Search

A two-year long-term workshop centered around a phenotypic whole-cell screening strategy for integrating cutting-edge knowledge and discovery-based laboratory experiences was developed to serve as a preparatory course for enhancing the teaching quality of the upper-level discovery-based research internship curriculum for pharmacy major undergraduates. The workshop comprises four modules that integrate lessons and experiments into a genuine research project, which initiates with a medicinal-chemistry course, run concurrently in the second year and culminates with the discovery-based research internship curriculum for pharmacy major students as a corequisite in the last year. The effective implementation of the featured pedagogical approaches in the modules is detailed as described. A group of students (N = 4) passed the instructor-student two-way choice and were enrolled in the senior-level phenotypic hit discovery laboratory project. The students synthesized a small library of molecules, tested them in an antibacterial assay, and further designed new compounds to analyze structure-activity relationships. Furthermore, positive feedback from students revealed that the phenotypic hit discovery oriented workshop enabled them to gain in-depth cutting-edge knowledge and provided an understanding of how medicinal chemists engage in new drug discovery research. The student's early exposure to troubleshooting or exploring unexpected results in an authentic scientific environment inspired them with ambition and confidence to engage with new drug discovery. We hope that this workshop will serve as a springboard for those wishing to educate medicinal chemists at an undergraduate level with modern strategies that are relevant to the current and future drug discovery landscape.

As a cross-cutting and comprehensive subject, medicinal chemistry involves the knowledge of chemical, biological, medical, and pharmaceutical sciences. A comprehensive medicinal chemistry experience for undergraduates is expected to train various experimental skills and enhance their scientific research ability. Herein, a series of laboratory and computational experiments performed by undergraduate students were described, including synthesis, acetylation, and activity testing of an acetylcholinesterase inhibitor, tacrine. The inhibition activities of tacrine and acetylated tacrine were discussed based on the results of computer simulations. Moreover, representative student-generated data, methods of the experiments, and an interpretation of student feedback on the project are presented.

Mentoring is suffering from a shortage of trained mentors which compromise the efficacy of novice mentoring or mentoring between a senior clinician and a junior clinician. E-mentoring is proposed as a means of supplementing this dominant form of mentoring in medicine by providing accessible, timely and longitudinal support for mentees. However, with little is known about e-mentoring nor its role in a blended mentoring approach, a systematic scoping review is proposed to evaluate these gaps in understanding in order to better understand e-mentoring and assess the viability of employing e-mentoring practice to support novice mentoring. Using Arksey and O'Malley's (Int J Soc Res Methodol 8(1):19-32, 2005) approach, 5 reviewers carried out independent literature reviews of e-mentoring as an adjuvant to novice mentoring in PubMed, Embase, PsycINFO, ERIC, Cochrane Database of Systematic Reviews, Google Scholar, Scopus, GreyLit, OpenGrey, and Web of Science databases. Braun and Clarke's (Qual Res Psychol 3(2):77-101, 2006) thematic analysis approach was used to thematically analyse accounts of e-mentoring across different settings. 6557 abstracts were identified, 109 full text articles were reviewed, and 18 articles were included and thematically analysed. The themes identified include definitions, role, stages, processes, platforms, evaluation, and relationships in e-mentoring. The themes identified provide a clinically relevant definition of e-mentoring, and in highlighting the similarities in the phases of novice and e-mentoring reaffirms the validity of a blended approach as a means of addressing shortfalls in mentoring in medicine.

This study aimed to investigate and compare the impact of pursuing top university status on the management and academic practices of two departments in a top-ranked institution in Taiwan. Qualitative interviews, official policy documents, website resources and relevant documents were the main sources of empirical data. Interview data were collected from 10 interviewees, the department heads and four full-time academics in both departments. This study found that departments and academics were required to plan and work in accordance with the university's overall development plan and the two departments played different roles in contributing to various aspects of the university managers' idea of what a world-class university is. This should be understood within the unique and complex academic tribes of different subject fields and the deeply rooted dimensions of Chinese culture in Taiwan.

KCNQ1/Kv7, a low-voltage-gated K+ channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca2+ flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca2+ channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and β-cell survival in hereditary diabetes pathology.

Abstract Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8+ T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8+ T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8+ T cells.

[Objective] To analyze the infection status of hepatitis E virus (HEV) among blood donors in Zhengzhou, so as to provide data support for formulating local blood screening strategies. [Methods] Random samples from blood donors from January to December 2022 were tested for HEV RNA using PCR technology. Reactive samples were sequenced for gene analysis, and the donors were followed up. [Results] Among 21 311 samples, 3(0.14‰) were reactive for HEV RNA, all of whom were male. Genetic sequencing results revealed that one strong positive sample was genotype 4, while sequencing failed for the other two due to low viral load. A follow-up of 25 strong positive donors showed that ALT significantly increased on day 7 after donation, anti-HEV IgM and anti-HEV IgG turned positive. On day 21, ALT returned to normal, and on day 35, HEV RNA turned negative. Notably, anti-HEV IgM and anti-HEV IgG persisted until day 482. [Conclusion] There is HEV infection among blood donors in Zhengzhou, and it is necessary to expand the screening scope to comprehensively explore the prevalence and genotype distribution of HEV among blood donors.

Abstract. Vascular aging (VA) is a common etiology of various chronic diseases and represents a major public health concern. Intermittent hypoxia (IH) associated with obstructive sleep apnea-hypopnea syndrome (OSAHS) is a primary pathological and physiological driver of OSAHS-induced systemic complications. A substantial proportion of OSAHS patients, estimated to be between 40% and 80%, have comorbidities such as hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, aneurysm, and stroke, all of which are closely associated with VA. This review examines the molecular and cellular features common to both OSAHS and VA, highlighting decreased melatonin secretion, impaired autophagy, increased apoptosis, increased inflammation and pyroptosis, increased oxidative stress, accelerated telomere shortening, accelerated stem cell depletion, metabolic disorders, imbalanced protein homeostasis, epigenetic alterations, and dysregulated neurohormonal signaling. The accumulation and combination of these features may underlie the pathophysiological link between OSAHS and VA, but the exact mechanisms by which OSAHS affects VA may require further investigation. Taken together, these findings suggest that OSAHS may serve as a novel risk factor for VA and related vascular disorders, and that targeting these features may offer therapeutic potential to mitigate the vascular risks associated with OSAHS.

Abstract. Background:. Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. Methods:. We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett’s multiple comparison and t-test were used to analyze the data. Results:. Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. Conclusions:. Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.

Abstract Research investigating the complex mechanical properties and energy evolution mechanisms of frozen calcareous clay under the influence of multiple factors is crucial for optimizing the artificial ground freezing method in shaft sinking, thereby enhancing construction quality and safety. In this study, a four-factor, four-level orthogonal test was devised, taking into account temperature, confining pressure, dry density, and water content. The complex nonlinear curvilinear relationship between deviatoric stress, volume strain, and axial strain of frozen calcareous clay under different interaction levels was analyzed. The sensitivity of each factor to the peak volume strain was explored, and the energy evolution mechanism of frozen calcareous clay during the triaxial compression process was analyzed. The findings are summarized as follows: (1) The deviatoric stress-axial strain curves demonstrate the strain-hardening characteristics of frozen calcareous clay specimens. Furthermore, as temperature decreases, the hardening degree increases. (2) Sensitivity analysis indicates that the factors’ influence on peak volumetric strain ranks as follows: dry density > confining pressure > temperature > water content. Under the various interactions, specimens exhibit significant volumetric shrinkage. When the temperature remains constant, peak volumetric strain is negatively correlated with dry density but positively correlated with confining pressure. (3) Input energy density, elastic strain energy density, and dissipated energy density of frozen calcareous clay all increase with axial strain. (4) When temperature is held constant, both peak input energy density and peak dissipated energy density rise with increasing confining pressure. Meanwhile, peak elastic strain energy density shows a linear increase with higher confining pressure and lower temperatures.

