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Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in-depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.

Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC.This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred.Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC.NCT03502850.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Campylobacter coli is a typical food-borne pathogen worldwide known to cause bacterial gastroenteritis in humans. This study reported a draft whole genome sequence of C. coli isolate obtained from the caecal contents of poultry in Jinhua, China.Whole genomic DNA was sequenced using an Illumina Novaseq 6000 platform in 150 bp paired-end mode. The generated reads were de novo assembled by SPAdes v.3.12.0. All probable coding sequences were annotated using the RAST (Rapid Annotation using Subsystem Technology), and antibiotic resistance-related genes were also further identified by ResFinder 4.1 and rgi 5.1.1.The draft genome contained 1 794 608 bp, a total of 69 contigs, belonging to sequence type (ST) ST825, comprising 1972 coding genes, 42 transfer RNAs, 2 ribosomal RNA, and with a GC content of 31.2%. The RAST analysis revealed a total of 698 subsystems in the genome of C. coli WL32 strain, with most of the genes associated with amino acids and derivatives (21.35%) and protein metabolism (17.05%). The genes related to antibiotic resistance, including erm(B) gene associated with macrolide resistance, blaWe report the draft genome sequence of C. coli ST825 isolate obtained from a poultry in China, which could provide potential information for tracking the potential spread of such a multidrug-resistant clone from poultry product processing to human beings.

The tumor microenvironment plays a central role in cancer initiation and progression. CD248 is expressed in tumor-associated stromal cells, particularly fibroblasts and pericytes. Exploring the function of CD248 has the potential to provide biological insights into tumor-supportive stroma and potential therapeutic targets. Here, we investigated the role of stromal CD248 in lung cancer. In orthotopic lung cancer transplantation models, tumor volume, density of vessels and pericytes, and functionality of tumor vessels were all lower in mice lacking Cd248 (Cd248LacZ/LacZ) compared with Cd248 wild-type or haploinsufficient mice. Two angiogenic factors, OPN and SERPINE1, were decreased in Cd248LacZ/LacZ pericytes, and supplementation with both factors rescued their proliferation and endothelial cell tube formation–promoting ability. Mechanistically, Wnt/β-catenin signaling induced Opn and Serpine1 expression and was suppressed in Cd248LacZ/LacZ pericytes. CD248 interacted with Wnt pathway repressors IGFBP4 and LGALS3BP, leading to increased Wnt/β-catenin signaling. Correspondingly, administration of a β-catenin inhibitor in Cd248+/LacZ mice mimicked the effect of Cd248 loss and blocked the growth of transplanted lung tumor cells that were resistant to this inhibitor in vitro. In addition, CD248+ pericytes coexpressed OPN and SERPINE1 and correlated with increased tumor size in human lung cancer. Additionally, high expression of CD248, OPN, and SERPINE1 was associated with poor survival in lung cancer patients. In summary, CD248 derepresses Wnt signaling and upregulates OPN and SERPINE1 in pericytes, resulting in enhanced angiogenesis and lung cancer growth. This novel axis of CD248–Wnt signaling–angiogenic factors in pericytes provides a potential target for lung cancer therapy. Significance: These findings demonstrate that CD248 maintains pericyte function in lung cancer through the Wnt signaling pathway and present CD248 as a potential therapeutic target.

To develop and validate a nomogram for predicting 6-week mortality in patients with liver cirrhosis and acute upper gastrointestinal bleeding (UGIB) and to compare it with other commonly used scoring systems.This retrospective study included cirrhotic patients with acute UGIB hospitalized between January 2013 and December 2020. Random sampling was used to divide patients into the training (n = 676) and validation cohorts (n = 291) at a 7:3 ratio. Multivariate logistic stepwise regression was used to establish a model for predicting 6-week mortality. Multiple indicators were used to validate the nomogram, including the area under the receiver operating characteristic curve (AUROC), calibration curve, and decision curve analysis (DCA).In the training cohort, total bilirubin (TBIL) (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.22-2.50), hemoglobin (Hb) (OR 0.97, 95% CI 0.95-0.99), C-reactive protein (OR 2.79, 95% CI 1.30-6.07), prothrombin time (OR 1.17, 95% CI 1.05-1.30), and hepatic encephalopathy (stage I-II: OR 4.15, 95% CI 1.73-9.61; stage III-IV: OR 19.6, 95% CI 5.33-76.8) were identified as independent factors of 6-week mortality. The AUROC of the UGIB-LC score was 0.873 (95% CI 0.820-0.927), which was higher than that of the Child-Pugh score (0.781), model for end-stage liver disease score (0.766), and neutrophil-to-lymphocyte ratio (0.716).The UGIB-LC score is useful for predicting 6-week mortality in patients with liver cirrhosis and acute UGIB, which is superior to the other three scoring systems.

Electrocardiogram (EKG) abnormalities are predictive of subsequent cardiovascular events. Cardiac involvement is common in systemic lupus erythematosus (SLE). We aimed to determine the prevalence of EKG abnormalities in SLE patients and to examine the factors associated with EKG abnormalities with machine learning approaches.Consecutive SLE patients' records were retrieved from the database of the hospital for the cross-sectional study. Abnormal EKGs with clinical significance were grouped by the presence of tachyarrhythmias, atrioventricular block, nonspecific ST segment changes, T wave abnormalities, ventricular hypertrophy, axis deviation, bundle branch block, and QT interval prolongation. Associated factors of the most common EKG abnormalities were assessed by comparing logistic regression and 4 other machine learning approaches.In the present study, 299 patients were enrolled, with 128 showing clinically significant abnormalities on EKG. T wave changes (52.3%), nonspecific ST segment-T wave (ST-T) changes (26.6%), and prolonged QT interval (8.6%) were the most prevalent abnormalities among patients with abnormal findings on EKG. Random forests models had the best performance in the discovery of associated factors. Age, disease duration, antinuclear antibody titer, disease activity (as measured by the Systemic Lupus Erythematosus Disease Activity Index 2000) were associated with nonspecific ST-T changes, prolonged QT interval, and T wave changes. Hypertension, positivity for anti-SSA antibodies, and secondary Sjögren's syndrome were influential factors for nonspecific ST-T changes, prolonged QT interval, and T wave changes, specifically.ST-T and T wave changes were the most common abnormalities seen on EKGs of SLE patients. Our finding suggests that age, longer disease duration, higher disease activity, hypertension, anti-SSA antibody positivity, and secondary Sjögren's syndrome are important and influential factors in these EKG abnormalities.

BACKGROUND: Addressing intensity inhomogeneity is critical in magnetic resonance imaging (MRI) because associated errors can adversely affect post-processing and quantitative analysis of images (i.e., segmentation, registration, etc.), as well as the accuracy of clinical diagnosis. Although several prior methods have been proposed to eliminate or correct intensity inhomogeneity, some significant disadvantages have remained, including alteration of tissue contrast, poor reliability and robustness of algorithms, and prolonged acquisition time. OBJECTIVE: In this study, we propose an intensity inhomogeneity correction method based on volume and surface coils simultaneous reception (VSSR). METHODS: The VSSR method comprises of two major steps: 1) simultaneous image acquisition from both volume and surface coils and 2) denoising of volume coil images and polynomial surface fitting of bias field. Extensive in vivo experiments were performed considering various anatomical structures, acquisition sequences, imaging resolutions, and orientations. In terms of correction performance, the proposed VSSR method was comparatively evaluated against several popular methods, including multiplicative intrinsic component optimization and improved nonparametric nonuniform intensity normalization bias correction methods. RESULTS: Experimental results show that VSSR is more robust and reliable and does not require prolonged acquisition time with the volume coil. CONCLUSION: The VSSR may be considered suitable for general implementation.

