Scope and new horizons for implementation of m-Health/e-Health services in pulmonology in 2019.

The reason for this review based on the results of many meta- analyses is the great assessed difference in the methods of most studies in e-Health, telemedicine and tele-rehabilitation. It consists of different understanding of new terms, using different hard- and software, including criteria, different methodology of patient's treatment and its evaluation. This status suggests that first of all m-Health/e-Health requires a unique ontology of terms using and methodology of studies comparing. In this review we try to describe shortly the most significant points of modern e-Health field of medicine. The basic parts include methodology of review formation, tele-communication implementation results, tele-education, interactive questioning, tele-consultation, telemedicine diagnosis, tele-monitoring, rehabilitation and tele-rehabilitation, gamification, acceptability of mobile electronic devices and software in e-Health and planning studies. At the end of the review the new ontological structure of digital medicine is presented.

A review of national guidelines for management of COPD in Europe.

The quality of care can be improved by the development and implementation of evidence-based treatment guidelines. Different national guidelines for chronic obstructive pulmonary disease (COPD) exist in Europe and relevant differences may exist among them.This was an evaluation of COPD treatment guidelines published in Europe and Russia in the past 7 years. Each guideline was reviewed in detail and information about the most important aspects of patient diagnosis, risk stratification and pharmacotherapy was extracted following a standardised process. Guidelines were available from the Czech Republic, England and Wales, Finland, France, Germany, Italy, Poland, Portugal, Russia, Spain and Sweden. The treatment goals, criteria for COPD diagnosis, consideration of comorbidities in treatment selection and support for use of long-acting bronchodilators, were similar across treatment guidelines. There were differences in measures used for stratification of disease severity, consideration of patient phenotypes, criteria for the use of inhaled corticosteroids and recommendations for other medications (e.g. theophylline and mucolytics) in addition to bronchodilators.There is generally good agreement on treatment goals, criteria for diagnosis of COPD and use of long-acting bronchodilators as the cornerstone of treatment among guidelines for COPD management in Europe and Russia. However, there are differences in the definitions of patient subgroups and other recommended treatments.

Associations between indicators of nitrosative stress and levels of soluble HLA-I, CD95 molecules in patients with COPD.

At the present stage of study of chronic obstructive pulmonary disease (COPD) one of the problem is the definition of new criteria for the topical and systemic chronic inflammation of this disease. The aim of the research was to study the concentration of nitric oxide metabolites, the level of soluble human leukocyte antigens class I (sHLA-I) and of soluble CD95 molecules (sCD95) in the serum of blood and exhaled breath condensate (EBC) in patients with exacerbation of COPD. We investigated 49 moderate-to-severe COPD patients with exacerbation, and 21 healthy nonsmokers. The concentration of sHLA-I and sCD95 molecules was studied in serum and in EBC using the ELISA method. The nitrosative stress was evaluated by the measurement of NO2(-) levels in the serum and the concentration of ΣNO2(2)/NO3(2) in the EBC. Exacerbation of COPD is associated with increasing concentrations of NO2(2) in the serum and of the levels of ΣNO2(2)/NO3(2) in the EBC, together with the changing concentration of sHLA-I and sCD95 molecules in the both biological liquid. An association was discovered between the exacerbation of COPD and the indicators of nitrosative stress, the parameters of lung function and the concentration of sHLA-I, sCD95 molecules. The findings suggest a pathogenetic role of nitrosative stress and of soluble molecules of HLA-I and CD95 in the progression of COPD. The studied markers can be used as predictors of unfavourable prognoses of COPD and as quantitative criteria in the diagnosis of exacerbation of moderate-to-severe COPD.

Secretory IgA and course of COVID-19 in patients receiving a bacteria-based immunostimulant agent in addition to background therapy.

