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Sepsis, a life-threatening condition, involves complex interactions among metabolic alterations, inflammatory mediators, and host responses. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationships between 1400 metabolites and sepsis, and the mediating role of inflammatory factors. We identified 36 metabolites significantly associated with sepsis (p < 0.05), with AXIN1, FGF-19, FGF-23, IL-4, and OSM showing an inverse association, suggesting a protective role, while IL-2 exhibited a positive correlation, indicating a potential risk factor. Among these metabolites, Piperine and 9-Hydroxystearate demonstrated particularly interesting protective effects against sepsis. Piperine’s protective effect was mediated through its interaction with AXIN1, contributing to a 16.296% reduction in sepsis risk. This suggests a potential pathway where Piperine influences sepsis outcomes by modulating AXIN1 levels. 9-Hydroxystearate also exhibited a protective role against sepsis, mediated through its positive association with FGF-19 and negative association with IL-2, contributing 9.436% and 12.565%, respectively, to its protective effect. Experimental validation confirmed significantly elevated IL-2 levels and reduced FGF-19, AXIN1, piperine, and 9-hydroxyoctadecanoic acid levels in sepsis patients compared to healthy controls. Piperine levels positively correlated with AXIN1, while 9-hydroxyoctadecanoic acid levels negatively correlated with IL-2 and positively correlated with FGF-19, supporting the Mendelian randomization findings. Our findings provide insights into the molecular mechanisms of sepsis, highlighting the unique roles and contributions of specific metabolites and their interactions with inflammatory mediators. This study enhances our understanding of sepsis pathophysiology and opens avenues for targeted therapeutic interventions and biomarker development for sepsis management. However, further research is essential to validate these pathways across diverse populations and fully explore the roles of these metabolites in sepsis.

BackgroundSepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection, yet the potential causal relationship between the immunophenotype and sepsis remains unclear.MethodsGenetic variants associated with the immunophenotype served as instrumental variables (IVs) in Mendelian randomization (MR) to elucidate the causal impact of the immunophenotype on three sepsis outcomes. Additionally, a two-step MR analysis was conducted to identify significant potential mediators between the immunophenotype and three sepsis outcomes.ResultsOur MR analysis demonstrated a significant association between the immunophenotype and sepsis outcome, with 36, 36, and 45 the immunophenotype associated with the susceptibility, severity, and mortality of sepsis, respectively. Specifically, our analysis highlighted the CD14+ CD16+ monocyte phenotype as a significant factor across all three sepsis outcomes, with odds ratios (ORs) and corresponding confidence intervals (CIs) indicating its impact on sepsis (OR = 1.047, CI: 1.001-1.096), sepsis in Critical Care Units (OR = 1.139, CI: 1.014-1.279), and sepsis-related 28-day mortality (OR = 1.218, CI: 1.104-1.334). Mediation analyses identified seven cytokines as significant mediators among 91 potential cytokines, including interleukin-5 (IL-5), S100A12, TNF-related apoptosis-inducing ligand (TRAIL), T-cell surface glycoprotein CD6 isoform, cystatin D, interleukin-18 (IL-18), and urokinase-type plasminogen activator (uPA). Furthermore, reverse MR analysis revealed no causal effect of sepsis outcomes on the immunophenotype.ConclusionOur MR study suggests that the immunophenotype is significantly associated with the susceptibility, severity, and mortality of patient with sepsis, providing, for the first time, robust evidence of significant associations between immune traits and their potential risks. This information is invaluable for clinicians and patients in making informed decisions and merits further attention.

LncRNAs are an essential type of non-coding RNAs, which have been reported to be involved in various human pathological conditions. Increasing evidence suggests that drugs can regulate lncRNAs expression, which makes it possible to develop lncRNAs as therapeutic targets. Thus, developing in-silico methods to predict lncRNA-drug associations (LDAs) is a critical step for developing lncRNA-based therapies. In this study, we predict LDAs by using graph convolutional networks (GCN) and graph attention networks (GAT) based on lncRNA and drug similarity networks. Results show that our proposed method achieves good performance (average AUCs > 0.92) on five datasets. In addition, case studies and KEGG functional enrichment analysis further prove that the model can effectively identify novel LDAs. On the whole, this study provides a deep learning-based framework for predicting novel LDAs, which will accelerate the lncRNA-targeted drug development process.

With the rapid development of power grid, the structure and technology of the secondary system in substations are also constantly innovating. The new generation of intelligent substations has achieved online monitoring functions for secondary equipment, making some state variables of relay protection equipment become observable indicators. Based on this, this paper proposes a novel relay protection equipment status evaluation strategy. Firstly, considering the fuzziness and uncertainty of the boundary division of relay protection evaluation levels, a relay protection risk assessment method based on normal cloud model has been proposed. Then, due to the particularity of historical statistical data, a weight calculation method combining analytical hierarchy process (AHP) and entropy weight method is adopted to eliminate subjective factors in the weight calculation process. Meanwhile, the equipment operation risk level was determined by calculating the certainty of the corresponding evaluation level for each indicator. Finally, in case study, the proposed method is used to evaluate the status of relay protection equipment, and the feasibility and accuracy of this method are verified through the analysis of the results.

BackgroundAcute pancreatitis (AP) is a severe digestive system disorder with a significant risk of progressing to sepsis, a major cause of mortality. Unraveling the immunological pathways in AP is essential for developing effective treatments, particularly understanding the role of specific immune cell traits in this progression.MethodsEmploying a bidirectional two-sample Mendelian Randomization (MR) approach, this study first examined the causal relationship between AP and 731 immune cell traits to identify those significantly associated with AP. Subsequently, we explored the causal associations between 731 immune cell traits and sepsis. The analysis utilized extensive genome-wide association studies (GWAS) summary datasets, with a focus on identifying common immune cell traits with statistically significant causal associations between AP and sepsis.ResultsOur investigation identified 44 immune cell traits unidirectionally associated with AP and 36 traits unidirectionally associated with sepsis. Among these, CD127 on CD28+ CD45RA- CD8+ T cells emerged as a common mediator, accounting for 5.296% of the increased risk of sepsis in AP patients. This finding highlights the significant role of specific memory CD8+ T cells in the pathophysiology of AP and its progression to sepsis.ConclusionThis study elucidates the critical role of specific immune cell traits, particularly CD127hi memory CD8+ T cells, in the progression of AP to sepsis. Our findings provide a foundation for future research into targeted immune-modulatory therapies, potentially improving patient outcomes in AP-related sepsis and offering new insights into the complex immunological dynamics of this condition.

With the large-scale integration of distributed renewable energy into low-voltage distribution station areas, rapidly growing services put forward new requirements on transparent monitoring. In order to accurately and objectively quantify the transparency of various distribution station areas and measure the impact of different dimensional indexes on the transparency evaluation of distribution station areas, this paper proposes a confidence relative off-target distance-based multi-dimensional transparency evaluation method. First, a multi-dimensional transparency evaluation index system with electrical and communication integration is constructed. Second, an improved gray target model combining both positive and negative target vectors is established to realize bi-directional quantitative analysis. Then, the relative off-target distance is calculated based on the endowment coefficient by leveraging both subjective and objective weights. Finally, the confidence of the relative off-target distance is calculated based on fuzzy entropy to improve the reliability of transparency evaluation. The simulation results show that this method can effectively distinguish the transparency gap between different distribution station areas, identify the single dimensional index with the greatest contribution or potential, and verify the effectiveness of the proposed method applied to the transparency evaluation of distribution station areas.