Objective This study aimed to compare the effects of nasal high-frequency oscillatory ventilation (NHFOV) and noninvasive positive-pressure ventilation (NIPPV) as the initial postextubation therapies on preventing extubation failure (EF) in high-risk infants younger than three months after congenital heart surgery (CHS). Design This was a single-center, randomized, unblinded clinical trial. Setting The study was performed in a teaching hospital. Participants Between January 2020 and January 2021, a total of 150 infants underwent CHS in the authors’ hospital. Interventions Infants younger than three months with a high risk for extubation failure who were ready for extubation were randomized to either an NHFOV therapy group or an NIPPV therapy group, and received the corresponding noninvasive mechanical ventilation to prevent EF. Measurements Primary outcomes were reintubation, long-term noninvasive ventilation (NIV) support (more than 72 hours), and the time in NIV therapy. The secondary outcomes were adverse events, including mild-moderate hypercapnia, severe hypercapnia, severe hypoxemia, treatment intolerance, signs of discomfort, unbearable dyspnea, inability to clear secretions, emesis, and aspiration. Main Results Of 92 infants, 45 received NHFOV therapy, and 47 received NIPPV therapy after extubation. There were no significant differences between the NHFOV and the NIPPV therapy groups in the incidences of reintubation, long-term NIV support, and total time under NIV therapy. No significant difference was found of the severe hypercapnia between the two groups, but NHFOV treatment significantly decreased the rate of mild-moderate hypercapnia (p Conclusions Among infants younger than three months after CHS who had undergone extubation, NIPPV therapy and NHFOV therapy were the equivalent NIV strategies for preventing extubation failure, and NHFOV therapy was more effective in avoiding mild-moderate hypercapnia.

Many drugs can bind directly to proteins or be bioactivated by metabolizing enzymes to form reactive metabolites (RMs) that rapidly bind to proteins to form drug-protein conjugates or metabolite-protein conjugates (DMPCs). The close relationship between DMPCs and idiosyncratic adverse drug reactions (IADRs) has been recognized; drug discovery teams tend to avoid covalent interactions in drug discovery projects. Covalent interactions in DMPCs can provide high potency and long action duration and conquer the intractable targets, inspiring drug design, and development. This forms the dual role feature of DMPCs. Understanding the functional implications of DMPCs in IADR control and therapeutic applications requires precise identification of these conjugates from complex biological samples. While classical biochemical methods have contributed significantly to DMPC detection in the past decades, the low abundance and low coverage of DMPCs have become a bottleneck in this field. An emerging transformation toward shotgun proteomics is on the rise. The evolving shotgun proteomics techniques offer improved reproducibility, throughput, specificity, operability, and standardization. Here, we review recent progress in the systematic discovery of DMPCs using shotgun proteomics. Furthermore, the applications of shotgun proteomics supporting drug development, toxicity mechanism investigation, and drug repurposing processes are also reviewed and prospected.

Flavonoid represents a significant class of secondary metabolites in Pu-erh tea with benefits to human health. For a rapid and complete discovery of such compounds, we established a data mining workflow that integrates software MS-DIAL, MS-FINDER, and molecular networking analysis. As a result, 181 flavonoids were tentatively annotated including 22 first found in Pu-erh tea, and two of them were potentially new molecules. The dynamic alteration of these flavonoids during Pu-erh fermentation was further investigated. They all showed a trend of first increasing and then decreasing. Moreover, statistical analysis showed that the first to third pile turnings of the fermentation process had a greater impact on the changes of flavonoids. Partial metabolic pathways were proposed. This study provides a quick and automatic strategy for flavonoid profiling. The temporal dimension of flavonoids during fermentation may serve as a theoretical basis for Pu-erh tea manufacturing technology and study on substance foundation.

Application of B-cell receptor (BCR) pathway inhibitor ibrutinib for chronic lymphocytic leukemia (CLL) is a major breakthrough, yet the downstream effects following inhibition of BCR signaling and during relapse await further clarification. By comparative phosphoproteomic profiling of B cells from patients with CLL and healthy donors, as well as CLL B cells collected at multiple time points during the course of ibrutinib treatment, we provided the landscape of dysregulated phosphoproteome in CLL and its dynamic alterations associated with ibrutinib treatment. Particularly, differential phosphorylation events associated with several signaling pathways, including BCR pathway, were enriched in patient CLL cells. A constitutively elevated phosphorylation level of KAP1 at serine 473 (S473) was found in the majority of CLL samples prior to treatment. Further verification showed that BCR activation promoted KAP1 S473 phosphorylation, whereas ibrutinib treatment abolished it. Depletion of KAP1 in primary CLL cells decelerated cell-cycle progression and ectopic expression of a KAP1 S473 phospho-mimicking mutant accelerated G2–M cell-cycle transition of CLL cells. Moreover, temporal phosphoproteomic profiles using a series of CLL cells isolated from one patient during the ibrutinib treatment revealed the dynamic changes of several molecules associated with BCR signaling in the ibrutinib responsive and recurrent stages. Implications: This phosphoproteomic analysis and functional validation illuminated the phosphorylation of KAP1 at S473 as an important downstream BCR signaling event and a potential indicator for the success of ibrutinib treatment in CLL.

Decoy receptor 3 (DcR3) is a soluble receptor for Fas ligand, LIGHT and TL1A, but it also exerts effector functions. Previously, we found that DcR3 is upregulated in the serum and lesional skin of patients with psoriasis and is upregulated by EGFR activation in proliferating primary human epidermal keratinocytes. However, the functional role of intracellular DcR3 in keratinocyte differentiation is still incompletely defined. Herein, primary cultured human epidermal keratinocytes were differentiated by phorbol 12-myristate 13-acetate (PMA) treatment, calcium treatment and cell confluence, which are three standard in vitro differentiation models. We found that the constitutive expression of the DcR3 gene and protein was progressively suppressed during terminal differentiation of keratinocytes. These changes were correlated with downregulation of EGFR activation during keratinocyte differentiation. EGFR inhibition by gefitinib further decreased confluence-induced suppression of DcR3 mRNA expression, and, vice versa, knocking down DcR3 expression attenuated EGFR and EGFR ligand expression as well as EGFR activation. Under conditions without a change in cell growth, DcR3 silencing reduced the expression of involucrin and transglutaminase 1 but enhanced the induction of the terminal differentiation markers keratin 10 and loricrin. Of note, DcR3 interacted with PKCα and PKCδ and enhanced PKC activity. In keratinocytes with PKCα and PKCδ silencing, differentiation markers were differentially affected. In conclusion, DcR3 expression in keratinocytes is regulated by EGFR and forms a positive feedback loop to orchestrate constitutive EGFR and PKC activity. During differentiation, DcR3 is downregulated and involved in modulating the pattern of terminal differentiation.