Mucosal immunity plays a major role not only in the prevention but probably also in the outcomes of COVID-19. An enhanced production of secretory immunoglobulin A (sIgA) might contribute to the activation of the immune response mechanisms. To assess the levels of sIgA produced by epithelial cells in the nasal and pharyngeal mucosa and those measured in salivary gland secretions and to study the course of COVID-19 following the combined scheme of intranasal and subcutaneous administration of a bacteria-based immunostimulant agent. This study included 69 patients, aged between 18 and 60, who had moderate COVID-19 infection. They were divided into two groups: Group 1 (control group) included 39 patients who received only background therapy, and Group 2 was made up of 30 patients who received background therapy in combination with the Immunovac VP4 vaccine, a bacteria-based immunostimulant agent, which was given for 11 days starting from the day of admission to hospital. The levels of sIgA were measured by ELISA in epithelial, nasal and pharyngeal swabs, and salivary gland secretions at baseline and on days 14 and 30. The combined scheme of intranasal and subcutaneous administration of the Immunovac VP4 vaccine in the complex therapy of patients with COVID-19 is accompanied by increased synthesis of sIgA in nasal and pharyngeal swabs, more intense decrease in the level of C-reactive protein (CRP) and reduction in the duration of fever and length of hospitalization compared to the control group. Prescribing a immunostimulant agent containing bacterial ligands in complex therapy for COVID-19 patients helps to enhance mucosal immunity and improves the course of the disease.

Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis: a prospective, multicenter, observational study (AVANTI).

BACKGROUND: Acute exacerbations of chronic bronchitis (AECB), including chronic obstructive pulmonary disease (AECOPD), represent a substantial patient burden. Few data exist on outpatient antibiotic management for AECB/AECOPD in Eastern/South Eastern Europe, in particular on the use of moxifloxacin (Avelox®), although moxifloxacin is widely approved in this region based on evidence from international clinical studies. METHODS: AVANTI (AVelox® in Acute Exacerbations of chroNic bronchiTIs) was a prospective, observational study conducted in eight Eastern European countries in patients > 35 years with AECB/AECOPD to whom moxifloxacin was prescribed. In addition to safety and efficacy outcomes, data on risk factors and the impact of exacerbation on daily life were collected. RESULTS: In the efficacy population (N = 2536), chronic bronchitis had been prevalent for > 10 years in 31.4% of patients and 66.0% of patients had concomitant COPD. Almost half the patients had never smoked, in contrast to data from Western Europe and the USA, where only one-quarter of COPD patients are non-smokers. The mean number of exacerbations in the last 12 months was 2.7 and 26.3% of patients had been hospitalized at least once for exacerbation. Physician compliance with the recommended moxifloxacin dose (400 mg once daily) was 99.6%. The mean duration of moxifloxacin therapy for the current exacerbation (Anthonisen type I or II in 83.1%; predominantly type I) was 6.4 ± 1.9 days. Symptom improvement was reported after a mean of 3.4 ± 1.4 days. After 5 days, 93.2% of patients reported improvement and, in total, 93.5% of patients were symptom-free after 10 days. In the safety population (N = 2672), 57 (2.3%) patients had treatment-emergent adverse events (TEAEs) and 4 (0.15%) had serious TEAEs; no deaths occurred. These results are in line with the known safety profile of moxifloxacin. CONCLUSIONS: A significant number of patients in this observational study had risk factors for poor outcome, justifying use of moxifloxacin. The safety profile of moxifloxacin and its value as an antibiotic treatment were confirmed. Physicians complied with the recommended 400 mg once-daily dose in a large proportion of patients, confirming the advantages of this simple dosing regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00846911.

Mucosal immunity in health care workers' respiratory tracts in the post-COVID-19 period.

Coronavirus disease (COVID-19) has generated interest in the assessment of systemic immune status, but existing knowledge about mucosal immunity is clearly insufficient to understand the full pathogenetic mechanisms of the disease. The aim of this study was to evaluate the long-term effects of novel coronavirus infection on mucosal immunity in the postinfection period among health care workers (HCWs). A total of 180 health care workers with and without a history of COVID-19 who ranged in age from 18 to 65 years were enrolled in this one-stage, cross-sectional study. The study subjects completed the 36-Item Short Form (36) Health Survey (SF-36) and the Fatigue Assessment Scale. Secretory immunoglobulin A (sIgA) and total immunoglobulin G (IgG) levels were quantified in saliva samples, induced sputum samples, and nasopharyngeal and oropharyngeal scrapings by an enzyme-linked immunosorbent assay. Specific anti-SARS-CoV-2 IgG antibodies were quantified in serum samples by chemiluminescence immunoassay. Analysis of the questionnaire data showed that all HCWs with a history of COVID-19 reported health problems that limited their daily activities and negative changes in their emotional health three months after the disease, regardless of its severity. The following shifts were detected in the adaptive arm of the immune response in different mucosal compartments. Among subjects who had severe or moderate-to-severe COVID-19, salivary sIgA levels were significantly higher than those in the control group (p < 0.05 and p < 0.005, respectively). Compared to the subjects in the control group, all subjects with prior COVID-19 had significantly higher levels of total IgG in induced sputum. In the group of patients who had had severe infection, total IgG in saliva was also higher (p < 0.05). A direct statistically significant correlation was also detected between the levels of total IgG in all studied samples and the levels of specific IgG antibodies against SARS-CoV-2 in the serum. A significant correlation was observed between total IgG levels and the parameters of physical and social activities, mental health, and fatigue levels. Our study demonstrated long-term changes in the humoral mucosal immune response, which were most pronounced in health care workers with a history of severe or moderate-to-severe COVID-19, and an association of these changes with certain clinical signs of post-COVID-19 syndrome.

