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Abstract Background Triglyceride-Glucose (TyG) index, a novel surrogate marker for insulin resistance, has been linked to the risk of various cancers, such as breast and colorectal cancers. However, the relationship between the TyG index and its related indices with the risk of pancreatic cancer(PC) remains unclear. Methods This large-scale, prospective cohort study utilized data from the UK Biobank, involving 428,152 participants who were free of PC at baseline. The primary outcome was incident PC. To evaluate the relationships between TyG-related indices and PC onset, covariate-adjusted Cox proportional hazards regression models and restricted cubic spline (RCS) analyses were employed. Additionally, we explored the relationships between TyG-related indices and incident PC within subgroups defined by age, gender, diabetes, hypertension, pancreatitis history, smoking status, and drinking status. Sensitivity analyses were conducted to confirm the robustness of our findings. Results Over an average follow-up period of 13.8 years, a total of 1,759 PC cases occurred. The risk of developing PC increased with higher levels of TyG-related indices. RCS curves illustrated a linear positive relationship between TyG-related indices and incident PC. Subgroup analyses indicated that the relationships between the TyG index, TyG-waist circumference, and TyG-waist-to-hip ratio and PC risk were more pronounced in participants without hypertension, without pancreatitis history, and those with drinking history (P for interaction

Abstract Background Standardized and systematic quality assessments of chronic pain management, particularly among older adult populations, are lacking in resource-limited community settings. A specific set of indicators to evaluate the quality of chronic pain management in this population has yet to be developed. Therefore, the present study constructed a set of indicators to assess the quality of chronic pain management in Chinese community-dwelling older adults, providing a standardized reference and guidance for community health centers to manage chronic pain in this population. Methods The indicator set was developed in three steps. Step 1 involved preparation by forming a research team and establishing the guiding theory. Step 2 included developing an expert inquiry questionnaire based on a literature review and semi-structured interviews. Step 3 completed the construction of the indicator set through the Delphi method and hierarchical analysis to quantify the relative importance of each indicator and ensure the development of a scientifically validated and practically applicable evaluation model. Results The final set of indicators for evaluating the quality of chronic pain management among community-dwelling older adults in China comprised three primary indicators: structural quality indicator, process quality indicator, and outcome quality indicator. Structural quality indicators included 3 secondary and 11 tertiary indicators; process quality indicators included 4 secondary and 21 tertiary indicators; and outcome quality indicators included 2 secondary and 4 tertiary indicators. Across two rounds of questionnaires, the response rate was 100%, with expert authority coefficients of 0.924 and 0.938, coefficients of variation ranging from 0 to 0.32 and 0 to 0.20, and Kendall’s concordance coefficients of 0.302 and 0.220, respectively. Hierarchical analysis showed that the consistency ratios of all indicators were

Abstract Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture (PMR) during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis is less well elucidated. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced only by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that the ferroptosis protective effect caused by NINJ1 knockdown can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhancing cystine uptake and thereby providing protection against ferroptosis. Conversely, NINJ1 overexpression reduced xCT levels and sensitized ferroptosis. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

Abstract The vertical variations and key drivers of ozone and its precursors, namely NOx and VOCs, in the atmospheric boundary layer, have vital impacts on surface ozone budgets but are poorly understood so far. Using online gradient measurements from a 356 m tower, we obtained continuous vertical profiles of ozone and its precursors, which exhibited strong gradients throughout the day. In the daytime, the vertical gradients of ozone precursors are significantly regulated by reactions with OH radicals. At night, our observations confirmed more intense VOC reactions with NO3 radicals in the residual layer than in the boundary layer. Additionally, we found that residual layer entrainment could contribute to over half of the boundary-layer ozone enhancements in the morning periods. Our results underscore the importance of considering vertical changes of ozone and its precursors in the atmospheric boundary layer when developing future ozone mitigation strategies.

Background: Photodynamic therapy (PDT) has been emerging as a promising treatment for unresectable cholangiocarcinoma (CCA). A number of experiments have demonstrated that PDT could enhance antitumor immunity significantly. However, the impact of PDT on peripheral immune system for unresectable CCA remains unclear. Methods: In a clinical trial comparing the perioperative and long-term outcomes of PDT+stent treatment and stent alone treatment for unresectable CCA, we tested the levels of lymphocytes (CD4+ T cells, CD8+ T cells, NK cells, B cells and Treg cells) and immune-related cytokines (IL-4, IL-6, IL-10, TNF-α, TGF-β, perforin, GM-CSF and IFN-γ) in peripheral blood before and after PDT+stent treatment or stent alone treatment and analyzed the influence of PDT on peripheral immune system for unresectable CCA. Results: Before treatment, the levels of all the immune cells and immune-related cytokines did not show significant differences between the PDT+stent group and stent alone group. The ratio of CD8+ T cells increased significantly after PDT treatment, but other kinds of lymphocytes did not show significant difference. Increased level of IL-6 and decreased level of perforin and TGF-β after PDT treatment were demonstrated, whereas no significant changes were found for other immune-related cytokines. Conclusion: PDT altered the levels of immune cells and immune-related cytokines in the peripheral blood of unresectable CCA patients, potentially correlating with the therapeutic efficacy of PDT in unresectable CCA treatment. Future studies could delve deeper into this aspect to explore how PDT can be more effectively utilized in the management of unresectable CCA.