Abstract Novel therapeutic agents including disitamab vedotin (RC48, an antibody-drug conjugate) and immune-checkpoint inhibitors (e.g., PD-1 inhibitors) have provided new hope as an advanced gastric-cancer (GC) treatment. This multicenter retrospective study studied RC48 monotherapy (MT)’s efficacy and safety against its combination with anti-PD-1 immunotherapy (IT) in advanced GC. Patients treated with RC48 MT or RC48 combined with anti-PD-1 IT from July 2021 to April 2023 were recruited for the study. The progression-free survival (PFS), overall survival (OS), objective-response rate (ORR), disease-control rate (DCR), and safety were studied. After propensity score matching (PSM) (1:1), this study included 34 in the RC48 plus anti-PD-1 IT group and 34 in the RC48 MT group. The median PFS was significantly longer in the combination-therapy (CT) group than in the MT group (5.3 versus 3.8 months, HR: 0.51, 95% CI: 0.31–0.85, p = 0.010), and the median OS was also notably increased (10.0 versus 6.8 months, HR: 0.45, 95% CI: 0.27–0.77, p = 0.003). The ORR and DCR were higher in the combination group (41.18% versus 14.71%, p = 0.031; 61.76% versus 35.30%, p = 0.052). Moreover, subgroup analyses further revealed that those in the CT group experienced a longer PFS and OS, particularly those with high HER2 expression or a PD-L1 CPS score of 1 or higher. The combination therapy (CT) achieved acceptable tolerability and manageable adverse events. Furthermore, the most common grade 3–5 treatment-related adverse events (TRAEs) included decreased white-blood-cell (WBC) count, decreased neutrophil count, and anemia. No new safety risks were observed. In sum, the RC48 and anti-PD-1 IT combination showed good efficacy and a manageable safety profile, indicating its strong potential as an advanced GC therapeutic option.

Abstract Background With the continuous development of educational methods, desktop virtual reality technology has gradually attracted widespread attention. Although current research has shown that this technology can promote learning among nursing students, the mechanism and intrinsic factors are not yet clear. This study aims to explore the mechanisms and factors of the application of desktop virtual reality technology in nursing students’ education and discuss the possible outcomes. Methods The realist review accords with the Realist and Meta-narrative Evidence Syntheses-Evolving Standards (RAMESES). The steps are mainly divided into the following three stages: (1) To determine the initial project theory; (2) To screen the published research and grey literature according to the inclusion criteria; (3) To analyze, extract, and synthesize the evidence of the included studies and then come to a conclusion. Data sources This study included the original research from the following 8 databases from the establishment of the database to November 2024: CNKI, Wanfang Database, CBMdisc, VIP database, Pubmed, Cochrane, Web of Science, Embase. Results A total of 14 papers were included. Six mechanisms and six Context-Mechanism-Outcome combinations were identified, which explained the favourable factors related to the application of desktop virtual reality technology to the education of nursing students. Mechanisms include (1) personalized education, (2) clinically relevant cases, (3) dynamic visualization, (4) good education conditions, (5) gaming education, and (6) interactive education. Conclusion This realist review demonstrates the underlying mechanisms, context, and outcomes, which will guide educators in using virtual reality technology to educate nursing students better.

Abstract Background Agonistic monoclonal antibodies targeting 4-1BB/CD137 have shown preclinical promise, but their clinical development has been limited by severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. Methods A novel anti-MSLN×4-1BB bispecific antibody (bsAb) was generated via antibody engineering, and its affinity and activity were detected via enzyme-linked immunosorbent assay (ELISA), flow cytometry, and T-cell activation and luciferase reporter assays. In vivo antitumour activity was assessed by establishing humanized mice bearing human MSLN-expressing MC38 (MC38/hMSLN) or CT26 (CT26/hMSLN) cells, and safety was further evaluated in cynomolgus monkeys. Results We generated two humanized anti-MSLN×4-1BB bsAbs (HK013-G1/G4) by fusing an anti-4-1BB scFv to the C-terminus of an anti-MSLN VHH with an intact Fc fragment from human IgG1 or IgG4. The two bsAbs were able to block the binding of CA125 to MSLN and stimulate 4-1BB signaling pathway, which was strictly dependent on MSLN expression. In particular, HK013-G1 retained Fc function and induced ADCC effect in tumour cells, whereas HK013-G4 did not. Strikingly, HK013-G1 showed superior antitumour activity to HK013-G4 both in vitro and in vivo and remained effective even in the presence of soluble MSLN. HK013-G1 enhanced antitumour immunity and induced durable antigen-specific immune memory to prevent rechallenged tumour growth, even at a dose as low as 1 mg/kg. Furthermore, HK013-G1 did not induce nonspecific production of proinflammatory cytokines and showed good tolerability up to the highest tested dose (30 mg/kg weekly) for 5 weeks, with no HK013-G1-related adverse effects observed in cynomolgus monkeys. In addition, the mean half-life of HK013-G1 was approximately 61 and 97 h at single doses of 3 and 30 mg/kg, respectively. Conclusion The optimal anti-MSLN×4-1BB bsAb HK013-G1 exhibited synergistic antitumour effects by inducing an ADCC effect (innate immunity) and stimulating the 4-1BB signaling pathway (adaptive immunity) upon cross-bridging with MSLN with no systemic toxicity, which may offer the promise of an improved therapeutic window relative to that of 4-1BB agonists.

Abstract Background Molecular-clinical prognostic models for Myelodysplastic syndromes (MDS) offer more accurate prognosis predictions, yet existing models often overlook the heterogeneity of mutational profiles against the cytogenetic background. Moreover, how to apply these models in regions where large panel NGS is unaffordable remains a significant challenge to be addressed. Methods A total of 237 NK MDS patients from our center were used as the training set to screen for key variables and develop a prognostic model with overall survival (OS) as the endpoint. The C-index was used as the main evaluation metric to assess the model’s performance. The IWG-PM cohort (n = 691) was used as an external independent validation set to evaluate the generalizability of the model. Results We developed a seven-parameter molecular-clinical prognostic model, the Molecular Prognostic Scoring System for NK MDS (NK-PSS-M), which only incorporates three gene mutations as parameters. The NK-PSS-M can reliably predict OS and leukemia-free survival (LFS). The performance of NK-PSS-M was comparable to that of the Molecular International Prognostic Scoring System (IPSS-M), and it significantly outperformed the Revised International Prognostic Scoring System for MDS (IPSS-R). Conclusions The NK-PSS-M model improved the risk stratification of non-molecular models and provided a reliable alternative to the IPSS-M. This strategy provides insights into how resource-scarce regions can apply molecular-clinical models.