BackgroundLiver cancer is one of the malignant tumors worldwide, while the prevention and control situation is grim at present, and the diffusion of its early screening technology still faces some challenges. This study aims to investigate the influencing mechanism of perceived ease of use, organizational support mechanism, and industry competitive pressure on hepatic early screening technologies use by physicians, so as to promote the wider use of corresponding technologies.MethodsUnder the theoretical guidance of technology-organization-environment framework and mindsponge theory, this study took hepatic contrast-enhanced ultrasound as an example, and conducted a cross-sectional questionnaire by randomly selecting physicians from Fujian and Jiangxi provinces in China with a high and low incidence of liver cancer, respectively. Structural equation modeling was used to determine the correlation among perceived ease of use, organizational support mechanism, and industry competitive pressure, as well as their impact on the physicians’ behavior toward contrast-enhanced ultrasound use.ResultsThe hypothesis model fits well with the data (χ2/df = 1.863, GFI = 0.937, AGFI = 0.908, RMSEA = 0.054, NFI = 0.959, IFI = 0.980, CFI = 0.980). Under technology-organization-environment framework, the perceived ease of use (β = 0.171, p

Over three years’ pandemic of 2019 novel coronavirus disease (COVID-19), multiple variants and novel subvariants have emerged successively, outcompeted earlier variants and become predominant. The sequential emergence of variants reflects the evolutionary process of mutation-selection-adaption of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Amino acid substitution/insertion/deletion in the spike protein causes altered viral antigenicity, transmissibility, and pathogenicity of SARS-CoV-2. Early in the pandemic, D614G mutation conferred virus with advantages over previous variants and increased transmissibility, and it also laid a conservative background for subsequent substantial mutations. The role of genomic recombination in the evolution of SARS-CoV-2 raised increasing concern with the occurrence of novel recombinants such as Deltacron, XBB.1.5, XBB.1.9.1, and XBB.1.16 in the late phase of pandemic. Co-circulation of different variants and co-infection in immunocompromised patients accelerate the emergence of recombinants. Surveillance for SARS-CoV-2 genomic variations, particularly spike protein mutation and recombination, is essential to identify ongoing changes in the viral genome and antigenic epitopes and thus leads to the development of new vaccine strategies and interventions.

IntroductionVibrio parahaemolyticus is a foodborne pathogen commonly found in seafood, and drug resistance poses significant challenges to its control. This study aimed to identify novel drug targets for antibacterial drug discovery.MethodsTo identify drug targets, we performed a pan-genome analysis on 58 strains of V. parahaemolyticus genomes to obtain core genes. Subsequently, subtractive proteomics and physiochemical checks were conducted on the core proteins to identify potential therapeutic targets. Molecular docking was then employed to screen for anti-V. parahaemolyticus compounds using a in-house compound library of Streptomyces parvus, chosen based on binding energy. The anti-V. parahaemolyticus efficacy of the identified compounds was further validated through a series of experimental tests.Results and DiscussionPangenome analysis of 58 V. parahaemolyticus genomes revealed that there were 1,392 core genes. After Subtractive proteomics and physiochemical checks, Flagellar motor switch protein FliN was selected as a therapeutic target against V. parahaemolyticus. FliN was modeled and docked with Streptomyces parvus source compounds, and Actinomycin D was identified as a potential anti-V. parahaemolyticus agent with a strong binding energy. Experimental verification confirmed its effectiveness in killing V. parahaemolyticus and significantly inhibiting biofilm formation and motility. This study is the first to use pan-genome and subtractive proteomics to identify new antimicrobial targets for V. parahaemolyticus and to identify the anti-V. parahaemolyticus effect of Actinomycin D. These findings suggest potential avenues for the development of new antibacterial drugs to control V. parahaemolyticus infections.

ObjectiveTo compare the sex differences in cognitive function and its influencing factors among Chinese older adults.MethodWe conducted a cross-sectional study by using data from the China Longitudinal Healthy Longevity Survey (CLHLS). According to the 32 provinces and 4 municipalities directly under the Central Government of China, 3–5 counties or districts were randomly selected in each province or city (except Tibet), and then 1–3 villages or streets were randomly selected in each county or district, from which the target population was sampled. Mini Mental State Examination (MMSE) was used to assess the cognitive function of 9,262 older adults aged 65 and above in China. Descriptive analysis was applied to demonstrate the participants’ demographic characteristics, health-related behaviors, social and non-social activity, disease status, mental and sleep condition. And then, univariate and multifactor analyses were performed to validate different risk factors for cognitive function, respectively in the general population, male older adults and female older adults.ResultThe older adults with cognitive impairment accounted for 10.4% of the total population. There are significant differences in cognitive function between male and female older adults. The odds of cognitive impairment in older adult women was 1.291 times that of older adult men (OR = 1.291, 95%CI: 1.084–1.538). Among the male older adults, those who were older, highly educated, spouseless, had depressive symptoms, and lacked social activities were more likely to have cognitive impairment, whereas among the female older adults, those who were older, highly educated, and lacked social activities were more likely to have cognitive impairment.ConclusionOverall, there are subtle differences in potential influencing factors for cognitive function between the male older adults and female older adults. Attention should be paid to the different cognitive protection measures for the older adults with different sexes.

Introduction: Rapid development in synthetic technologies has boosted DNA as a potential medium for large-scale data storage. Meanwhile, how to implement data security in the DNA storage system is still an unsolved problem.Methods: In this article, we propose an image encryption method based on the modulation-based storage architecture. The key idea is to take advantage of the unpredictable modulation signals to encrypt images in highly error-prone DNA storage channels.Results and Discussion: Numerical results have demonstrated that our image encryption method is feasible and effective with excellent security against various attacks (statistical, differential, noise, and data loss). When compared with other methods such as the hybridization reactions of DNA molecules, the proposed method is more reliable and feasible for large-scale applications.

Objective: To observe the clinical efficacy and safety of Yiqi Yangxue formula (YQYXF) on knee osteoarthritis (KOA), and to explore the underlying therapeutic mechanism of YQYXF through endogenous differential metabolites and their related metabolic pathways.Methods: A total of 61 KOA patients were recruited and divided into the treatment group (YQYXF, 30 cases) and the control group (celecoxib, Cxb, 31 cases). Effects of these two drugs on joint pain, swelling, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) were observed, and their safety and adverse reactions were investigated. In animal experiments, 63 SD rats were randomly divided into normal control (NC) group, sham operation (sham) group, model (KOA) group, Cxb group, as well as low-dose (YL), medium-dose (YM), and high-dose groups of YQYXF (YH). The KOA rat model was established using a modified Hulth method. Ultra-high-performance liquid chromatography/Q Exactive HF-X Hybrid Quadrupole-Orbitrap Mass (UHPLC-QE-MS)-based metabolomics technology was used to analyze the changes of metabolites in plasma samples of rats. Comprehensive (VIP) >1 and t-test p < 0.05 conditions were used to screen the disease biomarkers of KOA, and the underlying mechanisms of YQYXF were explored through metabolic pathway enrichment analysis. The related markers of YQYXF were further verified by ELISA (enzyme-linked immunosorbent assay).Results: YQYXF can improve joint pain, swelling, range of motion, joint function, Michel Lequesen index of severity for osteoarthritis (ISOA) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, ESR, and CRP. No apparent adverse reactions were reported. In addition, YQYXF can improve cartilage damage in KOA rats, reverse the abnormal changes of 16 different metabolites, and exert an anti-KOA effect mainly through five metabolic pathways. The levels of reactive oxygen species (ROS) and glutathione (GSH) were significantly decreased after the treatment of YQYXF.Conclusion: YQYXF can significantly improve the clinical symptoms of KOA patients without obvious adverse reactions. It mainly improved KOA through modulating lipid metabolism-related biomarkers, reducing lipid peroxidation and oxidative stress.

BackgroundTransition into menopause is associated with an increased risk of cardiovascular disease (CVD). However, it is unclear whether the association exists between premature menopause (defined as age at menopause 40 years) or early menopause (defined as age at menopause 40–45 years) and CVD or cardiovascular risk factors. The aim of this review was to comprehensively evaluate and meta-analyze the most reliable evidence about the relationship between menopausal age and the risk of long-term cardiometabolic disease.MethodsA comprehensive literature search of the PubMed, Web of Science, and Embase databases from inception to October 1, 2022, for titles and abstracts with a restriction to English language papers led to the discovery of the studies. Data are expressed as the Hazard Ratio (HR) with 95% confidence intervals (CI). The degree of heterogeneity was measured using the I-square (I2) index.Results921,517 participants from 20 cohort studies published between 1998 and 2022 were considered. Compared to women with menopause at age >45 years, women with premature menopause (PM) or early menopause (EM) had a higher risks of type 2 diabetes (RR: 1.32, 95% CI: 1.08–1.62; RR: 1.11, 95% CI: 0.91–1.36, respectively), hyperlipidemia (RR: 1.21, 95% CI: 1.05–1.39; RR: 1.17, 95% CI: 1.02–1.33, respectively), coronary heart disease (RR: 1.52, 95% CI: 1.22–1.91; RR: 1.19, 95% CI: 1.07–1.32, respectively), stroke (RR: 1.27, 95% CI: 1.02–1.58; RR: 1.13, 95% CI: 0.97–1.32, respectively) and total cardiovascular event (RR: 1.36, 95% CI: 1.16–1.60; RR: 1.14, 95% CI: 0.97–1.35, respectively). No difference was found for hypertension in PM or EM women (RR: 0.98, 95% CI: 0.89–1.07; RR: 0.97, 95% CI: 0.91–1.04, respectively). Additionally, we also found that PM women, but not EM women, were linked with an increased risk of ischemic and hemorrhagic stroke. However, this is not in line with the conclusion that both PM and EM had a higher risk of total stroke.ConclusionWomen with PM or EM have a higher risk of developing long-term CVD, compared to women with menopause at age >45 years. Therefore, we recommend early lifestyle interventions (e.g., maintaining a healthy lifestyle) and medical treatments (e.g., timely initiation of menopausal hormone therapy) to decrease the risk of cardiometabolic disease in early or premature menopausal women.Systematic Review RegistrationPROSPERO, identifier CRD42022378750