To examine the association of the working stress with posttraumatic stress disorder symptoms (PTSD), and burnout as the mediator for this association among emergency nurses during COVID-19 pandemic.Longitudinal survey study.Online survey was used to collect data during the period from August to November 2020 with a sample of 169 emergency nurses. They were invited to complete the following questionnaires at the 6th and 9th months after COVID-19 outbreak: Posttraumatic Symptom Scale (PTSS-10), the emergency nurses' COVID-19 stress questionnaire and Chinese version of 21-item Copenhagen Burnout Inventory (CBI).During the 3-month follow-up, there were no changes in the number of suspected PTSD cases (6 and above symptoms): 41% at the 6th month and 33.3% at the 9th month. The increases of the personal burnout levels and living apart from families were the main factors associated with the PTSD symptoms. The risk for emergency nurses suffering from PTSD is through stress levels increasing their burnout levels.Over 30 percent of emergency nurses remained at high risk for suspected PTSD. The burnout levels mediated the relationship between the stress levels and the risks of PTSD.Little as know about the impact of COVID-19 on emergency nurses' stress. This study found emergency nurses remained to be the high risk for the suspected PTSD cases. It is urged to develop a stress-reduction program targeting at causes of stress and improving burnout for emergency nurses during COVID-19 pandemic.

Purpose: To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non–small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II. Patients and Methods: This multicenter, open-label study included 367 adult Chinese patients. Abivertinib at doses of 50 mg twice a day to 350 mg twice a day was evaluated in phase I in continual 28-day cycles, and the RP2D of 300 mg twice a day was used in phase II in continual 21-day cycles. Primary endpoints include RP2D in phase I and objective response rate (ORR) at RP2D in phase II. Results: The RP2D of 300 mg twice a day for abivertinib was established based on pharmacokinetics, efficacy, and safety profiles across doses in phase I. In phase II, 227 patients received RP2D for a median treatment duration of 24.6 weeks (0.43–129). Among 209 response–evaluable patients, confirmed ORR was 52.2% [109/209; 95% confidence interval (CI): 45.2–59.1]. Disease control rate (DCR) was 88.0% (184/209; 95% CI: 82.9–92.1). The median duration of response (DoR) and progression-free survival (PFS) was 8.5 months (95% CI: 6.1–9.2) and 7.5 months (95% CI: 6.0–8.8), respectively. The median overall survival (OS) was 24.9 months [95% CI: 22.4–not reachable (NR)]. All (227/227) patients reported at least 1 adverse event (AE), with 96.9% (220/227) of treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed as treatment-related. Conclusions: Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy with manageable side effects in patients with EGFR T790M+ NSCLC.

Aims/Introduction We aimed to explore whether the association between obesity and congenital heart defects (CHDs) can be mediated by maternal pregestational diabetes (PGDM). Materials and Methods We included 53,708 mother‐infant pairs with deliveries between 2017 and 2019 from the Birth Cohort in Shenzhen. Mothers were categorized into four groups: the underweight group (body mass index [BMI]

Liver metastasis is common in advanced small cell lung cancer (SCLC). There is no evidence‐proven treatment beyond the second line in patients with SCLC and liver metastasis. This study aimed to investigate survival in patients with SCLC and liver metastasis treated with anlotinib compared with placebo. This study was a post hoc analysis of the phase II ALTER 1202 trial, including patients who had liver metastasis at baseline. The participants were randomized 2:1 to receive either 12 mg/day anlotinib (anlotinib group) or placebo (placebo group). Tumor response, progression‐free survival (PFS), and overall survival (OS) were compared. In the original trial, there were 39 participants with liver metastasis at baseline, including 27 and 12 in the anlotinib and placebo groups, respectively. The objective response rate was 3.7% and 0% in the anlotinib and placebo groups, respectively (p = 0.9999). An elevated disease control rate was found in the anlotinib group (44.4%) compared with the placebo group (8.3%, p = 0.0173). The median PFS was 1.51 vs. 0.71 months in favor of anlotinib (hazard ratio [HR] = 0.365, 95% confidence interval [CI]: 0.17–0.78; p = 0.0064), with no marked difference in median OS (3.29 vs. 1.91 months; HR = 0.51, 95% CI: 0.22–1.16; p = 0.0996). The most common AEs in the anlotinib group were hypertension (40.7%), fatigue (29.6%), loss of appetite (22.2%), and weight loss (22.2%). There were no grade 5 AE. In conclusion, anlotinib increased PFS compared with placebo in patients with SCLC and liver metastasis.

This study was performed to test the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker would be helpful for differentiation acute kidney injury (AKI) from chronic kidney disease (CKD) in kidney malfunction patients from the nephrology department.This retrospective study included 355 patients admitted from the nephrology department with modification of diet in renal disease estimated glomerular filtration rate (MDRD eGFR) 60 ml/min/1.73 mUrinary NGAL (uNGAL) level in the AKI group was higher than in the CKD group (372.10 (170.10-690.63) vs 88.10 (52.00-238.80), P 0.001), but there was no significant difference in serum NGAL (sNGAL). Both sNGAL and uNGAL had a correlation with MDRD eGFR in total patients, AKI patients, and CKD patients. The propensity-matched analysis enrolled 75 patients in each group. In matched AKI group, sNGAL was lower (401.20 (239.10-616.00) vs 468.50 (305.00-709.40), P = 0.049) and uNGAL was elevated (284.00 (136.90-690.90) vs 203.70 (69.20-596.00), P = 0.032), compared with the matched CKD group. In all patients (n = 355), the ratio of uNGAL and sNGAL (u/s NGAL), fractional excretion of NGAL (Fe NGAL) discriminated AKI from CKD (area under the curve, 0.803 and 0.790, respectively). After stratified kidney function, the sub-analyses found that u/s NGAL and Fe NGAL were shown to differ substantially between the AKI group and CKD group (all P 0.01). The u/s NGAL ratio always had the highest AUC area in the sub-analyses.u/s NGAL might be helpful to discriminate AKI from CKD in kidney malfunction patients admitted to the nephrology department. Further confirmatory studies might be warranted.

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC.To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC.This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021.Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks.The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P .012). There were 13 secondary outcomes, including progression-free survival and adverse events.Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group.Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population.ClinicalTrials.gov Identifier: NCT04063163.

BACKGROUND: Stomal-related complications (SRCs) increase the health care burden and impair quality of life. PURPOSE: To determine the incidence rates and predictors of stomal and peristomal complications (SCs and PCs, respectively). METHODS: This was a prospective cohort study. In total, 215 patients who had undergone ostomy were enrolled and followed-up at 3, 30, 90, 180, and 360 days after surgery. During the follow-up period, SRCs were assessed by 1 colorectal surgeon and 2 wound, ostomy, and continence nurses. The SRCs were classified into SCs and PCs. RESULTS: SRCs were observed in 105 patients (48.8%). The 105 patients had 145 SRCs (66 [45.5%] SCs and 79 [54.5%] PCs). A logistic regression analysis revealed that emergency surgery (odds ratio [OR]: 2.78; P = .041), laparoscopic surgery (OR: 2.91; P = .023), and inappropriate stomal location (OR: 19.23; P < .001) were significant predictors of SCs. Inappropriate stomal location also was significantly associated with PCs (OR: 7.70; P < .001). The cumulative incidence rate of SRCs was 73% in patients who underwent stomal surgery and were followed for 360 days. CONCLUSIONS: Stomas created through emergency or laparoscopic surgery and those created at inappropriate sites were associated with a higher risk of SCs. Inappropriate stomal site was found to be a significant predictor for SCs and PCs.