Abstract Background Homozygous familial hypercholesterolaemia (HoFH) increases risk of premature cardiovascular events and cardiac death. In severe cases of HoFH, clinical signs and symptoms cannot be controlled well by non-surgical treatments, liver transplantation (LT) currently represents the viable option. Method To assess the clinical efficacy, prognosis, and optimal timing of LT for HoFH, a retrospective analysis was conducted on the preoperative, surgical conditions, and postoperative follow-up of children who received an LT for HoFH at the Beijing Friendship Hospital over the period from December 2014 to August 2022. Results Xanthoma and decreased activity tolerance were the primary clinical manifestations in the 7 HoFH children initially assessed (one child died suddenly prior to surgery due to cardiac arrest). Accompanying these symptoms were increased blood total cholesterol (TC) and low density lipoprotein (LDL) levels, along with severe cardiovascular diseases. HoFH was confirmed in all cases by genetic and biochemical assays. Initial treatments administered to these patients consisted of low-fat diets and lipid-lowering drugs with poor outcomes. Accordingly, all 6 patients received orthotopic liver transplantations (OLT), with the result that significant postoperative reductions were observed in levels of TC and LDL. The median follow-up of these six cases was 37.41 months (range: 19.40–94.10 months). Regular postoperative follow-ups revealed that all survived and showed significant improvements in their clinical symptoms. Conclusion So far, LT is the only way to heal HoFH. LT before the appearance of obvious cardiovascular atherosclerotic lesions can significantly improve the quality of life and prognosis of patients. At the same time, the blood cholesterol level of patients should be continuously monitored after LT to further control the progression of vascular complications.

Abstract Hydroxytyrosol, a fine chemical, is widely utilized in food and pharmaceutical industries. In this study, we constructed a pathway to produce hydroxytyrosol by co-expressing tyrosin-phenol lyase (TPL), L-amino acid dehydrogenase (aadL), α-keto acid decarboxylase (KAD), aldehyde reductase (yahK) and glucose dehydrogenase (gdh). We changed combinations between plasmids with different copy numbers and target genes, resulting in 84% increase in hydroxytyrosol production. The yield of hydroxytyrosol was further increased 89.3% by optimizing the temperature and pH. Finally, 55.3 mM hydroxytyrosol was produced within 14 h by fed-batch biotransformation. This study provides a novel approach for hydroxytyrosol production.

Abstract New-onset atrial fibrillation (NOAF) is associated with increased morbidity and mortality. Despite identifying numerous factors contributing to NOAF, the underlying mechanisms remain uncertain. This study introduces the triglyceride-glucose index (TyG index) as a predictive indicator and establishes a clinical predictive model. We included 551 patients with acute myocardial infarction (AMI) without a history of atrial fibrillation (AF). These patients were divided into two groups based on the occurrence of postoperative NOAF during hospitalization: the NOAF group (n = 94) and the sinus rhythm (SR) group (n = 457). We utilized a regression model to analyze the risk factors of NOAF and to establish a predictive model. The predictive performance, calibration, and clinical effectiveness were evaluated using the receiver operational characteristics (ROC), calibration curve, decision curve analysis, and clinical impact curve. 94 patients developed NOAF during hospitalization. TyG was identified as an independent predictor of NOAF and was significantly higher in the NOAF group. Left atrial (LA) diameter, age, the systemic inflammatory response index (SIRI), and creatinine were also identified as risk factors for NOAF. Combining these with the TyG to build a clinical prediction model resulted in an area under the curve (AUC) of 0.780 (95% CI 0.358–0.888). The ROC, calibration curve, decision curve analysis, and clinical impact curve demonstrated that the performance of the new nomogram was satisfactory. By incorporating the TyG index into the predictive model, NOAF after AMI during hospitalization can be effectively predicted. Early detection of NOAF can significantly improve the prognosis of AMI patients.

Abstract Drought is one of the main environmental factors affecting plant survival and growth. Atraphaxis bracteata is a common desert plant mainly utilized in afforestation and desertification control. This study analyzed the morphological, physiological and molecular regulatory characteristics of different organs of A. bracteata under drought stress. The results showed that with the intensification of drought stress, the height, root length and leaf area of A. bracteata seedlings decreased, while the content of osmotic substances and antioxidant enzyme activity increased. Furthermore, a total of 63 907 non-redundant transcript sequences, of which 55 574 transcripts were annotated, 248 178 FLNC sequences, 107 112 high-quality consistent sequences and 291 314 CCSs were obtained from Iso-Seq. Meanwhile, a total of 2 039 AS events, 22 919 SSR, 40 404 CDS and 5 902 lncRNA were also obtained. The RNA-Seq analysis results revealed that a total of 2 821, 3 907 and 5 532 DETs were identified from roots, stems and leaves, respectively, and which had significantly enrichment in “circadian rhythm-plant” and “starch and sucrose metabolism” pathway. These results would be great significance for further research on the stress resistance of A. bracteata and these DETs function.

Abstract Early missed abortion is defined as a pregnancy of ≤ 12 weeks in which there is a cessation of life in the developing embryo or fetus, leading to its retention within the uterine cavity without being spontaneously expelled promptly. This condition is commonly observed and significantly impacts human reproductive health. This study aimed to identify key genes related to ferroptosis that could serve as novel biomarkers for early missed abortion. Findings from gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicate a correlation between iron- DEFRGS in key modules and the p53 signaling, mitophagy-animal, and protein digestion and absorption pathways. An analysis of the protein-protein interaction (PPI) network was conducted on DEFRGs, identifying five central genes (TP53, EZH2, TIMP1, SLC3A2, and GABARAPL2) using STRING and Cytohubba ROC curves. The expression of pivotal genes in both the missed-abortion and control groups was verified by RT-qPCR. CIBERSORT analysis revealed a notable increase in the infiltration levels of CD8 + T lymphocytes and M2 macrophages among individuals in the early missed abortion group. Additionally, a ceRNA network was constructed to predict interactions between mRNA, miRNA, and lncRNA of the central genes. However, the interacting miRNAs predicted for SLC3A2 in the miRanda, miRDB, and TargetScan databases were limited to hsa-miR-661 and hsa-miR-4311, with no interacting lncRNAs found in the spongeScan database. This research has identified novel genes that could be targeted for the early detection and management of missed abortions.

Abstract The novel pathogen, Elizabethkingia anophelis, has gained attention due to its high mortality rates and drug resistance facilitated by its inherent metallo-β-lactamases (MBLs) genes. This study successfully identified and outlined the functions of the B3-Q MBLs variant, GOB-38, in a clinical sample of E. anophelis. The T7 expression system was employed to stimulate the expression of recombinant protein in Escherichia coli, followed by an analysis of the biochemical properties of purified GOB-38. Our findings indicate that the enzyme GOB-38 displays a wide range of substrates, including broad-spectrum penicillins, 1–4 generation cephalosporins, and carbapenems, potentially contributing to in vitro drug resistance in E. coli through a cloning mechanism. It is important to highlight that GOB-38 exhibits a distinct active site composition compared to GOB-1/18, featuring hydrophilic amino acids Thr51 and Glu141 at both ends of its active center instead of hydrophobic alanine, potentially indicating a preference for imipenem. Furthermore, the co-isolation of Acinetobacter baumannii and E. anophelis, two opportunistic pathogens, from a single lung infection is noteworthy. Our in vitro co-culture experiments suggest that E. anophelis, carrying two MBL genes, may have the ability to transfer carbapenem resistance to other bacterial species through co-infection.

