Association of cigarette smoking with increased use of heated tobacco products in middle-aged and older adults with self-reported chronic obstructive pulmonary disease, asthma, and asthma-COPD overlap in Japan, 2022: the JASTIS study.

BACKGROUND: Smoking cessation is the most important intervention in chronic obstructive pulmonary disease (COPD), asthma, and asthma-COPD overlap (ACO); however, high rates of current cigarette smoking are observed in adults with these respiratory diseases. Meanwhile, rapidly increasing use of heated tobacco products (HTPs) is observed in Japan; however, the status of HTPs use has not been fully understood in adults with COPD, asthma, and ACO. This study aimed to reveal the association between COPD, asthma, and ACO and HTPs use in adults. METHODS: Data on Japanese individuals ≥ 40 years old obtained from the Japan Society and New Tobacco Internet Survey were analyzed. The prevalence of HTPs use in adults with COPD, asthma, and ACO, among individuals categorized into three groups according to cigarette smoking (never, former, and current), was calculated and the relationship between each disease and HTPs use were evaluated. The clinical diagnosis of these diseases was based on the self-reported diagnosis, as obtained from questionnaires. RESULTS: A total of 19,308 individuals were included. The proportions of never, past, and current cigarettes smokers were 10,900 (56.5%), 4,903 (25.4%), and 3,505 (18.2%), respectively, and that of HTPs use was 1,813 (9.4%). In current cigarettes smokers, the adjusted odds ratios (ORs) of HTPs use was 2.88 (95% CI [confidence interval], 1.86-4.47), 1.23 (95% CI, 0.99-1.52), and 5.81 (95% CI, 3.12-10.82) in adults with COPD, asthma, and ACO compared to those without these respiratory diseases, respectively. Meanwhile, in past cigarettes smokers, the adjusted ORs of HTPs use was 0.51 (95% CI, 0.24-1.08), 0.69 (95% CI, 0.53-0.88), and 0.25 (95% CI, 0.06-1.07) in adults with COPD, asthma, and ACO, respectively. CONCLUSIONS: HTPs use is more prevalent among current cigarettes smokers with COPD, asthma, and ACO compared to those without these respiratory diseases. Complete cessation of smoking both cigarettes and HTPs is the only way to achieve complete smoking cessation, therefore, adults with COPD, asthma, and ACO need to make greater efforts to quit smoking.

13C metabolic flux analysis clarifies distinct metabolic phenotypes of cancer cell spheroid mimicking tumor hypoxia.

Cancer cells adapt their intracellular energy metabolism to the oxygen-deprived tumor microenvironment (TME) to ensure tumor progression. This adaptive mechanism has focused attention on the metabolic phenotypes of tumor cells under hypoxic TME for developing novel cancer therapies. Although widely used monolayer (2D) culture does not fully reflect in vivo hypoxic TME, spheroid (3D) culture can produce a milieu similar to the TME in vivo. However, how different metabolic phenotypes are expressed in 3D cultures mimicking tumor hypoxia compared with 2D cultures under hypoxia remains unclear. To address this issue, we investigated the metabolic phenotypes of 2D- and 3D-cultured cancer cells by 13C-metabolic flux analysis (13C-MFA). Principal component analysis of 13C mass isotopomer distributions clearly demonstrated distinct metabolic phenotypes of 3D-cultured cells. 13C-MFA clarified that 3D culture significantly upregulated pyruvate carboxylase flux in line with the pyruvate carboxylase protein expression level. On the other hand, 3D culture downregulated glutaminolytic flux. Consistent with our findings, 3D-cultured cells are more resistant to a glutaminase inhibitor than 2D-cultured cells. This study suggests the importance of considering the metabolic characteristics of the particular in vitro model used for research on cancer metabolism.

Mortality changes for patients with pneumococcal pneumonia from 2012 to 2017 in Japan.