Changes in nasal, pharyngeal and salivary secretory IgA levels in patients with COVID-19 and the possibility of correction of their secretion using combined intranasal and oral administration of a pharmaceutical containing antigens of opportunistic microorganisms.

Background: Although extensive research has been conducted on the role of local immunity in patients with SARS-CoV-2, little is known about the production and concentrations of secretory IgA (SIgA) in different mucosal compartments. This article aims to assess the secretion of SIgA in the nasal and pharyngeal compartments and saliva of patients with COVID-19 and to investigate the possibility and efficiency of correction of their secretion using combined intranasal and oral administration of a pharmaceutical containing antigens of opportunistic microorganisms. Methods: This study included 78 inpatients, aged between 18 and 60 years, who had confirmed COVID-19 with moderate lung involvement. The control group (n=45) received basic therapy, and the treatment group (n=33) was additionally administered the bacteria-based pharmaceutical Immunovac VP4 from day 1 to day 10 of hospitalization. SIgA levels were measured by ELISA at baseline and on days 14 and 30. Results: No systemic or local reactions associated with Immunovac VP4 were reported. We observed a statistically significant reduction in the duration of fever and hospitalization in patients who received Immunovac VP4 compared with those from the control group (p=0.03 and p=0.05, respectively). Changes over time in SIgA levels in nasal swabs were found to be significantly different in the two treatment groups (F=7.9, p[78.0]<0.001). On day 14 of observation, patients in the control group showed a statistically significant reduction in SIgA levels from baseline (p=0.02), whereas patients in the Immunovac VP4 group had stable SIgA levels (p=0.07). On day 30 after the start of treatment, there was a statistically significant increase in SIgA levels in the Immunovac VP4 group compared with baseline (from 77.7 (40.5-98.7) µg/L to 113.4 (39.8-156.7) µg/L; p=0.05) and the levels measured on day 14 (from 60.2 (23.3-102.9) µg/L to 113.4 (39.8-156.7) µg/L; p=0.03). The control group showed a statistically significant decrease in levels of nasal SIgA (to 37.3) on day 30 (p=0.007 for comparison with baseline values and p=0.04 for comparison with levels measured on day 14). Changes over time in SIgA levels measured in pharyngeal swabs were also different between the two treatment groups, and this difference reached statistical significance (F=6.5, p[73.0]=0.003). In the control group, this parameter did not change throughout the study (p=0.17 for a comparison between the levels measured on day 14 and the baseline values, and p=0.12 for a comparison between the levels measured on day 30 and the baseline values). In the Immunovac VP4 group, there was a statistically significant increase from baseline in SIgA levels on study day 30: from 1.5 (0.2-16.5) µg/L to 29.8 (3.6-106.8) µg/L (p=0.02). Changes over time in salivary SIgA did not show a significant difference between study groups (F=0.3, p[66.3]=0.75). Conclusion: As part of combination therapy, the bacteria-based immunostimulant agent Immunovac VP4 increases SIgA levels in the nasal and pharyngeal compartments and induces clinical improvement. Induced mucosal immunity is central to the prevention of respiratory infections, particularly in patients with post-COVID-19 syndrome.

Thermovaccination - thermoheliox as a stimulator of the immune response. Kinetics of the synthesis of antibodies and C-reactive protein in coronavirus infection.

Clinical trials of thermoheliox application (inhalation with a high-temperature mixture of oxygen and helium, 90 °C) in the treatment of the acute phase of coronavirus infection were conducted. Dynamics of disease development in infected patients (PCR test for the virus) and, dynamics of changes in blood concentration of C-reactive protein, immunoglobulin M, specific immunoglobulin G were studied. High efficiency of thermoheliox in releasing the organism from the virus and stimulating the immune response (thermovaccination effect) was shown. The kinetic model of the process is proposed and analyzed.

