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Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

Abstract As a critical component of a welded structure, the integrity of the welded joint significantly affects the safety and reliability of the structure in service. Therefore, it is essential to investigate the integrity of welded joints. However, given the harshness of standard measurements renders them unsuitable for application to small volume zones, welded structures or in-service structures. In this study, the fracture properties of a Q235 steel butt-welded joint was evaluated by boundary effect modelling (BEM) method and the ball indentation (BI) method. The results demonstrate that the fracture toughness distribution obtained by the two methods are consistent, with the highest fracture toughness in the weld metal, followed by the heat-affected zone and the base metal, and the lowest fracture toughness in the fusion zone, which is in agreement with the results of the metallographic testing. Furthermore, the relative errors of the zones obtained by the ball indentation method and the boundary effect modelling method ranging from 10.16 to 19.05%, which indicates safety margin ought to be considered for employing the BI method to determine fracture properties of in-service structures.

Abstract Purpose Steatotic liver disease (SLD) has become the most common cause of chronic liver disease. Nevertheless, the non-invasive quantitative diagnosis of steatosis is still lacking in clinical practice. This study aimed to evaluate the reproducibility of the new parameter for steatosis quantification named ultrasound-derived fat fraction (UDFF). Materials and methods The UDFF values were independently executed by two operators in two periods. In the process, repeated measurements of the same patient were performed by the same operator under different conditions (liver segments, respiration, positions, and dietary). Finally, the results of some subjects (28) were compared with the MRI-derived proton density fat fraction (PDFF). The concordance analysis was mainly achieved by the intraclass correlation coefficient (ICC) and Bland–Altman. Results One hundred-five participants were included in the study. UDFF had good reliability in measuring the adult liver (ICCintra-observer = 0.96, ICCinter-observer = 0.94). Meanwhile, the ICC of the two operators increased over time. The variable measurement states did not influence the UDFF values on the surface, but they affected the coefficient of variation (Cov) of the results. Segment 8 (S8), end-expiratory, supine, and fasting images had the most minor variability. On the other hand, the UDFF value of S8 displayed satisfied consistency with PDFF (mean difference, −0.24 ± 1.44), and the results of both S5 (mean difference: −0.56 ± 3.95) and S8 (mean difference: 0.73 ± 1.87) agreed well with the whole-liver PDFF. Conclusion UDFF measurements had good reproducibility. Furthermore, the state of S8, end-expiration, supine, and fasting might be the more stable measurement approach. Critical relevance statement UDFF is the quantitative ultrasound parameter of hepatic steatosis and has good reproducibility. It can show more robust performance under specific measurement conditions (S8, end-expiratory, supine, and fasting). Trial registration The research protocol was registered at the Chinese Clinical Trial Registry on October 9, 2023 ( http://www.chictr.org.cn/ ). The registration number is ChiCTR 2300076457. Key Points There is a lack of non-invasive quantitative measurement options for hepatic steatosis. UDFF demonstrated excellent reproducibility in measuring hepatic steatosis. S8, end-expiratory, supine, and fasting may be the more stable measuring condition. Training could improve the operators’ measurement stability. Variable measurement state affects the repeatability of the UDFF values (Cov). Graphical Abstract

Abstract As the pathophysiological basis of type 2 diabetes mellitus (T2DM), insulin resistance (IR) is closely related to oxidative stress (OS) and inflammation, while nanozymes have a good therapeutic effect on inflammation and OS by scavenging reactive oxygen species (ROS). Hence, AuCePt porous hollow cascade nanozymes (AuCePt PHNs) are designed by integrating the dominant enzymatic activities of three metallic materials, which exhibit superior superoxide dismutase/catalase-like activities, and high drug loading capacity. In vitro experiments proved that AuCePt PHNs can ultra-efficiently scavenge endogenous and exogenous ROS. Moreover, AuCePt PHNs modified with lactobionic acid (LA) and loaded with disulfiram (DSF), named as AuCePt PHNs-LA@DSF, can significantly improve glucose uptake and glycogen synthesis in IR hepatocytes by regulating the insulin signaling pathways (IRS-1/AKT) and gluconeogenesis signaling pathways (FOXO-1/PEPCK). Intravenous administration of AuCePt PHNs-LA@DSF not only showed high liver targeting efficiency, but also reduced body weight and blood glucose and improved IR and lipid accumulation in high-fat diet-induced obese mice and diabetic ob/ob mice. This research elucidates the intrinsic activity of AuCePt PHNs for cascade scavenging of ROS, and reveals the potential effect of AuCePt PHNs-LA@DSF in T2DM treatment. Graphical abstract

