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Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves’ disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts (CBC) monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of CBC may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia.

Abstract Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.

Abstract Background COVID-19 is a new infectious disease. To investigate whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the adverse reactions of subcutaneous specific immunotherapy (SCIT) in children. Methods This study was conducted by collecting relevant data from children who underwent house dust mite SCIT from April 3, 2021, to March 18, 2023, including information on the time of COVID-19 infection, symptoms, and adverse reactions after each allergen injection. A mixed effects model was used to analyze the changes in adverse reactions before and after the COVID-19 infection. Results Among the records of adverse reactions from 2658 injections in 123 children who underwent SCIT, the overall adverse reaction rate before COVID-19 infection was 39.8% and 30.0% after COVID-19 infection. Compared with pre-infection with COVID-19, the risks of overall adverse reactions, local adverse reactions, and systemic adverse reactions of immunotherapy after COVID-19 infection were reduced (odds ratio [OR] = 0.24, 0.31, and 0.28, all P

Abstract. Background:. Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants. Methods:. A total of 3053 healthy Han Chinese adults (1922 women) aged 18–79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere–Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance. Results:. All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction

Fretting wear is the main factor restricting the application of titanium alloy as compressor blades. Preparing a kind of high entropy alloy (HEA) coating is an effective way to improve the fretting wear resistance under high temperature conditions. Thus, in the present work, the FeCrAlMoxNby HEA coating was fabricated on a Ti-64 substrate by the laser cladding technology. The phase composition, microstructure and fretting wear resistance of the coating at high temperatures (200 °C, 300 °C and 400 °C) were investigated. It was demonstrated that the laser cladding FeCrAlMoxNby HEA coatings exhibited dense and uniform microstructures consisting of a BCC phase and a Laves phase (Cr2Nb). In addition, the changing trend of phase content of BCC and Laves phase is the same as the trend of atomic content of Mo and Nb respectively. The presence of the Laves phase increases the hardness of the coating. Due to its high hardness and the formation of a protective oxide layer, the coating demonstrated significantly superior resistance to high-temperature fretting wear compared to the substrate. The lowest wear rate is Mo0·5Nb0.5 coating at 300 °C, only 1.3 × 10−6 mm3/N·m. The current results provide a new method to protect titanium alloy's surface from fretting wear damage in high-temperature service environments.

Abstract Background Huangkui Lianchang Decoction (HLD) is a traditional Chinese herbal formula for treating ulcerative colitis (UC). However, its mechanism of action remains poorly understood. The Study aims to validate the therapeutic effect of HLD on UC and its mechanism by integrating network pharmacology, bioinformatics, and experimental validation. Methods UC targets were collected by databases and GSE19101. The active ingredients in HLD were detected by ultra-performance liquid chromatography-tandem mass spectrometry. PubChem collected targets of active ingredients. Protein–protein interaction (PPI) networks were established with UC-related targets. Gene Ontology and Kyoto Encyclopedia (KEGG) of Genes and Genomes enrichment were analyzed for the mechanism of HLD treatment of UC and validated by the signaling pathways of HLD. Effects of HLD on UC were verified using dextran sulfate sodium (DDS)-induced UC mice experiments. Results A total of 1883 UC-related targets were obtained from the GSE10191 dataset, 1589 from the database, and 1313 matching HLD-related targets, for a total of 94 key targets. Combined with PPI, GO, and KEGG network analyses, the signaling pathways were enriched to obtain IL-17, Toll-like receptor, NF-κB, and tumor necrosis factor signaling pathways. In animal experiments, HLD improved the inflammatory response of UC and reduced UC-induced pro-inflammatory factors such as Tumor Necrosis Factor Alpha (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6). HLD suppressed proteins TLR4, MyD88, and NF-κB expression. Conclusions This study systematically dissected the molecular mechanism of HLD for the treatment of UC using a network pharmacology approach. Further animal verification experiments revealed that HLD inhibited inflammatory responses and improved intestinal barrier function through the TLR4/MyD88/NF-κB pathway.

Abstract The analysis of genomic variations in offspring after implantation has been infrequently studied. In this study, we aim to investigate the extent of de novo mutations in humans from developing fetus to birth. Using high-depth whole-genome sequencing, 443 parent-offspring trios were studied to compare the results of de novo mutations (DNMs) between different groups. The focus was on fetuses and newborns, with DNA samples obtained from the families’ blood and the aspirated embryonic tissues subjected to deep sequencing. It was observed that the average number of total DNMs in the newborns group was 56.26 (54.17–58.35), which appeared to be lower than that the multifetal reduction group, which was 76.05 (69.70–82.40) (F = 2.42, P = 0.12). However, after adjusting for parental age and maternal pre-pregnancy body mass index (BMI), significant differences were found between the two groups. The analysis was further divided into single nucleotide variants (SNVs) and insertion/deletion of a small number of bases (indels), and it was discovered that the average number of de novo SNVs associated with the multifetal reduction group and the newborn group was 49.89 (45.59–54.20) and 51.09 (49.22–52.96), respectively. No significant differences were noted between the groups (F = 1.01, P = 0.32). However, a significant difference was observed for de novo indels, with a higher average number found in the multifetal reduction group compared to the newborn group (F = 194.17, P

Subclinical hypothyroidism (SCH) is closely related to insulin resistance, and thyroid-stimulating hormone (TSH) level is an independent factor for insulin resistance associated with subclinical hypothyroidism. This study aims to explore the effects of TSH levels on insulin signal transduction in adipocytes and to establish the role of endoplasmic reticulum (ER) stress in this process. In this study, the SCH mouse model was established, and 3T3-L1 adipocytes were treated with TSH or tunicamycin (TM), with or without 4-phenylbutyric acid (4-PBA), an inhibitor of ER stress. Subclinical hypothyroidism mice exhibited impaired glucose tolerance, inactivation of the IRS-1/AKT pathway, and activation of the IRE1/JNK pathway in adipose tissue, which can all be alleviated by 4-PBA. Supplementation with levothyroxine restored the TSH to normal, alongside alleviated ER stress and insulin resistance in SCH mice, which is characterized by improved glucose tolerance, decreased mRNA expression of IRE1, and decreased phosphorylation of JNK in adipose tissue. In 3T3-L1 adipocytes, TSH induces insulin resistance, leading to a decrease in glucose uptake. This effect is mediated by the downregulation of IRS-1 tyrosine phosphorylation, reduced AKT phosphorylation, and inhibited GLUT4 protein expression. Notably, all these effects can be effectively reversed by 4-PBA. Moreover, TSH induced TNF-α and IL-6 production and upregulated the expression of ER stress markers. Similarly, these changes can be recovered by 4-PBA. These findings indicate that TSH has the capability to induce insulin resistance in adipocytes. The mechanism through which TSH disrupts insulin signal transduction appears to involve the ER stress–JNK pathway.

