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Pulmonary vein stump thrombosis (PVST) is uncommonly encountered postoperative in-situ thrombosis in the stump of pulmonary veins after lung resection. Data regarding the incidence and clinical behaviour of PVST are scarce. Thus, this study aims to investigate the incidence, clinical characteristics and outcome of PVST after lung resection in patients with lung cancer. Follow-up enhanced chest computed tomography (CT) scans acquired after the surgery were retrospectively reviewed to determine PVST presence for patients with lung cancer who underwent lung resection in two tertiary referral centres. Out of the 1885 patients with lung cancer who underwent lobectomy or more extensive lung resection, PVST was observed in 37 patients (2.0%) on their follow-up chest CT. Most stump thrombi were observed in the left superior pulmonary vein [35 (94.6%)] and in patients who underwent left upper lobectomy [34 (91.9%)]. At the last CT follow-up of each patient, 33 (89.2%) exhibited complete resolution, three partial resolution and one stabilization. Eleven (29.7%) patients received anticoagulant therapy after the diagnosis. The rate of complete PVST resolution did not differ significantly between the anticoagulation and nonanticoagulation groups. None of the PVST patients experienced systemic embolic events, regardless of anticoagulation. The PVST incidence diagnosed at routine chest CT follow-up following lung cancer surgery was 2%. PVST was characterized by a benign clinical course without progression and systemic embolization, regardless of anticoagulation. However, further studies are required to determine individualized therapeutic strategies, including anticoagulation.

Background: Although respiratory tract infection is one of the most important factors triggering acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), limited data are available to suggest an epidemiologic pattern of microbiology in South Korea.Methods: A multicenter observational study was conducted between January 2015 and December 2018 across 28 hospitals in South Korea. Adult patients with moderate-to-severe acute exacerbations of COPD were eligible to participate in the present study. The participants underwent all conventional tests to identify etiology of microbial pathogenesis. The primary outcome was the percentage of different microbiological pathogens causing AE-COPD. A comparative microbiological analysis of the patients with overlapping asthma–COPD (ACO) and pure COPD was performed.Results: We included 1,186 patients with AE-COPD. Patients with pure COPD constituted 87.9% and those with ACO accounted for 12.1%. Nearly half of the patients used an inhaled corticosteroid-containing regimen and one-fifth used systemic corticosteroids. Respiratory pathogens were found in 55.3% of all such patients. Bacteria and viruses were detected in 33% and 33.2%, respectively. Bacterial and viral coinfections were found in 10.9%. The most frequently detected bacteria were Pseudomonas aeruginosa (9.8%), and the most frequently detected virus was influenza A (10.4%). Multiple bacterial infections were more likely to appear in ACO than in pure COPD (8.3% vs. 3.6%, p=0.016).Conclusion: Distinct microbiological patterns were identified in patients with moderate-to-severe AE-COPD in South Korea. These findings may improve evidence-based management of patients with AE-COPD and represent the basis for further studies investigating infectious pathogens in patients with COPD.

Introduction Patients with aspiration pneumonia (AP) exhibit higher mortality than those with non-AP. However, data regarding predictors of short-term prognosis in patients with community-acquired AP are limited. Methods Patients hospitalized with community-acquired pneumonia (CAP) were retrospectively classified into aspiration pneumonia (AP) and non-AP groups. The AP patients were further divided into nonsurvivors and survivors by 30-day mortality, and various clinical variables were compared between the groups. Results Of 1249 CAP patients, 254 (20.3%) were classified into the AP group, of whom 76 patients (29.9%) died within 30 days. CURB-65, pneumonia severity index (PSI), and Infectious Diseases Society of America/American Thoracic Society criteria for severe CAP (SCAP) showed only modest prognostic performance for the prediction of 30-day mortality (c-statistics, 0.635, 0.647, and 0.681, respectively). Along with the PSI and SCAP, Eastern Cooperative Oncology Group performance status (ECOG-PS) and blood biomarkers, including, N-terminal of prohormone brain natriuretic peptide (NT-proBNP) and albumin, were independent predictors of 30-day mortality. In models based on clinical prediction rules, including CURB-65, PSI, and SCAP, the addition of ECOG-PS further improved their c-statistics compared to the clinical prediction rules alone. In the four combinations based on SCAP, ECOG-PS, and two blood biomarkers (NT-proBNP and albumin), the c-statistics further increased to reach approximately 0.8. Conclusions CURB-65, PSI, and SCAP exhibited only modest discriminatory power in predicting the 30-day mortality of patients with community-acquired AP. The addition of performance status and blood biomarkers, including NT-proBNP and albumin, further increased prognostic performance, showing good predictive accuracy in the SCAP-based model.

Recently, we reported that zinc regulates gliotoxin biosynthesis via ZafA, which is a zinc-responsive transcriptional activator. From an HPLC analysis of culture media of Aspergillus fumigatus, we found a trend of decreasing gliotoxin production but increasing pseurotin A and fumagillin production in proportion to the zinc concentration. The expression of the genes involved in pseurotin A biosynthesis was upregulated under high zinc concentrations. Furthermore, upregulated expression of pseurotin A biosynthetic genes and higher production of pseurotin A were observed in the zafA deletion strain. Interestingly, the deletion of gliZ, a transcriptional activator of gliotoxin biosynthesis genes, resulted in upregulated expression of pseurotin A biosynthetic genes and increased production of pseurotin A. We detected upregulation of fumR expression in the gliZ and zafA deletion mutants. The overexpression of gliZ observed in the zafA deletion mutant resulted in the failure of the mutant to increase pseurotin A production, which is a phenotype of the zafA deletion mutant. These results suggest that ZafA sequentially regulates pseurotin A biosynthesis through GliZ. Finally, we found through a murine virulence test that the gliZ and fumR double-deletion mutants showed a delayed death rate compared with the single-deletion mutants of either gliZ or fumR. Taken together, these results suggested that the biosynthesis of gliotoxin and pseurotin A are regulated in opposite ways by zinc utilization and that each secondary metabolite is synthesized when the synthesis of another secondary metabolite fails to protect it against the defense system of the host.

