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Abstract Background We evaluated the influence of different partial carbon dioxide pressure (PaCO2) levels on organ perfusion in patients with respiratory failure receiving pressure-support ventilation with veno-venous extracorporeal membrane oxygenation (V-V ECMO). Methods In this twelve patients prospective study, ECMO gas-flow was decreased from baseline (PaCO2

Abstract The commercialization of perovskite solar cells is badly limited by stability, an issue determined mainly by perovskite. Herein, inspired by a natural creeper that can cover the walls through suckers, we adopt polyhexamethyleneguanidine hydrochloride as a molecular creeper on perovskite to inhibit its decomposition starting from the annealing process. The molecule possesses a long-line molecular structure where the guanidinium groups can serve as suckers that strongly anchor cations through multiple hydrogen bonds. These features make the molecular creeper can cover perovskite grains and inhibit perovskite decomposition by suppressing cations’ escape. The resulting planar perovskite solar cells achieve an efficiency of 25.42% (certificated 25.36%). Moreover, the perovskite film and device exhibit enhanced stability even under harsh damp-heat conditions. The devices can maintain >96% of their initial efficiency after 1300 hours of operation under 1-sun illumination and 1000 hours of storage under 85% RH, respectively.

Abstract Background Mitochondrial dysfunction is one of the distinctive features of neurons in patients with Alzheimer’s disease (AD). Intraneuronal autophagosomes selectively phagocytose and degrade the damaged mitochondria, mitigating neuronal damage in AD. Panax notoginseng saponins (PNS) can effectively reduce oxidative stress and mitochondrial damage in the brain of animals with AD, but their exact mechanism of action is unknown. Methods Senescence-accelerated mouse prone 8 (SAMP8) mice with age-related AD were treated with PNS for 8 weeks. The effects of PNS on learning and memory abilities, cerebral oxidative stress status, and hippocampus ultrastructure of mice were observed. Moreover, changes of the PTEN-induced putative kinase 1 (PINK1)-Parkin, which regulates ubiquitin-dependent mitophagy, and the recruit of downstream autophagy receptors were investigated. Results PNS attenuated cognitive dysfunction in SAMP8 mice in the Morris water maze test. PNS also enhanced glutathione peroxidase and superoxide dismutase activities, and increased glutathione levels by 25.92% and 45.55% while inhibiting 8-hydroxydeoxyguanosine by 27.74% and the malondialdehyde production by 34.02% in the brains of SAMP8 mice. Our observation revealed the promotion of mitophagy, which was accompanied by an increase in microtubule-associated protein 1 light chain 3 (LC3) mRNA and 70.00% increase of LC3-II/I protein ratio in the brain tissues of PNS-treated mice. PNS treatment increased Parkin mRNA and protein expression by 62.80% and 43.80%, while increasing the mRNA transcription and protein expression of mitophagic receptors such as optineurin, and nuclear dot protein 52. Conclusion PNS enhanced the PINK1/Parkin pathway and facilitated mitophagy in the hippocampus, thereby preventing cerebral oxidative stress in SAMP8 mice. This may be a mechanism contributing to the cognition-improvement effect of PNS.

BackgroundPulmonary fibrosis (PF) emerges as a significant pulmonary sequelae in the convalescent phase of coronavirus disease 2019 (COVID-19), with current strategies neither specifically preventive nor therapeutic. Licoricesaponin G2 (LG2) displays a spectrum of natural activities, including antibacterial, anti-inflammatory, and antioxidant properties, and has been effectively used in treating various respiratory conditions. However, the potential protective effects of LG2 against PF remain underexplored.MethodsNetwork analysis and molecular docking were conducted in combination to identify the core targets and pathways through which LG2 acts against PF. In the model of bleomycin (BLM)-induced C57 mice and transforming growth factor-β1 (TGF-β1)-induced A549 and MRC5 cells, techniques such as western blot (WB), quantitative Real-Time PCR (qPCR), Immunohistochemistry (IHC), Immunofluorescence (IF), and Transwell migration assays were utilized to analyze the expression of Epithelial-mesenchymal transition (EMT) and inflammation proteins. Based on the analysis above, we identified targets and potential mechanisms underlying LG2’s effects against PF.ResultsNetwork analysis has suggested that the mechanism by which LG2 combats PF may involve the TNF-α pathway. Molecular docking studies have demonstrated a high binding affinity of LG2 to TNF-α and MMP9. Observations from the study indicated that LG2 may mitigate PF by modulating EMT and extracellular matrix (ECM) remodeling. It is proposed that the therapeutic effect is likely arises from the inhibition of inflammatory expression through regulation of the TNF-α pathway.ConclusionLG2 mitigates PF by suppressing TNF-α signaling pathway activation, modulating EMT, and remodeling the ECM. These results provide compelling evidence supporting the use of LG2 as a potential natural therapeutic agent for PF in clinical trials.

Anti-glomerular basement membrane (GBM) nephritis is a rare autoimmune disorder characterized by acute and rapidly progressive glomerulonephritis. In this report, we present the case of a 52-year-old woman with anti-GBM nephritis who was treated with Staphylococcus Protein A immunoadsorption in combination with glucocorticoids and cyclophosphamide. After 8 cycles of immunoadsorption, the patient's anti-GBM antibodies decreased from 363 AU/mL to less than 20 AU/mL, accompanied by a dropped immunoglobin G level, although renal impairment persisted. We reviewed the therapeutic options for anti-GBM nephritis and compared plasma exchange, double filtration plasmapheresis, and immunoadsorption with regard to plasma consumption, allergic events, and plasma components loss. Protein A immunoadsorption appears to be a promising treatment modality for anti-GBM nephritis.

Introduction Fluid resuscitation of patients with sepsis is crucial. This study explored the role of fluid balance in the early resuscitation of sepsis patients in the intensive care unit (ICU). Material and methods A retrospective study of patients with sepsis using the Peking Union Medical College Hospital Intensive Care Medical Information System and Database from January 2014 to June 2020 was performed. Based on the survival status on day 28, the training cohort was divided into an alive group (n = 1,803) and a deceased group (n = 429). Univariate and multivariate analyses were used to identify risk factors, and the integrated learning XGBoost algorithm was used to construct a model for predicting outcomes. ROC and Kaplan-Meier survival curves were used to evaluate the effectiveness of the model. A verification cohort (n = 433) was used to verify the model. Results Univariate analysis showed that fluid balance is an important covariate. Based on the scatterplot distribution, a significant difference in mortality was determined between groups stratified with a balance of 1000 ml. There were associations in the multivariate analysis between poor outcomes and sex, PO2/FiO2, serum creatinine, FiO2, platelets, respiratory rate, SPO2, temperature, and total fluid volume (1000 ml). Among these variables, total fluid balance (1000 ml) had an OR of 1.98 (CI: 1.41–2.77, p < 0.001). Therefore, the model was built with these nine factors using XGBoost. Cross validation was used to verify generalizability. This model performed better than the SOFA and APACHE II models. The result was well verified in the verification cohort. A causal forest model suggested that patients with hypoxemia may suffer from positive fluid balance. Conclusions Sepsis fluid resuscitation in the ICU should be a targeted and goal-oriented treatment. A new prognostic prediction model was constructed and indicated that a 6-hour positive fluid balance after ICU initial admission is a risk factor for poor outcomes in sepsis patients. A 6-hour fluid balance above 1000 ml should be performed with caution.

