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Background: The emergence of drug-resistant tuberculosis (TB) hampers TB control. Ten provinces in China performed drug resistance surveys among tuberculosis (TB) patients in 1996-2004 to assess levels of drug resistance.Methods: Provincial drug resistance surveys included all isolates from newly diagnosed, smear-positive TB patients. Drug susceptibility testing (DST) against isoniazid, rifampicin, streptomycin and ethambutol was carried out in the provincial laboratories. For purposes of quality assurance, a random sample (11.6%) was re-tested by the national reference laboratory (NRL).Results: Of 14,059 patients tested 11,052 (79%) were new TB cases. The weighted mean prevalence of multi-drug resistant tuberculosis (MDR-TB) among all cases was 9.3% (range 2.2%-10.4%); 5.4% (range 2.1% - 10.4%) among new cases and 25.6% (range 11.7%-36.9%) among previously treated cases. Adjusting the drug resistance proportions using the re-testing results did not change the estimated national mean prevalence significantly. However, in some individual provinces the estimated resistance proportions were greatly influenced, especially among re-treatment patients.Conclusion: MDR-TB levels varied greatly between provinces in China, but on average were high compared to the global estimated average of 4.8%. This study shows the importance of quality-assured laboratory performance. Programmatic management of drug-resistant TB, including high quality DST for patients at high risk of resistance and treatment with second-line drugs, should become the standard, especially in high MDR-TB settings. [ABSTRACT FROM AUTHOR]

Objective: The identification of risk factors is crucial for the clinical prevention and diagnosis of necrotizing enterocolitis (NEC). Monochorionic twins (MCT), due to the high genetic homogeneity, provided a valuable model for investigating the risk factors of various diseases. This study aimed to explore the risk factors for NEC using MCT., Methods: A retrospective review was conducted on the medical records of monochorionic twins (MCT) treated at Guangzhou Women and Children's Medical Center from January 2012 to March 2023. We compared perinatal condition, feeding and preceding condition between MCT pairs with NEC (NEC MCT) and without NEC(No NEC MCT).Logistic regression analysis was utilized to identify independent risk factors., Result: In 85 pairs of monochorionic twins (MCT), NEC occurred in one twin in 78.8% of cases, whereas both twins were affected in 21.2% of cases. In the final cohort of 60 pairs of MCT, several parameters were found to differ significantly between NEC MCT group and No NEC MCT group. Compared to No NEC MCT group, the incidence of umbilical cord abnormalities was significantly higher in the NEC MCT group (25% vs. 8.3%, P = 0.014). Meanwhile, NEC MCT group showed higher prevalence of SGA infants (48.3% vs. 21.7%, P = 0.002) and sFGR (38.3% vs. 6.7%, P = 0.000). Furthermore, TTTs (13.3% vs. 3.3%, P = 0.027) and septicemia (25% vs. 5%, P = 0.002) were more common in NEC MCT group. In a multivariable logistic regression model, sFGR (OR 6.81,95%CI 2.1-21.9, p = 0.001) was eventually output as an independent risk factor., Conclusion: Non-genetic factors play a predominant role in the pathogenesis of NEC. Umbilical cord abnormalities, SGA, sFGR, TTTs and septicemia significantly increase the risk of NEC. sFGR is an independent risk factor of NEC., Competing Interests: Declarations Ethics approval and consent to participate The research ethics committee of Guangzhou Women and Children’s Medical Center approved the study. Considering the retrospective nature of this study, ethics committee of Guangzhou Women and Children’s Medical Center approved the waiver of parents’ written consent. The waiver will not adversely affect the rights and welfare of the patients. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Neoantigen-targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies have been initiated globally. Accurate identification and prioritization of neoantigens is crucial for designing these trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel DNA and RNA sequencing technologies, it is now possible to computationally predict neoantigens based on patient-specific variant information. However, numerous factors must be considered when prioritizing neoantigens for use in personalized therapies. Complexities such as alternative transcript annotations, various binding, presentation and immunogenicity prediction algorithms, and variable peptide lengths/registers all potentially impact the neoantigen selection process. There has been a rapid development of computational tools that attempt to account for these complexities. While these tools generate numerous algorithmic predictions for neoantigen characterization, results from these pipelines are difficult to navigate and require extensive knowledge of the underlying tools for accurate interpretation. This often leads to over-simplification of pipeline outputs to make them tractable, for example, limiting prediction to a single RNA isoform or only summarizing the top ranked of many possible peptide candidates. In addition to variant detection, gene expression, and predicted peptide binding affinities, recent studies have also demonstrated the importance of mutation location, allele-specific anchor locations, and variation of T-cell response to long versus short peptides. Due to the intricate nature and number of salient neoantigen features, presenting all relevant information to facilitate candidate selection for downstream applications is a difficult challenge that current tools fail to address., Results: We have created pVACview, the first interactive tool designed to aid in the prioritization and selection of neoantigen candidates for personalized neoantigen therapies including cancer vaccines. pVACview has a user-friendly and intuitive interface where users can upload, explore, select, and export their neoantigen candidates. The tool allows users to visualize candidates at multiple levels of detail including variant, transcript, peptide, and algorithm prediction information., Conclusions: pVACview will allow researchers to analyze and prioritize neoantigen candidates with greater efficiency and accuracy in basic and translational settings. The application is available as part of the pVACtools software at pvactools.org and as an online server at pvacview.org., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests M.G. reports consulting fees from Jaime Leandro Foundation for Cancer Vaccines, Rare Cancer Research Foundation, and H37 and is on the Board of Directors of the Jaime Leandro Foundation for Cancer Vaccines. O.L.G. reports consulting fees from Jaime Leandro Foundation and is on the Board of Directors of the Cancer Genomics Consortium., (© 2024. The Author(s).)

Background: Stress urinary incontinence (SUI), a common disorder of the pelvic floor, often results in anxiety, poor quality of life, and psychological issues among its sufferers. The relationship between lipid accumulation products (LAP) and stress-related urine incontinence remains unclear. This research aimed to investigate any possible correlation between the risk of SUI and the level of lipid accumulation products., Methods: For this cross-sectional research, people with SUI who were 20 years of age or older were recruited using information from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. A weighted multivariate logistic regression model was used to evaluate the findings. As a potential biomarker, lipid accumulation product levels were sorted among individuals in ascending order and subjected to a trend test (P for trend). Additionally, a nonlinear analysis was conducted using smooth curve-fitting methods. Lipid accumulation products' effectiveness in predicting SUI was evaluated using receiver operating characteristic (ROC) curves. Finally, a subgroup analysis was performed to confirm that the connection between SUI and lipid accumulation products was consistent across all demographic groups., Results: A thorough survey performed on 14,945 participants indicated that 23.61% of the respondents had SUI. A noteworthy association was observed between higher lipid accumulation product values and a greater probability of SUI in multivariate logistic regression analysis. Specifically, the stratification of lipid accumulation products into quartiles demonstrated a substantial positive correlation between the upper and lower quartiles, as evidenced by an elevated odds ratio for SUI (OR = 1.92; 95%CI 1.51-2.44; P < 0.0001). The subgroup analysis supported link consistency across all cohorts under investigation. Finally, the ROC curve indicated that lipid accumulation products (AUC = 0.67, 95%CI 0.654-0.690) had a superior predictive effect on the likelihood of SUI., Conclusions: Increased lipid accumulation product values are associated with a higher chance of SUI in adult participants. This suggests that lipid accumulation products could be a valuable marker for detecting SUI, offering new perspectives for its evaluation and treatment., (© 2024. The Author(s).)

Background: Pantoea agglomerans (P. agglomerans) is a gram-negative bacterium that is commonly isolated from plant surfaces, seeds, and the environment. As an opportunistic pathogen, it can cause blood, urinary and soft tissue infections in immunocompromised patients. In central nervous system, P. agglomerans infection has been report in children and immune-compromised patients, however, infection by such bacterium in nontraumatized immune competent adults has not been reported. Here, we report a case of P. agglomerans cerebrospinal meningitis accompanied by positive anti-myeloperoxidase (MPO) antibody in a 49-year-old female who has a history of black fungus planting., Case Presentation: The patient manifested with repeated fever, headache, generalized muscle pain, and neurological defects. Cerebrospinal fluid (CSF) tests revealed a moderately elevated number of polymorphonuclear leukocytes (50-193 × 10 6 /L), low glucose levels (0.54-2.44 mmo1/L), and extremely high protein content (2.42-25.42 g/L). Blood tests showed positive anti-myeloperoxidase antibodies lasting for 1.5 year before turning negative. Spine MRI showed thickening and enhancement of the whole spinal meninges. CSF metagenomic next-generation sequencing (mNGS) revealed 75,189 specific DNA reads of P. agglomerans. The patient underwent spinal laminectomy due to meningeal adhesions. Pathological results revealed fibrous tissue proliferation, inflammatory infiltration with focal necrosis and calcification in the dura mater. The patient was successfully treated with sufficient antibiotics at 1-year follow-up., Conclusions: People should be alert to CNS infections caused by P. agglomerans which presented with relatively mild clinical symptoms at onset, especially for those who contucts relevant agricultural and forestry work. The CSF characterization of P. agglomerans meningitis is elevated multiple nuclei white blood cells, significantly reduced glucose content, and markedly increased protein level which may be related to the secondary spinal membrane adhesions., (© 2024. The Author(s).)