ObjectiveThe aim of this study was to assess the diagnostic performance of radiomics-based MRI in predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC).MethodThe databases of PubMed, Cochrane library, Embase, Web of Science, Ovid MEDLINE, Springer, and Science Direct were searched for original studies from their inception to 20 August 2022. The quality of each study included was assessed according to the Quality Assessment of Diagnostic Accuracy Studies 2 and the radiomics quality score. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated. The summary receiver operating characteristic (SROC) curve was plotted and the area under the curve (AUC) was calculated to evaluate the diagnostic accuracy. Sensitivity analysis and subgroup analysis were performed to explore the source of the heterogeneity. Deeks’ test was used to assess publication bias. ResultsA total of 15 studies involving 981 patients were included. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.79 (95%CI: 0.72–0.85), 0.81 (95%CI: 0.73–0.87), 4.1 (95%CI:2.9–5.9), 0.26 (95%CI: 0.19–0.35), 16 (95%CI: 9–28), and 0.87 (95%CI: 0.84–0.89), respectively. The results showed great heterogeneity among the included studies. Sensitivity analysis indicated that the results of this study were statistically reliable. The results of subgroup analysis showed that hepatocyte-specific contrast media (HSCM) had equivalent sensitivity and equivalent specificity compared to the other set. The least absolute shrinkage and selection operator method had high sensitivity and specificity than other methods, respectively. The investigated area of the region of interest had high specificity compared to the volume of interest. The imaging-to-surgery interval of 15 days had higher sensitivity and slightly low specificity than the others. Deeks’ test indicates that there was no publication bias (P=0.71).ConclusionRadiomics-based MRI has high accuracy in predicting MVI in HCC, and it can be considered as a non-invasive method for assessing MVI in HCC.

PurposeTo evaluate the diagnostic performance of radiomics model based on fully automatic segmentation of pancreatic tumors from non-enhanced magnetic resonance imaging (MRI) for differentiating pancreatic adenosquamous carcinoma (PASC) from pancreatic ductal adenocarcinoma (PDAC).Materials and methodsIn this retrospective study, patients with surgically resected histopathologically confirmed PASC and PDAC who underwent MRI scans between January 2011 and December 2020 were included in the study. Multivariable logistic regression analysis was conducted to develop a clinical and radiomics model based on non-enhanced T1-weighted and T2-weighted images. The model performances were determined based on their discrimination and clinical utility. Kaplan-Meier and log-rank tests were used for survival analysis.ResultsA total of 510 consecutive patients including 387 patients (age: 61 ± 9 years; range: 28–86 years; 250 males) with PDAC and 123 patients (age: 62 ± 10 years; range: 36–84 years; 78 males) with PASC were included in the study. All patients were split into training (n=382) and validation (n=128) sets according to time. The radiomics model showed good discrimination in the validation (AUC, 0.87) set and outperformed the MRI model (validation set AUC, 0.80) and the ring-enhancement (validation set AUC, 0.74).ConclusionsThe radiomics model based on non-enhanced MRI outperformed the MRI model and ring-enhancement to differentiate PASC from PDAC; it can, thus, provide important information for decision-making towards precise management and treatment of PASC.

BackgroundHand grip strength (HGS) is a fast, useful, and inexpensive outcome predictor of nutritional status and muscular function assessment. Numerous demographic and anthropometric factors were reported to be associated with HGS, while which one or several factors produce greater variations in HGS has not been discussed in detail. This is important for answering how should HGS be normalized for eliminating the influence of individual differences in clinical practice.AimsTo compare the contribution of age, sex, height, weight, and forearm circumference (FCF) to variations in HGS based on a large-scale sample.MethodsWe enrolled 1,511 healthy undergraduate students aged 18–23 years. Age, weight, height, and sex were obtained. HGS was measured using a digital hand dynamometer, and FCF was measured at the point of greatest circumference using a soft ruler in both hands. Pearson’s or Spearman’s correlation coefficients were calculated with data of women and men separated and mixed for comparison. Partial correlation analysis and multivariate linear regression were used to compare the effect of variables on HGS.ResultsAnalysis results confirmed the correlates of higher HGS include higher height, heavier weight, being men and dominant hand, and larger FCF. The correlation between HGS and FCF was the highest, and the bivariate correlation coefficient between weight and HGS was largerata of women and men were mixed, than that between height and HGS. When data of women and men were mixed, there were moderate correlations between HGS and height and weight (r = 0.633∼0.682). However, when data were separated, there were weak correlations (r = 0.246∼0.391). Notably, partial correlation analysis revealed no significant correlation between height and HGS after eliminating the weight effect, while the correlation between weight and HGS was still significant after eliminating the height effect. Multivariate linear regression analyses revealed sex was the most significant contributor to the variation in HGS (Beta = –0.541 and –0.527), followed by weight (Beta = 0.243 and 0.261) and height (Beta = 0.102 and 0.103).ConclusionHGS and FCF reference values of healthy college students were provided. Weight was more correlate with hand grip strength, at least among the healthy undergraduates.Clinical trial registrationhttp://www.chictr.org.cn/showproj.aspx?proj=165914, identifier ChiCTR2200058586.

This study was conducted to evaluate the effect of cholesterol (CHO) on ovarian development of Eriocheir sinensis through a feeding trial. Crabs (average weight 43.35 ± 0.05 g) were randomly fed with one of three diets: 0% CHO, 0.4% CHO and 1.6% CHO for 16 weeks. Results indicated that the hepatosomatic index (HSI) and gonad index (GSI) of crabs fed with 0.4% CHO diet were significantly higher than those in the control group. (P < 0.05). Meanwhile, 0.4% CHO can significantly increase the gene expression of vtg and vgr in ovary (P < 0.05), thus promoting the accumulation of Vtg. The protein expression of MEK1/2, ERK, p-ERK1/2, Cyclin B and CDC2 were significantly increased in the 0.4% CHO group, therefore dietary CHO might promote oocyte maturation by activating MAPK signal pathway and cooperating with maturation promoting factor (MPF). Further exploration results showed that 0.4% CHO was able to significantly up-regulate the protein expression of STAR and SR-B1 to promote the transport of CHO to ovary, thereby providing sufficient substrates for estradiol (E2) synthesis. In addition, the results in vivo and in vitro shown that CHO could regulate the activities of enzymes such as CYP11A1 and CYP19A1 through the cAMP-PKA-CREB/SF-1 signal pathway and then affects the level of E2 in the organism. In summary, supplementing the appropriate amount of CHO in the diet can improve the E2 level of the organism, thus increasing the accumulation of nutrients in the ovary, promoting the completion of meiosis, and finally achieving the purpose of promoting ovarian maturation.

