Real-Time Particle Emission Monitoring for the Non-Invasive Prediction of Lung Deposition via a Dry Powder Inhaler.

Although inhalation therapy represents a promising drug delivery route for the treatment of respiratory diseases, the real-time evaluation of lung drug deposition remains an area yet to be fully explored. To evaluate the utility of the photo reflection method (PRM) as a real-time non-invasive monitoring of pulmonary drug delivery, the relationship between particle emission signals measured by the PRM and in vitro inhalation performance was evaluated in this study. Symbicort® Turbuhaler® was used as a model dry powder inhaler. In vitro aerodynamic particle deposition was evaluated using a twin-stage liquid impinger (TSLI). Four different inhalation patterns were defined based on the slope of increased flow rate (4.9-9.8 L/s2) and peak flow rate (30 L/min and 60 L/min). The inhalation flow rate and particle emission profile were measured using an inhalation flow meter and a PRM drug release detector, respectively. The inhalation performance was characterized by output efficiency (OE, %) and stage 2 deposition of TSLI (an index of the deagglomerating efficiency, St2, %). The OE × St2 is defined as the amount delivered to the lungs. The particle emissions generated by four different inhalation patterns were completed within 0.4 s after the start of inhalation, and were observed as a sharper and larger peak under conditions of a higher flow increase rate. These were significantly correlated between the OE or OE × St2 and the photo reflection signal (p < 0.001). The particle emission signal by PRM could be a useful non-invasive real-time monitoring tool for dry powder inhalers.

Fabrication of polycrystalline phosphorus-doped diamond electrodes from red phosphorus.

Polycrystalline phosphorus-doped diamond was fabricated by the quartz-tube-type microwave plasma-assisted chemical vapor deposition method. Significantly, red phosphorus was used as a source of phosphorous, instead of PH3. Phosphorus-doped diamond electrodes with hydrogen-terminated and oxygen-terminated surfaces were investigated for the redox reactions of K3[Fe(CN)6] and [Ru(NH3)6]Cl3. The carrier concentration was estimated as 2.1-5.3 × 1018 cm-3 from electrochemical impedance measurements. Polycrystalline phosphorus-doped diamond shows great promise as chemical electrode materials.

Longitudinal assessment of interstitial lung abnormalities on CT in patients with COPD using artificial intelligence-based segmentation: a prospective observational study.

BACKGROUND: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts. METHODS: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans. RESULTS: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure. CONCLUSION: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD.

Pulmonary function and chest CT abnormalities 3 months after discharge from COVID-19, 2020-2021: A nation-wide multicenter prospective cohort study from the Japanese respiratory society.

BACKGROUND: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT. METHODS: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated. RESULTS: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity. CONCLUSION: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan.

Centrilobular emphysema and airway dysanapsis: factors associated with low respiratory function in younger smokers.

Background: Low respiratory function in young adulthood is one of the important factors in the trajectory leading to the future development of COPD, but its morphological characteristics are not well characterised. Methods: We retrospectively enrolled 172 subjects aged 40-49 years with ≥10 pack-years smoking history who underwent lung cancer screening by computed tomography (CT) and spirometry at two Japanese hospitals. Emphysema was visually assessed according to the Fleischner Society guidelines and classified into two types: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Airway dysanapsis was assessed with the airway/lung ratio (ALR), which was calculated by the geometric mean of the lumen diameters of the 14 branching segments divided by the cube root of total lung volume on a CT scan. Results: Among the subjects, CLE and PSE were observed in 20.9% and 30.8%, respectively. The mean ALR was 0.04 and did not differ between those with and without each type of emphysema. Multivariable regression analysis models adjusted for age, sex, body mass index and smoking status indicated that CLE and a low ALR were independently associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (estimate -1.64 (95% CI -2.68- -0.60) and 6.73 (95% CI 4.24-9.24), respectively) and FEV1 % pred (estimate -2.81 (95% CI -5.10- -0.52) and 10.9 (95% CI 5.36-16.4), respectively). Conclusions: CLE and airway dysanapsis on CT were independently associated with low respiratory function in younger smokers.