Background: Evidence has been presented that the tumor protein D52 (TPD52) family plays a critical role in tumor development and progression. As a member of the TPD52 family, the changes in TPD52L2 gene status are instrumental in kinds of cancer development. However, its effects on patient prognosis and immune infiltration in Head and Neck Squamous Carcinoma (HNSCC) are still poorly understood., Methods: The Tumor Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and c-BioPortal database was used to explore the expression pattern, prognostic value, and variation of gene status in HNSCC. The LinkedOmics database was used to obtain the co-expression genes of TPD52L2 and identify the diagnostic value of TPD52L2 in HNSCC. The correlations between TPD52L2 expression and six main types of immune cell infiltrations and immune signatures were explored using Tumor Immune Estimation Resource (TIMER). The correlation between TPD52L2 expression and immune checkpoint genes (ICGs) was analyzed by TCGA database. Immunohistochemistry (IHC) was performed to validate the expression of three ICGs (PDL1, PDL2, EGFR) and TPD52L2 using 5 paired HNSCC and normal head and neck tissues. Polymerase Chain Reaction (PCR) and Western Blot (WB) of HNSCC and normal head and neck cell lines were performed to verify the high level of TPD52L2 mRNA and protein expression. protein expression of TPD52L2 in pan-cancer was also validated using UALCAN., Results: TPD52L2 was overexpressed in tumor tissues, and it predicted worse survival status in HNSCC. ROC analysis suggested that TPD52L2 had a diagnostic value. Multivariate Cox analysis identified TPD52L2 as an independent negative prognostic marker of overall survival. Functional network analysis suggested that TPD52L2 was associated with immune-related signaling pathways, cell migration pathways, and cancer-related pathways. High expression of TPD52L2 was associated with a more mutant frequency of TP53. Notably, we found that the expression of TPD52L2 was closely negatively correlated with the infiltration levels of 15 types of immune cells and positively correlated with several immune markers. PCR, WB experiments, and UALCAN database verified the high level of TPD52L2 mRNA and protein expression., Conclusion: TPD52L2 is upregulated in HNSCC, which is an independent factor for adverse prognosis prediction. It probably plays a role in the negative regulation of immune cell infiltration. TPD52L2 might be a promising prognostic biomarker and therapeutic target in HNSCC., (© 2024. The Author(s).)

Background: With the release of the coronavirus disease 2019 (COVID-19) pandemic in late 2022 in China, the number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) roared, including neonatal cases. However, there were few studies on neonatal COVID-19, especially multi-center case reports. This study aimed to explore clinical characteristics and short-term outcomes of neonatal COVID-19 in China., Methods: We reviewed 187 cases of neonatal COVID-19 between December 11, 2022, and January 12, 2023. The diagnosis was assessed by symptoms, laboratory tests, X-ray manifestations, and diagnosis code. Clinical characteristics and outcomes were evaluated., Results: In 187 neonatal cases with COVID-19, 84 (44.9%) had severe SARS-CoV-2 infection. Most patients had confirmed exposure to SARS-CoV-2. Fever and respiratory symptoms were common (75.4% and 71.7%, respectively). Severe patients were more likely to have high alanine transaminase (ALT) (> 40U/L) (11.9% vs. 3.9%) and high N-terminal pro-brain natriuretic peptide (NT-proBNP) (> 2000pg/mL) (38.0% vs. 19.6%), compared with nonsevere ones (P < 0.05). None of the patients received COVID-19-specific medical interventions. A few severe patients received corticosteroids (1.1%), and immunoglobulin (0.5%), respectively. All patients were discharged home after the medical care with a median length of stay (LOS) of four days and none of them met the criteria of multisystem inflammatory syndrome in neonates (MIS-N)., Conclusions: After the release of the epidemic situation of COVID-19 in late 2022 in China, more neonatal cases with severe COVID-19 had high ALT and NT-proBNP level. Few specific medical interventions were given, and the outcome was satisfying., (© 2024. The Author(s).)

Background: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort., Methods: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro., Results: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC 50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC 50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC (0→t) , AUC (0→∞) , and T max rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib., Conclusions: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib., (© 2024. The Author(s).)

Background: To explore the functional and morphological variations of retinal vessels in diabetes with no clinically detectable retinopathy (NDR) and mild non-proliferative diabetic retinopathy (NPDR) and to establish a high-performance mild NPDR diagnostic model., Methods: Normal subjects and type 2 diabetes patients with NDR and mild NPDR were recruited. Oxygen-saturation-related functional parameter (optical density ratio ODR) and morphological characteristics (fractal dimension D f , vessel area rate VAR, mean vascular diameter D m , vessel tortuosity τ) of different vascular areas were extracted with single fundus photography and comprehensively analyzed among groups. An interpretable model combining marine predator algorithm (MPA) and support vector machine (SVM) based on characteristic selection was proposed for mild NPDR diagnosis., Results: A total of 91 NDR subjects, 75 mild NPDR subjects, and 111 sex- and age-matched normal controls were analyzed. Increased main vessels ODR, while lower VAR of all areas except outer ring macula, lower D m of all vessels and decreased τ of all areas were associate with NDR (e.g. main vessels ODR: OR [95%CI] 1.42[1.07-1.89], full macula τ:0.53[0.38-0.74]). Increased ODR of all areas, higher D m of all areas except inner ring macula, increased inner ring macula τ, while decreased D f of full and inner ring macula, lower VAR of all areas were associate with mild NPDR (e.g. main vessels ODR:5.68[3.03-10.65], inner ring macula VAR: 0.48[0.33-0.69]). The MPA-SVM model with selected characteristics obtained the best diagnosis performance (AUC:0.940 ± 0.014; Accuracy:90.4 ± 3.9%; Sensitivity:89.2 ± 6.4%; Specificity:91.3 ± 6.4%)., Conclusions: More significant retinal vascular variations are associate with the incidence of mild NPDR than NDR. High-precision mild NPDR diagnosis is achieved combining the morphological and functional vascular characteristics based on characteristic selection., (© 2024. The Author(s).)

Background: R2R3-MYB transcription factors belong to one of the largest gene subfamilies in plants, and they are involved in diverse biological processes. However, the role of R2R3-MYB transcription factor subfamily genes in the response of rice (Oryza sativa L.) to salt stress has been rarely reported., Results: In this study, we performed a genome-wide characterization and expression identification of rice R2R3-MYB transcription factor subfamily genes. We identified a total of 117 R2R3-MYB genes in rice and characterized their gene structure, chromosomal location, and cis-regulatory elements. According to the phylogenetic relationships and amino acid sequence homologies, the R2R3-MYB genes were divided into four groups. qRT-PCR of the R2R3-MYB genes showed that the expression levels of 10 genes significantly increased after 3 days of 0.8% NaCl treatment. We selected a high expression gene OsMYB2-115 for further analysis. OsMYB2-115 was highly expressed in the roots, stem, leaf, and leaf sheath. OsMYB2-115 was found to be localized in the nucleus, and the yeast hybrid assay showed that OsMYB2-115 has transcriptional activation activity., Conclusion: This result provides important information for the functional analyses of rice R2R3-MYB transcription factor subfamily genes related to the salt stress response and reveals that OsMYB2-115 may be an important gene associated with salt tolerance in rice., (© 2024. The Author(s).)

Purpose: This study aims to comprehensively assess the safety of Asenapine by conducting an comprehensive statistical analysis of adverse event reports in the FAERS database, with a particular focus on potential adverse reactions related to its use in the treatment of psychiatric disorders., Methods: Event reports from the first quarter of 2009 to the third quarter of 2023 were collected and analyzed. Detailed examinations of gender, age, reporter identity, and other aspects were conducted to reveal the fundamental characteristics of Asenapine-related adverse events. Signal mining techniques were employed to systematically evaluate various adverse reactions associated with Asenapine., Results: The study found that adverse event reports involving Asenapine were more common among female patients, with the age group mainly distributed between 18 and 45 years. Physicians were the primary reporters of adverse events, and psychiatric disorders, neurological disorders, and gastrointestinal disorders were the most common areas affected by adverse reactions. In addition to known adverse reactions, potential risks not mentioned in the drug label were identified, such as anosognosia, attentional drift, and psychogenic compensation disorder., Conclusion: Asenapine carries the risk of various adverse reactions alongside its therapeutic effects. In clinical practice, physicians should closely monitor the occurrence of neurological disorders, psychiatric disorders, and gastrointestinal system disorders., (© 2024. The Author(s).)