BackgroundMultimorbidity has become an essential public health issue that threatens human health and leads to an increased disease burden. Primary care is the prevention and management of multimorbidity by providing continuous, comprehensive patient-centered services. Therefore, the study aimed to investigate the determinants of primary care utilization and out-of-pocket expenses (OOPE) among multimorbid elderly to promote rational utilization of primary care and reduce avoidable economic burdens.MethodsThe study used data from CHARLS 2015 and 2018, which included a total of 4,384 multimorbid elderly aged 60 and above. Guided by Grossman theory, determinants such as education, gender, marriage, household economy, and so on were included in this study. A two-part model was applied to evaluate primary care utilization and OOPE intensity in multimorbid populations. And the robustness testing was performed to verify research results.ResultsPrimary care visits rate and OOPE indicated a decline from 2015 to 2018. Concerning primary outpatient care, the elderly who were female (OR = 1.51, P < 0.001), married (OR = 1.24, P < 0.05), living in rural areas (OR = 1.77, P < 0.001) and with poor self-rated health (OR = 2.23, P < 0.001) had a significantly higher probability of outpatient utilization, whereas those with middle school education (OR = 0.61, P < 0.001) and better household economy (OR = 0.96, P < 0.001) had a significantly less likelihood of using outpatient care. Rural patients (β = −0.72, P < 0.05) may have lower OOPE, while those with better household economy (β = 0.29, P < 0.05; β = 0.58, P < 0.05) and poor self-rated health (β = 0.62, P < 0.001) occurred higher OOPE. Regarding primary inpatient care, adults who were living in rural areas (OR = 1.48, P < 0.001), covered by Urban Employee Basic Medical Insurance (UEBMI) or Urban Rural Basic Medical Insurance (URBMI) (OR = 2.46, P < 0.001; OR = 1.81, P < 0.001) and with poor self-rated health (OR = 2.30, P < 0.001) had a significantly higher probability of using inpatient care, whereas individuals who were female (OR = 0.74, P < 0.001), with middle school education (OR = 0.40, P < 0.001) and better household economy (OR = 0.04, P < 0.001) had a significantly lower tendency to use inpatient care. Significantly, more OOPE occurred by individuals who were women (β = 0.18, P < 0.05) and with better household economy (β = 0.40, P < 0.001; β = 0.62, P < 0.001), whereas those who were covered by URBMI (β = −0.25, P < 0.05) and satisfied with their health (β = −0.21, P < 0.05) had less OOPE.ConclusionTo prompt primary care visits and reduce economic burden among subgroups, more policy support is in need, such as tilting professional medical staff and funding to rural areas, enhancing awareness of disease prevention among vulnerable groups and so on.

Segmental bone defects, accompanied by periosteum stripping or injury, usually lead to delayed bone union or nonunion, which have challenged orthopedic surgeons. The periosteum, which provides essential blood supply and initial stem cells for bone tissue, plays an important role in the repair of bone defects. The reconstruction of the destroyed periosteum has attracted the attention of researchers exploring more satisfactory therapies to repair bone defects. However, periosteum-like biomaterials have yet to meet the clinical requirements and resolve this challenging problem. In this study, we manufactured a nanofiber periosteum replacement based on poly-ε-caprolactone (PCL), in which tantalum nanoparticles (TaNPs) and nanoscale magnesium oxide (MgO) were introduced to enhance its osteogenic and angiogenic ability. The results of in vitro experiments indicated that the PCL/Ta/MgO periosteum replacement, with excellent cytocompatibility, promoted the proliferation of both bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs). Furthermore, the incorporation of TaNPs and nano-MgO synergistically enhanced the osteogenic differentiation of BMSCs and the angiogenic properties of EPCs. Similarly, the results of in vivo experiments from subcutaneous implantation and critical-sized calvarial defect models showed that the PCL/Ta/MgO periosteum replacement combined the osteogenesis and angiogenesis abilities, promoting vascularized bone formation to repair critical-sized calvarial defects. The results of our study suggest that the strategy of stimulating repairing bone defects can be achieved with the periosteum repaired in situ and that the proposed periosteum replacement can act as a bioactive medium to accelerate bone healing.

Primary membranous nephropathy (PMN), is an autoimmune glomerular disease and the main reason of nephrotic syndrome in adults. Studies have confirmed that the incidence of PMN increases yearly and is related to fine air pollutants particulate matter 2.5 (PM2.5) exposure. These imply that PM2.5 may be associated with exposure to PMN-specific autoantigens, such as the M-type receptor for secretory phospholipase A2 (PLA2R1). Emerging evidence indicates that Th17/Treg turns to imbalance under PM2.5 exposure, but the molecular mechanism of this process in PMN has not been elucidated. As an important indicator of immune activity in multiple diseases, Th17/Treg immune balance is sensitive to antigens and cellular microenvironment changes. These immune pathways play an essential role in the disease progression of PMN. Also, microRNAs (miRNAs) are susceptible to external environmental stimulation and play link role between the environment and immunity. The contribution of PM2.5 to PMN may induce Th17/Treg imbalance through miRNAs and then produce epigenetic affection. We summarize the pathways by which PM2.5 interferes with Th17/Treg immune balance and attempt to explore the intermediary roles of miRNAs, with a particular focus on the changes in PMN. Meanwhile, the mechanism of PM2.5 promoting PLA2R1 exposure is discussed. This review aims to clarify the potential mechanism of PM2.5 on the pathogenesis and progression of PMN and provide new insights for the prevention and treatment of the disease.

IntroductionIn December 2021, a large-scale epidemic broke out in Xi’an, China, due to SARS-CoV-2 infection. This study reports the effect of vaccination on COVID-19 and evaluates the impact of different vaccine doses on routine laboratory markers.MethodsThe laboratory data upon admission, of 231 cases with COVID-19 hospitalized from December 8, 2021 to January 20, 2022 in Xi’an, including blood routine, lymphocyte subtypes, coagulative function tests, virus specific antibodies and blood biochemical tests were collected and analyzed.ResultsOf the 231 patients, 21 were not vaccinated, 158 were vaccinated with two doses and 52 with three doses. Unvaccinated patients had a higher proportion of moderate and severe symptoms than vaccinated patients, while two-dose vaccinated patients had a higher proportion than three-dose vaccinated patients. SARS-CoV-2 specific IgG levels were significantly elevated in vaccinated patients compared with unvaccinated patients. Particularly, unvaccinated patients had lower counts and percentages of lymphocytes, eosinophils and CD8+ T-lymphocytes, and elevated coagulation-related markers. In addition, vaccination had no effect on liver and kidney function.ConclusionsVaccination against SARS-CoV-2, inducing high IgG level and increased CD8+ T cells and eosinophils, and regulating coagulation function, can significantly attenuate symptoms of COVID-19, suggesting that the vaccine remains protective against SARS-CoV-2.

Promoting clinicians’ knowledge sharing of appropriate health technology within the integrated care system (ICS) is of great vitality in bridging the technological gap between member institutions. However, the role of social networks in knowledge sharing of health technology is still largely unknown. To address this issue, the study aims to clarify the influence of clinicians’ social networks on knowledge sharing of health technology within the ICS. A questionnaire survey was conducted among the clinicians in the Alliance of Liver Disease Specialists in Fujian Province, China. Social network analysis was conducted using NetDraw and UCINET, and the quadratic assignment procedure (QAP) multiple regression was used to analyze the influencing factors of knowledge sharing of health technology. The results showed that the ICS played an insufficient role in promoting overall knowledge sharing, especially inter-institutional knowledge sharing. Trust, emotional support, material support, and cognitive proximity positively influenced knowledge sharing of health technology, while the frequency of interaction and relationship importance had a negative impact on it. The finding extended the research scope of social network theory to the field of healthcare and will bridge the evidence gap in the influence of the clinicians’ social networks on their knowledge sharing within the ICS, providing new ideas to boost knowledge sharing and diffusion of appropriate health technology.

