Response biomarkers of inhalation exposure to cigarette smoke in the mouse lung.

Cigarette smoking is known to increase the risk of cancer and chronic obstructive pulmonary disease (COPD). In this study, we evaluated the effects of short-term nose-only inhalation exposure to cigarette smoke in mice. Male 10-week-old C57BL mice were exposed to clean air (control) or mainstream cigarette smoke for 1 h/day, 5 days/week, for 2 or 4 weeks. Exposure to cigarette smoke increased the number of inflammatory cells, especially neutrophils, in the bronchoalveolar lavage fluid, increased inflammatory cell infiltration foci, and caused an increase in the thickness of the peripheral bronchial epithelium. Microarray gene expression analysis indicated that smoke exposure induced inflammatory responses, including leukocyte migration and activation of phagocytes and myeloid cells, as early as two weeks after the initiation of exposure. Importantly, chemokine (C-C motif) ligand 17, resistin-like alpha, and lipocalin 2 were upregulated and may serve as useful markers of the toxic effects of exposure to cigarette smoke before pulmonary histological changes become evident.

Possible role of insulin resistance in activation of plasma xanthine oxidoreductase in health check-up examinees.

We previously found an association of insulin resistance (IR) with plasma xanthine oxidoreductase (XOR) activity in a cross-sectional study. However, whether IR induces increased XOR activity has not been elucidated. This retrospective longitudinal observational study included 347 participants (173 males, 174 females) who underwent annual health examinations and were medication naïve. Homeostasis model assessment of IR (HOMA-IR) index, and physical and laboratory measurements were determined at the baseline. At baseline and 12-month follow-up examinations, plasma XOR activity was determined using our novel assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Subjects with IR, defined as HOMA-IR index ≥ 1.7 (n = 92), exhibited significantly (p < 0.001) higher plasma XOR activity levels than those without IR (n = 255), with an increase in that activity seen in 180 (51.9%) after 12 months. Multivariable linear and logistic regression analyses showed that IR, but not BMI or waist circumference, at baseline was significantly associated with plasma XOR activity (ß = 0.094, p = 0.033) and increased plasma XOR activity over the 12-month period (odds ratio, 1.986; 95% confidence interval, 1.048-3.761; p = 0.035), after adjustments for various clinical parameters, including plasma XOR activity at baseline. These results suggest that IR induces increased plasma XOR activity in a manner independent of adiposity.

Phase II Study of the Modified Weekly Nab-paclitaxel Regimen in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer.

OBJECTIVES: We conducted a clinical phase II study to evaluate the modified weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimen in pretreated patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This multicenter single-arm phase II study enrolled patients with advanced NSCLC who had previously received >1 chemotherapy regimen. Patients received nab-paclitaxel at 80 mg/m2 on days 1, 8, and 15 (21-d cycle). The primary endpoint was the investigator-assessed overall response rate (ORR). Secondary endpoints included overall survival, progression-free survival (PFS), disease control rate, and safety. The planned enrollment was 30 patients according to a Simon 2-stage minimax design. RESULTS: Thirty patients were enrolled between November 2015 and August 2017. Seventeen patients (56.7%) had received >2 regimens. The ORR was 23.3% (95% confidence interval [CI], 8.2%-38.4%), meeting the primary objective of the study. Median PFS was 5.7 months (95% CI, 3.4-9.0 mo), and median overall survival was 12.6 months (95% CI, 8.7-20.8 mo). The median number of treatment cycles was 4 (range, 1 to 20) over the entire study period, and median dose intensity was 63.6 mg/m2/wk (range, 45.7 to 100.0 mg/m2/wk). No new safety signals were reported; the most common grade ≥3 adverse events were neutropenia (56.7%), leukopenia (23.3%), and infection (10.0%). No cases of febrile neutropenia were observed. CONCLUSIONS: Nab-paclitaxel monotherapy with a dose and schedule suitable for outpatients showed high ORR, long median PFS, and acceptable toxicity for patients with previously treated NSCLC. This dosage method may be useful for selected patients.