Abstract Background Thoracic endovascular aortic repair (TEVAR) is a minimally invasive technique used to treat type B aortic dissections. Left subclavian artery (LSA) reconstruction is required when treating patients with involvement of LSA. The best antiplatelet therapy after LSA reconstruction is presently uncertain. Methods This study retrospectively analyzed 245 type B aortic dissection patients who underwent left subclavian artery revascularization during TEVAR. Out of 245 patients, 159 (64.9%) were in the single antiplatelet therapy (SAPT) group, receiving only aspirin, and 86 (35.1%) were in the dual antiplatelet therapy (DAPT) group, receiving aspirin combined with clopidogrel. During the 6-month follow-up, primary endpoints included hemorrhagic events (general bleeding and hemorrhagic strokes), while secondary endpoints comprised ischemic events (left upper limb ischemia, ischemic stroke, and thrombotic events), as well as death and leakage events. Both univariate and multivariate Cox regression analyses were performed on hemorrhagic and ischemic events, with the Kaplan-Meier method used to generate the survival curve. Results During the six-month follow-up, the incidence of hemorrhagic events in the DAPT group was higher (8.2% vs. 30.2%, P

Abstract Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis. Graphical Abstract

For the difficulty of pinpointing of tunneling machines in the complex environment of coal mine tunnels,a precise positioning method of roadheader based on inertial navigation and visual fusion is proposed, which uses a positioning scheme of inertial navigation plus "vision+laser target". With the designed four feature point large-sized laser target fixed on the roof of the tunnel and the camera on the tunneling machine to collect laser target images, the scheme uses the circular fitting method to locate the center of the light spot and the EPnP algorithm based on four feature points to calculate the position of the tunneling machine. A “vision+laser target” position detection experiment was conducted in simulated condition of heading face to verify the effectiveness of the method in detecting the position of tunneling machines. The results are as follows: within 30 meters tunnel, the maximum error in the width, position, and height are no more than 28.549, 78.868, and 44.459 mm, which shows accurate detection of the position of the tunneling machine. For the inaccurate pose detection of tunneling machines in inertial navigation measurement, induced by the accumulation of pose errors over time and the machine vibration on the combined positioning system, an improved Sage-Husa adaptive filtering method for inertial navigation and visual information fusion is proposed, which could correct measurement errors by detecting new variance values to improve positioning accuracy. A combined positioning experiment of inertial navigation plus “vision+laser target” was conducted in a simulated heading face environment, using improved Sage-Husa adaptive filtering algorithm to fuse inertial navigation and visual information for comparative analysis, which show that the improved Sage-Husa adaptive filtering algorithm fusion results in smaller positioning errors. The maximum errors of pitch angle, roll angle, and heading angle are 0.029°, 0.051°, and 0.0113°, respectively. Within 30 meters, the position error of tunnel width is within the range of 0.033 m, and the position error of tunnel excavation direction is within the range of 0.062 m. Overall, the proposed inertial navigation plus visual fusion positioning method can meet the accuracy requirements of tunnel excavation positioning.

Abstract Background Tertiary lymphoid structures (TLSs) affect the prognosis and efficacy of immunotherapy in patients with non‐small cell lung cancer (NSCLC), but the underlying mechanisms are not well understood. Methods TLSs were identified and categorized online from the Cancer Digital Slide Archive (CDSA). Overall survival (OS) and disease‐free survival (DFS) were analyzed. GSE111414 and GSE136961 datasets were downloaded from the GEO database. GSVA, GO and KEGG were used to explore the signaling pathways. Immune cell infiltration was analyzed by xCell, ssGSEA and MCP‐counter. The analysis of WGCNA, Lasso and multivariate cox regression were conducted to develop a gene risk score model based on the SU2C‐MARK cohort. Results TLS‐positive was a protective factor for OS according to multivariate cox regression analysis (p = 0.029). Both the TLS‐positive and TLS‐mature groups exhibited genes enrichment in immune activation pathways. The TLS‐mature group showed more activated dendritic cell infiltration than the TLS‐immature group. We screened TLS‐related genes using WGCNA. Lasso and multivariate cox regression analysis were used to construct a five‐genes (RGS8, RUF4, HLA‐DQB2, THEMIS, and TRBV12‐5) risk score model, the progression free survival (PFS) and OS of patients in the low‐risk group were markedly superior to those in the high‐risk group (p < 0.0001; p = 0.0015, respectively). Calibration and ROC curves indicated that the combined model with gene risk score and clinical features could predict the PFS of patients who have received immunotherapy more accurately than a single clinical factor. Conclusions Our data suggested a pivotal role of TLSs formation in survival outcome and immunotherapy response of NSCLC patients. Tumors with mature TLS formation showed more activated immune microenvironment. In addition, the model constructed by TLS‐related genes could predict the response to immunotherapy and is meaningful for clinical decision‐making.

Abstract Background This study was designed to assess the associations between emerging cardiometabolic indices—the atherogenic index of plasma (AIP), the stress hyperglycemia ratio (SHR), the triglyceride-glucose (TyG) index, and the homeostasis model assessment of insulin resistance (HOMA-IR)—and the incidence of diabetic kidney disease (DKD) in type 2 diabetes (T2D) patients. Methods We consecutively enrolled 4351 T2D patients. The AIP, SHR, TyG index, and HOMA-IR were calculated from baseline parameters. DKD was defined as a urine albumin/creatinine ratio > 30 mg/g or an eGFR

Abstract Background The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. Methods We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. Results The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients’ fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. Conclusions The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Introduction: Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce. Methods: We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing. Results: Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo). Conclusions: SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

Evaluating the health of river surface water is essential, as rivers support significant biological resources and serve as vital drinking water sources. While the Water Quality Index (WQI) is commonly employed to evaluate surface water quality, it fails to consider biodiversity and does not fully capture the ecological health of rivers. Here we show a comprehensive assessment of the ecological health of surface water in the lower Yangtze River (LYR), integrating chemical and biological metrics. According to traditional WQI metrics, the LYR's surface water generally meets China's Class II standards. However, it also contains 43 high-risk emerging contaminants; nitrobenzenes are found at the highest concentrations, representing 25–90% of total detections, while polycyclic aromatic hydrocarbons present the most substantial environmental risks, accounting for 81–93% of the total risk quotient. Notably, the plankton-based index of biological integrity (P-IBI) rates the ecological health of the majority of LYR water samples (59.7%) as ‘fair’, with significantly better health observed in autumn compared to other seasons (p

Summary: This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).