Most of the malignant melanomas are already in the middle and advanced stages when they are diagnosed, which is often accompanied by the metastasis and spread of other organs.Besides, the prognosis of patients is bleak. The characteristics of the local immune microenvironment in metastatic melanoma have important implications for both tumor progression and tumor treatment. In this study, data on patients with metastatic melanoma from the TCGA and GEO datasets were selected for immune, stromal, and estimate scores, and overlapping differentially expressed genes (DEGs) were screened. A nine-IRGs prognostic model (ALOX5AP, ARHGAP15, CCL8, FCER1G, GBP4, HCK, MMP9, RARRES2 and TRIM22) was established by univariate COX regression, LASSO and multivariate COX regression. Receiver operating characteristic (ROC) curves were used to test the predictive accuracy of the model. Immune infiltration was analyzed by using CIBERSORT, Xcell and ssGSEA in high-risk and low-risk groups. The immune infiltration of the high-risk group was significantly lower than that of the low-risk group. Immune checkpoint analysis revealed that the expression of PDCD1, CTLA4, TIGIT, CD274, HAVR2 and LAG3 were significantly different in groups with different levels of risk scores. WGCNA analysis found that the yellow-green module contained seven genes (ALOX5AP, FCER1G, GBP4, HCK, MMP9, RARRES2 and TRIM22) from the nine-IRG prognostic model, of which the yellow-green module had the highest correlation with risk scores. The results of GO and KEGG suggested that the genes in the yellow-green module were mainly enriched in immune-related biological processes. Finally, we analyzed the prognostic ability and expression characteristics of ALOX5AP, ARHGAP15, CCL8, FCER1G, GBP4, HCK, MMP9, RARRES2 and TRIM22 in metastatic melanoma. Overall, a prognostic model for metastatic melanoma based on the characteristics of the tumor immune microenvironment was established, which was helpful for further studies.It could function well in helping people to understand the characteristics of the immune microenvironment in metastatic melanoma and to find possible therapeutic targets.

Background The COVID-19 frontline nurses' stress-reduction program by the cooperation of manager with the nurses is not-well developed. Aim This study aimed to examine the effect of an emergency nurse-led stress reduction project on reducing stress levels during the COVID-19 pandemic. Methods The action research was conducted using online and person-to-person group brainstorming strategies. The online survey was used to evaluate emergency nurses' stress levels, causes of stress, and needs at the 50th, 80th, and 110th days of the pandemic from March to May 2020. Results The numbers of nurses participating in three-time survey were 160, 166, and 160, respectively. There was a decrease in the nurses' work-related stress after implementing the improvement strategies. Stress from PPE, information about infection control, family's worry about being infected reduced across 2 months. Needs regarding PPE, COVID-19 information, and a forum for sharing experiences of COVID-19 care decreased while needs of allowing more days off increased. Conclusions The stress-reduction project targeting at nurses' views of their needs can reduce their' stress during the COVID-19 pandemic. Implication for nursing management The online and person-to-person group brainstorming building a good partnership between nurses and managers can be an effective nursing management.

This research was to explore the accuracy of ultrasonic diagnosis based on artificial intelligence algorithm in the diagnosis of pregnancy complicated with brain tumors. In this study, 18 patients with pregnancy complicated with brain tumor confirmed by pathology were selected as the research object. Ultrasound contrast based on artificial bee colony algorithm was performed and diagnosed by experienced clinicians. Ultrasonic image will be reconstructed by artificial bee colony algorithm to improve its image display ability. The pathological diagnosis will be handed over to the physiological pathology laboratory of the hospital for diagnosis. The doctor’s ultrasonic diagnosis results were compared with the pathological diagnosis stage results of patients, and the results were analyzed by statistical analysis to evaluate its diagnostic value. The comparison results showed that the number and classification of benign tumors were the same, while in malignant tumors, the number diagnosis was the same, but there was one patient with diagnostic error in classification. One case of mixed glial neuron tumor was diagnosed as glial neuron tumor, and the diagnostic accuracy was 94.44% and the K value was 0.988. The diagnostic results of the two were in excellent agreement. The results show that, in the ultrasonic image diagnosis of patients with brain tumors during pregnancy based on artificial intelligence algorithm, most of them are benign and have obvious symptoms. Ultrasound has a good diagnostic accuracy and can be popularized in clinical diagnosis. The results can provide experimental data for the clinical application of ultrasonic image feature analysis based on artificial intelligence as the diagnosis of pregnancy complicated with brain tumors.

Background Chimeric antigen receptor T cells (CAR-Ts) have demonstrated remarkable efficacy in hematological cancers but have not yet translated in treating solid tumors. The significant hurdles limiting CAR-T therapy were from a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present TSH receptor (TSHR) as a putative target for CAR-T therapy of differentiated thyroid cancer (DTC). Methods We undertook a large-scale screen on thyroid cancer tissues and multiple internal organs through bioinformatical analysis and immunohistochemistry to date TSHR expression. Using 3 previously described monoclonal antibodies, we generated 3 third-generation CAR-Ts. We tested anti-TSHR CAR-T in vitro activity by T-cell function and killing assay. Then we tested preclinical therapeutical efficacy in a xenograft mouse model of DTC and analyzed mice’s physical conditions and histological abnormalities to evaluate anti-TSHR CAR-T’s safety. Results TSHR is highly and homogeneously expressed on 90.8% (138/152) of papillary thyroid cancer, 89.2% (33/37) of follicular thyroid cancer, 78.2% (18/23) of cervical lymph node metastases, and 86.7% of radioactive iodine resistance diseases. We developed 3 novel anti-TSHR CAR-Ts from monoclonal antibodies M22, K1-18, and K1-70; all 3 CAR-Ts mediate significant antitumor activity in vitro. Among these, we demonstrate that K1-70 CAR-T can have therapeutical efficacy in vivo, and no apparent toxicity has been observed. Conclusion TSHR is a latent target antigen of CAR-T therapy for DTC. Anti-TSHR CAR-T could represent a therapeutic option for patients with locoregional relapsed or distant metastases of thyroid cancer and should be tested in carefully designed clinical trials.

Objectives We aimed to quantitatively synthesize the association between maternal exposure to particulate matter (PM; including PM Study design Meta-analysis was used to quantitatively synthesize the results of similar independent studies. Methods Original documents were identified by searching six electronic bibliographic databases from their inceptions to August 17, 2021. Then we performed meta-analysis to combine the effect estimates if at least three estimates reported the same exposure and outcome and used stratified analysis to evaluate the impact of exposure assessment method, data source, and study area on heterogeneity. In addition, we used the 95% prediction interval to evaluate the potential effects of exposure in random effects meta-analysis. Results The overall meta-analysis showed that the risk of HDP was significantly associated with per 5 μg/m3 increase in PM2.5 exposure during T1 and PM10 exposure during T, with odds ratios [ORs] 1.06 (95% confidence interval [CI]: 1.01–1.12) and 1.04 (95% CI: 1.02–1.07), respectively. The results also showed that PM2.5 exposure during T1 and T2 and PM10 exposure during T1 increased the incidence of GH; the summary ORs were 1.11 (95% CI: 1.01–1.23), 1.16 (95% CI: 1.05–1.29), and 1.04 (95% CI: 1.02–1.07), respectively. Subgroup analyses showed that the pooled effects were generally significant or more apparent in studies using models to assess exposure, studies whose data derived from birth registers, and studies in Europe. Conclusions This meta-analysis showed that PM exposure was associated with increased HDP risks, and the association varied by study area, data source, and exposure assessment method. With the continuous improvement of research design and exposure assessment, future research may find higher risks.

