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Abstract Background This is a retrospective cohort study from a single center of Chest Medical District of Nanjing Brain Hospital Affiliated to Nanjing Medical University, Jiangsu Province, China. It was aim to evaluate the diagnostic value of radial endobronchial ultrasound (R-EBUS) combination with rapid on-site evaluation (ROSE) guided transbronchial lung biopsy (TBLB) for peripheral pulmonary lesions in patients with emphysema. Methods All 170 patients who underwent PPLs with emphysema received an R-EBUS examination with or without the ROSE procedure, and the diagnostic yield, safety, and possible factors influencing diagnosis were analyzed between the two groups by the SPSS 25.0 software. Results The pooled and benign diagnostic yields were not different in the two groups (P = 0.224, 0.924), but the diagnostic yield of malignant PPLs was significantly higher in the group with ROSE than the group without ROSE (P = 0.042). The sensitivity of ROSE was 79.10%, the specificity, 91.67%, the positive predictive value, 98.15%, and the negative predictive value, 84.62%. The diagnostic accuracy, was 95.52%. In the group of R-EBUS + ROSE, the procedural time and the number of times of biopsy or brushing were both significantly reduced (all P

Abstract Factor-dependent termination uses molecular motors to remodel transcription machineries, but the associated mechanisms, especially in eukaryotes, are poorly understood. Here we use single-molecule fluorescence assays to characterize in real time the composition and the catalytic states of Saccharomyces cerevisiae transcription termination complexes remodeled by Sen1 helicase. We confirm that Sen1 takes the RNA transcript as its substrate and translocates along it by hydrolyzing multiple ATPs to form an intermediate with a stalled RNA polymerase II (Pol II) transcription elongation complex (TEC). We show that this intermediate dissociates upon hydrolysis of a single ATP leading to dissociation of Sen1 and RNA, after which Sen1 remains bound to the RNA. We find that Pol II ends up in a variety of states: dissociating from the DNA substrate, which is facilitated by transcription bubble rewinding, being retained to the DNA substrate, or diffusing along the DNA substrate. Our results provide a complete quantitative framework for understanding the mechanism of Sen1-dependent transcription termination in eukaryotes.

Abstract Protein surfaces have pivotal roles in interactions between proteins and other biological molecules. However, the structural dynamics of protein surfaces have rarely been explored and are poorly understood. Here, the surface of a single‐stranded DNA (ssDNA) binding protein (SSB) with four DNA binding domains that bind ssDNA in binding site sizes of 35, 56, and 65 nucleotides per tetramer is investigated. Using oligonucleotides as probes to sense the charged surface, NaCl induces a two‐state structural transition on the SSB surface even at moderate concentrations. Chelation of sodium ions with charged amino acids alters the network of hydrogen bonds and/or salt bridges on the surface. Such changes are associated with changes in the electrostatic potential landscape and interaction mode. These findings advance the understanding of the molecular mechanism underlying the enigmatic salt‐induced transitions between different DNA binding site sizes of SSBs. This work demonstrates that monovalent salt is a key regulator of biomolecular interactions that not only play roles in non‐specific electrostatic screening effects as usually assumed but also may configure the surface of proteins to contribute to the effective regulation of biomolecular recognition and other downstream events.

Abstract Transmembrane protein 52B (TMEM52B), a newly identified tumor‐related gene, has been reported to regulate various tumors, yet its role in nasopharyngeal carcinoma (NPC) remains unclear. Transcriptomic analysis of NPC cell lines reveals frequent overexpression of TMEM52B, and immunohistochemical results show that TMEM52B is associated with advanced tumor stage, recurrence, and decreased survival time. Depleting TMEM52B inhibits the proliferation, migration, invasion, and oncogenesis of NPC cells in vivo. TMEM52B encodes two isoforms, TMEM52B‐P18 and TMEM52B‐P20, differing in their N‐terminals. While both isoforms exhibit similar pro‐oncogenic roles and contribute to drug resistance in NPC, TMEM52B‐P20 differentially promotes metastasis. This functional discrepancy may be attributed to their distinct subcellular localization; TMEM52B‐P18 is confined to the cytoplasm, while TMEM52B‐P20 is found both at the cell membrane and in the cytoplasm. Mechanistically, cytoplasmic TMEM52B enhances AKT phosphorylation by interacting with phosphoglycerate kinase 1 (PGK1), fostering NPC growth and metastasis. Meanwhile, membrane‐localized TMEM52B‐P20 promotes E‐cadherin ubiquitination and degradation by facilitating its interaction with the E3 ubiquitin ligase NEDD4, further driving NPC metastasis. In conclusion, the TMEM52B‐P18 and TMEM52B‐P20 isoforms promote the metastasis of NPC cells through different mechanisms. Drugs targeting these TMEM52B isoforms may offer therapeutic benefits to cancer patients with varying degrees of metastasis.

Objectives: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. Methods: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. Results: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). Conclusions: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Objective: Finding biomarkers related to non-small cell lung cancer (NSCLC) is helpful for the diagnosis and precise treatment of lung cancer. The relationship between serum tumor M2-pyruvate kinase (TuM2-PK), carcinoembryonic antigen (CEA), and cytokeratin 19 fragment (CYFRA21-1) and NSCLC was analyzed. Methods: The serum levels of TuM2-PK, CEA, and CYFRA21-1 in 184 patients with the NSCLC group, 60 patients with the benign lung disease (BLD) group, and 90 healthy controls (HC) group were detected. The levels of TuM2-PK were measured by using an enzyme-linked immunosorbent assay. The detection methods of CEA and CYFRA21-1 were electrochemiluminescence. The receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic value of TuM2-PK, CEA, and CYFRA21-1 on NSCLC. The Kaplan–Meier survival curve was drawn to evaluate the survival status in NSCLC patients with different serum levels of TuM2-PK, CEA, and CYFRA21-1. Results: Serum levels of TuM2-PK, CEA, and CYFRA21-1 in the NSCLC group were significantly higher than those in the BLD group and the HC group ( P

Abstract The structural diversity of biological macromolecules in different environments contributes complexity to enzymological processes vital for cellular functions. Fluorescence resonance energy transfer and electron microscopy are used to investigate the enzymatic reaction of T4 DNA ligase catalyzing the ligation of nicked DNA. The data show that both the ligase–AMP complex and the ligase–AMP–DNA complex can have four conformations. This finding suggests the parallel occurrence of four ligation reaction pathways, each characterized by specific conformations of the ligase–AMP complex that persist in the ligase–AMP–DNA complex. Notably, these complexes have DNA bending angles of ≈0°, 20°, 60°, or 100°. The mechanism of parallel reactions challenges the conventional notion of simple sequential reaction steps occurring among multiple conformations. The results provide insights into the dynamic conformational changes and the versatile attributes of T4 DNA ligase and suggest that the parallel multiple reaction pathways may correspond to diverse T4 DNA ligase functions. This mechanism may potentially have evolved as an adaptive strategy across evolutionary history to navigate complex environments.

