Exposure to the heated tobacco product IQOS generates apoptosis-mediated pulmonary emphysema in murine lungs.

Pulmonary emphysema is predominantly caused by chronic exposure to cigarette smoke (CS). Novel tobacco substitutes, such as heated tobacco products (HTPs), have emerged as healthier alternatives to cigarettes. IQOS, the most popular HTP in Japan, is advertised as harmless compared with conventional cigarettes. Although some studies have reported its toxicity, few in vivo studies have been conducted. Here, 12-wk-old C57BL6/J male mice were divided into three groups and exposed to air (as control), IQOS aerosol, or CS for 6 mo. After exposure, the weight gain was significantly suppressed in the IQOS and CS groups compared with the control (-4.93 g; IQOS vs. air and -5.504 g; CS vs. air). The serum cotinine level was significantly higher in the IQOS group than in the control group. The neutrophils and lymphocyte count increased in the bronchoalveolar lavage fluid of the IQOS and CS groups compared with those in the control group. Chronic IQOS exposure induced pulmonary emphysema similar to that observed in the CS group. Furthermore, expression levels of the genes involved in the apoptosis-related pathways were significantly upregulated in the lungs of the IQOS-exposed mice. Cytochrome c, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase-1 were overexpressed in the IQOS group compared with the control. Single-stranded DNA and TdT-mediated dUTP nick-end labeling-positive alveolar septal cell count significantly increased in the IQOS group compared with the control. In conclusion, chronic exposure to IQOS aerosol induces pulmonary emphysema predominantly via apoptosis-related pathways. This suggests that HTPs are not completely safe tobacco products.

Propylene glycol, a component of electronic cigarette liquid, damages epithelial cells in human small airways.

BACKGROUND: Electronic cigarettes (e-cigarettes) are used worldwide as a substitute for conventional cigarettes. Although they are primarily intended to support smoking cessation, e-cigarettes have been identified as a gateway to smoking habits for young people. Multiple recent reports have described the health effects of inhaling e-cigarettes. E-cigarette liquid (e-liquid) is mainly composed of propylene glycol (PG) and glycerol (Gly), and the aerosol generated by these devices primarily contains these two components. Thus, this study aimed to evaluate the effects of PG and Gly on human small airway epithelial cells (SAECs). METHODS: SAECs were exposed to PG or Gly, and cell proliferation, cell viability, lactate dehydrogenase (LDH) release, DNA damage, cell cycle, and apoptosis were evaluated. Additionally, SAECs derived from chronic obstructive pulmonary disease (COPD) patients (COPD-SAECs) were investigated. RESULTS: Exposure of SAECs to PG significantly inhibited proliferation (1%, PG, p = 0.021; 2-4% PG, p < 0.0001) and decreased cell viability (1-4% PG, p < 0.0001) in a concentration-dependent manner. Gly elicited similar effects but to a reduced degree as compared to the same concentration of PG. PG also increased LDH release in a concentration-dependent manner (3% PG, p = 0.0055; 4% PG, p < 0.0001), whereas Gly did not show a significant effect on LDH release. SAECs exposed to 4% PG contained more cells that were positive for phosphorylated histone H2AX (p < 0.0001), a marker of DNA damage, and an increased proportion of cells in the G1 phase (p < 0.0001) and increased p21 expression (p = 0.0005). Moreover, caspase 3/7-activated cells and cleaved poly (ADP-ribose) polymerase 1 expression were increased in SAECs exposed to 4% PG (p = 0.0054). Furthermore, comparing COPD-SAECs to SAECs without COPD in PG exposure, cell proliferation, cell viability, DNA damage and apoptosis were significantly greater in COPD-SAECs. CONCLUSION: PG damaged SAECs more than Gly. In addition, COPD-SAECs were more susceptible to PG than SAECs without COPD. Usage of e-cigarettes may be harmful to the respiratory system, especially in patients with COPD.

Impaired psychomotor vigilance associated with sleep-disordered breathing in women working in the care of older adults in Japan.