Abstract Chinese Painting and Calligraphy (ChP&C) holds significant cultural value, representing integral aspects of both Chinese culture and global art. A considerable amount of ChP&C works are dispersed worldwide. With the emergence of digital humanities, a vast collection of cultural artifacts data is now available online. However, the online databases of these artifacts remain decentralized and diverse, posing significant challenges to their effective organization and utilization. Addressing this, our paper focuses on the Wu Men School of Painting and proposes a framework for constructing a multimodal knowledge graph for the ChP&C domain. We construct the domain ontology by analyzing the ChP&C knowledge schema. Then, we acquire knowledge from diverse data sources, including textual and visual information. To enhance data collection around collecting historical context and subject matter, we propose methods for seal extraction and subject extraction specific to ChP&C. We validate the effectiveness of these methods on the constructed dataset. Finally, we construct the Wu Men Multimodal Knowledge Graph (WuMKG) and implement applications such as cross-modal retrieval, knowledge-based question-answering and visualization.

Summary: Purpose: Numerous barriers hinder individuals with mental illness from seeking medical assistance in rural regions, yet a comprehensive understanding of these challenges remains elusive. This meta-synthesis aims to understand the barriers and facilitators in medical help-seeking among rural individuals with mental illness. Methods: We systematically searched seven databases [PubMed, CINAHL, Medline (OVID), PsycINFO (OVID), Cochrane, Embase, and ProQuest] in May 2023 and included the studies if they reported the barriers or/and facilitators to seek healthcare in rural patients with mental illness. We conducted hand search and citation search on Google Scholar for literature supplements. Thematic analysis was employed. Results: The study included 27 articles reporting on the barriers and facilitators to seeking medical help in this population from 2007 to 2023. We ultimately identified themes at three levels: navigating the terrain of vulnerability and empowerment (the individual with mental illness), navigating the terrain of external environment (the external environment) and connectivity within the healthcare ecosystem for mental health (the health service system). Conclusions: We must design more effective strategies to improve mental healthcare access for rural patients, considering cultural nuances and health service utilization patterns. This requires a multi-level approach, tailored to the unique needs of diverse populations.

Road hazardous material transportation plays a critical role in road traffic management. Due to the dangerous nature of the cargo, hazardous material transportation trucks (HMTTs) have different route selection and driving characteristics compared to traditional freight trucks. These differences lead to unique travel and emission patterns, which in turn affect traffic management strategies and emission control measures. However, existing research predominantly focuses on safety aspects related to individual vehicle behavior, with limited exploration of the broader travel and emission characteristics of HMTTs. To bridge this gap, this study develops a comprehensive framework for analyzing the travel patterns and emissions of HMTTs. The methodology begins by applying a Gaussian mixture distribution model to identify vehicle stop points, eliminating biases associated with subjective settings. Origin–destination (OD) pairs are then determined through stop time clustering, followed by the extraction of travel characteristics using non-negative matrix factorization. Emissions are subsequently calculated based on the identified trip data. The relationship between emissions and land use characteristics is further analyzed using geographically weighted regression (GWR). Crucially, this study leverages data from the BeiDou Satellite Navigation System, focusing on HMTTs operating within Shanghai. The processed data reveal three distinct travel modes of HMTTs, categorized by spatiotemporal patterns: Daytime—Surrounding cities, Early morning—In-city, and Midnight—Scattered. Moreover, unlike other road vehicles, HMTT emissions are heavily influenced by industrial and company-related points of interest (POIs). These findings highlight the significant role of BeiDou Satellite Navigation System data in optimizing HMTT management strategies to reduce emissions and improve overall safety.

In the context of hepatocellular carcinoma (HCC) treatment, this study introduces a biomimetic “bomb” approach to target HCC by utilizing macrophages (MAs) as ultrasound-responsive carriers. This advanced biomimetic drug delivery system (MAs-DOX/PFP/Ms, MAs-DPM) encapsulates doxorubicin (DOX) and perfluoropentane (PFP) and is designed to precisely target HCC. MAs-DPM exhibits excellent drug loading capacity and biocompatibility, can effectively release DOX and enhance ultrasound imaging capabilities under ultrasound irradiation (UI). Experiments confirmed that MA maintained its biological activity and vitality during co-incubation and phagocytosis with DOX-loaded DPM, and microscopy confirmed that MA effectively engulfed DPM without changing cell morphology or function. Transwell experiments demonstrated that this bionic “bomb” (MAs-DPMs) not only retained the tumor targeting ability of macrophages, but also successfully delivered therapeutic drugs to tumor cells. Compared with samples without UI treatment, UI significantly increased the release of DOX from MAs-DPM, enhanced the drug release rate and inhibited the growth of HCC cells. Live/Dead staining experiments further intuitively revealed the precise “biobomb” effect of MAs-DPM under UI, effectively proving its ability to inhibit HCC cell proliferation. In vivo studies demonstrated that MAs-DPM was able to proficiently localize tumor sites within 24 h. Furthermore, the ultrasound-mediated phase transition of PFP enhanced the imaging efficacy, confirming the feasibility of macrophage-mimicking biological bombs for real-time in vivo ultrasound tracking. In the tumor-bearing nude mouse model, UI-treated MAs-DPMs remarkably delayed tumor growth and prolonged survival time compared with other groups. Subsequent histological and serum index evaluation further confirmed the in vivo safety of MAs-DPMs, and UI-treatment did not induce significant histological or pathological changes or statistical differences in vital organ or serum markers. These experiment results highlight the great potential of MAs-DPM as a strategic approach for the diagnosis and treatment of HCC.

