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Electron work function (EWF) has demonstrated its great promise in materials analysis and design, particularly for single-phase materials, e.g., solute selection for optimal solid-solution strengthening. Such promise is attributed to the correlation of EWF with the atomic bonding and stability, which largely determines material properties. However, engineering materials generally consist of multiple phases. Whether or not the overall EWF of a complex multi-phase material can reflect its properties is unclear. Through investigation on the relationships among EWF, microstructure, mechanical and electrochemical properties of low-carbon steel samples with two-level microstructural inhomogeneity, we demonstrate that the overall EWF does carry the information on integrated electron behavior and overall properties of multiphase alloys. This study makes it achievable to develop “electronic metallurgy”—an electronic based novel alternative methodology for materials design.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients’ outcome. 553 metastatic EGFR -mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99–1.48]; p = 0.053), ECOG PS 0–1 (HR 0.71 [95% CI 0.54–0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66–0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0–1 (HR 0.41 [95% CI 0.31–0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13–1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02–4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12–0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28–1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR -mutant NSCLC, whereas OS was mainly associated with EGFR subtype.

Heat shock proteins (HSPs) have been shown to modulate NF-κB activation. It is unknown whether HSP70 plays a role in modulating NF-κB-mediated pro-inflammatory cytokines released from alveolar macrophage (AM) of patients with active pulmonary tuberculosis (TB). Peripheral blood monocytes (PBMs) and AM were sampled from nineteen active TB patients and 14 healthy individuals. HSP70 expression was 3-fold higher in AMs of active TB patients than normal subjects, and declined after receiving 3-month anti-TB treatment. Overexpression of HSP70 by transfection with HSP70 plasmid decreased p-IκBα and p65 NF-κB activities. Inhibition of NF-κB activation using NF-κB or MAPK inhibitors increased HSP70 expression in AM of TB patients. Blocking p38- or ERK-MAPK decreased NF-κB and IκB activities, leading to up-regulated HSP70 expression. Overexpression of HSP70 alone or with p38 or ERK inhibitors decreased TNF-α (57%, 83% and 74%, respectively) and IL-6 (53%, 70%, and 67%, respectively) release from macrophages of TB patients. In conclusion, HSP70 modulates NF-κB activation in AM of TB patients, through inhibiting IκB-α phosphorylation or acting as a chaperon molecule to prevent NF-κB binding to the target genes by facilitating degradation. The upregulated HSP70 may suppress the release of pro-inflammatory cytokines during active PTB infection, and prevent overwhelming tissue damage.

The association of anosmia/ageusia with a positive severe respiratory syndrome coronavirus 2 (SARS-CoV-2) test is well-established, suggesting these symptoms are reliable indicators of coronavirus disease 2019 (COVID-19) infection. This study investigates the clinical characteristics and systemic inflammatory markers in hospitalized COVID-19 patients in Taiwan, focusing on those with anosmia/ageusia. We conducted a retrospective observational study on 231 hospitalized COVID-19 patients (alpha variant) from April to July 2021. Clinical symptoms, dyspnea grading, and laboratory investigations, including neutrophil-lymphocyte ratios (NLRs), platelet-lymphocyte ratios (PLRs), and ANDC scores (an early warning score), were analyzed. Cough (64.1%), fever (58.9%), and dyspnea (56.3%) were the most common symptoms, while anosmia/ageusia affected 9% of patients. Those with anosmia/ageusia were younger, had lower BMI, lower systemic inflammatory markers, and better ANDC scores than those without these symptoms. Female patients exhibited lower NLR values and ANDC scores compared to male patients (all p  < 0.05). Multivariable regression analysis demonstrated significant associations between NLR and CRP and ferritin levels (all p  < 0.01), and between PLR and ESR and ferritin levels ( p  < 0.01). Categorized ANDC scores significantly correlated with the total hospital length of stay (all p  < 0.05). Despite ethnic differences in the prevalence of anosmia/ageusia, our study highlights similar clinical presentations and inflammatory profiles to those observed in Western countries. The ANDC score effectively predicted hospital stay duration. These findings suggest that anosmia/ageusia may be associated with less severe disease and a lower inflammatory response, particularly in younger and female patients. The ANDC score can serve as a valuable prognostic tool in assessing the severity and expected hospital stay of COVID-19 patients.

Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases. To determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases. Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line. Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone's suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17. Up-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