Quantification of airway structures by persistent homology.

We propose two types of novel morphological metrics for quantifying the geometry of tubular structures on computed tomography (CT) images. We apply our metrics to identify irregularities in the airway of patients with chronic obstructive pulmonary disease (COPD) and demonstrate that they provide complementary information to the conventional metrics used to assess COPD, such as the tissue density distribution in lung parenchyma and the wall area ratio of the segmented airway. The three-dimensional shape of the airway and its abstraction as a rooted tree with the root at the trachea carina are automatically extracted from a lung CT volume, and the two metrics are computed based on a mathematical tool called persistent homology; treeH0 quantifies the distribution of branch lengths to assess the complexity of the tree-like structure and radialH0 quantifies the irregularities in the luminal radius along the airway. We show our metrics are associated with clinical outcomes.

Sleep Restfulness in Patients with Obstructive Sleep Apnea Undergoing Continuous Positive Airway Pressure Therapy.

Objective Sleep restfulness is closely associated with mortality. Thus, it is an important sleep-related symptom in the general population. However, it is rarely evaluated in patients with obstructive sleep apnea (OSA) syndrome. The present study examined the importance of sleep restfulness in patients with OSA receiving continuous positive airway pressure (CPAP) therapy. Materials and Methods We administered sleep-related questionnaires, which included items such as subjective sleep duration and sleep restfulness, to 775 patients with OSA receiving CPAP therapy. Sleep restfulness was rated using a 5-point Likert-type scale, with the score of 5 indicating restfulness. Good adherence to CPAP therapy was defined as the use of CPAP therapy for at least 4 h per night in 70% of nights. Results We excluded 105 patients with lacking data. Thus, 670 patients were finally examined. In total, 29 (4.3%), 124 (18.5%), 139 (20.8%), 235 (35.1%), and 143 (14.3%) patients answered restless (1), somewhat restless (2), neither (3), somewhat restful (4), and restful (5) respectively. A total of 467 (69.7%) patients had good adherence to CPAP therapy. Multivariate logistic regression analysis showed that sleep restfulness was independently and positively associated with subjective sleep duration (≥ 7 hours) and good adherence to CPAP therapy. Conclusion Sleep restfulness was associated with subjective sleep duration and good adherence to CPAP therapy in patients with OSA. Favorable outcomes are significantly correlated with good adherence to CPAP therapy. Thus, sleep restfulness can be an indicator of a subtype that has favorable outcomes in patients after CPAP therapy.

Associations of fractional exhaled nitric oxide with airway dimension and mucus plugs on ultra-high-resolution computed tomography in former smokers and nonsmokers with asthma.

BACKGROUND: Associations of fractional exhaled nitric oxide (FeNO) with airway wall remodeling and mucus plugs remain to be explored in smokers and nonsmokers with asthma. Ultra-high-resolution computed tomography (U-HRCT), which allows accurate structural quantification of airways >1 mm in diameter, was used in this study to examine whether higher FeNO was associated with thicker walls of the 3rd to 6th generation airways and mucus plugging in patients with asthma. METHODS: The retrospective analyses included consecutive former smokers and nonsmokers with asthma who underwent U-HRCT in a hospital. The ratio of wall area to summed lumen and wall area was calculated as the wall area percent (WA%). Mucus plugging was visually scored. RESULTS: Ninety-seven patients with asthma (including 59 former smokers) were classified into low (<20 ppb), middle (20-35 ppb), and high (>35 ppb) FeNO groups (n = 24, 26, and 47). In analysis including all patients and subanalysis including nonsmokers or former smokers, WA% in the 6th generation airways was consistently higher in the high FeNO group than in the low FeNO group, whereas WA% in the 3rd to 5th generation airways was not. In multivariable models, WA% in the 6th generation airways and the rate of mucus plugging were higher in the high FeNO group than in the low FeNO group after adjusting for age, sex, body mass index, smoking status, lung volume, and allergic rhinitis presence. CONCLUSIONS: Higher FeNO may reflect the inflammation and remodeling of relatively peripheral airways in asthma in both former smokers and nonsmokers.