PURPOSE: With a rapidly aging society, there is increasing interest in the health of female workers in the field of care services for older adults due to increasing demands to maintain 24-h care and to support older adults without errors or accidents. Therefore, the purpose of this cross-sectional study was to examine the association between sleep-disordered breathing (SDB) and sustained attention in women caring for older adults in Japan. METHODS: The study was conducted in women aged 18-67 years old working in care service facilities for older adults in Japan. The sustained attention of participants was measured by the 10-min psychomotor vigilance task (PVT). SDB was assessed based on the respiratory disturbance index (RDI), which was measured using an ambulatory airflow monitor with a polyvinylidene fluoride (PVDF) film sensor to monitor the respiratory airflow of nasal and oral breathing. The participants wore the monitor to record the breathing status while asleep at home. The severity of SDB was categorized as follows: normal, RDI < 5 events/h; mild SDB, RDI 5-10 events/h; and moderate-to-severe SDB, RDI ≥ 10 events/h. RESULTS: Of 688 women enrolled, medians of age, body mass index (BMI), sleep duration, and prevalence of hypertension tended to be higher with increasing RDI. No significant association was found between RDI and PVT parameters. However, when we limited the analysis to women with BMI ≥ 22 kg/m2, those with moderate-to-severe SDB had significantly higher odds of having the slowest 10% reaction times compared to those without SDB (OR = 2.03; 95% CI = 1.17-3.53). The association did not decrease after adjusting to account for sleep duration, alcohol drinking habits, and history of hypertension (OR = 1.97; 95% CI = 1.10-3.52). A significant increasing trend was also found between RDI and the slowest 10% of reaction times (p for trend = 0.03). CONCLUSIONS: Our findings suggest that SDB is associated with reduced sustained attention in participants with BMI ≥ 22 kg/m2, although the number of assessments of SDB and PVT was only once per participant due to the nature of the cross-sectional study.

Prognostic Impact of No-Flow Time on 30-Day Neurological Outcomes in Patients With Out-of-Hospital Cardiac Arrest Who Received Extracorporeal Cardiopulmonary Resuscitation.

BACKGROUND: How the time sequence of cardiopulmonary resuscitation (CPR) procedures is related to clinical outcomes in patients with out-of-hospital cardiac arrest (OHCA) remains unclear. This study examined the impact of the time interval from collapse to start of CPR (no-flow time, NF time) and the time interval from start of CPR to implementation of extracorporeal CPR (ECPR) (low-flow time, LF time) on neurological outcomes.Methods and Results:During the period from 2010 to 2015, we enrolled 85 patients who received ECPR. Fourteen patients (16.5%) showed favorable 30-day neurological recovery. NF time was shorter in the favorable neurological recovery group than in the unfavorable recovery group (1.4±3.0 vs. 5.2±5.8 min, P<0.05), though combined NF+LF times were similar in the 2 groups (50.1±13.2 vs. 55.1±14.8 min, P=0.25). Multivariate logistic regression analysis indicated that pupil diameter at arrival and NF time were independently associated with favorable neurological recovery. The optimal cut-off value of NF time to predict favorable neurological recovery was 5 min (area under curve: 0.70, P<0.05; sensitivity, 85.7%; specificity, 52.1%). CONCLUSIONS: The results suggest that NF time is a better predictor than NF+LF time for neurological outcomes in OHCA patients who received ECPR, and that start of CPR within 5 min after collapse is crucial for improving neurological outcomes followed by use of ECPR.

Correction to: The Association Between Obesity and Hyperactivity/Anxiety Among Elementary School Students in Japan.

The original article has been corrected.

The association between obesity and hyperactivity/anxiety among elementary school students in Japan.

