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Abstract Background The aim of this study was to conduct an in silico analysis of a novel compound heterozygous variant in breast cancer susceptibility gene 2 (BRCA2) to clarify its structure–function relationship and elucidate the molecular mechanisms underlying triple-negative breast cancer (TNBC). Methods A tumor biopsy sample was obtained from a 42-year-old Chinese woman during surgery, and a maxBRCA™ test was conducted using the patient’s whole blood. We obtained an experimentally determined 3D structure (1mje.pdb) of the BRCA2 protein from the Protein Data Bank (PDB) as a relatively reliable reference. Subsequently, the wild-type and mutant structures were predicted using SWISS-MODEL and AlphaFold, and the accuracy of these predictions was assessed through the SAVES online server. Furthermore, we utilized a high ambiguity-driven protein–protein docking (HADDOCK) algorithm and protein–ligand interaction profiler (PLIP) to predict the pathogenicity of the mutations and elucidate pathogenic mechanisms that potentially underlies TNBC. Results Histological examination revealed that the tumor biopsy sample exhibited classical pathological characteristics of TNBC. Furthermore, the maxBRCA™ test revealed two compound heterozygous BRCA2 gene mutations (c.7670 C > T.pA2557V and c.8356G > A.pA2786T). Through performing in silico structural analyses and constructing of 3D models of the mutants, we established that the mutant amino acids valine and threonine were located in the helical domain and oligonucleotide binding 1 (OB1), regions that interact with DSS1. Conclusion Our analysis revealed that substituting valine and threonine in the helical domain region alters the structure and function of BRCA2 proteins. This mutation potentially affects the binding of proteins and DNA fragments and disrupts interactions between the helical domain region and OB1 with DSS1, potentially leading to the development of TNBC. Our findings suggest that the identified compound heterozygous mutation contributes to the clinical presentation of TNBC, providing new insights into the pathogenesis of TNBC and the influence of compound heterozygous mutations in BRCA2.

Background: Left ventricular (LV) overload is a frequent complication during VA-ECMO associated with poor outcomes. Many strategies of LV unloading have been documented but lack of evidence shows which is better. We conducted a network meta-analysis to compare different LV unloading strategies. Methods: We searched databases for all published studies on LV unloading strategies during VA-ECMO. The pre-defined primary outcome was all-cause mortality. Results: 45 observational studies (34235 patients) were included. The Surface Under the Cumulative Ranking values (SUCRA) demonstrated that compared to no unloading strategy (15.4 %), IABP (73.8 %), pLVAD (60.8 %), atrial septostomy (51.2 %), catheter venting (48.8 %) were all associated with decreased all-cause mortality, in which IABP and pLVAD existed statistical significance. For secondary outcomes, no unloading group had the shortest VA-ECMO duration, ICU and hospital length of stay, and the lower risk of complications compared with unloading strategies. IABP was associated with reducing VA-ECMO duration, ICU and hospital length of stay, and the risk of complications (except for hemolysis as the second best) compared with other unloading strategies. Conclusions: LV unloading strategies during VA-ECMO were associated with improved survival compared to no unloading, but the tendency to increase the risk of various complications deserves more consideration.

Abstrct: Objectives: The FUWAI-SAVE system is a modified low-priming cardiopulmonary bypass (CPB) system. The study aimed to explore whether the FUWAI-SAVE system can reduce the perioperative blood transfusion and its impact on other postoperative complications during cardiac surgery. Metohds: This study was a single-center, single-blind, randomized controlled trial, registered at the Chinese Clinical Trial Registry (identifier: ChiCTR2100050488). Adult patients undergoing cardiac surgery with CPB and intermediate risk for transfusion risk stratification were randomly assigned to an intervention group (FUWAI-SAVE group) or a control group (conventional group). The primary endpoint of the study was the peri-CPB red blood cell transfusion (RBC) rate. The secondary endpoints included the transfusion rate of other blood products, the amount of blood products transfused, the incidence of major complications, in-hospital mortality, and others. Results: 360 patients were randomized from December 9, 2021, to January 30, 2023. The rate of the primary endpoint was significantly lower in the FUWAI-SAVE group compared to the control group [ OR (95%CI): 0.649 (0.424–0.994)]. Meanwhile, the amount of RBC transfusion during the peri-CPB period was significantly lower in the FUWAI-SAVE group compared to the control group, with a mean difference of −0.626 (−1.176 to −0.076) units. The occurrence rate of major complications did not differ significantly between the two groups. Conclusions: Among adult patients undergoing cardiac surgery with CPB, the application of the FUWAI-SAVE system significantly reduced RBC transfusion rate and amount. The FUWAI-SAVE system can be considered an important component of comprehensive blood management strategies in cardiac surgery.