INTRODUCTION: Pneumococcal pneumonia has a high morbidity and mortality in adults, especially those ≥65 years old. In the past decade, pneumococcal vaccination programs have been initiated worldwide, however, few data concerning mortality changes are available in pneumococcal pneumonia patients and there are no reports clarifying these current changes in Japan. METHODS: Japanese patients ≥65 years old hospitalized with pneumococcal pneumonia between April 2012 and March 2018 were analyzed using the Diagnostic Procedure Combination database. In-hospital mortality was evaluated, and the odds ratios for this outcome in each fiscal year compared with that in 2012 was analyzed using multivariable logistic regression models. RESULTS: Between 2012 and 2017, data of 47,375 pneumococcal pneumonia patients ≥65 years old were extracted. The incidence per 1000 person-years for in-hospital mortality was 60.4 in 2012, 56.8 in 2013, 63.2 in 2014, 56.1 in 2015, 73.0 in 2016, and 67.4 in 2017 and the odds ratios for in-hospital mortality in 2013, 2014, 2015, 2016, and 2017 compared with that in 2012 were 1.00, 1.05, 1.04, 1.06, and 0.98, respectively. There were no significant differences between 2012 and each year from 2013 to 2017. Low BMI; low ADL score; high A-DROP score; comorbid malignancy and heart failure; the coexistence of invasive pneumococcal infection; and the use of invasive mechanical ventilation were independent risk factors for in-hospital mortality. CONCLUSIONS: There were no changes in in-hospital mortality in pneumococcal pneumonia patients between 2012 or each year from 2013 to 2017 and further epidemiological observations are necessary.

Reduced phagocytic activity of human alveolar macrophages infected with Mycobacterium avium complex.

INTRODUCTION: Co-infection of nontuberculous mycobacteria (NTM) with other bacteria is associated with increased frequency of hospitalization and reduced quality of life. However, the clinical significance of co-infection with NTM and other bacteria remains unclear. Here, we investigated the distribution of alveolar macrophage populations, characterized their phagocytic function in bronchoalveolar lavage fluid (BALF), and assessed the bactericidal function of macrophages infected with NTM using cell lines. METHODS: BALF samples were prospectively obtained from 30 patients with suspected NTM lung disease to evaluate phagocytic activities of macrophages using immunostaining. Bactericidal activities of Staphylococcus aureus (S. aureus) and Mycobacterium intracellulare (M. intracellulare)-infected or -non-infected macrophages were evaluated using macrophage cell lines. RESULTS: Eleven patients with Mycobacterium avium complex (MAC) infection and 19 patients with chronic lower respiratory tract infections except for NTM infection (controls) were enrolled. The percentage of non-polarized (HLA-DR+, CD40-, and CD163-) macrophages in patients infected with MAC was significantly higher than that in controls; non-polarized macrophages demonstrated an impaired ability to phagocytose S. aureus. In vitro experiments revealed higher intracellular S. aureus colony-forming unit counts and proinflammatory cytokine levels in M. intracellulare-infected macrophages than in non-NTM-infected macrophages. Electron microscopy showed morphologically damaged macrophages and M. intracellulare and S. aureus growing in the same phagosome. CONCLUSION: The proportion of alveolar macrophages (HLA-DR+, CD40-, and CD163-) with impaired phagocytosis increased in MAC-infected individuals. M. intracellulare-infected macrophages reduced bactericidal activity in vitro. Dysfunction of alveolar macrophages may contribute to persistent infection by other bacteria, leading to MAC lung disease progression.

Comparative study of bacterial flora in bronchoalveolar lavage fluid of pneumonia patients based on their pneumonia subtypes and comorbidities using 16S ribosomal RNA gene analysis.