BackgroundInhibition of indolamine-2,3-dioxygenase 1 (IDO1) has been proposed as a promising strategy for cancer immunotherapy; however, it has failed in clinical trials. Macrophages in the tumor microenvironment (TME) contribute to immune escape and serve as potential therapeutic targets. This study investigated the expression pattern of IDO1 in TME and its impact on prognosis and therapeutic response of patients with esophageal squamous cell carcinoma (ESCC).MethodsRNA sequencing data from 95 patients with ESCC from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic value of IDO1. Bioinformatics tools were used to estimate scores for stromal and immune cells in tumour tissues, abundance of eight immune cell types in TME, and sensitivity of chemotherapeutic drugs and immune checkpoint (IC) blockage. The results were validated using digitalized immunohistochemistry and multiplexed immunofluorescence in ESCC tissue samples obtained from our clinical center.ResultsTCGA and validation data suggested that high expression of IDO1 was associated with poor patient survival, and IDO1 was an independent prognostic factor. IDO1 expression positively correlated with macrophages in TME and PDCD1 within diverse IC genes. Single-cell RNA sequencing data analysis and multiplexed immunofluorescence verified the coexpression of IDO1 and PD-1 in tumor-associated macrophages (TAMs). Patients with high IDO1 expression showed increased sensitivity to various chemotherapeutic drugs, while were more likely to resist IC blockage.ConclusionThis study identifies IDO1 as an independent prognostic indicator of OS in patients with ESCC, reveals a compelling connection of IDO1, PD-1, and TAMs, and explores the sensitivity of patients with high IDO1 expression to chemotherapeutic drugs and their resistance to IC blockade. These findings open new avenues for potential targets in ESCC immunotherapy.

Background: Fertility rates are declining globally, and male infertility is increasingly recognized as a significant challenge. This study aims to present the latest findings on the effectiveness and safety of combining traditional Chinese medicine (TCM) with L-carnitine (LC) for treating male infertility. Methods: We searched 8 databases. Randomized controlled trials of TCM combined with LC therapy versus LC alone in the treatment of male infertility. The outcome included: pregnancy rate, sperm motility, concentration, volume, viability and liquefaction time. Subgroup analyses were also performed according to type of TCM, type of dosage form, and different TCM treatments, and the source of the high heterogeneity was explored. The study is registered on PROSPERO (CRD42023421497). Results: 1129 subjects from 12 of the 1833 eligible studies fulfilled the criteria. Compared with LC treatment alone, the combination of TCM and LC significantly improved pregnancy rate [RR = 1.65, 95 % CI (1.37–2.00)], grade (a+b) sperm motility [SMD = 1.56, 95 % CI (1.12, 2.01)], grade (a) sperm motility [SMD = 1.04, 95 % CI (0.69, 1.38)], sperm concentration [SMD = 1.39, 95 % CI (0.91, 1.86)], and sperm viability [SMD = 1.72, 95 % CI (0.83, 2.60)]. Subgroup analyses indicated that Compound Xuanju Capsule and Yougui Capsule demonstrated better efficacy. And the decoction and not-decoction each had their own advantages. Conclusions: The combination of TCM with LC can have a dual effect: increasing pregnancy rates and sperm quality. Therefore, this combination is a recommended therapeutic strategy and a more appropriate type of TCM can be selected according to the patient's own characteristics.

A series of flavonol derivatives containing piperidine sulfonamide were designed and synthesized. The EC50 values for the curative of tobacco mosaic virus (TMV) by Z6 and Z22 were 108.2 and 102.7 μg/mL, respectively, outperforming the control agent ningenmycin (NNM) with an EC50 value of 253.8 μg/mL. Additionally, the EC50 values for the protective activity of Z6 and Z21 were 100.9 and 123.2 μg/mL, respectively, also surpassing the control agent NNM with an EC50 value of 203.7 μg/mL. Microscale thermophoresis (MST) and molecular docking test showed that Z6 bound well with tobacco mosaic virus coat protein (TMV-CP). The biological safety test showed that Z6 had almost no effect on seed germination and seedling growth. After treatment with Z6, the chlorophyll content and superoxide dismutase (SOD) activity in tobacco leaves increased, while the malondialdehyde (MDA) content decreased. Therefore, Z6 has a high probability as a potential antiviral agent.

BackgroundIn recent years, the decline in sperm quality in men has become a global trend. There is a close relationship between sperm quality and pregnancy outcome. There is a large body of literature supporting the role of plasma lipidome in male infertility, while the complex mechanisms between them and male infertility are still less clear. Systematic study of the causal relationship between plasma lipidome and MI can help to provide new therapeutic ideas and targets for male infertility.MethodsIn this study, we used a two-sample Mendelian randomization analysis based on Genome-wide association studies pooled data of 179 causal relationships between plasma lipidome and male infertility. We used employed the inverse variance weighted method as the main analysis to assess causality between exposure and outcome, in addition to MR-Egger, Weighted median as complementary methods, and tests for multiplicity and heterogeneity.ResultsWe identified 13 plasma lipidome comprising 4 types of plasma lipidome that were associated with male infertility. Among these, 9 plasma lipidome were found to be protective factors, while 4 were risk factors. Notably, the largest proportion of these plasma lipidome were triglyceride types, with Sphingomyelin (d40:1) exhibiting the strongest association with male infertility.ConclusionThese findings contribute to the current better understanding of male infertility and provide new perspectives on the underlying etiology of male infertility as well as prevention and treatment strategies. In addition, clinical trial validation is needed to assess the potential of these plasma lipidome as biomarkers.