Abstract Osteosarcoma (OS) is a prevalent invasive bone cancer, with numerous homeobox family genes implicated in tumor progression. This study aimed to develop a prognostic model using HOX family genes to assess osteosarcoma patient outcomes. Data from osteosarcoma patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were collected. LASSO regression and multivariate COX regression analyses were employed to create and validate a risk-prognosis model in a validation cohort. Four genes (HOXA1, HOXA5, HOXA6, HOXA13) were identified to construct the risk-prognosis model. Patients were categorized into high-risk and low-risk groups, with significantly better prognosis observed in the low-risk group. A nomogram was developed to predict patients’ overall survival. Variances in gene function were primarily concentrated in immune-related pathways. ssGSEA indicated that immune cell content and function were relatively deficient in the high-risk group. Notably, HOXA1 overexpression suppressed osteosarcoma cell proliferation, migration, invasion, and tumor growth. The model exhibited high accuracy and versatility, enhancing early diagnosis rates and aiding clinicians in decision-making and personalized treatment.

Background Central precocious puberty (CPP) is a common endocrine disease in children, which shows an increasing trend year by year in recent years. It can be divided into fast-progressing central precocious puberty (RP-CPP) and slow-progressing central precocious puberty (SP-CPP) through pubertal development. RP-CPP has great harm, but it is difficult to distinguish it from SP-CPP in early clinical stage, mainly relying on the progress of adolescent development and bone age during follow-up. At present, there is a lack of effective laboratory indicators to predict RP-CPP. Objective To investigate the relationship between luteinizing hormone (LH) /follicle-stimulating hormone (FSH) ratio and pubertal development. Methods CPP girls aged 4-10 years old (n=380) admitted to the Children's Hospital Affiliated to Zhengzhou University from January 2020 to May 2022 were regression selected and divided into RP-CPP group (n=130) and SP-CPP group (n=250 cases) according to indicators such as puberal development process. Clinical characteristics of the two groups were compared and analyzed. Univariate and multivariate Logistic regression analysis of the influencing factors of RP-CPP was performed, and ROC curve of LH/FSH ratio on the predictive value of RP-CPP was drawn. Results The height, weight, BMI, IGF-1, difference between bone age and actual age, bilateral ovarian volume, LH base value, estradiol level, LH base value /FSH base value, and LH peak /FSH peak value of girls in RP-CPP group were all higher than those in SP-CPP group, with statistical significance (P

Abstract Background Remimazolam is a benzodiazepine sedative that is indicated for induction and maintenance during general anaesthesia. Remimazolam is also used for sedation in outpatient surgery; however, most reports have focused on nonelderly patients, whereas only a few studies have reported the use of remimazolam for elderly patients when receiving regional nerve block anaesthesia. Aim The aim of this study was to evaluate the effects of different doses of remimazolam in elderly patients when specifically related to regional nerve block anaesthesia. Methods This study was conducted at a university hospital between February 2022 and March 2023. We included 80 patients aged 65 years or older under regional nerve block anaesthesia. After the effects of anaesthesia were determined, patients were intravenously administered different doses of the test drug, i.e. 4, 4.5, 5, 5.5, or 6 mg, which were named the R1, R2, R3, R4, and R5 groups, respectively. The primary outcome was the loss of consciousness time. The secondary outcomes included the maintenance time and the number of assisted ventilators needed. The exceptional response of patients in terms of loss of consciousness maintenance time, the mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), SpO2, and modified observers assessment of alertness/sedation (MOAA/S) scores were recorded at baseline (T0), 3 min after the injection of the test drug (T1), 6 min after the injection of the test drug (T2), 9 min after the injection of the test drug (T3), 12 min after the injection of the test drug (T4), 15 min after the injection of the test drug (T5), 18 min after the injection of the test drug (T6), 21 min after the injection of the test drug (T7), and 24 min after the injection of the test drug (T8). Results We included 80 patients according to the inclusion and exclusion criteria, with 16 patients in each group. There were no significant differences in sex, age, and BMI amongst the 5 groups. The loss of consciousness time was significantly greater in the R2 group than in the R3, R4, and R5 groups (p

Abstract Background Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC. Methods Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted. Results Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell–cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages. Conclusions Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.

Abstract Background Cochlear implants have helped over one million individuals restore functional hearing globally, but their clinical utility in suppressing tinnitus has not been firmly established. Methods In a decade-long study, we examined longitudinal effects of cochlear implants on tinnitus in 323 post-lingually deafened individuals including 211 with pre-existing tinnitus and 112 without tinnitus. The primary endpoints were tinnitus loudness and tinnitus handicap inventory. The secondary endpoints were speech recognition, anxiety and sleep quality. Results Here we show that after 24 month implant usage, the tinnitus cohort experience 58% reduction in tinnitus loudness (on a 0–10 scale from 4.3 baseline to 1.8 = −2.5, 95% CI: −2.7 to −2.2, p = 3 x 10−6; effect size d’ = −1.4,) and 44% in tinnitus handicap inventory (=−21.2, 95% CI: −24.5 to −17.9, p = 1 x 10−15; d’=−1.0). Conversely, only 3.6% of those without pre-existing tinnitus develop it post-implantation. Prior to implantation, the tinnitus cohort have lower speech recognition, higher anxiety and poorer sleep quality than the non-tinnitus cohort, measured by Mandarin monosyllabic words, Zung Self-rating Anxiety Scale and Pittsburgh Sleep Quality Index, respectively. Although the 24 month implant usage eliminate the group difference in speech and anxiety measures, the tinnitus cohort still face significant sleep difficulties likely due to the tinnitus coming back when the device was inactive at night. Conclusions The present result shows that cochlear implantation can offer an alternative effective treatment for tinnitus. The present result also identifies a critical need in developing always-on and atraumatic devices for tinnitus patients, including potentially those with normal hearing.

ObjectiveTo evaluate the impact of optimizing the stroke green channel on the efficiency of acute ischemic stroke management in a county hospital. MethodsA retrospective analysis of the emergency stroke green channel treatment data from Sixian People’s Hospital from May 2020 to April 2021 (before optimization of the green channel) and from May 2021 to April 2022 (after optimization of the green channel) was conducted. The rates of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) patients, as well as door-to-needle time (DNT), door-to-puncture time (DPT), and the modified Rankin scale (mRS) scores of patients three months post-treatment before and after the optimization of the stroke green channel were compared. ResultsWithin one year before and after optimization of the green channel, the number of acute visits for ischemic stroke was 3 143 and 2 623, respectively. Before optimization, 84 and 51 underwent IVT and MT, respectively. After optimization of the green channel, the ratios of patients underwent IVT (n＝215) and MT (n＝103) significantly increased, and both DNT and DPT were significantly shortened (P＜0.000 1); the proportion of MT patients with an mRS score of 0-2 at 3 months post-discharge significantly increased (46/99 vs 13/46, P＝0.038). ConclusionAfter optimizing the green channel at Sixian People’s Hospital, the efficiency of stroke treatment has significantly improved, and the patients’ prognosis improved.