Abstract Background Previous studies on physical activity (PA) and pelvic organ prolapse (POP) were largely limited to self-reported PA in athletes, soldiers, and women in postpartum. We aimed to investigate the association of accelerometer-measured PA and sedentary behavior with the risk of POP in middle-aged and elderly women. Methods In this prospective cohort derived from the UK Biobank, the intensity and duration of PA and sedentary behavior were measured with wrist-worn accelerometers over a 7-day period in 2013–2015 for 47,674 participants (aged 42.8–77.9 years) without pre-existing POP. Participants were followed up until the end of 2022, during which incident POP was ascertained mainly by the electronic health records. Multivariable-adjusted Cox proportional hazards models and restricted cubic splines were used to assess the associations of interest. Isotemporal substitution models were applied to test the effects of substituting a type of activity with equivalent duration of others. Results During a median follow-up of 8.0 years, 779 cases of POP were recorded. The duration of light-intensity PA (LPA) was positively whereas sedentary time was negatively associated with the risk of POP. Every additional 1 h/day of LPA elevated the risk of POP by 18% (95% confidence interval [CI], 10%–26%). In contrast, the risk decreased by 5% (95% CI, 0–8%) per 1 h/day increment in sedentary behavior. No associations were found between moderate-intensity PA (MPA) or vigorous-intensity PA (VPA) and POP, except that women who had a history of hysterectomy were more likely to develop POP when performing more VPA (53% higher risk for every additional 15 min/day). Substituting 1 h/day of LPA with equivalent sedentary time was associated with a 18% (95% CI, 11%–24%) lower risk of POP. The risk can also be reduced by 17% (95% CI, 7%–25%) through substituting 30 min/day of LPA with MPA. Conclusions More time spent in LPA or less sedentary time was linked to an elevated risk of POP in middle-aged and elderly women, while MPA or VPA was not. Substituting LPA with equivalent duration of sedentary behavior or MPA may lower the risk of POP.

Abstract Several studies have demonstrated that exosomes (Exos) are involved in the regulation of macrophage polarization and osteoclast differentiation. However, the characteristics as well as roles of exosomes from human periodontal ligament cells (hPDLCs-Exos) in M1/M2 macrophage polarization and osteoclast differentiation remain unclear. Here, periodontal ligament cells were successfully extracted by method of improved Type-I collagen enzyme digestion. hPDLCs-Exos were extracted by ultracentrifugation. hPDLCs-Exos were identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). Osteoclast differentiation was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR), WB and tartrate-resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization were evaluated by RT-qPCR and WB. The results showed hPDLCs-Exos promoted osteoclast differentiation and M2 macrophage polarization, but inhibited M1 macrophage polarization. Moreover, M1 macrophages inhibited osteoclast differentiation, whereas M2 macrophages promoted osteoclast differentiation. It has shown that hPDLCs-Exos promoted osteoclast differentiation by inhibiting M1 and promoting M2 macrophage polarization.

Background Anti-glomerular basement membrane (anti-GBM) disease presents with rapidly progressive glomerulonephritis and alveolar hemorrhage, requiring urgent management. In this study, we analyzed the relationship between plasmapheresis strategy, immunosuppressive therapy and the prognosis of anti-GBM disease patients.Method We screened newly diagnosed anti-GBM disease patients at West China Hospital of Sichuan University from 2010 to 2021. The primary outcome was a composite endpoint of in-hospital death or dialysis dependency upon discharge.Results This study enrolled 107 anti-GBM disease patients. The use of plasmapheresis was independently associated with a reduced risk of primary outcome (OR: 0.179, 95% Cl: 0.051–0.630, p = 0.007), better 2-year (HR: 0.146; 95% CI: 0.038–0.553; p = 0.005) and 8-year patient survival (HR: 0.309; 95% CI: 0.112–0.850; p = 0.023). Restricted cubic spline regression suggested that patients with 5–10 sessions of plasmapheresis had already achieved maximum risk reduction in the primary outcome. Patients who started plasmapheresis at lower serum creatinine (42.9% vs. 96.2%, p

The Cong-Chi decoction (CCD) is composed of Allium ascalonicum L. bulbs and Sojae Semen Praeparatum. Food-based therapy exhibits minimal side effects when compared to the conventional use of antipyretic and analgesic drugs for treating common cold (wind-cold type). However, the current state of research is deficient in exploring the components of CCD, and there is a lack of assessment regarding the fever-reducing and anti-inflammatory mechanisms associated with CCD. This study synergizes Ultra-Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS) with bioinformatics, validating the anti-inflammatory components of CCD and predicting its anti-inflammatory mechanisms. Our results reveal that UPLC-MS/MS identified 33 components in CCD. Notably, components such as genistein, glycitein, daidzein, scopoletin, and 7-hydroxycoumarin demonstrated a high binding affinity with the core protein Tumor Necrosis Factor-alpha (TNF-α). They inhibited the expression of TNF-α and Interleukin-6 (IL-6) in a Lipopolysaccharide (LPS)-induced inflammation model. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicates that anti-inflammatory mechanisms of CCD involve pathways related to cell apoptosis, arginine and proline metabolism, and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling.

Context Forsythoside A (FSA) was extracted from Forsythia suspensa, a traditional Chinese medicine, which has been demonstrated to exert anti-inflammatory, antibacterial, and other pharmacological effects. However, the anticancer effect of FSA in esophageal squamous cell carcinoma (ESCC) has not been documented.Objective The present study aimed to elucidate the mechanism of FSA against ESCC.Materials and methods Network pharmacology and molecular docking were employed to predict the mechanism. FSA was utilized to treat ESCC cell lines KYSE450 and KYSE30, followed by CCK-8 assay, cell cloning formation assay, flow cytometry, Western blot, RNA-seq analysis, and subsequent in vivo experiments.Results Network pharmacology and molecular docking predicted that the therapeutic effect of FSA in ESCC is mediated through proteins such as BCL2 and BAX, influencing KEGG pathways associated with apoptosis. In vitro experiments showed that FSA inhibited cell proliferation and plate clone formation, promoted cell apoptosis and impacted the cell cycle distribution of G2/M phase by regulating BCL2, BAX, and p21. Further RNA-seq in KYSE450 cells showed that FSA regulated the expression of 223 genes, specifically affecting the biological process of epidermal development. In vivo experiments showed that gastric administration of FSA resulted in notable reductions in both tumor volume and weight by regulating BCL2, BAX, and p21. 16S rRNA sequencing showed that FSA led to significant changes of beta diversity. Abundance of 11 specific bacterial taxa were considerably changed following administration of FSA.Conclusions This study presents a novel candidate drug against ESCC and establishes a foundation for future clinical application.