Abstract Background Determining the optimal timing of surgical intervention for Neonatal necrotizing enterocolitis (NEC) poses significant challenges. This study develops a predictive model using the long short-term memory network (LSTM) with a focal loss (FL) to identify infants at risk of developing Bell IIB + NEC early and issue timely surgical warnings. Methods Data from 791 neonates diagnosed with NEC are gathered from the Neonatal Intensive Care Unit (NICU), encompassing 35 selected features. Infants are categorized into those requiring surgical intervention (n = 257) and those managed medically (n = 534) based on the Mod-Bell criteria. A fivefold cross-validation approach is employed for training and testing. The LSTM algorithm is utilized to capture and utilize temporal relationships in the dataset, with FL employed as a loss function to address class imbalance. Model performance metrics include precision, recall, F1 score, and average precision (AP). Results The model tested on a real dataset demonstrated high performance. Predicting surgical risk 1 day in advance achieved precision (0.913 ± 0.034), recall (0.841 ± 0.053), F1 score (0.874 ± 0.029), and AP (0.917 ± 0.025). The 2-days-in-advance predictions yielded (0.905 ± 0.036), recall (0.815 ± 0.057), F1 score (0.857 ± 0.035), and AP (0.905 ± 0.029). Conclusion The LSTM model with FL exhibits high precision and recall in forecasting the need for surgical intervention 1 or 2 days ahead. This predictive capability holds promise for enhancing infants’ outcomes by facilitating timely clinical decisions.

Abstract Background Digital health literacy (DHL) is pivotal for individuals to access trustworthy health information and make informed decisions, closely intertwined with health behaviors and psychological resilience—these factors collectively shape an individual’s approach to health management. Despite extensive research on digital health literacy in broader populations, the specific dynamics of digital health literacy in relation to health behaviors and psychological resilience among undergraduate nursing students in China remain understudied, highlighting a gap that this research endeavors to address. This study aims to assess the levels of digital health literacy among undergraduate nursing students in China, and to explore its association with health lifestyles and psychological resilience, which are considered influential factors. Methods Employing a descriptive cross-sectional research design, eligible Chinese nursing undergraduates were surveyed from June to October 2023. This study recruited a total of 418 undergraduate nursing students. After excluding 11 students on leave, 407 students participated in questionnaire completion and submission. The College Students’ Digital Health Literacy Scale, Healthy Lifestyle Assessment Scale and The Psychological Resilience Scale were used in this study. Results The mean scores for digital health literacy, health lifestyles, and psychological resilience were 74.78 ± 8.44, 127.14 ± 11.22, and 79.21 ± 11.02, respectively. Pearson correlation analysis results indicated that the correlations between digital health literacy and both health lifestyles (r = 0.707, P

Abstract Background Hypertension continues to increase in prevalence, and it has become a major cause of increased mortality globally. Physical activity (PA) has been shown to be a first-line treatment for controlling blood pressure. However, participation rates in PA are still poor. Therefore, it’s imperative to explore the factors that affect patient PA adherence. Methods A synthesis of qualitative research of the PA experience of patients with hypertension was conducted. We systematically searched for qualitative studies published in English from inception to May 2023 in the databases of PubMed, Embase, Web of Science, CINAHL, PsycINFO, and Cochrane Library. The Joanna Briggs Institute tool was used to extract data, and the Capability, Opportunity, Motivation-Behaviour model was used to synthesize data. Results This qualitative research included 17 studies, identified 85 findings, summarized 9 categories, and finally meta-aggregated 3 synthesized findings, including capabilities of patients with hypertension, PA opportunities and PA motivators. The capabilities included age, other health problems, and PA knowledge and skills. Opportunities included time constraints, environmental factors, physical activity resources, and social support. Motivators included self-efficacy, pursuing physical health, and experience from PA. Conclusion The available evidence contributes to a comprehensive understanding of the barriers and facilitators of PA in patients with hypertension. Most of these barriers can be addressed and improved. When designing and implementing physical activity programs for patients with hypertension, an individualized PA program should first be designed, tailored to the patient’s capacity. Secondly, patients should be provided with additional PA resources and enhanced social support. Lastly, patients’ motivation can be increased by enhancing their PA experience.