Background: Pseudomonas juntendi is a newly identified opportunistic pathogen, of which we have limited understanding. P. juntendi strains are often multidrug resistant, which complicates clinical management of infection., Methods: A strain of Pseudomonas juntendi (strain L4326) isolated from feces was characterized by MALDI-TOF-MS and Average Nucleotide Identity BLAST. This strain was further subject to whole-genome sequencing and Maximum Likelihood phylogenetic analysis. The strain was phenotypically characterized by antimicrobial susceptibility testing and conjugation assays., Results: We have isolated the novel P. juntendi strain L4236, which was multidrug resistant, but retained sensitivity to amikacin. L4236 harbored a megaplasmid that encoded bla OXA-1 and a novel bla IMP-1 resistance gene variant. P. juntendi strain L4236 was phylogenetically related to P. juntendi strain SAMN30525517., Conclusion: A rare P. juntendi strain was isolated from human feces in southern China with a megaplasmid coharboring bla IMP-1-like and bla OXA-1 . Antimicrobial selection pressures may have driven acquisition of drug-resistance gene mutations and carriage of the megaplasmid., (© 2024. The Author(s).)

Background: The 2-phenylethanol (2-PE) tolerance phenotype is crucial to the production of 2-PE, and Pdr1p mutation can significantly increase the tolerance of 2-PE in Saccharomyces cerevisiae. However, its underlying molecular mechanisms are still unclear, hindering the rational design of superior 2-PE tolerance performance., Results: Here, the physiology and biochemistry of the PDR1&#95;862 and 5D strains were analyzed. At 3.5 g/L 2-PE, the ethanol concentration of PDR1&#95;862 decreased by 21%, and the 2-PE production of PDR1&#95;862 increased by 16% than those of 5D strain. Transcriptome analysis showed that at 2-PE stress, Pdr1p mutation increased the expression of genes involved in the Ehrlich pathway. In addition, Pdr1p mutation attenuated sulfur metabolism and enhanced the one-carbon pool by folate to resist 2-PE stress. These metabolic pathways were closely associated with amino acids metabolism. Furthermore, at 3.5 g/L 2-PE, the free amino acids content of PDR1&#95;862 decreased by 31% than that of 5D strain, among the free amino acids, cysteine was key amino acid for the enhancement of 2-PE stress tolerance conferred by Pdr1p mutation., Conclusions: The above results indicated that Pdr1p mutation enhanced the Ehrlich pathway to improve 2-PE production of S. cerevisiae, and Pdr1p mutation altered the intracellular amino acids contents, in which cysteine might be a biomarker in response to Pdr1p mutation under 2-PE stress. The findings help to elucidate the molecular mechanisms for 2-PE stress tolerance by Pdr1p mutation in S. cerevisiae, identify key metabolic pathway responsible for 2-PE stress tolerance., (© 2024. The Author(s).)

Background: With the profound changes in the global climate, the issue of grassland degradation is becoming increasingly prominent. Grassland degradation poses a severe threat to the carbon cycle and carbon storage within grassland ecosystems. Additionally, it will adversely affect the sustainability of food production. The grassland ecosystem in the northwest region of Liaoning Province, China, is particularly vulnerable due to factors such as erosion from the northern Horqin Sandy Land, persistent arid climate, and issues related to overgrazing and mismanagement of grassland. The degradation issue is especially pronounced in this ecological environment. However, previous research on the carbon density of degraded grasslands in Northeast China has predominantly focused on Inner Mongolia, neglecting the impact on the grasslands in the northwest of Liaoning Province. Therefore, this experiment aims to assess the influence of grassland degradation intensity on the vegetation and soil carbon density in the northwest of Liaoning Province. The objective is to investigate the changes in grassland vegetation and soil carbon density resulting from different degrees of grassland degradation., Methodology: This study focuses on the carbon density of grasslands at different degrees of degradation in the northwest of Liaoning Province, exploring the variations in vegetation and soil carbon density under different levels of degradation. This experiment employed field sampling techniques to establish 100 × 100 m plots in grasslands exhibiting varying degrees of degradation. Six replications of 100 × 100 m plots per degradation intensity were sampled. Vegetation and soil samples were collected for analysis of carbon density., Results: The results indicate that in the context of grassland degradation, there is a significant reduction in vegetation carbon density. Furthermore, it was found that root carbon density is the primary contributor to vegetation carbon density. In comparison to mildly degraded grasslands, moderately and severely degraded grasslands experience a reduction in vegetation carbon density by 25.6% and 52.6%, respectively. However, with regard to the impact of grassland degradation on soil carbon density, it was observed that while grassland degradation leads to a slight decrease in soil carbon density, there is no significant change in soil carbon density in the short term under the influence of grassland degradation., Conclusions: Therefore, grassland degradation has exerted a negative impact on aboveground vegetation carbon density, reducing the carbon storage of above-ground vegetation in grasslands. However, there was no significant effect on grassland soil carbon density., (© 2024. The Author(s).)

Objective: Autologous iliac bone is commonly used as a bone graft material to achieve solid fusion in craniocervical junction (CVJ) surgery. However, the developing iliac bone of children is less than ideal as a bone graft material. The matured rib bone of children presents a potential substitute material for iliac bone. The aim of this study was to evaluate the efficacy of autologous rib grafts for craniocervical junction surgery in children., Methods: The outcomes of 10 children with abnormalities of the craniocervical junction who underwent craniocervical junction surgery between January 2020 and December 2022 were retrospectively reviewed. All patients underwent posterior fusion and internal fixation surgery with autologous rib grafts. Pre- and post-operative images were obtained and clinical follow-ups were conducted to evaluate neurological function, pain level, donor site complications, and bone fusion rates., Results: All surgeries were successful. During the 8- to 24-month follow-up period, all patients achieved satisfactory clinical results. Computed tomography at 3-6 months confirmed successful bone fusion and regeneration of the rib defect in all patients with no neurological or donor site complications., Conclusion: Autologous rib bone is a safe and effective material for bone grafting in craniocervical junction fusion surgery for children that can reduce the risks of donor site complications and increase the amount of bone graft, thereby achieving a higher bone fusion rate., (© 2024. The Author(s).)

Background: Human lysozyme (hLYZ) is a natural antibacterial protein with broad applications in food and pharmaceutical industries. Recombinant production of hLYZ in Komagataella phaffii (K. phaffii) has attracted considerable attention, but there are very limited strategies for its hyper-production in yeast., Results: Here through Atmospheric and Room Temperature Plasma (ARTP)-based mutagenesis and transcriptomic analysis, the expression of two genes MYO1 and IQG1 encoding the cytokinesis core proteins was identified downregulated along with higher hLYZ production. Deletion of either gene caused severe cytokinesis defects, but significantly enhanced hLYZ production. The highest hLYZ yield of 1,052,444 ± 23,667 U/mL bioactivity and 4.12 ± 0.11 g/L total protein concentration were obtained after high-density fed-batch fermentation in the Δmyo1 mutant, representing the best production of hLYZ in yeast. Furthermore, O-linked mannose glycans were characterized on this recombinant hLYZ., Conclusions: Our work suggests that cytokinesis-based morphology engineering is an effective way to enhance the production of hLYZ in K. phaffii., (© 2024. The Author(s).)

Septic cardiomyopathy is one of the most severe and common complications in patients with sepsis and poses a great threat to their prognosis. However, the potential mechanisms and effective therapeutic drugs need to be explored. The control of cardiac cell death by miRNAs has emerged as a prominent area of scientific interest in the diagnosis and treatment of heart disorders in recent times. In the present investigation, we discovered that overexpression of miR-31-5p prevented LPS-induced damage to H9C2 cells and that miR-31-5p could inhibit BAP1 production by binding to its 3'-UTR. BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase. BAP1 upregulation blocked effect of miR-31-5p on H9C2 cell injury. Moreover, BAP1 inhibited the expression of solute carrier family 7 member 11 (SLC7A11) by deubiquitinating histone 2 A (H2Aub) on the promoter of SLC7A11. Furthermore, overexpression of miR-31-5p and downregulation of BAP1 inhibited SLC7A11 mediated ferroptosis. In addition, the downregulation of SLC7A11 reversed the inhibitory effect of miR-31-5p on the expression of myocardial injury and inflammatory factors, and cell apoptosis was reversed. In conclusion, these results indicate that miR-31-5p alleviates malignant development of LPS-induced H9C2 cell injury by targeting BAP1 and regulating SLC7A11 deubiquitination-mediated ferroptosis, which confirmed the protective effect of miR-31-5p on H9C2 cell injury and revealed potential mechanisms that may provide new targets for treatment of septic cardiomyopathy., (© 2024. The Author(s).)

Background: This study aims to implement a validated prediction model and application medium for postoperative pneumonia (POP) in elderly patients with hip fractures in order to facilitate individualized intervention by clinicians., Methods: Employing clinical data from elderly patients with hip fractures, we derived and externally validated machine learning models for predicting POP. Model derivation utilized a registry from Nanjing First Hospital, and external validation was performed using data from patients at the Fourth Affiliated Hospital of Nanjing Medical University. The derivation cohort was divided into the training set and the testing set. The least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression were used for feature screening. We compared the performance of models to select the optimized model and introduced SHapley Additive exPlanations (SHAP) to interpret the model., Results: The derivation and validation cohorts comprised 498 and 124 patients, with 14.3% and 10.5% POP rates, respectively. Among these models, Categorical boosting (Catboost) demonstrated superior discrimination ability. AUROC was 0.895 (95%CI: 0.841-0.949) and 0.835 (95%CI: 0.740-0.930) on the training and testing sets, respectively. At external validation, the AUROC amounted to 0.894 (95% CI: 0.821-0.966). The SHAP method showed that CRP, the modified five-item frailty index (mFI-5), and ASA body status were among the top three important predicators of POP., Conclusion: Our model's good early prediction ability, combined with the implementation of a network risk calculator based on the Catboost model, was anticipated to effectively distinguish high-risk POP groups, facilitating timely intervention., (© 2024. The Author(s).)