Summary: Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs.

The molecular mechanisms driving the onset and metastasis of prostate cancer remain poorly understood. Actin, under the control of actin-binding proteins (ABPs), plays a crucial role in shaping the cellular cytoskeleton, which in turn supports the morphological alterations in normal cells, as well as the invasive spread of tumor cells. Previous research indicates that ABPs of various types serve distinct functions, and any disruptions in their activities could predispose individuals to prostate cancer. These ABPs are intricately implicated in the initiation and advancement of prostate cancer through a complex array of intracellular processes, such as severing, linking, nucleating, inducing branching, assembling, facilitating actin filament elongation, terminating elongation, and promoting actin molecule aggregation. As such, this review synthesizes existing literature on several ABPs linked to prostate cancer, including cofilin, filamin A, and fascin, with the aim of shedding light on the molecular mechanisms through which ABPs influence prostate cancer development and identifying potential therapeutic targets. Ultimately, this comprehensive examination seeks to contribute to the understanding and management of prostate diseases.

The hydrolysis of MgH2 delivers high hydrogen capacity (15.2 wt%), which is very attractive for real-time hydrogen supply. However, the formation of a surface passivation Mg(OH)2 layer and the large excess of H2O required to ensure complete hydrolysis are two key challenges for the MgH2 hydrolysis systems. Now, a low-cost method is reported to synthesize MgH2@Mg(BH4)2 composite via ball-milling MgH2 with cheap and widely available B2O3 (or B(OH)3). By adding small amounts of B2O3, the in-situ formed Mg(BH4)2 could significantly promote the hydrolysis of MgH2. In particular, the MgH2–10 wt% B2O3 composite releases 1330.7 mL·g−1 H2 (close to 80% theoretical hydrogen generation H2) in H2O and 1520.4 mL·g−1 H2 (about 95%) in 0.5 M MgCl2 in 60 min at 26 °C with hydrolysis rate of 736.9 mL·g−1·min−1 and 960.9 mL·g−1·min−1 H2 during the first minute of the hydrolysis, respectively. In addition, the MgCl2 solution allows repeated use by filtering and exhibits high cycle stability (20 cycles), therefore leading to much reduced capacity loss caused by the excess H2O. We show that by introducing B2O3 and recycling the 0.5 M MgCl2 solution, the system hydrogen capacity can approach 5.9 wt%, providing a promising hydrogen generation scheme to supply hydrogen to the fuel cells.

Abstract Effective conflict management is pivotal for achieving innovation performance within standardization alliances, particularly those for the Belt and Road Initiative (B&R Initiative). However, existing research has paid limited attention to the interdependent relationship between influencing factors of conflicts in these alliances. To address this gap, this paper employs the interpretative structure model (ISM) to establish mutual relationships among 16 identified influencing factors. The results show that target difference, unbalanced input of resources, and unreasonable distribution of benefits are recognized as key facilitators at the top level, while political risks, impact of financial factors, and policy changes are identified as foundational drivers at the bottom level. At the intermediate level, factors such as demand difference, technical capabilities difference, cognitive difference, value pursuit difference, information asymmetry, lack of trust, poor communication, resource dependency, and unreasonable contribution evaluation are positioned. These identified interdependence relationships offer crucial reference information for conflict management in standardization alliances for the B&R Initiative.

In the evolving landscape of global education, understanding the intricacies of interpersonal dynamics in academic settings across different linguacultures is paramount for building effective multicultural teaching environments. This study investigates the usage of T/V pronominal forms of address within teacher-student interactions in Chinese and Russian academic contexts. It aims to reveal similarities and differences in the usage of pronominal forms of address in the two linguacultural contexts and unveil the impact of sociocultural factors, namely power and solidarity, on their choice. The data were obtained from a parallel questionnaire survey with the participation of 360 students (260 Chinese mainland students and 100 Russian students) and an interview with 30 students from each country. Employing a comprehensive dual-methodology approach, this study combines quantitative analyses of T/V forms of address frequencies with qualitative insights on their pragmatics, appropriateness, and students’ preferences from interviews. The findings revealed distinct T/V form usage strategies in Chinese and Russian academic discourse. They showed that Chinese teachers predominantly use the T form for students, while students use both V and T forms for teachers. Conversely, Russian settings show a prevalence of the reciprocal V form in teacher-student interactions, with some limited usage of the T form by teachers with students. The results underscore the significance of hierarchical relationships, the demonstration of power distance, and, at the same time, solidarity in the Chinese context, while Russian students and teachers emphasise reciprocal formality in relationships and maintain boundaries. We suggest that different types of interaction between teachers and students in two cultural contexts are due to differences in the sociocultural organisation of society and cultural values. The study provides insights for educators and researchers navigating linguistic and cultural diversity in academic contexts and contributes to effective interaction in a multicultural educational environment.

Abstract Background Traditional pesticides are poorly water-soluble and suffer from low bioavailability. N-succinyl chitosan (NSCS) is a water-soluble chitosan derivative, has been recently used to encapsulate hydrophobic drugs to improve their bioavailability. However, it remains challenging to synthesize pesticides of a wide variety of water-soluble drugs and to scale up the production in a continuous manner. Results A synthetic method for preparing water-soluble nanopesticides with a polymer carrier was applied. The bioactive molecule BTL-11 was loaded into hollow NSCS to promote drug delivery, improve solubility and anti-fungal activity. The synthesized nanopesticides had well controlled sizes of 606 nm and the encapsulation rate was 80%. The release kinetics, drug toxicity and drug activity were further evaluated. The inhibitory activity of nanopesticides against Rhizoctonia solani (R. solani) was tested in vivo and in vitro. In vivo against R. solani trials revealed that BTL-11 has excellent control efficiency for cultivated rice leaf and sheath was 79.6 and 76.5%, respectively. By contrast, for BTL-11@NSCS NPs, the anti-fungal ability was strongly released and afforded significant control efficiencies of 85.9 and 81.1%. Those effects were significantly better than that of the agricultural fungicide azoxystrobin (51.5 and 66.5%). The proposed mechanism was validated by successfully predicting the synthesis outcomes. Conclusions This study demonstrates that NSCS is a promising biocompatible carrier, which can enhance the efficacy of pesticides, synergistically improve plant disease resistance, protect crop growth, and can be used for the delivery of more insoluble pesticides. Graphical Abstract