Background Erectile dysfunction (ED) is a common issue among males, and the use of platelet-rich plasma (PRP) therapy for treating ED has gained increasing attention, but there is still no conclusive evidence regarding its efficacy.Aim To evaluate the efficacy of PRP therapy for ED.Methods We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases up to November 2023 to identify randomized controlled trials (RCTs) on PRP therapy for ED. We used Review Manager version 5.4 for data analysis and management.Result After applying inclusion and exclusion criteria for screening, a total of 4 studies involving 413 patients were finally included in our meta-analysis. According to our analysis, the PRP group showed significant advantages over the placebo group in terms of MCID at the first month (p = 0.03) and sixth months (p = 0.008), while there was no significant difference between the two groups at the third month (p = 0.19). Additionally, in terms of IIEF, PRP showed significantly better efficacy than placebo at the first, third, and sixth months (p

ABSTRACTThe “reemergence of pertussis” has elicited international concerns, occurring paradoxically amidst the expansion of immunization programs. This study was aimed to evaluate quantitatively the economic burden and identify the determinants that influence the cost associated with treating pertussis in Chinese children. We evaluated the economic burden by Chinese children diagnosed with pertussis at the Children’s Hospital, Zhejiang University School of Medicine in 2022. Direct medical expenses and the utilization of medical resources attributed to pertussis were calculated. A generalized linear regression model was applied to analyze the determinants that were associated with the direct medical expenses among patients. Among the 1110 pertussis patients included in the study, 1060 were outpatients and 50 were inpatients. The average direct medical cost was ¥1878.70(i.e. $279.33). Living in urban areas (OR:1.27, p = .04), complications (OR:1.40, p

Background Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a prognostic marker for various diseases, but whether NLR dynamics (ΔNLR) is related to mortality and disease severity in patients with septic acute kidney injury (AKI) has not been determined.Methods Between August 2013 and August 2021, septic AKI patients at our center were retrospectively enrolled. ΔNLR was defined as the difference between the NLR at septic AKI diagnosis and at hospital admission. The relationship between the ΔNLR and mortality was evaluated by Kaplan–Meier curves, Cox proportional hazards, and cubic spline analyses. The prediction values were compared by area under the receiver-operating characteristic curve (AUROC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses.Results Of the 413 participants, the mean age was 63 ± 17 years, and 134 were female (32.4%). According to the median value, patients in the high-ΔNLR group had significantly greater 90-d mortality (74.4% vs. 46.6%, p

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease with a prevalence of 150–250 cases per million individuals. Autoantibodies include long-lived antibodies against the acetylcholine receptor (AChR), mainly of the IgG1 subclass, and IgG4, produced almost exclusively by short-lived plasmablasts, which are prevalent in muscle-specific tyrosine kinase (MuSK) myasthenia gravis. Numerous investigations have demonstrated that MG patients receiving conventional medication today still do not possess satisfactory symptom control, indicating a substantial disease burden. Subsequently, based on the type of the autoantibody and the pathogenesis, we synthesized the published material to date and reached a conclusion regarding the literature related to personalized targeted therapy for MG. Novel agents for AChR MG have shown their efficacy in clinical research, such as complement inhibitors, FcRn receptor antagonists, and B-cell activating factor (BAFF) inhibitors. Rituximab, a representative drug of anti-CD20 therapy, has demonstrated benefits in treatment of MuSK MG patients. Due to the existence of low-affinity antibodies or unidentified antibodies that are inaccessible by existing methods, the treatment for seronegative MG remains complicated; thus, special testing and therapy considerations are necessary. It may be advantageous to initiate the application of novel biologicals at an early stage of the disease. Currently, therapies can also be combined and individualized according to different types of antibodies. With such a wide range of drugs, how to tailor treatment strategies to patients with various conditions and find the most suitable solution for each MG profile are our necessary and urgent aims.

Objective: To explore the value of ear morphological inspection in identifying the nine constitutions of traditional Chinese medicine (TCM) by analyzing the correlation between these two research objects. Methods: A cross-sectional research design was employed. The participants' ear morphology was determined using the Ear Morphology Inspection Information Evaluation Form, while constitution was assessed using the Constitution in Chinese Medicine Questionnaire. Data were statistically analyzed, and one-way and multi-factor logistic regression analyses were conducted. Results: Among 888 participants, 270 (30.41%) had a balanced constitution, and 618 (69.59%) had different biased constitution types. The analysis revealed that thick auricles (P

In this study, proteins were prepared from Schizochytrium pombe residue after oil extraction using isoelectric point precipitation, and their physicochemical and emulsifying properties were investigated. Our objective was to assess the suitability of these proteins for functional ingredient applications. Through a one-way experiment and optimization using response surface design, the effects of time, temperature, pH, and the material–liquid ratio of NaOH alkaline extraction were explored. The isoelectric point is verified by isoelectric point precipitation; the results revealed that crude protein from Schizochytrium (SCP) is minimally soluble at pH 4.2. Compared with whey protein (WP), it promotes better emulsion stability through the emulsification test. This study suggests that Schizochytrium oil-processing byproducts represent a promising source of protein, with potential applications as functional ingredients, offering implications for the usage of these byproducts in various industries.

BackgroundLive attenuated vaccines may be used to prevent nontargeted diseases such as lower respiratory tract infections (LRTIs) due to their nonspecific effects (NSEs). ObjectiveWe aimed to analyze the NSEs of the Japanese encephalitis vaccine on pediatric LRTIs in children aged 25 months to 35 months. MethodsA retrospective cohort study was conducted by using a population-based electronic health record database in Zhejiang, China. Enrolled participants were children born from January 1, 2017, to December 31, 2017, and who were inoculated with the live-attenuated Japanese encephalitis vaccine (JE-L) or inactivated Japanese encephalitis vaccine (JE-I) as the most recent vaccine at 24 months of age. The study was carried out between January 1, 2019, and December 31, 2019. All inpatient and outpatient hospital visits for LRTIs among children aged 25 months to 35 months were recorded. The Andersen-Gill model was used to assess the NSEs of JE-L against LRTIs in children and compared with those of JE-I as the most recent vaccine. ResultsA total of 810 children born in 2017 were enrolled, of whom 585 received JE-L (JE-L cohort) and 225 received JE-I (JE-I cohort) as their last vaccine. The JE-L cohort showed a reduced risk of LRTIs (adjusted hazard ratio [aHR] 0.537, 95% CI 0.416-0.693), including pneumonia (aHR 0.501, 95% CI 0.393-0.638) and acute bronchitis (aHR 0.525, 95% CI 0.396-0.698) at 25 months to 35 months of age. The NSEs provided by JE-L were especially pronounced in female children (aHR 0.305, 95% CI 0.198-0.469) and children without chronic diseases (aHR 0.553, 95% CI 0.420-0.729), without siblings (aHR 0.361, 95% CI 0.255-0.511), with more than 30 inpatient and outpatient hospital visits prior to 24 months of age (aHR 0.163, 95% CI 0.091-0.290), or with 5 to 10 inpatient and outpatient hospital visits due to infectious diseases prior to 24 months old (aHR 0.058, 95% CI 0.017-0.202). ConclusionsCompared with JE-I, receiving JE-L as the most recent vaccine was associated with lower risk of inpatient and outpatient hospital visits for LRTIs among children aged 25 months to 35 months. The nature of NSEs induced by JE-L should be considered for policymakers and physicians when recommending JE vaccines to those at high risk of infection from the Japanese encephalitis virus.

