previous studies in patients with hereditary angioedema. ClinicalTrials. gov Identifier NCT04409509. Date of registration: 28 May, 2020., Author(s): Alberto Papi [sup.1], Renee D. Stapleton [sup.2], Paul M. Shore [sup.3], Mihai Alexandru Bica [sup.4], Younan Chen [sup.5], Michael Larbig [sup.6], Tobias Welte [sup.7] Author Affiliations: (1) grid.8484.0, 0000 [...]

Abstract Background Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) α1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD. Methods Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and “normal” MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR. Results A total of 162 genes were found to be differentially expressed (p-value ≤ 0.05 and |FC| ≥ 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Krüppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy. Conclusions These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.

Abstract Background The aim of our study was to investigate the predictive value of the biomarkers interleukin 6 (IL-6), interleukin 10 (IL-10) and lipopolysaccharide-binding protein (LBP) compared with clinical CRB and CRB-65 severity scores in patients with community-acquired pneumonia (CAP). Methods Samples and data were obtained from patients enrolled into the German CAPNETZ study group. Samples (blood, sputum and urine) were collected within 24 h of first presentation and inclusion in the CAPNETZ study, and CRB and CRB-65 scores were determined for all patients at the time of enrollment. The combined end point representative of a severe course of CAP was defined as mechanical ventilation, intensive care unit treatment and/or death within 30 days. Overall, a total of 1,000 patients were enrolled in the study. A severe course of CAP was observed in 105 (10.5%) patients. Results The highest IL-6, IL-10 and LBP concentrations were found in patients with CRB-65 scores of 3-4 or CRB scores of 2-3. IL-6 and LBP levels on enrollment in the study were significantly higher for patients with a severe course of CAP than for those who did not have severe CAP. In receiver operating characteristic analyses, the area under the curve values for of IL-6 (0.689), IL-10 (0.665) and LPB (0.624) in a severe course of CAP were lower than that of CRB-65 (0.764) and similar to that of CRB (0.69). The accuracy of both CRB and CRB-65 was increased significantly by including IL-6 measurements. In addition, higher cytokine concentrations were found in patients with typical bacterial infections compared with patients with atypical or viral infections and those with infection of unknown etiology. LBP showed the highest discriminatory power with respect to the etiology of infection. Conclusions IL-6, IL-10 and LBP concentrations were increased in patients with a CRB-65 score of 3-4 and a severe course of CAP. The concentrations of IL-6 and IL-10 reflected the severity of disease in patients with CAP. The predictive power of IL-6, IL-10 and LBP for a severe course of pneumonia was lower than that of CRB-65. Typical bacterial pathogens induced the highest LBP, IL-6 and IL-10 concentrations.

Abstract Background Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH). Methods GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein. Results GDF-15 expression was found to be increased in lung specimens from PAH patients, com-pared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein. Conclusions GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.

Abstract Background Micro-computed tomography (micro-CT) is a novel tool for monitoring acute and chronic disease states in small laboratory animals. Its value for assessing progressive lung fibrosis in mice has not been reported so far. Here we examined the importance of in vivo micro-CT as non-invasive tool to assess progression of pulmonary fibrosis in mice over time. Methods Pulmonary fibrosis was induced in mice by intratracheal delivery of an adenoviral gene vector encoding biologically active TGF-ß1 (AdTGF-ß1). Respiratory gated and ungated micro-CT scans were performed at 1, 2, 3, and 4 weeks post pulmonary adenoviral gene or control vector delivery, and were then correlated with respective histopathology-based Ashcroft scoring of pulmonary fibrosis in mice. Visual assessment of image quality and consolidation was performed by 3 observers and a semi-automated quantification algorithm was applied to quantify aerated pulmonary volume as an inverse surrogate marker for pulmonary fibrosis. Results We found a significant correlation between classical Ashcroft scoring and micro-CT assessment using both visual assessment and the semi-automated quantification algorithm. Pulmonary fibrosis could be clearly detected in micro-CT, image quality values were higher for respiratory gated exams, although differences were not significant. For assessment of fibrosis no significant difference between respiratory gated and ungated exams was observed. Conclusions Together, we show that micro-CT is a powerful tool to assess pulmonary fibrosis in mice, using both visual assessment and semi-automated quantification algorithms. These data may be important in view of pre-clinical pharmacologic interventions for the treatment of lung fibrosis in small laboratory animals.