Objective To observe the effects of nutritional support on nutritional status and calcium and phosphorus metabolism in maintenance hemodialysis （MHD） patients. Methods From June 2023 to August 2023， patients with end-stage renal disease （ESRD） on MHD were randomized into two groups of nutritional-support and conventional-treatment （n = 35 each）. Conventional-treatment group received routine treatment while nutritional-support group had dietary and nutritional intervention on the basis of routine treatment in control group. The incidence of malnutrition， nutritional parameters， inflammatory factors， calcium and phosphorus metabolism parameters and complications were compared between two groups. Results After 3/6-month intervention， the incidence of malnutritionwas lower in nutritional-support group than that in conventional-treatment group （31.43% vs 57.14%，11.43% vs 34.29%，P＜0.05）； after 3-month intervention， the levels of hemoglobin （Hb）[（126.78 ± 11.22）g/L vs （115.39 ± 10.04）g/L]，prealbumin （PA）[（316.44 ± 25.26）g/L vs （287.54 ± 26.10）g/L] and albumin （Alb）[（46.08 ± 8.15）g/L vs （38.73 ± 8.11）g/L] increased in both groups and nutritional-support group was higher than conventional-treatment group（P＜0.05）；after 3-month intervention， serum levels of C-reactive protein （CRP）[（2.16 ± 0.45）mg/L vs （2.61 ± 0.51）mg/L]， interleukin-6 （IL-6）[（10.83 ± 2.61）ng/L vs （13.43 ± 2.42）ng/L] and tumor necrosis factor-α （TNF-α）[（89.52 ± 9.13）ng/L vs （101.64 ± 9.44）ng/L] decreased in both groups and the nutritional-support group was lower than conventional-treatment group （P＜0.05）； after 3-month intervention， serum levels of calcium （S-Ca）[（2.06 ± 0.20）mmol/L vs （2.25 ± 0.19）mmol/L]， phosphorus （S-P）[（2.20 ± 0.23）mmol/L vs （2.42 ± 0.26）mmol/L]，intact parathyroid hormone （iPTH）[（180.38 ± 44.82）mmol/L vs （216.54 ± 48.44）mmol/L] and Ca×P [（4.53 ± 0.49）mmol/L vs （5.45 ± 0.51）mmol/L] decreased in both groups and nutritional-support group was lower than conventional-treatment group （P＜0.05）； overall incidence of complications was lower in nutritional-support group than that in conventional-treatment group（χ2 = 4.629，P = 0.031）. Conclusion Nutritional support may alleviate the inflammatory response， improve their nutritional status and disrupt calcium and phosphorus metabolism in MHD patients.

Abstract Skin cancer is a common disease resulting from genetic defects, and early detection is critical to improve treatment outcomes. Diagnostic programs that use computer aid especially those that use supervised learning are very useful in early diagnosis of skin cancer. This research therefore presents a new approach that integrates optimization methods with supervised learning to improve skin cancer diagnosis using machine vision approach. The presented method is initiated by data pre-processing that involves the removal of unnecessary data. Then, to segment the images, a combination of K-means clustering and social spider optimization technique is employed. The region of interest is then extracted from the segmented image and from this region a convolutional neural network extracts the significant features. To enhance the classification performance as compared with the standard classifiers, this research introduces a new concept of error correcting output codes coupled with a weighted Hamming distance in the group of gamma classifiers. The ability of the proposed approach in segmentation of skin lesions and classifying them was tested using samples from the ISIC-2017 and ISIC-2016 databases. The introduced method obtained state-of-the-art accuracy on both datasets (ISIC-2016: 97.10%, ISIC-2017: 95.17%). In particularly, the accuracy of the introduced approach for both these databases is at least 1.17% higher than the compared methods. This proves the high performance of the suggested method based on the usage of the convolutional neural networks for feature extraction and gamma classifiers with error correcting output codes for classification in skin cancer detection.

Abstract Rapid and sensitive nucleic acid detection is vital in disease diagnosis and therapeutic assessment. Herein, we propose a co-freezing localized CRISPR-Cas12a (CL-Cas12a) strategy for sensitive nucleic acid detection. The CL-Cas12a was obtained through a 15-minute co-freezing process, allowing the Cas12a/crRNA complex and hairpin reporter confined on the AuNPs surface with high load efficiency, for rapid sensing of nucleic acid with superior performance to other localized Cas12a strategies. This CL-Cas12a based platform could quantitatively detect targets down to 98 aM in 30 min with excellent specificity. Furthermore, the CL-Cas12a successful applied to detect human papillomavirus infection and human lung cancer-associated single-nucleotide mutations. We also achieved powerful signal amplification for imaging Survivin mRNA in living cells. These findings highlight the potential of CL-Cas12a as an effective tool for nucleic acid diagnostics and disease monitoring. Graphical abstract

Abstract Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.