Background Insulin resistance as a significant vascular risk factor has been studied in relation to cerebral small vessel disease (SVD). Evidence suggests that insulin resistance might trigger high blood pressure (BP). Therefore, we aimed to investigate whether insulin resistance impacts SVD with a mediating effect of BP in nondiabetic subjects. Methods and Results PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study participants underwent brain and vascular imaging techniques and metabolomic risk factors measurements. Insulin resistance was evaluated by the insulin sensitivity index and the Homeostatic Model Assessment for Insulin Resistance based on the standard oral glucose tolerance test. On average, 2752 nondiabetic subjects (47.1% men) aged 60.9 years were included. The multivariable logistic regression model and linear regression model tested the association of insulin resistance with BP components (including systolic BP [SBP], diastolic BP (DBP), and pulse pressure [PP]) and SVD, and of BP components with SVD. In the mediation analysis, SBP, DBP, and PP were found to partially mediate the detrimental effect of insulin resistance (assessed by the insulin sensitivity index) on lacunes (mediation percentage: SBP, 31.15%; DBP, 34.21%; PP, 10.43%), white matter hyperintensity (mediation percentage: SBP, 37.34%; DBP, 44.15%; PP, 9.80%), and SVD total burden (mediation percentage: SBP, 42.07%; DBP, 49.29%; PP, 11.71%) (all P

Background: Concerns have been raised about the increasing prevalence of both spontaneous and induced abortions worldwide, yet their effect on premature mortality remains poorly understood. We aimed to examine the associations between abortion and all-cause and cause-specific premature mortality, and the potential effect modification by maternal characteristics. Methods: Women aged 39 to 71 years at baseline (2006 to 2010) with prior pregnancies were derived from the UK Biobank and categorized as no abortion history, spontaneous abortion alone, induced abortion alone, and both spontaneous and induced abortions. All-cause and cause-specific mortality were ascertained through linkage to death certificate data, with premature death defined as occurring before the age of 70. Results: Of the 225,049 ever gravid women, 43,418 (19.3%) reported spontaneous abortion alone, 27,135 (12.1%) reported induced abortion alone, and 10,448 (4.6%) reported both spontaneous and induced abortions. During a median of 14.4 years of follow-up, 5,353 deaths were recorded, including 3,314 cancer-related and 1,444 cardiovascular deaths. Compared with no abortion history, spontaneous abortion alone was associated with an increased risk of all-cause premature mortality (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 1.02 to 1.17), and induced abortion alone was associated with increased risks of all-cause (aHR 1.12, 95% CI 1.04 to 1.22) and cardiovascular mortality (aHR 1.27, 95% CI 1.09 to 1.48). The aHRs for all-cause and cardiovascular mortality were higher for recurrent abortions, whether spontaneous or induced (Ptrend < 0.05). The increased risk of all-cause mortality associated with induced abortion was higher in women with hypertensive disorders of pregnancy than in those without (40% vs. 9%, Pinteraction = 0.045). Conclusions: Either spontaneous or induced abortion alone was associated with an increased risk of premature mortality, with induced abortion alone particularly linked to cardiovascular death. Future studies are encouraged to explore the underlying mechanisms.

Background. In order to prevent the recurrence and progression of intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), various bladder instillation therapies have been developed in recent years. Among these, device-assisted Hyperthermic Intravesical Chemotherapy (HIVEC) has received a great deal of attention. Objective. To identify the efficacy and safety of HIVEC, we conducted this meta-analysis. Methods. We identified relevant articles from PubMed, Embase, and Cochrane Library databases. All published randomized controlled trials (RCTs) describing the role of bladder instillation for the treatment of intermediate- and high-risk NMIBC were involved. Outcomes included 1–3 years Recurrence-Free Survival (RFS), 1–3 years Progression-Free Survival (PFS), 5 years Overall Survival (OS), Adverse Events (AEs), and relevant subgroup analyses. Result. Our study involved a total of 10 RCTs and 1360 patients. In subgroup analysis, we found that compared to MMC instillation, HIVEC decreased the 1–3 years RFS (OR = 0.51; p=0.009) while not increasing the incidence of AEs (OR = 0.86; p=0.30). Compared with BCG instillation, HIVEC reduced the incidence of serious AEs (OR = 0.21; p=0.04) while bringing the same efficacy (OR = 0.78; p=0.63). Conclusion. HIVEC combined the advantages of efficacy and safety compared with the two recommended instillation modalities. As a potential alternative therapy, its widespread clinical effect remains to be further evaluated.

ObjectivesWe conducted a comprehensive meta-analysis to compare the effectiveness and safety of fluoroscopy-guided air enema reduction (FGAR) and ultrasound-guided hydrostatic enema reduction (UGHR) for the treatment of intussusception in pediatric patients.MethodsA systematic review and meta-analysis were conducted on retrospective studies obtained from various databases, including PUBMED, MEDLINE, Cochrane, Google Scholar, China National Knowledge Infrastructure (CNKI), WanFang, and VIP Database. The search included publications from January 1, 2003, to March 31, 2023, with the last search done on Jan 15, 2023.ResultsWe included 49 randomized controlled studies and retrospective cohort studies involving a total of 9,391 patients, with 4,841 in the UGHR and 4,550 in the FGAR. Specifically, UGHR exhibited a significantly shorter time to reduction (WMD = -4.183, 95% CI = (-5.402, -2.964), P < 0.001), a higher rate of successful reduction (RR = 1.128, 95% CI = (1.099, 1.157), P < 0.001), and a reduced length of hospital stay (WMD = -1.215, 95% CI = (-1.58, -0.85), P < 0.001). Furthermore, UGHR repositioning was associated with a diminished overall complication rate (RR = 0.296, 95% CI = (0.225, 0.389), P < 0.001) and a lowered incidence of perforation (RR = 0.405, 95% CI = (0.244, 0.670), P < 0.001).ConclusionUGHR offers the benefits of being non-radioactive, achieving a shorter reduction time, demonstrating a higher success rate in repositioning in particular, resulting in a reduced length of postoperative hospital stay, and yielding a lower overall incidence of postoperative complications, including a reduced risk of associated perforations.

6-BA, a small molecule compound of cytokinins, has been proven to delay leaf senescence in different species, including Chinese flowering cabbage; however, its specific mechanism remains relatively unknown. In this study, the application of external 6-BA delayed leaf senescence in Chinese flowering cabbage, showing that 6-BA effectively prevented the decrease in the maximum quantum yield (Fv/Fm) and overall chlorophyll content and suppressed the expression of the senescence-associated gene BrSAG12 over a 7-day period of storage. Moreover, treatment with 6-BA decreased the respiratory rate, NAD(H) content, the activities of hexose phosphate isomerase (PHI), succinate dehydrogenase (SDH), cytochrome c oxidase (CCO), and ascorbic acid oxidase (AAO) using enzyme-linked immunosorbent assay, and the transcriptional abundance of related genes by real-time quantitative polymerase chain reaction. Furthermore, 6-BA also increased the activity and expression levels of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphate gluconate dehydrogenase (6-PGDH). The group treated with 6-BA retained elevated levels of NADP (H), ATP, total ATPase, and nicotinamide adenine dinucleotide kinase (NADK) activity, as well as the expression of respiratory enzymes. Molecular docking indicated that 6-BA hinders the glycolysis pathway (EMP), tricarboxylic acid cycle (TCA), and cytochrome pathway (CCP), and sustains elevated levels of the pentose phosphate pathway (PPP) through interactions with the PHI, SDH, 6-PGDH, G6PDH, CCO, and AAO proteins, consequently delaying postharvest leaf senescence in Chinese flowering cabbage.