Reports regarding the composition and functions of microorganisms in activated sludge from wastewater treatment plants for treating tuna processing wastewater remains scarce, with prevailing studies focusing on municipal and industrial wastewater. This study delves into the efficiency and biological dynamics of activated sludge from tuna processing wastewater, particularly under conditions of high lipid content, for pollutant removal. Through metagenomic analysis, we dissected the structure of microbial community, and its relevant biological functions as well as pathways of nitrogen and lipid metabolism in activated sludge. The findings revealed the presence of 19 phyla, 1,880 genera, and 7,974 species, with Proteobacteria emerging as the predominant phylum. The study assessed the relative abundance of the core microorganisms involved in nitrogen removal, including Thauera sp. MZ1T and Alicycliphilus denitrificans K601, among others. Moreover, the results also suggested that a diverse array of fatty acid-degrading microbes, such as Thauera aminoaromatica and Cupriavidus necator H16, could thrive under lipid-rich conditions. This research can provide some referable information for insights into optimizing the operations of wastewater treatment and identify some potential microbial agents for nitrogen and fatty acid degradation.

Abstract Background Pancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of LINC00909 in regulating pancreatic cancer stemness and cancer metastasis. Methods The expression level and clinical characteristics of LINC00909 were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People’s Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding LINC00909 was experimented for subsequent bioinformatics analysis. The effect of LINC00909 in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between LINC00909 with SMAD4 and the pluripotency factors were studied. Results LINC00909 was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of LINC00909 enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of LINC00909 decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, LINC00909 inversely regulated SMAD4 expression, knock-down of SMAD4 rescued the effect of LINC00909-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of LINC00909 on pluripotency factors and CSC phenotype was dependent on SMAD4 and MAPK/JNK signaling pathway, another downstream pathway of SMAD4 was also activated by LINC00909. Specifically, LINC00909 was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the SMAD4 mRNA. Finally, we found over-expression of LINC00909 not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models. Conclusion We demonstrate LINC00909 inhibits SMAD4 expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.

Abstract Decoupled electrolysis for hydrogen production with the aid of a redox mediator enables two half-reactions operating at different rates, time, and spaces, which offers great flexibility in operation. Herein, a pre-protonated vanadium hexacyanoferrate (p-VHCF) redox mediator is synthesized. It offers a high reversible specific capacity up to 128 mAh g−1 and long cycling performance of 6000 cycles with capacity retention about 100% at a current density of 10 A g−1 due to the enhanced hydrogen bonding network. By using this mediator, a membrane-free water electrolytic cell is built to achieve decoupled hydrogen and oxygen production. More importantly, a decoupled electrolysis system for hydrogen production and hydrazine oxidation is constructed, which realizes not only separate hydrogen generation but electricity generation through the p-VHCF-N2H4 liquid battery. Therefore, this work enables the flexible energy conversion and storage with hydrogen production driven by solar cell at day-time and electricity output at night-time.

Seawater intrusion poses a significant threat to the water supply of coastal cities both presently and in the future. It is crucial to identify the controllable factors influencing seawater intrusion, both natural and anthropogenic, in order to ensure water supply security. This study examined seawater intrusion characteristics using monitoring data from 1994 to 2019. Factors such as daily flow rate, duration of intrusion, water quality, and tidal level were analyzed to establish correlations and identify the primary influencing factors in the Yangtze River Estuary. The findings reveal that seawater intrusion in this area is most prevalent from November to April, peaking in February and March. The key controllable factors affecting chloride levels at the intake are the daily flow rate at Datong Station and the tidal range at Xuliujing Station. Additionally, the study proposes control methods to safeguard water supply, including providing daily flow rate values for flushing seawater intrusion at Datong Station under different tidal ranges and intrusion durations. These research results provide valuable guidance for the emergency operation of the Three Gorges-centered reservoir group against seawater intrusion.

Objectives: SARS-CoV-2 pneumonia poses significant challenges to health systems worldwide, particularly, in severe and critical cases. Immunosuppressed renal transplant recipients appear to be at a particularly high risk for severe or critical COVID-19 illness. However, few studies elucidated the risk factors of SARS-CoV-2 pneumonia in renal transplant recipients with COVID-19. Methods: A postinfection cross-sectional survey was conducted in 312 renal transplant recipients and 503 age- and sex-matched controls to explore risk factors for SARS-CoV-2 pneumonia in immunosuppressed renal transplant recipients. Results: The results showed that renal transplant recipients had a much higher incidence of SARS-CoV-2 pneumonia (48.1%) after infection with the SARS-CoV-2 Omicron variant than controls (5.6%). The multivariate binary logistic regression analysis identified older age, lower creatinine clearance before infection, and higher dose of prednisone before infection as risk factors for SARS-CoV-2 pneumonia in renal transplant recipients. Preexisting renal dysfunction was a major risk factor for SARS-CoV-2 pneumonia, with an odds ratio of 3.27 (1.01-10.61). Conclusions: Preexisting renal graft dysfunction was a major risk factor for SARS-CoV-2 Omicron variant pneumonia. It is suggested that high-risk renal transplant recipients should undergo computed tomography scanning within 14 days after infection with SARS-CoV-2.

