Biodistribution of cerium dioxide and titanium dioxide nanomaterials in rats after single and repeated inhalation exposures.

BACKGROUND: Physiologically based kinetic models facilitate the safety assessment of inhaled engineered nanomaterials (ENMs). To develop these models, high quality datasets on well-characterized ENMs are needed. However, there are at present, several data gaps in the systemic availability of poorly soluble particles after inhalation. The aim of the present study was therefore to acquire two comparable datasets to parametrize a physiologically-based kinetic model. METHOD: Rats were exposed to cerium dioxide (CeO2, 28.4 ± 10.4 nm) and titanium dioxide (TiO2, 21.6 ± 1.5 nm) ENMs in a single nose-only exposure to 20 mg/m3 or a repeated exposure of 2 × 5 days to 5 mg/m3. Different dose levels were obtained by varying the exposure time for 30 min, 2 or 6 h per day. The content of cerium or titanium in three compartments of the lung (tissue, epithelial lining fluid and freely moving cells), mediastinal lymph nodes, liver, spleen, kidney, blood and excreta was measured by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) at various time points post-exposure. As biodistribution is best studied at sub-toxic dose levels, lactate dehydrogenase (LDH), total protein, total cell numbers and differential cell counts were determined in bronchoalveolar lavage fluid (BALF). RESULTS: Although similar lung deposited doses were obtained for both materials, exposure to CeO2 induced persistent inflammation indicated by neutrophil granulocytes influx and exhibited an increased lung elimination half-time, while exposure to TiO2 did not. The lavaged lung tissue contained the highest metal concentration compared to the lavage fluid and cells in the lavage fluid for both materials. Increased cerium concentrations above control levels in secondary organs such as lymph nodes, liver, spleen, kidney, urine and faeces were detected, while for titanium this was found in lymph nodes and liver after repeated exposure and in blood and faeces after a single exposure. CONCLUSION: We have provided insight in the distribution kinetics of these two ENMs based on experimental data and modelling. The study design allows extrapolation at different dose-levels and study durations. Despite equal dose levels of both ENMs, we observed different distribution patterns, that, in part may be explained by subtle differences in biological responses in the lung.

Comparison of inhaled salbutamol and salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses: a randomized clinical trial.

OBJECTIVE: To compare the efficacy of inhaled salbutamol with salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses. STUDY DESIGN: Prospective, randomized, clinical study. ANIMALS: A total of 108 client-owned horses (American Society of Anesthesiologists status I-V) anaesthetized for elective and emergency procedures. METHODS: Horses were premedicated with acepromazine [intramuscularly 0.1 mg kg-1 or intravenously (IV) 0.05 mg kg-1] and xylazine (0.6 mg kg-1 IV). Midazolam (0.06 mg kg-1 IV) and ketamine (2.2 mg kg-1 IV) were combined to induce anaesthesia, and isoflurane in oxygen/air mixture (inspired oxygen fraction 0.7) was used for maintenance of anaesthesia. Mechanical ventilation was initiated without delay using the following ventilator settings: tidal volume 10 mL kg-1, respiratory rate 8 breaths minute-1, inspiratory-to-expiratory time ratio 1:2, no positive end-expiratory pressure. If arterial blood gas analysis revealed PaO2 < 100 mmHg (13.3 kPa), the administration of either inhaled salbutamol (2 µg kg-1) or salmeterol (0.5 µg kg-1) was randomly assigned Blood gas analysis was repeated 15 and 30 minutes after treatment. The intervention was considered successful when PaO2 after treatment ≥ 1.2 × PaO2 before treatment (i.e. ≥20% increase). PaO2 at 15 and 30 minutes was compared between groups using Mann-Whitney U test; p < 0.05 was considered significant. RESULTS: Of the 108 horses, 60 were administered salbutamol, 65% and 60% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 38% and 44%, respectively. The other 48 horses were administered salmeterol, 35% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 3% and 4%, respectively. PaO2 was significantly higher after salbutamol than after salmeterol at 15 and 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Using the described protocol, inhaled salbutamol was more effective than salmeterol in improving PaO2 in anaesthetized horses with value < 100 mmHg (13.3 kPa).

Inhalable mucin-permeable nanomicelles deliver antibiotics for effective treatment of chronic pneumonia.

