Telehealth mitigates COPD disease progression compared to standard of care: a randomized controlled crossover trial.

BACKGROUND: We showed excellent adherence and satisfaction with our telehealth care (TC) approach for COPD. Here, the results of a consecutive randomized controlled trial are presented. METHODS: Patients were randomly assigned to TC or standard care (SC). During TC, patients answered six daily questions online, and focused on the early recognition of exacerbations, in addition to SC. RESULTS: The mean increase in COPD assessment test (CAT) was 1.8 vs. 3.6 points/year in the TC and SC groups, respectively (P = 0.0015). Satisfaction with care (VAS) at baseline was 8.2; at the end of SC, 8.5 (P = 0.062); and after TC, 8.8 (P < 0.001). We detected significantly more moderate exacerbations during TC. CONCLUSION: Whilst receiving TC, the slope of the CAT increase - an indicator of the naturally progressive course of COPD - was reduced by 50%. Satisfaction with care increased with TC. The higher number of detected moderate exacerbations probably indicates a higher diagnostic sensitivity than without TC.

Fractal Folding and Medium Viscoelasticity Contribute Jointly to Chromosome Dynamics.

Chromosomes are key players of cell physiology, their dynamics provides valuable information about its physical organization. In both prokaryotes and eukaryotes, the short-time motion of chromosomal loci has been described with a Rouse model in a simple or viscoelastic medium. However, little emphasis has been put on the influence of the folded organization of chromosomes on the local dynamics. Clearly, stress propagation, and thus dynamics, must be affected by such organization, but a theory allowing us to extract such information from data, e.g., on two-point correlations, is lacking. Here, we describe a theoretical framework able to answer this general polymer dynamics question. We provide a scaling analysis of the stress-propagation time between two loci at a given arclength distance along the chromosomal coordinate. The results suggest a precise way to assess folding information from the dynamical coupling of chromosome segments. Additionally, we realize this framework in a specific model of a polymer whose long-range interactions are designed to make it fold in a fractal way and immersed in a medium characterized by subdiffusive fractional Langevin motion with a tunable scaling exponent. This allows us to derive explicit analytical expressions for the correlation functions.

Effective Hamiltonian of topologically stabilized polymer states.

Topologically stabilized polymer conformations in melts of nonconcatenated polymer rings and crumpled globules are considered to be a good candidate for the description of the spatial structure of mitotic chromosomes. Despite significant efforts, the microscopic Hamiltonian capable of describing such systems still remains unknown. We describe a polymer conformation by a Gaussian network - a system with a Hamiltonian quadratic in all coordinates - and show that by tuning interaction constants, one can obtain equilibrium conformations with any fractal dimension between 2 (an ideal polymer chain) and 3 (a crumpled globule). Monomer-to-monomer distances in topologically stabilized states, according to available numerical data, fit very well the Gaussian distribution, giving an additional argument in support of the quadratic Hamiltonian model. Mathematically, the polymer conformations are mapped onto the trajectories of a subdiffusive fractal Brownian particle. Moreover, we explicitly show that the quadratic Hamiltonian with a hierarchical set of coupling constants provides the microscopic background for the description of the path integral of the fractional Brownian motion with an algebraically decaying kernel.

Anomalous diffusion in fractal globules.

The fractal globule state is a popular model for describing chromatin packing in eukaryotic nuclei. Here we provide a scaling theory and dissipative particle dynamics computer simulation for the thermal motion of monomers in the fractal globule state. Simulations starting from different entanglement-free initial states show good convergence which provides evidence supporting the existence of a unique metastable fractal globule state. We show monomer motion in this state to be subdiffusive described by ⟨X(2)(t)⟩∼t(αF) with αF close to 0.4. This result is in good agreement with existing experimental data on the chromatin dynamics, which makes an additional argument in support of the fractal globule model of chromatin packing.

Islands of stability in motif distributions of random networks.

We consider random nondirected networks subject to dynamics conserving vertex degrees and study, analytically and numerically, equilibrium three-vertex motif distributions in the presence of an external field h coupled to one of the motifs. For small h, the numerics is well described by the "chemical kinetics" for the concentrations of motifs based on the law of mass action. For larger h, a transition into some trapped motif state occurs in Erdos-Rényi networks. We explain the existence of the transition by employing the notion of the entropy of the motif distribution and describe it in terms of a phenomenological Landau-type theory with a nonzero cubic term. A localization transition should always occur if the entropy function is nonconvex. We conjecture that this phenomenon is the origin of the motifs' pattern formation in real evolutionary networks.

Assessment of panobacumab as adjunctive immunotherapy for the treatment of nosocomial Pseudomonas aeruginosa pneumonia.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

Nearest-neighbor directed random hyperbolic graphs.