Abstract The incidence of nosocomial pneumonia involving methicillin-resistant Staphylococcus aureus strains (MRSA) is on the rise worldwide. For years, vancomycin has been used as the drug of choice in the treatment of MRSA infections and was recommended as such by clinical guidelines. There is growing evidence that vancomycin, despite low resistance rates is a suboptimal therapeutic option in critically ill patients, particularly in patients with pneumonia. Disadvantages of vancomycin are i) slow bactericide action, ii) poor penetration into pulmonary tissue, iii) the globally slowly increasing vancomycin MICs ("creep") that result in increased clinical failure despite being susceptible according to defined break points and iv) nephrotoxicity. In contrast to other novel antibiotics with MRSA activity, Linezolid is currently approved for the treatment of nosocomial pneumonia in the USA and Europe. Several studies have compared vancomycin with linezolid for nosocomial pneumonia with conflicting results. This review compares both substances regarding pharmacodynamics, resistance, safety and clinical efficacy and discusses preliminary data of the ZEPHyR study. This study compared linezolid versus vancomycin in patients with proven MRSA pneumonia and was the largest trial ever conducted in this population.

Abstract Background Diseases associated with smoking are a foremost cause of premature death in the world, both in developed and developing countries. Eliminating smoking can do more to improve health and prolong life than any other measure in the field of preventive medicine. Today's medical students will play a prominent role in future efforts to prevent and control tobacco use. Methods A cross-sectional, self-administered, anonymous survey of fifth-year medical students in Berlin, Germany was conducted in November 2007. The study explored the prevalence of smoking among medical students. We assessed their current knowledge regarding tobacco dependence and the effectiveness of smoking cessation methods. Students' perceived competence to counsel smokers and promote smoking cessation treatments was also explored. Analyses were based on responses from 258 students (86.6% response rate). Results One quarter of the medical students surveyed were current smokers. The smoking rate was 22.1% among women, 32.4% among men. Students underestimated smoking-related mortality and the negative effect of smoking on longevity. A considerable number of subjects erroneously assumed that nicotine causes coronary artery disease. Students' overall knowledge of the effectiveness of smoking cessation methods was inadequate. Only one third of the students indicated that they felt qualified to counsel patients about tobacco dependence. Conclusions This study reveals serious deficiencies in knowledge and counseling skills among medical students in our sample. The curriculum of every medical school should include a tobacco module. Thus, by providing comprehensive training in nicotine dependence interventions to medical students, smokers will have access to the professional expertise they need to quit smoking.

Abstract Background Aim of this study was to evaluate the correlation of inflammatory markers procalcitonin (PCT), C-reactive protein (CRP) and leukocyte count (WBC) with microbiological etiology of CAP. Methods We enrolled 1337 patients (62 ± 18 y, 45% f) with proven CAP. Extensive microbiological workup was performed. In all patients PCT, CRP, WBC and CRB-65 score were determined. Patients were classified according to microbial diagnosis and CRB-65 score. Results In patients with typical bacterial CAP, levels of PCT, CRP and WBC were significantly higher compared to CAP of atypical or viral etiology. There were no significant differences in PCT, CRP and WBC in patients with atypical or viral etiology of CAP. In contrast to CRP and WBC, PCT markedly increased with severity of CAP as measured by CRB-65 score (p < 0.0001). In ROC analysis for discrimination of patients with CRB-65 scores > 1, AUC for PCT was 0.69 (95% CI 0.66 to 0.71), which was higher compared to CRP and WBC (p < 0.0001). CRB-65, PCT, CRP and WBC were higher (p < 0.0001) in hospitalised patients in comparison to outpatients. Conclusion PCT, CRP and WBC are highest in typical bacterial etiology in CAP but do not allow individual prediction of etiology. In contrast to CRP and WBC, PCT is useful in severity assessment of CAP.