Pseudomonas aeruginosa (P. aeruginosa) pneumonia can have serious physiological consequences, particularly when P. aeruginosa biofilms are formed. Although inhaled therapy is preferred, inhaled drugs tend to get trapped by pulmonary mucus, which hinders efficient antibiotic permeability through mucus and biofilms. In this study, we prepare poly[2-(pentamethyleneimino)ethyl methacrylate]-block-poly[2-(N-oxide-pentamethyleneimino)ethyl methacrylate] (PPEMA-b-PPOEMA) micelles loaded with azithromycin (AZM) using reversible addition-fragmentation chain transfer (RAFT) polymerization to achieve effective treatment of P. aeruginosa pneumonia. The zwitterionic structure on the surface of the micelle facilitates the successful traversal of the mucus and optimal concentration within the biofilm. Furthermore, the protonation of piperidine in the polymer enables the micelles to exhibit a positive charge in the acidic environment of a bacterial infection, enhancing AZM's interaction with the bacterium. Both in vivo and in vitro experiments demonstrate that this transmucosal zwitterionic polymer, in combination with a charge reversal strategy, effectively promotes the enrichment of micelles at the site of bacterial infection, thereby increasing the number of antibiotics reaching the bacterial interior and demonstrating remarkable antibacterial synergy. Overall, this work offers a promising approach for trans-airway drug delivery in the treatment of pneumonia.

Reshaping respiratory care: potential advances in inhaled pharmacotherapy in asthma.

INTRODUCTION: Asthma is a common disease with a global burden of 358 million patients. Despite improvements in pharmacological and non-pharmacological treatments, many patients still do not achieve complete asthma control. Therefore, innovative pharmacotherapy is important. AREAS COVERED: Following a semi-structured search in Pubmed, an overview of advances in inhaled asthma therapy is provided, looking at innovations in digital inhalers, eco-friendly inhalers and novel inhaled biologic therapies, antibiotics and vaccines, as well as other potential novel asthma therapy targets. EXPERT OPINION: Digital inhalers, sending reminders and monitoring inhalation technique electronically, can support medication adherence and improve asthma control. To reduce the global warming potential of traditional aerosols used in pressurized metered-dose inhalers (HFA-134a, HFA-227ea), greener alternatives are under development (HFA-152a, HFO-1234ze) that are expected to be available by 2025. Current pharmacological advances in asthma therapy are mainly achieved by novel biologicals (anti-IgE, anti-IL5, anti-IL4/13, and anti-TSLP) targeting specific severe asthma phenotypes. While injection is the usual administration route for biologics and vaccines used in asthma, inhalation is an option being explored, although several (mainly formulation) challenges need to be overcome. Other potential novel future inhaled asthma therapies include anti-IL-33/ST2 biologicals and JAK inhibitors, all still requiring more clinical evidence.

Dos and don'ts to optimize transnasal aerosol drug delivery in clinical practice.

INTRODUCTION: Transnasal aerosol drug delivery has become widely accepted for treating acutely ill infants, children, and adults. More recently aerosol administration to wider populations receiving high and low-flow nasal oxygen has become common practice. AREAS COVERED: Skepticism of insufficient aerosol delivery to the lungs has been tempered by multiple in vitro explorations of variables to optimize delivery efficiency. Additionally, clinical studies demonstrated comparable clinical responses to orally inhaled aerosols. This paper provides essential clinical guidance on how to improve transnasal aerosol delivery based on device-, settings-, and drug-related optimization to serve as a resource for educational initiatives and quality enhancement endeavors at healthcare institutions. EXPERT OPINION: Transnasal aerosol delivery is proliferating worldwide, but indiscriminate use of excessive-high flows, poor selection and placement of aerosol devices and circuits can greatly reduce aerosol delivery and efficacy, potentially compromising treatment to acute and critically ill patients. Attention to these details can improve inhaled dose by an order of magnitude, making the difference between effective treatment and the progression to more invasive ventilatory support, with greater inherent risk and cost. These revelations have prompted specific recommendations for optimal delivery, driving advancements in aerosol generators, formulations, and future device designs to administer aerosols and maximize treatment effectiveness.

Sedation with inhaled sevoflurane in the intensive care unit.