New Anti-Chemokine Oral Drug XC8 in the Treatment of Asthma Patients with Poor Response to Corticosteroids: Results of a Phase 2A Randomized Controlled Clinical Trial.

INTRODUCTION: A significant number of patients with moderate asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS). These patients do not yet meet the criteria for oral corticosteroids (OCS) and monoclonal antibodies. The new anti-chemokine oral drug XC8 could represent an alternative treatment option for these patients. The objective of this trial was to evaluate the effect of different doses of the XC8 in patients with partly controlled asthma in a phase 2a clinical trial. METHODS: A double-blind, parallel-group, randomized, multicenter, phase 2a trial was conducted at 12 sites in Russia. Patients with asthma were randomized into four groups (n = 30 each) to receive XC8 at 2 mg, 10 mg, 100 mg or placebo once-daily for 12 weeks in addition to low-dose ICS with or without LABA. Efficacy and safety parameters were evaluated at weeks 0, 2, 6, and 12. RESULTS: No statistically significant difference between the treatment arms in the number of patients with adverse events was observed. The primary endpoint, improvement of forced expiratory volume in 1 s (FEV1) % predicted over 12 weeks compared to placebo, was not statistically significant. The treatment of patients with XC8 (100 mg) resulted in statistically and clinically significant improvements in FEV1 compared to baseline (7.40% predicted, p < 0.001). Patients with elevated peripheral blood eosinophil count (PBEC, > 300 cells/µl) or serum interferon-γ (IFN-γ) level (> 100 pg/mL) treated with XC8 (100 mg) achieved a statistically significant improvement in FEV1 (11.33% predicted or 8.69% predicted, respectively, p < 0.05) as compared to the baseline versus the placebo. The strongest effect was observed in patients with both high PBEC and IFN-γ level. Pharmacodynamic engagement was demonstrated through the reduction of serum levels of C-C motif ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10). Treatment with XC8 (100 mg) alleviated resistance to maintenance ICS therapy in patients with elevated IFN-γ level. CONCLUSIONS: Given the high safety, oral route of administration, and efficacy, XC8 may provide a promising treatment option for patients with mild-to-moderate asthma. TRIAL REGISTRATION: 795-30/12/2015 (Ministry of Health Russian Federation), NCT03450434 (ClinicalTrials.gov).

Chemical kinetics of the development of coronaviral infection in the human body: Critical conditions, toxicity mechanisms, "thermoheliox", and "thermovaccination".

Kinetic modeling of the behavior of complex chemical and biochemical systems is an effective approach to study of the mechanisms of the process. A kinetic model of coronaviral infection development with a description of the dynamic behavior of the main variables, including the concentration of viral particles, affected cells, and pathogenic microflora, is proposed. Changes in the concentration of hydrogen ions in the lungs and the pH -dependence of carbonic anhydrase activity (a key breathing enzyme) are critical. A significant result is the demonstration of an acute bifurcation transition that determines life or system collapse. This transition is connected with exponential growth of concentrations of the process participants and with functioning of the key enzyme carbonic anhydrase in development of toxic effects. Physical and chemical interpretations of the therapeutic effects of the body temperature rise and the potential therapeutic effect of "thermoheliox" (respiration with a thermolized mixture of helium and oxygen) are given. The phenomenon of "thermovaccination" is predicted, which involves stimulation of the immune response by "thermoheliox".

Tobramycin for inhalation in cystic fibrosis: Beyond respiratory improvements.

European consensus guidelines recommend nebulised antibiotics for maintenance therapy in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection. Two formulations of tobramycin for inhalation are available in Europe (Tobi; Novartis AG, Switzerland; Bramitob; Chiesi Farmaceutici S.p.A., Italy). Data from a series of randomised controlled studies in patients with mild-to-moderate cystic fibrosis and chronic P. aeruginosa infection show that both Tobi and Bramitob significantly improve lung function and reduce the density of P. aeruginosa in sputum. Bacterial resistance may develop but does not seem to be clinically important. Other benefits, such as improved patient nutritional status and reductions in the need for hospitalisation, antipseudomonal antibiotics and productivity losses have also been documented with Tobi and Bramitob. Both formulations of inhaled tobramycin are well tolerated with no evidence of renal or ototoxicity. Improved patient compliance may be achieved through reducing nebulisation time, either by using Bramitob, which is formulated in a smaller volume than Tobi, or with new generation nebulisers. In conclusion, inhaled tobramycin not only improves lung function in patients with cystic fibrosis, but also offers other benefits which have implications for healthcare costs and patient quality of life.