INTRODUCTION: The culture method is the gold standard for identifying pathogenic bacteria in patients with pneumonia but often does not reflect the exact bacterial flora in pulmonary lesions of pneumonia, partly owing to easiness or difficulties in culturing certain bacterial species. We aimed to evaluate bacterial flora in bronchoalveolar lavage fluid (BALF) samples directly obtained from pneumonia lesions using 16S ribosomal RNA (rRNA) gene analysis to compare the results of the BALF culture method in each category of pneumonia. METHODS: Bacterial florae were detected by a combination of the culture method, and the clone library method using the 16S rRNA gene sequencing in BALF directly obtained from pneumonia lesions in pneumonia patients from April 2010 to March 2020 at the University of Occupational and Environmental Health, Japan, and affiliated hospitals. Clinical information of these patients was also collected, and lung microbiome was evaluated for each pneumonia category. RESULTS: Among 294 pneumonia patients (120 with community-acquired pneumonia (CAP), 101 with healthcare-associated pneumonia (HCAP), and 73 with hospital-acquired pneumonia (HAP)), significantly higher percentages of obligate anaerobes were detected in CAP than in HCAP and HAP patients by the clone library method. Corynebacterium species were significantly highly detected in HAP patients and patients with cerebrovascular diseases than in patients without, and Streptococcus pneumoniae was frequently detected in patients with diabetes mellitus. CONCLUSION: Obligate anaerobes may be underestimated in patients with CAP. Corynebacterium species should be regarded as the causative bacteria for pneumonia in patients with HAP and cerebrovascular diseases.

Effects of additive corticosteroid therapy on 90-day survival in patients with community-onset pneumonia.

INTRODUCTION: Systemic corticosteroid therapy is occasionally used as an additive therapy, especially for patients with severe pneumonia. However, its recommendation for use in patients with pneumonia varies worldwide, and its efficacy is unclear. METHODS: Adult Japanese patients hospitalized with community-onset pneumonia between January and December 2012 were analyzed using the Diagnostic Procedure Combination database. The patients were classified into mild-to-moderate and severe groups using the A-DROP (age, dehydration, respiration, orientation, and blood pressure) system. The 90-day survival rate was evaluated between the presence or absence of corticosteroid treatment using the Kaplan-Meier method in the overall, mild-to-moderate and severe groups, respectively. The patients' clinical characteristics were adjusted between the two groups using the inverse probability of treatment weighting method. RESULTS: Among 123,811, 110,534 patients were classified as mild-to-moderate grade (corticosteroid group: 8,465, non-corticosteroid group: 102,069) and 13,277 patients were classified as severe grade (corticosteroid group: 1,338, non-corticosteroid group: 11,939). The 90-day survival rate was higher in the non-corticosteroid group than in the corticosteroid group in patients with pneumonia of overall grade (weighted hazard ratio [HR]: 1.36; P < 0.001) and those with mild-to-moderate grade (weighted HR: 1.46; P < 0.001). However, there were no significant differences in the outcomes between the two groups in those with severe grade (weighted HR: 1.08; P = 0.38). CONCLUSIONS: Additive systemic corticosteroid therapy may be related to poor 90-day prognosis in patients with mild-to-moderate grade community-onset pneumonia, although it may not be positively associated with its prognosis in those with severe grade.

Distribution and annual changes in the proportion of Streptococcus pneumoniae serotypes in Japanese adults with pneumococcal pneumonia from 2011 to 2017.

In 2014, vaccinations with 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13) were implemented in Japan for all adults aged ≥65 years. We previously clarified reductions in the proportions of PCV7-, PCV13-, and PPSV23-covered serotypes in patients with pneumococcal pneumonia after the initiation of PCV7 and PCV13 vaccinations for Japanese children; however, information about the annual changes in the proportion of Streptococcus pneumoniae serotypes in patients with pneumococcal pneumonia after the initiation of routine PPSV23 vaccinations remains unclear. We retrospectively studied 229 adults with pneumococcal pneumonia which S. pneumoniae was cultured from their lower respiratory tract samples between 2011 and 2017 and investigated the annual changes in the proportion of S. pneumoniae serotypes. The proportion of PPSV23-covered serotypes decreased from 71.4% in 2011 to 52.2% in 2014, but it remained essentially unchanged from 2015 to 2017. The proportions of PCV7-covered serotypes decreased from 46.4% in 2011 to 4.3% in 2014; however, this rate increased beginning in 2015 and reached 20.6% in 2017. Among the PCV7-covered serotypes, the proportion of the 19F serotype increased from 2015 to 2017. In conclusion, there were no obvious changes in the proportion of PPSV23-covered and PCV13-covered serotypes in patients with pneumococcal pneumonia after the initiation of routine PPSV23 vaccinations.