Abstract Background Breast cancer (BC) metastasis is the common cause of high mortality. Conventional prognostic criteria cannot accurately predict the BC metastasis risk. The machine learning technologies can overcome the disadvantage of conventional models. Aim We developed a model to predict BC metastasis using the random survival forest (RSF) method. Methods Based on demographic data and routine clinical data, we used RSF‐recursive feature elimination to identify the predictive variables and developed a model to predict metastasis using RSF method. The area under the receiver operating characteristic curve (AUROC) and Kaplan–Meier survival (KM) analyses were plotted to validate the predictive effect when C‐index was plotted to assess the discrimination and Brier scores was plotted to assess the calibration of the predictive model. Results We developed a metastasis prediction model comprising three variables (pathological stage, aspartate aminotransferase, and neutrophil count) selected by RSF‐recursive feature elimination. The model was reliable and stable when assessed by the AUROC (0.932 in training set and 0.905 in validation set) and KM survival analyses (p

Objective Digital health has recently gained a foothold in monitoring and improving diabetes care. We aim to explore the views of patients, carers and healthcare providers (HCPs) regarding the use of a novel patient-owned wound surveillance application as part of outpatient management of patients with diabetic foot ulcers (DFUs). Methods Semi-structured online interviews were conducted with patients, carers and HCPs in wound care for DFUs. The participants were recruited from a primary care polyclinic network and two tertiary hospitals in Singapore, within the same healthcare cluster. Purposive maximum variation sampling was used to select participants with differing attributes to ensure heterogeneity. Common themes relating to the wound imaging app were captured. Results A total of 20 patients, 5 carers and 20 HCPs participated in the qualitative study. None of the participants have used a wound imaging app before. Regarding a patient-owned wound surveillance app, all were open and receptive to the system and workflow for use in DFU care. Four major themes emerged from patients and carers: (1) technology, (2) application features and usability, (3) feasibility of using the wound imaging application and (4) logistics of care. Four major themes were identified from HCPs: (1) attitudes towards wound imaging app, (2) preferences regarding functionality, (3) perceived challenges for patients/carers and (4) perceived barriers for HCPs. Conclusion Our study highlighted several barriers and facilitators from patients, carers and HCPs regarding the use of a patient-owned wound surveillance app. These findings demonstrate the potential of digital health and areas to improve and tailor a DFU wound app suitable for implementation in the local population.

Besides insulin deficiency, glucagon excess is also regarded as a critical factor of type 2 diabetes mellitus (T2DM) according to the bi-hormonal hypothesis. Triterpenic acid-enriched fraction (TAE) of Cyclocarya paliurus leaves have been proved to effectively inhibit glucagon secretion, but the active ingredient for the efficacy and mechanism of TAE on glucagon secretion remains unclear. The present study was designed to identify the therapeutic component of TAE to treat T2DM and explore the exact mechanism. Herein, arjunolic acid (AA) screened from TAE selectively inhibited glucagon secretion in palmitate (PA)-induced αTC1-6 cells and isolated islets. Additionally, AA ameliorated hyperglycemia and hyperglucagonemia and improve pancreatic islet morphology and function in streptozotocin (STZ)-induced T2DM mice. Noticeably, the selective inhibition effect of AA on glucagon secretion from α-cell was regulated by facilitating ephrin-A1 and EphA4 interaction, subsequently activating PI3K and Akt pathway. Therefore, AA may be a promising agent for T2DM treatment.