BackgroundAccurate detection of the histological grade of pancreatic neuroendocrine tumors (PNETs) is important for patients’ prognoses and treatment. Here, we investigated the performance of radiological image-based artificial intelligence (AI) models in predicting histological grades using meta-analysis.MethodA systematic literature search was performed for studies published before September 2023. Study characteristics and diagnostic measures were extracted. Estimates were pooled using random-effects meta-analysis. Evaluation of risk of bias was performed by the QUADAS-2 tool.ResultsA total of 26 studies were included, 20 of which met the meta-analysis criteria. We found that the AI-based models had high area under the curve (AUC) values and showed moderate predictive value. The pooled distinguishing abilities between different grades of PNETs were 0.89 [0.84-0.90]. By performing subgroup analysis, we found that the radiomics feature-only models had a predictive value of 0.90 [0.87-0.92] with I2 = 89.91%, while the pooled AUC value of the combined group was 0.81 [0.77-0.84] with I2 = 41.54%. The validation group had a pooled AUC of 0.84 [0.81-0.87] without heterogenicity, whereas the validation-free group had high heterogenicity (I2 = 91.65%, P=0.000). The machine learning group had a pooled AUC of 0.83 [0.80-0.86] with I2 = 82.28%.ConclusionAI can be considered as a potential tool to detect histological PNETs grades. Sample diversity, lack of external validation, imaging modalities, inconsistent radiomics feature extraction across platforms, different modeling algorithms and software choices were sources of heterogeneity. Standardized imaging, transparent statistical methodologies for feature selection and model development are still needed in the future to achieve the transformation of radiomics results into clinical applications.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022341852.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an extremely poor prognosis. Cancer stem cells (CSCs) are considered to be responsible for the poor survival, recurrence and therapy resistance of PDAC. Ferroptosis plays a crucial role in the sustain and survival of CSCs. Here, we employed a rigorous evaluation of multiple datasets to identify a novel stemness-based and ferroptosis-related genes (SFRGs) signature to access the potential prognostic application. This work we retrieved RNA-sequencing and clinical annotation data from the TCGA, ICGC, GTEx and GEO database, and acquired 26 stem cell gene sets and 259 ferroptosis genes from StemChecker database and FerrDb database, respectively. Based on consensus clustering and ssGSEA analysis, we identified two expression patterns of CSCs traits (C1 and C2). Then, WGCNA analysis was implemented to screen out hub module genes correlated with stemness. Furthermore, differential expression analysis, Pearson correlation analysis, and the Least absolute shrinkage and selection operator (LASSO) and Cox regression were performed to identify the SFRGs and to construct model. In addition, the differences in prognosis, tumor microenvironment (TME) components and therapy responses were evaluated between two risk groups. Finally, we verified the most influential marker ARNTL2 experimentally by western blot, qRT-PCR, sphere formation assay, mitoscreen assay, intracellular iron concentration determination and MDA determination assays. In conclusion, we developed a stemness-based and ferroptosis-related prognostic model, which could help predict overall survival for PDAC patients. Targeting ferroptosis may be a promising therapeutic strategy to inhibit PDAC progression by suppressing CSCs.

Abstract Background The incidence of pancreatic cancer (PC) is higher in diabetic patients due to disturbances in glucose and lipid metabolism caused by insulin resistance (IR). However, the effect of diabetes as well as IR on the prognosis of PC patients remains inconclusive. Our study aims to assess the impact of IR on the prognosis of PC patients with diabetes. Methods We conducted a retrospective analysis of 172 PC patients with diabetes in our institute from 2015 to 2021. Prognostic assessment was performed using univariate/multifactorial analysis and survival analysis. The predictive efficacy of metabolic indices was compared using receiver operator characteristic (ROC) curve analysis. Results One hundred twenty‐one of 172 patients died during follow‐up, with a median follow‐up of 477 days and a median overall survival (OS) of 270 days. Survival analysis showed a significant difference in OS by IR related parameters, which were triglyceride‐glucose index (TyG), triglyceride‐glucose index‐body mass index (TyG‐BMI), and triglyceride/high‐density lipoprotein cholesterol ratio (TG/HDL‐c). The ROC curve indicated that TyG, TyG‐BMI, and TG/HDL‐c had prognostic efficacy for PC with diabetes. We next optimized TyG‐BMI and obtained a new parameter, namely glucose‐lipid metabolism index (GLMI), and the patients were classified into GLMI low group and high group based on the calculated cutoff value. The GLMI high group had higher TyG, TyG‐BMI, TyG/HDL‐c, BMI, TG, total cholesterol (TC), TC/HDL‐c, fasting plasma glucose, CA199, and more advanced tumor stage compared to low group. Univariate and multivariate analyses showed that GLMI was an independent prognostic factor. Furthermore, the patients of GLMI high group had worse OS compared to low group and the ROC curves showed GLMI had better predictive ability than TyG and TyG‐BMI. Conclusions IR is associated with the outcome of PC patients with diabetes and higher level of IR indicates worse prognosis. GLMI has a good predictive value for PC with diabetes.