Temporal echocardiographic assessment of pulmonary hypertension in idiopathic pulmonary fibrosis patients treated with nintedanib with or without oxygen therapy.

BACKGROUND: Nintedanib is an inhibitor of receptor tyrosine kinases, including vascular endothelial growth factor receptor, but its effects on pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) patients with chronic hypoxia were unclear. METHODS: This study included a nintedanib prospective study and historical control study. In the nintedanib prospective study, pulmonary artery systolic pressure (PASP) measured using transthoracic echocardiography was evaluated at six points during 48 weeks in 16 IPF patients in whom nintedanib was started. In the historical control study, adjusted annual change in PASP was compared between patients treated with (n = 16) and without (n = 15) nintedanib. RESULTS: In the nintedanib prospective study, the mean PASP at 48 weeks after starting nintedanib was significantly higher compared to that at baseline. When IPF patients were divided into two groups, IPF patients with or without long-term oxygen treatment (LTOT), mean PASP at 48 weeks was significantly higher than that at baseline only in IPF patients receiving LTOT (P = 0.001). In the historical control study, adjusted annual change in PASP in IPF patients treated with nintedanib was significantly lower than that in patients treated with no antifibrotic agents when considering patients without LTOT (0.26 mmHg vs 7.05 mmHg; P = 0.011). CONCLUSIONS: We found differential effects of nintedanib on PH between IPF patients with or without LTOT. Nintedanib may have a disadvantageous effect on PH in IPF patients with LTOT. Conversely, nintedanib treatment may be beneficial to PH in IPF patients without LTOT.

The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear. METHODS: Serum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration. RESULTS: Serum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice. CONCLUSIONS: PRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

Hard Metal Lung Disease with Favorable Response to Corticosteroid Treatment: A Case Report and Literature Review.

Hard metal lung disease (HMLD) is a pneumoconiosis caused by occupational exposure to hard metals such as tungsten carbide and cobalt, but the treatment strategies for HMLD have not been well established. A 68-year-old Japanese man with occupational history as a grinder of hard metals for 18 years referred to our hospital because of dry cough and dyspnea. A chest computed tomography (CT) on admission revealed centrilobular micronodules, ground-glass opacities, and reticular opacities in the peripheral zone of both lungs. Mineralogic analyses of lung tissues detected components of hard metals, such as tungsten, titanium and iron, and the same metals were also detected in the sample of the dust of his workplace. Thus, the patient was diagnosed as having HMLD based on occupational exposure history and radiologic and mineralogic analyses of the lung. Corticosteroid therapy was initiated, which resulted in partial improvements in his symptoms, radiological and pulmonary functional findings. In a review of the 18 case reports of HMLD treated with corticosteroids, including our case, the majority of patients (77.8%) showed favorable responses to corticosteroid treatment. Furthermore, the presence of fibrotic changes, such as reticular opacity, in radiological examinations was associated with the resistance to corticosteroids. In conclusion, the majority of patients with HMLD are expected to favorable response to corticosteroid treatment, whereas chest CT findings such as fibrotic changes may be predictive of the resistance of corticosteroid treatment. Lastly, proper prevention of hard metal exposure is most important as the first step.