In response to the growing demand for railway obstacle monitoring, lidar technology has emerged as an up-and-coming solution. In this study, we developed a mechanical 3D lidar system and meticulously calibrated the point cloud transformation to monitor specific areas precisely. Based on this foundation, we have devised a novel set of algorithms for obstacle detection within point clouds. These algorithms encompass three key steps: (a) the segmentation of ground point clouds and extraction of track point clouds using our RS-Lo-RANSAC (region select Lo-RANSAC) algorithm; (b) the registration of the BP (background point cloud) and FP (foreground point cloud) via an improved Robust ICP algorithm; and (c) obstacle recognition based on the VFOR (voxel-based feature obstacle recognition) algorithm from the fused point clouds. This set of algorithms has demonstrated robustness and operational efficiency in our experiments on a dataset obtained from an experimental field. Notably, it enables monitoring obstacles with dimensions of 15 cm × 15 cm × 15 cm. Overall, our study showcases the immense potential of lidar technology in railway obstacle monitoring, presenting a promising solution to enhance safety in this field.

This article presents a high-precision obstacle detection algorithm using 3D mechanical LiDAR to meet railway safety requirements. To address the potential errors in the point cloud, we propose a calibration method based on projection and a novel rail extraction algorithm that effectively handles terrain variations and preserves the point cloud characteristics of the track area. We address the limitations of the traditional process involving fixed Euclidean thresholds by proposing a modulation function based on directional density variations to adjust the threshold dynamically. Finally, using PCA and local-ICP, we conduct feature analysis and classification of the clustered data to obtain the obstacle clusters. We conducted continuous experiments on the testing site, and the results showed that our system and algorithm achieved an STDR (stable detection rate) of over 95% for obstacles with a size of 15 cm × 15 cm × 15 cm in the range of ±25 m; at the same time, for obstacles of 10 cm × 10 cm × 10 cm, an STDR of over 80% was achieved within a range of ±20 m. This research provides a possible solution and approach for railway security via obstacle detection.

Abstract Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. “Human intestinal cancer organoids” is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications.

Abstract Organoids have attracted great interest for disease modelling, drug discovery and development, and tissue growth and homeostasis investigations. However, lack of standards for quality control has become a prominent obstacle to limit their translation into clinic and other applications. “Human intestinal organoids” is the first guideline on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods, inspection rules for human intestinal organoids, which is applicable to quality control during the process of manufacturing and testing of human intestinal organoids. It was originally released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of human intestinal organoids for applications.

Abstract Background Continuous renal replacement therapy (CRRT) is a widely used standard therapy for critically ill patients with acute kidney injury (AKI). Despite its effectiveness, treatment is often interrupted due to clot formation in the extracorporeal circuits. Anticoagulation is a crucial strategy for preventing extracorporeal circuit clotting during CRRT. While various anticoagulation options are available, there were still no studies synthetically comparing the efficacy and safety of these anticoagulation options. Methods Electronic databases (PubMed, Embase, Web of Science, and the Cochrane database) were searched from inception to October 31, 2022. All randomized controlled trials (RCTs) that examined the following outcomes were included: filter lifespan, all-cause mortality, length of stay, duration of CRRT, recovery of kidney function, adverse events and costs. Results Thirty-seven RCTs from 38 articles, comprising 2648 participants with 14 comparisons, were included in this network meta-analysis (NMA). Unfractionated heparin (UFH) and regional citrate anticoagulation (RCA) are the most frequently used anticoagulants. Compared to UFH, RCA was found to be more effective in prolonging filter lifespan (MD 12.0, 95% CI 3.8 to 20.2) and reducing the risk of bleeding. Regional-UFH plus Prostaglandin I2 (Regional-UFH + PGI2) appeared to outperform RCA (MD 37.0, 95% CI 12.0 to 62.0), LMWH (MD 41.3, 95% CI 15.6 to 67.0), and other evaluated anticoagulation options in prolonging filter lifespan. However, only a single included RCT with 46 participants had evaluated Regional-UFH + PGI2. No statistically significant difference was observed in terms of length of ICU stay, all-cause mortality, duration of CRRT, recovery of kidney function, and adverse events among most evaluated anticoagulation options. Conclusions Compared to UFH, RCA is the preferred anticoagulant for critically ill patients requiring CRRT. The SUCRA analysis and forest plot of Regional-UFH + PGI2 are limited, as only a single study was included. Additional high-quality studies are necessary before any recommendation of Regional-UFH + PGI2. Further larger high-quality RCTs are desirable to strengthen the evidence on the best choice of anticoagulation options to reduce all-cause mortality and adverse events and promote the recovery of kidney function. Trial registration The protocol of this network meta-analysis was registered on PROSPERO ( CRD42022360263 ). Registered 26 September 2022.

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Phenol in waste water threatens human health and is difficultly to be decomposed by nature. Efficient degradation of high-loaded phenol in water under mild condition is still a great challenge. Herein, ionic liquids with tungstate anion were designed and prepared. It was found that dodecyltrimethylammonium tungstate could catalyzed degradation of phenol into gases and water thoroughly at 323 k in 8 h. Tungstate anion revealed good catalytic oxidative activity and long carbon chain group connecting with cation of ionic liquids enriched phenol around catalysts, which induced the complete degradation of phenol at mild conditions. Increasing the amounts of hydrogen peroxide benefited to the total degradation of phenol. In addition, the ionic liquid could be reused for its excellent thermal stability. Our work provided a different strategy to treat waste water containing phenol efficiently.

This study addresses the problem of prolonged precooling time and excessive weight loss of fruits and vegetables during postharvest processes. Ice slurry precooling system shows potential but faces challenges like low undercooling and ice blockage. Dispersants are introduced to optimize heat and moisture transfer as well as the flow characteristics of the ice slurry. This research investigates the effects of four dispersants on the performance of an ice slurry-based wet precooling system through experiments. Key parameters analyzed include temperature and humidity in the chamber, cooling rate, and weight loss rate of the tested load. Results show that the addition of dispersants effectively reduces the freezing temperature, enhancing the cooling rate in the system. Among the four dispersants tested, sodium diacetate yields the lowest freezing temperature of −6.4 °C and the highest cooling rate of 0.3 °C min−1. Furthermore, dispersants influence moisture transfer between ice slurry and circulating air, impacting the humidity within the precooling chamber. Notably, the addition of sodium diacetate results in the lowest weight loss rate of 2.74 %. This research shows the potential of using dispersants in ice slurry-based wet precooling systems to enhance the postharvest preservation of fruits and vegetables.