Abstract Background Nicastrin, a subunit of the γ-secretase complex, is encoded by the NCSTN gene and regulates notch signaling, it is involved in the pathogenesis of hidradenitis suppurativa (HS), Alzheimer disease (AD), and liver cancer. However, the animal models for studying HS are relatively scarce. Methods CRISPR/Cas-mediated genetic engineering was used to generate targeted knockout offspring mice (C57BL/6J). Different doses (10 mg/kg, 20 mg/kg, and 30 mg/kg) and injection methods (subcutaneous/intraperitoneal/gavage injection) of tamoxifen were used to induce the construction of NCSTN knockout mice (mice model). The expressions of nicastrin, NICD1, hes1 in skin, brain, and liver tissue in mice model and wild-type (WT) mice were measured by qRT-PCR and IHC. Results The construction of mice model was successfully induced by tamoxifen, knockout efficiency was 93%, there was no difference in knockout efficiency among three doses, injection methods, genders (P > 0.05). HS-like lesions appeared on the skin of NCSTN knockout mice after 1 month of treatment with tamoxifen, male mice had a higher number of skin lesions compared to female mice (male vs female = 76.5% vs 41.7%, P = 0.027). Compared with WT mice, the expressions of nicastrin (skin P = 0.0009, brain P = 0.0194, liver P = 0.0066), NICD1 (skin P = 0.0115, brain P = 0.0307, liver P = 0.008), hes1 (skin P = 0.0476, brain P = 0.0143, liver P = 0.0003) in mice model all decreased. Conclusions The NCSTN knockout mouse might be employed as HS animal model; Reducing nicastrin may affect the expression of notch1–hes1 pathway molecules in skin, brain, and liver tissues; low dose (10 mg/kg/d) tamoxifen could be used to induce the deletion of the target gene in mice.

Abstract Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, with a high incidence rate and mortality. The analysis of serum biomarkers for colorectal cancer diagnosis has attracted more and more attention because of its low cost, repeatability, and quantification. This study was aimed to evaluate the diagnostic performance of serum Ephrin-A1 in patients with CRC. We retrospectively analyzed CRC cases in a test cohort (121 patients and 108 controls) and validated them in a validation cohort (119 patients and 118 controls). The concentration of Ephrin-A1 in serum was detected by Enzyme-linked immunosorbent assay (ELISA) and the diagnostic performance of serum Ephrin-A1 was evaluated by receiver operating characteristic (ROC) analysis. In the test cohort, serum Ephrin-A1 levels in patients with all-stage CRC and early-stage CRC were significantly higher than those in healthy controls. The area under the ROC curve (AUC), sensitivity and specificity of all-stage CRC and early-stage CRC were 0.709 (95% CI 0.644–0.775) and 0.660 (95% CI 0.530–0.790), 48.76% and 45.00%, 81.48% and 81.48%, respectively. Similar results were observed in the validation cohort. Serum Ephrin-A1 might be served as a potential biomarker in the diagnosis of CRC.

Abstract Periodontitis is closely related to lifestyle habits. Our objective was to examine the relationship between the Life’s Essential 8 (LE8) and the prevalence of periodontitis in American adults. This study used data from the 2009–2014 National Health and Nutrition Examination Survey (NHANES). LE8 scores (range 0–100) were measured according to the definition by the American Heart Association (AHA) and were categorized as low (0–49), medium (50–79), and high (80–100). The NHANES database on periodontal health was used to data to determine the prevalence of periodontitis. Multivariate regression models and restricted cubic spline (RCS) models were used to assess correlations. Weighted quantile sum (WQS) regression was used to explore the association of LE8 and its components with periodontitis risk. Stratified analysis and interaction analysis were conducted to assess the consistency of the results. In addition, mediation analyses were performed to investigate the role of systemic inflammation in mediating the association of LE8 with periodontitis risk. Participants with moderate (LE8 score 50–79) and high (LE8 score 80–100) scores had 58% (95% CI 0.43–0.79, P

Abstract Planting structure adjustment (PSA) affects agricultural water saving, and is an essential part of water-saving agricultural construction. This study introduced virtual water theory and innovatively constructed a model to assess the water-saving effects of PSA in Shiyang River Basin over the past 38 years, explore the relationship between planting structure and water saving, and clarify the most water-saving planting structure. The results showed that the sown area of economic crops consistently increased as food crop areas decreased in the four counties (districts) from 1980 to 2017. Being considered a “big water consumer”, wheat has lost its dominant position. The water requirements of major crops in the four counties and districts showed an increasing trend. The total area proportion of vegetables, wheat, corn, and oil-bearing crops (Abbreviated as TPVWCO) directly determined the water-saving amount. The lower the TPVWCO, the better the water-saving effect. Taking 1980 as the reference year, the most water-saving years in Gulang, Liangzhou, Yongchang, and Minqin were 2007, 1981, 2008, and 2005, respectively. Taking 2007 as the reference year, there were no water-saving years available after that due to the higher TPVWCO. Taking into account food security, ecological and economic benefits, it was recommended to control the TPVWCO at 40% in the Shiyang River Basin in the future. The land vacated should be planted with cotton in Minqin, while the land vacated in the other three counties should be planted with fruits. The research results would provide scientific basis for optimizing the planting structure and managing agricultural water resources in inland river basins in arid regions.

Abstract Hospital-acquired infections (HAIs) are serious complication for patients with acute ischemic stroke (AIS), often resulting in poor functional outcomes. However, no existing model can specifically predict HAI in AIS patients. Therefore, we employed the Gradient Boosting matching learning algorithm to establish predictive models for HAI occurrence in AIS patients and poor 30-day functional outcomes (modified Rankin Scale > 2) in AIS patients with HAI by analyzing electronic health records from 6560 AIS patients. Model performance was evaluated through internal cross-validation and external validation using an independent cohort of 3521 AIS patients. The established models demonstrated robust predictive performance for HAI in AIS patients, achieving area under the receiver operating characteristic curves (AUROCs) of 0.857 ± 0.008 during internal validation and 0.825 ± 0.002 during external validation. For AIS patients with HAI, the second model effectively predict poor 30-day functional outcomes, with AUROCs of 0.905 ± 0.009 during internal validation and 0.907 ± 0.002 during external validation. In conclusion, machine learning models effectively identify the HAI occurrence and predict poor 30-day functional outcomes in AIS patients with HAI. Future prospective studies are crucial for validating and refining these models for clinical application, as well as for developing an accessible flowchart or scoring system to enhance clinical practices.

Abstract The effect of sexual dimorphism on the metabolism of patients with Parkinson’s disease has not been clarified. A group of patients with Parkinson’s disease and healthy controls were recruited, and their clinical characteristics and plasma were collected. Untargeted liquid chromatography-mass spectrometry-based plasma metabolomics profiling was performed. Differentially expressed metabolites between patients and healthy controls were respectively identified in the male and female participants and metabolite set enrichment analyses were further employed. A total of 75 patients with Parkinson’s disease (37 males and 38 females) and 31 healthy controls (16 males and 15 females) were enrolled while no significant differences can be discovered in clinical characteristics. The constructed male-specific metabolic model from orthogonal partial least squares-discriminant analysis can’t well recognize female patients and the female-specific model also can’t accurately identify male patients. There were 55 differentially expressed metabolites in the male participants, and fatty acids and conjugates and eicosanoids were the significantly enriched metabolite sets. Meanwhile, 86 metabolites were differentially expressed in the female participants while fatty acids and conjugates and glycerophosphocholines were enriched. Only 17 metabolites were simultaneously changed in both male and female patients. Significant sex differences of lipid metabolism were found in patients with Parkinson’s disease.