Abstract Background During the last two decades the German hospital sector has been engaged in a constant process of transformation. One obvious sign of this is the growing amount of hospital privatization. To date, most research studies have focused on the effects of privatization regarding financial outcomes and quality of care, leaving important organizational issues unexplored. Yet little attention has been devoted to the effects of privatization on physicians' working routines. The aim of this observational real-time study is to deliver exact data about physicians' work at hospitals of different ownership. By analysing working hours, further impacts of hospital privatization can be assessed and areas of improvement identified. Methods Observations were made by shadowing 100 physicians working in private, for-profit or non-profit as well as public hospital departments individually during whole weekday shifts in urban German settings. A total of 300 days of observations were conducted. All working activities were recorded, accurate to the second, by using a mobile personal computer. Results Results have shown significant differences in physicians' working activities, depending on hospital ownership, concerning working hours and time spent on direct and indirect patient care. Conclusion This is the first real-time analysis on differences in work activities depending on hospital ownership. The study provides an objective insight into physicians' daily work routines at hospitals of different ownership, with additional information on effects of hospital privatization.

Abstract Background Currently, broad empiric antimicrobial treatment including atypical coverage is recommended for patients with mild to moderate community-acquired pneumonia (CAP). Therefore, the relative impact of each atypical pathogen, particularly Mycoplasma pneumoniae deserves renewed attention. Methods Based on prospective data from 4532 patients with CAP included in the German CAP-Competence Network (CAPNETZ), we studied the incidence, clinical characteristics, and outcome of patients with Mycoplasma pneumoniae pneumonia (MPP). The diagnosis of MPP was based on a positive PCR from respiratory samples and/or a positive IgM-titer from an acute phase serum sample. Results 307 patients (6.8%) had definite MPP (148 with positive PCR, 204 with positive IgM, 46 with positive PCR and IgM). Compared to patients with other definite and unknown etiologies, patients with MPP were significantly younger (41 ± 16 versus 62 ± 17 and 61 ± 18 years), had fewer co-morbidities, presented with a less severe disease, showed a lower inflammatory response in terms of leukocyte counts (median 8850 versus 13200 and 11000 μL) and CRP values (60 versus 173 and 73 mg/L), and had better outcomes, including a shorter length of hospitalization (9 ± 5 versus 14 ± 11 and 12 ± 9 days), fewer patients requiring mechanical ventilation (0.3 versus 4.5 and 2.1%), and a minimal mortality (0.7 versus 8.7 and 6.5%). Conclusion In this large series of patients with definite MPP according to very strict criteria, MPP appears as a condition with a high incidence, quite specific clinical presentation, and a largely benign course. In view of a widely favorable clinical outcome, recent recommendations including regular coverage of atypical pathogens in patients with mild to moderate CAP might be reconsidered for patients in Germany as well as in other countries with comparable epidemiological settings.

Abstract Background Burden of disease studies indicate major socio-economic burdens since many years. They should be used for the allocation of funding. However, imbalances are present in funding policies and therefore benchmarking becomes increasingly important in health services research. Methods The present study assessed benchmarking approaches. Using large data base analyses, research was analyzed for different health research output parameters. The fields of cardiovascular and respiratory medicine served as models to assess irregular patterns of health research. For visualization, density equalizing mapping procedures were used. Results Specific areas of major research activity were identified for European countries and large differences were found. Spatial distribution of published items for cardiac and cardiovascular systems differed in comparison to the distribution for the respiratory system. In general, large countries dominated the overall number of published items. When qualitative measures such as citation analysis were assessed, differing results were achieved. In this category, mostly Scandinavian countries dominated. Conclusion The present approach of comparative output benchmarking can be used to assess institutional operating figures at the national and international level and to analyze imbalances in health and research funding.