The objective of this paper was to analyze the difference of composition between hybrid sorghum and conventional sorghum in southwest China, and to establish the method of variety identification. The basic physical and chemical components of 29 sorghum samples were determined, and the metabolite composition of 29 sorghum samples was determined by ultra high performance liquid chromatography coupled with Q Exactive HF-X mass spectrometry. The marker component screening and construction of variety identification model were carried out using stoichiometry, which included principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), cluster analysis and receiver operating characteristic (ROC) curve analysis. The model was based on the basic physicochemical composition and all metabolites. The results showed that the contents of amylopectin and tannin of the conventional varieties form southwest China were higher than that of hybrid varieties, while the contents of amylose and 1000-grain weight were lower. By analyzing the physicochemical properties, it was possible to identify certain samples. The OPLS-DA model was constructed with all 1048 compounds variables, and 46 of the differential metabolites that had a significant impact on the model identification were screened out. A novel OPLS-DA identification model was developed for sorghum varieties, achieving a 100% accuracy in identification. The conventional varieties from southwest China exhibited a relatively high concentration of phenolic compounds. Furthermore, after conducting receiver operating characteristic (ROC) curve analysis and assessing the relative standard deviation (RSD) of quality control sample (QC), 20 feature components that exhibited both high diagnostic accuracy and good reproducibility were identified. Among them, syringetin 3-glucoside and 6"-o-acetyldaidzein had higher expression abundance in conventional sorghum varieties, while D-glucarate, putsutrine, N-acetylputsutrine and L-glutamine had higher content in hybrid sorghum varieties. This study unveiled the disparity in metabolites between hybrid sorghum and conventional sorghum. The study successfully developed a scientifically rigorous and precise untargeted metabolomics approach using UHPLC-Q Exactive HF-X-MS. This method can be effectively utilized for the identification of sorghum varieties, offering a novel strategy for sorghum variety identification.

BACKGROUND: Exertional heat stroke (EHS) is a clinical entity characterized by abnormalities of the central nervous system (CNS) and is associated with multiple organ injury, some of which may be irreversible. It is valuable to establish an optimized model of EHS that is able to induce and assess damage to the CNS and multiple organs. METHODS: We induced EHS by using an environmental chamber with adjustable temperature and humidity and a mice forced running wheel. The endpoint for the EHS was defined as either exhaustion or a core temperature of 42.5°C being reached. Injury to the liver, kidney, and CNS of mice in the EHS group was revealed through pathological studies using hematoxylin and eosin staining of harvested organs at different time points and detection of biomarkers. The depressive-like behavior of EHS mice was assessed through open field tests, forced swimming tests, and tail suspension tests. RESULTS: The favorable environmental conditions for induction of EHS based on this presented model are 38°C, 70% RH. The EHS mice developed thermoregulatory dysfunction and experienced a significantly higher weight loss ratio compared to the SHE (sham heat exercise) group. The liver, kidney, and brain tissues of EHS mice were significantly damaged, and the pathological damage scores for each organ were significantly higher than those of the SHE group. In the open field test (OFT), compared to the SHE group, there was a significant reduction in the number and time of EHS mice entering the center of the open field. Additionally, there was a significant increase in immobile time during forced swimming test (FST) and tail suspension test (TST). CONCLUSION: This study presents an improved animal model that has the potential to assess for neurological and multiple organ injury caused by EHS and simultaneously, while accurately reflecting the clinical characteristics observed in EHS patients.