BACKGROUND: We aimed to evaluate the association between hyperactivity/anxiety and obesity among elementary school students in Matsuyama City, Japan. METHODS: We conducted a cross-sectional study of all 46 elementary school students (24, 296 students) in Matsuyama City. The questionnaire included question items from the Strengths and Difficulties Questionnaire (SDQ), as well as questions about height and weight. The students were classified into two groups according to Rohrer index. After separating the data by gender, we examined the association between (1) obesity and hyperactivity, (2) obesity and anxiety, and (3) obesity and combination of hyperactivity and anxiety, by estimating relative risk using Poisson regression model. We also conducted stratified analyses to examine the effect modification by age groups and unbalance of diet on those associations. Moreover, we calculated relative excess risk due to the interaction (RERI) to examine whether there was an additive interaction between hyperactivity and anxiety. RESULTS: Sixteen thousand forty-eight students were included in the present analysis. The prevalence ratio (PR) of being obese in girls who had both hyperactivity and anxiety was higher compared to girls without those symptoms (PR = 1.80; 95% CI 1.04-3.13). There was no significant difference in the prevalence ratio for obesity in boys, whether they were hyperactive, anxious, or neither. RERI was 0.00 for boys and 0.18 for girls. CONCLUSION: We found a significant association between obesity and co-existence of hyperactivity and anxiety among elementary school girls. Our findings strengthen the need to further explore the association between childhood obesity, hyperactivity, and anxiety.

Prevalence of sleep-disordered breathing among women working in the aged care services in Japan.

OBJECTIVES: The aim of this study was to examine the prevalence of sleep-disordered breathing (SDB) in women working in the field of aged care in Japan. METHODS: A cross-sectional study was conducted for female employees aged 18-60 years in aged care facilities in Japan. The analyzed set consisted of 712 participants with complete data. SDB was determined by respiratory disturbance index (RDI), measured using an ambulatory airflow monitor with a polyvinylidene fluoride film sensor to detect nasal and oral airflow overnight at home. Based on the findings of previous studies, RDI 10 was considered equivalent to apnea-hypopnea index (AHI) 15. RESULTS: The prevalence of moderate-to-severe SDB (RDI ≥ 10) was 22.8%. The mean age was 38.1 years, and mean sleeping time of participants was 6.1 h. The median body mass index (BMI) was 22.0. Women with moderate-to-severe SDB (RDI ≥ 10) had a higher age, neck circumference, neck-height ratio, BMI, systolic blood pressure, and increased prevalence of hypertension, short sleepers (amount of sleep on the SDB testing day < 6 h), and habitual snorers, compared to women with no or mild SDB (RDI < 10). CONCLUSIONS: Our study found that women working in the aged care services in Japan were heavily burdened by SDB even though they were relatively young and slim. To prevent CVD from developing in the future, programs through which workplaces can help their employees improve their lifestyle, and early diagnosis and treatment of SDB are highly recommended.

Regional heterogeneity in response of airway epithelial cells to cigarette smoke.

BACKGROUND: Cigarette smoke (CS) exposure causes an abnormal inflammatory response, which can result in chronic obstructive pulmonary disease (COPD). Previous studies show that this disorder predominantly occurs in peripheral or small-airway areas, whereas the same condition has not been identified in the larger airways during the course of COPD. However, the different biochemical and genetic alterations occurring in response to CS exposure among airway epithelial cells from different sites in the lungs have not been fully investigated. METHODS: Human small airway epithelial cells (SAECs) and normal human bronchial epithelial cells (NHBEs) were exposed to CS extract (CSE), and microarray analysis was used to determine gene- and protein-expression profiles and identify alterations following CSE exposure in both cell types. An in vivo smoking experiment was also performed to confirm differential responses to CS between sites in the lung. RESULTS: Microarray analysis of SAECs and NHBEs following 24 h of CSE exposure showed that inflammatory related pathways and terms, including the tumor necrosis factor-signaling pathway, were overrepresented, especially in SAECs. Clustering analysis highlighted prostaglandin-endoperoxide synthase-2 [also known as cyclooxygenase (COX)-2] as a gene specifically upregulated in SAECs, with COX-2 mRNA and protein expression significantly elevated by CSE exposure in SAECs (3.1- and 3.1-fold, respectively), but not in NHBEs. Furthermore, time-course analysis of COX-2 expression revealed earlier increases in SAECs compared with NHBEs following CS exposure. Short-term exposure of mouse lungs to CS was found to predominantly induce COX-2 expression in the small airway. CONCLUSIONS: The small airway is more susceptible to CSE than the large airway and could be the initial site of development of CS-related respiratory diseases, such as COPD.