To alleviate the selenium (Se) stress in fruit trees and improve its accumulation, the effects of exogenous indole-3-acetic acid (IAA) on the growth and Se accumulation of grapevine under Se stress were studied. The application of exogenous IAA increased the biomass of grapevine, and the concentration of exogenous IAA had a regression relationship with the biomass. The root and shoot biomass were the maximum at 60 mg L - 1 IAA, increasing by 15.61% and 23.95%, respectively, compared with the control. Exogenous IAA also increased the photosynthetic pigments and the activities of superoxide dismutase and peroxidase in grapevine. Moreover, exogenous IAA increased the contents of total Se, organic Se, and inorganic Se, and the concentration of exogenous IAA had a regression relationship with the total Se content. The highest contents of root total Se and shoot total Se were accumulated at 90 mg L - 1 IAA, increasing by 29.94% and 55.77% respectively,. In addition, the correlation and path analyses revealed that the carotenoid content and root total Se content were closely associated with the shoot total Se content. Therefore, the application of exogenous IAA can alleviate the stress of Se to grape and promote its uptake and the most effective amount for the uptake of Se is 90 mg L - 1 IAA., (© 2024. The Author(s).)

Purpose: The purpose of this study was to compare the learning in the implant dentistry hands-on course to that of the flipped classroom (FC) and the traditional lecture cohorts (control)., Materials and Methods: In this study,80 students were enrolled for the first time in an implant dentistry program. Subsequently, they were divided into two groups. The first, the FC group, which had free access to a video with a PowerPoint presentation on the Chaoxing-WHU-MOOC platform about the implant placement on first molar sites before class. The second, the control group, which attended a didactic lecture describing implant practice on the first molar site via a bidirectional multimedia interactive teaching demonstration and then operated on a simulation model. Cone beam computed tomography (CBCT) and the deviation gauge were utilized to analyze the accuracy of the implant placement in the students' models. An online satisfaction questionnaire was distributed to both groups one week after the class., Results: The linear deviation of the CBCT examination did not show any statistical difference between the two groups concerning cervical, apex, and angular. A significant buccal deviation was observed in the control group compared with the FC group (mean: 0.7436 mm vs. 0.2875 mm, p = 0.0035), according to the restoration-level deviation gauge. A total of 74.36% of students in the FC group placed implant within 0.5 mm buccal-to-lingual deviations, but only 41.03% of students in the control group reached within 0.5 mm buccal-to-lingual deviation ranges. Additionally, 91.67% of the students in the FC group and 97.5% of the students in the control group were satisfied with the practical implant class., Conclusion: FC was more effective than a didactic lecture for implant dentistry practical skill acquisition., (© 2024. The Author(s).)

Background: Mosquito-borne viruses cause various infectious diseases in humans and animals. Oya virus (OYAV) and Ebinur Lake virus (EBIV), belonging to the genus Orthobunyavirus within the family Peribunyaviridae, are recognized as neglected viruses with the potential to pose threats to animal or public health. The evaluation of vector competence is essential for predicting the arbovirus transmission risk., Methods: To investigate the range of mosquito vectors for OYAV (strain SZC50) and EBIV (strain Cu20-XJ), the susceptibility of four mosquito species (Culex pipiens pallens, Cx. quinquefasciatus, Aedes albopictus, and Ae. aegypti) was measured through artificial oral infection. Then, mosquito species with a high infection rate (IR) were chosen to further evaluate the dissemination rate (DR), transmission rate (TR), and transmission efficiency. The viral RNA in each mosquito sample was determined by RT-qPCR., Results: The results revealed that for OYAV, Cx. pipiens pallens had the highest IR (up to 40.0%) among the four species, but the DR and TR were 4.8% and 0.0%, respectively. For EBIV, Cx. pipiens pallens and Cx. quinquefasciatus had higher IR compared to Ae. albopictus (1.7%). However, the EBIV RNA and infectious virus were detected in Cx. pipiens pallens, with a TR of up to 15.4% and a transmission efficiency of 3.3%., Conclusions: The findings indicate that Cx. pipiens pallens was susceptible to OYAV but had an extremely low risk of transmitting the virus. Culex pipiens pallens and Cx. quinquefasciatus were susceptible to EBIV, and Cx. pipiens pallens had a higher transmission risk to EBIV than Cx. quinquefasciatus., (© 2024. The Author(s).)

Background: Hypertension is one of the major public health problems in China. Limited evidence exists regarding sex differences in the association between hypertension and air pollutants, as well as the impact of dietary factors on the relationship between air pollutants and hypertension. The aim of this study was to investigate the sex-specific effects of dietary patterns on the association between fine particulate matter (PM 2.5 ), ozone(O 3 ) and hypertension in adults residing in Jiangsu Province of China., Methods: A total of 3189 adults from the 2015 China Adult Chronic Disease and Nutrition Surveillance in Jiangsu Province were included in this study. PM 2.5 and O 3 concentrations were estimated using satellite space-time models and assigned to each participant. Dietary patterns were determined by reduced rank regression (RRR), and multivariate logistic regression was used to assess the associations of the obtained dietary patterns with air pollutants and hypertension risk., Results: After adjusting for confounding variables, we found that males were more sensitive to long-term exposure to PM 2.5 (Odds ratio (OR) = 1.42 95%CI:1.08,1.87), and females were more sensitive to long-term exposure to O 3 (OR = 1.61 95%CI:1.15,2.23). Traditional southern pattern identified through RRR exhibited a protective effect against hypertension in males (OR = 0.73 95%CI: 0.56,1.00). The results of the interaction between dietary pattern score and PM 2.5 revealed that adherence to traditional southern pattern was significantly associated with a decreased risk of hypertension in males (P < 0.05), while no significant association was observed among females., Conclusions: Our findings suggested that sex differences existed in the association between dietary patterns, air pollutants and hypertension. Furthermore, we found that adherence to traditional southern pattern may mitigate the risk of long-term PM 2.5 exposure-induced hypertension in males., (© 2024. The Author(s).)

One of the pathogenic causes of thoracic aortic aneurysm (TAA), a dangerous vascular condition that can cause aortic rupture, is autoimmune disorders. Currently, immune cell clustering is becoming more and more refined, and the specific immune cell phenotypes involved are yet unknown. Here, we want to clarify the causal link between TAA risk and 731 immune cell traits. There was a Mendelian randomization analysis (MR). We discovered that the presence of TAA led to an increase in CD45 on CD33 - HLA-DR - myeloid cells, an increase in CD45 on natural killer cells, and a decrease in FSC-A on granulocytes after applying FDR correction. Our research also revealed a strong correlation between the incidence of TAA and an increase in immune cells with CD3 on CD39 + CD4 + , and CD25 on IgD - CD27 - phenotypes. Through genetic techniques, our research has shown the intimate relationship between immune cells and TAA, offering direction for future clinical investigations., (© 2024. The Author(s).)

Alternative splicing (AS), a pivotal post-transcriptional regulatory mechanism, profoundly amplifies diversity and complexity of transcriptome and proteome. Liriodendron chinense (Hemsl.) Sarg., an excellent ornamental tree species renowned for its distinctive leaf shape, which resembles the mandarin jacket. Despite the documented potential genes related to leaf development of L. chinense, the underlying post-transcriptional regulatory mechanisms remain veiled. Here, we conducted a comprehensive analysis of the transcriptome to clarify the genome-wide landscape of the AS pattern and the spectrum of spliced isoforms during leaf developmental stages in L. chinense. Our investigation unveiled 50,259 AS events, involving 10,685 genes (32.9%), with intron retention as the most prevalent events. Notably, the initial stage of leaf development witnessed the detection of 804 differentially AS events affiliated with 548 genes. Although both differentially alternative splicing genes (DASGs) and differentially expressed genes (DEGs) were enriched into morphogenetic related pathways during the transition from fishhook (P2) to lobed (P7) leaves, there was only a modest degree of overlap between DASGs and DEGs. Furthermore, we conducted a comprehensively AS analysis on homologous genes involved in leaf morphogenesis, and most of which are subject to post-transcriptional regulation of AS. Among them, the AINTEGUMENTA-LIKE transcript factor LcAIL5 was characterization in detailed, which experiences skipping exon (SE), and two transcripts displayed disparate expression patterns across multiple stages. Overall, these findings yield a comprehensive understanding of leaf development regulation via AS, offering a novel perspective for further deciphering the mechanism of plant leaf morphogenesis., (© 2024. The Author(s).)