Abstract Background Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in “carrier” or “pathogenic” states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet. Methods In this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo‐floxed IAβ+/− mice were crossbred with Ella‐Cre and further crossbred with HLA DP401 or HLA‐DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ−/− mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108 CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice. Results We evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN‐γ and IL‐6 protein was observed in HLA DRA‐IAβ−/− mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLA DP401‐IAβ−/− mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ−/− mice and HLA DP401‐IAβ−/− mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ−/− mice and HLA DP401‐IAβ−/− mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ−/− genetic background mice. Conclusion These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection.

Abstract Objective This study aimed to investigate the efficacy and safety of PD‐1/PD‐L1 inhibitors in treatment of elderly patients with advanced non‐small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC ≥70 years old who received PD‐1/PD‐L1 inhibitors in our hospital were retrospectively analyzed. According to age, the patient were stratified as follows: 70–75 years old, 76–80 years old, and >80 years old. Kaplan–Meier method was used for survival analysis, and univariate and multivariate Cox proportional hazards regression models were used to analyze the correlation between different clinical characteristics and survival. Results A total of 58 elderly patients with advanced non‐small cell cancer were enrolled in this study. Patients aged 70–75, 76–80, and >80 years old were 32, 19, and 7, respectively. For the all, median OS was 17.0 months, and PFS was 7.0 months. PFS and OS did not differ according to age (P = 0.396, 0.054, respectively). Univariate analysis showed that PS of 0–1, stage III, first‐line therapy and irAEs were associated with longer PFS, and PS of 0–1, stage III, and first‐line therapy were associated with longer OS. Multivariate analysis showed that patients with stage III had longer PFS. PFS and OS of patients with PS ≥ 2 were significantly shorter than those of patients with PS of 0–1. Conclusions In the present real‐world retrospective cohort, PD‐1/PD‐L1 inhibitors are effective and well tolerated in elderly patients with advanced NSCLC. Immunotherapy should be actively used as early as possible in older patients advanced NSCLC.

Objective To investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for the efficacy and prognosis of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors in driver-gene-negative advanced non-small-cell lung cancer (NSCLC). Methods A retrospective analysis of 107 advanced NSCLC patients without gene mutations who received PD-1/PD-L1 inhibitors in our hospital from January 2020 to June 2022 was performed. NLR and PLR were collected before PD-1/PD-L1 inhibitors, the optimal cut-off values of NLR and PLR were determined according to the receiver operating characteristic (ROC) curve, and the effects of NLR and PLR on the efficacy of PD-1/PD-L1 inhibitors in advanced NSCLC patients were analyzed. Results A total of 107 patients were included in this study. Receiver operating characteristic analysis showed that the optimal cut-off values of NLR and PLR were 3.825, 179, respectively. Kaplan–Meier curve showed that low baseline levels NLR and PLR were associated with an improvement in both progression-free survival (PFS) ( P

Abstract Aim This study aims to investigate the relationship between two novel inflammatory markers, namely, the Systemic Inflammatory Response Index (SIRI) and the Systemic Immune Inflammatory Index (SII), as well as the all-cause and cardiovascular disease (CVD) mortality in the obese population. Materials and methods We conducted a prospective cohort study based on the data of 13,026 obese adults (age ≥ 18 years) from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 and followed until December 2019. SIRI was calculated by the formula: (neutrophil count × monocyte count) / lymphocyte count, while that of SII was: (platelet count × neutrophil count)/lymphocyte count. The association of SIRI and SII with all-cause and CVD mortality was evaluated using Cox regression. In addition, the nomogram was performed to predict 10-year survival probability. Results During a median follow-up of 137 months, 1959 and 553 all-cause and CVD deaths were recorded, respectively. Spearman correlation analysis indicated that SIRI and SII were unrelated to almost all baseline characteristics (r

Abstract Considering that no current limiting inductances (CLIs) are installed at the end of the DC line in the flexible DC distribution grid, the protections relying on line boundary are no longer applicable. To overcome this problem, the paper proposes a single‐ended protection method independent of line boundary. Firstly, the Peterson equivalent circuit is applied to analyze the amplitude‐time ratio of initial voltage travelling wave (ARIVTW) under internal and external faults. Secondly, the fault direction criterion based on the fault component current and the fault type criterion based on the pole voltage are built. Subsequently, the fault identification criterion is constructed by using the ARIVTW, and the corresponding protection method is formed. Finally, the flexible DC distribution grid is built in PSCAD to verify the proposed method. The simulation results show that the method is robust to fault resistance and noise. Besides, the method realizes the protection of the whole line, which has good selectivity and engineering applicability.

Although single-drug chemotherapy regimens were used as second-line chemotherapy for advanced lung squamous cell carcinoma (LSCC) patients, there are still no standard guidelines for second-line chemotherapy. The purpose of this study was to compare the efficacy and safety of docetaxel combined with nedaplatin or carboplatin in the second-line treatment of advanced LSCC patients. One hundred and ninety-six LSCC patients receiving docetaxel plus nedaplatin (DN, n = 96) or carboplatin (DC, n = 100) were retrospectively collected until disease progression or unacceptable toxicity. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed in the two groups. The ORR was 18.8% versus 16.0%, and the DCR was 39.6% versus 34.0% in DN group and DC group ( P > .05 and P > .05), respectively. The PFS was 5.3 versus 3.8 months, and the OS was 8.5 and 6.7 months in DN group and DC group ( P = .013 and P = .404), respectively. The rate of digestive reaction and hepatotoxicity was similar in DN and DC groups, whereas more patients in DC group than in DN group suffered from leucopenia ( P

ObjectiveWhether neutrophil-lymphocyte ratio (NLR) is an applicative predictor of poor prognosis in patients with hepatocellular carcinoma (HCC) remains controversial. In response to the current conflicting data, this meta-analysis was conducted to gain a comprehensive and systematic understanding of prognostic value of NLR in HCC.MethodsSeveral English databases, including PubMed, EMBASE, and the Cochrane Library, with an update date of February 25, 2023, were systematically searched. We set the inclusion criteria to include randomized controlled trial (RCT) studies that reported the prognostic value of serum NLR levels in patients with HCC receiving treatment. Both the combined ratio (OR) and the diagnosis ratio (DOR) were used to assess the prognostic performance of NLR. Additionally, we completed the risk of bias assessment by Cochrane Risk of Bias Assessment Tool.ResultsThis meta-analysis ultimately included 16 studies with a total of 4654 patients with HCC. The results showed that high baseline NLR was significantly associated with poor prognosis or recurrence of HCC. The sensitivity of 0.67 (95% confidence interval [CI]. 0.59-0.73); specificity of 0.723 (95% CI: 0.64-0.78) and DOR of 5.0 (95% CI: 4.0-7.0) were pooled estimated from patient-based analyses. Subsequently, the combined positive likelihood ratio (PLR) and negative likelihood ratio (NLHR) were calculated with the results of 2.4 (95% CI: 1.9-3.0) and 0.46 (95% CI: 0.39-0.56), respectively. In addition, area under the curve (AUC) of the summary receiver operating characteristic (SROC) reflecting prognostic accuracy was calculated to be 0.75 (95% CI: 0.71-0.78). The results of subgroup analysis suggested that high NLR was an effective predictive factor of poor prognosis in HCC in mainland China as well as in the northern region.ConclusionOur findings suggest that high baseline NLR is an excellent predictor of poor prognosis or relapse in patients with HCC, especially those from high-incidence East Asian populations.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42023440640.