Serum Soluble Interleukin-2 Receptor Is a Biomarker for Pneumocystis jirovecii Pneumonia among Patients with Rheumatoid Arthritis under Methotrexate Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation and may manifest as interstitial pneumonia (IP). Methotrexate (MTX) is one of the main therapeutic drugs used for RA, but MTX could cause severe side effects, including Pneumocystis jirovecii pneumonia (PCP) and IP. Owing to similar symptoms, it is sometimes difficult to discriminate MTX therapy-associated PCP (MTX-PCP) and MTX therapy-associated IP (MTX-IP). Soluble interleukin-2 receptor (sIL-2R) is considered a marker of T-cell activation, and serum sIL-2R levels are elevated in RA and PCP. This led us to hypothesize that serum sIL-2R is a potential biomarker for discriminating MTX-PCP and MTX-IP. Accordingly, we carried out a retrospective analysis of 20 MITX-PCP cases, 30 MTX-IP cases, and as controls, 16 patients with RA-associated IP (RA-IP) and 13 patients with PCP without MTX treatment (PCP group). C-reactive protein and alveolar-arterial oxygen differences were higher in the MTX-PCP group than those in the RA-IP and MTX-IP groups. Importantly, serum levels of sIL-2R in MTX-PCP were significantly higher than those in other three groups. Based on the receiver operating characteristic curve, the cut-off level of sIL-2R resulting in the highest diagnostic accuracy for MTX-PCP was 1,311.5 U/mL, discriminating between MTX-PCP and other groups with 91.7% sensitivity and 78.6% specificity. Thus, patients with MTX-PCP show a higher degree of systemic inflammation, severe hypoxemia, and increased sIL-2R levels compared with those in MTX-IP cases. In conclusion, serum sIL-2R could be a biomarker for PCP diagnosis among patients with RA under MTX therapy.

[Microbiology of Aspiration Pneumonia].

The number of patients with pneumonia has been increasing as the population ages, and most fatal pneumonia cases are the elderly with aspiration pneumonia. Although aspiration pneumonia leads to poor short- and long-term prognosis, there have been no practical ways to diagnose it precisely. Persistent subclinical aspiration without any subjective symptoms is problematic in clinical practice in patients with aspiration pneumonia, and physicians can only use aspiration risks such as brain infarction to diagnose aspiration pneumonia. Anaerobes have been believed to be major causative pathogens in aspiration pneumonia, based on data from the 1970's. In relation to these data, Marik insisted that there is a possible overestimation of anaerobes because 1) the sampling of microbiologic specimens was in the late phase in the course of the illness, especially frequently after developing complications such as abscesses, necrotizing pneumonia, or empyema thoracis; 2) the organisms recovered by percutaneous transtracheal aspiration (PTA) sampling could have been contaminated by the aspiration of oropharyngeal flora during the PTA procedure or colonized in the trachea; and 3) many of the patients had chronic alcoholism or were under general anesthesia. In addition, 4) oral care was not common in the 1970s, and 5) the patients in these reports were relatively young. Molecular biological approaches using the 16S ribosomal RNA (rRNA) gene have recently been used, and have enabled us to detect more exact pathogens compared to conventional bacterial culture. Using the method with the detection of the 16S rRNA gene, we evaluated the bacterial phylotypes in bronchoalveolar lavage fluid in patients with aspiration pneumonia and found that oral streptococci were the most detected phylotypes (31.0%), while anaerobes were only 6.0%. Our results suggest that oral streptococci are important, and anaerobes may have been overestimated as causative pathogens in patients with aspiration pneumonia.

[A Case of Drug-Induced Lung Injury Caused by Kamikihito].

An eighty-nine-year-old Japanese male was admitted to our hospital due to dry cough and dyspnea. Respiratory symptoms appeared soon after an administration of an oriental medicine, Kamikihito for tinnitus. Upon admission, chest computed tomography showed patchy consolidations and ground-glass opacities in the right upper lobe of the lungs, and ground-glass opacities in the bilateral lower lobes. Sulbactam-ampicillin combination (SBT/ABPC, 3 g × 2/day) was started in addition to the change or cessation of several other drugs, including Kamikihito, resulting in respiratory symptoms and chest radiographic exacerbations. Bronchoalveolar lavage fluid obtained from the right S3 showed an increase in the total cell number of lymphocytes. A drug lymphocyte stimulation test (DLST) for Kamikihito was also positive. Kamikihito-induced lung injury was most likely, and treatment with prednisolone (50 mg/day) was started. His respiratory symptoms and chest radiographic findings improved rapidly soon after initiating oral prednisolone. This is the first report of Kamikihito-induced lung injury.