Undirected hyperbolic graph models have been extensively used as models of scale-free small-world networks with high clustering coefficient. Here we presented a simple directed hyperbolic model where nodes randomly distributed on a hyperbolic disk are connected to a fixed number m of their nearest spatial neighbors. We introduce also a canonical version of this network (which we call "network with varied connection radius"), where maximal length of outgoing bond is space dependent and is determined by fixing the average out-degree to m. We study local bond length, in-degree, and reciprocity in these networks as a function of spacial coordinates of the nodes and show that the network has a distinct core-periphery structure. We show that for small densities of nodes the overall in-degree has a truncated power-law distribution. We demonstrate that reciprocity of the network can be regulated by adjusting an additional temperature-like parameter without changing other global properties of the network.

Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms.

Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD) and emphysema. Although cigarette smoke represses cellular proliferation, the molecular mechanisms underlying this phenomenon are unknown. CCAAT/enhancer-binding proteins (C/EBPs) are key regulators of cell cycle progression, differentiation and pro-inflammatory gene expression, are regulated predominantly at the translational level and may be involved in the pathogenesis of COPD. The aim of this study was to assess the effect of cigarette smoke on proliferation and the expression and translational regulation of C/EBPα and C/EBPß in nondiseased primary human lung fibroblasts. Fibroblasts were exposed to cigarette smoke-conditioned medium (10% and 20% for 24 h). Proliferation was determined by [(3)H]thymidine incorporation. Protein expression levels were determined by immunoblotting and translation was monitored using a translation control reporter system. Cigarette smoke significantly reduced fibroblast proliferation and significantly upregulated full-length C/EBPα and C/EBPß proteins due to a shift in the translational control of CEBPA and CEBPB mRNAs. This shift involved the re-initiation of mRNA translation via the regulatory upstream open reading frame, which coincided with increased interleukin-8 release and a decrease in functional elastin level. These findings provide a novel mechanism to understanding the tissue remodelling observed in the lungs of COPD patients.

New alphabet-dependent morphological transition in random RNA alignment.

We study the fraction f of nucleotides involved in the formation of a cactuslike secondary structure of random heteropolymer RNA-like molecules. In the low-temperature limit, we study this fraction as a function of the number c of different nucleotide species. We show, that with changing c, the secondary structures of random RNAs undergo a morphological transition: f(c)→1 for c≤c(cr) as the chain length n goes to infinity, signaling the formation of a virtually perfect gapless secondary structure; while f(c)<1 for c>c(cr), which means that a nonperfect structure with gaps is formed. The strict upper and lower bounds 2≤c(cr)≤4 are proven, and the numerical evidence for c(cr) is presented. The relevance of the transition from the evolutional point of view is discussed.

Human metapneumovirus infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The clinical characteristics of human metapneumovirus (hMPV)-associated lower respiratory tract infection (LRTI) after allogeneic hematopoietic stem cell transplantation (HSCT) is not well described. We describe the clinical course in eight HSCT recipients suffering from hMPV infection. METHODS: We prospectively included all patients with hMPV-associated LRTI after allogeneic HSCT during a period of 1 year. hMPV was diagnosed by multiplex polymerase chain reaction (PCR) from bronchoalveolar lavage (BAL). RESULTS: Eight patients with hMPV-associated LRTI were identified from 93 BAL samples. Three of the eight patients had co-infections with other pathogens. The median age of the patients was 45 years [interquartile range (IQR) 36.8-53.5], the median time posttransplant was 473 days (IQR 251-1,165), 5/8 patients had chronic graft-versus-host disease (cGvHD), and 6/8 patients received immunosuppression. Chest computed tomography (CT) scanning showed a ground-glass pattern in 7/8 patients. Seven of eight patients required hospitalization due to severe symptoms and hypoxemia. All were treated with intravenous immunoglobulin (IVIG), which was combined with oral ribavirin in six patients. The mortality rate was 12.5 % (1/8). CONCLUSIONS: hMPV-associated LRTI in allogeneic HSCT recipients are not uncommon and present with unspecific respiratory symptoms, ground-glass pattern in CT scanning, and co-infection.

[Occupational rhinitis and asthma]. / Berufliche Rhinitis und Asthma.

Allergic rhinoconjunctivits and asthma are frequent diseases. About one in ten asthma cases is caused by an occupational hazard, either by an allergic or a non-immunologic mechanism. Primary or secondary preventive measures should be able to prevent these cases. Often, occupational rhinitis precedes the development of occupational asthma. Important causative agents are flours, plant and enzyme powders, laboratory animals, latex, isocyanates and hardeners, epoxy resins, acrylates, formaldehyde and welding fumes. Early diagnosis and the installation of protective measures are decisive for the prognosis of occupational respiratory disease.