ObjectiveTo investigate the effect of hemoglobin, albumin, lymphocytes, platelet (HALP) score and platelet to albumin ratio (PAR) on prognosis of patients with lung adenosquamous carcinoma (ASC) after surgery.Patients and methodsA total of 52 patients diagnosed with ASC after surgical resection were collected from Nanjing Chest Hospital from 2012 to 2021, and their general clinical data, pathological data and laboratory indexes were collected. The changes of Alb and Plt levels before and after surgery, HALP scores (hemoglobin albumin lymphocytes/platelets), and postoperative PAR, PLR, NLR were retrospectively analyzed, and their influence on the prognosis of patients with ASC was investigated. The cut-off value of △Alb, △Plt, postoperative PAR, PLR and NLR were determined by the receiver operating characteristic (ROC) curve, the optimal cut-off value of HALP score before and after surgery was calculated by using X-tile software, and the clinicopathological characteristics were compared between the high PAR and low PAR groups and between high HALP score and low HALP score group to analyze the factors influencing the prognosis of patients with ASC. Univariate and multivariate Cox proportional regression analyses were used to assess independent risk factors affecting overall survival (OS) and disease-free survival (DFS) in patients with ASC. Kaplan-Meier method was used to evaluate the correlation between OS, DFS and PAR and HALP score.ResultsA critical value of PAR was 7.40×10^9 and an area under the curve (AUC) of 0.737 (95%CI: 0.597-0.876, P = 0.004). The best cut-off value of the preoperative HALP score was 24.3. Univariate Cox analysis showed that the cut margin (P = 0.013), the degree of differentiation (P = 0.021), N stage (P = 0.049), △Plt (P = 0.010), △Alb (P = 0.016), PAR (P = 0.003), NLR (P = 0.025), PLR (P = 0.029), preoperative HALP score (P = 0.000) and post-operative HALP score (P = 0.010) were all associated with postoperative OS in ASC patients. Cut margin (P = 0.029), the degree of differentiation (P = 0.045), maximum tumor diameter (P = 0.018), N stage (P = 0.035), △Plt (P = 0.007), △Alb (P = 0.007), PAR (P = 0.004), NLR (P = 0.041), PLR (P = 0.030), preoperative HALP score (P = 0.000), and postoperative HALP score (P = 0.011) were related to postoperative DFS in ASC patients. Multivariate analysis revealed that PAR (HR: 6.877, 95%CI: 1.817-26.038, P = 0.005), differentiation degree (HR: 0.059, 95%CI: 0.006-0.591, P = 0.016) and preoperative HALP score (HR: 0.224, 95%CI: 0.068-0.733, P = 0.013) had significant effect on OS. Tumor maximum diameter (HR: 3.442, 95%CI: 1.148-10.318, P = 0.027) and preoperative HALP score (HR: 0.268, 95%CI: 0.085-0.847, P = 0.025) had significant influence on DFS.ConclusionPAR and preoperative HALP score were potentially useful biomarkers for evaluating the outcome of patients with postoperative ASC. PAR, the degree of differentiation and preoperative HALP score were independent prognostic factors for postoperative OS in ASC patients. Maximum tumor diameter and preoperative HALP score were independent prognostic factors for postoperative DFS in ASC patients.

This study examined the role of pretreatment albumin-to-fibrinogen ratio (AFR) in the prognosis of small-cell lung cancer (SCLC) patients receiving first-line platinum-based chemotherapy. A total of 131 SCLC patients were enrolled. The predictive value of the AFR for progression free survival (PFS) and overall survival (OS) were evaluated by receiver operating characteristic (ROC) curve analysis. The predictive factor of survival was assessed by univariate and multivariate Cox proportional regression analysis. The correlation between OS, PFS and AFR was determined by the log-rank test using the Kaplan-Meier method. AFR was an effective predictor of OS in SCLC patients with a cut-off value of 7.78. AFR was independent risk factors for OS and PFS. Kaplan Meier analysis showed that PFS and OS in patients with high AFR levels were significantly higher than those with low AFR levels. These results suggest that AFR could be an effective predictor of survival in patients with SCLC.

Abstract Background Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with different subtypes, multidisciplinary teams-led management, and a poor prognosis. Currently, the clinical benefits of stage III NSCLC in the neoadjuvant setting are still unclear. We performed a meta-analysis of published data on neoadjuvant chemoimmunotherapy in stage III NSCLC to systematically evaluate its efficacy and safety. Methods We searched the databases to identify eligible studies of neoadjuvant chemoimmunotherapy for stage III NSCLC. The primary outcomes mainly included pathological and radiological response outcomes, the feasibility of surgery, and the safety of the regimen. The pathological and radiological response included the rate of major pathologic response (MPR), complete pathologic response (pCR), radiological response outcomes, and R0 resection; The feasibility included the rate of surgical resection, conversion to thoracotomy, surgical complications, pathological downstaging of clinical disease stage. The safety included the incidence of treatment-related adverse events (TRAEs) and severe adverse events (SAEs). R 4.1.3 software was conducted for data analysis, and p