ObjectiveAs a member of interleukin-12 family, interleukin-35 (IL-35) plays an important regulatory role in immune response. The relationship between IL-35 and idiopathic membranous nephropathy (IMN) is still unclear, and the purpose of this study is to clarify the relationship between IL-35 and disease activity and remission of IMN.MethodsThis study was a single-center, retrospective study in which all patients were diagnosed with IMN by renal biopsy or aPLA2R titer and treated with Mahuang Fuzi and Shenzhuo Decoction (MFSD). A follow-up was conducted with the endpoint of clinical complete or partial remission (CR+PR). Levels of serum IL-35 were measured and its relationship with IMN remission were analyzed. The regulatory T cell (Treg) and inducible IL-35 producing Tregs (iTR35) in peripheral blood of IMN patients were detected by flow cytometry.ResultsA total of 76 IMN patients (age 51.95 ± 13.29) were followed-up for 18 (12, 24) months. The level of serum IL-35 in all patients increased after treatment, but the degree of increase in remission group was significantly higher than that in no remission (NR) group (117.6% vs 83.7%, P 203.05 pg/ml) (12mon vs. 24mon, P

BackgroundNumerous studies showed that preoperative platelet-albumin-bilirubin (PALBI) grade was closely related to the prognostic outcome of patients with hepatocellular carcinoma (HCC). However, the conclusions were inconsistent. Therefore, we implemented the study to comprehensively evaluate the association between PALBI grade and prognosis in patients with HCC.MethodsRelevant articles were collected from the specified databases until February 10, 2022. We included all studies exploring the relationship between PALBI grade and prognosis in HCC patients. We used the hazard ratio (HR) and 95% confidence interval (CI) to calculate the comprehensive analysis. All data analyses were performed using STATA 12.0.ResultsThirteen retrospective articles containing 15534 patients were included in the meta-analysis. The pooled results displayed that the high PALBI grade was obviously correlated with poor overall survival (OS) (HR: 1.71, 95% CI: 1.46-2.02) and disease-free survival/relapse-free survival (DFS/RFS) (HR:1.31; 95% CI: 1.11–1.54). Subgroup analyses further confirmed the reliability of the comprehensive results.ConclusionsPALBI may be a valid prognostic indicator in HCC patients. More investigations were needed to test our findings.

CD4+ T cells, also known as T helper (Th) cells, contribute to the adaptive immunity both in the periphery and in the central nervous system (CNS). At least seven subsets of Th cells along with their signature cytokines have been identified nowadays. Neuroinflammation denotes the brain’s immune response to inflammatory conditions. In recent years, various CNS disorders have been related to the dysregulation of adaptive immunity, especially the process concerning Th cells and their cytokines. However, as the functions of Th cells are being discovered, it’s also found that their roles in different neuroinflammatory conditions, or even the participation of a specific Th subset in one CNS disorder may differ, and sometimes contrast. Based on those recent and contradictory evidence, the conflicting roles of Th cells in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, epilepsy, traumatic brain injury as well as some typical mental disorders will be reviewed herein. Research progress, limitations and novel approaches concerning different neuroinflammatory conditions will also be mentioned and compared.

BackgroundThe contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to primary liver cancer (PLC) and their association with cancer aggressiveness remains uncertain in China, a country with half of global PLC. We aimed to characterize this using data from four representative medical centers.MethodsIn total, 15,801 PLC patients were enrolled from the centers distributed in Easter5n, Southern, Northern, and Western China from 2003 to 2020. Of those, 7585 with curative surgery were involved in survival analysis. A nomogram was constructed using preoperative parameters to predict postoperative survival.ResultsHepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma accounted for 93.0%, 4.3%, and 1.6% in PLC, respectively. The seropositivities of HBV and HCV were 84.4% and 3.2% in HCC, respectively. The seropositivity of anti-HCV antibody was significantly higher in HBV-negative than in HBV-positive HCC patients (13.2% vs. 1.1%). Compared to HCV-positive HCC (HCV-HCC), HBV-positive HCC (HBV-HCC) was associated with 12-year earlier onset, higher proportions of males, high α-fetoprotein, large tumor size, advanced Barcelona Clinic Liver Cancer (BCLC) stage, and vascular tumor thrombus. The proportions of HCC and HBV seropositivity increased, whereas that of anti-HCV decreased, from 2003 to 2020. Postoperative five-year survival rate was 73.5%, 64.1%, 34.9%, and 19.7% in HCC at BCLC stage 0, A, B, and C, respectively. The multivariate Cox regression analysis showed that HBV seropositivity, incomplete tumor capsule, vascular tumor thrombus, tumor diameter (≥3 cm), advanced BCLC stage (B+C), α-fetoprotein (≥20ng/ml), and direct bilirubin (>8µmol/L) contributed independently to shorter overall survival (OS); whereas post-operative radiofrequency ablation and second resection independently improved OS in HCC. HCV-HCC had a more favorable prognosis than did HBV-HCC (Log-rank test, P

BackgroundFamily doctor contract services (FDCS) has played a key role in diabetes management in China since 2016. The influence of FDCS on the physiological indexes of individuals with diabetes has been examined. However, little attention has been paid to its effect on the Health-Related Quality of Life (HRQoL). This study aims to fill this knowledge gap by evaluating the effect of FDCS on the HRQoL of individuals with diabetes.MethodsWe identified 382 individuals with diabetes receiving all follow-up surveys in 2013, 2015, and 2018 from the China Health and Retirement Longitudinal Study (CHARLS). The HRQoL of the included individuals was estimated using results from the Short Form 36 (SF-36) questionnaire. The propensity score matching with the difference-in-differences (PSM-DID) approach was applied to quantify the effect of FDCS on the HRQoL among individuals with diabetes. A robust test was performed by setting the 2015 data as the treatment group for the placebo test.ResultsThe mean score of role-emotional (RE) increased from 54.25 to 61.63 among those who signed up to receive FDCS, while the corresponding score decreased from 57.77 to 51.04 among those who did not receive FDCS. Results from the regression analysis indicated that the use of FDCS was associated with significant improvement in RE (+14.10, p = 0.04) among individuals with diabetes. We did not find a statistically meaningful association between the FDCS and any of the other HRQoL domains: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), and mental health (MH), respectively. The robustness analysis of the model indicated that the results were robust.ConclusionThe FDCS for diabetes in China was associated with a significant improvement in RE. Due to a limited time since the launch of FDCS (i.e., 2016), the recipient's physical health did not show marked improvement. In the future, FDCS should pay more attention to the physiological health of individuals with diabetes. Moreover, psychological services also need to be maintained and not slackened. At the same time, it is strongly recommended to pay more attention to the HRQoL of individuals with diabetes and more comprehensive health.

Carboxypeptidase N2 (CPN2) is a plasma metallo-protease that cleaves basic amino acids from the C-terminal of peptides and proteins. Emerging evidence showed that carboxypeptidases perform many diverse functions in the body and play key roles in tumorigenesis. However, the clinical significance and biological functions of CPN2 in lung adenocarcinoma remain unclear. Our study aimed to explore the potential role and functions of CPN2 in lung adenocarcinoma. The results showed that the transcription level of CPN2 was significantly increased in the tumor tissues of lung adenocarcinoma patients compared to the adjacent normal tissues in The Cancer Genome Atlas cohort (P < 0.05). The survival plots showed that the overall survival of patients with a high expression of CPN2 was significantly lower than that of patients with a low expression of CPN2, both in the Kaplan–Meier database and the clinical sample cohort (P < 0.05). The tissue microarray analysis found that CPN2 protein expression was significantly positively correlated with node status and tumor stage as well as tumor malignancy (P < 0.05). Further univariate and multivariate Cox regression analyses showed that CPN2 may act as an independent prognostic factor in patients with lung adenocarcinoma (P < 0.05). In addition, the analysis of co-expression genes from LinkedOmics showed that CPN2 was positively associated with many genes of fibrillar collagen family members and the PI3K-Akt pathway. The gene set enrichment analysis showed that a higher expression of CPN2 may participate in mTOR, TGF-BETA, NOTCH, TOLL-like-receptor, WNT, and MAPK signaling pathway in lung adenocarcinoma. Notably, the knockdown of CPN2 significantly inhibited the ability of cell proliferation, clone formation, invasion, and migration. Our findings suggested that the upregulation of CPN2 is associated with a worse clinical outcome in lung adenocarcinoma and cancer-related pathways, which laid the foundation for further research on CPN2 during carcinogenesis.