Background Police officers are a high-stress group with special job characteristics, and the Chinese police management system places particularly high demands on police officers. Whether the influence of job demands on officers’ job burnout can be deduced to general stress response needs to be verified. Based on the JD-R model, the study aims to explore the impact of job demands on police stress response, whether job autonomy as a job resource has a moderating effect, and whether basic psychological needs mediate this effect. Methods A total of 251 police officers in a district-level public security bureau of China, were surveyed using Chinese-language versions of the Job Demands Scale, the Stress Response Scale, the Job Autonomy Scale, and the Basic Psychological Needs Scale. The mediating effect of basic psychological needs and the moderating effect of job autonomy were tested by regression analysis and bootstrap test. Results Job demands increase police officers’ stress response, and job autonomy does not play a buffer role but enhances this impact, and job demands can partially reduce the police stress response through the satisfaction of basic psychological needs, that is, there is a masking effect of basic psychological needs. Conclusions Adjusting and optimizing the ratio of job demands and autonomy in police work to provide high guidance under high demands is of great value to reduce the negative stress responses among police officers.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by low-grade inflammation and insulin resistance. In this process, innate immune cells play a crucial role in recognizing the stimuli (free fatty acid, lipopolysaccharide, and cytokines) and mediating the inflammatory response, contributing to the development of T2DM. Neutralizing inflammatory cytokines and blocking the inflammation cascade provide great potential for the treatment of T2DM. Here, we applied a macrophage membrane as a bait, which could specifically recognize and bind the stimuli, to encapsulate nanoparticles and capture the stimuli, further preventing inflammation. The

Signal peptide (SP) plays an important role in membrane targeting for insertion of secretory and membrane proteins during translocation processes in prokaryotes and eukaryotes. Beside the targeting functions, SP has also been found to affect the stability and folding of several proteins. Serum amyloid A (SAA) proteins are apolipoproteins responding to acute-phase inflammation. The fibrillization of SAA results in a protein misfolding disease named amyloid A (AA) amyloidosis. The main disease-associated isoform of human SAA, SAA1.1, is expressed as a precursor protein with an N-terminal signal peptide composed of 18 residues. The cleavage of the SP generates mature SAA1.1. To investigate whether the SP affects properties of SAA1.1, we systematically examined the structure, protein stability, and fibrillization propensity of pre-SAA1.1, which possesses the SP, and Ser-SAA1.1 without the SP but containing with an additional N-terminal serine residue. We found that the presence of the SP did not significantly affect the predominant helical structure but changed the tertiary conformation as evidenced by intrinsic fluorescence and exposed hydrophobic surfaces. Pre-SAA1.1 and Ser-SAA1.1 formed distinct oligomeric assemblies in which pre-SAA1.1 populated as tetramer and octamer, whereas Ser-SAA1.1 existed as a predominant hexamer. Pre-SAA1.1 was found significantly more stable than Ser-SAA1.1 upon thermal and chemical unfolding. Ser-SAA1.1, but not pre-SAA1.1, is capable of forming amyloid fibrils in protein misfolding study, indicating a protective role of the SP. Altogether, our results demonstrated a novel role of the SP in SAA folding and misfolding and provided a novel direction for therapeutic development of AA amyloidosis.

Given its complex pathological anatomy, recurrent left atrioventricular valve regurgitation after partial atrioventricular septal defect repair remains a challenge for surgical correction. Here, we introduce a modified bridging technique by shortening the anteroposterior leaflet distance in selected patients with inadequate coaptation to compensate for the short leaflet height, specifically that of the anterior leaflet.

Pathological angiogenesis (PA) contributes to various ocular diseases, including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, which are major causes of blindness over the world. Current treatments focus on anti-vascular endothelial growth factor (VEGF) therapy, but persistent avascular retina, recurrent intravitreal neovascularization, and general adverse effects are reported. We have previously found that recombinant thrombomodulin domain 1 (rTMD1) can suppress vascular inflammation. However, the function of rTMD1 in VEGF-induced PA remains unknown. In this study, we found that rTMD1 inhibited VEGF-induced angiogenesis in vitro. In an oxygen induced retinopathy (OIR) animal model, rTMD1 treatment significantly decreased retinal neovascularization but spared normal physiological vessel growth. Furthermore, loss of TMD1 significantly promoted PA in OIR. Meanwhile, hypoxia-inducible factor-1α, the transcription factor that upregulates VEGF, was suppressed after rTMD1 treatment. The levels of interleukin-6, and intercellular adhesion molecule-1 were also significantly suppressed. In conclusion, our results indicate that rTMD1 not only has dual effects to suppress PA and inflammation in OIR, but also can be a potential HIF-1α inhibitor for clinical use. These data bring forth the possibility of rTMD1 as a novel therapeutic agent for PA.

Obesity is an independent risk factor for worse outcomes in various surgical settings. Whether obesity is a prognostic factor for postoperative morbidity and mortality of colorectal cancer (CRC) is inconclusive. This study aimed to determine the impact of obesity on short-term postoperative outcomes in CRC patients undergoing laparoscopic surgery. Data of a total of 23,898 CRC patients aged ≥ 20 years and undergoing laparoscopic resection were extracted from the US National Inpatient Sample (NIS) database and analyzed. The study endpoints were in-hospital mortality, any postoperative complications, infection/sepsis, acute kidney injury (AKI), deep vein thrombosis (DVT)/pulmonary embolisms (PE), and extended hospital stay. Univariate and multivariate logistic regression analyses were performed to examine the associations between patients’ obesity status (morbid obese: BMI > = 40 kg/m2; obese: BMI 30–39.9 kg/m2) and the study outcomes. In 23,898 CRC patients undergoing laparoscopic resection, the prevalence of obesity prevalence was 11.8%. After adjustment, the results revealed that morbid obesity was significantly associated with increased risk for in-hospital mortality (aOR = 2.06, 95%CI: 1.11–3.83), AKI (aOR = 1.78, 95%CI = 1.34–2.36), DVT/PE (aOR = 2.88, 95%CI = 1.70–4.88), and extended LOS (aOR = 1.21, 95%CI = 1.02–1.43), while non-morbid obesity was significantly associated with more DVT/PE (aOR = 2.12, 95%CI = 1.32–3.41) as compared with non-obesity. In patients with CRC undergoing laparoscopic surgery, morbid obesity is strongly associated with worse postoperative outcomes, including increased in-hospital mortality, postoperative AKI and DVT/PE, and extended LOS. The findings of the present study highlight the importance of obesity status in risk stratification for laparoscopic CRC surgery.