Abstract Background This study aimed to evaluate stomatological students’ learning efficacy and their attitude towards Lecture-Team-Based Learning (LTBL) on topics regarding the design of removable partial dentures via in-class, online, and both in combination. Methods Students from seven distinct grades participated in the course in their fourth academic year (Years 2015, 2016, 2017, 2018, 2019, 2020, and 2021). Students of Years 2015–2019 attended in-class LTBL, students of Year 2020 attended online LTBL, and students of Year 2021 attended the combination mode. The scores of three examinations were compared, namely, individual readiness assessment test, team readiness assurance test, and individual application test. Visual Analog Scales (VAS) were used for students to self-assess their mastery of prosthodontics knowledge before and after the course. Anonymous questionnaires were delivered to evaluate their satisfaction with LTBL via a Likert scale. Results In each academic year, the three exam scores were significantly improved as the course progressed and VAS-post scores were significantly higher than VAS-pre scores. The three examination and VAS scores of students in Year 2020 were significantly lower than those in Years 2019 and 2021. Students were highly satisfied with the LTBL course based on the three parameters of knowledge acquisition, teamwork, and classroom atmosphere. Conclusion Students were highly satisfied with the LTBL course and their learning performance was improved as the course progressed both in-class and online. Online LTBL could be adopted when students have to study online, while in-class LTBL could perform better when combined with video records of an online LTBL course.

Abstract Background Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. Method Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. Result Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved β cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. Conclusion Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

Abstract Background Roux-en-Y gastric bypass (RYGB) surgery is an effective metabolic surgery against diabetes and obesity. Clinical evidence indicates that patients with severe obesity have a poor curative effect in losing weight if they suffer from leptin or its receptor deficiency, but the underlying mechanism remains elusive. Here, we investigated the effect of leptin receptor deficiency on metabolic dysfunction in db/db mice treated by RYGB surgery. Methods The db/db mice and their heterozygote control db/m mice were subjected to RYGB or sham surgery. Body weight, blood glucose, food intake and glucose tolerance were evaluated. Micro-PET/CT and histological analysis were performed to examine the glucose uptake of tissues and the fat changes in mice. The key factors in glucose and fatty acid metabolism were detected by western blot analysis. Results Compared with the sham group, the db/db mice in the RYGB group showed more significant weight regain after surgical recovery and improvement in hyperinsulinemia and glucose tolerance. However, the total body fat and multiple organ lipid deposition of RYGB-treated db/db mice was increased. The underlying mechanism studies suggested that the activation of AMPK regulated GLUT4 to increase glucose uptake, but AMPK could not promote fatty acid oxidation through the JAK2/STAT3 pathway under leptin receptor deficiency in db/db mice. Conclusion We conclude that leptin receptor deficiency impedes the AMPK activation-mediated fat catabolism but does not affect AMPK-related glucose utilization after metabolic surgery in db/db mice. This result helps select surgical indications for patients with obesity and diabetes.

Abstract Background Right-side aortic arch concomitant with Kommerell’s diverticulum (KD) is a rare and complex ailment, and there is no consensus on the optimal strategy to deal with this congenital anomaly. We retrospectively analyzed and summary of the cases treated in our center with individual treatment methods for different situations. Methods Between September 2018 and December 2021, 10 patients experienced surgical therapy at our institution who presented with a Kommerell’s diverticulum arising from an aberrant subclavian artery from the right-side aortic arch. Four main surgical techniques were applied to those patients: 1. total arch replacement with frozen elephant trunk implantation (n = 2); 2. hybrid procedure combining open arch repair and endovascular intervention (n = 1); 3. total endovascular repair using thoracic endovascular aortic repair (TEVAR) with or without left subclavian artery (LSCA) revascularization (n = 6); 4. direct repair underwent endoaneurysmorrhaphy. Clinical characteristics and outcomes were collected. Results The mean age of these 10 patients was 56.5 years (range 29–79 years) and only 1 woman. The pathology includes aortic dissection (n = 6) and aneurysm (n = 4). The mean diverticulum size was 41.4 [24.2–56.8] mm. There were no in-hospital deaths, and the median hospital stay was 22 [15–43] days. During the follow-up period (21.4 months, 1–44 months), one died of an unknown cause and one died of esophageal fistula. Two patients underwent second-stage endovascular intervention for distal lesion. And none of the patients had endoleak during the follow-up period. Conclusions Each of the procedures we have mentioned here has its advantages and disadvantages; individualized treatment should meet the appropriate indications. A single-branched stent graft is feasible and effective in the treatment of aortic disease combined with Kommerell’s diverticulum.

In this article, we develop a generic controlled alternate quantum walk model by combining parity-dependent quantum walks with distinct arbitrary memory lengths and propose a hash function (called QHFM-P) based on this model. The statistical properties of the proposed scheme are stable with respect to the coin parameters of the underlying controlled quantum walks, and with certain parameter values, the collision resistance property of QHFM-P is better than that of the state-of-the-art hash functions based on discrete quantum walks. Moreover, the proposed hash function can also maintain near-ideal statistical performance when the input message is of small length. In addition, we derive a type of inappropriate initial states of hash functions based on 1-D one-particle quantum walks (with ordinary shift operator) on cycles, with which all messages will be mapped to the same hash value, regardless of the angles adopted by the coin parameters.