House dust mite extract downregulates C/EBPα in asthmatic bronchial smooth muscle cells.

Reduced translation of CEBPA mRNA has been associated with increased proliferation of bronchial smooth muscle (BSM) cells of asthma patients. Here, we assessed the effect of house dust mite (HDM) extracts on the cell proliferation ([(3)H]-thymidine incorporation), inflammation (interleukin (IL)-6 release) and upstream translation regulatory proteins of CCAAT/enhancer-binding protein (C/EBP)α in human BSM cells of healthy controls and asthmatic patients. HDM extract significantly increased IL-6 protein and proliferation of BSM cells of asthma patients only. HDM extract reduced the C/EBPα expression in BSM cells of asthma patients, which coincided with significantly increased levels of calreticulin (CRT) protein, an inhibitor of CEBPA mRNA translation. HDM extract elicited both protease-dependent and -independent responses, which were mediated via protease-activated receptor (PAR)2 and CRT, respectively. In conclusion, HDM extract reduced CEBPA mRNA translation, specifically in asthmatic BSM cells, and 1) upregulated CRT, 2) activated PAR2, and increased 3) IL-6 expression and 4) the proliferation of asthmatic BSM cells. Hence, HDM exposure contributes to inflammation and remodelling by a nonimmune cell-mediated mechanism via a direct interaction with BSM cells. These findings may potentially explain several pathological features of this disease, in particular BSM cell hyperplasia.

Propofol versus propofol plus hydrocodone for flexible bronchoscopy: a randomised study.

Propofol and the combination of a benzodiazepine and an opiate have been established for sedation in flexible bronchoscopy. It is as yet unknown whether propofol in combination with an opiate is superior to propofol alone to suppress cough during the procedure. 300 consecutive patients undergoing flexible bronchoscopy at a tertiary care university hospital were randomly allocated to receive either the combination propofol and hydrocodone or propofol alone in a double-blind fashion. The primary end-point was the cough score during the procedure as estimated by the physician using a visual analogue scale. Demographics were similar in both groups. Compared with propofol alone, median (interquartile range) cough scores assessed by physicians, nurses and patients were significantly lower in the group randomised to the combination propofol and hydrocodone (2.5 (1.5-4.0) versus 2.0 (1.0-3.0), respectively, p=0.011). Additionally, patients receiving the combination required significantly lower doses of propofol than those receiving propofol alone (200 mg (140-280) versus 260 mg (180-350), p<0.0001). Complex examinations, including bronchoalveolar lavage or transbronchial biopsy, benefited more from additional opiate. The duration of the procedure, time to discharge and complication rate were similar in both groups. The combination of propofol and hydrocodone is safe and superior to propofol alone for cough suppression in flexible bronchoscopy.

Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP.

Ventilator-associated pneumonia (VAP) affects mortality, morbidity and cost of critical care. Reliable risk estimation might improve end-of-life decisions, resource allocation and outcome. Several scoring systems for survival prediction have been established and optimised over the last decades. Recently, new biomarkers have gained interest in the prognostic field. We assessed whether midregional pro-atrial natriuretic peptide (MR-proANP) and procalcitonin (PCT) improve the predictive value of the Simplified Acute Physiologic Score (SAPS) II and Sequential Related Organ Failure Assessment (SOFA) in VAP. Specified end-points of a prospective multinational trial including 101 patients with VAP were analysed. Death <28 days after VAP onset was the primary end-point. MR-proANP and PCT were elevated at the onset of VAP in nonsurvivors compared with survivors (p = 0.003 and p = 0.017, respectively) and their slope of decline differed significantly (p = 0.018 and p = 0.039, respectively). Patients with the highest MR-proANP quartile at VAP onset were at increased risk for death (log rank p = 0.013). In a logistic regression model, MR-proANP was identified as the best predictor of survival. Adding MR-proANP and PCT to SAPS II and SOFA improved their predictive properties (area under the curve 0.895 and 0.880). We conclude that the combination of two biomarkers, MR-proANP and PCT, improve survival prediction of clinical severity scores in VAP.

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator of the lung. In this study, we demonstrate that PAF receptor mRNA and protein is expressed by human lung fibroblasts. Interaction of PAF with its specific receptor resulted in increases of tyrosine phosphorylation of several intracellular proteins, indicating that the PAF-receptor might be functionally active. PAF-induced transcription of protooncogenes c-fos and c-jun as well as of interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF enhanced proliferation of fibroblasts in a concentration-dependent manner. Using signaling inhibitors, we demonstrate that PAF-induced transcription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine kinases, and protein kinase C (PKC). In contrast, transcription of c-jun was blocked by pertussis toxin, but not by inhibitors for tyrosine kinases or PKC. These data suggest that PAF stimulates distinct signaling pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the expression of proinflammatory cytokines, which may contribute to the pathophysiological changes in pulmonary inflammation.