To identify the infection mechanism of Aspergillus fumigatus, which is an opportunistic fungal pathogen, we analyzed the expression profile of the whole genome of A. fumigatus during the infection of murine macrophages. A previously reported RNA-seq data analysis showed that many genes involved in cell wall synthesis were upregulated during the infection process. Interestingly, AfSec1 (3g12840), which encodes a putative signal peptidase, was upregulated dramatically, and its putative target protein Gel1, which encodes a 1,3-β-glucanosyltransferase, was also upregulated. Instead of the AfSec1 deletion strain, the AfSec1-ΔP strain was constructed, in which the promoter region of AfSec1 was deleted, and AfSec1 expression was not detected in the AfSec1-ΔP strain. The expression of AfSec1 was recovered by the introduction of the promoter region (the AfSec1-ΔP/P strain). The nonprocessed form of Gel1 was identified in the AfSec1-ΔP strain, which lacked the promoter, but mature forms of Gel1 were found in the wild-type and in AfSec1-ΔP/P, which was the promoter complementation strain. In the plate assay, the AfSec1-ΔP strain showed higher sensitivity against caspofungin than the wild-type. However, compared with the wild-type, the deletion strain showed no difference in the sensitivity to other antifungal drugs, such as amphotericin B and voriconazole, which inhibit different targets compared with caspofungin. The AfSec1-ΔP strain exhibited ∼20% lower levels of β-glucan in the cell wall than the wild-type. Finally, the virulence decreased when the promoter region of AfSec1 was deleted, as observed in the murine infection test and conidia-killing assay using human macrophages and neutrophils. These results suggest that AfSec1 exerts signal peptidase activity on its target Gel1 and has an important role in fungal pathogenesis.

Differential leukocyte counts of pleural fluid are routinely recommended for the early diagnosis and management of exudative pleural effusions. Rapid automated cellular analysis agrees strongly with standard manual microscopic counts and has become a reality in many clinical laboratories. However, discordant results sometimes observed between automated and manual analyses raise concern about using automated analysis to aid prompt differential diagnosis. This study aimed to evaluate the real-world disagreement between automated and manual leukocyte analyses in exudative pleural effusions and to investigate whether the discordant results occur in specific cellular ranges or randomly. We conducted a retrospective study of patients who were diagnosed with parapneumonic pleural effusions (PPE), tuberculous pleural effusions (TPE), and malignant pleural effusions (MPE) between September 2018 and December 2020. Differential and predominant leukocyte counts were performed using an automated XN-350 analyzer with a two-part differential count consisting of polymorphonuclear (PMN) and mononuclear (MN) leukocytes and a manual method with Wright-stained cytospin slides. We compared the two methods on cases of 109 PPEs, 50 TPEs, and 116 MPEs. Although the overall correlation between the two methods for differential leukocyte counts was excellent, there were etiologic variations; MPEs showed a lower correlation compared to PPEs and TPEs. Automated-PMN predominance almost corresponded to manual cytospin-neutrophilic predominance. In contrast, ~10% of the automated-MN predominance did not correspond with the cytospin-lymphocytic predominance. These discrepancies occurred most in the automated-MN% range of 51% to 60%, followed by 61% to 70%. The PMN% range ≥50% and30% on the automated analysis reliably corresponds to the neutrophilic and lymphocytic predominance, respectively. However, the MN% range of 51% to 70% may not coincide with lymphocytic predominance on manual cytospin analysis. This range leaves the potential cause of exudative pleural effusions open.

Neurogenic differentiation factor 1 (NEUROD1) is frequently overexpressed in small-cell lung cancer (SCLC). NEUROD1 plays an important role in promoting malignant behavior and survival. In this study, we evaluated the association between putative functional polymorphisms in 45 NEUROD1 target genes and chemotherapy response and survival outcomes in 261 patients with SCLC. Among the 100 single nucleotide polymorphisms (SNPs) studied, two were significantly associated with both chemotherapy response and overall survival (OS) of patients with SCLC. The SNP rs3806915C>A in semaphorin 6A (SEMA6A) gene was significantly associated with better chemotherapy response and OS (P = 0.04 and P = 0.04, respectively). The SNPrs11265375C>T in nescient helix-loop helix 1 (NHLH1) gene was also associated with better chemotherapy response and OS (P = 0.04 and P = 0.02, respectively). Luciferase assay showed a significantly higher promoter activity of SEMA6A with the rs3806915 A allele than C allele in H446 lung cancer cells (P = 4 × 10-6). The promoter activity of NHLH1 showed a significantly higher with the rs11265375 T allele than C allele (P = 0.001). These results suggest that SEMA6A rs3806915C>A and NHLH1 rs11265375C>T polymorphisms affect the promoter activity and expression of the genes, which may affect the survival outcome of patients with SCLC.

Objective: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. Methods: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. Results: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36–0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09–1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. Conclusion: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.