ObjectiveThe association of age-related macular degeneration (AMD) with the intake of high and low fatty acids (FAs), respectively, remains controversial. To this end, we performed a comprehensive meta-analysis of all the existing studies on the association of various intake levels of FA subtypes with AMD to determine these associations.MethodsA systematic search of PubMed, Web of Science, Cochrane Library, and EMBASE databases was conducted from inception to September 2023. To compare the highest and lowest groups, odds ratio (OR) with 95% confidence intervals (CIs) was analyzed with a random-effects model/fixed-effects model.ResultsA high intake of omega-3 LCPUFAs (OR:0.67; 95%CI:[0.51, 0.88]; p = 0.004), DHA (OR:0.80; 95%CI:[0.70, 0.90]; p

Epidermoid cyst of the spleen is a rare disease, and relatively few cases were reported by literatures. Most published case reports provided inadequate information on the impact of splenic epidermoid cyst on tumor markers. A 32-year-old woman with a giant splenic epidermoid cyst was reported, for whom the serum concentration of a collection of tumor markers (CA19–9, CEA, CA125, CA242, and CA50) increased abruptly accompanied by left upper abdominal pain for 5 days. After comprehensive preoperative examination and multidisciplinary team discussion, we ruled out any concurrent malignancy and a laparoscopic total splenectomy was performed, during which the splenic cyst spontaneously ruptured unexpectedly. After surgery, the elevated serum tumor marker levels decreased sharply until reaching normal range 3 months later. Learning from the case, we conclude that interval monitoring of serum tumor markers is of critical value for patients with splenic epidermoid cyst. Abrupt elevation of tumor marker levels and abdominal pain may serve as signs of cyst rupture, which is strongly indicative of surgical intervention as soon as possible. Total removal of the splenic cyst is strongly suggested considering the recurrence and malignant potential of the splenic epidermoid cyst.

Objective: Prostate cancer, marked by a high incidence and mortality rate, presents a significant challenge, especially in the context of castration-resistant prostate cancer (CRPC) with limited treatment options due to drug resistance. This study aims to explore the anti-tumor effects of Xihuang Pills (XHP) on CRPC, focusing on metabolic reprogramming and the Wnt/β-catenin pathway. Methods: In vitro and in vivo biofunctional assays were employed to assess the efficacy and mechanisms of XHP. Subcutaneous xenografts of PC3 in mice served as an in vivo model to evaluate XHP's anti-tumor activity. Tumor volume, weight, proliferation, and apoptosis were monitored. Various assays, including CCK8, TUNEL assay, QRT-PCR, and Western Blotting, were conducted to measure metabolic reprogramming, proliferation, apoptosis, and cell cycle in prostate cancer cells. RNA-seq analysis predicted XHP's impact on prostate cancer, validating the expression of Wnt/β-catenin-related proteins and mRNA. Additionally, 58 compounds in XHP were identified via LC-MS/MS, and molecular docking analysis connected these compounds to key genes. Results: In vitro and in vivo experiments demonstrated that XHP significantly inhibited CRPC cell viability, induced apoptosis, and suppressed invasion and migration. mRNA sequencing revealed differentially expressed genes, with functional enrichment analysis indicating modulation of key biological processes. XHP treatment downregulated Wnt signaling pathway-related genes, including CCND2, PRKCG, and CCN4. Moreover, XHP effectively inhibited glucose uptake and lactate production, leading to reduced HIF-1α and glycolytic enzymes (GLUT1, HK2, PKM2), suggesting its potential in attenuating the Warburg effect. Molecular docking analysis suggested a plausible interaction between XHP's active compounds and Wnt1 protein, indicating a mechanism through which XHP modulates the Wnt/β-catenin pathway. Conclusion: XHP demonstrated remarkable efficacy in suppressing the growth, proliferation, apoptosis, migration, and invasiveness of prostate tumors. The interaction between XHP's active constituents and Wnt1 was evident, leading to the inhibition of Wnt1 and downstream anti-carcinogenic factors, thereby influencing the β-catenin/HIF-1α-mediated glycolysis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome with heterogeneous symptoms, which makes it a challenge for early diagnosis. The mutation of VPS13A is considered intimately related to the pathogenesis of ChAc. To date, diverse mutation patterns of VPS13A, consisting of missense, nonsense, and frameshift mutations, have been reported. In this study, we first report a clinical case that was misdiagnosed as epilepsy due to recurrent seizures accompanied by tongue bite for 9 months, which was not rectified until seizures were controlled and involuntary orolingual movements with awareness became prominent and were confirmed to be orolingual dyskinesia. The patient was eventually diagnosed as ChAc based on whole-exome sequencing revealing novel homozygous c.2061dup (frameshift mutation) and c.6796A > T dual mutations in VPS13A. The patient from a family with consanguineous marriage manifested epileptic seizures at onset, including both generalized tonic–clonic seizures and absence but normal long-term electroencephalography, and gradually developed orofacial dyskinesia, including involuntary tongue protrusion, tongue biting and ulcers, involuntary open jaws, occasionally frequent eye blinks, and head swings. The first test of the peripheral blood smear was negative, and repeated checks confirmed an elevated percentage of acanthocytes by 15–21.3%. Structural brain MRI indicated a mildly swollen left hippocampus and parahippocampal gyrus and a progressively decreased volume of the bilateral hippocampus 1 year later, along with atrophy of the head of the caudate nucleus but no progression in 1 year. We deeply analyzed the reasons for long-term misdiagnosis in an effort to achieve a more comprehensive understanding of ChAc, thus facilitating early diagnosis and treatment in future clinical practice.

Using data from 30-province/autonomous in China, this study systematically examines the impact and transmission mechanism of increased income and climate change on energy consumption. This study innovatively uses urbanization and industrial structure upgrade indicators to examine the indirect mechanism of income impact on energy consumption. The findings indicate that income has direct and indirect impacts on energy consumption. Income can directly affect energy consumption and the impact has an inverted U shape. In addition, income can indirectly reduce energy consumption by promoting urbanization and industrial structure upgrading. Climate change also has a significant negative effect on energy consumption; however, the climate effect of energy consumption is smaller than the income effect. Additionally, the impact of income on energy consumption has significant temporal and regional differences. Temporally, income shows a significant upward trend in reducing energy consumption. Regionally, in the developed eastern region, income has a negative impact on energy consumption. In the underdeveloped western region, income has a significant positive impact on energy consumption. Considering the characteristics of China's energy consumption, we should resist the “one size fits all” energy policy and focus on improving energy consumption on income growth, urbanization, and industrial structure, enhancing the efficiency and targeting.