Abstract Background Immune checkpoint inhibitors (ICIs) have dramatically prolonged survival in non-small cell lung cancer (NSCLC) patients, but little research had focused on its impact on quality of life (QoL). The purpose of our study was to compare the QoL in patients with NSCLC treated with programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors versus chemotherapy. Methods We searched for randomized controlled trials utilizing the Quality of Life Questionnaire Core 30 items (QLQ-C30) and the EuroQol Five Dimensions Questionnaire-3L (EQ-5D-3L) to assess the QoL of NSCLC treated with PD-1/PD-L1 inhibitors versus chemotherapy. We collected hazard ratios (HRs) for the time from baseline to the first clinically significant deterioration (TTD) and effect size as the difference in mean change between and within treatment groups in patients’ reported outcomes (PROs). (PROSPERO registration number: CRD42022296680). Results In the five trials reported by QLQ-C30, TTD was longer in PD-1/PD-L1 inhibitors compared with control groups (HR = 0.86; 95% CI = 0.76, 0.97; P = 0.013), with similar results in terms of physical function, role function, and pain. The difference in mean change between the PD-1/PD-L1 inhibitors group and the chemotherapy group in QLQ-C30 and EQ-5D VAS was 3.64 (95% CI = 1.62, 5.66; P = 0.001) and 4.74 (95% CI = 2.65, 6.83; P = 0.001), which supported PD-1/PD-L1 inhibitors. However, for the EQ-5D utility index, there was no statistically significant difference between the two groups, with a mean change difference of 0.03 (95% CI = −0.01, 0.07; P = 0.094). The mean change from baseline to follow-up in PD-1/PD-L1 inhibitors group was 2.57 (95% CI = 0.43, 4.71; P = 0.019), and chemotherapy group was −1.31 (95% CI = −3.71, 1.09; P = 0.284), correspondingly. The subgroup analysis showed that no difference was observed between open-label and double-blind trials in patients treated with chemotherapy or PD-1/PD-L1 inhibitors. Conclusion In conclusion, PD-1/PD-L1 inhibitors could improve the QoL of patients with NSCLC compared to chemotherapy and reduce unfavorable symptoms during treatment.

BackgroundSignificant evidence suggests that asthma might originate from low-grade systemic inflammation. Previous studies have established a positive association between the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI) levels and the risk of stroke. However, it remains unclear whether SII, SIRI and the prevalence of stroke are related in individuals with asthma.MethodsThe present cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. SII was calculated using the following formula: (platelet count × neutrophil count)/lymphocyte count. SIRI was calculated using the following formula: (neutrophil count × monocyte count)/lymphocyte count. The Spearman rank correlation coefficient was used to determine any correlation between SII, SIRI, and the baseline characteristics. Survey-weighted logistic regression was employed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to determine the association between SII, SIRI, and stroke prevalence. The predictive value of SII and SIRI for stroke prevalence was assessed through receiver operating characteristic (ROC) curve analysis, with the area under the ROC curve (AUC) being indicative of its predictive value. Additionally, clinical models including SIRI, coronary heart disease, hypertension, age, and poverty income ratio were constructed to evaluate their clinical applicability.ResultsBetween 1999 and 2018, 5,907 NHANES participants with asthma were identified, of which 199 participants experienced a stroke, while the remaining 5,708 participants had not. Spearman rank correlation analysis indicated that neither SII nor SIRI levels exhibited any significant correlation with the baseline characteristics of the participants (r

Abstract Cripto‐1 (CR‐1) facilitates vascular endothelial growth factor (VEGF) expression, and these markers are associated with various tumor cell proliferation, angiogenesis, and metastasis. The main aim of our study was to investigate the clinical value of CR‐1 and VEGF for non‐small cell lung cancer (NSCLC) patients. Serum samples were collected from 312 patients with NSCLC and 120 healthy controls. The levels of CR‐1 and VEGF were measured by enzyme‐linked immunosorbent assay (ELISA). The serum levels of CR‐1 and VEGF in NSCLC patients were significantly higher than those of healthy controls (p

Abstract Objective To evaluate the diagnostic value of tumor M2-pyruvate kinase (TuM2-PK) and carcinoembryonic antigen (CEA) levels in both pleural effusion and serum in the differential diagnosis of benign and malignant pleural effusion. Methods This prospective study was conducted among 80 patients with benign pleural effusion (BPE group) and 125 patients with malignant pleural effusion associated with lung cancer (MPE group). The levels of TuM2-PK and CEA were measured by using sandwich enzyme-linked immunosorbent assay and electrochemiluminescence. The receiver-operating characteristic curve (ROC) analysis was used to confirm the cutoff value to evaluate the diagnostic efficiency of TuM2-PK and CEA. Results The TuM2-PK and CEA levels in pleural effusion and serum, and their ratio (P/S) were higher in MPE group than that in BPE group (P

Abstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. Methods KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. Results In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. Conclusions Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK + NSCLC refractory to earlier-generation ALK inhibitors. Trial registration Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

Laboratory analysis of returned Chang’E-5 samples from the lunar surface show their hydroxyl contents to be on the weak end of lunar hydration features.

IntroductionCerebral sparganosis is a rare parasitic infection of the brain tissue. The remission of MRI change and clinical symptom has been used to evaluate the therapeutic effect. However, there is no study to correlate the serum IgG antibody level of sparganum to the prognosis of disease after treatment. Methods87 patients with cerebral sparganosis were collected from three medical centers. Clinical symptoms and MRI changes were evaluated at 12 months after initial treatment, and serum IgG antibody level of sparganum was evaluated at 2, 6, and 12 months after treatment. The positive cut-off value was based on 2.1 times the optical density (OD) of negative control. The index value was defined as the sample OD divided by the cut-off value.ResultsAmong the 87 patients after treatment, 71 patients had good clinical outcomes, and 16 had poor clinical outcomes. The area under the curve (AUC) showed that the index value measured at 12 months after treatment had the best prediction effect, with a value of 2.014. In the good-outcome group, the index values were less than 2.014 in all 71 patients, and only 8 patients had mildly enhanced residual lesions on MRI. In the poor-outcome group, the index values were more than 2.014 in all 16 patients, and all patients still showed significantly enhanced lesions on MRI. Compared with poor-outcome patients, only 2 patients with good outcomes had disease recurrence after treatment.DiscussionThis study provided evidence that the serum IgG antibody level of sparganum was a promising biomarker to evaluate the prognosis of patients with cerebral sparganosis after treatment.

Abstract Background The incidence of sparganosis, especially intracranial live sparganosis is very low in China. Due to the lack of typical clinical manifestations, it is difficult to make a clear preoperative diagnosis of the disease, which often leads to delays the disease and serious consequences. Case presentation A 23-year-old man presented with a 17-year history of intermittent seizures and right extremity numbness and weakness. Magnetic resonance imaging (MRI) showed patchy, nodular and line-like enhancement. Enzyme-linked immunosorbent assay (ELISA) detected positive antibodies to Spirometra mansoni in peripheral blood and cerebrospinal fluid (CSF). In addition, during the operation, an ivory-colored live sparganosis was removed under the precise positioning of neuronavigation, and the patient was diagnosed with cerebral sparganosis. The patient began praziquantel and sodium valproate treatment after the operation, and was followed up for 3 months. There was no recurrence of epilepsy, and the weakness and numbness of the right limb improved. Conclusion Nonspecific clinical manifestations often make the diagnosis of cerebral sparganosis difficult, and a comprehensive diagnosis should be made based on epidemiological history, clinical manifestations, ELISA results and imaging findings. Surgery is the preferred method for the treatment of cerebral sparganosis, and more satisfactory results can be achieved under the precise positioning of neuronavigation.