Abstract The relationship between the weight-adjusted waist circumference index (WWI) and the senescence-inhibitory protein Klotho remains unknown. Therefore, this study aimed to investigate the relationship between WWI and soluble Klotho (s-Klotho). This study analyzed 9,928 participants based on the 2007–2016 National Health and Nutrition Examination Survey (NHANES). Three multiple linear regression models and a restricted cubic spline (RCS) were constructed to assess the association between WWI and s-Klotho levels. Further stratified analyses and interaction tests were performed to evaluate the stability of this association. Piecewise multivariate regression modeling was applied to detect threshold effects. The fully adjusted model showed a negative correlation between continuous WWI and s-Klotho levels (β = −23.65, 95% CI: −36.55, −10.76, P

Abstract Background Nuclear medicine is an interdisciplinary field that integrates basic science with clinical medicine. The traditional classroom teaching model lacks interactive and efficient teaching methods and does not adequately address the learning needs and educational goals associated with standardized training for residents. The teaching model that combines Small Private Online Courses (SPOCs) with a flipped classroom approach is more aligned with the demands of real-life scenarios and workplace requirements, thereby assisting students in developing comprehensive literacy and practical problem-solving skills. However, this innovative teaching model has yet to be implemented in Nuclear medicine courses. This study aimed to explore whether the post-training competence for residents can be improved based on this new teaching model. Methods A total of 103 first-year residents from Sichuan Provincial People’s Hospital were randomly assigned to either an experimental group (n = 52) or a control group (n = 51) between July 2019 and June 2023. The experimental group utilized a SPOC and flipped classroom-blended teaching model, while the control group received traditional lecture-based learning (LBL). We assessed the theoretical evaluation scores and questionnaire responses from both groups to determine the effectiveness of the new pedagogical approach. Results Residents in the experimental group demonstrated a superior understanding of nuclear medicine content compared to those in the control group, achieving higher scores on pre-class assessments, after-class tests, and final exams (P

Abstract A randomized double-blind phase 3 trial (CHOICE-01, NCT03856411) demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients without pretreatment. This study presents the prespecified final analysis of overall survival (OS) and biomarkers utilizing circulating tumor DNA (ctDNA) and tissue-based sequencing. Additionally, the analysis revealed a higher median overall survival (OS, 23.8 months) in the toripalimab group than that in the control group (17.0 months). (HR = 0.69, 95%CI: 0.57–0.93, nominal P = 0.01). This survival benefit was particularly notable in the non-squamous subgroup. As the first phase 3 study to perform both baseline tissue whole-exome sequencing (WES) and peripheral blood ctDNA testing, we investigated efficacy predictive biomarkers based on both tissue and ctDNA, Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden, as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment. Furthermore, a ctDNA response observed on cycle 3 day 1, was associated with improved clinical outcomes for patients treated with the combination therapy. In conclusion, Toripalimab plus chemotherapy yields significant improvements in OS as a first-line treatment. The study highlights the utility of ctDNA as a proxy for tumor tissue, providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.

Abstract Background Preeclampsia (PE) is a pregnancy-specific, multisystemic disorder that affects 2–8% pregnancies worldwide and is a leading cause of maternal and perinatal mortality. At present, there is no cure for PE apart from delivery the placenta. Therefore, it is important and urgent to possess a suitable animal model to study the pathology and treatment of PE. When exogenous soluble fms-like tyrosine kinase-1 (sFlt-1) is administered, pregnant animals develop a PE-like phenotype. However, there is no report on the comparison between different methods of constructing PE mouse models using sFlt-1. Methods In this study, the adenovirus carrying sFlt-1(ADV-Flt-1) and recombinant murine sFlt-1 protein (RM Flt-1) are two different methods were used to induce and compare PE-like mouse models. Pregnancy outcomes were examined on E14.5 and E17.5. Results Our data showed that on E14.5, the adenovirus carrying sFlt-1 induced PE-like phenotype, whereas recombinant murine sFlt-1 protein not. On E17.5, both the two methods induced PE-like phenotype including hypertension, proteinuria, fetal growth restriction, placental and glomerular endotheliosis. Importantly, in the adenoviral-mediated sFlt-1 group, the circulating concentration of sFlt-1 were higher than in the recombinant sFlt-1 group, leading to earlier and more severe symptoms of PE. The ADV-Flt-1 group is easy to operate, quickly effective and efficient. The RM Flt-1 group is safer and more stable, with good repeatability, but slower to take effect. Conclusions We proposed that the adenoviral-mediated sFlt-1 model can better simulate early-onset and severe PE.

Abstract Healthy ageing plays an important role in ageing societies in many countries, and centenarians are a sign of longevity. Longevity and its determinants have become issues of global concern and also a focus of research. Although many disciplines have conducted out a series of studies on longevity phenomena, few studies have systematically considered the impact of geographical environmental factors. Guangxi is one of the provinces with the highest centenarian ratio in mainland China, while Hechi City has the highest ratio of centenarians in Guangxi Province, and contains the world-famous longevity belt. This study took Hechi City, “the world’s longevity city”, as a model research area. First, the basic characteristics of the geographical environmental factors in Hechi City were analysed, and then geographical information system techniques and eXtreme Gradient Boosting machine learning methods were applied to systematically analyse the coupling relationship between the spatial distribution of the longevity population and the geographical environmental factors. In addition, the geographical environmental factors closely related to longevity were filtered and investigated. It was found that the centenarian is distributed along a belt-like pattern. It is mostly located in rocky mountainous areas with low elevations, small to medium undulations, medium slopes and brown calcareous soils, but is rarely found near the non-ferrous mining industry. This work provides a scientific basis for identifying the mechanisms that contribute to regional longevity and theoretical references for improving the health level of the elderly population according to local conditions.

Abstract To investigate for the risk of uveitis among such patients. A retrospective cohort study utilized the TriNetX database and recruited pediatric autoimmune patients diagnosed between January 1st 2004 and December 31st 2022. The non-autoimmune cohort were randomly selected control patients matched by sex, age, and index year. The main outcome is the incidence of new-onset uveitis. 175,328 pediatric patients with autoimmune diseases (mean age 10.7 +/- 5.1 years; 55.8% female; 66.2% White) and 175,328 pediatric patients without autoimmune diseases (mean age 10.8+/- 5.1 years; 55.7% female; 66% White) were recruited. The autoimmune cohort demonstrated a significantly increased uveitis risk across our 18-year study period (HR 4.42 [95% CI 3.98–4.90]). Iridocyclitis, chorioretinal inflammation, unspecified purulent endophthalmitis, panuveitis, retinal vasculitis, and sympathetic uveitis were uveitis conditions significantly associated with autoimmune diseases. Autoimmune patients who had used immunosuppressant medications had increased uveitis risk compared to those who had never used immunosuppressants. Our subgroup analysis also demonstrated a significantly increased uveitis risk associated with specific autoimmune conditions. Conditions include inflammatory arthritis, systemic autoimmune rheumatic diseases, systemic vasculitis, inflammatory bowel disease, psoriasis, multiple sclerosis, and immune thrombocytopenic purpura. Using hazard ratios HR for comparison, we were able to identify that, out of the previously broadly defined category of autoimmune diseases, only these specific conditions were significantly associated with pediatric uveitis. Uveitis was significantly associated with autoimmune diseases among the pediatric population.