Uric acid shown to contribute to increased oxidative stress level independent of xanthine oxidoreductase activity in MedCity21 health examination registry.

Uric acid has both antioxidant and pro-oxidant properties in vitro by scavenging and production of reactive oxygen species (ROS). This cross-sectional study examined whether uric acid possesses effects on oxidative stress under physiological conditions independent of xanthine oxidoreductase (XOR), which is involved in uric acid and ROS production. Serum uric acid level was measured, while plasma XOR activity was determined using our high-sensitive assay in 192 participants (91 males, 101 females) who underwent health examinations and were not taking an antihyperuricemic agent. For antioxidant potential and oxidative stress level, biological antioxidant potential (BAP) and derivative of reactive oxygen metabolites (d-ROMs) in serum, respectively, were measured. Median uric acid level and plasma XOR activity were 5.6 mg/dL and 26.1 pmol/h/mL, respectively, and BAP and d-ROMs levels were 2112.8 µmol/L and 305.5 Carr U, respectively. Multivariable regression analyses revealed no significant association of serum uric acid level with BAP level, whereas serum uric acid level showed a significant association with d-ROMs level independent of plasma XOR activity (p = 0.045), which was prominent in females (p = 0.036; p for interaction = 0.148). Uric acid might contribute to increased oxidative stress independent of XOR activity by increasing ROS production, without affecting ROS scavenging, especially in females.

Association of plasma xanthine oxidoreductase activity with blood pressure affected by oxidative stress level: MedCity21 health examination registry.

Xanthine oxidoreductase (XOR) inhibitor administration reduces uric acid and reactive oxygen species (ROS) production, and also lowers blood pressure (BP). However, the associations of plasma XOR activity, uric acid level, and oxidative stress levels with BP remain unclear. This cross-sectional study included 156 subjects (68 males, 88 females) registered in the MedCity21 health examination registry without anti-hypertensive or anti-hyperuricemic agent administration. Plasma XOR activity was measured using our highly sensitive novel assay, which is unaffected by uric acid in the sample. BP was also determined, and serum uric acid and derivative of reactive oxygen metabolites (d-ROMs) levels were simultaneously measured. Median plasma XOR activity, serum uric acid, d-ROMs, and mean arterial pressure (MAP) values were 25.7 pmol/h/mL, 5.4 mg/dL, 305 Carr U, and 89.0 mmHg, respectively. Multiple regression analysis showed that plasma XOR activity (ß = 0.211, p = 0.019), but not serum uric acid (ß = 0.072, p = 0.502), was significantly associated with MAP. In subjects with lower but not higher d-ROMs level, an independent association of plasma XOR activity with MAP was observed (ß = 0.428, p = 0.001 and ß = 0.019, p = 0.891, respectively; p for interaction = 0.046). XOR may contribute to the pathophysiology of higher BP through ROS but not uric acid production, especially in patients with lower oxidative stress.

Crystal structure and metallization mechanism of the π-radical metal TED.

Radical electrons tend to localize on individual molecules, resulting in an insulating (Mott-Hubbard) bandgap in the solid state. Herein, we report the crystal structure and intrinsic electronic properties of the first single crystal of a π-radical metal, tetrathiafulvalene-extended dicarboxylate (TED). The electrical conductivity is up to 30 000 S cm-1 at 2 K and 2300 S cm-1 at room temperature. Temperature dependence of resistivity obeys a T 3 power-law above T > 100 K, indicating a new type of metal. X-ray crystallographic analysis clarifies the planar TED molecule, with a symmetric intramolecular hydrogen bond, is stacked along longitudinal (the a-axis) and transverse (the b-axis) directions. The π-orbitals are distributed to avoid strong local interactions. First-principles electronic calculations reveal the origin of the metallization giving rise to a wide bandwidth exceeding 1 eV near the Fermi level. TED demonstrates the effect of two-dimensional stacking of π-orbitals on electron delocalization, where a high carrier mobility of 31.6 cm2 V-1 s-1 (113 K) is achieved.