INTRODUCTION: Critically ill patients often develop the Post-Intensive Care Syndrome (PICS). Current sedation guidelines mainly rely on intravenous agents. Inhaled sedatives are a promising alternative with favorable pharmacokinetics and potential benefits in critical care settings. However, their application in Latin America remains unexplored. METHODS: Case-series study that included adult ICU patients who underwent deep sedation with sevoflurane using the SEDANA anesthetic conserving device. Data on demographics, sedation protocols, adverse events, and outcomes were collected. Statistical analysis assessed changes over time in laboratory parameters. RESULTS: Eleven patients were included, with sevoflurane administered via artificial airways. Inhaled sedation led to the successful cease of intravenous sedatives in 10 of 11 patients, and reduction of at least 30% in opioid dose. No significant adverse effects were observed. Barriers to adherence included device-related issues and challenges in healthcare staff training. CONCLUSION: Sevoflurane effectively achieved sedation goals in ICU patients, reducing the need for additional sedatives and opioids. Our findings support the safety and efficacy of inhaled sedatives in ICU settings and highlight the importance of further research in this area. Longer-term studies are needed to fully determine the impact of inhaled sedatives in ICU patients.

Introducción: Los pacientes críticamente enfermos a menudo desarrollan el Síndrome Post-Cuidados Intensivos (PICS). Las pautas actuales de sedación se basan principalmente en agentes intravenosos. Los sedantes inhalados son una alternativa prometedora con farmacocinética favorable y beneficios potenciales en entornos de cuidados críticos. Sin embargo, su aplicación en América Latina sigue sin explorarse. Métodos: Estudio de serie de casos que incluyó a pacientes adultos de UCI que recibieron sedación profunda con sevoflurano utilizando el dispositivo conservador anestésico SEDANA. Se recopilaron datos demográficos, protocolos de sedación, eventos adversos y resultados. El análisis estadístico evaluó los cambios en el tiempo en los parámetros de laboratorio. Resultados: Se incluyeron once pacientes, a quienes se les administró sevoflurano a través de vías respiratorias artificiales. Se incluyeron once pacientes, a quienes se les administró sevoflurano a través de vías respiratorias artificiales. La sedación inhalada llevó a la cesación exitosa de sedantes intravenosos en 10 de los 11 pacientes, con una reducción de al menos 30% la dosis de opioides. No se observaron efectos adversos significativos. Las barreras para la adherencia incluyeron problemas relacionados con el dispositivo y desafíos en la capacitación del personal de salud. Conclusión: El sevoflurano logró de manera efectiva los objetivos de sedación en pacientes de UCI, reduciendo la necesidad de sedantes y opioides adicionales. Nuestros hallazgos respaldan la seguridad y eficacia de los sedantes inhalados en entornos de UCI y resaltan la importancia de una mayor investigación en esta área. Se necesitan estudios a más largo plazo para determinar completamente el impacto de los sedantes inhalados en pacientes de UCI.

Inhalable Stem Cell Exosomes Promote Heart Repair After Myocardial Infarction.

BACKGROUND: Exosome therapy shows potential for cardiac repair after injury. However, intrinsic challenges such as short half-life and lack of clear targets hinder the clinical feasibility. Here, we report a noninvasive and repeatable method for exosome delivery through inhalation after myocardial infarction (MI), which we called stem cell-derived exosome nebulization therapy (SCENT). METHODS: Stem cell-derived exosomes were characterized for size distribution and surface markers. C57BL/6 mice with MI model received exosome inhalation treatment through a nebulizer for 7 consecutive days. Echocardiographies were performed to monitor cardiac function after SCENT, and histological analysis helped with the investigation of myocardial repair. Single-cell RNA sequencing of the whole heart was performed to explore the mechanism of action by SCENT. Last, the feasibility, efficacy, and general safety of SCENT were demonstrated in a swine model of MI, facilitated by 3-dimensional cardiac magnetic resonance imaging. RESULTS: Recruitment of exosomes to the ischemic heart after SCENT was detected by ex vivo IVIS imaging and fluorescence microscopy. In a mouse model of MI, SCENT ameliorated cardiac repair by improving left ventricular function, reducing fibrotic tissue, and promoting cardiomyocyte proliferation. Mechanistic studies using single-cell RNA sequencing of mouse heart after SCENT revealed a downregulation of Cd36 in endothelial cells (ECs). In an EC-Cd36fl/- conditional knockout mouse model, the inhibition of CD36, a fatty acid transporter in ECs, led to a compensatory increase in glucose utilization in the heart and higher ATP generation, which enhanced cardiac contractility. In pigs, cardiac magnetic resonance imaging showed an enhanced ejection fraction (Δ=11.66±5.12%) and fractional shortening (Δ=5.72±2.29%) at day 28 after MI by SCENT treatment compared with controls, along with reduced infarct size and thickened ventricular wall. CONCLUSIONS: In both rodent and swine models, our data proved the feasibility, efficacy, and general safety of SCENT treatment against acute MI injury, laying the groundwork for clinical investigation. Moreover, the EC-Cd36fl/- mouse model provides the first in vivo evidence showing that conditional EC-CD36 knockout can ameliorate cardiac injury. Our study introduces a noninvasive treatment option for heart disease and identifies new potential therapeutic targets.