Aims: Type 2 diabetes mellitus (T2DM) is no longer regarded as a coronary risk equivalent, and heterogeneity of cardiovascular risk exists, suggesting that further risk stratification should be mandatory. This study aimed to determine the prevalence and clinical predictors of coronary artery calcium (CAC) score, and evaluate the CAC score as a predictor of cardiovascular outcome in a large asymptomatic T2DM cohort. Methods: A total of 2,162 T2DM patients were recruited from a Diabetes Shared Care Network and the CAC score was measured. Cardiovascular outcomes were obtained for 1,928 patients after a follow-up of 8.4 years. Multiple regression analysis and Cox proportional hazard regression were applied to identify clinical predictors of CAC and calculate the incidence and hazard ratios (HRs) for all-cause mortality and cardiovascular events by CAC category. Results: Of the recruited patients, 96.8% had one or more risk factors. The distribution of CAC scores was as follows: CAC=0 in 24.2% of the patients, 0 ＜CAC ≤ 100 in 41.5%, 100 ＜CAC ≤ 400 in 20.3%, CAC ＞400 in 14.7%. The multivariable predictor of increased CAC included age (years) (odds ratio, 1.07; 95% confidence interval, 1.06–1.08), male sex (1.82; 1.54–2.17), duration (years) of T2DM (1.07; 1.05–1.09), and multiple risk factors (1.94; 1.28–2.95). Increasing severity of CAC was associated with higher all-cause or cardiac mortality and higher incident cardiovascular events. The HRs for cardiac death or major cardiac events in CAC ＞400 vs CAC=0 were 8.67 and 10.52, respectively ( p ＜0.001) Conclusion: CAC scoring provides better prognostication of cardiovascular outcome than traditional risk factors in asymptomatic T2DM patients, and may allow identifying a high-risk subset for enhancing primary prevention.

This systematic review with a meta-regression was conducted to determine the risk of depression after mastectomy compared to breast reconstruction among women with breast cancer 1 year after surgery. A literature search was conducted according to PRISMA guidelines using 4 databases: Medline (Ovid), Embase, Cinahl, and the Cochrane Library for the period January 2000 to March 2019. Studies that measured the status of depression within 1 year and immediately after surgery were included. Outcomes related to depression were analyzed by using a pool of event rates and a risk ratio of 95% confidence interval (CI), P value, and a fitting model based on the results of a heterogeneity test of mastectomy and BR. The statistical analysis was conducted using Comprehensive Meta-analysis 3.0 software. Nine studies met the inclusion criteria. There were 865 cases of mastectomy only, with a 22.2% risk of depression (95% CI, 12.4-36.2). In 869 women who underwent BR, the risk of depression was 15.7% (95% CI, 8.8-26.2). The depression risk ratio for mastectomy compared to BR was 1.36 (95% CI, 1.11-1.65). Patients with delayed reconstruction exhibited lower levels of depression (risk ratio 0.96, 95% CI 0.57-1.01). The Beck Depression Inventory (BDI) scale showed high sensitivity, and the Hospital Anxiety Depression Scale (HADS) with a cutoff of > 7 could measure even low to moderate depressive symptoms. One in 4 women with breast cancer had symptoms of depression after mastectomy; both surgeries were associated with depression in women 1 year after surgery. Our results will permit the development of proactive treatment plans before and after surgery to mitigate risk and prevent depression through the use of sensitive depression scales like BDI.

Background The presence of pleural effusion is an independent predictor for poor survival in patients with small‐cell lung cancer (SCLC). The aim of this study was to assess the efficacy and safety of anlotinib in patients with SCLC and pleural effusion. Methods This was a randomized, double‐blind, multicenter, phase II trial. Patients histologically diagnosed with SCLC and pleural effusion and had received at least two lines of chemotherapy were enrolled into the study. The patients received anlotinib 12 mg/day or a placebo. Results The overall response rate (ORR) was 3.7% for anlotinib (n = 27) and 0% in the placebo group (n = 15) (p = 1.000). The disease control rate (DCR) of the anlotinib group (63.0%) was higher than that of the placebo group (0%, p, Patients with pleural effusion in this study came from a double‐blind, randomized, multicenter, controlled, phase II study, which was designed to examine the efficacy and safety of anlotinib in limited‐ or extensive‐stage SCLC. The median PFS (mPFS) was higher in the anlotinib group (2.8, 95% CI: 1.4–4.1) months compared to the placebo group (0.7, 95% CI: 0.5–0.7) months. The HR of PFS for the anlotinib group vs. the placebo group was 0.10 (95% CI: 0.03–0.28, p

Background Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first‐line treatment of Chinese patients with advanced or recurrent non‐squamous non‐small cell lung cancer (NSCLC). Methods Stage IIIB‐IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4‐6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression‐free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). Results Between December 15th, 2017, and May 15th, 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th, 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1‐6) and median duration of treatment of 3.0 (range 0.0‐5.1) months. ORR of response‐evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80‐1.04, within the prespecified equivalence margin of 0.75‐1.33). Up to May 15th, 2020, with a median follow‐up of 13.6 (range 0.8‐28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1‐year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. Conclusions LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non‐squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non‐squamous NSCLC patients in the first‐line setting., This study demonstrated similarity between LY01008 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity in combination with paclitaxel and carboplatin as first‐line treatment in Chinese patients with advanced non‐squamous NSCLC.

Summary Background Icotinib has provided survival benefits for patients with advanced, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). We aimed to compare icotinib with chemotherapy in patients with EGFR-mutant stage II–IIIA NSCLC after complete tumour resection. Here, we report the results from the preplanned interim analysis of the study. Methods In this multicentre, randomised, open-label, phase 3 trial done at 29 hospitals in China, eligible patients were aged 18–70 years, had histopathogically confirmed stage II–IIIA NSCLC, had complete resection up to 8 weeks before random assignment, were treatment-naive, and had confirmed activation mutation in exon 19 or exon 21 of the EGFR gene. Participants were randomly assigned (1:1) with an interactive web-based response system to receive either oral icotinib 125 mg thrice daily for 2 years or four 21-day cycles of intravenous chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 of each cycle plus cisplatin 75 mg/m2 on day 1 of each cycle for adenocarcinoma or squamous carcinoma; or pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 every 3 weeks for non-squamous carcinoma). The primary endpoint was disease-free survival assessed in the full analysis set. Secondary endpoints were overall survival assessed in the full analysis set and safety assessed in all participants who received study drug. This trial is registered with ClinicalTrials.gov , NCT02448797 . Findings Between June 8, 2015, and August 2, 2019, 322 patients were randomly assigned to icotinib (n=161) or chemotherapy (n=161); the full analysis set included 151 patients in the icotinib group and 132 in the chemotherapy group. Median follow-up in the full analysis set was 24·9 months (IQR 16·6–36·4). 40 (26%) of 151 patients in the icotinib group and 58 (44%) of 132 patients in the chemotherapy group had disease relapse or death. Median disease-free survival was 47·0 months (95% CI 36·4–not reached) in the icotinib group and 22·1 months (16·8–30·4) in the chemotherapy group (stratified hazard ratio [HR] 0·36 [95% CI 0·24–0·55]; p Interpretation Our results suggest that compared with chemotherapy, icotinib significantly improves disease-free survival and has a better tolerability profile in patients with EGFR-mutant stage II–IIIA NSCLC after complete tumour resection. Funding Betta Pharmaceuticals Translation For the Chinese translation of the abstract see Supplementary Materials section.

Cardiovascular and cerebrovascular diseases are leading causes of death worldwide, accounting for more than 40% of all deaths in China. Acute myocardial infarction (AMI) is a common cardiovascular disease and traditionally divided into ST-segment (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), which are known with different prognoses and treatment strategies. However, key regulatory genes and pathways involved in AMI that may be used as potential biomarker for prognosis are unknown. In this study, we employed both bulk and single-cell RNA-seq to construct gene regulatory networks and cell-cell communication networks. We first constructed weighted gene co-expression networks for differential expressed genes between STEMI and NSTEMI patients based on whole-blood RNA-seq transcriptomics. Network topological attributes (e.g., node degree, betweenness) were analyzed to identify key genes involved in different functional network modules. Furthermore, we used single-cell RNA-seq data to construct multilayer signaling network to infer regulatory mechanisms of the above key genes. PLAUR (receptor for urokinase plasminogen activator) was found to play a vital role in transducing inter-cellular signals from endothelial cells and fibroblast cells to intra-cellular pathways of myocardial cells, leading to gene expression involved in cellular response to hypoxia. Our study sheds lights on identifying molecular biomarkers for diagnosis and prognosis of AMI, and provides candidate key regulatory genes for further experimental validation.