Correction: Crystal structure and metallization mechanism of the π-radical metal TED.

[This corrects the article DOI: 10.1039/D0SC03521A.].

Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

OBJECTIVES: Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. MATERIALS AND METHODS: Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). RESULTS: Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P =  0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P =  0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. CONCLUSION: EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.

Exercise Ameliorates Emphysema Of Cigarette Smoke-Induced COPD In Mice Through The Exercise-Irisin-Nrf2 Axis.

Background: Oxidative stress is one of the important mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD). Irisin is a type of myokine secreted from the muscle during exercise and acts against oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with antioxidant properties. Here, we examined the emphysema suppressive effects of the exercise-irisin-Nrf2 axis in mice. Methods: Mice were divided into three groups, namely, the control, smoking, and exercise + smoking groups. All mice from the smoking and exercise + smoking groups were exposed to cigarette smoke once a day. The mice from the exercise + smoking group were adapted to a treadmill once a day. To investigate the Nrf2 cascade, after 12 weeks, serum irisin concentration and Nrf2 and heme oxygenase-1 (HO-1) expression in the lung homogenate were determined. To evaluate cigarette smoke-induced COPD, the number of inflammatory cells in bronchoalveolar lavage fluid (BALF), mean linear intercept (MLI), and destructive index in the lung tissue were examined. Results: Serum irisin concentration and the expression levels of Nrf2 and HO-1 in the lung homogenate were significantly higher in mice from the exercise + smoking group than in those from the control and smoking groups. The proportion of neutrophils in the BALF was significantly lower in the exercise + smoking group than in the smoking group. The MLI and destructive index were also significantly smaller in mice from the exercise + smoking group than mice from the smoking group. Conclusion: Irisin secreted from the muscle during exercise may exert protective effects against oxidative stress via Nrf2 and HO-1, and ameliorate emphysema of cigarette smoke-induced COPD. The exercise-irisin-Nrf2 axis may serve as a novel target for COPD treatment.

Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice.

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key cellular defense mechanism against oxidative stress. Recent studies have shown that astaxanthin protects against oxidative stress via Nrf2. In this study, we investigated the emphysema suppression effect of astaxanthin via Nrf2 in mice. Mice were divided into four groups: control, smoking, astaxanthin, and astaxanthin + smoking. The mice in the smoking and astaxanthin + smoking groups were exposed to cigarette smoke for 12 weeks, and the mice in the astaxanthin and astaxanthin + smoking groups were fed a diet containing astaxanthin. Significantly increased expression levels of Nrf2 and its target gene, heme oxygenase-1 (HO-1), were found in the lung homogenates of astaxanthin-fed mice. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was significantly decreased, and emphysema was significantly suppressed. In conclusion, astaxanthin protects against oxidative stress via Nrf2 and ameliorates cigarette smoke-induced emphysema. Therapy with astaxanthin directed toward activating the Nrf2 pathway has the potential to be a novel preventive and therapeutic strategy for COPD.

Single-crystalline boron-doped diamond superconducting quantum interference devices with regrowth-induced step edge structure.

Superconducting quantum interference devices (SQUIDs) are currently used as magnetic flux detectors with ultra-high sensitivity for various applications such as medical diagnostics and magnetic material microstructure analysis. Single-crystalline superconducting boron-doped diamond is an excellent candidate for fabricating high-performance SQUIDs because of its robustness and high transition temperature, critical current density, and critical field. Here, we propose a fabrication process for a single-crystalline boron-doped diamond Josephson junction with regrowth-induced step edge structure and demonstrate the first operation of a single-crystalline boron-doped diamond SQUID above 2 K. We demonstrate that the step angle is a significant parameter for forming the Josephson junction and that the step angle can be controlled by adjusting the microwave plasma-enhanced chemical vapour deposition conditions of the regrowth layer. The fabricated junction exhibits superconductor-weak superconductor-superconductor-type behaviour without hysteresis and a high critical current density of 5800 A/cm2.