Nebulized enriched heparin improves respiratory parameters in patients with COVID-19: a phase I/II randomized and triple-blind clinical trial.

To evaluate the safety and the potential antiviral treatment of inhaled enriched heparin in patients with COVID-19. The specific objectives were to investigate the anticoagulation profile, antiviral and anti-inflammatory effects, and respiratory evolution of inhaled enriched heparin. We conducted a randomized, triple-blind, placebo-controlled Phase I/II clinical trial in hospitalized adults with COVID-19 receiving inhalation of enriched heparin or saline (placebo) every 4 h for 7 days. Among the 27 patients who completed the study, no changes in blood coagulation parameters were observed, indicating the safety of inhaled enriched heparin. The group receiving enriched heparin showed a significant reduction in the need for supplemental oxygen and improvement in respiratory parameters, such as the PaO2/FiO2 ratio. Inhalation of enriched heparin is shown to be safe and has also demonstrated potential therapeutic benefits for patients with COVID-19. These promising results justify the continuation of the study to the next phase, Phase II/III, to further evaluate the therapeutic efficacy of inhaled enriched heparin in the treatment of COVID-19-associated viral pneumonia.Trial registration: ClinicalTrials.gov. 08/02/2021. Identifier: NCT04743011.

A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.

Inhaled tea polyphenol-loaded nanoparticles coated with platelet membranes largely attenuate asthmatic inflammation.

BACKGROUND: Tea polyphenols (TPs), prominent constituents of green tea, possess remarkable antioxidant and anti-inflammatory properties. However, their therapeutic potential is limited due to low absorption and poor bioavailability. To address this limitation and enhance their efficacy, we developed a biomimetic nanoplatform by coating platelet membrane (PM) onto poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) to create targeted delivery vehicles for TPs (PM@TP/NPs) to the inflamed tissues in asthma. METHODS: After synthesizing and characterizing PM@TP/NPs, we assessed their biocompatibility and biosafety through cell viability assays, hemolysis tests, and inflammation analysis in vivo and in vitro. The therapeutic effect of PM@TP/NPs on asthma was then evaluated using a mouse model of HDM-induced asthma. Additionally, PM@TP/NPs-mediated reactive oxygen species (ROS) scavenging capacity, as well as the activation of signaling pathways, were analyzed in HBE cells and asthmatic mice via flow cytometry, RT-qPCR, and western blotting. RESULTS: Compared with free TPs, PM@TP/NPs demonstrated excellent biocompatibility and safety profiles in both in vitro and in vivo, as well as enhanced retention in inflamed lungs. In HDM-induced mouse asthma model, inhaled PM@TP/NPs largely attenuated lung inflammation and reduced the secretion of type 2 pro-inflammatory cytokines in the lungs compared to free TPs. The therapeutic effects of PM@TP/NPs on asthma might be associated with an enhanced ROS scavenging capacity, increased activation of the Nrf2/HO-1 pathway, and decreased activation of the CCL2/MAPK and TLR4/NF-κB pathway in the lungs. CONCLUSIONS: Our findings demonstrate that inhalation of PM@TP/NPs largely attenuated lung inflammation in HDM-induced asthmatic mice. These results suggest that PM@TP/NPs might be a novel therapeutic strategy for asthma.

Evaluation of Adherence and Persistence to Triple Therapy in Patients with COPD: A German Claims Data Study.