The clinical relevance of concomitant deep vein thrombosis (DVT) in patients with pulmonary embolism remains controversial. The aim of the present study was to assess clinical characteristics of patients with isolated pulmonary embolism, thereby investigating isolated pulmonary embolism related clinical factors. Patients hospitalized for pulmonary embolism who underwent DVT workup within 3 days of pulmonary embolism diagnosis were retrospectively classified into two groups: patients with isolated pulmonary embolism and patients with DVT-associated pulmonary embolism (DVT-PE). The clinical, laboratorial and radiological parameters were compared between the two groups. Of 1012 patients, 322 (31.8%) presented with isolated pulmonary embolism, and 690 (68.2%) presented with DVT-PE. In a multivariate analysis, female sex was an independent factor for predicting isolated pulmonary embolism [odds ratio (OR) 1.69, 95% confidence interval (CI) 1.26-2.26, P < 0.001], whereas cancer (OR 0.64, 95% CI 0.43-0.96, P = 0.031), leg pain or swelling (OR 0.08, 95% CI 0.04-0.18, P < 0.001), and central pulmonary embolism (OR 0.44, 95% CI 0.32-0.59, P < 0.001) were negatively associated with isolated pulmonary embolism. There were no significant differences between the two groups with regard to risk stratification and short-term prognosis of pulmonary embolism, including adverse outcomes and pulmonary embolism related in-hospital mortality. Of pulmonary embolism patients who underwent imaging tests for DVT, approximately 32% presented with isolated pulmonary embolism. Isolated pulmonary embolism was positively associated with female sex, whereas it was negatively associated with cancer, leg pain or swelling, and central pulmonary embolism. The presence or absence of concomitant DVT did not influence the severity and short-term prognosis of pulmonary embolism.

Tyrosinase is a key enzyme that has long been considered as a biomarker for melanoma as it catalyzes the oxidation of tyrosine and l-DOPA in melanogenesis. Recent studies also suggest a link between tyrosinase activity and Parkinson’s disease; however, the mechanism of tyrosinase-mediated melanin formation in the brain is poorly understood. To better understand this connection, more advanced tools for the detection of tyrosinase in the brain are required. Herein, we successfully designed and synthesized a tyrosinase-targeting Gd(iii)-based MR contrast agent Tyr-GBCA 1. Tyr-GBCA 1 was synthesized by linking m-hydroxyphenyl to Gd-DOTA via a self-immolative linker. Tyr-GBCA 1 shows a 21% increase in the T(1) relaxation rate (R(1)) in the presence of tyrosinase in artificial cerebral spinal fluid. Furthermore, Tyr-GBCA 1 is unreactive to hydrogen peroxide, which is a potential interferent in oxidation-based tyrosinase sensing systems. The reaction mechanism of the probe was studied by electrospray ionization (ESI) mass spectrometry and supports the cleavage of a reaction site.

To understand the relationship between carbon or nitrogen utilization and iron homeostasis, we performed an iron uptake assay with several deletion mutants with partial defects in carbon or nitrogen metabolism. Among them, some deletion mutants defective in carbon metabolism partially and the MEP2 deletion mutant showed lower iron uptake activity than the wild type. Mep2 is known as a high-affinity ammonia transporter in Saccharomyces cerevisiae. Interestingly, we found that nitrogen starvation resulted in lower iron uptake activity than that of wild-type cells without downregulation of the genes involved in the high-affinity iron uptake system FET3/FTR1. However, the gene expression of FRE1 and CTR1 was downregulated by nitrogen starvation. The protein level of Ctr1 was also decreased by nitrogen starvation, and addition of copper to the nitrogen starvation medium partially restored iron uptake activity. However, the expression of MAC1, which is a copper-responsive transcriptional activator, was not downregulated by nitrogen starvation at the transcriptional level but was highly downregulated at the translational level. Mac1 was downregulated dramatically under nitrogen starvation, and treatment with MG132, which is an inhibitor of proteasome-dependent protein degradation, partially attenuated the downregulation of Mac1. Taken together, these results suggest that nitrogen starvation downregulates the high-affinity iron uptake system by degrading Mac1 in a proteasome-dependent manner and eventually downregulates copper metabolism.

This study was conducted to explore whether polymorphisms of glucose transporter 3 (GLUT3) gene affect the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Four single nucleotide polymorphisms (SNPs) in GLUT3 were investigated in a total of 782 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. Among the four SNPs investigated, GLUT3 rs7309332C>T was significantly associated with OS and DFS in multivariate analyses. The SNP was associated with significantly worse OS (adjusted hazard ratio [aHR] = 1.62, 95% confidence interval [CI] = 1.04–2.53, P = 0.03, under recessive model), and worse DFS (aHR = 1.64, 95% CI = 1.18–2.29, P = 0.003, under recessive model). When stratified by tumor histology, the association between the GLUT3 rs7309332C>T and OS/DFS was not limited to either squamous cell carcinoma (SCC) or adenocarcinoma (AC), although the significant association remained only in AC for OS (P = 0.40 for SCC and P = 0.04 for OS) and only in SCC for DFS (P = 0.03 for SCC and P = 0.08 for OS). When AC patients were stratified according to EGFR mutation status, the SNP was significantly associated with DFS in patients with EGFR mutant tumors (aHR = 2.47, 95% CI = 1.15–5.30, P = 0.02, under recessive model), but not in those with EGFR wild-type tumors. This study suggests that genetic variation in GLUT3 may be useful in predicting survival of patients with early stage NSCLC.

Background: Data regarding community-acquired pneumonia (CAP) identified on chest computed tomography (CT) but not on chest radiography (CR) are limited. Objectives: The present study aimed to investigate the clinical and radiological features of these patients. Methods: We retrospectively compared the clinical characteristics, etiological agents, treatment outcomes, and CT findings between CAP patients with negative CR and positive CT findings (negative CR group) and those with positive CR as well as CT findings (control group). Results: Of 1,925 patients, 94 patients (4.9%) were included in the negative CR group. Negative CR findings could be attributed to the location of the lesions (e.g., those located in the dependent lung) and CT pattern with a low attenuation, such as ground-glass opacity (GGO). The negative CR group was characterized by a higher frequency of aspiration pneumonia, lower incidences of complicated parapneumonic effusion or empyema and pleural drainage, and lower blood levels of inflammatory markers than the control group. On CT, the negative CR group exhibited higher rates of GGO- and bronchiolitis-predominant patterns and a lower rate of consolidation pattern. Despite shorter length of hospital stay in the negative CR group, 30-day and in-hospital mortalities were similar between the two groups. Conclusions: CAP patients with negative CR findings are characterized by lower blood levels of inflammatory markers, a higher incidence of aspiration pneumonia, and a lower incidence of complicated para­pneumonic effusion or empyema than those with positive CR findings. Chest CT scan should be considered in suspected CAP patients with a negative CR, especially in bedridden patients.