ABSTRACTTeachers played an important role on the transmission of influenza in schools and communities. The study aims to investigate the influenza vaccination coverage and the factors determining flu vaccination acceptance among teachers in Hangzhou, China. A total of 1039 junior high school teachers in Hangzhou were recruited. The self-made questionnaire was used to investigate the influenza vaccine coverage among teachers and the influencing factors of influenza vaccination acceptance. Univariate analysis using the chi-square test and multivariable analysis using binary logistic regression were conducted to determine the relative predictors. The Influenza vaccine coverage among teachers was 5.9% (62/1039). 52.9% of teachers had the intention to receive influenza vaccine, 25.3% (247/977)/21.8% (213/977) of participants was hesitant/did not have the intention to get influenza vaccine. The top three sources for teachers to gain knowledge about influenza were website (72%), TV/radio (66.1%) and social media (58%). Whether get influenza vaccination before, knowledge about influenza and influenza vaccine, the beliefs for the likelihood of catching flu, the severity of getting flu, the effectiveness of influenza vaccine, the possibility of side effects after vaccination, and the troublesome of vaccination, doctors’ recommendation, as well as the situation of vaccination among other teachers were the associated factors of influenza vaccination acceptance. The influenza vaccination coverage was low but the intentions were relatively high among junior high school teachers. Future research should focus on the relationship between vaccination acceptance and behavior to increase influenza vaccination rates.

Ferroptosis, as a way of cell death, participates in the body's normal physiological and pathological regulation. Recent studies have shown that ferroptosis may damage glucose-stimulated islets β Insulin secretion and programmed cell death of T2DM target organs are involved in the pathogenesis of T2DM and its complications. Targeting suppression of ferroptosis with specific inhibitors may provide new therapeutic opportunities for previously untreated T2DM and its target organs. Current studies suggest that natural bioactive compounds, which are abundantly available in drugs, foods, and medicinal plants for the treatment of T2DM and its target organs, have recently received significant attention for their various biological activities and minimal toxicity, and that many natural compounds appear to have a significant role in the regulation of ferroptosis in T2DM and its target organs. Therefore, this review summarized the potential treatment strategies of natural compounds as ferroptosis inhibitors to treat T2DM and its complications, providing potential lead compounds and natural phytochemical molecular nuclei for future drug research and development to intervene in ferroptosis in T2DM.

The supercritical carbon dioxide (S–CO2) Brayton cycle is considered a promising power generation system because of its high efficiency, simple layout, and compact configuration. Furthermore, it is applicable to thermal and nuclear power generation. Because the key end equipment of this system is exposed to a high-temperature and high-pressure S–CO2 environment for a long duration, the high-temperature corrosion resistance of this equipment has been investigated extensively. This paper provides a review of recent studies pertaining to the corrosion behavior of candidate materials for high-temperature components in the S–CO2 Brayton cycle system. Additionally, the effects of internal microstructure, metal element content and external environment (temperature, pressure, impurities, etc.) on the corrosion behavior of alloys, including oxidation and carburizing corrosion are analyzed. Problems pertaining to the corrosion behavior of candidate materials are highlighted, and possible areas for future research are proposed.

Guavas are typical tropical fruit with high nutritional and commercial value. Because of their thin skin and high metabolic rate, guavas are highly susceptible to water loss, physical damage, and spoilage, severely limiting their shelf-life. Guavas can typically only be stored for approximately one week at room temperature, making transportation, storage, and handling difficult, resulting in low profit margins in the industry. This review focuses on the physiological and biochemical changes and their molecular mechanisms which occur in postharvest guavas, and summarizes the various management strategies for extending the shelf-life of these sensitive fruits by means of physical and chemical preservation and their combinations. This review also suggests future directions and reference ideas for the development of safe and efficient shelf-life extension techniques.

The mitochondrial C-to-U RNA editing factor PPR56 of the moss Physcomitrium patens is an RNA-binding pentatricopeptide repeat protein equipped with a terminal DYW-type cytidine deaminase domain. Transferred into Escherichia coli, PPR56 works faithfully on its two native RNA editing targets, nad3eU230SL and nad4eU272SL, and also converts cytidines into uridines at over 100 off-targets in the bacterial transcriptome. Accordingly, PPR56 is attractive for detailed mechanistic studies in the heterologous bacterial setup, allowing for scoring differential RNA editing activities of many target and protein variants in reasonable time. Here, we report (i) on the effects of numerous individual and combined PPR56 protein and target modifications, (ii) on the spectrum of off-target C-to-U editing in the bacterial background transcriptome for PPR56 and two variants engineered for target re-direction and (iii) on combinations of targets in tandem or separately at the 5'- and 3'-ends of large mRNAs. The latter experimentation finds enhancement of RNA editing at weak targets in many cases, including cox3eU290SF as a new candidate mitogenome target. We conclude that C-to-U RNA editing can be much enhanced by transcript features also outside the region ultimately targeted by PPRs of a plant editing factor, possibly facilitated by its enrichment or scanning along transcripts.

Abstract Messenger ribonucleic acid (mRNA) vaccines are a relatively new class of vaccines that have shown great promise in the immunotherapy of a wide variety of infectious diseases and cancer. In the past 2 years, SARS‐CoV‐2 mRNA vaccines have contributed tremendously against SARS‐CoV2, which has prompted the arrival of the mRNA vaccine research boom, especially in the research of cancer vaccines. Compared with conventional cancer vaccines, mRNA vaccines have significant advantages, including efficient production of protective immune responses, relatively low side effects and lower cost of acquisition. In this review, we elaborated on the development of cancer vaccines and mRNA cancer vaccines, as well as the potential biological mechanisms of mRNA cancer vaccines and the latest progress in various tumour treatments, and discussed the challenges and future directions for the field.

Summary: The mitogen-activated protein kinase (MAPK) cascade consisting of MKKK, MKK, and MPK plays an indispensable role in various plant physiological processes. Previously, we showed that phosphorylation of MabZIP21 by MaMPK6-3 is involved in banana fruit ripening, but the regulatory mechanism by which MKK controls banana fruit ripening remains unclear. Here, ripening-induced MaMKK1 from banana fruit is characterized, and transiently overexpressing and silencing of MaMKK1 in banana fruit accelerates and inhibits fruit ripening, respectively, possibly by influencing phosphorylation and activity of MPK. MaMKK1 interacts with and phosphorylates MaMPK6-3 and MaMPK11-4 mainly at the pTEpY residues, resulting in MPK activation. MaMPK11-4 phosphorylates MabZIP21 to elevate its transcriptional activation ability. Transgenic tomato fruit expressing MabZIP21 ripen quickly with a concomitant increase in MabZIP21 phosphorylation. Additionally, MabZIP21 activates MaMPK11-4 and MaMKK1 transcription to form a regulatory feedback loop. Collectively, here we report a regulatory pathway of the MaMPK6-3/11-4-MabZIP21 module in controlling banana fruit ripening.