The increased incidence of membranous nephropathy (MN) has made it the most common pathological type of primary nephrotic syndrome in adults in China. According to the theory of Traditional Chinese Medicine (TCM), Mahuang Fuzi (Chinese ephedra and Radix Aconiti Lateralis Preparata) and Shenzhuo Decoction (MFSD) could be used to treat such diseases. We treated patients of MN with MFSD, and observed comparable efficacy to glucocorticoid and/or immunosuppressants. In this study, we observed the therapeutic effect of MFSD on the rat model of passive Heymann nephritis (PHN), a classical MN model. Our results showed that MFSD treatment significantly reduced urinary protein level and podocyte injury in PHN rats, and correspondingly improved renal pathology, with the improvement effect on MN comparable to that of Cyclosporine A (CsA) alone. To explore the potential therapeutical mechanism of MFSD, the main chemical components of MFSD were determined by High-performance liquid chromatography-mass spectrometry (HPLC-MS). There were about 30 active components of MFSD. Next, based on network pharmacology methods, we screened related targets of MSFD on MN, which provided a preliminary understanding of the MFSD bioactive compounds. The clustering analysis showed that its active site might be in the autophagy-related protein and Wnt/β-catenin pathway, which was related to podocyte injury. Finally, we observed an improvement in renal autophagy and a down-regulation of the Wnt/β-catenin pathway after MSFD treatment in a PHN rat model. According to this study, autophagy and Wnt/β-catenin pathway may be potential targets for MFSD in the treatment of MN.

This study aimed to evaluate the efficiency and safety of indocyanine green (ICG) fluorescence real-time imaging-guided technology in laparoscopic hepatectomy. A retrospective analysis of patients with primary liver cancer in the First Affiliated Hospital of USTC from January 2018 to October 2021, including 48 cases of fluorescence-guided laparoscopic hepatectomy (FGLH) and 60 cases of traditional laparoscopic hepatectomy (LH), was conducted. R0 resection rate, operation time, intraoperative blood loss, complications, hospital stay, and other intraoperative and postoperative indicators of the two groups were analyzed to determine the clinical feasibility and safety of ICG fluorescence real-time imaging-guided technology in laparoscopic hepatectomy. Related databases were searched for retrospective cohort studies and randomized controlled trials comparing FGLH with LH, studies were screened according to preset inclusion and exclusion criteria, literature quality was evaluated, and data were extracted. RevMan 5.3 software was used to conduct a meta-analysis on the extracted data. The results of our clinical data and meta-analysis showed that compared with LH, FGLH increased the R0 resection rate, shortened the operation time and postoperative hospital stay, and reduced blood loss and the occurrence of postoperative complications. Compared with LH, FGLH has a better application effect in laparoscopic hepatectomy, and it is worthy of promotion as it is safe and feasible.

BackgroundThe prognostic significance of tumor burden score (TBS) on patients who underwent curative-intent resection of intrahepatic cholangiocarcinoma (ICC) has not been evaluated. The present study aimed to investigate the impact of TBS and its synergistic effect with CA19-9 (combination of TBS and CA19-9, CTC grade) on long-term outcomes.MethodsPatients who underwent radical resection of ICC between 2009 and 2017 were retrospectively identified from a multi-center database. The overall survival (OS) and recurrence-free survival (RFS) were examined in relation to TBS, serum preoperative CA19-9, and CTC grade.ResultsA total of 650 patients were included in our study (509 in the derivation cohort and 141 in the validation cohort). Kaplan–Meier curves showed that both TBS and CA19-9 levels were strong predictors of survival outcomes. Patients with elevated TBS grade or elevated CA19-9 were associated with worse OS and RFS (both p < 0.001). As expected, CTC grade also performed well in predicting long-term outcomes. Patients with low TBS/low CA19-9 (CTC grade 1) were associated with the best OS as well as RFS, while high TBS/high CA19-9 (CTC grade 3) correlated to the worst outcomes. In the validation cohort, TBS grade, preoperative CA19-9, and CTC grade also stratified prognosis among patients (p < 0.001 for each).ConclusionsBoth tumor morphology (tumor burden) and tumor-specific biomarker (serum CA19-9) were important when evaluating prognosis of patients with resectable ICC. Serum CA19-9 and TBS showed a synergistic effect on prognostic evaluation. CTC grade was a promising tool in stratifying prognosis of ICC patients after curative resection.

BackgroundPromoting technology diffusion and utilization is a key measure to address the great disparity in technical capacity within integrated health systems. However, even the effectiveness and appropriateness regarding technology has been widely recognized, its diffusion and utilization are still stagnant. The mechanisms that influence the technology from being recognized to being widely applied in practice remain largely unknown.PurposeTaking hepatic contrast-enhanced ultrasound (CEUS) as an example, this study aimed to investigate the comprehensive influencing mechanism of organizational atmosphere and organizational practice on the knowledge, attitude, and practice toward diffusion and utilization of hepatic CEUS in the medical alliance.MethodsBased on the integration of organizational ready for change (ORC) and knowledge-attitude-practice (KAP), a structured questionnaire was developed. A multistage random sampling method was applied to investigate physicians who directly use CEUS working at the liver disease-related departments of sampled health institutions. Structural equation modeling (SEM) was used to verify the proposed hypotheses, and determine the relationship between the factors.ResultsIn total, 292 physicians were included. SEM results demonstrated that knowledge influenced both attitude and practice, while attitude positively predicted practice. Organizational practice and organizational atmosphere associated positively with each other. Organizational atmosphere positively affected the physicians' attitude toward CEUS diffusion and utilization (β = 0.425, p < 0.001), while organizational practice positively affected corresponding knowledge (β = 0.423, p < 0.001) and practice (β = 0.275, p < 0.001). Additionally, there was a partial mediating effect between organizational practice and physicians' CEUS diffusion and utilization behavior.ConclusionBy verifying the influencing mechanism of organizational atmosphere and organizational practice on the physicians' KAP of hepatic CEUS diffusion and utilization, this study benefit tailoring strategies for promoting technology diffusion and utilization within medical alliance. It is recommended to develop an organizational atmosphere of advocating technology innovation, establish organizational support mechanism (SM) with multiple concrete supporting countermeasures, and so on.

We aimed to elucidate the mechanism by which hepatitis B virus X (HBx) mutations increase the occurrence of hepatocellular carcinoma (HCC) and identify novel putative therapeutic targets. Wild-type HBx (WT-HBx) and four HBx mutants (M1, A1762T/G1764A; M2, T1674G+T1753C+A1762T/G1764A; M3, C1653T+T1674G+A1762T/G1764A; and Ct-HBx, carboxylic acid-terminal truncated HBx) were delivered into Sleeping Beauty (SB) mouse models. The HCC incidence was higher in the M3-HBx- and Ct-HBx-injected SB mice. M3-HBx had a stronger capacity of upregulating inflammatory cytokines than other HBx variants. Ectopic expression of M3-HBx and Ct-HBx significantly increased proliferation and S phase proportion of HepG2 and HeLa cells, compared to WT-HBx. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors by cDNA microarray analysis. M3-HBx and Ct-HBx significantly upregulated the expression of PAI1 and CDC20 in HepG2 and HeLa cells as well as the livers of SB mice. Silencing PAI1 attenuated the effects of M3-HBx and Ct-HBx on the growth of HepG2 and HeLa cells. PAI1, an important player bridging the HBx mutants and HCC, should be a promising candidate as a prognostic biomarker and therapeutic target in HBV-related HCC.

Pluripotency is a transient state in early embryos, which is regulated by an interconnected network of pluripotency-related genes. The pluripotent state itself seems to be highly dynamic, which leads to significant differences in the description of induced pluripotent stem cells from different species at the molecular level. With the application of cell reprogramming technology in fish, the establishment of a set of molecular standards for defining pluripotency will be important for the research and potential application of induced pluripotent stem cells in fish. In this study, by BLAST search and expression pattern analysis, we screen out four pluripotent genes (Oct4, Nanog, Tdgf1, and Gdf3) in zebrafish (Danio rerio) and crucian carp (Carassius). These genes were highly expressed in the short period of early embryonic development, but significantly down-regulated after differentiation. Moreover, three genes (Oct4, Nanog and Tdgf1) have been verified that are suitable for identifying the pluripotency of induced pluripotent stem cells in zebrafish and crucian carp. Our study expands the understanding of the pluripotent markers of induced pluripotent stem cells in fish.

Breast cancer is a heterogeneous disease, and its development is closely associated with the underlying molecular regulatory network. In this paper, we propose a new way to measure the regulation strength between genes based on their expression values, and construct the dysregulated networks (DNs) for the four subtypes of breast cancer. Our results show that the key dysregulated networks (KDNs) are significantly enriched in critical breast cancer-related pathways and driver genes; closely related to drug targets; and have significant differences in survival analysis. Moreover, the key dysregulated genes could serve as potential driver genes, drug targets, and prognostic markers for each breast cancer subtype. Therefore, the KDN is expected to be an effective and novel way to understand the mechanisms of breast cancer.