Abstract Background There are several ways to conduct a job task analysis in medical work environments including pencil-paper observations, interviews and questionnaires. However these methods implicate bias problems such as high inter-individual deviations and risks of misjudgement. Computer-based observation helps to reduce these problems. The aim of this paper is to give an overview of the development process of a computer-based job task analysis instrument for real-time observations to quantify the job tasks performed by physicians working in different medical settings. In addition reliability and validity data of this instrument will be demonstrated. Methods This instrument was developed in consequential steps. First, lists comprising tasks performed by physicians in different care settings were classified. Afterwards content validity of task lists was proved. After establishing the final task categories, computer software was programmed and implemented in a mobile personal computer. At least inter-observer reliability was evaluated. Two trained observers recorded simultaneously tasks of the same physician. Results Content validity of the task lists was confirmed by observations and experienced specialists of each medical area. Development process of the job task analysis instrument was completed successfully. Simultaneous records showed adequate interrater reliability. Conclusion Initial results of this analysis supported the validity and reliability of this developed method for assessing physicians' working routines as well as organizational context factors. Based on results using this method, possible improvements for health professionals' work organisation can be identified.

Abstract Background Historical, social and economic reasons can lead to major differences in the allocation of health system resources and research funding. These differences might endanger the progress in diagnostic and therapeutic approaches of socio-economic important diseases. The present study aimed to assess different benchmarking approaches that might be used to analyse these disproportions. Research in two categories was analysed for various output parameters and compared to input parameters. Germany was used as a high income model country. For the areas of cardiovascular and respiratory medicine density equalizing mapping procedures visualized major geographical differences in both input and output markers. Results An imbalance in the state financial input was present with 36 cardiovascular versus 8 respiratory medicine state-financed full clinical university departments at the C4/W3 salary level. The imbalance in financial input is paralleled by an imbalance in overall quantitative output figures: The 36 cardiology chairs published 2708 articles in comparison to 453 articles published by the 8 respiratory medicine chairs in the period between 2002 and 2006. This is a ratio of 75.2 articles per cardiology chair and 56.63 articles per respiratory medicine chair. A similar trend is also present in the qualitative measures. Here, the 2708 cardiology publications were cited 48337 times (7290 times for respiratory medicine) which is an average citation of 17.85 per publication vs. 16.09 for respiratory medicine. The average number of citations per cardiology chair was 1342.69 in contrast to 911.25 citations per respiratory medicine chair. Further comparison of the contribution of the 16 different German states revealed major geographical differences concerning numbers of chairs, published items, total number of citations and average citations. Conclusion Despite similar significances of cardiovascular and respiratory diseases for the global burden of disease, large input and output imbalances have been revealed in the present study which point to a need for changes in funding policies. The present study supplies data that could be used for decision making in the field of health systems funding.

Abstract Background Lung fibrosis is a devastating pulmonary disorder characterized by alveolar epithelial injury, extracellular matrix deposition and scar tissue formation. Due to its potent collagenolytic activity, cathepsin K, a lysosomal cysteine protease is an interesting target molecule with therapeutic potential to attenuate bleomycin-induced pulmonary fibrosis in mice. We here tested the hypothesis that over-expression of cathepsin K in the lungs of mice is protective in bleomycin-induced pulmonary fibrosis. Methods Wild-type and cathepsin K overexpressing (cathepsin K transgenic; cath K tg) mice were challenged intratracheally with bleomycin and sacrificed at 1, 2, 3 and 4 weeks post-treatment followed by determination of lung fibrosis by estimating lung collagen content, lung histopathology, leukocytic infiltrates and lung function. In addition, changes in cathepsin K protein levels in the lung were determined by immunohistochemistry, real time RT-PCR and western blotting. Results Cathepsin K protein levels were strongly increased in alveolar macrophages and lung parenchymal tissue of mock-treated cathepsin K transgenic (cath K tg) mice relative to wild-type mice and further increased particularly in cath K tg but also wild-type mice in response to bleomycin. Moreover, cath K tg mice responded with a lower collagen deposition in their lungs, which was accompanied by a significantly lower lung resistance (RL) compared to bleomycin-treated wild-type mice. In addition, cath K tg mice responded with a lower degree of lung fibrosis than wild-type mice, a process that was found to be independent of inflammatory leukocyte mobilization in response to bleomycin challenge. Conclusion Over-expression of cathepsin K reduced lung collagen deposition and improved lung function parameters in the lungs of transgenic mice, thereby providing at least partial protection against bleomycin-induced lung fibrosis.

Abstract Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.