Abstract Background Epilepsy, as a chronic noncommunicable disease with recurrent seizures, may be a marker of deterioration or alteration in other underlying neurological diseases. This study aimed to investigate the relationship of epilepsy with brain function, other common brain disorders, and their underlying mechanisms. Methods The study was based on clinical diagnostic and test data from 426,527 participants in the UK Biobank, of whom 3,251 were diagnosed with epilepsy at baseline. Multiple linear and Cox regression models were used to explore the association between epilepsy, brain function, and other brain disorders. Results This study demonstrated consistent deleterious effects of epilepsy on cognitive and motor function and mental health. The risk of neurological diseases and psychiatric disorders was significantly elevated in the epilepsy population during the 17-year follow-up period, according to the longitudinal analysis. We also identified several brain regions associated with epilepsy, including the pallidum, hippocampus, and precentral regions. Mediation analyses revealed mediating effects of peripheral markers and proteins (e.g., GGT, HDL, ACE2, and GDF15), suggesting that liver function and lipid metabolism may be involved in the development of other brain disorders in individuals with epilepsy. Conclusions Our study provides robust evidence of the association between epilepsy and poor brain health, underscoring the importance of early intervention for epilepsy.

Abstract This multicohort phase II trial (ALTER-G-001; NCT05262335) aimed to assess the efficacy of first-line anlotinib plus chemotherapy for gastrointestinal (GI) cancer patients with unresectable liver metastases. Eligible patients with colorectal cancer (Cohort A) or noncolorectal and nonesophageal GI cancer (Cohort C) received six cycles of anlotinib plus standard chemotherapeutic regimens followed by anlotinib plus metronomic capecitabine as a maintenance therapy. Liver metastasectomy can be performed when liver metastases are converted to resectable lesions. The primary outcome was the investigator-confirmed objective response rate (ORR) in the intention-to-treat population. Among the 47 patients in Cohort A, the ORR was 40.4% (95% CI 26.4–55.7), including 1 with a complete response (CR) and 18 who achieved a partial response (PR). The median progression-free survival (PFS) was 8.7 months (95% CI 7.3-NE), and the median overall survival (OS) was not reached. In Cohort C, 14 of 44 patients achieved a PR, with an ORR of 31.8% (95% CI 18.6–47.6). The PFS and OS were 5.8 months (95% CI 4.8–6.5) and 11.4 months (95% CI 5.8–19.3), respectively. The liver metastasectomy rate in patients with liver-limited disease was 22.7% (5/22) in Cohort A and 6.7% (2/30) in Cohort C. For pancreatic cancer patients, the ORR of the efficacy-evaluable population was 36.0% (9/25), and those with liver-limited metastasis had better survival. Moreover, no new safety concerns emerged. In conclusion, an anlotinib-based first-line regimen demonstrated promising antitumor activity among GI cancer patients with unresectable liver metastases and led to liver metastasectomy in selected patients.

Abstract As the core component of a swivel bridge, the spherical hinge structure exhibits complex mechanical behavior under high pressure, making it challenging to describe accurately through theoretical analysis or on-site monitoring. In this context, this paper systematically examined the mechanical characteristics and key design parameters of a simplified spherical hinge structure using numerical simulations and formula derivation. Additionally, an indoor scaled test was conducted based on a representative spherical hinge structure to further investigate its mechanical properties. The findings indicated that contact pressure along the spherical hinge interface increased radially outward and followed a cubic distribution pattern. The support radius was identified as the most critical factor influencing the maximum stress value within the spherical hinge structure. In the aperture ratio range of 0.042 to 0.083, the upper and lower spherical hinges are unable to achieve coordinated deformation under high pressure, resulting in negative pressure at the edge of the pin hole. Furthermore, for spherical hinge structures with sliders, the presence of the slider introduced additional complexity to the stress state, leading to a coexistence of tension and compression on the surface of the lower spherical hinge. The highest stress occurred between the inner ring slider and the pin hole, an area that requires careful monitoring. The research provides valuable insights for the design of spherical hinges in swivel bridges and can guide the development of spherical hinge structures tailored to different bridge types in the future.

Abstract The association between admission hyperglycemia and postoperative pneumonia is unclear in hip fracture patients. We investigated the relationship between admission hyperglycemia and postoperative pneumonia after hip fracture surgery. This retrospective study analyzed data from 1,267 geriatric patients admitted for hip fractures. Patients were categorized into normoglycemic (

Abstract The enhancement of soil aggregate size and stability is crucial for mitigating climate change and improving carbon sequestration in forest ecosystems. Biochar, derived from rice husks, has been suggested as an effective mean to increase soil carbon storage. However, isolating biochar’s specific effects on soil aggregate formation and carbon sink capacity can be complex due to the overlapping influences of fertilization and understory vegetation cultivation. Our study circumvented these variables by incorporating different amounts of biochar into plantation soil without any additional cultivation or fertilization, conducting a detailed two–year field experiment. The findings revealed that biochar significantly increased the organic carbon content and density in the uncultivated under–forest Ferralsols, thus enhancing its carbon sink function. Intriguingly, while biochar raised the proportion of small soil aggregates ( 0.25 mm), adversely affecting soil aggregate stability. These results suggest that biochar may compromise soil aggregate structure and stability in the absence of plant growth. The positive impact of biochar on soil carbon storage was found to depend more on its inherent inert carbon content than on soil type. Moreover, biochar alone was insufficient to increase the quantity of soil macroaggregates without the binding action of plant root exudates. Biochar’s key function appears to be in enhancing the soil aggregate–forming processes facilitated by plant roots and microorganisms. Therefore, for optimal carbon sequestration in forest soils, integrating biochar application with appropriate agricultural practices is advisable.

Abstract Small interfering RNAs (siRNA) technology has emerged as a promising therapeutic tool for human health conditions like cancer due to its ability to regulate gene silencing. Despite FDA-approved, their delivery remains localized and limiting their systemic use. This study used single-walled carbon nanotubes (SWNTs) functionalized with polyethylene glycolated (PEGylated) phospholipids (PL-PEG) derivatives for systemic siRNA delivery. We developed an siRNA systemic delivery vehicle (SWNT-siRNA) by conjugating SWNT functionalized with PL-PEG containing either amine (PA) or maleimide (MA). The functionalized SWNT with a lower molecular weight of PA produced the SWNT-siRNA conjugate system with the highest stability and high siRNA loading quantity. The system delivered siRNA to a panel of tumour cell lines of different organs (i.e. HeLa, H1299 and MCF-7) and a non-cancerous human embryonic kidney 293 cells (HEK293T) with high biocompatibility and low toxicity. The cellular uptake of SWNT-siRNA conjugates by epithelial cells was found to be energy dependent. Importantly, the presence of P-glycoprotein, a marker for drug resistance, did not inhibit SWNT-mediated siRNA delivery. Mouse xenograft model further confirmed the potential of SWNT-siRNA conjugates with a significant gene knock-down without signs of acute toxicity. These findings pave the way for potential gene therapy applications using SWNTs as delivery vehicles.