Longitudinal changes in respiratory reactance in patients with COPD: associations with longitudinal change in air-trapping, exacerbations, and mortality.

INTRODUCTION: Air-trapping affects clinical outcomes in patients with chronic obstructive pulmonary disease (COPD) and may be detected by reactance at 5 Hz (X5) on respiratory oscillometry because X5 sensitively reflects the elasticity of the chest wall, airway and lung. However, the longitudinal association between X5 and air-trapping remains to be explored. This study aimed to test whether longitudinal changes in X5 could be associated with air-trapping progression, exacerbations, and mortality in patients with COPD. METHODS: In this prospective COPD observational study, the follow-up period consisted of the first 4 years to obtain longitudinal changes in X5 and residual volume (RV) and number of exacerbations and the remaining years (year 4 to 10) to test mortality. Patients were divided into large, middle, and small X5 decline groups based on the tertiles of longitudinal change in X5, and mortality after 4 years was compared between the groups. RESULTS: Patients with COPD (n = 114) were enrolled. The large X5 decline group (n = 38) showed a greater longitudinal change in RV and more exacerbations compared with the small X5 decline group (n = 39) in multivariable models adjusted for age, sex, body mass index, and smoking history. Long-term mortality after the 4-year follow-up was higher in the large X5 decline group than in the small X5 decline group (hazard ratio [95 % confidence interval] = 8.37[1.01, 69.0]) in the multivariable Cox proportional hazard model. CONCLUSION: Longitudinal changes in respiratory reactance could be associated with progressive air-trapping, exacerbation frequency, and increased mortality in patients with COPD.

Associations between Nocturnal Hypoxemia and Retinal Nerve Fiber Layer Thinning: The Nagahama Study.

Rationale: There have been meta-analyses that showed reduced retinal nerve fiber layer (RNFL) thickness, which is a surrogate marker of glaucoma, in patients with obstructive sleep apnea (OSA). However, the sample sizes in these reports were small (<300), and the mechanism of RNFL thinning in patients with OSA was not revealed.Objectives: To investigate the relationship of RNFL thickness with nocturnal hypoxemia or hypoxemic burden in a large-scale study.Methods: In this epidemiological study, 8,309 community residents were enrolled. The actigraphy-modified 3% oxygen desaturation index (acti-ODI3%) and cumulative percentage of sleep time with oxygen saturation <90% (acti-CT90) modified by objective sleep duration using actigraphy were measured. The hypoxemic burden is shown as acti-CT90. Circumpapillary RNFL thickness was determined using optical coherence tomography.Results: Multivariable logistic analysis models revealed that an increase in acti-CT90 was significantly associated with mean RNFL thinning after adjusting for several factors in participants without glaucoma diagnosed or treated previously (ß = -0.037; P = 0.009). There were significant differences in mean RNFL thickness among participants stratified according to acti-CT90 (>1.5 vs. ⩽1.5; P = 0.04). Although acti-ODI3% was significantly associated with acti-CT90 (ß = 0.72; P < 0.0001), acti-ODI3% was not significantly associated with mean RNFL thickness in the multivariable logistic analysis (ß = -0.011; P = 0.48). In addition, acti-CT90 was significantly associated with mean RNFL thickness both in the elderly (⩾60 yr; ß = -0.058; P = 0.002) and nonelderly (<60 yr; ß = -0.054; P = 0.007).Conclusions: Acti-CT90, but not acti-ODI3%, was associated with mean RNFL thinning in participants irrespective of age in the elderly or nonelderly. Further prospective studies are required to investigate whether the prevention of hypoxic burden, which was shown as acti-CT90 in this study, is favorable for RNFL thinning.

Increased blood eosinophils and airflow obstruction as new-onset asthma predictors in the elderly: The Nagahama study.