ObjectivesThe aim of this study was to determine whether behavioral responses elicited by olfactory stimulation are a predictor of conscious behavioral response and prognosis of patients with disorders of consciousness (DOC).MethodsTwenty-three DOC patients (8 unresponsive wakefulness syndrome [UWS]; 15 minimally conscious state [MCS]) were recruited for this study in which 1-Octen-3-ol (familiar neutral odor) and pyridine were used to test odor behavioral responses, and water was used as an odorless stimulus. One rater presented the three odors in front of each patient’s nose randomly, and another one videotaped all behavioral responses (e.g., pouting, wrinkling nose, slightly shaking head, frowning, etc.). Two independent raters, blind to the stimuli and the patient’s diagnosis, gave the behavioral results according to the recorded videos. One-, 3-, and 6-month follow-up evaluations were conducted to obtain a good prognostic value.ResultsAll MCS patients showed behavioral responses to the 1-Octen-3-ol stimulus; nine MCS and one UWS showed olfactory emotional responses to the pyridine, and two MCS showed olfactory emotional responses to the water stimulus. The incidence of behavioral response was significantly higher using 1-Octen-3-ol than it was for water by McNemar test (p < 0.001), significantly higher using pyridine than it was for water (p < 0.01). The χ2 test results indicated that there were significant differences between MCS and UWS to 1-Octen-3-ol (p < 0.001). For MCS patients, the incidence of behavioral response was no different between using 1-Octen-3-ol and pyridine (p > 0.05). There was no significant relationship between the olfactory behavioral response and the improvement of consciousness based on the χ2 test analysis (p > 0.05).ConclusionOlfactory stimuli, especially for the familiar neutral odor, might be effective for eliciting a conscious behavioral response and estimating the clinical diagnosis of DOC patients.Clinical Trial Registration[https://clinicaltrials.gov/ct2/show/NCT03732092], [identifier NCT03732092].

Interferon-induced protein 44-like (IFI44L), a type I interferon-stimulated gene (ISG), has been reported to be involved in innate immune processes and to act as a tumor suppressor in several cancers. However, its immune implication on lung cancer remains unclear. Here, we systemically analyzed the immune association of IFI44L with multiple tumor-infiltrating immune cells (TIICs) and immunomodulators through bioinformatics methods in The Cancer Genome Atlas (TCGA) lung cancer cohorts. Then, the IFI44L-related immunomodulators were selected to construct the prognostic signatures in the lung adenocarcinoma (LUAD) cohort and the lung squamous cell carcinoma (LUSC) cohort, respectively. Concordance index and time-dependent receiver operating characteristics (ROC) curves were applied to evaluate the prognostic signatures. GSE72094 and GSE50081 were used to validate the TCGA-LUAD signature and TCGA-LUSC signature, respectively. A nomogram was established by risk score and clinical features in the LUAD cohort. Finally, the prognostic value and biological function of IFI44L were verified in a real-world cohort and in vitro experiments. The results indicated that IFI44L showed significant correlation with TIICs in LUAD and LUSC samples. Functional enrichment analysis showed that IFI44L may participate in various cancer/immune-related pathways, including JAK/STAT signaling pathway and NF-κB signaling pathway. A total of 44 immunomodulators presented obvious association with IFI44L in the TCGA-LUAD cohort and a robust 10-immunomodulator signature was constructed. Patients in the higher-risk group presented worse prognosis than those in the lower-risk group. Notably, the risk signature was successfully validated in GSE72094. Multivariate Cox regression suggested that the risk signature could act as independent prognostic factors in both TCGA-LUAD and GSE72094 cohorts. Besides, a 17-immunomodulator signature was established in the TCGA-LUSC cohort and similar results were presented through analysis. The nomogram exhibited good accuracy in predicting overall survival (OS) outcome among TCGA-LUAD patients than the risk signature and other clinical features, with the area under curve values being 0.782 at 1 year, 0.825 at 3 years, and 0.792 at 5 years. Finally, tissue microarray analysis indicated that higher expression of IFI44L presented opposite relationship with pathological stage (p = 0.016) and a better outcome among lung cancer patients (p = 0.024). Functional experiments found that IFI44L overexpression significantly inhibited the proliferation, migration, and invasion in LUAD and LUSC cells; RT-qPCR experiments verified the correlation between the expression level of IFI44L with multiple immunomodulators in SPC-A-1 and NCI-H520 cells. In conclusion, our research highlighted that IFI44L is associated with tumor immune infiltration and provided information on IFI44L’s immune implication, which indicates that IFI44L has potential clinical immunotherapeutic value and the proposed nomogram is a promising biomarker for non-small cell lung cancer patients.

Background: Both membranous nephropathy (MN) and lupus nephritis (LN) are autoimmune kidney disease. In recent years, with the deepening of research, some similarities have been found in the pathogenesis of these two diseases. However, the mechanism of their interrelationship is not clear. The purpose of this study was to investigate the differences in molecular mechanisms and key biomarkers between MN and LN.Method: The expression profiles of GSE99325, GSE99339, GSE104948 and GSE104954 were downloaded from GEO database, and the differentially expressed genes (DEGs) of MN and LN samples were obtained. We used Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis of DEGs. A protein-protein interaction (PPI) network of DEGs was constructed using Metascape. We filtered DEGs with NetworkAnalyst. Finally, we used receiver operating characteristic (ROC) analysis to identify the most significant DEGs for MN and LN.Result: Compared with LN in the glomerulus, 14 DEGs were up-regulated and 77 DEGs were down-regulated in MN. Compared with LN in renal tubules, 21 DEGs were down-regulated, but no up-regulated genes were found in MN. According to the result of GO and KEGG enrichment, PPI network and Networkanalyst, we screened out six genes (IFI6, MX1, XAF1, HERC6, IFI44L, IFI44). Interestingly, among PLA2R, THSD7A and NELL1, which are the target antigens of podocyte in MN, the expression level of NELL1 in MN glomerulus is significantly higher than that of LN, while there is no significant difference in the expression level of PLA2R and THSD7A.Conclusion: Our study provides new insights into the pathogenesis of MN and LN by analyzing the differences in gene expression levels between MN and LN kidney samples, and is expected to be used to prepare an animal model of MN that is more similar to human.

The technique of induced pluripotent stem cells has significant application value in breeding and preserving the genetic integrity of fish species. However, it is still unclear whether the chemically induced pluripotent stem cells can be induced from non-mammalian cells or not. In this article, we first verify that fibroblasts of fish can be chemically reprogrammed into pluripotent stem cells. These induced pluripotent stem-like cells possess features of colony morphology, expression of pluripotent marker genes, formation of embryoid bodies, teratoma formation, and the potential to differentiate into germ cell-like cells in vitro. Our findings will offer a new way to generate induced pluripotent stem cells in teleost fish and a unique opportunity to breed commercial fish and even save endangered fish species.

In our previous research, SP600125 (Anthrapyrazolone) was used to induce autotetraploid of crucian carp cells (SP4N cells), and tetraploid fry was generated from the SP4N cells by somatic cell nuclear transfer technique. However, it is still unclear about biological characteristics of the SP4N cells. In this article, the cytological characteristic and gene expression profiles of the SP4N cells are investigated in comparison with the crucian carp cells (2N cells) and the tetraploid crucian carp cells (CC4N cells). The SP4N cells have tetraploid characteristics in terms of morphology and DNA ploidy levels, and their chromosome behavior is stable during the cell proliferation. The migration ability and the mtDNA copy number of SP4N cells are both lower than those in the CC4N cells and the 2N cells, but there exist giant mitochondria in the SP4N cells. The similar expression trends in the cell cycle regulation genes of the SP4N cells and 2N cells, while the corresponding expression profiles are clearly different between the SP4N cells and the CC4N cells. Moreover, the significant difference genes are associated with energy metabolism pathways among the SP4N cells, 2N cells and CC4N cells. These results can provide deeper understanding of SP600125 induction, as well as finding applications in polyploidization breeding of fish species.