Abstract Background Studies have found dysbiosis of the gut microbiota in individuals infected with the hepatitis B virus (HBV). Tenofovir dipivoxil (TDF) is one of the preferred oral antiviral drugs used for the treatment of chronic hepatitis B (CHB), but the extent to which TDF is able to affect the gut microbiota and inflammatory factors of a patient remains largely unexplored. In this study, we collected stool samples from HBV patients prior to medication and from CHB patients treated with TDF. Results The gut microbiota and inflammatory factors were assessed in 42 healthy subjects (HC group), 109 HBV-infected subjects, including 48 CHB patients who were not medicated with nucleoside analogue drugs (No-NAs group), and 61 CHB patients who were medicated with TDF (TDF group). 16 S rRNA sequencing revealed that TDF treatment caused significant changes in the gut microbiota of HBV-infected individuals; however, the gut microbiota of HBV-infected individuals did not fully recover to a pre-dysbiosis state. The relative abundance of Bacteroidota gradually decreased from the HC group to the No-NAs and TDF groups. The relative abundance of Fusobacteriota was significantly higher in the No-NAs group than in the HC group. At the genus level, Dialister, Eubacterium_hallii_group, Halomonas, Collinsella, Sphingomonas, Xanthomonadaceae_unclassified, and Rhizobiaceae_unclassified were overrepresented; while the abundance of Bacteroides and Fusobacterium decreased significantly in the No-NAs and TDF groups. Conclusions This study showed that TDF treatment significantly improved the regulation of the gut microbiota and aided in dysbiosis recovery. We did not observe significant improvement in serum inflammatory factor concentrations, which may be related to the relatively short duration of TDF administration in this study.

Abstract Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome sequencing to identify MME (Membrane Metalloendopeptidase)-expressing CAFs in pancreatic cancer. Systematic screening was conducted based on tumor differentiation, lymph node metastasis, and T-stage parameters to identify and confirm the existence of a subpopulation of fibroblasts termed MME+CAFs. Subsequent analyses included temporal studies, exploration of intercellular communication patterns focusing on the hypoxia signaling pathway, and investigation of MME+CAF functions in the pancreatic cancer microenvironment. The pathway enrichment analysis and clinical relevance revealed a strong association between high MME expression and glycolysis, hypoxia markers, and pro-cancer inflammatory pathways. The role of MME+CAFs was validated through in vivo and in vitro experiments, including high-throughput drug screening to evaluate potential targeted therapeutic strategies. Single-cell transcriptome sequencing revealed tumor-associated fibroblasts with high MME expression, termed MME+CAF, exhibiting a unique end-stage differentiation function in the TME. MME+CAF involvement in the hypoxia signaling pathway suggested the potential effects on pancreatic cancer progression through intercellular communication. High MME expression was associated with increased glycolysis, hypoxia markers (VEGF), and pro-cancer inflammatory pathways in pancreatic cancer patients, correlating with lower survival rates, advanced disease stage, and higher oncogene mutation rates. Animal experiments confirmed that elevated MME expression in CAFs increases tumor burden, promotes an immunosuppressive microenvironment, and enhances resistance to chemotherapy and immunotherapy. The developed MME+CAF inhibitor IOX2 (a specific prolyl hydroxylase-2 (PHD2) inhibitor), combined with AG (Paclitaxel + Gemcitabine) and anti-PD1 therapy, demonstrated promising antitumor effects, offering a translational strategy for targeting MME in CAFs of pancreatic cancer. The study findings highlighted the significant role of MME+CAF in pancreatic cancer progression by shaping the TME and influencing key pathways. Targeting MME presented a promising strategy to combat the disease, with potential implications for therapeutic interventions aimed at disrupting MME+CAF functions and enhancing the efficacy of pancreatic cancer treatments.

Abstract Protein Disulfide-Isomerase A2 (PDIA2) is a gene that encodes proteins, responsible for protein folding and modification within cells. The development and course of many disorders are intimately linked to the aberrant expression of PDIA2. Nevertheless, more research is necessary to fully understand PDIA2’s biological significance in pan-cancer, notably in prostate cancer (PCa). PDIA2 expression is elevated in various tumors and closely related to patient prognosis. Patients with prostate cancer who express PDIA2 high in particular have a bad prognosis in terms of progression-free survival. In addition, the upregulation of PDIA2 expression in prostate cancer patients is accompanied by higher Gleason scores, advanced tumor staging, lymph node metastasis, and elevated PSA levels. Detailed experiments further demonstrate that PDIA2 is a carcinogenic gene affecting prostate cancer cells’ response to dasatinib therapy. For patients with prostate cancer, there is a clear positive connection between the expression level of PDIA2 and a bad prognosis. The prostate cancer treatment efficacy of dasatinib is hampered by PDIA2, which is intimately linked to the growth, invasion, and metastasis of PCa cells. In summary, our research highlights the potential of PDIA2 as a biomarker for the diagnosis and management of PCa.