The outcome and risk factors for recurrence and extended hospitalization of secondary spontaneous pneumothorax.

PURPOSE: Secondary spontaneous pneumothorax (SSP) is difficult to treat by itself and due to its association with serious underlying diseases. It has a high rate of recurrence and often requires extended hospitalization. Therefore, we evaluated the outcome and risk factors associated with recurrence and extended hospitalization. METHODS: We retrospectively examined 61 patients with SSP, and evaluated the patients' characteristics, underlying diseases, introduction of home oxygen therapy, Brinkman index, and X-ray imaging findings to determine the risk factors for recurrence and extended hospitalization. RESULTS: There were 28 patients (46.0%) with chronic obstructive pulmonary disease, 8 (13.1%) with interstitial pneumonia, 16 (26.2%) with massive emphysema, and 9 (14.8%) with other diseases. Adhesion and mediastinal shift visualized by X-ray imaging were observed in 37 (37.9%) and 25 patients (40.1%), respectively. Recurrence occurred in 25 patients (40.9%) and the average hospitalization duration was 14.5 days (±11.2). A multivariate analysis showed that adhesion on X-ray imaging was a significant risk factor for recurrence (odds ratio 4.90, 95% confidence interval 1.38-21.44) and mediastinal shift on X-ray imaging was a significant risk factor for extended hospitalization (odds ratio 6.05, 95% confidence interval 1.44-31.06). CONCLUSIONS: Findings from X-ray imaging, and not underlying diseases, are risk factors for recurrence and extended hospitalization.

Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice.

Chronic obstructive pulmonary disease (COPD) is predominantly a cigarette smoke (CS)-triggered disease with features of chronic systemic inflammation. Oxidants derived from CS can induce DNA damage and stress-induced premature cellular senescence in the respiratory system, which play significant roles in COPD. Therefore, antioxidants should provide benefits for the treatment of COPD; however, their therapeutic potential remains limited owing to the complexity of this disease. Recently, molecular hydrogen (H2) has been reported as a preventive and therapeutic antioxidant. Molecular H2 can selectively reduce hydroxyl radical accumulation with no known side effects, showing potential applications in managing oxidative stress, inflammation, apoptosis, and lipid metabolism. However, there have been no reports on the efficacy of molecular H2 in COPD patients. In the present study, we used a mouse model of COPD to investigate whether CS-induced histological damage in the lungs could be attenuated by administration of molecular H2. We administered H2-rich pure water to senescence marker protein 30 knockout (SMP30-KO) mice exposed to CS for 8 weeks. Administration of H2-rich water attenuated the CS-induced lung damage in the SMP30-KO mice and reduced the mean linear intercept and destructive index of the lungs. Moreover, H2-rich water significantly restored the static lung compliance in the CS-exposed mice compared with that in the CS-exposed H2-untreated mice. Moreover, treatment with H2-rich water decreased the levels of oxidative DNA damage markers such as phosphorylated histone H2AX and 8-hydroxy-2'-deoxyguanosine, and senescence markers such as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 1, and ß-galactosidase in the CS-exposed mice. These results demonstrated that H2-rich pure water attenuated CS-induced emphysema in SMP30-KO mice by reducing CS-induced oxidative DNA damage and premature cell senescence in the lungs. Our study suggests that administration of molecular H2 may be a novel preventive and therapeutic strategy for COPD.

[Mediastinal Pancreatic Pseudocyst with Pancreatic Pleural Effusion].