Nanoparticles represent an interesting platform that demonstrates properties absent from bulk materials. Although the employment of nanoparticles for environmental remediation has attracted tremendous attentions in both scientific research and industrial applications, there is still a huge gap between the clear mechanism understandings and their deliverable activities due to the complex reaction kinetics. Herein, we report the synthesis of high-quality, monodispersed Cu7S4 nanoparticles as a model nano system to investigate the degradation mechanism of organic pollutants. The morphology, chemical composition and atomic structure of the as-prepared Cu7S4 have been characterized by Transmission Electron Microscope (TEM), X-ray photoelectron spectroscopy (XPS), X-ray powder diffractometer (XRPD) and Fourier transform infrared spectra (FT-IR). In addition, it is revealed that the Cu7S4 particles can effectively degrade organic pollutants, like Orange I and Orange II through a slow and controllable release of Cu cations process coupled with surface catalysis. The detailed study shows that the small amounts of released Cu cations from Cu7S4 nanoparticles are first coordinated with the organic pollutants and the resultant complexes are then degraded on the surface of nanoparticles in the presence of H2O2.

The flexible DC distribution grid is suitable for distributed energy resource integration and DC load power supply. However, the fast-increasing fault current has a great impact on the system when a short circuit fault occurs. Besides, the existing main protections are easily affected by high resistance faults and converters. To solve the aforementioned problems, a pilot protection method using frequency domain (FD) impedance was proposed. Firstly, a direction criterion based on the polarity of FD reactance is constructed to identify the reverse fault. Furthermore, the values of FD reactance and resistance are used to distinguish the forward internal and external faults. The method uses only local information to identify the close-up fault, and the pilot protection criterion to identify the remote-end or high resistance faults. This combination of single-end and pilot protection criteria makes the method have high reliability and fast speed. Moreover, no data synchronization is needed. Finally, extensive simulations were utilized to verify the effectiveness of the proposed method.

Gram-negative bacteria are major pathogens that can cause illnesses in giant pandas. Lipopolysaccharides (LPS), components of Gram-negative bacteria, can activate immune responses in mammals (i.e., humans and mice) through recognition by toll-like receptors (TLRs). However, the giant pandas’ immune response to LPS stimulation and the differences between the giant panda and other mammals are not fully known. In this study, we administrated peripheral blood mononuclear cells (PBMCs) from giant pandas, humans, C57BL/6 mice, and rhesus monkeys by LPS treatment at 6 h followed by RNA sequencing (RNA-seq), respectively, with control of non-stimulation. KEGG analyses of differentially expressed genes (DEGs) pathways indicated that LPS could activate the classic signaling pathway of NF-κB in PBMCs from those four tested species. Thus, similar to the other three species, NF-κB is an LPS-responsive regulator of innate immune responses in giant pandas. Furthermore, the expression patterns of adapter genes, inflammatory cytokine genes, chemokines, interferon genes, cytokine genes related to cell growth and development, costimulatory molecules, Th1/Th2 cytokine genes, Th17 cytokine genes, Th9, and Th22 cytokine genes were compared among giant pandas and three other species. Our data indicated that in addition to the similar expression patterns of certain genes among giant pandas and other species, the unique expression pattern response to LPS in giant pandas was also discovered. Furthermore, Th9, Th17, and Th22 cells might be involved in the response to LPS in giant pandas at this tested time point. This study reveals that LPS-induced immune responses have different sensitivities and response timelines in giant pandas compared with other mammals. This study facilitates further understanding of the role of the TLR signaling pathway and the immune system in giant pandas, which might be helpful for disease prevention and protection.

ObjectiveInvasive lung adenocarcinoma is composed of five different histological subgroups with diverse biological behavior and heterogeneous morphology, the acinar/papillary-predominant lung adenocarcinomas are the most common subgroups and recognized as an intermediate-grade group. In the real world, clinicians primarily consider predominant patterns and ignore the impact of minor components in the prognosis of lung adenocarcinoma. The study evaluated the clinicopathologic characteristics of the lepidic, solid, and micropapillary patterns as non-predominant components and whether the minimal patterns had prognostic value on acinar/papillary-predominant lung adenocarcinomas.MethodsA total of 153 acinar/papillary-predominant lung adenocarcinoma patients with tumor size ≤4 cm were classified into four risk subgroups based on the presence of lepidic and micropapillary/solid components: MP/S−Lep+, MP/S+Lep+, MP/S−Lep−, and MP/S+Lep− groups. The Cox-proportional hazard regression model was used to assess disease-free survival (DFS).ResultsThe risk subgroups based on the non-predominant patterns were associated with differentiation (P = 0.001), lymphovascular invasion (P = 0.001), and recurrence (P = 0.003). In univariate analysis, DFS was correlated with non-predominant components (P = 0.014), lymphovascular invasion (P = 0.001), carcinoembryonic antigen (CEA) (P = 0.001), and platelet-to-lymphocyte ratio (PLR) (P = 0.012). In the multivariate analysis, non-predominant components (P = 0.043) and PLR (P = 0.032) were independent prognostic factors for DFS. The 5-year survival rates of MP/S−Lep+, MP/S+Lep+, MP/S−Lep− and MP/S+Lep− subgroups were 93.1%,92.9%,73.1%,61.9%, respectively. The MP/S−Lep+ subgroup had the favorable prognosis than MP/S+Lep− subgroup with a statistically significant difference (P = 0.002). As minor components, the lepidic patterns were a protective factor, and the solid and micropapillary components were poor factors. The recurrence was related to the presence of non-predominant patterns rather than their proportion. Adjuvant chemotherapy did not significantly improve the prognosis of the MP/S+Lep- subgroup (P = 0.839).ConclusionsRegardless of the proportion, the presence of micropapillary/solid components and the absence of lepidic patterns are aggressive factors of DFS in patients with resected stage I acinar- or papillary-predominant lung adenocarcinoma.