The relationship between the composite dietary antioxidant index (CDAI), a comprehensive measure of individual dietary antioxidants, and the prevalence and mortality of metabolic syndrome (MetS) remains unknown. We aimed to explore these relationships in the National Health and Nutrition Examination Survey (NHANES). We explored these relationships using two independent cohorts. First, we addressed CDAI and the prevalence of MetS in the general population; second, we explored the association between CDAI and mortality in patients with MetS by following NHANES 2001–2018 participants through December 31, 2019. In addition, restricted cubic spline (RCS), stratified analysis, and sensitivity analysis were used for further interpretation. We included 24,514 participants aged 20–85 years, in which the prevalence of MetS was 27.61 %. CDAI was negatively and dose-responsively associated with the prevalence of MetS, however it was not associated with mortality in patients with MetS. In addition, CDAI was associated with a reduced prevalence of certain components of MetS, including dyslipidemia and central obesity. RCS showed a linear correlation between CDAI and MetS and the above components. Stratified analyses indicated that alcohol consumption was a significant influence of CDAI-MetS and that socioeconomic status and lifestyle specificity existed. Sensitivity analysis confirmed the stability of the results. CDAI was protective against the development of MetS in the general population, but not against mortality in patients with MetS. Clinicians need to develop individualized prevention strategies to reduce the development of MetS by modifying CDAI.

ObjectiveThis study was conducted to develop a comprehensive nomogram for individuals with choroidal melanoma (CM) to determine their cancer-specific survival (CSS).MethodsData of individuals with CM, diagnosed between 2004 and 2015, were accessed at the Surveillance, Epidemiology, and End Results (SEER) database. The selected individuals were randomly categorized into a training and validation cohort. Multivariate Cox regression analysis was applied to screen the relevant variables. Followed by the development of a nomogram based on independent variables. Ultimately, the net reclassification index (NRI), concordance index (C-index), calibration charts, integrated discrimination improvement (IDI), receiver operating characteristic curves (ROC), area under the curve (AUC), and decision-curve analysis (DCA), were utilized to evaluate the discrimination, accuracy, and effectiveness of the model.ResultsThis study enrolled 3,782 patients. Seven independent factors linked to prognosis were screened via multivariate Cox regression analysis, encompassing age at diagnosis; race; AJCC (American Joint Committee on Cancer) stage; histologic type; and therapy method of radiotherapy, surgery, and chemotherapy. The respective C-indexes of the training and validation cohorts were 0.709 and 0.726, indicative of the excellent accuracy of the nomogram. Furthermore, the AUCs of the training and validation cohorts across 3, 5, and 8 years were 0.767, 0.744, and 0.722 as well as 0.772, 0.770, and 0.753, respectively. Evident of the superiority of the established nomogram over the AJCC staging, both the NRI and IDI values exhibited improvement. The favorable clinical impact and good performance of the nomogram were evident via decision curve analyses (DCAs) and calibration plots, respectively.ConclusionThis research dealt with establishing and validating a nomogram as a prognostic tool for assessing the prognosis of adult patients with CM utilizing the SEER database. A comprehensive assessment of the nomogram via diverse variables demonstrated its accuracy in predicting the CSS probabilities of CM patients across 3, 5, and 8 years in clinical settings. Notably, its performance surpassed that of the AJCC staging system.

Abstract Three‐dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D‐RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D‐RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D‐RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor‐dependent and vendor‐independent software platforms were used to analyze the 3D‐RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D‐RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D‐RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D‐RV values should be stratified by sex, age, race, and vendor.

BackgroundPostoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of renal function recovery, and their heterogeneity, may underpin poor success in identifying effective therapies.MethodsThis was a retrospective, single-center cohort study in a regional Great Vessel Center including patients undergoing aortic dissection surgery. Estimated glomerular filtration rate (eGFR) recovery trajectories of PO-AKI were defined through the unsupervised latent class mixture modeling (LCMM), with an assessment of patient and procedural characteristics, complications, and early-term survival. Internal validation was performed by resampling.ResultsA total of 1,295 aTAAD patients underwent surgery and 645 (49.8%) developed PO-AKI. Among the PO-AKI cohort, the LCMM identified two distinct eGFR trajectories: early recovery (ER-AKI, 51.8% of patients) and late or no recovery (LNR-AKI, 48.2% of patients). Binary logistic regression identified five critical determinants regarding poor renal recovery, including chronic kidney disease (CKD) history, renal hypoperfusion, circulation arrest time, intraoperative urine, and myoglobin. LNR-AKI was associated with increased mortality, continuous renal replacement therapies, mechanical ventilation, ICU stay, and hospital stay. The assessment of the predictive model was good, with an area under the curve (AUC) of 0.73 (95% CI: 0.69–0.76), sensitivity of 61.74%, and specificity of 75.15%. The internal validation derived a consistent average AUC of 0.73. The nomogram was constructed for clinicians' convenience.ConclusionOur study explored the PO-AKI recovery patterns among surgical aTAAD patients and identified critical determinants that help to predict individuals at risk of poor recovery of renal function.

Introduction Drivers for remission, relapse and violence-related behaviour among patients with schizophrenia are the most complicated issue.Methods and analysis This study aims to recruit a longitudinal cohort of patients with schizophrenia. Two suburban districts and two urban districts were randomly selected according to health service facilities, population, geographical region and socioeconomic status. Individuals (>18 years old) who received a diagnosis of schizophrenia following the International Classification of Diseases (10th edition) criteria within the past 3 years will be invited as participants. Assessments will be carried out in local community health centres. Data will be used to (1) establish a community-based schizophrenia cohort and biobank, (2) prospectively determine the course of multidimensional functional outcomes of patients with schizophrenia who are receiving community-based mental health treatment, and (3) map the trajectories of patients with schizophrenia and prospectively determine the course of multidimensional outcomes based on the differential impact of potentially modifiable moderators.Ethics and dissemination The study has been reviewed and approved by the Human Research Ethics Committee of Shanghai Mental Health Center (2021-67). Results of the study will be disseminated through peer-reviewed journals. If effective, related educational materials will be released to the public.

The amyloid plaque is a hallmark of Alzheimer's disease. The accumulation of the amyloid precursor protein (APP) in the neuronal structure is assumed to lead to amyloid plaque formation through the excessive production of β-amyloid protein. To study the relationship between the neuronal accumulation of APP and amyloid plaque formation, we histologically analyzed their development in the different brain regions in 3xTg-AD mice, which express Swedish mutated APP (APPSWE) in the neurons. Observation throughout the brain revealed APPSWE-positive somata in the broad regions. Quantitative model analysis showed that the somatic accumulation of APPSWE developed firstly in the hippocampus from a very early age (

Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.