A 72-year-old man with chronic alcohol related pancreatitis was admitted for dyspnea and pain at the upper body. Chest X-ray showed right massive pleural effusion. Chest and abdominal contrast enhanced thin slice computed tomography revealed the route from the pancreatic head reaching the right thoracic cavity via the esophagus hiatus and the communication between the cystic lesion and main pancreatic duct. We drained the pleural effusion that showed abnormally high amylase activity. We diagnosed his illness as mediastinal pancreatic pseudocyst with pancreatic pleural effusion. Endoscopic Nasopancreatic Drainage catheter was placed in the main pancreatic duct, and the pleural effusion disappeared.

Selective antagonization of activated Nrf2 and inhibition of cancer cell proliferation by procyanidins from Cinnamomi Cortex extract.

Nuclear factor-E2-related factor 2 (Nrf2) is an important transcription factor and plays a central role in inducible expression of many cytoprotective genes. Recent studies have reported that various cancer cells having unrestrained Nrf2 due to its overexpression exhibit increased proliferation and resistance to chemotherapy. Suppression of abnormal Nrf2 activation is needed for a new therapeutic approach against these cancers. Our previous study found that procyanidins prepared from Cinnamomi Cortex extract (CCE) have an ability to suppress Nrf2-regulated enzyme activity and Nrf2 expression in human lung cancer A549 cells. In the present study, we investigated the effect of CCE procyanidins on Nrf2 activity and cell proliferation in several cancer cells, which have normal or constitutively active Nrf2. Interestingly, CCE procyanidin treatment selectively reduced Nrf2 expression and inhibited cell proliferation in cancer cells that overexpress Nrf2, but these phenomena were not seen in cells with low Nrf2 expression. Moreover, transfection assay demonstrated that CCE procyanidins had selective inhibition of activated Nrf2. These results suggest that CCE procyanidins might be an effective cancer therapeutic agent to selectively suppress abnormal Nrf2 activation responsible for enhanced proliferation.

Enhanced Electron Transfer Efficiency of Fructose Dehydrogenase onto Roll-to-Roll Thermal Stamped Laser-Patterned Reduced Graphene Oxide Films.

Herein, a strategy to stamp laser-produced reduced graphene oxide (rGO) onto flexible polymers using only office-grade tools, namely, roll-to-roll thermal stamping, is proposed, proving for the first time its effectiveness for direct bioelectrocatalysis. This straightforward, scalable, and low-cost approach allows us to overcome the limits of the integration of laser-induced rGO-films in bioanalytical devices. Laser-produced rGO has been thermally stamped (TS) onto different polymeric substrates (PET, PVC, and EVA) using a simple roll-laminator; the obtained TS-rGO films have been compared with the native rGO (untransferred) via morphochemical and electrochemical characterization. Particularly, the direct electron transfer (DET) reaction between fructose dehydrogenase (FDH) and TS-rGO transducers has been investigated, with respect to the influence of the amount of enzyme on the catalytic process. Remarkable differences have been observed among TS-rGO transducers; PET proved to be the elective substrate to support the transfer of the laser-induced rGO, allowing the preservation of the morphochemical features of the native material and returning a reduced capacitive current. Noteworthily, TS-rGOs ensure superior electrocatalysis using a very low amount of FDH units (15 mU). Eventually, TS-rGO-based third-generation complete enzymatic biosensors were fabricated via low-cost benchtop technologies. TS-rGOPET exhibited bioanalytical performances superior to the native rGO, allowing a sensitive (0.0289 µA cm-2 µM-1) and reproducible (RSD = 3%, n = 3) d-fructose determination at the nanomolar level (LOD = 0.2 µM). TS-rGO exploitability as a point-of-need device was proved via the monitoring of d-fructose during banana (Musa acuminata) postharvest ripening, returning accurate (recoveries 110-90%; relative error -13/+1%) and reproducible (RSD ≤ 7%; n = 3) data.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

[Current understanding and perspectives of lymphangioleiomyomatosis].