BackgroundLaboratory activated partial thromboplastin time (LAB-aPTT) is a widely used laboratory assay for monitoring unfractionated heparin (UFH) therapy during extracorporeal membrane oxygenation (ECMO). But LAB-aPTT is confined to a central laboratory, and the procedure is time-consuming. In comparison, point-of-care aPTT (POC-aPTT) is a convenient and quick assay, which might be a promising method for anticoagulation monitoring in ECMO. This study was aimed to evaluate the agreement between POC-aPTT (hemochron Jr. Signature instruments) and LAB-aPTT for anticoagulation monitoring in adult ECMO patients.MethodsData of ECMO-supported adult patients anticoagulated with UFH in our institute from January 2017 to December 2020 was retrospectively reviewed. POC-aPTT and LAB-aPTT results measured simultaneously were paired and included in the analysis. The correlation between POC-aPTT and LAB-aPTT was assessed using Spearman’s correlation coefficient. Bias between POC-aPTT and LAB-aPTT were described with the Bland-Altman method. Influence factors for bias were identified using multinomial logistic regression analysis.ResultsA total 286 pairs of aPTT results from 63 patients were included in the analysis. POC-aPTT and LAB-aPTT correlated weakly (r = 0.385, P < 0.001). The overall bias between POC-aPTT and LAB-aPTT was 7.78 [95%CI (−32.49, 48.05)] s. The overall bias between POC-aPTT and LAB-aPTT ratio (to normal value) was 0.54 [95%CI (−0.68, 1.76)]. A higher plasma fibrinogen level [OR 1.353 (1.057, 1.733), P = 0.017] was associated with a higher chance of POC-aPTT underestimating LAB-aPTT. While a lower plasma fibrinogen level [OR 0.809 (0.679, 0.963), P = 0.017] and lower UFH rate [OR 0.928 (0.868, 0.992), P = 0.029] were associated with a higher chance of POC-aPTT overestimating LAB-aPTT.ConclusionThe present study showed poor agreement between POC-aPTT and LAB-aPTT. POC-aPTT was not suitable for anticoagulation monitoring in adult ECMO patients.

Background: This study sought to evaluate the incidence of acute kidney injury (AKI) defined by the Kidney Disease: Improving Global Outcomes (KDIGO) group in patients supported by veno-arterial extracorporeal membrane oxygenation (VA ECMO) after post-cardiotomy cardiogenic shock (PCS), and to identify the risk factors for AKI ≥3. Methods: Patients with and without AKI ≥3 were divided into two groups. Potential risk factors for developing AKI ≥3 were evaluated by univariate logistic regression analysis. Patient risk factors (p < 0.1) in the univariate analysis were entered into the multivariable logistic regression model. The tolerance and variance inflation factors (VIF) were calculated to evaluate the collinearity of the potential variables. Results: 136 patients with a mean age of 53.6 ± 13.9 years (66.9% male) were enrolled in the study. 80 patients (58.8%) developed AKI ≥3. Patients with AKI ≥3 required significantly longer mechanical ventilation (200.9 [128.0, 534.8] hours vs. 78.9 [13.0, 233.0] hours, p < 0.001). The ICU stay and hospital stay of patients with AKI ≥3 were much longer than patients with AKI

The study aims to validate the Chinese version of Personal Accountability Measure (PAM-Ch), which is used to assess the subjective aspect of teacher accountability, by surveying 1146 teachers enrolled in professional development courses offered by a public university in Beijing. The validation process involved two phases. First, the samples were randomly divided into three subgroups—for subgroup 1 (n = 390), exploratory factor analysis was computed; for subgroup 2 (n = 359), confirmatory factor analysis (CFA) was computed; and, for subgroup 3 (n = 381), a new CFA was performed for cross-validation. Second, Cronbach’s α, composite reliability (CR), average variance extracted (AVE), maximum shared variance (MSV), and average shared variance (ASV) were calculated for testing the reliability and validity. Throughout the process, three measurement models were tested for the adaptation of the PAM-Ch in this study. The results found that Model 2 was the best fit for the data, whose factor loadings ranged from 0.72–0.95 for internal accountability (factor 1) and 0.75–0.89 for external accountability (factor 2). The CRs of these two factors were 0.963 and 0.916, respectively, and the AVE values were 0.790 and 0.645, respectively, indicating that the PAM-Ch is a reliable and valid measure.