Abstract This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab–chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA–IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9–81.0%). For patients with ctDNA– vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Permian Wujiaping Formation in Hongxing area of eastern Sichuan is rich in high-quality shale, and multiple wells have achieved high productivity of industrial gas. It is an important replacement block for the natural gas production capacity of the Jianghan Oilfield. However, due to the complex structure and lithology, deep burial depth of the target layer, and large fluctuations in the attitude of thin reservoirs, complex situations such as well leakage and collapse occuring frequently, low mechanical drilling speed, long drilling cycles, and difficulty in ensuring the drilling rate of high-quality reservoirs seriously restrict the benefit development. Based on the summary of previous data, the drilling difficulties were analyzed, the optimal design of drilling engineering was carried out, and some key rock breaking tools were selected to optimize the density and sealing performance of drilling fluid. The "three opening" wellbore structure with three different diameters, "irregular tooth PDC and mixed drill bits + high torque equal wall thickness screw + reinforced parameter drilling", simple pressure control by a rotary control head, and low density and strong sealing drilling fluid technology for "both leakage and collapse treatment" were formed. We have established a geological engineering integrated guidance technology based on "vertical depth prediction, segmented slope control, and five charts and one table", and proposed the direction for further improvement. The on-site application shows that: (1) the "three opening" wellbore structure with three different diameters meets the safety drilling requirements in Hongxing area, laying the foundation for drilling speed increase. The parameter drilling was enhanced by high-performance PDC, and the mechanical drilling speed of each opening is significantly improved. The drilling speed of the third opening section in the Permian formation increased by 15%, and the horizontal section increased by 22%; (2) The density reduction and nano sealing drilling fluid technology effectively reduced the number and time of complex treatments, and the time for complex treatments was reduced by 20.5% compared to the early implementation of wells; (3) The penetration rate of high-quality reservoirs significantly increased to 93.27%, an increase of 19.85% compared to the previous period.

Abstract Aluminium adjuvants are commonly used in vaccines to stimulate the immune system, but they have limited ability to promote cellular immunity which is necessary for clearing viral infections like hepatitis B. Current adjuvants that do promote cellular immunity often have undesired side effects due to the immunostimulants they contain. In this study, a hybrid polymer lipid nanoparticle (HPLNP) was developed as an efficient adjuvant for the hepatitis B surface antigen (HBsAg) virus-like particle (VLP) vaccine to potentiate both humoral and cellular immunity. The HPLNP is composed of FDA approved polyethylene glycol-b-poly (l-lactic acid) (PEG-PLLA) polymer and cationic lipid 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP), and can be easily prepared by a one-step method. The cationic optimised vaccine formulation HBsAg/HPLNP (w/w = 1/600) can maximise the cell uptake of the antigen due to the electrostatic adsorption between the vaccine nanoparticle and the cell membrane of antigen-presenting cells. The HPLNP prolonged the retention of the antigen at the injection site and enhanced the lymph node drainage of antigen, resulting in a higher concentration of serum anti-HBsAg IgG compared to the HBsAg group or the HBsAg/Al group after the boost immunisation in mice. The HPLNP also promoted a strong Th1-driven immune response, as demonstrated by the significantly improved IgG2a/IgG1 ratio, increased production of IFN-γ, and activation of CD4 + and CD8 + T cells in the spleen and lymph nodes. Importantly, the HPLNP demonstrated no systemic toxicity during immunisation. The advantages of the HPLNP, including good biocompatibility, easy preparation, low cost, and its ability to enhance both humoral and cellular immune responses, suggest its suitability as an efficient adjuvant for protein-based vaccines such as HBsAg-VLP. These findings highlight the promising potential of the HPLNP as an HBV vaccine adjuvant, offering an alternative to aluminium adjuvants currently used in vaccines.

Abstract SUMOylation is an evolutionary conserved regulatory mechanism, in which Ubc9 is the only E2 conjugating enzyme. Previous studies demonstrated that SUMOylation is involved in multiple biological processes, but its role in dendritic cells (DCs) remains to be fully addressed. Herein in this report, we found that DCs deficient in Ubc9 protected mice from dextran sulfate sodium (DSS)-induced colitis, as evidenced by the ameliorated weight loss, colon length, and disrupted colon structure. Mechanistically, Ubc9 mediated SUMOylation of RBPJ, by which it stabilized RBPJ from ubiquitin-mediated degradation to enhance its transcriptional activity, while Ciita, a critical transcription factor, is a direct target downstream of RBPJ, which forms an enhanceosome complex to transcribe the expression of MHC II genes. Therefore, loss of Ubc9 abolished RBPJ SUMOylation, which was coupled with reduced Ciita transcription, thereby attenuating the expression of MHC class II genes. As a consequence of defective MHC II expression, Ubc9 -/- DCs were featured by the impaired capability to process antigen and to prime effector CD4+ T cells, thereby protecting mice from DSS-induced colitis. Together, our results shed novel insight into the understanding of SUMOylation in the regulation of DC functions in pathological conditions.

Abstract Background Artificial induction of polyploidy is the most common and effective way to improve the biological properties of Populus and develop new varieties of this tree. In this study, in order to confirm and expand earlier findings, we established a protocol using colchicine and based on an efficient shoot regeneration system of leaf blades to induce tetraploidy in vitro in three genotypes from diploid Populus hopeiensis. The stomatal characteristics, leaf blade size, and growth were evaluated for diploids and tetraploids of three genotypes. Results We found that genotype, preculture duration, colchicine concentration, and colchicine exposure time had highly significant effects on the tetraploid induction rate. The optimal protocol for inducing tetraploidy in P. hopeiensis was to preculture leaf blades for 7 days and then treat them for 4 days with 40 mg/L colchicine. The tetraploid induction rates of genotypes BT1, BT3, and BT8 were 21.2, 11.4 and 16.7%, respectively. A total of 136 tetraploids were identified by flow cytometry analysis and somatic chromosome counting. The stomatal length, width, and density of leaf blades significantly differed between diploid and tetraploid plants. Compared with their diploid counterparts, the tetraploids produced larger leaf blades and had a slower growth rate. Our findings further document the modified morphological characteristics of P. hopeiensis following whole-genome duplication (e.g., induced tetraploidy). Conclusions We established a protocol for in vitro induction of tetraploidy from diploid leaf blades treated with colchicine, which can be applied to different genotypes of P. hopeiensis.