Cucumber is one of the most widely consumed vegetables worldwide, and the fruit spine is an important fruit quality trait. Expansins play critical roles in fruit development; however, the regulation of expansins in cucumber fruit spine development has not been reported. In this study, 33 expansin genes were identified in the cucumber genome V3; additionally, expansin genes in Citrullus lanatus, Cucumis melo, Cucurbita maxima, Lagenaria siceraria, and Benincasa hispida were also identified. Phylogenetic analysis of expansin proteins in Cucurbitaceae and Arabidopsis showed that they evolved separately in each plant species. Phylogenetic analysis showed that C. maxima was derived earlier than the other five Cucurbitaceae species. The expression of CsEXPA2, CsEXPA14, and CsEXLA3 varied in cucumber lines with different fruit spine densities. A yeast two-hybrid assay showed that a putative auxin transporter encoded by numerous spine gene (ns) interacts with CsEXLA2, which may be involved in the development of the numerous spines in cucumber. These results provide novel insights into the expansins related to plant development and fruit spine development in cucumber.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA, and involved in various biological processes in plants. However, the distribution features and functions of mRNA m6A methylation have been poorly explored in woody perennial plants. In this study, a new natural variety with yellow-green leaves, named Maiyuanjinqiu, was screened from the seedlings of Catalpa fargesii. Based on the preliminary experiment, the m6A methylation levels in the leaves of Maiyuanjinqiu were significantly higher than those in C. fargesii. Furthermore, a parallel analysis of m6A-seq and RNA-seq was carried out in different leaf color sectors. The result showed that m6A modification were mostly identified around the 3’-untranslated regions (3’-UTR), which was slightly negatively correlated with the mRNA abundance. KEGG and GO analyses showed that m6A methylation genes were associated with photosynthesis, pigments biosynthesis and metabolism, oxidation-reduction and response to stress, etc. The overall increase of m6A methylation levels in yellow-green leaves might be associated with the decreased the expression of RNA demethylase gene CfALKBH5. The silencing of CfALKBH5 caused a chlorotic phenotype and increased m6A methylation level, which further confirmed our hypothesis. Our results suggested that mRNA m6A methylation could be considered as a vital epigenomic mark and contribute to the natural variations in plants.

ABSTRACT Colistin is one of the last-resort antibiotics for treating infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, mcr genes conferring resistance to colistin have been widely identified, which is considered a global threat to public health. Here, we investigated the prevalence and characteristics of mcr-harboring Escherichia coli strains isolated from humans, animals, and foods in China by PCR, antimicrobial susceptibility testing, conjugation experiments, molecular typing, genome sequencing, and bioinformatics analysis. In total, 135 mcr-1-harboring E. coli isolates were acquired from 847 samples, and 6 isolates carried mcr-3. Among them, 131 isolates were MDR bacteria. Sixty-five resistance genes conferring resistance to multiple antimicrobials were identified in 135 isolates. The diverse pulsed-field gel electrophoresis (PFGE) patterns and sequence types (STs) of mcr-1-carrying isolates demonstrated that clonal dissemination was not the dominant mode of mcr-1 transmission. Seven types of plasmids were able to carry mcr-1 in this study, including IncI2, IncX4, IncHI2, p0111, IncY, and two hybrid plasmids. The genetic structures carrying mcr-1 of 60 isolates were successfully transferred into the recipient, including 25 IncI2 plasmids, 23 IncX4 plasmids, and an IncHI2 plasmid. mcr-1–pap2 was the dominant mcr-1-bearing structure, followed by ISApl1–mcr-1–pap2–ISApl1 (Tn6330) and ISApl1–mcr-1–pap2, among 7 mcr-1-bearing structures of 135 isolates. In conclusion, IncI2, IncX4, and IncHI2 plasmids were the major vectors spreading mcr-1 from different geographical locations and sources. The prevalence of Tn6330 may accelerate the transmission of mcr-1. Continuous surveillance of mcr-1 and variants in bacteria is vital for evaluating the public health risk posed by mcr genes. IMPORTANCE The spread of polymyxin-resistant Enterobacteriaceae poses a significant threat to public health and challenges the therapeutic options for treating infections on a global level. In this study, mcr-1-bearing ST10 E. coli was isolated from pigs, pork, and humans simultaneously, which demonstrated that ST10 E. coli was an important vehicle for the spread of mcr-1 among animals, foods, and humans. The high prevalence of mcr-1-positive E. coli strains in pigs and pork and the horizontal transmission of mcr-1-bearing plasmids in diverse E. coli strains suggest that pigs and pork are important sources of mcr-1-positive strains in humans and pose a potential threat to public health. Additional research on the prevalence and characteristics of mcr-1-positive E. coli is still required to facilitate early warning to improve polymyxin management in hospitals.

Background13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) has been introduced in Hangzhou since 2017, whereas its current immunization state in children is not clear. Therefore, this study aims to describe the PCV13 vaccination distribution among children born in Hangzhou from 2017 to 2021 to provide data for reducing vaccination differences among different populations.MethodsDescriptive epidemiology was used for data analysis and PCV13 vaccination related information of children was collected from children vaccination management system of Zhejiang Province (ZJCVMS).ResultsAmong the 649,949 children born in Hangzhou from 2017 to 2021, 169,230 were vaccinated with an average full course vaccination rate of 26.0%. The full course vaccination rates in 5 years were different (P = 0.000) with an increasing trend (Pfortrend < 0.01). The first dose vaccination rates were different in 5 years (P = 0.000) with an increasing trend (Pfortrend < 0.01). The distribution of age when first dose PCV13 was administered varied, most people at 2 months and least people at 5 months. The full course vaccination rate varied by areas, highest in central urban areas and lowest in remote areas respectively (all P-value < 0.05). Overall, the full course vaccination rate of PCV13 was higher in the registered residence population than the non-registered residence population, which was 136,693 (31.4%) and 32,537 (15.1%) respectively (P = 0.000). The full course vaccination rates were the same between men and women (P = 0.502), which was 87,844 for men (26.0%) and 81,386 for women (26.1%).ConclusionAlthough the number of people who received PCV13 full course vaccination and received the first dose vaccination showed yearly increasing trends in Hangzhou, the full course vaccination rate for the whole population was relatively low. In addition, the PCV13 vaccination rates also differed by geography and household registration status. Measures such as expanding vaccination publicity or including national immunization should be taken to increase vaccination rates and reduce the differences in vaccination among groups with different characteristics.

Background: An increasing number of Chinese patent medicines (CPM) have been widely used in East Asian and North American countries, and the safety and efficacy of CPM have highly attracted public attention. However, it is difficult to supervise the authenticity of multiple biological ingredients within CPM based on microscopic inspection and physical and chemical detection. The raw materials may have similar characteristics of tissue structures and ergastic substances or similar chemical composition and contents when substitutes and/or adulterants are added. DNA molecular markers have been used to distinguish the biological ingredients within CPM based on conventional PCR assay. However, it was proved to be time- and labor-consuming and reagent-wasting, as multiple PCR amplification strategies were required for identifying the complex species composition within CPM. Here, we took the CPM (Danggui Buxue pill) as an example and aimed to establish a specific SNP-based multiplex PCR assay and simultaneously determine the authenticity of the two biological ingredients (Angelicae Sinensis Radix and Astragali Radix) within this CPM.Methods: We, respectively, designed the species-specific primers based on highly variable nrITS for discriminating Angelicae Sinensis Radix and Astragali Radix from their common substitutes and adulterants. The specificity of the primers was checked through conventional PCR assay and multiplex PCR assay. Furthermore, we used a handcrafted Danggui Buxue pill sample (DGBXP) to optimize annealing temperatures for the primers with multiplex PCR, and the sensitivity was also assessed. Finally, fourteen batches of commercial Danggui Buxue pills were used to verify the stability and practicability of the established multiplex PCR assay.Results: Two pairs of highly species-specific primers for amplifying Angelicae Sinensis Radix and Astragali Radix were screened, and our established multiplex PCR assay showed high specificity and sensitivity (lowest detection concentration: 4.0 × 10−3 ng/μL) at an optimal annealing temperature of 65°C. The method could simultaneously identify both biological ingredients within the Danggui Buxue pill.Conclusion: The specific SNP-based multiplex PCR provided a simple, time-, and labor-saving method for the simultaneous identification of the two biological ingredients within Danggui Buxue pills. This study was expected to provide a novel qualitative quality control strategy for CPM.