Abstract Background There is a growing trend to include non-randomised studies of interventions (NRSIs) in rare events meta-analyses of randomised controlled trials (RCTs) to complement the evidence from the latter. An important consideration when combining RCTs and NRSIs is how to address potential bias and down-weighting of NRSIs in the pooled estimates. The aim of this study is to explore the use of a power prior approach in a Bayesian framework for integrating RCTs and NRSIs to assess the effect of rare events. Methods We proposed a method of specifying the down-weighting factor based on judgments of the relative magnitude (no information, and low, moderate, serious and critical risk of bias) of the overall risk of bias for each NRSI using the ROBINS-I tool. The methods were illustrated using two meta-analyses, with particular interest in the risk of diabetic ketoacidosis (DKA) in patients using sodium/glucose cotransporter-2 (SGLT-2) inhibitors compared with active comparators, and the association between low-dose methotrexate exposure and melanoma. Results No significant results were observed for these two analyses when the data from RCTs only were pooled (risk of DKA: OR = 0.82, 95% confidence interval (CI): 0.25–2.69; risk of melanoma: OR = 1.94, 95%CI: 0.72–5.27). When RCTs and NRSIs were directly combined without distinction in the same meta-analysis, both meta-analyses showed significant results (risk of DKA: OR = 1.50, 95%CI: 1.11–2.03; risk of melanoma: OR = 1.16, 95%CI: 1.08–1.24). Using Bayesian analysis to account for NRSI bias, there was a 90% probability of an increased risk of DKA in users receiving SGLT-2 inhibitors and an 91% probability of an increased risk of melanoma in patients using low-dose methotrexate. Conclusions Our study showed that including NRSIs in a meta-analysis of RCTs for rare events could increase the certainty and comprehensiveness of the evidence. The estimates obtained from NRSIs are generally considered to be biased, and the possible influence of NRSIs on the certainty of the combined evidence needs to be carefully investigated.

Abstract With the outbreak and continued spread of the COVID-19 pandemic, people's demand for daily disinfection products has increased rapidly, and its innovative design has received widespread attention. In this context, this study aims to propose a design methodology for home entrance disinfection devices based on AHP-FAST-FBS. Firstly, the design requirements of the home entrance disinfection device were collected and analyzed through in-depth interviews and the KJ method, and a hierarchical model of design demand indicators was constructed. Secondly, the Analytical Hierarchy Process (AHP) was employed to quantify these design demand indicators, and core design demands for home entrance disinfection devices were identified by weight calculations. On this basis, the Functional Analysis System Technique (FAST) method was combined to rationally transform the design demands into product functional indicators, constructing a functional system model for the home entrance disinfection device through systematic decomposition and categorization. Lastly, based on the Function-Behavior-Structure (FBS) theoretical model, the mapping of each function of the product to its structure was realized, the product structure modules were determined, and the comprehensive design and output of the innovative design scheme for the home entrance disinfection device were completed. The results of this study indicate that the design methodology combining AHP-FAST-FBS can effectively improve the scientific rigor and effectiveness of the home entrance disinfection device design, thereby generating an ideal product design scheme. This study provides systematic theoretical guidance and practical reference for designers of subsequent related disinfection products and also offers a new path for improving social health and safety.

The Lower Ordovician Tongzi Formation containing abundant shoal sediments is the most promising stratum for the petroleum exploration in the Sichuan Basin. However, the current studies mainly focus on the central part of the Basin, the systematic analysis of the southeastern part with well-developed shoal facies is lacking. This paper aims to clarify the characteristics and genesis of the Tongzi Formation reservoir in Southeastern Sichuan Basin, following an analysis of sedimentary facies within the sequence stratigraphic framework. The research shows that the main types of reservoir rocks are oolitic, intraclastic and bioclastic dolostones. And the reservoir spaces consist mainly of intergranular (dissolved) pores, intercrystalline (dissolved) pores, intragranular dissolved pores and fractures. Among them, intergranular pores account for the highest proportion, which is followed by intragranular dissolved pores. In addition, most throats are necking and flaky which mainly connect intergranular and intercrystalline pores, respectively. The diagenetic sequence shows that penecontemporaneous karst well improved the porosity of the reservoir in the early-stage although the cementation and compaction reduced parts of pores. The reservoir formation is associated with the tectonic-depositional settings, diageneses and terrigenous contamination. Paleohighlands and submerged uplifts, forming in the early Ordovician amalgamation between Yangtze and Cathaysia blocks, accumulated shoal sediments as the material basis for the reservoir formation. Penecontemporaneous karst forming intragranular dissolved pores and the dolomitization aiding grainstones to resist the pressure solution are the key to increasing porosity and preserving pores. The absence of terrigenous contamination prevented intergranular pores from being strongly cemented, which resulted in the reservoir difference between the central and southeastern Sichuan Basin. The study can be used as a reference for the further exploration of Ordovician petroleum in the Sichuan Basin and other regions owning similar geological settings.