Background: Varicocele is the most prevalent correctable cause of male infertility. Currently, surgical treatment is the primary method to enhance fertility.For many young varicocele patients who have postponed surgery due to time constraints, daytime surgery is especially crucial. Thus, this study aims to investigate the clinical and nursing application value of the Plan-Do-Check-Act (PDCA) cycle in daytime varicocelectomy., Methods: Retrospective collection of clinical data was conducted on 130 patients undergoing laparoscopic varicocelectomy in the Third Affiliated Hospital of Southern Medical University, Guangzhou,China.Among them, 65 patients who underwent daytime surgery were assigned to the observation group, while 65 patients who underwent routine hospital surgeries were assigned to the control group.The former also implemented PDCA cycle management.A comparison was made between the two groups regarding hospitalization time, hospitalization costs, and patient satisfaction., Results: The observation group exhibited a shorter hospitalization time and lower hospitalization costs compared to the control group, with higher patient satisfaction and pre-discharge visual analog scale (VAS) scores noted (P < 0.05).No significant difference was observed in the incidence of postoperative complications between the two groups during hospitalization (P > 0.05). The implementation of the PDCA cycle in the observation group has demonstrated its effectiveness, ensuring the smooth conduct of the daytime varicocelectomy., Conclusion: In conclusion,daytime varicocelectomy can reduce hospitalization time,lower hospitalization costs, improve patient satisfaction. The PDCA Cycle enhances the rationality and efficacy of the daytime varicocelectomy procedure and is highly recommended. Furthermore, it offers valuable reference for the application of the PDCA Cycle in various other diseases and nursing management approaches., Trial Registration: The Trial Registration Number: ChiCTR2300077465;Date of registration: November 9, 2023., (© 2024. The Author(s).)

Background: Metagenomic next-generation sequencing (mNGS) could improve the diagnosed efficiency of pathogens in bloodstream infections or sepsis. Little is known about the clinical impact of mNGS test when used for the early diagnosis of suspected infections. Herein, our main objective was to assess the clinical efficacy of utilizing blood samples to perform mNGS for early diagnosis of suspected infections, as well as to evaluate its potential in guiding antimicrobial therapy decisions., Methods: In this study, 212 adult hospitalized patients who underwent blood mNGS test in the early stage of suspected infections were enrolled. Diagnostic efficacy of mNGS test and blood culture was compared, and the clinical impact of mNGS on clinical care was analyzed., Results: In our study, the total detection rate of blood mNGS was significantly higher than that of culture method (74.4% vs. 12.1%, P < 0.001) in the paired mNGS test and blood culture. Blood stream infection (107, 67.3%) comprised the largest component of all the diseases in our patients, and the detection rate of single blood sample subgroup was similar with that of multiple type of samples subgroup. Among the 187 patients complained with fever, there was no difference in the diagnostic efficacy of mNGS when blood specimens or additional other specimens were used in cases presenting only with fever. While, when patients had other symptoms except fever, the performance of mNGS was superior in cases with specimens of suspected infected sites and blood collected at the same time. Guided by mNGS results, therapeutic regimens for 70.3% cases (149/212) were changed, and the average hospitalized days were significantly shortened in cases with the earlier sampling time of admission., Conclusion: In this study, we emphasized the importance of blood mNGS in early infectious patients with mild and non-specific symptoms. Blood mNGS can be used as a supplement to conventional laboratory examination, and should be performed as soon as possible to guide clinicians to perform appropriate anti-infection treatment timely and effectively. Additionally, combining the contemporaneous samples from suspected infection sites could improve disease diagnosis and prognoses. Further research needs to be better validated in large-scale clinical trials to optimize diagnostic protocol, and the cost-utility analysis should be performed., (© 2024. The Author(s).)

Background: To analyze and compare the biomechanical characteristics of the new combined cervical fusion device (NCCFD) and the traditional cage-plate construct (CPC) to ascertain its effectiveness in anterior cervical discectomy and fusion (ACDF) using finite element analysis., Methods: A finite element model of the cervical spine, inclusive of the occipital bone was created and validated. In the ACDF model, either CPC or NCCFD was implanted at the C2-C3 segment of the model. A pure moment of 1.0 Nm combined with a follower load of 50 N was directed onto the superior surfaces of the occipital bone to determine flexion, extension, lateral bending (left and right), and axial rotation (left and right). The range of motion (ROM), stress distribution at the bone-implant interface, and facet joint forces were investigated and compared between CPC and NCCFD systems., Result: The results showed that the ROMs of the fused levels in both models were nearly zero, and the motions of the unfused segments were similar. In addition, the maximum displacement exhibited nearly identical values for both models. The maximum stress of NCCFD screws in lateral bending and rotational conditions is significantly higher than that of the CPC, while the NCCFD model's maximum stress remains within an acceptable range. Comparing the maximum fusion stress, it was found that the CPC experiences much lower fusion stress in anterior flexion and extension than the NCCFD, with no significant difference between the two in lateral bending and rotational states. Stress on the cage was mainly concentrated on both sides of the wings. Comparing the maximum IDP in the CPC and NCCFD, it was observed that maximum stresses rise in extension and lateral bending for both models. Lastly, stress distributions of the facet joints were generally similar across the two devices., Conclusion: NCCFD not only provides the same level of biomechanical stability as CPC but also avoids postoperative complications associated with uneven force damage to the implant. The device offers a novel surgical alternative for ACDF in C2-C3 level., (© 2024. The Author(s).)

Background: Haloxylon ammodendron holds significance as an ecological plant, showcasing remarkable adaptability to desert conditions, halophytic environments, and sand fixation. With its potential for carbon sequestration, it emerges as a promising candidate for environmental sustainability. Furthermore, it serves as a valuable C4 plant model, offering insights into the genetic foundations of extreme drought tolerance. Despite the availability of plastid and nuclear genomes, the absence of a mitochondrial genome (mitogenome or mtDNA) hinders a comprehensive understanding of its its mtDNA structure, organization, and phylogenetic implications., Results: In the present study, the mitochondrial genome of H. ammodendron was assembled and annotated, resulting in a multi-chromosomal configuration with two circular chromosomes. The mtDNA measured 210,149 bp in length and contained 31 protein-coding genes, 18 tRNA and three rRNA. Our analysis identified a total of 66 simple sequence repeats along with 27 tandem repeats, 312 forward repeats, and 303 palindromic repeats were found. Notably, 17 sequence fragments displayed homology between the mtDNA and chloroplast genome (cpDNA), spanning 5233 bp, accounting for 2.49% of the total mitogenome size. Additionally, we predicted 337 RNA editing sites, all of the C-to-U conversion type. Phylogenetic inference confidently placed H. ammodendron in the Amaranthacea family and its close relative, Suaeda glacum., Conclusions: H. ammodendron mtDNA showed a multi-chromosomal structure with two fully circularized molecules. This newly characterized mtDNA represents a valuable resource for gaining insights into the basis of mtDNA structure variation within Caryophyllales and the evolution of land plants, contributing to their identification, and classification., (© 2024. The Author(s).)

Purpose: The choice of continuous renal replacement therapy (CRRT) anticoagulation program for patients at high risk of bleeding has always been a complex problem in clinical practice. Clinical regimens include regional citrate anticoagulation (RCA) and nafamostat mesylate (NM). This study aimed to evaluate the efficacy and safety of these two anticoagulants for CRRT in patients at high risk of bleeding to guide their clinical use better., Patients and Methods: Between January 2021 and December 2022, 307 patients were screened for this study. Forty-six patients were finally enrolled: 22 in the regional citrate anticoagulation group and 24 in the nafamostat mesylate group. We collected patients' baseline characteristics, laboratory indicators before CRRT, and CRRT-related data. We then performed a statistical analysis of the data from both groups of patients., Results: In our study, the baseline characteristics did not differ significantly between the two groups; the baseline laboratory indicators before CRRT of patients in the two groups were not significantly different. The duration of CRRT was 600 min in the regional citrate anticoagulation (RCA) group, 615 min in the nafamostat mesylate (NM) group; the success rate was 90.7% in the RCA group, and 85.6% in the NM group, the anticoagulant efficacy between the two groups was comparable. There was no significant difference in the safety of anticoagulation between the two groups. We used Generalized Estimating Equations (GEE) to test whether different anticoagulation methods significantly affected the success rate of CRRT and found no statistical difference between RCA and NM., Conclusion: Our study suggests that nafamostat mesylate's anticoagulant efficacy and safety are not inferior to regional citrate anticoagulation for continuous renal replacement therapy in patients at high risk of bleeding., (© 2024. The Author(s).)

Background: Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical factor for the poor prognosis of CRC. Here, we investigated the expression and role of PLOD3 in CRC., Methods: Different liver metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse CRC cells into the spleen of mice to verify the tumorigenicity and metastasis ability in vivo., Results: We identified PLOD3 is significantly overexpressed in liver metastasis samples of CRC. High expression of PLOD3 was significantly associated with poor survival of CRC patients. The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in CRC cells, while the opposite results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver metastasis of CRC cells in different xenografts models, while stable overexpression of PLOD3 promotes liver metastasis and tumor progression. Further studies showed that PLOD3 facilitated the T cell activation in the tumor microenvironment and affected the TNF-α/ NF-κB pathway., Conclusions: This study revealed the essential biological functions of PLOD3 in colon cancer progression and metastasis, suggesting that PLOD3 is a promising translational medicine target and bioengineering targeting PLOD3 overcomes CRC liver metastasis., (© 2024. The Author(s).)