Conclusion: The colonization rate of GBS in the reproductive tract of pregnant women in late pregnancy in the Linyi region is 7.07%. Having a college degree or above, absence of pregnancy vomiting, elevated levels of albumin, globulin, direct bilirubin, glutamyl transferase, and total bile acids, and decreased levels of alkaline phosphatase and lactate dehydrogenase are high-risk factors for GBS infection; ST10, ST19, ST529, and ST862 are the main genotypes prevalent in this region; there are regional differences in the distribution of GBS genotypes and CC groups; there are statistically significant differences in the distribution of virulence factors among GBS strains with different MLST genotypes (p

Underwater target detection is an essential topic in the applications of underwater exploration. However, underwater target detection faces serious challenges, such as complex scattering, low visibility, and target clutter. Here a polarization-enhanced underwater multiple material target detection method is proposed to address these challenges. The similarity principle of locally backscattered polarization features is utilized to suppress the influence of backscattered light. Our target detection model combines polarization gradient and edge detection techniques to optimize the detection process, enabling superior target detection and feature extraction. Experimental results indicate that our method has significantly enhanced the detection performance in multiple (overlapping or nonoverlapping) material targets, especially in high turbid underwater scattering environments. This research provides a promising new approach for polarized target detection in underwater environments and opens up new possibilities for underwater multiple-material target detection.

Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated nuclease 9 (Cas9) screening is a simple screening method for locating loci under specific conditions, and it has been utilized in tumor drug resistance research for finding potential drug resistance-associated genes. This screening strategy has significant implications for further treatment of malignancies with acquired drug resistance. In recent years, studies involving genome-wide CRISPR/Cas9 screening have gradually increased. Here we review the recent application of genome-wide CRISPR/Cas9 screening for drug resistance, involving mitogen-activated protein kinase (MAPK) pathway inhibitors, poly (ADP-ribose) polymerase inhibitors (PARPi), alkylating agents, mitotic inhibitors, antimetabolites, immune checkpoint inhibitors (ICIs), and cyclin-dependent kinase inhibitors (CDKI). We summarize drug resistance pathways such as the KEAP1/Nrf2 pathway MAPK pathway, and NF-κB pathway. Also, we analyze the limitations and conditions for the application of genome-wide CRISPR/Cas9 screening techniques.

Background: Co-diabetes pancreatic adenocarcinoma has a poorer prognosis than pancreatic adenocarcinoma without diabetes. This study aimed to develop a reliable prognostic model for patients with co-diabetes pancreatic adenocarcinoma. Method: Overall, 169 patients with co-diabetes pancreatic adenocarcinoma were included in our study. First, the independent risk factors affecting the prognosis of patients with co-diabetes pancreatic adenocarcinoma were determined by univariate and multivariate Cox regression analyses. Based on these identified risk factors, we developed a nomogram and evaluated its predictive ability using the concordance index, receiver operating characteristic curve, calibration plot, decision curve, and net reclassification index. Results: In this study, prealbumin, transferrin, carcinoembryonic antigen, distant metastasis, tumor differentiation neutrophil count, lymphocyte count and fasting blood glucose were confirmed as significant prognostic factors. Based on these predictors, a new nomogram was developed. Compared with the American Joint Committee on Cancer 8 staging system and other models, the nomogram achieved a higher concordance index in the training (0.795) and validation (0.729) queues. The area under the nomogram's curve for predicting patient survival at 0.5, 1, and 1.5 years in the training queue was >0.8. Patients were risk-stratified using the nomogram, and Kaplan–Meier survival curves of subgroups were plotted. The Kaplan–Meier curve also showed better separation than the American Joint Committee on Cancer 8 staging system, indicating that our model has a better risk hierarchical ability. Conclusions: Compared to the American Joint Committee on Cancer 8 staging system and other predictive models, our model showed better predictive ability for patients with co-diabetes pancreatic adenocarcinoma. Our model will help in patients’ risk stratification and improves their prognosis.

Middle and outer ear diseases are common otological diseases worldwide. Otoscopy and otoendoscopy examinations are essential first steps in the evaluation of patients with otological diseases. Misdiagnosis often occurs when the doctor lacks experience in interpreting the results of otoscopy or otoendoscopy, leading to delays in treatment or complications. Using deep learning to process otoscopy images and developing otoscopic artificial-intelligence-based decision-making systems will become a significant trend in the future. However, the uneven quality of otoscopy images is among the major obstacles to development of such artificial intelligence systems, and no standardized process for data acquisition, and annotation of otoscopy images in intelligent medicine has yet been fully established. The standards for data storage and data management are unified with those of other specialties and are introduced in detail here. This expert recommendation criterion improved and standardized the collection and annotation procedures for otoscopy images and fills the current gap in otologic intelligent medicine; it would thus lay a solid foundation for the standardized collection, storage, and annotation of otoscopy images and the application of training algorithms, and promote the development of automatic diagnosis and treatment for otological diseases. The full text introduced image collection (including patient preparation, equipment standards, and image storage), image annotation standards, and quality control.

The ability of cancer stem cells (CSCs) to self-renew, differentiate, and generate new tumors is a significant contributor to drug resistance, relapse, and metastasis. Therefore, the targeting of CSCs for treatment is particularly important. Recent studies have demonstrated that CSCs are more susceptible to ferroptosis than non-CSCs, indicating that this could be an effective strategy for treating tumors. Ferroptosis is a type of programmed cell death that results from the accumulation of lipid peroxides caused by intracellular iron-mediated processes. CSCs exhibit different molecular characteristics related to iron and lipid metabolism. This study reviews the alterations in iron metabolism, lipid peroxidation, and lipid peroxide scavenging in CSCs, their impact on ferroptosis, and the regulatory mechanisms underlying iron metabolism and ferroptosis. Potential treatment strategies and novel compounds targeting CSC by inducing ferroptosis are also discussed.