[A Case of Left Upper Lobe Lung Cancer Successfully Diagnosed by Transesophageal Endoscopic Ultrasound with Bronchoscope-Guided Fine Needle Aspiration Alone].

A 58-year-old Japanese woman with fever and cough visited A hospital. Her chest X-ray and CT showed a tumor attached to the mediastinum in the left upper lobe with mediastinal lymphadenopathy (#4R). After an introduction from A hospital to our hospital, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the mediastinal lymphadenopathy and a simultaneous approach to the mass lesion in the left upper lobe were performed. In spite of twice aspiration by EBUS-TBNA for mediastinal lymphadenopathy, we failed to obtain enough specimens, and, as the mass lesion in the left upper lobe was invisible in the endobronchial ultrasound, we could not approach it. Then using the same ultrasound bronchoscope, we subsequently performed a transesophageal endoscopic ultrasound with bronchoscope-guided fine needle aspiration (EUS-B-FNA) to the mass lesion in the left upper lobe twice, with the result that sufficient tissues were obtained. Then we changed from the ultrasound bronchoscope to a normal bronchoscope and we performed brushing and transbronchial lung biopsy for the left upper lobe mass lesion. Pathological results revealed that only the specimens obtained by EUS-B-FNA were diagnostic for adenocarcinoma; the other specimens obtained using EBUS-TBNA and normal bronchoscope failed to be diagnostic. EUS-B-FNA in combination with EBUS-TBNA has been recommended for the diagnosis of mediastinal and near-mediastinal lesions in the guidelines of the American College of Chest Physicians in 2013, but EUS-B-FNA has not been widely used in Japan. As shown in our present patient who was successfully diagnosed as having lung cancer by EUS-B-FNA alone, respiratory physicians should be aware of being skillful at performing EUS-B-FNA to accurately and effectively approach target lesions.

[Evaluation of the Influence of the Experience and Training of EBUS-TBNA on Diagnostic Rate and Safety].

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used in Japan. The guidelines of the American College of Chest Physicians has recommended that EBUS-TBNA should be performed by well-trained operators who can perform highly accurate procedures, but the indicators of the degree of experience and training are unclear. In our department, physicians who do not have enough experience perform EBUS-TBNA under the supervision of bronchoscopic instructors who have EBUS-TBNA techniques (Board Certified Member of the Japan Society for Respiratory Endoscopy) after guidance and training in EBUS-TBNA using a simulator as an operator and helper. In order to evaluate the influence of the experience and training of EBUS-TBNA on diagnostic accuracy and safety, we retrospectively compared the diagnostic accuracy and safety of EBUS-TBNA performed by physicians within one year of experience of EBUS-TBNA and those performed by physicians with more than one year of experience. A total of 111 cases (148 lesions) who were eventually diagnosed as having primary lung cancer and underwent EBUS-TBNA in our department between April 2014 and January 2016 were divided into two groups. Group A (43 cases, 57 lesions) was examined by third-year doctors within one year of experience of EBUS-TBNA, and group B (68 cases, 91 lesions) was examined by doctors with four or more years of experience and with more than one year of experience of EBUS-TBNA. Diagnostic rate, examination time, and complications were evaluated. There were no significant differences between the two groups in the diagnostic rate (A, 89.5% vs. B, 90.1%, P = 1.0) or examination time (A, 27 min vs. B, 23 min, P = 0.149), and no complications were observed in either group. This study suggests that even less-experienced physicians may safely perform EBUS-TBNA as well as moderately-experienced physicians with more than 1 year experience of EBUS-TBNA with similar diagnostic rates when proper training and supervision are supplied.