A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison.

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400microg or placebo via multi-dose dry powder inhaler, or indacaterol 400microg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC(22-24h)) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC(22-24h) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200microg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile.

Salmeterol/fluticasone propionate via Diskus once daily versus fluticasone propionate twice daily in patients with mild asthma not previously receiving maintenance corticosteroids.

BACKGROUND AND OBJECTIVE: The efficacy and safety of twice-daily inhaled salmeterol/fluticasone propionate combination (SFC) therapy have been well established in the treatment of adults and adolescents with asthma. Once-daily administration of SFC could also be appropriate in patients with mild persistent asthma. This study aimed to investigate whether once-daily SFC 50 microg/100 microg was at least as effective as fluticasone propionate (FP) 100 microg twice daily, and more effective than twice-daily placebo, over 52 weeks as initial maintenance therapy in patients with mild persistent asthma. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, multicentre, parallel-group study carried out in primary and secondary care. Patients aged between 12 and 79 years with a documented clinical history of asthma for > or =6 months who were currently receiving inhaled short-acting beta(2)-adrenoceptor agonists only were enrolled. Patients were randomized to receive either once-daily inhaled SFC 50 microg/100 microg, twice-daily inhaled FP 100 microg (i.e. twice the dose of FP compared with SFC) or placebo for 52 weeks. The primary efficacy endpoints were mean morning peak expiratory flow (PEF), as recorded by patients prior to the use of bronchodilator or study medication, and the rate of investigator-recorded asthma exacerbations. RESULTS: Patients receiving twice-daily FP and once-daily SFC showed greater improvements in mean morning PEF compared with those receiving placebo (FP, difference in means 20.1 L/min; 95% CI 14.7, 25.5; p < 0.001; SFC, difference in means 14.8 L/min; 95% CI 9.4, 20.2; p < 0.001). The difference in adjusted mean PEF between once-daily SFC and twice-daily FP was -5.3 L/min (95% CI -9.1, -1.6). PEF results showed that once-daily SFC was non-inferior to twice-daily FP. Over 52 weeks, there was a 35% reduction in exacerbation rates with once-daily SFC, which in this respect demonstrated superiority over placebo (p < 0.001). Non-inferiority between once-daily SFC and twice-daily FP with respect to exacerbation rates was not shown. Once-daily SFC significantly improved clinic forced expiratory flow between 25% and 75% of forced vital capacity (difference in means 0.129 L/s; p < 0.001) and clinic PEF (difference in means 10.8 L/min; p < 0.001) compared with twice-daily FP. Both treatments were well tolerated and the safety profile of each was similar to that seen with placebo. CONCLUSION: In patients with mild persistent asthma not previously receiving maintenance therapy, once-daily SFC 50 microg/100 microg is an effective treatment compared with placebo, and was non-inferior to twice-daily FP 100 microg with respect to mean morning PEF. However, in this study, once-daily SFC was not as efficacious as twice-daily FP in reducing asthma exacerbation rates. This study confirms the benefits of regular maintenance treatment in patients with mild persistent asthma.

Russian guidelines for the management of COPD: algorithm of pharmacologic treatment.

The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A-D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation.

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.

A formulation of aerosolized tobramycin (Bramitob) in the treatment of patients with cystic fibrosis and Pseudomonas aeruginosa infection: a double-blind, placebo-controlled, multicenter study.