Purpose: Triple therapy (long-acting muscarinic antagonist/long-acting ß2-agonist/inhaled corticosteroid) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence. This study assessed comparative adherence and persistence to single-inhaler triple therapy (SITT) versus MITT among patients with COPD in a real-world setting in Germany. Patients and Methods: This retrospective analysis using the WIG2 benchmark database identified patients with COPD newly initiating triple therapy with MITT or SITT (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or formoterol/beclomethasone/glycopyrronium bromide [FOR/BDP/GLY]) November 2017-June 2019. Eligible patients were ≥35 years with 1 year's continual insurance prior to triple therapy initiation and no previous record of triple therapy. Inverse probability of treatment weighting was used to balance baseline characteristics. Adherence was measured using proportion of days covered (PDC) at 6, 12, and 18 months post-treatment initiation; persistence (time until treatment discontinuation) was measured at 6, 12, and 18 months, with a gap of >30 days used to define non-persistence. Results: Of 5710 patients included in the analysis (mean age 66 years), 71.4% initiated MITT and 28.6% initiated SITT (FF/UMEC/VI: 41.4%; FOR/BDP/GLY: 58.6%). Mean PDC was higher among SITT versus MITT users at all time points; at each time point, mean PDC was highest among FF/UMEC/VI users. During the first 6 months following treatment initiation, higher adherence was exhibited by FF/UMEC/VI (29%) and FOR/BDP/GLY (19%) users versus MITT users. Over the entire observation period, FF/UMEC/VI users had the highest proportion of persistent patients; at 18 months, 16.5% of FF/UMEC/VI users were persistent versus 2.3% of MITT users. Conclusion: Patients initiating SITT in Germany had significantly higher adherence and persistence compared with patients initiating MITT over 6 to 18 months following treatment initiation. Among SITT, FF/UMEC/VI users had the highest proportion of adherence and persistence.

Application of haloinhalations at the sanatorium-resort stage of rehabilitation of patients after COVID-19.

BACKGROUND: After suffering from COVID-19, a large number of patients need respiratory rehabilitation. One of the methods of rehabilitation is inhalation with salt aerosols. OBJECTIVE: Our work aimed to study the effectiveness of inhalations of a dry aerosol of salt precipitated from the mineral water of the "Teplitsa multidisciplinary sanatorium", Transcarpathian region of Ukraine. MATERIAL AND METHODS: 30 male patients were examined after suffering from COVID-19. We formed two groups of patients, control and main, 15 people each. Patients in the control group received inhalation with a dry aerosol of table salt of the "Aero-M-sol". In contrast, patients in the main group received a course of inhalations with a dry aerosol of salt precipitated from the mineral water. RESULTS AND DISCUSSION: Under the influence of the rehabilitation complex in both groups, there is a performance improvement but significant changes are observed only in patients of the main group. The indicator Forced Vital Сapacity1 increased to the greatest extent, which after rehabilitation is significantly higher than in the control group (p<0.05). As a result, the Tiffeneau index significantly increases in the main group compared to the control group, reaching normal values. The main effect is associated with a decrease in obstructive complications of the respiratory tract as a result of a decrease in inflammation. The use of iodine-bromine brines (as in our case) for inhalation in the treatment of respiratory diseases has been proven to be effective, with systemic effects in the form of decreased IgE and increased IgA in the blood serum having been noticed. CONCLUSIONS: The use of haloinhalations with MW salts in the rehabilitation of patients after suffering from COVID-19 disease significantly improves the clinical condition of convalescents.

COMPARATIVE ANALYSIS OF MEMORY AND BEHAVIORAL CHANGES AFTER RADON-CONTAINED MINERAL WATER INHALATION THERAPY IN AGED RATS.

This research article elucidates the pivotal role of radiopharmacy in the contemporary landscape, underscoring its potential therapeutic efficacy in addressing symptoms associated with aged-related neurocognitive processes. Clinical trials, characterized by the judicious application of modest radiation doses, exemplified by low-dose radon, have yielded affirmative outcomes in the amelioration of aged, related symptoms. MATERIAL AND METHODS: The study was conducted on an animal model. The effect of low doses of radon on cognitive processes is being studied by inhalation of randomized mineral water. Changes in the clinical picture were studied using behavioral tests, namely the Barnes maze tests. At the cellular level, radon-contained water inhalation causes different changes: in the fraction of synaptic membranes (determined by Na, K-ATPase activity), aged, related changes by telomerase activity and oxidative stress level changes. RESULTS: Our studies show that age-related changes in brain tissue are less noticeable after radon inhalation, namely, the concentration of amyloid plaques decreases in a group of aged rats after radon therapy. A significant improvement in cognitive function was observed after radon inhalation in aged rats. CONCLUSION: The results show that exposure to radon-containing mineral water leads to improved spatial perception, potentially improving age-related cognitive functions not only at the level of neurocognitive tests, but also changes at the level of cellular functioning.

Quality by Design in Pulmonary Drug Delivery: A Review on Dry Powder Inhaler Development, Nanotherapy Approaches, and Regulatory Considerations.

Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.

Comparisons between In-Check DIAL® and PF810® in evaluation and training inspiratory capacity for using dry powder inhalers.