Abstract This study is to analyse the failure patterns and long-term survival after stereotactic body radiotherapy (SBRT) in patients with T1-3N0M0 inoperable non-small cell lung cancer (NSCLC). Early-stage NSCLC patitents who received SBRT at Zhejiang Cancer Hospital from January 2012 to September 2018 were retrospectively analyzed. The primary endpoint were the patterns of disease progression, which were divided into local recurrence, regional failure, and distant metastasis. Kaplan-Meier method survival analysis was used to calculate overall survival (OS), progression-free survival (PFS). Cox model was used for univariate analysis and multivariate analysis. A total of 215 patients with 224 lesions were enrolled. After the median follow-up time of 50.8 months (1.0-117.9 months), 76 (35.3%) patients progressed, with regional progression occurring in 4 cases (1.8%), local and local-regional progression in 17 cases (7.9%), various distant metastases developing in 55 cases (25.6%). The OS rates at 1, 3, and 5 years were 97.1%, 80.9%, and 63.8%, respectively, with a median OS of 92.2 months (95%CI, 61.5-122.9 months). The PFS rates at 1, 3, and 5 years were 87.5%, 65.9%, and 50.8%, respectively, with a median PFS of 62.2 months (95% CI, 45.0-59.4 months). There was no significant difference in OS (P = 0.832) and PFS (P = 0.672) between the two groups with or without pathology. Multivariate analysis showed that BED and patient age were independent prognostic factors affecting early-stage lung cancer survival (all P

The effect of caffeine on the behavior and sleep patterns of zebrafish larvae, as well as its underlying mechanisms, has been a topic of great interest. This study aimed to investigate the impact of caffeine on zebrafish larval sleep/wake behavior and the expression of key regulatory genes such as cAMP-response element binding protein (CREB) and adenosine (ADA) in the sleep pathway. To begin, the study determined the optimal dose and duration of caffeine exposure, with the optimal doses found to be 31.25 μM, 62.5 μM, and 120 μM. Similarly, the optimal exposure time was established as no more than 120 h, ensuring a mortality rate of less than 10%. The confirmation of these conditions was achieved through the assessment of angiogenesis and the inflammatory reaction. As a result, the treatment time point of 24 h post-fertilization (hpf) was selected to examine the effects of caffeine on zebrafish larval sleep rhythm (48 h, with a light cycle of 14:10). Furthermore, the study analyzed the expression of clock genes (bmal1a, per1b, per2, per3, cry2), adenosine receptor genes (adora1a, adora1b, adora2aa, adora2ab, adora2b), and key regulatory factors (CREB and ADA). The research confirmed that caffeine could induce sleep pattern disorders, significantly upregulate adenosine receptor genes (adora1a, adora1b, adora2a, adora2ab, adora2b) (p < 0.05), and markedly decrease the total sleep time and sleep efficiency of the larvae. Additionally, the activity of ADA significantly increased during the exposure (p < 0.001), and the tissue-specific expression of CREB was also significantly increased, as assessed by immunofluorescence. Caffeine may regulate circadian clock genes through the ADA/ADORA/CREB pathway. These findings not only enhance our understanding of the effects of caffeine on zebrafish larvae but also provide valuable insights into the potential impact of caffeine on human behavior and sleep.

Abstract. Background:. Rapid initiation of antiretroviral therapy (ART) is recommended by guidelines, however, real-world studies of same-day initiation of ART in China are limited, and an optimal treatment regimen has yet to be identified. The study aims to provide a realistic reference for rapid initiation of ART. Methods:. We retrospectively analyzed the clinical data of treatment-naïve people with human immunodeficiency virus (PWHs) who were diagnosed and prescribed same-day ART initiation from January 1, 2021 to December 31, 2022 at Chongqing Public Health Medical Center. PWHs voluntarily chose an ART regimen that divided them into two groups: National Free Antiretroviral Treatment Program (NFATP)-recommended regimens group (2 nucleoside reverse transcriptase inhibitors + non-nucleoside reverse transcriptase inhibitors/protease inhibitors) and bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) group. The primary endpoint was the virological outcome of the two groups for same-day ART initiation at 24 weeks and 48 weeks. The secondary endpoints included changes in CD4 counts, maintenance of the original ART regimen at 48 weeks, and lipid levels and renal function at 48 weeks. Results:. A total of 255 PWHs were included in the study, including 131 (51.4%) in the NFATP group and 124 (48.6%) in the BIC/FTC/TAF group. The overall virological suppression rates at 24 weeks and 48 weeks were 78.2% (165/211) and 95.4% (207/217), respectively. At 24 weeks, the virologic suppression rate in the NFATP group was lower than that in the BIC/FTC/TAF group (65.3% [66/101] vs. 90.0% [99/110], P

Introduction: This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of adjunct systemic corticosteroid therapy in patients admitted to the intensive care unit (ICU) with bacterial community-acquired pneumonia (CAP). Method: We searched MEDLINE, Embase and the Cochrane Library to identify randomised controlled trials (RCTs) published from the databases’ inception to February 2024. All RCTs evaluating the effect of systemic corticosteroids on mortality, compared to standard of care among adult bacterial CAP patients admitted to ICU were included. Bayesian meta-analysis was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Independent authors reviewed each study for eligibility, extracted data and assessed risk of bias in duplicate, with discrepancies referred to senior reviewers. Results: A total of 6 RCTs comprising 1585 patients were included for analysis. In ICU patients with severe CAP who were treated with corticosteroids, there was no significant reduction in hospital mortality (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.39–1.14, certainty of evidence: ⊕⊕⊝⊝ low) or all-cause mortality (RR 0.68, 95% CI 0.34–1.22, ⊕⊕⊝⊝ low) compared with placebo. The use of corticosteroids showed a significant reduction in mechanical ventilation post-intervention (RR 0.58, 95% CI 0.37–0.86, ⊕⊕⊕⊕ high) compared with placebo. In a subgroup analysis of patients treated with hydrocortisone, hospital mortality was significantly reduced (RR 0.45, 95% CI 0.20–0.88, ⊕⊕⊝⊝ low) compared with placebo. There was no significant increase in gastrointestinal bleeding, secondary infections or hyperglycaemia in patients treated with corticosteroids. Conclusion: Corticosteroids significantly reduced mechanical ventilation requirements, and hydrocortisone significantly reduced hospital mortality. Further work is required to determine whether other corticosteroids reduce mortality among ICU patients with CAP.

Abstract The purpose of this study is to investigate the relationship between chronic pain and the mortality rate of cerebrovascular disease (CVD) in cancer patients. Thus, we performed a case-control investigation was conducted by utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2019. Multiple demographics, pain rating and other clinical characteristics were extracted to assess predictors for the death from CVD in cancer patients. Different machine learning algorithms were applied to construct pain-related prediction model. The analysis involved 16,850 case patients and 710,729 controls. Among cancer patients, approximately 2.3% succumbed to subsequent CVD. Cancer pain (Pain rating II) was associated with a decreased risk of CVD. Univariate and multivariate COX analyses indicated that older age at cancer diagnosis, male gender, single marital status, Black or Other race, and lack of systemic therapy correlated with a higher risk of CVD-related death. Propensity score matching revealed a significantly lower proportion of Pain rating II in the case group. The logistic regression algorithm demonstrated superior predictive ability for 5-year and 10-year CVD risk in cancer patients. Notably, survival time, age, and pain rating emerged as the top three crucial variables. This study firstly investigated pain and various risk factors for CVD in cancer patients, highlighting pain as a novel and possible protective factor for CVD. The development of a risk model based on pain could aid in identifying individuals at high risk for CVD and may inspire innovative strategies for preventing CVD in cancer patients.