Background: The escalation of viruses over the past decade has highlighted the need to determine their respective hosts, particularly for emerging ones that pose a potential menace to the welfare of both human and animal life. Yet, the traditional means of ascertaining the host range of viruses, which involves field surveillance and laboratory experiments, is a laborious and demanding undertaking. A computational tool with the capability to reliably predict host ranges for novel viruses can provide timely responses in the prevention and control of emerging infectious diseases. The intricate nature of viral-host prediction involves issues such as data imbalance and deficiency. Therefore, developing highly accurate computational tools capable of predicting virus-host associations is a challenging and pressing demand., Results: To overcome the challenges of virus-host prediction, we present HostNet, a deep learning framework that utilizes a Transformer-CNN-BiGRU architecture and two enhanced sequence representation modules. The first module, k-mer to vector, pre-trains a background vector representation of k-mers from a broad range of virus sequences to address the issue of data deficiency. The second module, an adaptive sliding window, truncates virus sequences of various lengths to create a uniform number of informative and distinct samples for each sequence to address the issue of data imbalance. We assess HostNet's performance on a benchmark dataset of "Rabies lyssavirus" and an in-house dataset of "Flavivirus". Our results show that HostNet surpasses the state-of-the-art deep learning-based method in host-prediction accuracies and F1 score. The enhanced sequence representation modules, significantly improve HostNet's training generalization, performance in challenging classes, and stability., Conclusion: HostNet is a promising framework for predicting virus hosts from genomic sequences, addressing challenges posed by sparse and varying-length virus sequence data. Our results demonstrate its potential as a valuable tool for virus-host prediction in various biological contexts. Virus-host prediction based on genomic sequences using deep neural networks is a promising approach to identifying their potential hosts accurately and efficiently, with significant impacts on public health, disease prevention, and vaccine development., (© 2023. The Author(s).)

Background: The efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients harboring neurotrophin receptor kinase (NTRK) family mutations remains obscure., Methods: The Zehir cohort from cBioPortal was used to analyze the mutations (MT) frequency of NTRK family in patients with NSCLC, and their correlation with clinical characteristics and patient survival. The influence of NTRK MT on ICIs efficacy was evaluated in ICIs-treated patients from Samstein cohort and further validated by use of data from OAK/POPLAR cohort., Results: In the Zehir cohort, a significant difference was observed in median overall survival (mOS) between patients with NTRK MT and wild-type (WT) (mOS: 18.97 vs. 21.27 months, HR = 1.34, 95%CI 1.00-1.78; log-rank P = 0.047). In Samstein cohort, the mOS of NTRK mutant patients receiving ICIs has improved compared to WT patients (mOS: 21.00 vs. 11.00 months, log-rank P = 0.103). Notably, in subgroup analysis, ICIs significantly prolonged mOS in patients with NTRK3 MT than in WT patients (mOS: not available vs. 11.00 months, HR = 0.36, 95%CI 0.16-0.81; log-rank P = 0.009). Identical mOS between NTRK MT and WT patients receiving ICIs treatment (mOS: 13.24 vs. 13.50 months, log-rank P = 0.775) was observed in OAK/POPLAR cohort. Moreover, a similar programmed death ligand 1 (PD-L1) expression, but higher tumor mutational burden (TMB), blood TMB (bTMB) and enriched anti-tumor immunity were observed in NTRK MT compared to WT (P < 0.05)., Conclusion: Taking high TMB or bTMB into consideration, patients with NTRK mutant NSCLC could benefit from ICIs treatment., (© 2023. The Author(s).)

Backgrounds: This study aimed to compare whether Calcium phosphate cement (CPC) promotes the stability of osteoporotic lumbar pedicle screw by enhancer-injecters with different number of holes., Methods: Through a self-designed bone cement injection device, the pedicle screw canal was strengthened with calcium phosphate bone cement, and divided into 4-hole group, 6-hole group, 8-hole group, straight pore group and the control group. The screw was inserted into the mechanical test module, the Maximum insertion torque and Maximum axial pull-out strength were recorded, and the distribution of calcium phosphate bone cement was analyzed by CT and X-ray. The data results were analyzed using SPSS19.0 statistical software package., Results: The distribution of bone cement in different reinforcement groups was different and showed regularity. The bone cement in the 4-hole group was roughly located in the head 1/3 of the screw, the 6-hole group was located in the middle 1/3 of the screw, and the 8-hole group was located in the caudal 1/3 of the screw. Compared with the control group, the maximum axial pull-out force of screws in the lateral hole and full screw tunnel reinforcement group was significantly increased. There was no significant difference between the 4-hole, 6-hole and straight pore groups. There was no difference in the screw-in torque between the reinforcement groups, and they all increased significantly compared with the control group, and the difference was statistically significant. After the screw was pulled out, the interface between the bone cement and the polyurethane material was fractured, and a tight package was formed with the screw., Conclusions: Enhancer syringes with different hole numbers combined with CPC bone cement injection can significantly increase the maximum screw pull-out force. The 8-hole group has a smaller pull-out force and is relatively prone to leakage of reinforcing material, which lacks safety in use. The local reinforcement of 4-hole and 6-hole sheath can play a similar role to that of total nail tunnel reinforcement., (© 2023. The Author(s).)

Background: To explore the predictive value of Ellipsoid Zone (EZ) -related angle parameters for the outcome of primary macular hole surgery., Methods: This was a retrospective study. Patients diagnosed with large macular hole (MH) (minimum diameter > 500 μm) between 2018 and 2021 were enrolled. All patients underwent 25-gauge pars plana vitrectomy, internal limiting membrane (ILM) peeling and air tamponade. Spectral-domain OCT (SD-OCT) and best corrected visual acuity (BCVA) were measured in preoperative and 2-week post-operative. Classic and angle related parameters were measured via ImageJ. Angle regularity (AR) were defined as the standard deviation of the angle parameters in vertical and horizontal direction., Results: Seventy-six eyes were included for analysis; 24 eyes showed an unclosed macular hole at the 2-week postoperative and 52 eyes showed a closed hole. Preoperatively, MLD (P < 0.001), BD (P = 0.009) and diameter of EZ/ELM disruption (P = 0.002 and 0.025) in patients failed to close the hole after primary surgery were significantly larger than those succeeded. EZ-MH (P = 0.018), EZ-NFL (P = 0.006), EZ-GCL (P = 0.004), EZ-INL (P = 0.002), EZ-OPL (P = 0.009) and EZ-ONL (P = 0.011) angles were smaller in patients with unclosed hole. AR of the EZ-NFL (P = 0.009), EZ-GCL (P = 0.009), EZ-OPL (P = 0.023), EZ-ONL (P = 0.048) and Basal-NFL (P = 0.030) angles among the unclosed patients were significantly larger than those of the closed group. EZ-NFL (P = 0.015), EZ-GCL (P = 0.004), EZ-INL (P < 0.001), EZ-OPL (P < 0.001), EZ-ONL (P < 0.001), Basal (P = 0.023) and Basal-NFL (P < 0.001) angles of hole-unclosed patients enlarged significantly after the surgery., Conclusions: Patients with large macular holes and an increased EZ-related angle and angle AR are more likely to experience unsuccessful outcomes following primary MH surgery. Therefore, EZ-related angles hold potential as valuable parameters for predicting the surgical outcome., (© 2023. The Author(s).)

Background: Migraine is a common disabling neurological disorder with severe physical and psychological damage, but there is a lack of convenient and effective non-invasive early prediction methods. This study aimed to develop a new series of non-invasive prediction models for migraine with external validation., Methods: A total of 188 and 94 subjects were included in the training and validation sets, respectively. A standardized professional questionnaire was used to collect the subjects' 9-item traditional Chinese medicine constitution (TCMC) scores, Pittsburgh Sleep Quality Index (PSQI) score, Zung's Self-rating Anxiety Scale and Self-rating Depression Scale scores. Logistic regression was used to analyze the risk predictors of migraine, and a series of prediction models for migraine were developed. Receiver operating characteristic (ROC) curve and calibration curve were used to assess the discrimination and calibration of the models. The predictive performance of the models were further validated using external datasets and subgroup analyses were conducted., Results: PSQI score and Qi-depression score were significantly and positively associated with the risk of migraine, with the area of the ROC curves (AUCs) predicting migraine of 0.83 (95% CI:0.77-0.89) and 0.76 (95% CI:0.68-0.84), respectively. Eight non-invasive predictive models for migraine containing one to eight variables were developed using logistic regression, with AUCs ranging from 0.83 (95% CI: 0.77-0.89) to 0.92 (95% CI: 0.89-0.96) for the training set and from 0.76 (95% CI: 0.66-0.85) to 0.83 (95% CI: 0.75-0.91) for the validation set. Subgroup analyses showed that the AUCs of the eight prediction models for predicting migraine in the training and validation sets of different gender and age subgroups ranged from 0.80 (95% CI: 0.63-0.97) to 0.95 (95% CI: 0.91-1.00) and 0.73 (95% CI: 0.64-0.84) to 0.93 (95% CI: 0.82-1.00), respectively., Conclusions: This study developed and validated a series of convenient and novel non-invasive prediction models for migraine, which have good predictive ability for migraine in Chinese adults of different genders and ages. It is of great significance for the early prevention, screening, and diagnosis of migraine., (© 2023. The Author(s).)