Identifying metabolic elements that contribute to productivity of 1-propanol bioproduction using metabolomic analysis.

INTRODUCTION: Previously constructed Escherichia coli strains that produce 1-propanol use the native threonine pathway, or a heterologous citramalate pathway. However, based on the energy and cofactor requirements of each pathway, a combination of the two pathways produces synergistic effects that increase the theoretical maximum yield with a simultaneous unexplained increase in productivity. OBJECTIVE: Identification of key factors that contribute to synergistic effect leading to 1-propanol yield and productivity improvement in E. coli with native threonine pathway and heterologous citramalate pathway. METHOD: A combination of snapshot metabolomic profiling and dynamic metabolic turnover analysis were used to identify system-wide perturbations that contribute to the productivity improvement. RESULT AND CONCLUSION: In the presence of both pathways, increased glucose consumption and elevated levels of glycolytic intermediates are attributed to an elevated phosphoenolpyruvate (PEP)/pyruvate ratio that is known to increase the function of the native phosphotransferase. Turnover analysis of nitrogen containing byproducts reveals that ammonia assimilation, required for the threonine pathway, is streamlined when provided with an NAD(P)H surplus in the presence of the citramalate pathway. Our study illustrates the application of metabolomics in identification of factors that alter cellular physiology for improvement of 1-propanol bioproduction.

Usefulness of myeloperoxidase as a biomarker for the ranking of pulmonary toxicity of nanomaterials.

BACKGROUND: In order to examine whether myeloperoxidase (MPO) can be a useful marker for evaluating the pulmonary toxicity of nanomaterials, we analyzed MPO protein in bronchoalveolar lavage fluid (BALF) samples obtained from previous examinations of a rat model. In those examinations we performed intratracheal instillation exposures (dose: 0.2-1.0 mg) and inhalation exposures (exposure concentration: 0.32-10.4 mg/m3) using 9 and 4 nanomaterials with different toxicities, respectively. Based on those previous studies, we set Nickel oxide nanoparticles (NiO), cerium dioxide nanoparticles (CeO2), multi wall carbon nanotubes with short or long length (MWCNT (S) and MWCNT (L)), and single wall carbon nanotube (SWCNT) as chemicals with high toxicity; and titanium dioxide nanoparticles (TiO2 (P90) and TiO2 (Rutile)), zinc oxide nanoparticles (ZnO), and toner with external additives including nanoparticles as chemicals with low toxicity. We measured the concentration of MPO in BALF samples from rats from 3 days to 6 months following a single intratracheal instillation, and from 3 days to 3 months after the end of inhalation exposure. RESULTS: Intratracheal instillation of high toxicity NiO, CeO2, MWCNT (S), MWCNT (L), and SWCNT persistently increased the concentration of MPO, and inhalation of NiO and CeO2 increased the MPO in BALF. By contrast, intratracheal instillation of low toxicity TiO2 (P90), TiO2 (Rutile), ZnO, and toner increased the concentration of MPO in BALF only transiently, and inhalation of TiO2 (Rutile) and ZnO induced almost no increase of the MPO. The concentration of MPO correlated with the number of total cells and neutrophils, the concentration of chemokines for neutrophils (cytokine-induced neutrophil chemoattractant (CINC)-1 and heme oxygenase (HO)-1), and the activity of released lactate dehydrogenase (LDH) in BALF. The results from the receiver operating characteristics (ROC) for the toxicity of chemicals by the concentration of MPO proteins in the intratracheal instillation and inhalation exposures showed that the largest areas under the curves (AUC) s in both examinations occurred at 1 month after exposure. CONCLUSION: These data suggest that MPO can be a useful biomarker for the ranking of the pulmonary toxicity of nanomaterials, especially at 1 month after exposure, in both intratracheal instillation and inhalation exposure.

Using oral health assessment to predict aspiration pneumonia in older adults.