Background To assess pulmonary arteriovenous malformation (PAVM) recanalization after embolization based on PAVM diameter changes on computed tomography (CT), with pulmonary angiography used as a gold standard. Methods A retrospective review was done of patients from 2008 to 2019 with a PAVM treated with endovascular embolization. The treatment outcome was determined by conventional angiography. Follow-up pulmonary angiography was performed when recanalization was suspected on CT, or embolization of all lesions in multiple PAVM patients could not be completed in a single session. Patients who had no preprocedural or follow-up CT were excluded. Draining vein, feeding artery, and venous sac diameter were measured on CT, and diameter reduction rates were compared with the widely-used, binary 70 % criteria. Results Forty-one patients with 114 PAVMs were treated during the study period. Eight patients with 50 PAVMs met the inclusion criteria. Mean vein, artery, and venous sac diameter reduction rates were as follows: 59.2 ± 9.3 %, 47.5 ± 10.6 %, and 62.6 ± 13.2 %, respectively, in the occluded group and 5.4 ± 19.5 %, 11.3 ± 17.7 %, and 26.8 ± 14.2 %, respectively, in the recanalized group. The area under the receiver operating characteristic curves for PAVM recanalization for the draining vein was 1.00, showing a better result than the artery (0.97) and sac (0.99). Patients showed > 42 % draining vein diameter reduction in the occluded group and Conclusions The widely-used 70 % binary criteria showed limited performance in predicting outcomes in this angiographically-confirmed case series. Further investigations are warranted to establish a strategy for detecting recanalization after PAVM embolization.

The cause of epithelioid granulomatous inflammation varies widely depending on the affected organ, geographic region, and whether the granulomas morphologically contain necrosis. Compared with other organs, the etiological distribution and morphological patterns of pleural epithelioid granulomas have rarely been investigated. We evaluated the final etiologies and morphological patterns of pleural epithelioid granulomatous inflammation in a tuberculosis (TB)-prevalent country. Of 83 patients with pleural granulomas, 50 (60.2%) had confirmed TB pleurisy (TB-P) and 29 (34.9%) had probable TB-P. Four patients (4.8%) with non-TB-P were diagnosed. With the exception of microbiological results, there was no significant difference in clinical characteristics and granuloma patterns between the confirmed TB-P and non-TB-P groups, or between patients with confirmed and probable TB-Ps. These findings suggest that most pleural granulomatous inflammation (95.2%) was attributable to TB-P in TB-endemic areas and that the granuloma patterns contributed little to the prediction of final diagnosis compared with other organs., Graphical Abstract

Objectives The Cat Eye Syndrome Critical Region, Candidate 1 (CECR1) gene encoding adenosine deaminase 2 (ADA2) is mainly expressed by macrophages. Given the immunomodulatory functions of butyrate, we examined the effect of butyrate on CECR1 expression of macrophages and the relationship between ADA2 and M1/M2 macrophages-associated chemokines in pleural fluid of patients with tuberculous pleural effusion (TPE). Methods Expression of CECR1 was evaluated in lipopolysaccharide (LPS)-stimulated and/or butyrate treated THP-1 cells. The role of CECR1 on butyrate-induced immune response was evaluated using siRNA transfected THP-1 cells. M1/M2 chemokines and ADA2 were measured in pleural fluid of patients with TPE. Results Butyrate promoted the expression of CECR1 and M2-macrophage markers in THP-1 cells. CECR1 was found to be involved in regulating M2 polarization in THP-1 cells treated with LPS and butyrate. Among chemokines measured in pleural fluid of patients with TPE, there was a significant negative correlation between CCL21 and ADA2 levels and between CCL25 and ADA2 levels, and a significant positive correlation between TGF-β and ADA2 levels and between IL-22 and ADA2 levels. Conclusions CECR1 played an important role in the butyrate-modulated inflammatory responses in LPS-stimulated THP-1 cells. ADA2 may exert anti-inflammatory effects during the process of pleural inflammation in patients with TPE.

Background Data regarding predictors of the outcome for patients with community-acquired complicated parapneumonic effusion (CPPE) or empyema are insufficient. Method Patients with community-acquired pneumonia (CAP) were classified into CPPE or empyema and control groups based on pleural fluid analysis and microbiological data. The patients with CPPE or empyema were further divided into longer and shorter length of stay (LOS) groups, and clinical characteristics, pleural fluid data, and computed tomographic (CT) findings were compared between the two groups. Result Of outcome variables, LOS was significantly longer in CPPE or empyema group than in the control group (13 days [interquartile range, 10-17 days] versus 8 days [6-12 days], p < 0.001), whereas 30-day mortality and in-hospital mortality were not significantly different between the two groups. Patients with CPPE or empyema were divided into the shorter (≤ 13 days) and longer LOS (≥ 14 days) groups. Multivariate analysis demonstrated that pneumonia severity index (PSI) class IV-V (odds ratio [OR] 2.79, 95% CI 1.35-5.76, p=0.006), increased attenuation of extrapleural fat (OR 2.26, 95% CI 1.06-4.80, p=0.034), and air bubbles in pleural space (OR 3.93, 95% CI 1.03-14.98, p=0.045) were independent predictors of prolonged LOS in CAP patients with CPPE or empyema. Conclusion Increased attenuation of extrapleural fat and air bubbles in pleural space assessed with CT and PSI class IV-V independently predicted prolonged LOS in CAP patients with CPPE or empyema. These findings may be helpful to identify patients who need more intensive evaluation and intervention.