Background: Lycium barbarum polysaccharide (LBP) is an active ingredient extracted from Lycium barbarum that inhibits neuroinflammation, and Lycium barbarum glycopeptide (LbGp) is a glycoprotein with immunological activity that was purified and isolated from LBP. Previous studies have shown that LbGp can regulate the immune microenvironment, but its specific mechanism of action remains unclear., Aims: In this study, we aimed to explore the mechanism of action of LbGp in the treatment of spinal cord injury through metabolomics and molecular experiments., Methods: SD male rats were randomly assigned to three experimental groups, and after establishing the spinal cord hemisection model, LbGp was administered orally. Spinal cord tissue was sampled on the seventh day after surgery for molecular and metabolomic experiments. In vitro, LbGp was administered to mimic the inflammatory microenvironment by activating microglia, and its mechanism of action in suppressing neuroinflammation was further elaborated using metabolomics and molecular biology techniques such as western blotting and q-PCR., Results: In vivo and in vitro experiments found that LbGp can improve the inflammatory microenvironment by inhibiting the NF-kB and pyroptosis pathways. Furthermore, LbGp induced the secretion of docosahexaenoic acid (DHA) by microglia, and DHA inhibited neuroinflammation through the MAPK/NF-κB and pyroptosis pathways., Conclusions: In summary, we hypothesize that LbGp improves the inflammatory microenvironment by regulating the secretion of DHA by microglia and thereby inhibiting the MAPK/NF-κB and pyroptosis pathways and promoting nerve repair and motor function recovery. This study provides a new direction for the treatment of spinal cord injury and elucidates the potential mechanism of action of LbGp., (© 2023. The Author(s).)

Background: Treatment of displaced intra-articular calcaneal fractures (DIACFs) with percutaneous screw fixation remains defective in some aspects. A novel three-dimensional (3D) printed cast was devised to assist screw placement. This study assessed the radiological and functional outcomes of 3D-printed cast assisted screw fixation for patients with DIACFs., Methods: Patients with unilateral Sanders type II or III DIACFs admitted to a single-centre hospital underwent either 3D-printed cast assisted screw fixation (3D group) or minimally invasive plate fixation (control group) from September 2020 to November 2022. All patients were assessed at one, two, three, and six months of follow-up. Comparison between groups was conducted in operative duration, fluoroscopic times, radiographic measurements of the calcaneus, and the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score., Results: A total of 32 patients were enrolled (19 in the 3D group versus 13 in the control group). Significant differences were detected between the 3D group and control group in operative duration (53.63±8.95 min, 95.08±8.31 min, P <0.001), fluoroscopic times (7.37±1.21, 16.85±1.57, P <0.001). At a follow-up of six months, the 3D group showed better restoration than the control group in calcaneal width, height, Bohler angle, and AOFAS Ankle-Hindfoot scores (all P <0.001). No significant differences were shown in calcaneal length and Gissane angle (P >0.05). No wound-related complications occurred in either group., Conclusion: The 3D-printed cast assisted screw fixation has shown superiority over minimally invasive plate fixation in the operative duration, fluoroscopic exposure, morphological restoration of the calcaneus, and functional outcomes in the treatment of DIACFs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: New oral anticoagulants (NOACs) have been becoming prevalent in recent years and are increasingly used in the treatment of port vein thrombosis. The difference of the efficacy and safety between rivaroxaban and dabigatran remains unclear in the treatment of cirrhotic patients with acute portal vein thrombosis (PVT)., Methods: This retrospective study included all consecutive cirrhotic patients with acute portal vein thrombosis in our institute from January 2020 to December 2021. The patients received oral anticoagulation with rivaroxaban or dabigatran. The demographic, clinical, and imaging data of patients were collected. The diagnosis of acute PVT was confirmed by imaging examinations. The severity of liver cirrhosis was assessed using Child-Pugh score and Model for End-Stage Liver Disease (MELD) score. Outcomes included recanalization (complete, partial, and persistent occlusion), liver function, bleedings, and survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: A total of 94 patients were included, 52 patients (55%) received rivaroxaban and 42 (45%) with dabigatran. The complete and partial recanalization of PVT was observed in 41 patients. There was no significant difference in complete recanalization, partial recanalization, and persistent occlusion between the two groups. With multivariate analysis, D-dimer (HR 1.165, 95% CI 1.036-1.311, p = 0.011) was independent predictors of complete recanalization. The Child-Pugh score (p = 0.001) was significantly improved in both two groups after anticoagulation, respectively. However, there was no difference between the two groups. The probability of survival was 94%, 95% in the rivaroxaban and dabigatran groups (log-rank p = 0.830). Major bleedings were reported in 3 patients (6%) in rivaroxaban group and 1 patient (2%) in dabigatran group (p = 0.646). Six patients (12%) in rivaroxaban group experienced minor bleeding, and five (12%) from dabigatran group (p = 0.691)., Conclusions: The efficacy and safety were comparable between rivaroxaban and dabigatran in the treatment of cirrhotic patients with acute portal vein thrombosis. And D-dimer can contribute to the prediction of PVT recanalization in cirrhotic patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Intranasal agents may be ideal for the treatment of migraine patients. Many new acute intranasal-specific therapies have been developed, but few of them have been directly compared. The aim of this network meta-analysis (NMA) was to compare the efficacy and safety of various intranasal agents for the treatment of acute migraine in adult patients., Methods: The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to 15 August 2023. Randomized controlled trials (RCTs) using intranasal agents (no restrictions on dose, formulation, dosing regimen or timing of the first dose) to treat adult patients with acute migraine were included. The primary efficacy endpoint was pain freedom at 2 h, and the primary safety endpoint was adverse events (AEs). The analysis process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: Nineteen studies (21 RCTs, 9738 participants) were included. Compared to the placebo, 5 mg of zolmitriptan using a conventional liquid nasal spray device was the most effective for pain freedom at 2 h [odds ratio (OR): 4.67, 95% confidence interval (CI): 3.43 to 6.43] and 24 h (OR: 5.49, 95% CI: 3.58 to 8.42) among all the interventions. Butorphanol nasal spray 1 mg was the most effective (OR: 8.62, 95% CI: 1.11 to 66.92) for pain freedom at 1 h, but with low-quality evidence. DFN-02 presented the highest freedom from nausea (OR: 4.95, 95% CI: 1.29 to 19.01) and phonophobia (OR: 5.36, 95% CI: 1.67 to 17.22) at 2 h, albeit with lower odds of achieving complete pain freedom. ROX-828 showed the highest improvement in freedom from photophobia at 2 h (OR: 4.03, 95% CI: 1.66 to 9.81). Dihydroergotamine nasal spray was significantly associated with the highest risk of AEs (OR: 9.65, 95% CI: 4.39 to 21.22) and was not recommended for routine use. Zavegepant nasal spray demonstrated the lowest risk of AEs (OR: 2.04, 95% CI: 1.37 to 3.03). The results of sensitivity analyses for the primary endpoints (pain freedom at 2 h and AEs) were generally consistent with those of the base case model., Conclusions: Compared with other new intranasal-specific therapies in treating migraine attacks, zolmitriptan nasal spray 5 mg was the most effective agent for pain freedom at 2 h. Zavegepant nasal spray 10 mg had the fewest adverse side effects., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy., (© 2023. University of Wroclav.)