OBJECTIVE: To investigate the significance of comprehensive assessment of oral health using the revised oral assessment guide (ROAG) in older adults with pneumonia. BACKGROUND: Oral health plays a major role in the eating-swallowing process. The role of comprehensive assessment of oral health in older adults with aspiration pneumonia has not been evaluated in detail. The ROAG is a screening tool for comprehensive assessment and has been shown to have a high sensitivity and specificity for the assessment of oral health. MATERIALS AND METHODS: We retrospectively studied 238 adults with pneumonia, aged 65 years and above, in whom the ROAG score had been assessed between December 2014 and June 2016. Participants were divided into two groups based on aspiration risk, as defined by Marik et al; correlation between the ROAG score and the risk of aspiration was evaluated. RESULTS: Two hundred and fifteen adults (90.3%) were found to be at aspiration risk. According to the ROAG score, mild-to-moderate and severe oral problems were noted in 38 (16.0%) and 200 (84.0%) adults, respectively. Aspiration risk was noted in 68.4% and 94.5% of adults with mild-to-moderate and severe oral problems, respectively (P < .0001). The area under the receiver operating characteristics curve for ROAG to predict aspiration risk was 0.72 (95% confidence interval: 0.60-0.84). Furthermore, a high ROAG score was an independent predictor of aspiration risk in our study population. CONCLUSION: In clinical practice, oral health assessment using ROAG can help predict aspiration risk in older adults with pneumonia.

Cancer Risks of Hexavalent Chromium in the Respiratory Tract.

Hexavalent chromium (Cr(VI)) compounds are recognized as carcinogens in the respiratory tract, giving rise to cancers of the lung, nose and nasal sinuses, especially in certain occupational environments. Inhalation exposure of Cr(VI)-containing particles, dusts and fumes commonly occurs in chromium-related occupational environments, such as chromium production, plating, welding of chromium-containing metals and alloys, electroplating, chromium-containing pigments and paints. Epidemiological surveys of chromium compounds have shown strong associations between exposure to Cr(VI) and mortality due to lung cancer, as well as positive associations with cancers of the nose and nasal cavity. Nasal symptoms, such as nasal irritation, ulceration and perforation of the nasal septum, nasal turbinate engorgement and hypertrophy, are important signs for the early diagnosis of lung cancer and cancers of the nose and nasal cavity in those with an occupational history of Cr(VI) exposure. Cr(VI) exposure in the workplace remains a serious problem as a cause of lung cancer and cancers of nose and nasal cavity, especially in relatively small enterprises that use chromium compounds. Appropriate protection for workers should be considered in occupations that involve exposure to chromium compounds.

[Efficacy and Safety of Carboplatin/Nanoparticle Albumin-Bound Paclitaxel Combination Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer or Recurrent Non-Small-Cell Lung Cancer Following Surgery].

OBJECTIVE: A retrospective analysis on carboplatin(CBDCA)/nanoparticle albumin-boundpaclitaxel(nab-PTX)combination chemotherapy was conducted in patients with non-small-cell lung cancer(NSCLC)to evaluate both the efficacy and toxicity based on age, treatment line, histology, and underlying diseases. SUBJECTS: A total of 27 patients with advanced or recurrent NSCLC following surgery who receivedCBDCA /nab-PTX as first- andsecond -line combination chemotherapy, respectively, were investigatedfrom March 2013 to December 2015. RESULTS: The overall response rate, median progressionfree survival, andmed ian overall survival of all patients were 37.0%, 5.5 months, and 11.4 months, respectively. With regard to toxicity, 3.7%and 14.8%of all patients had peripheral disorder and interstitial lung disease(ILD), respectively. Treatmentrelatedd eaths were not observed. No difference in the efficacy basedon age, treatment line, histology, andund erlying diseases was observed. CONCLUSION: CBDCA/nab-PTX combination chemotherapy was safe for elderly patients and those with ILD. However, the occurrence of new interstitial lung lesions should be carefully considered.