BACKGROUND. Ultrasound (US)-guided percutaneous pleural needle biopsy (PCPNB) is widely used to evaluate pleural lesions, although its diagnostic accuracy is variable. OBJECTIVE. The purpose of this study is to assess the diagnostic yield of US-guided PCPNB for small (≤ 2 cm) pleural lesions and the impact of CT and US morphologic and technical factors. METHODS. A total of 103 patients (73 men and 30 women; mean [± SD] age, 68.0 ± 13.3 years) who underwent US-guided PCPNB of a small pleural lesion performed by a single experienced operator from July 2013 to December 2019 were retrospectively analyzed. Final diagnosis was established via histopathologic results, including findings from repeat US-guided and CT-guided biopsies as well as imaging and clinical follow-up. Pleural morphology and thickness were assessed on CT and US, and needle pathway length throughout the pleura was measured on US. Accuracy, sensitivity, specificity, PPV, and NPV were calculated. The association of diagnostic yield with imaging and technical factors was evaluated. ROC curve analysis was used to determine the optimal CT pleural thickness cutoff value. Multivariable logistic regression was performed to identify independent predictors of diagnostic yield. RESULTS. The diagnostic accuracy, sensitivity, specificity, PPV, and NPV of US-guided PCPNB were 85.4%, 84.8%, 100.0%, 100.0%, and 21.1%, respectively. Diagnostic, compared with nondiagnostic, procedures more commonly (p ≤ .002) revealed nodular morphology on CT (96.4% vs 3.6%) and US (97.3% vs 2.7%,), greater pleural thickness on CT (7.5 vs 3.2 mm) and US (7.4 vs 3.0 mm), and a greater needle pathway length (11.0 vs 6.1 mm). The optimal cutoff value for pleural thickness on CT was 4.5 mm. Diagnostic yield was 96.4% for nodular lesions, 95.0% for diffuse lesions that had a thickness of 4.5 mm or greater on CT, 55.6% for diffuse lesions that had a thickness less than 4.5 mm on CT, and 100% for diffuse lesions on CT that had nodular morphology on US. Nodular morphology on US (p = .002) and needle pathway length (p = .04) were independent predictors of diagnostic yield. CONCLUSION. US-guided PCPNB has excellent diagnostic accuracy for small pleural lesions; imaging characteristics influence this accuracy. CLINICAL IMPACT. US-guided PCPNB is highly likely diagnostic for small pleural lesions with nodular morphology on either CT or US or with a pleural thickness of 4.5 mm or greater.

This study was conducted to investigate the impact of genetic variants of immune checkpoint genes on the treatment outcome in small cell lung cancer (SCLC). In the present study, 261 platinum doublet-treated SCLC patients were enrolled. A total of 96 polymorphisms in 33 immune checkpoint-related genes were selected, and their association with chemotherapy response and survival outcomes were analyzed. Among the polymorphisms studied, CD155 rs1058402G > A (Ala67Thr, A67T) and CD226 rs763361C > T (Gly307Ser, G307S) were significantly associated with SCLC treatment outcome. The rs1058402G > A had a worse chemotherapy response and overall survival (under a dominant model, adjusted odds ratio [aOR] = 0.52, 95% confidence interval [CI] = 0.27–0.99, P = 0.05; adjusted hazard ratio [aHR] = 1.55, 95% CI = 1.12–2.14, P = 0.01, respectively). The rs763361C > T had better chemotherapy response and overall survival (under a dominant model, aOR = 2.03, 95% CI = 1.10–3.75, P = 0.02; aHR = 0.69, 95% CI = 0.51–0.94, P = 0.02, respectively). When the rs1058402GA/AA and rs763361CC genotypes were combined, the chemotherapy response and overall survival were significantly decreased as the number of bad genotypes increased (aOR = 0.52, 95% CI = 0.33–0.81, Ptrend = 0.004; aHR = 1.48, 95% CI = 1.19–1.84, Ptrend = 4 × 10−4, respectively). The 3-D structural model showed that CD155 A67T created a new hydrogen bond and structural change on CD155. These changes resulted in extending the distance and losing the hydrogen bonds between CD155 and CD226, thus weakening CD155/CD226 binding activity. In conclusion, CD155 rs1058402G > A and CD226 rs763361C > T may be useful for predicting the clinical outcomes of SCLC patients after chemotherapy.

Introduction Few studies have investigated the influence of emphysema on clinical features of patients presenting with community-acquired pneumonia (CAP). Objectives The aim of this study was to examine the clinical and microbiological features of patients with both CAP and emphysema. Methods This retrospective study included patients with CAP who underwent computed tomography (CT) scan at the time of presentation. Patients were allocated into emphysema and control groups, and clinical variables were compared between the 2 groups. The emphysema group was further divided into 3 subgroups (mild, moderate, and severe) according to the extent of emphysema on CT scan. The clinical variables of each subgroup were compared with the control group. Results Of 1676 patients, 431 patients (25.7%) were classified into the emphysema group. CAP patients with emphysema were more likely to have a high CURB-65 score and pneumonia severity index and a lower incidence of complicated parapneumonic effusion or empyema. The emphysema group exhibited longer hospital stay. In addition, 30-day mortality in the severe emphysema group was significantly higher compared with the control group. As etiological agents, Streptococcus pneumoniae, Pseudomonas aeruginosa, Enterobacteriaceae, and multi-drug resistant pathogens were significantly more common in the emphysema group compared with the control group. Conclusions The presence of emphysema in CAP patients was associated with a more severe form of CAP, a longer hospital stay, and a lower incidence of complicated parapneumonic effusion or empyema. Moreover, CAP patients with severe emphysema exhibited higher 30-day mortality than those without emphysema.