ObjectiveThe mortality of type A aortic dissection (TAAD) is extremely high. The effect of postoperative hyperglycemia (PHG) on the prognosis of TAAD surgery is unclear. This study aims to investigate the prognosis of patients with PHG after TAAD surgery and construct prediction model for PHG.MethodsPatients underwent TAAD surgery from January 2016 to December 2020 in Xiangya Hospital were collected. A total of 203 patients were included and patients were divided into non PHG group and PHG group. The occurrence of postoperative delirium, cardiac complications, spinal cord complication, cerebral complications, acute kidney injury (AKI), hepatic dysfunction, hypoxemia, and in-hospital mortality were compared between two groups. Data from MIMIC-IV database were further applied to validate the relationship between PHG and clinical outcomes. The prediction model for PHG was then constructed using Extreme Gradient Boosting (XGBoost) analysis. The predictive value of selected features was further validated using patient data from MIMIC-IV database. Finally, the 28-days survival rate of patient with PHG was analyzed using data from MIMIC-IV database.ResultsThere were 86 patients developed PHG. The incidences of postoperative AKI, hepatic dysfunction, and in-hospital mortality were significant higher in PHG group. The ventilation time after surgery was significant longer in PHG group. Data from MIMIC-IV database validated these results. Neutrophil, platelet, lactic acid, weight, and lymphocyte were selected as features for prediction model. The values of AUC in training and testing set were 0.8697 and 0.8286 respectively. Then, five features were applied to construct another prediction model using data from MIMIC-IV database and the value of AUC in the new model was 0.8185. Finally, 28-days survival rate of patients with PHG was significantly lower and PHG was an independent risk factor for 28-days mortality after TAAD surgery.ConclusionPHG was significantly associated with the occurrence of AKI, hepatic dysfunction, increased ventilation time, and in-hospital mortality after TAAD surgery. The feature combination of neutrophil, platelet, lactic acid, weight, and lymphocyte could effectively predict PHG. The 28-days survival rate of patients with PHG was significantly lower. Moreover, PHG was an independent risk factor for 28-days mortality after TAAD surgery.

ObjectivesPostoperative acute kidney injury (pAKI) is a serious complication of Stanford type A aortic dissection (TAAD) surgery, which is significantly associated with the inflammatory response. This study aimed to explore the relationship between blood count-derived inflammatory markers (BCDIMs) and pAKI and to construct a predictive model for pAKI.MethodsPatients who underwent TAAD surgery were obtained from our center and the Medical Information Mart for Intensive Care (MIMIC)-IV database. The differences in preoperative BCDIMs and clinical outcomes of patients with and without pAKI were analyzed. Logistic regression was used to construct predictive models based on preoperative BCDIMs or white cell counts (WCCs). The performance of the BCDIMs and WCCs models was evaluated and compared using the receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), Hosmer–Lemeshow test, calibration plot, net reclassification index (NRI), integrated discrimination improvement index (IDI), and decision curve analysis (DCA). The Kaplan–Meier curves were applied to compare the survival rate between different groups.ResultsThe overall incidence of pAKI in patients who underwent TAAD surgery from our center was 48.63% (124/255). The presence of pAKI was associated with longer ventilation time, higher incidence of cerebral complications and postoperative hepatic dysfunction, and higher in-hospital mortality. The results of the logistic regression indicated that the monocyte–lymphocyte ratio (MLR) was an independent risk factor for pAKI. The BCDIMs model had good discriminating ability, predictive ability, and clinical utility. In addition, the performance of the BCDIMs model was significantly better than that of the WCCs model. Analysis of data from the MIMIC-IV database validated that MLR was an independent risk factor for pAKI and had predictive value for pAKI. Finally, data from the MIMIC-IV database demonstrated that patients with a high MLR had a significantly poor 28-day survival rate when compared to patients with a low MLR.ConclusionOur study suggested that the MLR is an independent risk factor for pAKI. A predictive model based on BCDIMs had good discriminating ability, predictive ability, and clinical utility. Moreover, the performance of the BCDIMs model was significantly better than that of the WCCs model. Finally, a high MLR was significantly associated with poor short-term survival of patients who underwent TAAD surgery.

Parental burnout is a prominent topic in current family research, with proven detrimental effects on the well-being of both parents and children. However, the specific mechanism by which parenting burnout impacts the parent–child relationship within families remains unclear. Furthermore, there is limited research exploring whether parenting burnout has a direct impact on the parent–child relationship. This study aims to address this gap by constructing an actor-partner interdependent mediation model of parental harsh parenting in order to explore the influence of parents’ own and their spouse’s parenting burnout on their respective parent–child relationships, as well as the mediating effect of their own harsh parenting and that of their spouse. A convenient sampling method was used to select 405 parents from two middle schools in Yichun, Heilongjiang Province as participants for this investigation. The Chinese version of the Parenting Burnout Inventory, Harsh Parenting Scale, and Parent–child Relationship Scale were utilized for data collection over half year period. The findings revealed that (1) parenting burnout significantly negatively predicts both one’s own and one’s spouse’s parent–child relationships; (2) parenting burnout affects one’s own parent–child relationship through their own harsh parenting; (3) parenting burnout influences one’s spouse’s parent–child relationship through their spouse’s harsh parenting. This study sheds light on the influence and mechanisms underlying parental burnout on the parent–child relationship, offering valuable insights for preventing parental burnout and enhancing family dynamics. [ABSTRACT FROM AUTHOR]