Background: The efficacy of washed microbiota transplantation (WMT) in terms of refractory functional constipation (FC)-related therapeutic targets and influencing factors have not been elucidated. This study aimed to assess the efficacy and influencing factors of WMT in treating refractory FC-related therapeutic targets., Methods: The clinical data of patients diagnosed with refractory FC and received with WMT were retrospectively collected. The therapeutic targets included straining, hard stools, incomplete evacuation, a sense of anorectal obstruction, manual maneuvers, and decreased stool frequency. Each target was recorded as 1 (yes) or 0 (no). All patients were followed up for approximately 24 weeks from the end of the first course of WMT. The primary outcomes were the improvement rates for the individual therapeutic targets and the overall response in respect of the therapeutic targets decreased by 2 at weeks 4, 8, and 24. The secondary outcomes were the clinical remission rate (i.e., the proportion of patients with an average of 3 or more spontaneous complete bowel movements per week), clinical improvement rate (i.e., the proportion of patients with an average increase of 1 or more SCBMs/week or patients with remission), stool frequency, Wexner constipation score, Bristol Stool Form Scale (BSFS) score, and adverse events. The factors influencing the efficacy were also analyzed., Results: Overall, 63 patients with 112 WMT courses were enrolled. The improvement rates at weeks 8 and 24 were 45.6% and 35.0%, 42.9% and 38.6%, 45.0% and 35.7%, 55.6% and 44.4%, and 60.9% and 50.0%, respectively, for straining, hard stools, incomplete evacuation, a sense of anorectal obstruction, and decreased stool frequency. The overall response rates were 49.2%, 50.8%, and 42.9%, respectively, at weeks 4, 8, and 24. The rates of clinical remission and clinical improvement were 54.0% and 68.3%, respectively, at weeks 4. The stool frequency, BSFS score, and Wexner constipation score tended to improve post-WMT. Only 22 mild adverse events were observed during the 112 WMT courses and the follow-up. The number of WMT courses was identified to be the independent factor influencing the efficacy., Conclusions: WMT is efficacious in improving refractory FC-related therapeutic targets. The effectiveness of WMT in the management of FC is enhanced with the administration of multiple courses., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death due to early metastasis or recurrence. Tumor angiogenesis plays an essential role in the tumorigenesis of HCC. Accumulated studies have validated the crucial role of lncRNAs in tumor angiogenesis. Here, we established an angiogenesis-related multi-lncRNAs risk model based on the machine learning for HCC prognosis prediction. Firstly, a total of 348 differential expression angiogenesis-related lncRNAs were identified by correlation analysis. Then, 20 of these lncRNAs were selected through univariate cox analysis and used for in-depth study of machine learning. After 1,000 random sampling cycles calculating by random forest algorithm, four lncRNAs were found to be highly associated with HCC prognosis, namely LUCAT1, AC010761.1, AC006504.7 and MIR210HG. Subsequently, the results from both the training and validation sets revealed that the four lncRNAs-based risk model was suitable for predicting HCC recurrence. Moreover, the infiltration of macrophages and CD8 T cells were shown to be closely associated with risk score and promotion of immune escape. The reliability of this model was validated by exploring the biological functions of lncRNA MIR210HG in HCC cells. The results showed that MIR210HG silence inhibited HCC growth and migration through upregulating PFKFB4 and SPAG4. Taken together, this angiogenesis-related risk model could serve as a reliable and promising tool to predict the prognosis of HCC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Metagenomic next-generation sequencing (mNGS) is a novel nucleic acid method for the detection of unknown and difficult pathogenic microorganisms, and its application in the etiological diagnosis of fever of unknown origin (FUO) is less reported. We aimed to comprehensively assess the value of mNGS in the etiologic diagnosis of FUO by the pathogen spectrum and diagnostic performance, and to investigate whether it is different in the time to diagnosis, length of hospitalization, antibiotic consumption and cost between FUO patients with and without early application of mNGS., Methods: A total of 149 FUO inpatients underwent both mNGS and routine pathogen detection was retrospectively analyzed. The diagnostic performance of mNGS, culture and CMTs for the final clinical diagnosis was evaluated by using sensitivity, specificity, positive predictive value, negative predictive value and total conforming rate. Patients were furtherly divided into two groups: the earlier mNGS detection group (sampling time: 0 to 3 days of the admission) and the later mNGS detection group (sampling time: after 3 days of the admission). The length of hospital stay, time spent on diagnosis, cost and consumption of antibiotics were compared between the two groups., Results: Compared with the conventional microbiological methods, mNGS detected much more species and had the higher negative predictive (67.6%) and total conforming rate (65.1%). Patients with mNGS sampled earlier had a significantly shorter time to diagnosis (6.05+/-6.23 vs. 10.5+/-6.4 days, P < 0.001) and days of hospital stay (13.7+/-20.0 vs. 30.3 +/-26.9, P < 0.001), as well as a significantly less consumption (13.3+/-7.8 vs. 19.5+/-8.0, P < 0.001) and cost (4543+/-7326 vs. 9873 +/- 9958 China Yuan [CNY], P = 0.001) of antibiotics compared with the patients sampled later., Conclusions: mNGS could significantly improve the detected pathogen spectrum, clinical conforming rate of pathogens while having good negative predictive value for ruling out infections. Early mNGS detection may shorten the diagnosis time and hospitalization days and reduce unnecessary consumption of antibiotics., (© 2023. The Author(s).)

Background: Weight management has been an important component of the service in obstetric care offered to pregnant women. Current gestational weight gain recommendations were primarily for the general obstetric population, raising concern about the applicability to women with gestational diabetes mellitus (GDM). We aimed to assess the difference in weight progression and adherence to the recommended gestational weight gain targets between women with gestational diabetes mellitus (GDM) and women with normal glucose tolerance (NGT)., Methods: This was a hospital-based retrospective study of 56,616 pregnant women (9,430 GDM women and 47,186 NGT women) from Guangzhou between 2017 and 2021. The average change in weight progression was estimated based on serial weight measurements throughout pregnancy, using a mixed effects model with a random intercept to account for repeated measures of the same individual., Results: Women with GDM gained less weight (12.07 [SD 5.20] kg) than women with NGT (14.04 [SD 5.04] kg) throughout pregnancy. Before OGTT, a small difference was observed in the average change in weight progression between the two groups (GDM, 0.44 kg/week vs. NGT, 0.45 kg/week, p < 0.001), however, this gap widened significantly after the test (0.34 vs. 0.50 kg/week, p < 0.001). GDM individuals were identified with an approximately 4-fold increased proportion of insufficient weight gain (41.1% vs. 10.4%) and a 2-fold decreased proportion of excessive weight gain (22.6% vs. 54.2%) compared to NGT individuals. These results were consistently observed across different BMI categories, including underweight (insufficient: 52.7% vs. 19.9%; excessive: 15.6% vs. 35.3%), normal weight (insufficient 38.2% vs. 7.4%; excessive: 22.2% vs. 57.3%), and overweight/obese (insufficient: 43.1% vs. 9.8%; excessive: 30.1% vs. 68.8%)., Conclusion: Weight progression varied significantly between GDM and NGT individuals, resulting in a substantial difference in identifying insufficient and excessive weight gain between the two groups under current gestational weight gain guidelines., (© 2023. The Author(s).)

Background: Atherosclerosis (AS) is a chronic inflammatory disease that might induce severe cardiovascular events, such as myocardial infarction and cerebral infarction. These risk factors in the pathogenesis of AS remain uncertain and further research is needed. This study aims to explore the potential molecular mechanisms of AS by bioinformatics analyses., Methods: GSE100927 gene expression profiles, including 69 AS samples and 35 healthy controls, were downloaded from Gene Expression Omnibus database and indenfied for key genes and pathways in AS., Results: A total of 443 differentially expressed genes (DEGs) between control and AS were identified, including 323 down-regulated genes and 120 up-regulated genes. The Gene ontology terms enriched by the up-regulated DEGs were associated with the regulation of leukocyte activation, endocytic vesicle, and cytokine binding, while the down-regulated DEGs were associated with negative regulation of cell growth, extracellular matrix, and G protein-coupled receptor binding. KEGG pathway analysis showed that the up-regulated DEGs were enriched in Osteoclast differentiation and Phagosome, while the down-regulated DEGs were enriched in vascular smooth muscle contraction and cGMP-PKG signaling pathway. Using the modular analysis of Cytoscape, we identified 3 modules mainly involved in Leishmaniasis and Osteoclast differentiation. The GSEA analysis showed the up-regulated gene sets were enriched in the ribosome, ascorbated metabolism, and propanoate metabolism. The LASSO Cox regression analysis showed the top 3 genes were TNF, CX3CR1, and COL1R1. Finally, we found these immune cells were conferred significantly higher infiltrating density in the AS group., Conclusions: Our data showed the pathway of Osteoclast differentiation and Leishmaniasis was involved in the AS process and we developed a three-gene model base on the prognosis of AS. These findings clarified the gene regulatory network of AS and may provide a novel target for AS therapy., (© 2023. The Author(s).)

Exosomal miRNAs are known to play important roles in ovarian cancer and chemotherapeutic resistance. However, a systematic evaluation of characteristics of exosomal miRNAs involved in cisplatin resistance in ovarian cancer remains totally unclear. Exosomes (Exo-A2780, Exo-A2780/DDP) were extracted from cisplatin-sensitive cells (A2780) and cisplatin-resistant cells (A2780/DDP). Differential exosomal miRNA expression profiles were found by high-throughput sequencing (HTS). Target genes of the exo-miRNAs were predicted by using two online databases to increase the prediction accuracy. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were utilized to find biological relationships with chemoresistance. RT‒qPCR of three exosomal miRNAs was performed, and a protein‒protein interaction (PPI) network was established to identify the hub genes. The GDSC database was used to prove the association between hsa-miR-675-3p expression and the IC50 value. An integrated miRNA-mRNA network was constructed to predict miRNA-mRNA associations. The connection between hsa-miR-675-3p and ovarian cancer was discovered by immune microenvironment analyses. The upregulated exosomal miRNAs could regulate gene targets through signalling pathways such as the Ras, PI3K/Akt, Wnt, and ErbB pathways. GO and KEGG analyses indicated that the target genes were involved in protein binding, transcription regulator activity and DNA binding. The RT‒qPCR results were consistent with the HTS data, and the results of PPI network analysis suggested that FMR1 and CD86 were the hub genes. GDSC database analysis and construction of the integrated miRNA-mRNA network suggested that hsa-miR-675-3p was associated with drug resistance. Immune microenvironment analyses showed that hsa-miR-675-3p was crucial in ovarian cancer. The study suggested that exosomal hsa-miR-675-3p is a potential target for treating ovarian cancer and overcoming cisplatin resistance., (© 2023. The Author(s).)

Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs. Video Abstract., (© 2023. The Author(s).)