Background: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). Methods: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. Results: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54–0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13–4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08–1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10–3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41–1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11–6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17–2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12–6.88, p = 0.03, respectively). Conclusions: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

Deltex‐1 (DTX1) is a negative regulator of the Notch signaling pathway. Here, we investigated the clinical effect of DTX1 rs1732786A > G, which is associated with better prognosis in patients with early‐stage non‐small cell lung cancer (NSCLC), in 261 patients with small cell lung cancer (SCLC). DTX1 rs1732786A > G was associated with a significantly worse chemotherapy response and lower overall survival in the codominant model (odds ratio = 0.42, 95% confidence interval [CI]: 0.26–0.66, P = 2 × 10−4; hazard ratio = 1.47, 95% CI: 1.17–1.84, P = 0.001, respectively). An in vitro luciferase assay was performed, and the 1732786G allele demonstrated significantly higher promoter activity than the 1732786A allele (P = 2 × 10−7). In summary, DTX1 rs1732786A > G was associated with poor prognosis in patients with SCLC as opposed to patients with NSCLC. Key points Significant findings of the study DTX1 rs1732786A > G was associated with better prognosis in patients with early‐stage non‐small cell lung cancer (NSCLC) in our previous study. What this study adds DTX1 rs1732786A > G was associated with a significantly worse chemotherapy response and lower overall survival in small cell lung cancer (SCLC)., DTX1 rs1732786A>G was associated with better prognosis in patients with early‐stage non‐small cell lung cancer, in the previous study. DTX1 rs1732786A>G was associated with a significantly worse chemotherapy response and lower overall survival in small cell lung cancer.

The answer to the letter ‘Absent regulation of iron acquisition by the copper regulator Mac1 in A. fumigatus’ has been prepared. We explained our data and showed supplementary information to answer the questions. And we respect the results of other groups first and explain the differences from our results.

Background We conducted this study to identify regulatory variants in cancer-related pathway genes which can predict clinical outcomes of chemotherapy in advanced NSCLC, using a comprehensive list of regulatory SNPs prioritized by RegulomeDB. Methods A total of 509 potentially functional SNPs in cancer-related pathway genes were evaluated. The SNPs were analyzed in a discovery set (n = 198), and an independent validation set (n = 181). The associations of the SNPs with chemotherapy response and overall survival (OS) were analyzed. Results In the discovery set, 95 SNPs were significantly associated with clinical outcomes. Among the 95 SNPs, only rs10414193A > G in the intronic region of ARID3A, an eQTL for LKB1, was consistently associated with chemotherapy response and OS in the validation set. In combined analysis, the rs10414193A > G was significantly associated with worse response to chemotherapy (adjusted odds ratio = 0.63, 95% CI = 0.47–0.85, P = 0.002), and with worse OS (adjusted hazard ratio = 1.25, 95% CI = 1.08–1.45, P = 0.004). Luciferase assay showed a significantly higher LKB1 promoter activity associated with rs10414193G allele compared with rs10414193A allele (P = 0.0009). Conclusions Our results suggest that rs10414193A > G may be useful for the prediction of clinical outcomes of chemotherapy in advanced NSCLC.

International audience; As the symbol of beauty, floral objects have been one of the most popular subjects of artistic drawing. However, designing 3D floral models is generally time-and resource-consuming, because of their structural and geometrical complexity. In this paper, we address the problem of reconstructing floral objects from sketch input. The user draws a relatively clean sketch of a flower and a few additional guide markings from an arbitrary view to rapidly create quality geometric models of flowers. Our system offers a novel modeling scheme compared to several existing flower modelers accepting sketch as input, where the user is required to work with different views, providing step-by-step sketch input. Given the silhouette and the guide strokes, an assumed, common botanical structure is estimated, i.e. a cone for each ring of petals. The cones and the silhouette sketch that we segment into elementary curves are used to retrieve model elements from the pre-constructed shape database. These elements are then placed together around the cone, where an additional, per-element deformation is performed so as to maximize the silhouette similarity between the user sketch and the 3D flower model from the chosen view. Our system has shown to robustly create a variety of flowers in various configurations, including flower models with several petal layers and various blooming degrees, drawn from different views.

Although iron and copper are co-ordinately regulated in living cells, the homeostatic effects of each of these metals on the other remain unknown. Here, we show the function of AfMac1, a transcriptional activator of the copper and iron regulons of Aspergillus fumigatus, on the interaction between iron and copper. In addition to the copper-specific AfMac1-binding motif 5′-TGTGCTCA-3′ found in the promoter region of ctrC, the iron-specific AfMac1-binding motif 5′-AT(C/G)NN(A/T)T(A/C)-3′ was identified in the iron regulon but not in the copper regulon by ChIP sequence analysis. Furthermore, mutation of the AfMac1-binding motif of sit1 eliminated AfMac1-mediated sit1 up-regulation. Interestingly, the regulation of gene expression in the iron regulon by AfMac1 was not affected by copper and vice versa. AfMac1 localized to the nucleus under iron- or copper-depleted conditions, and AfMac1 was mostly detected in the cytoplasm under iron- or copper-replete conditions. Taken together, these results suggest that A. fumigatus independently regulates iron and copper homeostasis in a manner that involves AfMac1 and mutual interactions.