Abstract This study investigated the exosomal circular RNAs (CircRNAs) produced by tumor-associated macrophages and delivered into the microenvironment of cholangiocarcinoma cells in order to use them as molecular targets for clinical therapy. Tumor-associated M2 macrophages (TAMs) were induced from THP-1 cells and identified by flow cytometry. The TAM-secreted exosomes were isolated from conditioned medium and a CircRNA microarray assay was performed to identify CircRNAs that were uniquely expressed in the isolated exosomes. Circ_0020256 was especially identified based on having the highest differential expression level among all of the CircRNA candidates. In vitro and in vivo experiments were performed to assess the effects of TAMs, exosomes, and Circ_0020256 on the growth and migration of cholangiocarcinoma (CCA) cells. The induced TAMs promoted the proliferation, migration, and invasion of CCA cells and those effects were mediated by exosomes secreted by the TAMs. In CCA cells (RBE and HCCC-9810), Circ_0020256 significantly promoted cellular activity by interacting with its intra-cellular microRNA target, miR-432-5p. In contrast, overexpression of transcription factor E2F3 in CCA cells restored the CCA cellular activities that were inhibited by miR-432-5p. On the other hand, treatment with small interference RNA (siRNA) for Circ_0020256 inhibited CCA cell proliferation, migration, and invasion both in vitro and in vivo. In conclusion, Circ_0020256 in TAM-secreted exosomes promoted the proliferation, migration, and invasion of CCA cells, and that promotional activity was regulated via a Circ_0020256/miR-432-5p/E2F3 axis.

ObjectivesIdiopathic pulmonary artery hypertension (IPAH) is a rare but life-threaten disease. However, the mechanism underlying IPAH is unclear. In this study, underlying mechanism, infiltration of immune cells, and immune-related hub genes of IPAH were analyzed via bioinformatics.MethodsGSE15197, GSE48149, GSE113439, and GSE117261 were merged as lung dataset. Weighted gene correlation network analysis (WGCNA) was used to construct the co-expression gene networks of IPAH. Gene Ontology and pathway enrichment analysis were performed using DAVID, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA). Infiltration of immune cells in lung samples was analyzed using CIBERSORT. GSE22356 and GSE33463 were merged as peripheral blood mononuclear cells (PBMCs) dataset. Immune-related differentially expressed genes (IRDEGs) of lung and PBMCs dataset were analyzed. Based on the intersection between two sets of IRDEGs, hub genes were screened using machine learning algorithms and validated by RT-qPCR. Finally, competing endogenous RNA (ceRNA) networks of hub genes were constructed.ResultsThe gray module was the most relevant module and genes in the module enriched in terms like inflammatory and immune responses. The results of GSEA and GSVA indicated that increasement in cytosolic calcium ion, and metabolism dysregulation play important roles in IPAH. The proportions of T cells CD4 memory resting and macrophage M1 were significantly greater in IPAH group, while the proportions of monocytes and neutrophils were significantly lower in IPAH group. IRDEGs of two datasets were analyzed and the intersection between two set of IRDEGs were identified as candidate hub genes. Predictive models for IPAH were constructed using data from PBMCs dataset with candidate hub genes as potential features via LASSO regression and XGBoost algorithm, respectively. CXCL10 and VIPR1 were identified as hub genes and ceRNA networks of CXCL10 was constructed.ConclusionInflammatory response, increasement in cytosolic calcium ion, and metabolism dysregulation play important roles in IPAH. T cells CD4 memory resting and macrophage M1 were significantly infiltrated in lung samples from patients with IPAH. IRDEGs of lung dataset and PBMCs dataset were analyzed, and CXCL10 and VIPR1 were identified as hub genes.

Background: Atrial fibrillation (AF) increases the risk of stroke and heart failure. Postoperative AF (POAF) increases the risk of mortality after cardiac surgery. This study aims to explore mechanisms underlying AF, analyze infiltration of immune cells in left atrium (LA) from patients with AF, and identify potential circular RNA (circRNA) biomarkers for POAF.Methods: Raw data of GSE797689, GSE115574, and GSE97455 were downloaded and processed. AF-related gene co-expression network was constructed using weighted gene correlation network analysis and enrichment analysis of genes in relevant module was conducted. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to investigate pathways significantly enriched in AF group. Infiltration of immune cells was analyzed using single-sample GSEA. Differentially expressed genes (DEGs) between patients with or without AF were identified and competing endogenous RNA (ceRNA) networks of DEGs were constructed. To screen biomarkers for POAF, differentially expressed circRNAs (DEcircRNAs) between patients with or without POAF were identified. Intersection between DEcircRNAs and circRNAs in ceRNA networks of DEGs were extracted and circRNAs in the intersection were further screened using support vector machine, random forest, and neural network to identify biomarkers for POAF.Results: Three modules were found to be relevant with AF and enrichment analysis indicated that genes in these modules were enriched in synthesis of extracellular matrix and inflammatory response. The results of GSEA and GSVA suggested that inflammatory response-related pathways were significantly enriched in AF group. Immune cells like macrophages, mast cells, and neutrophils were significantly infiltrated in LA tissues from patients with AF. The expression levels of immune genes such as CHGB, HLA-DRA, LYZ, IGKV1-17 and TYROBP were significantly upregulated in patients with AF, which were correlated with infiltration of immune cells. ceRNA networks of DEGs were constructed and has_circ_0006314 and hsa_circ_0055387 were found to have potential predictive values for POAF.Conclusion: Synthesis of extracellular matrix and inflammatory response were main processes involved in development and progression of AF. Infiltration of immune cells was significantly different between patients with or without AF. Has_circ_0006314 and hsa_circ_0055387 were found to have potential predictive values for POAF.