Purpose Multidrug-resistant (MDR) bacteria impose a considerable health-care burden and are associated with bronchiectasis exacerbation. This study investigated the clinical outcomes of adult patients with bronchiectasis following MDR bacterial infection. Methods From the Chang Gung Research Database, we identified patients with bronchiectasis and MDR bacterial infection from 2008 to 2017. The control group comprised patients with bronchiectasis who did not have MDR bacterial infection and were propensity-score matched at a 1:2 ratio. The main outcomes were in-hospital and 3-year mortality. Results In total, 554 patients with both bronchiectasis and MDR bacterial infection were identified. The types of MDR bacteria that most commonly affected the patients were MDR- Acinetobacter baumannii (38.6%) and methicillin-resistant Staphylococcus aureus (18.4%), Extended-spectrum-beta-lactamases (ESBL)- Klebsiella pneumoniae (17.8%), MDR- Pseudomonas (14.8%), and ESBL- E. coli (7.5%). Compared with the control group, the MDR group exhibited lower body mass index scores, higher rate of chronic bacterial colonization, a higher rate of previous exacerbations, and an increased use of antibiotics. Furthermore, the MDR group exhibited a higher rate of respiratory failure during hospitalization (MDR vs. control, 41.3% vs. 12.4%; p  < 0.001). The MDR and control groups exhibited in-hospital mortality rates of 26.7% and 7.6%, respectively ( p  < 0.001); 3-year respiratory failure rates of 33.5% and 13.5%, respectively ( p  < 0.001); and 3-year mortality rates of 73.3% and 41.5%, respectively ( p  < 0.001). After adjustments were made for confounding factors, the infection with MDR and MDR bacteria species were determined to be independent risk factors affecting in-hospital and 3-year mortality. Conclusions MDR bacteria were discovered in patients with more severe bronchiectasis and were independently associated with an increased risk of in-hospital and 3-year mortality. Given our findings, we recommend that clinicians identify patients at risk of MDR bacterial infection and follow the principle of antimicrobial stewardship to prevent the emergence of resistant bacteria among patients with bronchiectasis.

Background Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan. Methods This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed non-cystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis. Results The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture. Pseudomonas aeruginosa (5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%), Haemophilus influenzae (3.4%) and Klebsiella pneumoniae (3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria than P. aeruginosa . Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups ( p  < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies. Conclusions Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.

Influenza infection is a cause of exacerbations in patients with chronic pulmonary diseases. The aim of this study was to investigate the clinical outcomes and identify risk factors associated with hospitalization and mortality following influenza infection in adult patients with bronchiectasis. Using the Chang Gung Research Database, we identified patients with bronchiectasis and influenza-related infection (ICD-9-CM 487 and anti-viral medicine) between 2008 and 2017. The main outcomes were influenza-related hospitalization and in-hospital mortality rate. Eight hundred sixty-five patients with bronchiectasis and influenza infection were identified. Five hundred thirty-six (62%) patients with bronchiectasis were hospitalized for influenza-related infection and 118 (22%) patients had respiratory failure. Compared to the group only seen in clinic, the hospitalization group was older, with more male patients, a lower FEV1, higher bronchiectasis aetiology comorbidity index (BACI), and more acute exacerbations in the previous year. Co-infections were evident in 55.6% of hospitalized patients, mainly caused by Pseudomonas aeruginosa (15%), fungus (7%), and Klebsiella pneumoniae (6%). The respiratory failure group developed acute kidney injury (36% vs. 16%; p < 0.001), and shock (47% vs. 6%; p < 0.001) more often than influenza patients without respiratory failure. The overall mortality rate was 10.8% and the respiratory failure group exhibited significantly higher in-hospital mortality rates (27.1% vs. 6.2%; p < 0.001). Age, BACI, and previous exacerbations were independently associated with influenza-related hospitalization. Age, presence of shock, and low platelet counts were associated with increased hospital mortality. Influenza virus caused severe exacerbation in bronchiectasis, especially in those who were older and who had high BACI scores and previous exacerbations. A high risk of respiratory failure and mortality were observed in influenza-related hospitalization in bronchiectasis. We highlight the importance of preventing or treating influenza infection in bronchiectasis.

Background Treatment for stage III non‐small cell lung cancer (NSCLC) of unresectable disease mainly involves concurrent chemoradiation (CRT). Post‐CRT consolidation treatment with durvalumab is a major therapeutic advance that provides survival benefit in this group of patients. However, the performance of this treatment strategy remains to be studied in a real‐world setting. Methods A total of 31 patients who had disease control post‐CRT were included in the durvalumab early access program (EAP) as an intent‐to‐treat cohort and retrospectively reviewed for post‐CRT progression‐free survival (PFS) and time to metastatic disease or death (TMDD). The neutrophil‐to‐lymphocyte ratio (NLR) at the initiation of durvalumab was analyzed in 29 patients. Results The median time from the completion of concurrent CRT to the initiation of durvalumb was 2.8 months. The objective response was 25.8% and the 12 month PFS and TMDD‐free rate were 56.4% and 66.9%, respectively. The low NLR patients showed a significantly longer post‐CRT PFS (not reach vs. 12.0 months [95% CI: 5.5–not estimable]; P = 0.040; the hazard ratio for disease progression or death, 0.23 [95% CI: 0.05–1.00]; P = 0.048) and the 12 month post‐CRT PFS rate (82.5 vs. 42.6%). The post‐CRT TMDD (not reach vs. 12.6 months, [95% CI: 10.8–not estimable]; P = 0.010; the hazard ratio for distant metastasis or death, 0.11 [95% CI: 0.01–0.88]; P = 0.037) and 12 month post‐CRT TMDD‐free rate (90.9 vs. 57.1%) were also significantly higher in the low NLR patients. Conclusions Durvalumab consolidation treatment in real‐world patients showed substantial efficacy and the correlation with the NLR level warrants further investigation.

Background Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. Methods Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. Results Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31–1.17; p  = 0.135). Multivariate Cox regression showed ECOG PS (0–1 vs. 2–3 HR 0.09 [95% CI, 0.02–0.33]; p  < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26–5.99]; p  = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01–0.78; p  = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08–1.06]; p  = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. Conclusion Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.