Mesenchymal stem cell (MSCs)-derived exosomes have been frequently used as useful tools in disease control. This research aimed to study the function of MSC-derived exosomes (Exo) in the stemness of cancer stem cells (CSCs) of hepatocellular carcinoma (HCC) and the molecular mechanism. Exo from the procured human bone marrow-MSCs were extracted and identified. CSCs from HCC cell lines were collected. The CSCs were treated with Exo, and then the proliferation, migration, invasion, angiogenesis-stimulating and self-renewal abilities of the Hep3B-CSCs and HuH7-CSCs were significantly reduced. C5orf66-AS1 was found as the most upregulated long noncoding RNAs (lncRNAs) in CSCs after Exo treatment. The integrated bioinformatic analyses and luciferase assays suggested that C5orf66-AS1 upregulated DUSP1 expression through sequestering microRNA-127-3p (miR-127-3p). Either artificial overexpression of miR-127-3p or silencing of DUSP1 blocked the inhibitory functions of Exo in the CSCs. DUSP1 inhibition increased the phosphorylation of ERK. Similar results were reproduced in vivo where Exo reduced the growth of xenograft formed by CSCs in nude mice, and this reduction was blocked upon miR-127-3p overexpression or DUSP1 silencing. To conclude, this research reported that MSC-derived Exo block malignant behaviors of HCC-sourced CSCs through a C5orf66-AS1/miR-127-3p/DUSP1/ERK axis.

Objective: The study aimed to evaluate the improvement of patient knowledge of warfarin use, satisfaction with pharmacists, and the quality of international normalized ratio (INR) control after the implementation of an anticoagulant clinic (ACC) service.Methods: This was a prospective single-group pre- and post-comparison study. Patients who were at least 20 years of age and participated in a pharmacist-managed ACC service were enrolled from February 2012 to September 2015. Each participant completed a self-administered questionnaire before and after the ACC service to evaluate changes in warfarin knowledge. Another questionnaire was distributed after the ACC to evaluate participants' satisfaction with the pharmacist service in the ACC. The INR levels before and after the ACC intervention were obtained to calculate the proportion of time spent in the therapeutic INR range (time in therapeutic range, TTR). Paired t-tests were used to compare changes in participants' knowledge related to warfarin use. Multiple linear regressions were performed to explore the predictors associated with the participants' knowledge scores and TTR after the ACC intervention.Results: One hundred and forty-eight participants were enrolled in this study. A significant improvement (31.5%,p

Purpose To investigate and identify first-trimester fasting plasma glucose (FPG) is related to gestational diabetes mellitus (GDM) and other adverse pregnancy outcomes in Shenzhen population. Methods We used data of 48,444 pregnant women that had been retrospectively collected between 2017 and 2019. Logistic regression analysis was used to evaluated the associations between first-trimester FPG and GDM and adverse pregnancy outcomes, and used to construct a nomogram model for predicting the risk of GDM. The performance of the nomogram was evaluated by using ROC and calibration curves. Decision curve analysis (DCA) was used to determine the clinical usefulness of the first-trimester FPG by quantifying the net benefits at different threshold probabilities. Results The mean first-trimester FPG was 4.62 ± 0.42 mmol/L. A total of 6998 (14.4%) pregnancies developed GDM.489(1.01%) pregnancies developed polyhydramnios, the prevalence rates of gestational hypertensive disorder (GHD), cesarean section, primary cesarean section, preterm delivery before 37 weeks (PD) and dystocia was 1130 (2.33%), 20,426 (42.16%), 7237 (14.94%), 2386 (4.93%), and 1865 (3.85%), respectively. 4233 (8.74%) of the newborns were LGA, and the number of macrosomia was 2272 (4.69%), LBW was 1701 (3.51%) and 5084 (10.49%) newborns had admission to the ICU, which all showed significances between GDM and non-GDM groups (all P 1, all P P P Conclusions FPG in the first trimester was an independent risk factor for GDM which can be used as a screening test for identifying pregnancies at risk of GDM and adverse pregnancy outcomes.

OBJECTIVES Osimertinib is the main treatment choice for pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) T790M mutations. However, the choice of subsequent therapy when progressive disease has developed after osimertinib treatment remains a major therapeutic challenge. This study evaluated the efficacy of osimertinib-based combination therapies in patients who developed progressive disease after treatment with osimertinib. MATERIAL AND METHODS We enrolled NSCLC patients harbouring T790M mutations pretreated with first- or second-generation EGFR tyrosine-kinase inhibitors and were receiving osimertinib at two tertiary referral centres between August 2015 and July 2019, and the subsequent treatment efficacy was assessed. RESULTS Osimertinib-based combination therapy yielded better overall survival (OS) than chemotherapy alone (not achieved vs. 7.8 months; hazard ratio, 0.39; 95 % confidence interval 0.17-0.89; P = 0.025) according to the Cox proportional hazards model adjusted for possible confounders. Synergism (combination index

The increasing use of biologics is accompanied by a risk of hepatitis B (HBV) and C virus (HCV) reactivation.To determine the predictors of HBV and HCV reactivation in patients with psoriasis receiving biologics.This study screened 2060 patients with psoriasis (3562 treatment episodes) who were taking biologics from 2009 to 2018. There were 359 patients with psoriasis with HBV (561 treatment episodes) and 61 with HCV infection (112 treatment episodes).During 8809 and 1522 person-months of follow-up, 88 treatment episodes for HBV involved HBV reactivation, and 14 episodes of HCV involved reactivation. The reactivation rate was significantly higher in treatment episodes of chronic HBV infection than in that of occult HBV (34.3% vs 3.2%, P = .001) and resolved HBV (34.3% vs 5.0%, P .001). The multivariate analysis revealed that being hepatitis B surface antigen seropositive, being hepatitis B e-antigen seropositive, and tumor necrosis factor-α-inhibitor therapy were risk factors for HBV reactivation, whereas antiviral prophylaxis was effective in reducing the risk of HBV reactivation. No predictors were significantly associated with HCV reactivation.Observational design and a lack of a comparison group.Patients with psoriasis on biologics have a risk of HBV and HCV reactivations, particularly those who are seropositive for hepatitis B surface antigen and hepatitis B e-antigen and undergoing tumor necrosis factor-α-inhibitor therapy.