BACKGROUND: Asthma in the elderly needs more attention in an aging society. However, it is likely to remain underdiagnosed and undertreated. This study aimed to clarify clinical characteristics of new-onset asthma in the elderly, describing the prevalence, predictive factors, and comorbidities after asthma diagnosis of new-onset asthma in the elderly in the general population. METHODS: This community-based prospective cohort study enrolled 9804 generally healthy participants (30-74 years old) in Nagahama City, and conducted a follow-up assessment after 5 years. Elderly participants were those aged ≥65 years at baseline. Patients with new-onset asthma were defined as participants without asthma at baseline assessment and with asthma at the follow-up assessment. RESULTS: Among the 7948 participants analyzed in this study, 28 (1.4%) elderly and 130 (2.2%) non-elderly had new-onset asthma. Multiple logistic regression analysis revealed low forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and high blood eosinophil counts at baseline as predicting factors for new-onset asthma in the elderly. Additionally, subsequent incidence of new-onset asthma was higher in elderly participants with both predictors (high blood eosinophil counts and low FEV1/FVC at baseline) than those with none or one of the predictors before asthma diagnosis. Lastly, elderly patients with new-onset asthma had more frequent comorbidity of moderate to severe sleep disordered breathing than those non-elderly. CONCLUSIONS: Eosinophilic inflammation and airflow obstruction may predict subsequent new-onset asthma after the age of 65 years. Revealing the characteristics of new-onset asthma in the elderly can aid in the prevention of underdiagnosed asthma.

Evaluation of Bone Mineral Density in Lung Transplant Recipients by Chest Computed Tomography.

INTRODUCTION: Lung transplantation (LT) recipients are at risk of bone mineral density (BMD) loss. Pre- and post-LT BMD loss has been reported in some cross-sectional studies; however, there are limited studies regarding the serial BMD change in LT recipients. The aim of this study was to investigate the serial BMD changes and the clinical characteristics associated with BMD decline. METHODS: This was a single-center, retrospective observational study. BMD was serially measured in thoracic vertebral bodies (Th4, 7, 10) using computed tomography (CT) before and 3 and 12 months after LT. The frequency of osteoporosis and factors associated with pre-LT osteoporosis and post-LT BMD loss were evaluated. The frequency of post-LT compression fracture and its associated factors were also analyzed. RESULTS: This study included 128 adult LT recipients. LT recipients had decreased BMD (151.8 ± 42.2 mg/mL) before LT compared with age-, sex-, and smoking index-matched controls (176.2 ± 35.7 mg/mL). The diagnosis of COPD was associated with pre-LT osteoporosis. LT recipients experience further BMD decline after transplantation, and the percentage of recipients classified as exhibiting osteoporosis increased from 20% at baseline to 43% at 12 months. Recipients who had been taking no or small doses of glucocorticoids before LT had rapid BMD loss after LT. Early bisphosphonate use (within 3 months) after LT attenuated BMD loss and decreased new-onset compression fracture. CONCLUSION: LT recipients are at high risk for BMD loss and compression fracture after LT. Early bisphosphonate use may decrease BMD loss and compression fracture.

Perioperative changes in radiographic density in erector spinae muscle and mortality after lung transplantation.

RATIONALE: The radiographic density of the erector spinae muscle (ESM) is often decreased early after lung transplantation (LTx). The prognostic impact of this change has not been elucidated. OBJECTIVE: To investigate whether the decrease in the radiographic density of ESMs early after LTx is associated with a poor prognosis. METHODS: This study is a single center retrospective cohort study. Routine follow-up chest computed tomography scan data just before and 12 weeks after LTx were retrospectively retrieved for adult patients who underwent primary LTx at Kyoto University Hospital. The radiographic density of ESM was quantitatively evaluated as the mean attenuation of the ESM (ESMct), and the impact of the decreased ESMct during the 12 weeks after LTx on overall survival (OS) was examined by Cox proportional hazard regression. RESULTS: A total of 151 recipients (94 cadaveric LTx, 57 living-donor lobar LTx) were included in this study. The median duration of postoperative observation was 4.4 years, during which time 39 recipients (26%) died. Decreased postoperative ESMct was significantly associated with poor OS (HR, 1.64; 95% CI, 1.14-2.35, P = 0.008 per 1 Z score decrease) in the multivariate model adjusted for age, sex, episodes of acute rejection, and preoperative ESMct. Similar results were obtained when the subjects were limited to those with cadaveric LTx. CONCLUSION: A decreased perioperative ESMct was strongly associated with a poor prognosis after LTx in addition to low preoperative ESMct. Maintaining postoperative muscle radiographic density, which reflects muscle quality, may be important for a better prognosis after LTx.