Narrow-escape times for diffusion in microdomains with a particle-surface affinity: mean-field results.

We analyze the mean time t(app) that a randomly moving particle spends in a bounded domain (sphere) before it escapes through a small window in the domain's boundary. A particle is assumed to diffuse freely in the bulk until it approaches the surface of the domain where it becomes weakly adsorbed, and then wanders diffusively along the boundary for a random time until it desorbs back to the bulk, etc. Using a mean-field approximation, we define t(app) analytically as a function of the bulk and surface diffusion coefficients, the mean time it spends in the bulk between two consecutive arrivals to the surface and the mean time it wanders on the surface within a single round of the surface diffusion.

Quality of spirometry in primary care for case finding of airway obstruction in smokers.

BACKGROUND: Diagnosis of chronic obstructive pulmonary disease (COPD) and its severity determination is based on spirometry. The quality of spirometry is crucial. OBJECTIVES: Our aim was to assess the quality of spirometry performed using a spirometer with automated feedback and quality control in a general practice setting in Switzerland and to determine the prevalence of airflow limitation in smokers aged > or =40 years. METHOD: Current smokers > or =40 years of age were consecutively recruited for spirometry testing by general practitioners. General practitioners received spirometry training and were provided with an EasyOne spirometer. Spirometry tests were assigned a quality grade from A to D and F, based on the criteria of the National Lung Health Education Program. Only spirometry tests graded A-C (reproducible measurements) were included in the analysis of airflow limitation. RESULTS: A total of 29,817 spirometries were analyzed. Quality grades A-D and F were assigned to 33.9, 7.1, 19.4, 27.8 and 11.8% of spirometries, respectively. 95% required < or =5 trials to achieve spirometries assigned grade A. The prevalence of mild, moderate, severe and very severe airway obstruction in individuals with spirometries graded A-C was 6, 15, 5 and 1%, respectively. CONCLUSION: Spirometries in general practice are of acceptable quality with reproducible spirometry in 60% of measurements. Airway obstruction was found in 27% of current smokers aged > or =40 years. Office spirometry provides a simple and quick means of detecting airflow limitation, allowing earlier diagnosis and intervention in many patients with early COPD.

Dimethylfumarate inhibits NF-{kappa}B function at multiple levels to limit airway smooth muscle cell cytokine secretion.

The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-kappaB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFalpha-induced asthma-relevant cytokines and NF-kappaB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1-100 microM) and/or dexamethasone (0.0001-0.1 microM), NF-kappaB p65 siRNA (100 nM), the NF-kappaB inhibitor helenalin (1 microM) before stimulation with PDGF-BB or TNFalpha (10 ng/ml). Cytokine release was measured by ELISA. NF-kappaB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFalpha-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-kappaB p65 siRNA and/or the NF-kappaB inhibitor helenalin reduced PDGF-BB- and TNFalpha-induced cytokine expression, suggesting the involvement of NF-kappaB signaling. DMF inhibited TNFalpha-induced NF-kappaB p65 phosphorylation, NF-kappaB nuclear entry, and NF-kappaB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-kappaB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-kappaB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-kappaB but a wider range of NF-kappaB-linked signaling proteins, which may explain its potential beneficial effect in asthma.

Propofol versus combined sedation in flexible bronchoscopy: a randomised non-inferiority trial.

Combined sedation with a benzodiazepine and an opiate has been proposed as standard sedation for bronchoscopy. Propofol is a sedative-hypnotic with a rapid onset of action and fast recovery time, but carries the potential risk of respiratory failure. Consecutive patients (n = 200) were randomly allocated to receive either the combination midazolam and hydrocodone or intravenous propofol. The primary end-points were the mean lowest arterial oxygen saturation during bronchoscopy and the readiness-for-discharge score 1 h after the procedure. The mean lowest arterial oxygen saturation during bronchoscopy did not differ across treatment groups (p = 0.422), and the number of patients recording an arterial oxygen saturation of < or =90% on at least one occasion was similar in both groups (p = 0.273). The median (interquartile range) readiness-for-discharge score 1 h after the procedure was significantly higher in the propofol group than in the combined sedation group (8 (6-9) versus 7 (5-9); p = 0.035). Patients assigned propofol exhibited less tachycardia during bronchoscopy and for > or =1 h after the examination. Minor procedural complications were noted in 71 (35.5%) patients and exhibited a similar incidence in both treatment arms (p = 0.460). Propofol is as effective and safe as combined sedation in patients undergoing flexible bronchoscopy, thus representing an appealing option if timely discharge is a priority.

Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.

In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2-21) days versus 9.5 (1.5-17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02-2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.