BackgroundPatients with severe acute kidney injury (AKI) may require renal replacement therapy (RRT), such as hemodialysis and peritoneal dialysis. Neutrophil gelatinase-associated lipocalin (NGAL) is a sensitive indicator for early diagnosis and recognition of AKI; however, its predictive value of AKI-associated need for RRT needs further evaluation.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, relevant articles were systematically searched and selected from seven databases. The random effects model was applied to evaluate the predictive performance of NGAL for AKI requiring RRT. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of each included study.ResultsA total of 18 studies including 1,787 patients with AKI and having an average NOS score of 7.67 were included in the meta-analysis. For plasma/serum NGAL, the pooled sensitivity and specificity with corresponding 95% confidence interval (CI) were 0.75 (95% CI: 0.68–0.81) and 0.76 (95% CI: 0.70–0.81), respectively. The pooled positive likelihood ratio (PLR) was 2.9 (95% CI: 2.1–4.1), and the pooled negative likelihood ratio (NLR) was 0.34 (95% CI: 0.25–0.46). Subsequently, the pooled diagnostic odds ratio (DOR) was 9 (95% CI: 5–16) using a random effects model, and the area under the curve (AUC) of summary receiver operating characteristic to summarize predictive accuracy was 0.82 (95% CI: 0.79–0.85). For urine NGAL, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC values were 0.78 (95% CI: 0.61–0.90), 0.77 (95% CI: 0.65–0.85), 3.4 (95% CI: 2.4–4.8), 0.28 (95% CI: 0.15–0.52), 12 (95% CI: 6–24), and 0.84 (95% CI: 0.80–0.87), respectively.ConclusionPlasma/serum and urine NGAL levels performed comparably well in predicting AKI requiring RRT. Our findings suggested that NGAL is an effective predictive biomarker for the AKI-associated need for RRT. Nevertheless, more pieces of high-quality evidence and future trials with larger sample sizes are needed for further improvement of patient outcomes.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022346595], identifier [CRD42022346595].

Objective: To investigate the value of computed tomography-guided percutaneous lung biopsy (CT-PLB) combined with rapid on-site evaluation (ROSE) in the diagnosis of peripheral pulmonary lesions (PPLs). Methods: A total of 108 patients who diagnosed with PPLs by chest CT examination were prospectively collected and randomly divided into ROSE group (n = 56) and No-ROSE group (n = 52). Both groups received CT-PLB and pathological examination. The smear submitted for ROSE was stained using Diff Quik dye. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), number of punctures, puncture time and incidence of complications were compared between the two groups. Results: The accuracy, sensitivity, specificity, PPV, and NPV of the ROSE group were 89.29%, 87.50%, 91.67%, 93.33%, and 84.62%, respectively. The number of punctures in the ROSE group was significantly lower than that in the No-ROSE group ( P .05). ROSE has good concordance with routine pathological examination in the diagnosis of unidentified PPLs (Kappa = 0.786, P

C12orf59 is a novel gene widely expressed in diverse normal human tissues. Aberrant expression of C12orf59, which is involved in tumor progression, has been reported in a few types of cancer. However, its expression and biological function in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that the mRNA and protein levels of C12orf59 were prominently higher in both tumor tissues and most ESCC cell lines. Functionally, C12orf59 overexpression promoted ESCC cell proliferation, migration and invasion, whereas C12orf59 depletion worked oppositely. Mechanistically, C12orf59 exerted its oncogenic function through the induction of epithelial-mesenchymal transition (EMT) of ESCC cells, which relied on Yes-associated protein (YAP) dephosphorylation and nuclear translocation. Constitutively active YAP further facilitated cell migration, invasion and EMT induced by enforced C12orf59 overexpression. On the contrary, increased cell motility and EMT caused by enforced C12orf59 overexpression were dramatically repressed upon YAP inactivation by verteporfin. Thus, we conclude that YAP activation driven by C12orf59 contributes to the malignancy of ESCC through EMT and that targeting drugs for C12orf59 combined with YAP inhibitor may be a potential therapeutic strategy for ESCC.

Aiming at the problem of matching and optimization of the power transmission system of two-speed electric vehicles， according to the design parameters and target requirements of the whole vehicle， the power matching of the core components such as the drive motor， power battery， and transmission of the pure electric vehicle is carried out through theoretical calculations， and by using the Cruise simulation software， the vehicle model of the target vehicle is established， and the matching result is simulated and verified. On the premise that the dynamic performance meets the design requirements， in order to further improve the economy， a joint simulation model of Cruise and Isight is built， and an improved non-dominated sorting genetic algorithm （NSGA-Ⅱ） is adopted to optimize the transmission ratio of the transmission system with multiple objectives to achieve the best solution for power and economy. The optimization results show that the power consumption under the optimized NEDC （New european driving cycle） cycle is reduced by 0.38 kWh/100 km， and the economy is increased by 2.4%. The acceleration time of 0~100 km/h is reduced by 0.95 s compared with that before the optimization， and the power performance increased by 7.5%.

Abstract Background Osteopontin (OPN) is closely related to tumor occurrence and metastasis. This study explored the clinical value of serum OPN levels in small cell lung cancer (SCLC) patients. Methods The ELISA method was used to determine the OPN level of 96 SCLC patients before and after first-line chemotherapy, and compared with 60 healthy controls. Results The serum OPN level of SCLC patients before treatment was significantly higher than that of the healthy control (P

Purpose. To explore the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in stage I non-small-cell lung cancer (NSCLC) undergoing surgery. Patients and Methods. Between 2014 and 2016, a total of 190 patients with postoperative pathology of stage I NSCLC who underwent radical surgery at Nanjing Chest Hospital were studied. Clinical data were analyzed and classified into low-risk, moderate-risk, and high-risk groups based on independent risk factors to assess the prognosis. Results. NLR was associated with histological type and gender, and patients with an elevated NLR have poor overall survival (OS). Lymphovascular invasion, red blood cell distribution width-standard deviation (RDW-SD), and carcinoembryonic antigen (CEA) were independent prognostic factors for progression-free survival (PFS) in postoperative patients with stage I NSCLC, while NLR, RDW-SD, and CEA were independent risk factors for OS. Both PFS and OS were shorter in the low-risk group than in the medium-risk and high-risk groups. Conclusions. NLR, RDW-SD, CEA, and lymphovascular invasion are independent risk factors for postoperative prognosis in patients with stage I NSCLC, and the combination has a predictive value.

Summary: The RecQ family of helicases are important for maintenance of genomic integrity. Although functions of constructive subdomains of this family of helicases have been extensively studied, the helical hairpin (HH) in the RecQ-C-terminal domain (RQC) has been underappreciated and remains poorly understood. Here by using single-molecule fluorescence resonance energy transfer, we found that HH in the human BLM transiently intercepts different numbers of nucleotides when it is unwinding a double-stranded DNA. Single-site mutations in HH that disrupt hydrogen bonds and/or salt bridges between DNA and HH change the DNA binding conformations and the unwinding features significantly. Our results, together with recent clinical tests that correlate single-site mutations in HH of human BLM with the phenotype of cancer-predisposing syndrome or Bloom's syndrome, implicate pivotal roles of HH in BLM's DNA unwinding activity. Similar mechanisms might also apply to other RecQ family helicases, calling for more attention to the RQC helical hairpin.

Abstract In order to explore the effect of different the welding heat input on microstructure and impact properties in coarse grain zone in heat affected zone (CGHAZ) of ultra-low carbon bainitic steel welded joint. In this paper, Gleeble-3500 thermal simulation testing machine was used to simulate different heat input, to study the effect of linear energy on the microstructure and impact toughness of the CGHAZ of Q420qEN steel joint. The scanning electron microscope (SEM), oscillographic impact microscope and transmission electron microscope (TEM) were used. The results show that the microstructure of CGHAZ is mainly the lath bainite and granular bainite. When the welding heat input is 30kJ•cm-1, the CGHAZ grains have obvious growth phenomenon. With the increase of the welding heat input, the grain size also grows. Meanwhile, as the welding heat input increases from 18kJ•cm-1 to 30kJ•cm-1, the impact toughness of the CGHAZ of joint increases first and then decreases at -20°C.