BACKGROUND AND AIM: Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) causes progressive deterioration in lung function. The purpose of this trial was to assess the efficacy and tolerability of a tobramycin highly concentrated solution for inhalation (TSI) [300mg/4mL; Bramitob when added to other antipseudomonal therapies in CF patients with chronic P. aeruginosa infection. METHODS: In a multinational, double-blind, multicenter study, CF patients with chronic P. aeruginosa infection were randomized to receive nebulized tobramycin or placebo over a 24-week study period in which 4-week treatment periods ('on' cycles) were followed by 4-week periods without treatment ('off' cycles). Forced expiratory volume in 1 second (FEV(1)) percentage of predicted normal was used as the primary efficacy outcome parameter. Forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF(25)(-)(75%)), P. aeruginosa susceptibility, minimum concentration required to inhibit 90% of strains (MIC(90)), rates of P. aeruginosa-negative culture, P. aeruginosa persistence and superinfection, need for hospitalization and parenteral antipseudomonal antibiotics, loss of school/working days due to the disease, and nutritional status (bodyweight and body mass index) were considered as secondary efficacy outcome parameters. Adverse events reporting, audiometry, and renal function were monitored to evaluate the tolerability and safety of TSI. RESULTS: A total of 247 patients were randomized in the study. At endpoint time assessment (week 20), FEV(1) was significantly increased in the tobramycin group and the adjusted mean difference between groups (intention-to-treat population) was statistically significant (p < 0.001). At the same time, clinically relevant improvements in FVC and FEF(25-75%) were detected in the TSI group (p = 0.022 and p = 0.001, respectively). The microbiologic outcomes at the end of the last 'on' cycle period were significantly better in the TSI group than the placebo group (p = 0.024), although there was a concomitant trend toward an increase in the MIC of isolated P. aeruginosa strains. The percentage of patients hospitalized as well as the need for parenteral antipseudomonal antibiotics was significantly lower in the TSI group (p = 0.002 and p = 0.009, respectively). Patients treated with TSI had fewer lost school/working days due to the disease (p < 0.001). A favorable effect of tobramycin in terms of an increase in bodyweight and body mass index was also noted, when compared with placebo, at all time points (p < 0.01 and p < 0.001, respectively). No significant changes in serum creatinine and auditory function were detected. The proportion of patients with drug-related adverse events was 15% in both treatment groups. CONCLUSIONS: Long-term, intermittent administration of this aerosolized tobramycin formulation (300mg/4mL) in CF patients with P. aeruginosa chronic infection significantly improved pulmonary function and microbiologic outcome, decreased hospitalizations, increased nutritional status, and was well tolerated.

Safety and tolerability of indacaterol in asthma: a randomized, placebo-controlled 28-day study.

The safety and tolerability of indacaterol, a novel once-daily beta(2)-agonist bronchodilator with a fast onset of action, were assessed in 156 asthma patients in a multicentre, randomized, double-blind, placebo-controlled study. Patients received indacaterol 200, 400 or 600 microg or placebo once daily for 28 days. Adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, spirometry and physical examinations were monitored. Indacaterol pharmacokinetics were assessed. There was no evidence of dose-related increases in AE incidence or clinically significant hypokalaemia or hyperglycaemia in indacaterol-treated patients. Mean pulse rate changes were minor in any group, with maximum 1-h post-dose changes from baseline of -3.7, -3.3 and -2.2 bpm for indacaterol 200, 400 and 600 microg, respectively, and -2.9 bpm for placebo. Mean QTc interval was similar between groups; change from baseline >60 ms occurred in only two patients. Mean FEV(1) increased after the first indacaterol dose; baseline-adjusted pre-dose (trough) values remained >or=166 mL higher than placebo at all subsequent visits, supporting a 24-h bronchodilator effect. Pre-dose (but not post-dose) serum indacaterol concentrations indicated a slight trend for accumulation. Once-daily indacaterol 200-600 microg has a favourable therapeutic index. It is well tolerated, and is not associated with any adverse cardiac or metabolic effects, while providing effective 24-h bronchodilation.

Relationship of the Content of Systemic and Endobronchial Soluble Molecules of CD25, CD38, CD8, and HLA-I-CD8 and Lung Function Parameters in COPD Patients.

The definition of new markers of local and systemic inflammation of chronic obstructive pulmonary disease (COPD) is one of the priority directions in the study of pathogenesis and diagnostic methods improvement for this disease. We investigated 91 patients with COPD and 21 healthy nonsmokers. The levels of soluble CD25, CD38, CD8, and HLA-I-CD8 molecules in the blood serum and exhaled breath condensate (EBC) in moderate-to-severe COPD patients during exacerbation and stable phase were studied. An unidirectional change in the content of sCD25, sCD38, and sCD8 molecules with increasing severity of COPD was detected. The correlations between the parameters of lung function and sCD8, sCD25, and sHLA-I-CD8 levels in the blood serum and EBC were discovered in patients with severe COPD. The findings suggest a pathogenetic role of the investigated soluble molecules of the COPD development and allow considering the content of sCD8, sCD25, and sHLA-I-CD8 molecules as additional novel systemic and endobronchial markers of the progression of chronic inflammation of this disease.