Sputum microbiota and inflammatory subtypes in asthma, COPD, and its overlap.

Background: Airway microbiota in asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) remains unknown. Objective: This study with ACO-enriched population aimed to clarify airway microbiota in ACO and in mixed granulocytic inflammation, often detected in ACO and chronic airway diseases. Methods: This is an observational cross-sectional study. Patients with asthma with airflow limitation, ACO, and COPD were enrolled. Blood tests, pulmonary function, exhaled nitric oxide, and sputum tests were conducted. Sputum microbiota was evaluated using the 16S rRNA gene sequencing technique. Results: A total of 112 patients (13 asthma, 67 ACO, and 32 COPD) were examined. There were no significant differences in α-diversity among the 3 diseases. The relative abundances of phylum Bacteroidetes, class Bacteroidia, and genus Porphyromonas were associated with decreased eosinophilic inflammation, and were significantly lower in ACO than in COPD. In a comparison of sputum inflammatory subtypes, the proportion of Haemophilus was numerically highest in the mixed granulocytic subtype, followed by the neutrophilic subtype. Likewise, the proportion of Haemophilus was the highest in the intermediate-high (2%-8%) sputum eosinophil group and lowest in the severe (≥8%) eosinophil group. Clinically, Haemophilus proportion was associated with sputum symptoms. Finally, the proportion of Streptococcus was associated with higher blood eosinophil counts and most severe airflow limitation. Conclusions: Bacteroidia and Porphyromonas abundances in sputum are associated with the eosinophil-low phenotype, and ACO may be characterized by a decrease in these taxa. A mild elevation in sputum eosinophil does not preclude the presence of Haemophilus, which should be noted in the management of obstructive airway diseases.

A reference equation for lung volume on computed tomography in Japanese middle-aged and elderly adults.

BACKGROUND: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion. METHODS: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability. RESULTS: In all asymptomatic never smokers, the variance explained by the predicted values (R2) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT. CONCLUSIONS: The MESA equation was optimized for Japanese middle-aged and elderly adults.

Impact of wearing a surgical facemask during exercise on dyspnea in patients with chronic pulmonary infections: A randomized crossover study.

BACKGROUND: Wearing facemasks in public is effective in preventing viral transmission. However, no study has evaluated the impact of wearing facemasks during exercise on dyspnea in patients with chronic pulmonary infections from multifaceted aspects, including sensory qualities and emotional responses. The aim of this study was to evaluate facemask-related dyspnea during exercise in this patient population. METHODS: We conducted a randomized crossover study involving adult patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD) or bronchiectasis who participated in exercise sessions, both with (mask-on) and without (mask-off) surgical facemasks. The sensory and emotional dimensions of dyspnea during each exercise session were assessed using the Multidimensional Dyspnea Profile. Statistical analyses were performed to identify factors associated with worsening scores for each dimension. RESULTS: Thirty-four patients (mean age [standard deviation]: 71.6 [8.6] years) were included in the analysis. The median [interquartile range] total scores for the sensory and emotional dimensions of dyspnea were 3.5 [1, 9.5] (mask-off) vs. 10 [5.5, 23.8] (mask-on) (P < 0.001) and 0 [0, 5] (mask-off) vs. 3 [0.8, 10.3] (mask-on) (P = 0.115), respectively. "Air hunger" was the primary sensory descriptor of mask-related dyspnea. Vital capacity (VC) < 80% of the predicted value was a significant risk factor for worsening sensory dimension scores when wearing masks (odds ratio [95% confidence interval]: 5.5 [1.16-26.1], P = 0.038). CONCLUSIONS: The findings of this study indicate that patients with NTM-PD or bronchiectasis, particularly those with VC <80% of the predicted value, are likely to experience the sensory dimension of dyspnea during exercise while wearing surgical facemasks.