Introduction: With the development of photothermal technology, the appearance of composite photothermal hydrogels has increased the selectivity of treating infectious skin defects. However, how to design composite photothermal hydrogel with better antibacterial performance, reduce the resistance rate of bacteria, and the damage rate of normal tissue still needs further study.Methods: The Prussian blue and tannic acid were loaded on polyacrylamide hydrogels. Characterization of DLS, Zeta potential, UV absorption spectrum, hydrogel swelling rate, scanning electronic microscopic, drug release profile, photothermal properties, in vitro cytocompatibility, and antibacterial properties. Experiments were measured by skin defect repair, antibacterial detection, and histological staining experiments.Results: The polyacrylamide hydrogel with photothermal effect and controllable release of tannic acid was successfully prepared. The hydrogel has strong light transmittance and adhesion, and the swelling rate can reach 600%, which improves the self-cleaning ability. SEM results showed the porous structure of hydrogels, promoting cell growth. Through photothermal switches, the composite hydrogel represented adjustable and controllable drug release ability. Combined with the synergistic antibacterial effect of tannic acid, this further enhanced the antibacterial ability and reduced the probability of antibiotic resistance. The in vitro and in vivo experiments showed the hydrogel had good biocompatibility and excellent antibacterial properties, which could promote the repair of infectious skin defects in SD rats.Conclusion: We fabricated a hydrogel with a triggering drug release rate, alleviating heat damage, transparent morphology, mechanical stability, strong adhesion, good biocompatibility, and synergistic antibacterial ability, which presents new treatment options for infectious skin defect repair.

Chronic inflammation is a prerequisite for the development of cancers. Here, we present the framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev) based on the current understanding of inflammation-related carcinogenesis, especially hepatocarcinogenesis induced by chronic infection with hepatitis B virus. The interaction between genetic predispositions and environmental exposures, such as viral infection, maintains chronic non-resolving inflammation. Pollution, metabolic syndrome, physical inactivity, ageing, and adverse psychosocial exposure also increase the risk of cancer via inducing chronic low-grade smoldering inflammation. Under the microenvironment of non-resolving inflammation, pro-inflammatory factors facilitate the generation of somatic mutations and viral mutations by inducing the imbalance between the mutagenic forces such as cytidine deaminases and mutation-correcting forces including uracil–DNA glycosylase. Most cells with somatic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of mutated cells survive, adapt to the hostile environment, retro-differentiate, and function as cancer-initiating cells via altering signaling pathways. These cancer-initiating cells acquire stem-ness, reprogram metabolic patterns, and affect the microenvironment. The carcinogenic process follows the law of “mutation-selection-adaptation”. Chronic physical activity reduces the levels of inflammation via upregulating the activity and numbers of NK cells and lymphocytes and lengthening leukocyte telomere; downregulating proinflammatory cytokines including interleukin-6 and senescent lymphocytes especially in aged population. Anti-inflammation medication reduces the occurrence and recurrence of cancers. Targeting cancer stemness signaling pathways might lead to cancer eradication. Cancer Evo-Dev not only helps understand the mechanisms by which inflammation promotes the development of cancers, but also lays the foundation for effective prophylaxis and targeted therapy of various cancers.

Objective: To explore the clinical effect of Mahuang Fuzi and Shenzhuo Decoction on idiopathic membranous nephropathy.Methods: This study is a multicenter, nonrandomized, single-arm clinical trial carried out as per the objective performance criteria, with the target being set at 35.0%. 184 cases of patients suffering from idiopathic membranous nephropathy with Shaoyin Taiyin syndrome were collected. These patients were treated with Mahuang Fuzi and Shenzhuo Decoction with a follow-up period of 3 years. The 24-hour urine protein and blood albumin were observed, and the remission rates of the patients were compared with the target.Results: The mean follow-up time was 18 (12.5, 30) months, and the remission rate was 61.4%, which is a statistically significant difference from the target group of 35%. The remission rates for patients who had and had not used immunosuppressive therapy were 59.6 and 65.5%, respectively, but the difference was not statistically significant (p = 0.254). However, the albumin before the treatment and the course of treatment of the patients was significantly correlated with the disease remission (p < 0.05). However, the albumin before the treatment and the course of treatment of the patients was significantly correlated with the disease remission (p < 0.05). There were no significant changes in renal function before and after treatment, and no severe adverse events occurred during treatment.Conclusion: Mahuang Fuzi and Shenzhuo Decoction have significant effects on idiopathic membranous nephropathy, and has the same effect on patients with membranous nephropathy who are newly treated as well as those who have been treated with immunosuppressive therapy without remission. In addition, the efficacy of this regimen is related to the albumin and the duration of the therapy, but not to 24-hour urine protein or other factors.

BackgroundCancer becomes the leading cause of premature death in China. Primary objective of this study was to determine the major risk factors especially glucose intolerance for cancer prophylaxis.MethodsA cluster sampling method was applied to enroll 10,657 community-based adults aged 15-92 years in Shanghai, China in 2013. A structured questionnaire and physical examination were applied in baseline survey. Prediabetes was diagnosed using 75-g oral glucose tolerance test. After excluding 1433 subjects including 224 diagnosed with cancer before and 1 year after baseline survey, the remaining 9,224 subjects were followed-up to December 31, 2020.ResultsA total of 502 new cancer cases were diagnosed. The cancer incidence was 10.29, 9.20, and 5.95/1,000 person-years in diabetes patients, those with prediabetes, and healthy participants, respectively (p

Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the immune system produces an antibody response to its own antigens due to impaired immune tolerance. Although antibodies are derived from plasma cells differentiated by B cells, the T-B cells also contribute a lot to the immune system. In particular, the subsets of helper T (Th) cells, including the dominant subsets such as Th2, Th17, and follicular helper T (Tfh) cells and the inferior subsets such as regulatory T (Treg) cells, shape the immune imbalance of IMN and promote the incidence and development of autoimmune responses. After reviewing the physiological knowledge of various subpopulations of Th cells and combining the existing studies on Th cells in IMN, the role model of Th cells in IMN was explained in this review. Finally, the existing clinical treatment regimens for IMN were reviewed, and the importance of the therapy for Th cells was highlighted.

High performance thermosetting resins are targeted in many exigent applications, such as aerospace and marine fields, for the development of lightweight structural composites. Till now, these industries only rely on petroleum-based materials for their supposedly better performances. However, the latest developments in the field suggest otherwise. In fact, many reports confirmed that sustainable and ecofriendly thermosetting polymers can display similar or even better performances. Additionally, exploring alternative renewable feedstock’s to meet the ever increasing demands of these industries is an essential step towards sustainable development. Aiming to unravel the potential of these materials, the present review summarizes the most relevant chemical routes allowing the preparation of fully or partially bio-based thermosetting resins. Meanwhile, the overall performances of these exceptional materials are also compared with their petroleum-based counterparts.

Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation, subchondral bone remodeling and osteophyte formation. Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) has not been fully investigated in the pathogenesis of OA. In this study, we found that SHP2 expression was significantly increased after interleukin-1β (IL-1β) treatment in primary mouse chondrocytes. Inhibition of SHP2 using siRNA reduced MMP3, MMP13 levels, but increased AGGRECAN, COL2A1, SOX9 expression in vitro. On the contrary, overexpression of SHP2 exerted the opposite results and promoted cartilage degradation. Mechanistically, SHP2 activated Wnt/β-catenin signaling possibly through directly binding to β-catenin. SHP2 also induced inflammation through activating Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Our in vivo studies showed that SHP2 knockdown effectively delayed cartilage destruction and reduced osteophyte formation in the mouse model of OA induced by destabilization of the medial meniscus (DMM). Altogether, our study identifies that SHP2 is a novel and potential therapeutic target of OA.

Polycarbonate (PCL) has been widely used in tissue engineering, but its hydrophobicity and low biological activity limit its further promotion and application. By adding nanoparticles, the hydrophilicity and biological activity of PCL can be improved. In this study, different amounts of Ta (1–10%wt) were added to PCL, and then their mechanical and biological properties were studied in vitro. XRD found that 5%Ta-PCL has the highest crystallinity. At the same time, cell experiments CCK8, cell adhesion, osteogenic differentiation, and osteogenesis related gene expression showed that Ta can enhance the mechanical and biological properties of PCL, while 5% Ta-PCL showed the best mechanical and biological properties. This composite of tantalum and PCL could have a clinical potential for orthopedic implants.