Lymphangioleiomyomatosis (LAM) is a slowly progressive neoplastic disease characterized with proliferation of abnormal smooth muscle-like cells (LAM cells) in the lungs and along axial lymphatics. Proliferation of LAM cells are considered to be driven by dysregulated mTORC1 signaling, that is caused by mutations in either the TSC1 or TSC2 gene in LAM cells. The MILES trial has successfully demonstrated that sirolimus, a mTORC1 inhibitor, can stabilize pulmonary function in LAM, but its effect disappears once sirolimus is discontinued. Limited ability of sirolimus may be due to concomitant activation of autophagy in LAM cells when mTORC1 activity is suppressed by sirolimus. Recently animal models for LAM have been independently established by several groups, which may provide a platform for developing drugs interfering various steps in disease progression.

[Effects of psychological distress due to the Great East Japan Earthquake, tsunami, Fukushima Nuclear Power Plant disasters on psychiatric symptoms in patients with mental disorders: observational studies in Tochigi].

BACKGROUND: The Great East Japan Earthquake and subsequent tsunami of March 11, 2011 severely damaged a widespread region of northeastern Japan. Consequently, the Fukushima Nuclear Power Plant experienced a level seven 3 reactors melted down, which released a large amount of radioactive materials into the air. Due to the structural damage and radiation leaks, the victims are facing prolonged psychological distress. METHODS: Eighty-two subjects with mental disorders who made their initial visit during the first 4 months after the earthquake and one hundred and ninety-four subjects with mental disorders who had been admitted during the first one year after the earthquake to the Jichi Medical University Hospital, which is located at the edge of the disaster-stricken region, were recruited for this study. Enrolled participants were assessed according to ICD-10. A questionnaire survey was employed to evaluate the severity of psychological distress and total amount of damage. RESULTS: The conditions of 22% of the outpatients had been worsened by the psychological distress related to the earthquake. Seven percent of the patients who had been hospitalized showed marked exacerbations due to the psychological distress associated with the disaster. COMMENTS: It is of note that the exacerbation of psychiatric symptoms due to the disaster was evident among patients with mental disorders who lived even at the edge of the disaster area (i. e., subject to an earthquake intensity of 5 upper and 150 km from the Fukushima Nuclear Power Plant). The results suggest that the close follow-up of disaster victims with mental disorders is of critical importance.

Lab-made flexible third-generation fructose biosensors based on 0D-nanostructured transducers.

Herein, we report a scalable benchtop electrode fabrication method to produce highly sensitive and flexible third-generation fructose dehydrogenase amperometric biosensors based on water-dispersed 0D-nanomaterials. The electrochemical platform was fabricated via Stencil-Printing (StPE) and insulated via xurography. Carbon black (CB) and mesoporous carbon (MS) were employed as 0D-nanomaterials promoting an efficient direct electron transfer (DET) between fructose dehydrogenase (FDH) and the transducer. Both nanomaterials were prepared in water-phase via a sonochemical approach. The nano-StPE exhibited enhanced electrocatalytic currents compared to conventional commercial electrodes. The enzymatic sensors were exploited for the determination of D-fructose in model solutions and various food and biological samples. StPE-CB and StPE-MS integrated biosensors showed appreciable sensitivity (∼150 µA cm-2 mM-1) with µmolar limit of detection (0.35 and 0.16 µM, respectively) and extended linear range (2-500 and 1-250 µM, respectively); the selectivity of the biosensors, ensured by the low working overpotential (+0.15 V), has been also demonstrated. Good accuracy (recoveries between 95 and 116%) and reproducibility (RSD ≤8.6%) were achieved for food and urine samples. The proposed approach because of manufacturing versatility and the electro-catalytic features of the water-nanostructured 0D-NMs opens new paths for affordable and customizable FDH-based bioelectronics.

A retrospective study of the efficacy of combined EGFR­TKI plus VEGF inhibitor/cytotoxic therapy vs. EGFR­TKI monotherapy for PD­L1­positive EGFR­mutant non­small cell lung cancer: North Japan Lung Cancer Study Group 2202.