Effect of tiotropium/olodaterol on sedentary and active time in patients with COPD: post hoc analysis of the VESUTO® study.

Background: Patients with COPD are less physically active. This post hoc analysis of a randomized, double-blind, active-controlled, crossover trial assessed the efficacy of once-daily tiotropium/olodaterol combination therapy versus tiotropium monotherapy in Japanese patients with COPD. Patients and methods: Patients were provided with a three-axis accelerometer to measure sedentary and active behavior defined as 1.0-1.5 metabolic equivalents (METs), ≥2.0 METs, and ≥3.0 METs, respectively. Of the 182 patients enrolled, 131 satisfied the conditions for the present analysis and were randomized to tiotropium monotherapy (n=62) or tiotropium/olodaterol combination therapy (n=69). Results: Tiotropium/olodaterol combination therapy significantly reduced the duration of 1.0-1.5 MET activity by 8.64 mins (p=0.040) and significantly increased the duration of ≥2.0 MET and ≥3.0 MET activity by 6.51 mins (p=0.017) and 2.60 mins (p=0.008), respectively, compared with tiotropium alone. Subgroup analyses showed that better lung function, milder dyspnea, and higher levels of physical activity at baseline were associated with reduced sedentary time and increased duration of physical activity. Conclusion: Tiotropium/olodaterol combination therapy significantly reduced sedentary time and improved physical activity compared with tiotropium monotherapy. This trial was registered in ClinicalTrials.gov (NCT02629965).

Isoflavone Aglycones Attenuate Cigarette Smoke-Induced Emphysema via Suppression of Neutrophilic Inflammation in a COPD Murine Model.

Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.

Handgrip strength measurement in patients with chronic obstructive pulmonary disease: Possible predictor of exercise capacity.

BACKGROUND: Impaired exercise capacity is one of the most important prognostic factors for patients with chronic obstructive pulmonary disease (COPD). The 6-min walk test (6MWT) is a widely used method for assessing exercise capacity in patients with COPD. However, the 6MWT requires considerable effort from patients. Therefore, a less physically demanding, but also noninvasive, method is warranted. The objective of this study was to determine the predictors of the 6MWT distance (6MWD) in patients with COPD. METHODS: This retrospective observational study enrolled 133 Japanese patients with COPD. All patients underwent the 6MWT, COPD assessment test (CAT), spirometry, respiratory muscle strength evaluation, body composition assessment, and handgrip strength (HGS) measurement. We examined the associations between the 6MWD and evaluated parameters. RESULTS: From single regression analysis, the 6MWD was significantly correlated with age, CAT score, several spirometric measurements (e.g., percentages of forced vital capacity, forced expiratory volume in 1 s, and carbon monoxide diffusing capacity of the lungs [%DLCO]), respiratory muscle strength parameters (e.g., percentages of maximal expiratory and inspiratory pressures), skeletal muscle mass index, and HGS. In multiple regression analysis, age, CAT score, %DLCO, and HGS were independent predictors of the 6MWD. The %DLCO and HGS were strongly correlated as predictors of the 6MWD (p < 0.001). CONCLUSIONS: We found that HGS was significantly correlated with the 6MWD compared with spirometric measurements or respiratory muscle strength parameters in Japanese patients with COPD, suggesting that HGS could be a simple and noninvasive predictor of the 6MWD in patients with COPD.

Efficacy and safety of ultrasound (US) guided percutaneous needle biopsy for peripheral lung or pleural lesion: comparison with computed tomography (CT) guided needle biopsy.