ObjectivesThe mortality rate of abdominal aortic aneurysm (AAA) is extremely high in the older population. This study aimed to identify potential biomarkers of AAA and aortic rupture and analyze infiltration of immune cells in stable and ruptured AAA samples.MethodsRaw data of GSE47472, GSE57691, and GSE98278 were downloaded. After data processing, the co-expression gene networks were constructed. Gene Ontology and pathway enrichment analysis of AAA- and aortic rupture-related gene modules were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used for further enrichment analysis. The CIBERSORT tool was used to analyze the relative abundance of immune cells in samples. Differentially expressed immune-related genes were analyzed between different samples. Predictive models were constructed via extreme gradient boosting, and hub genes were identified according to feature importance.ResultsBlue and yellow modules were significantly related to AAA, and genes in these modules were associated with the aortic wall and immune response, respectively. In terms of aortic rupture, the most relevant module was significantly enriched in the inflammatory response. The results of GSEA and GSVA suggested that immune cells and the inflammatory response were involved in the development of AAA and aortic rupture. There were significant differences in the infiltration of immune cells and expression levels of immune-related genes among different samples. NFKB1 might be an important transcription factor mediating the inflammatory response of AAA and aortic rupture. After the construction of a predictive model, CD19, SELL, and CCR7 were selected as hub genes for AAA whereas OAS3, IFIT1, and IFI44L were identified as hub genes for aortic rupture.ConclusionWeakening of the aortic wall and the immune response both contributed to the development of AAA, and the inflammatory response was closely associated with aortic rupture. The infiltration of immune cells was significantly different between different samples. NFKB1 might be an important transcription factor in AAA and aortic rupture. CD19, SELL, and CCR7 had potential diagnostic value for AAA. OAS3, IFIT1, and IFI44L might be predictive factors for aortic rupture.

Background: Evidence suggests that glucocorticoids are important in the treatment of sudden hearing loss (SHL) and Meniere’s disease (MD). However, different glucocorticoid administration methods may have a significant impact on treatment outcomes. Objective: This study aimed to investigate effects of different glucocorticoid administration methods on sudden hearing loss and Meniere’s disease. Methods: In this study, glucocorticoids were administered orally in 18 patients, by retroauricular injection in 15 patients and by intratympanic injection in 15 patients. White blood cell (WBC) count, serum K+, fasting plasma glucose (FPG), body temperature, heart rate and blood pressure were used to evaluate effects of glucocorticoids on patients with hearing loss. Visual analog scale (VAS) of pain and sleep disorders were also surveyed, and pure tone audiometry (PTA) results were compared among groups to evaluate efficacy of different glucocorticoids administration methods. Result: WBC count, heart rate and blood pressure were higher in patients taking oral glucocorticoids, while body temperature, serum K+ and FPG levels did not change in all three groups. However, patients who received intratympanic injection of glucocorticoids experienced more pain, while those taking oral glucocorticoids reported more sleep impairment. Treatment efficacy on hearing loss was not significantly different among the three groups. Conclusion: These findings suggest that systemic glucocorticoid administration can result in greater whole body responses than local administration, but with similar hearing treatment efficacy.

Abstract Background Epicardial adipose tissue (EAT) remodeling and adipocytokines are associated with structural remodeling in atrial fibrillation (AF). However, the role of omentin-1, a novel adipocytokine, in structural remodeling remains unknown. Methods Hematoxylin and eosin (H&E) and Masson’s trichrome stains were used to investigate the histology of EAT and right atrial appendages. The expression levels of adipocytokines in these human samples were determined by immunohistochemical assay and western blotting. Models of transforming growth factor (TGF)-β1-induced activation of cardiac fibroblasts (CFs) and TGF-β1-induced endothelial-mesenchymal transition (EndMT) of human umbilical vein endothelial cell (HUVEC) were established to explore roles of omentin-1 in these processes. To determine changes in adipocytokines secretion under hypoxia conditions, adipocytes were treated with 5% O2 and 95% N2, and then CFs and HUVECs were co-cultured with the conditioned medium of adipocytes to determine the effects of hypoxia-treated adipocytes on these cells. Results Expression of omentin-1 was downregulated in the EAT and right atrial appendages from patients with AF compared to samples from patients without AF, while the TGF-β1 level was upregulated in EAT from patients with AF. EAT from patients with AF exhibited adipocyte hypertrophy and severe interstitial fibrosis. Omentin-1 inhibited TGF-β1-induced CF activation and reversed TGF-β1-induced HUVEC EndMT. Adipocytes treated with hypoxia exhibited downregulation of omentin-1 and partly activated CFs. Conclusions This study demonstrated that omentin-1 was an antifibrotic adipocytokine and was downregulated in patients with AF, which was partly mediated by hypoxia.

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