Background Clonorchiasis caused by Clonorchis sinensis is a zoonotic parasitic disease characterized by cholangitis, biliary proliferation, biliary fibrosis, and even cholangiocarcinoma. Our previous study showed that the expression of interleukin (IL)-33 is increased in both humans and mice infected by C. sinensis, suggesting that IL-33 is potentially involved in the pathogenesis of clonorchiasis. However, the roles and potential mechanism of IL-33 underlying remain unknown. Methods Wild-type (WT) and IL-33 knockout (KO) mice (BALB/c female mice) were orally infected with 45 metacercariae of C. sinensis for 8 weeks. Biliary injuries and fibrosis were extensively evaluated. Hepatic type II cytokines (IL-4, IL-13, and IL-10) were detected by ELISA. Results For wild-type mice, we found that the mice infected with C. sinensis showed severe biliary injuries and fibrosis compared with the normal mice that were free from worm infection. In addition, the levels of type II cytokines such as IL-4, IL-13, and IL-10 in infected wild-type mice were significantly higher than in the control mice without infection (P IL-33 KO) prevents the augmentation of biliary injuries and fibrosis caused by C. sinensis infection. Furthermore, the increased levels of these type II cytokines induced by worm infection were also reversed in IL-33 KO mice. Conclusion Our present study demonstrates that IL-33 contributes to the pathogenesis of C. sinensis-induced biliary injuries and repair, which can potentially orchestrate type 2 responses. These findings highlight the pathophysiological role of IL-33 in the progression of clonorchiasis.

BackgroundEvidence from previous studies has confirmed that functionally impaired elderly individuals are susceptible to comorbid anxiety and depression. Network theory holds that the comorbidity emerges from interactions between anxiety and depression symptoms. This study aimed to investigate the fine-grained relationships among anxiety and depression symptoms in the functionally impaired elderly and identify central and bridge symptoms to provide potential targets for intervention of these two comorbid disorders.MethodsA total of 325 functionally impaired elderly individuals from five communities in Xi'an, China, were recruited for our investigation. The GAD-7 and PHQ-9 were used to measure anxiety and depression, respectively. SPSS 22.0 software was used for descriptive statistics, and R 4.1.1 software was used for network model construction, expected influence (EI) evaluation and bridge expected influence (BEI) evaluation.ResultsIn the network, there were 35 edges (indicating partial correlations between symptoms) across the communities of anxiety and depression, among which the strongest edge was A1 “Nervousness or anxiety”-D2 “Depressed or sad mood.” A2 “Uncontrollable worry” and D2 “Depressed or sad mood” had the highest EI values in the network, while A6 “Irritable” and D7 “Concentration difficulties” had the highest BEI values of their respective community. In the flow network, the strongest direct edge of D9 “Thoughts of death” was with D6 “Feeling of worthlessness.”ConclusionComplex fine-grained relationships exist between anxiety and depression in functionally impaired elderly individuals. “Uncontrollable worry,” “depressed or sad mood,” “irritable” and “concentration difficulties” are identified as the potential targets for intervention of anxiety and depression. Our study emphasizes the necessity of suicide prevention for functionally impaired elderly individuals, and the symptom “feeling of worthlessness” can be used as an effective target.

To explore the relationship between maternal sleep in the third trimester and 10-year risk of cardiovascular disease(CVD).From March 2015 to July 2020, a total of 3034 pregnant women aged 18 to 45 years old with single pregnancy at the gestational age of 28 to 40 weeks in 3 hospitals in Hefei were enrolled in the study. Questionnaire survey was conducted to collect general demographic characteristics, lifestyles and sleep status. Total cholesterol(TC) and high-density lipoprotein cholesterol(HDL-C) were measured in venous blood. Restricted cubic spline regression model, Logistic regression model and stratified analysis were used to explore the association between sleep status and 10-year CVD risk.In the third trimester, the average sleep duration was(7.6±1.1) hours and the proportion of bedtime ≥22:00 was 82.7%. Sleep midpoint ≥02:30 accounted for 66.4% and wake up ≥07:00 accounted for 57.6%. The 10-year CVD risk prediction was(2.03±1.86)% and high-risk accounted for 10%(303 cases). In the restricted cubic spline regression, night sleep duration, bedtime, and getup with 10-year CVD risk had a downward trend(Plt;0.001). Logistic regression model result showed that short sleep duration(less than 8 hours) and wake up early(before 07:00 oapos;clock) and sleep midpoint before 02:30 was associated with a significantly higher 10-year CVD risk(OR=1.35, 95%CI 1.05-1.75;OR=2.23, 95%CI 1.71-2.90;OR=1.63, 95%CI 1.26-2.11). Further stratified analysis found that only among pregnant women with later bedtime(after 22:00 oapos;clock), short sleep duration(less than 8 hours) and wake up early(before 07:00 oapos;clock) and sleep midpoint before 02:30 was associated with significantly increased 10-year CVD risk(OR=1.53, 95%CI 1.14-2.05;OR=2.44, 95%CI 1.81-3.28;OR=1.85, 95%CI 1.37-2.50).In the third trimester, exposure to shorter sleep duration(less than 8 hours) or wake up early(before 07:00 oapos;clock) or sleep midpoint before 02:30 may increase the risk of 10-year CVD risk, in particular, for the pregnant women later bedtime(after 22:00 oapos;clock).

The association between human immunodeficiency virus (HIV)/AIDS and suicidality is not well understood, partly because of variability in results. This meta-analysis aimed to investigate the predictive value of HIV/acquired immune deficiency syndrome for incident suicidality.A literature review was conducted of articles published between January 1, 2010, and October 31, 2021. The following databases were searched: Embase, MEDLINE, CINAHL, Web of Science, and Scopus. The search terms included human immunodeficiency virus (HIV), suicidal behavior, auto mutilation, and self-injurious behavior. Observational studies were screened following a registered protocol, and eligible ones were meta-analyzed and followed by meta-regression.A total of 43 studies were included in this systematic review, and a meta-regression included 170,234 participants. The pooled prevalence estimates of suicidal ideation, attempted suicide, and deaths by suicide were 22.3%, 9.6%, and 1.7%, respectively. The following significant risk factors for suicide ideation were found: substance use, depression, low quality of life, low social support, without HIV status disclosure, living alone, low level of memory problems, family history of suicide, and stage III of HIV. Risk factors for suicide attempts were depression and family history of suicide. An elevated risk for suicide-related death was found for people living with HIV (PLHIV) who had a psychiatric disorder and in studies conducted in hospital-based settings (versus national database studies or HIV clinic settings).The risk of suicidality is high among PLHIV within all six World Health Organization regions during the modern antiretroviral therapy era. Assessment of socioeconomic and psychological factors is recommended for further management to prevent suicide among PLHIV. The present findings are useful for design of intervention protocols and development of clinical practice guidelines intended to manage the well-being of PLHIV worldwide.

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

Boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and anti-tumor efficacy. Atopic dermatitis is a chronic, non-infectious inflammatory skin disease. However, the effects of α-boswellic acid on atopic dermatitis have not been studied. Therefore, in this study we examined the expression level of pro-inflammatory cytokines, histopathological analysis, and physiological data from BALB/c mice with atopic-like dermatitis induced by 2,4-dinitrochlorobenzene and TNF-α/IFN-γ-stimulated HaCaT cells to better understand the agent’s anti-atopic dermatitis efficacy. First, we found that α-boswellic reduced the epidermal thickening, mast cell numbers, and dermal infiltration of 2,4-dinitrochlorobenzene-induced atopic-like dermatitis in BALB/c mice. Furthermore, we also found that α-boswellic acid can restore transepidermal water loss and skin reddening in mice. In human keratinocytes inflamed by TNF-α/IFN-γ, α-boswellic acid inhibited MAP kinase activation and showed a reduction in NF-κB nuclear translocation. Finally, α-boswellic acid can reduce the expression level of cytokines (IL-1β, IL-6, and IL-8) following the stimulation of TNF-α/IFN-γ in HaCaT cells. Taken together, our study suggests that α-boswellic acids are a potential component for the development of anti-atopic dermatitis drugs.