The present multicenter study was performed to compare the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy with that of combined EGFR-TKI plus vascular endothelial growth factor receptor (VEGF) inhibitor/cytotoxic therapy in patients with programmed death-ligand 1 (PD-L1)-positive EGFR-mutant non-small cell lung cancer (NSCLC). Data from patients with PD-L1-positive EGFR-mutant NSCLC were collected from 12 institutes. Survival in patients treated with first- and second-generation EGFR-TKIs, osimertinib (third-generation EGFR-TKI), and combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy was analyzed by multiple regression analysis with adjustments for sex, performance status, EGFR mutation status, PD-L1 expression level, and the presence or absence of brain metastasis using a Cox proportional hazards model. Data from a total of 263 patients were analyzed, including 111 (42.2%) patients who had received monotherapy with a first- or second-generation EGFR-TKI, 132 (50.2%) patients who had received osimertinib monotherapy, and 20 (7.6%) patients who had received combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy (hereafter referred to as combined therapy). Multiple regression analysis using the Cox proportional hazards model showed that the hazard ratio (95% confidence interval) for progression-free survival was 0.73 (0.54-1.00) in the patients who had received osimertinib monotherapy and 0.47 (0.25-0.90) in patients who had received combined therapy. The hazard ratio for overall survival was 0.98 (0.65-1.48) in the patients who had received osimertinib monotherapy and 0.52 (0.21-1.31) in patients who had received combined therapy. In conclusion, combined therapy was associated with a significant reduction in the risk of progression compared with first- and second-generation EGFR-TKI monotherapy, and therefore, may be promising for the treatment of patients of NSCLC.

Blood Eosinophil Count as a Predictive Biomarker of Chronic Obstructive Pulmonary Disease Exacerbation in a Real-World Setting.

Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death, and COPD exacerbation worsens the prognosis. Eosinophilic airway inflammation is a COPD phenotype that causes COPD exacerbation and is correlated with peripheral blood eosinophil count. We analyzed real-world data of COPD patients to assess the risk factors of COPD exacerbation focusing on blood eosinophils. Materials and Methods: Patients with COPD who visited our hospital between January 1, 2018, and December 31, 2018, were recruited, and their background information, spirometry data, laboratory test results, and moderate-to-severe exacerbation events during the one-year follow-up period were collected from the electronic medical records and analyzed. The COPD exacerbation risk factors were assessed using univariate and multivariate logistic regression analyses. Results: Twenty-two of 271 (8.1%) patients experienced moderate-to-severe exacerbation. Patients with exacerbation showed worse pulmonary function, and we found that a high blood eosinophil count (≥350 cells/µL; p=0.014), low % FEV1 (<50%; p=0.002), increase in white blood cell (≥9000 cells/µL; p=0.039), and use of home oxygen therapy (p=0.005) were risk factors for future exacerbations. We also found a strong correlation between eosinophil count cut-offs and exacerbation risk (r = 0.89, p < 0.001). On the other hand, there was no relation between exacerbation risk and inhalation therapy for COPD. Conclusion: In a real-world setting, peripheral blood eosinophil count could be a predictor of future COPD exacerbation.

Micro-/Nano-Texturing onto Plasma-Nitrided Tool Surface by Laser Printing for CNC Imprinting and Piercing.

A new data transformation method for micro-manufacturing using a topological model for a micro-/nano-texture was proposed for a surface-decorated product. Femtosecond laser printing was utilized to form the micro-/nano-textures into the hardened thick layer of dies by plasma nitriding. At first, the plasma-nitrided AISI316L flat substrate was laser-printed as a punch to imprint the tailored nano-textures onto the AA1060 aluminum plate for its surface decoration with topological emblems. Second, the plasma-nitrided SKD11 cylindrical punch was laser-trimmed to form the nanostructures on its side surface. This nano-texture was imprinted onto the hole surface concurrently with piercing a circular hole into electrical steel sheet. The fully burnished surface had a shiny, metallic quality due to the nano-texturing. The plasma nitriding, the laser printing and the CNC (computer numerical control) imprinting provided a way of transforming the tailored textures on the metallic product.