An S-doped CdO@In2O3 nanofiber was successfully designed by in-situ electrospinning along and subsequent calcination treatment. Under artificial sunlight illumination, the S/CdO@In2O3-25 displayed a superior photocatalytic hydrogen evolution rate of 4564.58 μmol·g−1·h−1, with approximately 22.0 and 1261.0-fold of those shown by the S/CdO and S/In2O3 samples, respectively. The experimental and theoretical analyses illustrate that the unique one-dimensional (1D) nanofiber morphology and rich oxygen vacancies optimized the electronic structure of the nanofibers and adsorption/desorption behaviors of reaction intermediates, contributing to the realization of the remarkable solar-to-H2 conversion efficiencies. Moreover, the staggered band structure and intimate contact heterointerfaces facilitate the formation of a type-II double charge-transfer pathway, promoting the spatial separation of photoexcited charge carriers. These results could inform the design of other advanced catalyst materials for photocatalytic reactions.

Background: Large animal models are developed to help understand physiology and explore clinical translational significance in the continuous development of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) technology. The purpose of this study was to investigate the establishment methods and management strategies in an ovine model of VA-ECMO.Methods: Seven sheep underwent VA-ECMO support for 7 days by cannulation via the right jugular vein and artery. The animals were transferred into the monitoring cages after surgery and were kept awake after anesthesia recovery. The hydraulic parameters of ECMO, basic hemodynamics, mental state, and fed state of sheep were observed in real time. Blood gas analysis and activated clotting time (ACT) were tested every 6 h, while the complete blood count, blood chemistry, and coagulation tests were monitored every day. Sheep were euthanized after 7 days. Necropsy was performed and the main organs were removed for histopathological evaluation.Results: Five sheep survived and successfully weaned from ECMO. Two sheep died within 24–48 h of ECMO support. One animal died of fungal pneumonia caused by reflux aspiration, and the other died of hemorrhagic shock caused by bleeding at the left jugular artery cannulation site used for hemodynamic monitoring. During the experiment, the hemodynamics of the five sheep were stable. The animals stayed awake and freely ate hay and feed pellets and drank water. With no need for additional nutrition support or transfusion, the hemoglobin concentration and platelet count were in the normal reference range. The ECMO flow remained stable and the oxygenation performance of the oxygenator was satisfactory. No major adverse pathological injury occurred.Conclusions: The perioperative management strategies and animal care are the key points of the VA-ECMO model in conscious sheep. This model could be a platform for further research of disease animal models, pathophysiology exploration, and new equipment verification.

Arjunolic acid (AA), as the most abundant triterpenoid component in Cyclocarya paliurus (Batal) Iljinskaja, previously displayed delipidating effects in free fatty acid (FFA)-induced HepG2 steatosis cells. However, whether AA still possesses the ameliorative effects on nonalcoholic fatty liver disease (NAFLD) in normal hepatocytes and in vivo remains vacant and the detailed mechanisms are not defined. In vitro, AA dose-dependently alleviated lipid accumulation in FFA-challenged primary hepatocytes without cytotoxicity. In vivo, AA showed pleiotropic benefits, including attenuating adiposity, mitigating hepatic steatosis and inflammation, improving lipid disorders and insulin resistance, and restoring the impaired gut barrier. Mechanically, we found that AA indirectly activated Sirt1/AMPK-modulated lipid metabolism through elevating NAMPT-mediated NAD+ level, and triggering autophagy, together mediating the lipid-lowering effects. Collectively, our results convey that AA can substantially mitigate NAFLD via indirectly activating Sirt1/AMPK signaling, inducing autophagy and restoring gut barrier, and will be considered as a promising candidate for NAFLD therapy.