2-(2,5-Dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine (25N-NBOMe, 2C-N-NBOMe, NBOMe-2C-N) is a novel synthetic psychoactive substance of the phenethylamine chemical class. A few metabolism studies have been conducted for 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe, and others, whereas 25N-NBOMe metabolism has not been researched. In this study, the in vitro metabolism of 25N-NBOMe was investigated with human liver microsomes, and the reaction mixture was analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS). Formation of 14 metabolites (M1-M14) was yielded with incubation of 25N-NBOMe in human liver microsomes in the presence of NADPH. The metabolites were structurally characterized on the basis of accurate mass analysis and MS/MS fragmentation patterns. The biotransformations included hydroxylation, O-demethylation, N-dealkylation, nitro reduction, dehydrogenation, carbonylation, and combinations thereof. Hydroxyl metabolite was the most abundant compound after the phase I process. These results provide helpful information establishing biomarkers in case of 25N-NBOMe ingestion.

Background Data on the relationship between the clinical and microbiological features of community-acquired pneumonia (CAP) and its computed tomography (CT) findings are limited. The aim of the present study was to investigate the clinic-microbiological features of patients with CAP presenting with ground-glass opacity (GGO) and centrilobular nodules or tree-in-bud pattern on CT images. Methods Patients with CAP who underwent a CT scan at presentation were retrospectively classified using CT findings into consolidation, GGO and bronchiolitis groups. These 3 groups were compared in terms of clinical parameters and microbiological data. Results A total of 40 patients (2.4%) were allocated to the bronchiolitis group and 46 (2.8%) to the GGO group. The most common pathogen in the bronchiolitis group was Mycoplasma pneumoniae, which was significantly more frequently isolated in this group. The bronchiolitis group was characterized by a higher percentage of cough, a lower percentage of chest pain and lower blood levels of inflammatory markers. Common pathogens in the GGO group were not significantly different from those in the other 2 groups. Unlike that observed in the consolidation group, complicated parapneumonic effusion or empyema was not observed in the bronchiolitis or GGO group. Outcome variables were similar in the 3 groups. Conclusions The bronchiolitis group was characterized by a higher frequency of M. pneumoniae and a less severe form of CAP. The GGO and consolidation groups was similar with respect to causative microorganisms and the clinical features of CAP. No patient in the bronchiolitis or GGO group exhibited complicated parapneumonic effusion or empyema.

Predicting drug–drug interactions (DDIs) is an important step during drug development to avoid unexpected side effects. Cytochrome P450 (CYP) 3A4 is the most abundant human hepatic phase I enzyme, which metabolizes >50% of therapeutic drugs. Therefore, it is essential to test the potential of a drug candidate to induce CYP3A4 expression or inhibit its activity. Recently, 3-dimensional (3-D) mammalian cell culture models have been adopted in drug discovery research to assess toxicity, DDIs, and pharmacokinetics. In this study, we applied a human 3-D spheroid culture protocol using HepaRG cells combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess its ability to predict CYP3A4 inhibition. Levels of midazolam, a specific substrate of CYP3A4, were used to determine the long-term metabolic capacity of CYP3A4. Midazolam was decreased in the 3-D HepaRG culture system by ∼80% over 7 days, whereas its primary metabolite, 1-hydroxymidazolam, increased by ∼40%. Next, we assessed hepatotoxicity by determining the cytotoxicity of known hepatotoxicants in HepaRG spheroids, HepG2 cells, and primary human hepatocytes. Significant differences in cytotoxicity were detected in the system using 3-D HepaRG spheroids. These results suggest that 3-D HepaRG spheroids are a good model for prediction of CYP inhibition and hepatotoxicity in screening of early drug candidates.

Ni-rich LiNixCoyMn1-x-yO2 (Ni-rich NCM; x ≥ 0.8, 0 4.3 V). Herein, 2,4-difluorobiphenyl (FBP) is proposed as a fluorine-based cathode electrolyte interphase (CEI)-forming additive for Ni-rich LiNi0.83Co0.11Mn0.06O2 (NCM83). The structural characteristics of FBP originate from the overcharge protection of biphenyl, whereas the fluorine atoms are preferable for high-voltage conditions. The addition of 1 wt% FBP to the electrolyte enhances the cycling stability at the 4.5 V cut-off voltage. Electrochemical impedance spectroscopy and rate capability results indicate a fast kinetics at the NCM83 surface with FBP additive upon the formation of a stable CEI. Images from scanning electron microscopy and transmission electron microscopy after 150 cycles of NCM83 show the thin deposit layer of CEI upon introduction of FBP. The X-ray photoelectron spectroscopy results demonstrate the suppression of electrolyte and salt decomposition. This work suggests an opportunity to develop a completely new functional additive by introducing a fluorine component to existing additives.

Anthrax, a bacteriogenic fatal infectious disease against human beings, demands early and ready detection of its bacterial endospores. We disclose here poly(diacetylene acid) derived liposomes functionalized with Eu(III)-EDTA complexes as a novel ratiometric fluorescence detection system for dipicolinate, an anthrax biomarker and the major component of the endospores. The red fluorescence of the polymerized liposomes offers a biult-in reference signal, allowing us to monitor the relative change of europium luminescence sensitized by the bound dipicolinate with respect to the reference liposome emission. The liposome based integrated sensing system shows reasonable sensitivity as well as remarkable selectivity toward dipicolinate over other structurally related analytes. We also show paper stripe sensors based on the polymerized liposome for the detection of dipicolinate by naked eyes.