BACKGROUND: Dry powder inhalers (DPIs) rely on both internal resistance and patients' inspiratory capacity for effective operation. Optimal inspiratory technique is crucial for DPI users. This study assessed the accuracy and repeatability of two available devices, PF810® and In-Check DIAL®, and analyzed their measurement errors and consistency in detecting inspiratory capacity. METHODS: The accuracy and repeatability of peak inspiratory flow (PIF) and forced inspiratory vital capacity (FIVC) against various internal resistances of the two devices were assessed using standard waveforms generated by a breathing simulator. The agreement of PIF measurements between the two devices in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients was analyzed with the intraclass correlation coefficient and Bland-Altman graphical analysis. RESULTS: PF810® showed great accuracy and repeatability in measuring PIF, except for square waveforms at the lowest flow rate (20 L/min). In-Check DIAL® exhibited poor accuracy against high resistance levels. In scenarios with no resistance, In-Check DIAL® had significantly smaller measurement errors than PF810®, but larger errors against high resistance levels. The two devices showed excellent agreement (ICC > 0.80, P < 0.05), except for healthy volunteers against medium to high resistance (R3-R5) where the ICC was insignificant. Bland-Altman plots indicated small disagreements between the two devices for both healthy volunteers and COPD patients. CONCLUSIONS: In-Check DIAL® exhibited poor accuracy and larger measurement errors than PF810® when detecting PIFs against higher internal resistances. However, its good performance against lower internal resistances, along with its cost-effectiveness and convenience made it appropriate for primary care. PF810® showed good accuracy and repeatability and could detect additional parameters of inspiratory capacity beyond PIF, though required further studies to confirm its clinical benefits.

Benefits of budesonide/glycopyrronium/formoterol fumarate dihydrate on lung function and exacerbations of COPD: a post-hoc analysis of the KRONOS study by blood eosinophil level and exacerbation history.

BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity. METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

Long-term inhaling ultrafine zinc particles increases cardiac wall stresses elevated by myocardial infarction.

The analysis of cardiac wall mechanics is of importance for understanding coronary heart diseases (CHD). The inhalation of ultrafine particles could deteriorate CHD. The aim of the study is to investigate the effects of cardiac wall mechanics on rats of myocardial infarction (MI) after long-term inhalation of ultrafine Zn particles. Cardiac wall stresses and strains were computed, based on echocardiographic and hemodynamic measurements. It was found that MI resulted in the significantly elevated stresses and the reduced strains. The short-term inhalation of ultrafine Zn particles decreased stresses and increased strains in MI rats, but the long-term inhalation had the opposite effects. Hence, the short-term inhalation of ultrafine Zn particles could alleviate the MI-induced LV dysfunction while the long-term inhalation impaired it.

Retrospective, observational study of different medication regimens and outcome in children with cough variant asthma.

OBJECTIVE: This retrospective longitudinal cohort study aimed to explore the best therapeutic regimen and treatment duration of cough variant asthma (CVA) in children. METHODS: A total of 314 children with CVA were divided into receive inhaled corticosteroids (ICS) combined with long-acting beta2-agonist (LABA) group, ICS combined with leukotriene receptor antagonists (LTRA) group, ICS monotherapy group and LTRA monotherapy group. All clinical data were statistically analyzed. Logistic regression model was used to compare the advantages and disadvantages of different treatment schemes at each follow-up time point and the best treatment scheme. The Cox proportional hazard regression model based on inverse probability weighting was used to compare the effects of different medication regimens on adverse outcomes with asthma recurrence or progression as the end point. RESULTS: (1) After comprehensive analysis, ICS + LABA group was the preferred control regimen for CVA within 8 weeks. After 8 weeks of diagnosis, the efficacy of ICS group or LTRA group was comparable to that of ICS + LABA group and ICS + LTRA group. (2) The ICS + LABA group showed a significant improvement in cough at an early stage, particularly at 4 weeks; the symptoms of ICS + LTRA and ICS groups were significantly improved at 36 weeks. The LTRA group alone showed significant improvement at 20 weeks. CONCLUSION: ICS + LABA, ICS + LTRA, ICS alone and LTRA alone can effectively treat CVA. ICS + LABA could improve the symptoms most quickly within 8 weeks after CVA diagnosis, followed by ICS + LATR group. After 8 weeks, it can be reduced to ICS alone to control CVA for at least 36 weeks based on the remission of symptoms in children.