BACKGROUND: Ultrasound (US)-guided percutaneous needle biopsy is a useful diagnostic technique with short examination time and real-time monitoring at the bedside. However, there are only a few studies that report on thoracic lesions, whereas the computed tomography (CT)-guided biopsy is well established. There is also limited data comparing US- and CT-guided biopsy. We aimed to clarify the efficacy and safety of US-guided biopsy for thoracic lesions adjacent to the chest wall. METHODS: We retrospectively enrolled consecutive patients who underwent US- or CT-guided percutaneous biopsies for thoracic lesions adjacent to the chest wall between April 2012 and December 2017. Clinical characteristics, lesion size, lesion-pleura contact arc length (LPCAL), diagnostic rate, and complications were compared between the 2 groups. RESULTS: This study enrolled 61 US-guided and 70 CT-guided biopsies. No significant difference was found in age or sex. The lesion size and LPCAL in the US-guided group were significantly larger than those in the CT-guided group (P<0.0001). The diagnostic rate was marginally higher in the US-guided group (93.4%) than in the CT-guided group (84.3%) (P=0.101). When the median cut-off of the LPCAL was defined as 40 mm in all cases, the diagnostic rate for lesion size >40 mm was significantly higher in the US-guided group than in the CT-guided group (P=0.009). Complication rates were significantly lower in the US-guided group (3.3%) than in the CT-guided group (24.3%) (P<0.001). CONCLUSIONS: US-guided percutaneous needle biopsy for thoracic lesions adjacent to the chest wall is a feasible technique compared with CT-guided biopsy because of its higher diagnostic rate with a longer LPCAL and reduced complications.

Obesity and hiatal hernia may be non-allergic risk factors for esophageal eosinophilia in Japanese adults.

BACKGROUND: Esophageal eosinophilia (EE) is a basal condition of eosinophilic esophageal disorders including eosinophilic esophagitis (EoE) and asymptomatic EE. EoE is considered as an allergic disorder, while it is unclear whether other non-allergic conditions are involved in the pathophysiology of EE. The aim of this study is to investigate the non-allergic risk factors for EE. METHODS: This cross-sectional study included subjects who underwent esophagogastroduodenoscopy on a medical health check-up. We compared clinical characteristics between subjects with EE (n = 27) and those without EE (n = 5937). RESULTS: The detection rate of EE was 0.45% (27/5964 persons). Of 27 subjects with EE, 20 subjects were symptomatic and 7 were asymptomatic. On univariate analysis, subjects with EE significantly had higher body mass index (BMI) compared to those without EE; 23.4 (4.4) vs 22.3 (4.5) kg/m2, median (interquartile range), p = 0.005. Endoscopic findings revealed that subjects with EE had significantly higher proportion of hiatal hernia (29.6% vs 14.7%; p = 0.049). Subjects with EE were significantly younger and had higher proportion of bronchial asthma; 45 (11.5) vs 51 (18) years, p = 0.013; 25.9% vs 5.2%, p < 0.001, respectively. Multivariate analysis showed that subjects with EE were positively associated with BMI [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.20; p = 0.010) and hiatal hernia (OR 2.63; 95% CI 1.12-6.18; p = 0.026) compared to those without EE. On trend test, advanced BMI classification had significant trend for increased prevalence of EE (p = 0.002). CONCLUSIONS: Obesity and hiatal hernia may be non-allergic risk factors for EE in Japanese adults.

Association between Functional Dyspepsia and Gastric Depressive Erosions in Japanese Subjects.

Objective The association between functional dyspepsia (FD) and endoscopic findings has not been fully elucidated. Helicobacter pylori infection is considered a key factor in the pathophysiology of FD. The Kyoto Classification of Gastritis (KCG) was proposed in 2014 to evaluate endoscopic findings based on the H. pylori status. We investigated the endoscopic findings associated with FD according to the KCG. Methods This cross-sectional study included subjects who underwent esophagogastroduodenoscopy during a medical health check-up. We compared the endoscopic findings between subjects with FD and healthy controls (HCs) according to the KCG. Results A total of 456 subjects were analyzed. Among them, the detection rate of FD was 5.5% (25/456 persons). In a univariate analysis of the endoscopic findings, a significantly lower proportion of subjects with FD had gastric red streak in comparison to HCs (0% vs. 18.6%, respectively; p=0.0124). Subjects with FD were more likely to have gastric depressive erosion (20.0% vs. 7.9%; p=0.0522). A higher proportion of the erosion-positive subjects had FD in comparison to erosion-negative subjects (12.8% vs. 4.8%). There were no significant differences in the other endoscopic findings, including gastric atrophy, intestinal metaplasia, enlarged fold, nodularity, and diffuse redness. A multivariate analysis revealed that gastric depressive erosion was significantly and independently associated with FD (odds ratio, 2.92; 95% confidence interval, 1.03-8.26; p=0.0436). In contrast, gastric red streak was not associated with FD (p=0.989). Conclusion Gastric depressive erosions may be associated with dyspepsia.