Abstract Objective Deep medullary veins (DMVs) were not considered a typical marker of cerebral small vessel disease (CSVD) due to limited understanding of their involvement in pathology of CSVD. This study aimsto investigate potential vascular risk factors for DMVs and their associations with CSVD. Methods In total, 1909 community‐dwelling participants were included in this analysis. Demographic, clinical, laboratory, and imaging data were collected. DMV scores (0–18) werecalculated as the sum of bilateral frontal, parietal, and occipital regional scores using a semiquantitative visual scale (0–3). The presence, total burden, and imaging markers of CSVD were assessed. Linear regression analyses were conducted to explore potential vascular factors for DMV scores. Binary and ordinal logistic regression analyses were performed to investigate the associations of DMV scores with CSVD and its markers. Results Mean age was 61.8 (SD 6.5) years, and 1027 (53.8%) of participants were men. The median DMV scores were14 (IQR 12–16). DMV scores wererelated to age, male sex, body mass index, diastolic blood pressure, hypercholesterolaemia, atrial fibrillation, current drinking, total cholesterol, triglycerides, low‐density lipoprotein, hemoglobin A1c, leukocytes, lymphocytes, hemoglobin, and platelets (p

Abstract Lawsonia intracellularis is the causative agent of proliferative enteropathy. While it harbors genes encoding the entire apparatus required for the type III secretion system (T3SS) and the expression of some of these components has been detected during experimental infection, the identification of L. intracellularis T3SS substrates (effector proteins) has been hampered. The Yersinia T3SS and yeast growth inhibition assays are two important heterologous systems used for the characterization of effector proteins. Bacterial EPIYA effectors are a distinct class of bacterial effectors defined by the presence of EPIYA or the EPIYA-related motif. When delivered into host cells via a T3SS or type IV secretion system, these effectors undergo tyrosine phosphorylation of the EPIYA motif, which enables them to manipulate host cell signaling by promiscuously interacting with multiple SH2 domain-containing proteins. A previous study showed that L. intracellularis LI0666 contains two EPIYA motifs and speculated that this protein could be a T3SS effector. In this study, we show that LI0666 is secreted by Yersinia in a T3SS-dependent manner and inhibits yeast growth. LI0666 is phosphorylated at tyrosine residues in porcine intestinal epithelial cells and in human epithelial cells. Like the archetypal EPIYA effector CagA, the EPIYA-containing region is not required for LI0666 association with yeast and mammalian cell membranes. Our results indicate that LI0666 is an authentic bacterial EPIYA effector. Identification of the tyrosine kinases that are responsible for LI0666 phosphorylation and the SH2 domain-containing host proteins that LI0666 interacts with will help to explore the molecular mechanisms of LI0666 in disease development.

Abstract Background Previous studies found that high levels of ventilatory ratio (VR) were associated with a poor prognosis due to worse ventilatory efficiency in acute respiratory distress syndrome patients. However, relatively few large studies have assessed the association between VR and intensive care unit (ICU) mortality in the general adult ventilated population. Methods The present study is a retrospective cohort study. Patients mechanically ventilated for more than 12 h were included. VR was calculated based on a previously reported formula. Restricted cubic spline models were used to fit the relationship between VR and mortality risks. Results A total of 14,328 mechanically ventilated ICU patients were included in the study, of which 1311 died within 28 days. The results of the study are as follows: (1) In the general adult ventilated population, VR was positively associated with 28-day mortality when VR ≥ 1.3 (increase of 0.1 per VR; HR 1.05, p

The role of gut microbiota in terms of host health is becoming increasingly important. In this study, the comparative effects of tea polyphenols (TPs) on weight loss and lipid metabolism on conventionalized mice (CVZ) and pseudo germ-free (PGF) mice (treated with antibiotics) were investigated. Our findings revealed that high fat (HF) diet considerably increased the body weight, total fat and upsurge lipid indices in CVZ mice but PGF mice were not sensitive to the effect of HF diet as CVZ mice. After the dietary administration of TP, body weight, perirenal fat and epididymal fat, liver weight, glucose (GLU) level, total chloestrol (TC level), high density lipoprotein-cholesterol (HDL-C) level significantly lowered in PGF mice as compared to CVZ mice group. However, the area of fat cells and triglyceride (TG) level were significantly increased in PGF mice. In CVZ mice, TP intervention resulted in a considerable drop in the Firmicutes/Bacteroides ratio as compared to PGF mice. The intestinal flora of PGF mice was severely reduced after antibiotic treatment, while TP administration restored intestinal diversity; the abundance of Akkermansia and Lactobacillus increased, whereas the abundance of Enterobacteriaceae and Prevotella reduced. Overall, we can assume that PGF obese mice administered with TP have less anti-obesity effects compared to obese CVZ mice.

Abstract Background The activation of immune response driven by the eggs of Schistosoma japonicum and the subsequent secretions is the culprit behind granulomatous inflammation and liver fibrosis. Evidence suggests that PKCλ/ι participates in a variety of physiological and pathological processes, including the regulation of metabolism, growth, proliferation and differentiation of cells. However, the role of PKCλ/ι in liver disease caused by Schistosoma japonicum remains unclear. Methods In the present study, we observe the pathological changes of egg-induced granulomatous inflammation and fibrosis in the liver of mice infected by Schistosoma japonicum by using conditional PKCλ/ι-knockout mice and wild-type control. Immune cytokines and fibrogenic factors were analyzed by performing flow cytometry and real-time fluorescence quantitative PCR. Results The results of H&E and Masson staining show that the degree of granulomatous lesions and fibrosis in the liver of the infected PKCλ/ι-knockout mice was significantly reduced compared with those of the infected wild-type mice. The mean area of single granuloma and hepatic fibrosis in the PKCλ/ι-knockout mice was significantly lower than that of the wild-type mice (85,295.10 ± 5399.30 μm2 vs. 1,433,702.04 ± 16,294.01 μm2, P

Abstract Background This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD). Methods A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed. Results At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05–1.70; cOR 1.28, 95% CI 1.02–1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00–1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25–3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14–2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16–2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08–1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20–2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04–1.39) and small vessel stroke (OR 1.21, 95% CI 1.06–1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p