Background: Small cell lung cancer (SCLC) is a type of highly malignant tumor. It is easy to relapse and high resistant to second-line chemotherapy. There is not a standard plan for third-line and subsequent-line treatment, hence the current study aimed to explore the performance of nanoparticle albumin bound paclitaxel (Nab-P) in the third-line treatment of recurrent SCLC. Methods: A retrospective analysis of pathologically confirmed third-line SCLC patients was conducted to observe the efficacy and adverse reactions of Nab-P treatment. Results: Among the 37 SCLC patients included in the study, objective response rate was 24.32%, and disease control rate was 81.08%. The main adverse reactions were gastrointestinal reactions, bone marrow suppression, muscle and joint aches and fatigue. Adverse reactions ≥ level 3 included leukopenia & neutropenia (24.32%), thrombocytopenia (5.41%) and anemia (2.70%). Conclusions: As a single-agent third-line treatment for patients with relapsed SCLC, Nab-P was effective and safe.

A pandemic of coronavirus diseases 2019 (COVID-19) outbreak is a major public health emergency that has spread in the fastest speed, and caused the most extensive infection world widely. Transbronchial biopsy (TBB) and computed tomography guided percutaneous needle biopsy (CTPNB) is the most common and significant method for the diagnosis of lung cancer. During the COVID-19 pandemic, the indications of TBB and CTPNB must be managed strictly. Therefore, it is extremely indispensable to perform meticulous and individualized management for lung cancer patients to protect the patients from COVID-19.

Pulmonary actinomycosis (PA) is an uncommon pulmonary infectious disease that often is misdiagnosed. Metagenomic next-generation sequencing (mNGS) is a highly sensitive and culture-independent new molecular technology for precise infectious disease diagnosis. Here we report a PA case diagnosed by the combination of a radial endobronchial-ultrasonography guide sheath (R-EBUS-GS) and mNGS, along with a brief review of the literature.

Abstract Background More than 100 different pathogens can cause encephalitis. Testing of all the neurological pathogens by conventional methods can be difficult. Metagenomic next-generation sequencing (NGS) could identify the infectious agents in a target-independent manner. The role of this novel method in clinical diagnostic microbiology still needs to be evaluated. In present study, we used metagenomic NGS to search for an infectious etiology in a human immunodeficiency virus (HIV)-infected patient with lethally diffuse brain lesions. Sequences mapping to Toxoplasma gondii were unexpectedly detected. Case presentation A 31-year-old HIV-infected patient presented to hospital in a critical ill condition with a Glasgow coma scale score of 3. Brain magnetic resonance imaging showed diffuse brain abnormalities with contrast enhancement. Metagenomic NGS was performed on DNA extract from 300 μL patient’s cerebrospinal fluid (CSF) with the BGISEQ-50 platform. The sequencing detection identified 65,357 sequence reads uniquely aligned to the Toxoplasma gondii genome. Presence of Toxoplasma gondii genome in CSF was further verified by Toxoplasma gondii-specific polymerase chain reaction and Sanger sequencing. Altogether, those results confirmed the diagnosis of toxoplasmic encephalitis. Conclusions This study suggests that metagenomic NGS may be a useful diagnostic tool for toxoplasmic encephalitis. As metagenomic NGS is able to identify all pathogens in a single run, it may be a promising strategy to explore the clinical causative pathogens in central nervous system infections with atypical features.

Municipal solid waste (MSW) management is one of the most important issues in urban environments, especially in developing countries. In this work, a comprehensive assessment framework for MSW management is proposed to evaluate and screen the optimal scenario. The best-worst method (BWM) is utilized to determine the optimal weight of each criterion for each disposal scenario. However, the original BWM model is difficult to be solved globally. A linear model is presented to solve the model and an interval model is employed to verify the optimality of the linear model. The results indicate that the results of the linear model and interval model are consistent. A case study of MSW disposal in Qingdao City is used to demonstrate the application of the proposed method. The results indicate that a combination of landfilling, incineration technology with energy recovery facility is preferred for the current MSW management in Qingdao from the chosen criteria. The framework proposed in this work can be assisted to help the decision-makers to identify the priority sequence of MSW management scenarios.

Objectives To evaluate the value of rapid on-site evaluation (ROSE) during radial probe endobronchial ultrasound transbronchial lung biopsy (rpEBUS-TBLB) for peripheral pulmonary lesions (PPLs). Methods One hundred and six patients with PPLs who received rpEBUS-TBLB were enrolled in this study. One specimen was immediately examined by ROSE and the other was sent to the central laboratory for cytologic diagnosis. The results of ROSE were compared with those of pathological diagnosis. Results The diagnostic accuracy, sensitivity, and specificity of ROSE during rpEBUS-TBLB for PPLs were 82.1%, 89.6%, and 77.1%, respectively. The procedure times and number of biopsies were less for procedures when ROSE was positive compared with those when ROSE was negative (procedure time: 20.5 ± 7.9 vs. 28.3 ± 7.6 minutes; number of biopsies: 1.6 ± 0.9 vs. 2.8 ± 0.6 times). No serious procedural complications were observed. Conclusions ROSE has value for diagnosing PPLs during rpEBUS. It can reduce procedure time, number of biopsies, and complications. ROSE combined with rpEBUS is an effective and safe method for the diagnosis of PPLs.