Zinc performs diverse physiological functions, and virtually all living organisms require zinc as an essential trace element. To identify the detailed function of zinc in fungal pathogenicity, we carried out cDNA microarray analysis using the model system of Aspergillus fumigatus, a fungal pathogen. From microarray analysis, we found that the genes involved in gliotoxin biosynthesis were upregulated when zinc was depleted, and the microarray data were confirmed by northern blot analysis. In particular, zinc deficiency upregulated the expression of GliZ, which encodes a Zn2-Cys6 binuclear transcription factor that regulates the expression of the genes required for gliotoxin biosynthesis. The production of gliotoxin was decreased in a manner inversely proportional to the zinc concentration, and the same result was investigated in the absence of ZafA, which is a zinc-dependent transcription activator. Interestingly, we found two conserved ZafA-binding motifs, 5′-CAAGGT-3′, in the upstream region of GliZ on the genome and discovered that deletion of the ZafA-binding motifs resulted in loss of ZafA-binding activity; gliotoxin production was decreased dramatically, as demonstrated with a GliZ deletion mutant. Furthermore, mutation of the ZafA-binding motifs resulted in an increase in the conidial killing activity of human macrophage and neutrophil cells, and virulence was decreased in a murine model. Finally, transcriptomic analysis revealed that the expression of ZafA and GliZ was upregulated during phagocytosis by macrophages. Taken together, these results suggest that zinc plays an important role in the pathogenicity of A. fumigatus by regulating gliotoxin production during the phagocytosis pathway to overcome the host defense system.

Background Risk stratification is important for the management of community-acquired pneumonia (CAP). The present study aimed to investigate the clinical impact of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on prognosis and to identify clinical characteristics associated with NT-proBNP elevation in CAP patients. Methods This retrospective study included patients hospitalized for CAP at a tertiary referral center and who underwent measurement plasma NT-proBNP levels. Based on 30-day mortality, patients (n = 1,821) were divided into 2 groups, survivors (n = 150) and nonsurvivors (n = 1,671), and clinical and laboratory findings were compared. Results In multivariate analysis, blood levels of NT-proBNP (>942.5 pg/mL), albumin ( 0.018 ng/mL) independently predicted 30-day mortality. Of these blood biomarkers, NT-proBNP exhibited the highest C-statistic, followed by albumin. NT-proBNP level/CURB-65 score and NT-proBNP level/pneumonia severity index (PSI) class exhibited significantly higher C-statistics than CURB-65 score and PSI class alone, respectively. The 3-test combinations of CURB-65 score/NT-proBNP level/albumin level and PSI class/NT-proBNP level/albumin level exhibited significantly higher C-statistics than the 2-test combinations. NT-proBNP elevation was associated with increased age, heart disease and chronic kidney disease and NT-proBNP levels only weakly or moderately correlated with other blood biomarkers. Conclusions NT-proBNP level was a useful marker for the prediction of 30-day mortality in patients hospitalized with CAP, and provided additional prognostic value to PSI or CURB-65 alone.

BACKGROUND: Lymphoma-associated malignant pleural effusions (L-MPE) can mimic tuberculous pleural effusion (TPE) characterized by lymphocytic exudate with high adenosine deaminase (ADA) levels. Furthermore, the low cytological yield of L-MPE makes differentiation between L-MPE and TPE more challenging. However, there are few data regarding differential diagnosis of L-MPE and TPE. METHODS: All consecutive patients diagnosed with L-MPE or TPE between January 2011 and December 2016 were retrospectively recruited using the Electronic Medical Record database. Clinical symptoms and laboratory and pleural fluid data [including serum lactate dehydrogenase (LDH), C-reactive protein, and pleural fluid ADA levels] were compared between L-MPE and TPE. Useful variables in the differential diagnosis of L-MPE and TPE were evaluated by multivariate logistic regression analysis. RESULTS: Seventeen patients with L-MPE and 216 patients with TPE were included in this study. In the multivariate analysis, fever was negatively associated with L-MPE [odds ratio (OR): 0.175, 95% confidence interval (CI): 0.033–0.941, P=0.042], while serum LDH levels were positively associated with L-MPE (OR: 1.005, 95% CI: 1.003–1.007, P460 U/L provided a sensitivity of 76% and a specificity of 81% to distinguish L-MPE and TPE. In contrast, serum C-reactive protein and pleural fluid ADA levels were not significantly different between the groups. CONCLUSIONS: Patients with L-MPE and TPE present very similar clinical, laboratory, and pleural fluid characteristics. Fever and serum LDH levels may be helpful in guiding the differential diagnosis of L-MPE and TPE. Lymphoma should be kept in mind in the differential diagnosis in patients with lymphocytic pleural effusion and high ADA levels.

Objective: This study was conducted to investigate whether polymorphisms in glycolysis-related genes are associated with clinical outcomes of patients with advanced-stage non-small cell lung cancer (NSCLC) undergoing chemotherapy. Methods: A total of 377 patients with NSCLC were enrolled. Sixty-five single-nucleotide polymorphisms in 26 genes involved in the glycolytic pathway were evaluated. The associations of the variants with the chemotherapy response and overall survival (OS) were analyzed. Results: Among the 65 variants investigated, PFKL rs2073436C>G and GPI rs7248411C>G significantly correlated with clinical outcomes after chemotherapy in multivariate analyses. PFKL rs2073436C>G was significantly associated with both a worse response to chemotherapy (adjusted odds ratio [aOR] = 0.64, 95% CI = 0.45–0.90, p = 0.01) and a worse OS (adjusted hazard ratio [aHR] = 1.35, 95% CI = 1.14–1.61, p = 0.001). GPI rs7248411C>G was significantly associated with both a better chemotherapy response (aOR = 1.58, 95% CI = 1.07–2.23, p = 0.02) and a better OS (aHR = 0.80, 95% CI = 0.66–0.98, p = 0.03). When stratified by tumor histology, PFKL rs2073436C>G was significantly associated with OS only in squamous cell carcinoma, whereas GPI rs7248411C>G exhibited a significant association with the chemotherapy response and OS only in adenocarcinoma. Conclusion: This result suggests that the PFKL rs2073436C>G and GPI rs7248411C>G are useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.