COPD uncovered: a cross-sectional study to assess the socioeconomic burden of COPD in Japan.

Background: COPD remains a major health problem in Japan. Patients with COPD experience a reduced quality of life (QoL) and have a higher chance of work impairment and productivity loss. However, there is a lack of data on the impact of COPD in terms of QoL and work activity impairment in Japan. This study assessed the socioeconomic burden of COPD in Japan and the impact it may have on the working age population. Patients and methods: This was a 2-year retrospective chart review in COPD patients aged ≥40 years, with at least one health care visit to clinic or hospital in the previous 12 months. Patients were required to have available medical charts for at least the previous 24 months. Symptoms were assessed using COPD assessment test score; EuroQoL Group 5 Dimension (EQ-5D-5L) and work productivity and activity impairment general health questionnaires were used to evaluate health-related QoL and work productivity, and health care resource utilization data were obtained from clinical charts. Results: In total, 71 patients aged <65 years, and 151 patients aged ≥65 years were included; the majority of patients had moderate or severe airflow limitation. Exacerbations (moderate or severe) were reported by ~35% of patients in both age groups; 52.1% and 62.9% of patients in the <65-year and ≥65-year age groups had COPD assessment test scores ≥10. EQ-5D-5L index scores in the <65-year and ≥65-year age groups were 0.79 and 0.77, respectively. Work productivity and activity impairment scores were higher in <65-year age group. Annual costs of health care resource use per patient in the <65-year and ≥65-year age groups were ¥438,975 (US$4,389) and ¥467,871 (US$4,678), respectively. Costs due to productivity loss were estimated to be ¥5,287,024 (US$52,870) in the <65-year age group and ¥3,018,974 (US$30,187) in the ≥65-year age group. Conclusion: COPD represents a significant socioeconomic burden in Japan. Patients with COPD report significant use of health care resources. Higher impact on work impairment and productivity loss was observed frequently in the working age population.

Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity.

Purpose: This study evaluated the efficacy of tiotropium/olodaterol vs tiotropium on lung function, exercise capacity, and physical activity in patients with COPD. Patients and methods: A total of 184 patients aged ≥40 years with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) received tiotropium/olodaterol for 6 weeks, then tiotropium for 6 weeks, or vice versa. The primary endpoint was inspiratory capacity (IC) at peak post-dose. Results: Adjusted mean IC after 6-week treatment was 1.990 L with tiotropium/olodaterol vs 1.875 L with tiotropium (difference: 115 mL; 95% CI: 77, 153; p<0.0001). Forced expiratory volume in 1 s (difference: 105 mL; 95% CI: 88, 123), forced vital capacity (difference: 163 mL; 95% CI: 130, 197), and slow vital capacity (difference: 134 mL; 95% CI: 91, 176) improved with tiotropium/olodaterol (all p<0.0001). Adjusted mean 6-min walk distance was similar between treatments in the overall population but was significantly increased with tiotropium/olodaterol in the subgroup with Global Initiative for Chronic Obstructive Lung Disease stage III/IV at baseline (difference: 18.1 m; 95% CI: 2.3, 33.9; p=0.0254). In a post hoc analysis, tiotropium/olodaterol improved the values for ≥2.0 metabolic equivalents (difference: 5.0 min; 95% CI: 0.4, 9.7; p=0.0337). Conclusion: Tiotropium/olodaterol significantly improved IC compared with tiotropium and potentially enhanced the exercise capacity in COPD patients. A slight improvement in physical activity of relatively more than moderate intensity was also seen with tiotropium/olodaterol.