T cells play a critical role in coronavirus diseases. How they do so in COVID-19 may be revealed by analyzing the epigenetic chromatin accessibility of cis- and trans-regulatory elements and creating transcriptomic immune profiles. We performed single-cell assay for transposase-accessible chromatin (scATAC) and single-cell RNA (scRNA) sequencing (seq) on the peripheral blood mononuclear cells (PBMCs) of severely ill/critical patients (SCPs) infected with COVID-19, moderate patients (MPs), and healthy volunteer controls (HCs). About 76,570 and 107,862 single cells were used, respectively, for analyzing the characteristics of chromatin accessibility and transcriptomic immune profiles by the application of scATAC-seq (nine cases) and scRNA-seq (15 cases). The scATAC-seq detected 28,535 different peaks in the three groups; among these peaks, 41.6 and 10.7% were located in the promoter and enhancer regions, respectively. Compared to HCs, among the peak-located genes in the total T cells and its subsets, CD4+ T and CD8+ T cells, from SCPs and MPs were enriched with inflammatory pathways, such as mitogen-activated protein kinase (MAPK) signaling pathway and tumor necrosis factor (TNF) signaling pathway. The motifs of TBX21 were less accessible in the CD4+ T cells of SCPs compared with those in MPs. Furthermore, the scRNA-seq showed that the proportion of T cells, especially the CD4+ T cells, was decreased in SCPs and MPs compared with those in HCs. Transcriptomic results revealed that histone-related genes, and inflammatory genes, such as NFKBIA, S100A9, and PIK3R1, were highly expressed in the total T cells, CD4+ T and CD8+ T cells, both in the cases of SCPs and MPs. In the CD4+ T cells, decreased T helper-1 (Th1) cells were observed in SCPs and MPs. In the CD8+T cells, activation markers, such as CD69 and HLA class II genes (HLA-DRA, HLA-DRB1, and HLA-DRB5), were significantly upregulated in SCPs. An integrated analysis of the data from scATAC-seq and scRNA-seq showed some consistency between the approaches. Cumulatively, we have generated a landscape of chromatin epigenetic status and transcriptomic immune profiles of T cells in patients with COVID-19. This has provided a deeper dissection of the characteristics of the T cells involved at a higher resolution than from previously obtained data merely by the scRNA-seq analysis. Our data led us to suggest that the T-cell inflammatory states accompanied with defective functions in the CD4+ T cells of SCPs may be the key factors for determining the pathogenesis of and recovery from COVID-19.

Objective: X-ray guided transbronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) can improve the diagnostic yield of peripheral pulmonary lesions (PPLs), but it needs special requirements. The purpose of this study was to investigate the clinical value of virtual bronchoscopy navigation (VBN) combined with EBUS-TBLB in the diagnosis of PPLs without X-ray guidance. Methods: The 105 patients with PPLs underwent EBUS-TBLB with or without VBN randomly. The diagnostic yield, the operation time and complications were evaluated in the 2 groups. Results: No significant difference was found between the VBN+EBUS group and the EBUS group (76.0% vs. 65.5%, P = 0.287). The operation time of VBN+EBUS group was significantly shorter than that of EBUS group (20.6 ± 12.8 min vs. 28.6 ± 14.3 min, P = 0.023). No severe procedure related complications occurred. Conclusions: VBN can shorten the operation time. The combination of VBN and EBUS-TBLB is a safe and effective diagnosis technique for PPLs.

Objective: To evaluate the diagnostic value of radial endobronchial ultrasound (R-EBUS) combination with rapid on-site evaluation (ROSE) guided transbronchial lung biopsy (TBLB) for peripheral pulmonary lesions. Methods: Peripheral pulmonary lesions identified by computed tomography underwent R-EBUS with or without ROSE randomly from February 2016 to August 2017. The diagnostic yield and the operation time were compared. Results: In total, 158 patients were involved in and completed this research, including 84 cases in the group of R-EBUS with ROSE, and 74 in the group without ROSE. The diagnostic yield of ROSE group was 85.7%. Among these positive cases, 69.4% cases were malignant tumors, and 30.6% cases were benign lesions. The operation time was (24.6 ± 6.3) min. In the group without ROSE, the diagnostic yield was 70.3%, including 35 malignant tumors (67.3%), and 17 benign lesions (32.7%). The operation time was (31.5 ± 6.8) min. There were significant differences between both groups in the diagnostic yield (χ2 = 5.556, P = 0.018) and in the operation time (t = 3.187, P < 0.01). No serious procedure related complications were observed, such as pneumothorax and hemorrhage. Conclusion: ROSE can improve the diagnostic yield, and shorten the operation time. R-EBUS combined with ROSE is a safe and effective technique for peripheral pulmonary lesions.

Abstract The avian origin influenza A virus (IAV) H7N9 has caused a considerable number of human infections associated with high rates of death since its emergence in 2013. As a vital component of the host innate immune system, the nucleotide-binding domain leucine-rich repeat containing receptor, pyrin domain containing 3 (NLRP3) inflammasome plays a critical role against H1N1 viral infection. However, the function of NLRP3 inflammasome in host immunological responses to the lethal H7N9 virus is still obscure. Here, we demonstrated that mice deficient for NLRP3 inflammasome components, including NLRP3, caspase-1, and Apoptosis-associated speck-like protein containing a CARD (ASC), were less susceptible to H7N9 viral challenge than wild type (WT) controls. Inflammasome deficiency in these animals led to significantly milder mortality and less pulmonary inflammation compared with WT mice. Furthermore, IL-1 receptor deficient mice also exhibited a higher survival rate than WT controls. Thus, our study reveals that the NLRP3 inflammasome is deleterious for the host during H7N9 infection in mice, which is due to an overwhelming inflammatory response via caspase-1 activation and associated IL-1 signal. Therefore, fine-tuning the activity of NLRP3 inflammasome or IL-1 signaling may be beneficial for the host to control H7N9 associated lethal pathogenesis.

Transcutaneous vagus nerve stimulation (tVNS), a non-invasive method of brain stimulation through the auricular branch of the vagus nerve, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism by which the effect on depression might be achieved has not been fully investigated, with only a few neuroimaging studies demonstrating tVNS-induced changes in the brains of healthy volunteers. Identifying specific neural pathways, which are influenced by tVNS compared with sham in depressed individuals, as well as determining neurobiomarkers of tVNS treatment success are needed to advance the application of tVNS for MDD. In order to address these questions, we measured fMRI brain activity of thirty-eight depressed patients assigned to undergo tVNS (n = 17) or sham (n = 21) treatment for 4 weeks, during the first stimulation session. The results showed significant fMRI signal increases in the left anterior insula, revealed by a direct comparison of tVNS and sham stimulation. Importantly, the insula activation level during the first stimulation session in the tVNS group was significantly associated with the clinical improvement at the end of the four-week treatment, as indicated by the Hamilton Depression Rating Scale (HAM-D) score. Our findings suggest that anterior insula fMRI activity could serve as a potential cortical biomarker and an early predictor of tVNS longitudinal treatment success.

In view of the short-circuit fault characteristics, the protection technique of the dc lines limits the development of the modular multi-level converter (MMC)-based HVDC grid in a large extent. This study derives the calculation formulas of the transient voltages of internal and external faults and proposes a single-end protection scheme based on the transition period (TP) from the abrupt changing point to the first extreme point of the fault voltage. Due to the current-limiting reactors, the TP of the internal fault is much shorter than that of the external fault, which is used to discriminate internal fault from external fault. A four-terminal symmetrical bipolar HVDC grid based on MMC is modelled using PSCAD/EMTDC, and simulation results demonstrate the validity of the new proposed dc transmission line protection method.

Assessing protein localization within lipid membranes is problematic. Here, the authors describe a single molecule visualization method based on surface-induced fluorescence attenuation (SIFA) to determine the insertion depth and lateral diffusion of a peptide in a lipid bilayer.