Background Study: As flipped learning is a flexible pedagogical methodology to tailor students' needs and maximize the learning effects, this study integrated peer learning with MosoTeach-supported flipped mode in an undergraduate blended EFL course. MosoTeach is a popular online learning platform in China with a variety of learning resources. Objectives: The study aimed to test the impact of MosoTeach flipped learning (MTFL) mode on undergraduate EFL students' perceived motivation, participation, feedback, and test performance. Methods: A quasi-experimental design was carried out in Z university during the spring semester of 2020, with the experimental group (n = 34) adopting the MTFL model and a control group (n = 33) the non-flipped mode. Results and Conclusions: The independent t-test results showed that the experimental MTFL group outperformed the control group in post-test scores, and a positive correlation was found in the relationship between the experimental MTFL group's post-test scores and MosoTeach learning experience points (LEPs). Moreover, the course perception questionnaire survey indicated a higher level of students' perceived motivation, participation, and feedback in the experimental MTFL group, which corresponded to the results of the content analysis of students' responses to open-ended questions and reflective reports. But students in both groups experienced challenges such as isolation, procrastination and technological anxiety.

The timing of autism spectrum disorder detection in research and clinical practice is characterised by substantial heterogeneity ranging from infancy to school age. In this study, we examined the age of diagnosis and its associated individual and socio-familial factors in Chinese children diagnosed with autism spectrum disorder. A sample of 1235 autism spectrum disorder children from 132 rehabilitation organisations in Shenzhen was investigated in 2021. We found a mean age of diagnosis of 31.4 ± 12.7 months and a median of 30.0 months. Although 71.7% of the children received their diagnosis between 25 and 36 months of age, and 13.3% were diagnosed early (?24 months), 15.1% did not have their symptoms detected until preschool or later years (>36 months). The diagnosis was likely delayed (>36 months) if the children were older, were less severe and presented with no intellectual impairment. The odds of delayed autism spectrum disorder diagnosis were more than 9 times higher among migrant autism spectrum disorder children than those with local household registrations. The study underscores the importance of identifying culturally sensitive socio-economic determinants in autism spectrum disorder detection in addition to clinical factors, as the former are likely to affect the quality of life of many autism spectrum disorder children and their families.

Background: Hemorrhagic events cause numerous deaths annually worldwide, highlighting the urgent need for effective hemostatic drugs. The glucosyloxybenzyl 2-isobutylmalates Control Extract (BSCE) from the orchid plant Bletilla striata (Thunb.) Rchb.f. has demonstrated significant hemostatic activity in both in vitro and in vivo studies. However, the effect and mechanism of BSCE on non-traumatic bleeding remain unclear. Methods: Pulmonary hemorrhage was induced in 40 Sprague-Dawley rats by administering Zingiber officinale Roscoe. for 14 days. These rats were then randomly divided into five groups: model (Mod), positive control (YNBY), and BSCE low, medium, and high-dose groups. An additional 8 rats served as the control group (Con). The BSCE groups received different doses of BSCE for 10 days, while the YNBY group received Yunnan Baiyao suspension. The effects on body weight, food and water intake, red blood cell count (RBC), hemoglobin concentration (HGB), lung tissue pathology, platelet count, coagulation parameters, and fibrinolytic system markers were evaluated. Network pharmacology and molecular docking analyses were also conducted to identify potential targets and pathways involved in BSCE's effects. Results: BSCE treatment significantly improved body weight, food intake, and water consumption in rats with pulmonary hemorrhage. RBC and HGB levels increased significantly in the BSCE medium and high-dose groups compared to the Mod group (P

Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.

C17H12FN3O, orthorhombic, Pbca (no. 61), a = 14.7608(7) Å, b = 7.2802(4) Å, c = 24.4842(13) Å, V = 2,631.1(2) Å3, Z = 8, Rgt(F) = 0.0900, wRref(F2) = 0.1841, T = 170 K.