Background: Extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support for critically ill patients. Portable ECMO devices can be applied in both in-hospital and out-of-hospital emergency conditions. We evaluated the safety and biocompatibility of a novel centrifugal pump and ECMO device of the OASSIST ECMO System (Jiangsu STMed Technologies Co., Suzhou, China) in a 168-h ovine ECMO model.Methods: The portable OASSIST ECMO system consists of the control console, the pump drive, and the disposable centrifugal pump. Ten healthy sheep were used to evaluate the OASSIST ECMO system. Five were supported on veno-venous ECMO and five on veno-arterial ECMO, each for 168 h. The systemic anticoagulation was achieved by continuous heparin infusion to maintain the activated clotting time (ACT) between 220 and 250 s. The rotary speed was set at 3,200–3,500 rpm. The ECMO configurations and ACT were recorded every 6 hours (h). The free hemoglobin (fHb), complete blood count, and coagulation action test were monitored, at the 6th h and every 24 h after the initiation of the ECMO. The dissection of the pump head and oxygenator were conducted to explore thrombosis.Results: Ten sheep successfully completed the study duration without device-related accidents. The pumps ran stably, and the ECMO flow ranged from 1.6 ± 0.1 to 2.0 ± 0.11 L/min in the V-V group, and from 1.8 ± 0.1 to 2.4 ± 0.14 L/min in the V-A group. The anticoagulation was well-performed. The ACT was maintained at 239.78 ± 36.31 s, no major bleeding or thrombosis was observed during the ECMO run or in the autopsy. 3/5 in the V-A group and 4/5 in the V-V group developed small thrombus in the bearing pedestal. No obvious thrombus formed in the oxygenator was observed. The hemolytic blood damage was not significant. The average fHb was 0.17 ± 0.12 g/L. Considering hemodilution, the hemoglobin, white blood cell, and platelets didn't reduce during the ECMO runs.Conclusions: The OASSIST ECMO system shows satisfactory safety and biocompatibility for the 168-h preclinical evaluation in the ovine model. The OASSIST ECMO system is promising to be applied in clinical conditions in the future.

Deep hypothermic circulatory arrest (DHCA) can induce systemic inflammatory response syndrome, including neuroinflammation. Finding suitable compounds is necessary for attenuating neuroinflammation and avoiding cerebral complications following DHCA. In the present study, we established DHCA rat models and monitored the vital signs during the surgical process. After surgery, we found significantly increased proinflammatory cytokines (IL-6, IL-1β, and TNF-α) in DHCA rats. Quantitative proteomics analysis was performed for exploring the differentially expressed proteins in hippocampus of DHCA rats and the data showed the adiponectin receptor 1 protein was upregulated. More importantly, administration of AdipoRon, a small-molecule adiponectin receptor agonist, could improve the basic vital signs and attenuate the increased IL-6, IL-1β, and TNF-α in DHCA rats. Furthermore, AdipoRon inhibits the activation of microglia (M1 state) and promotes their transition to an anti-inflammatory state, via promoting the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), and downregulating nuclear factor kappa B (NF-κB) in DHCA rats. Consistently, we used LPS-treated BV2 cells to mimic the neuroinflammatory condition and found that AdipoRon dose-dependently decreased cytokines, along with increased phosphorylation of AMPK and downregulated NF-κB. In conclusion, our present data supported that AdipoRon inhibited DHCA-induced neuroinflammation via activating the hippocampal AMPK/NF-κB pathway.

With the rapid development of the Internet of Things (IoT) industry, the smart home is fully integrated with people’s shelter and transportation, which facilitates people’s daily life. A smart home without a security authentication mechanism will inevitably cause a series of security threats. This is essentially a problem of symmetry model worth solving. In fact, researchers have designed various authentication schemes to verify the identity of users and to ensure smart devices can be legally accessed through authorization in the smart home. In 2021, Yu proposed a three-factor anonymous authentication scheme for smart homes using lightweight symmetric encryption primitives and stated that their scheme is resistant to various known security attacks. However, after careful analysis, we found that Yu’s scheme needs further improvement in node capture attack and offline password guessing attack and that forward security cannot be guaranteed. Therefore, we first design a robust three-factor anonymous authentication scheme for smart homes based on asymmetric encryption Elliptic Curve Cryptography (ECC). Then, we perform formal and informal security analysis in which the formal analysis tools include Burrows-Abadi-Needham (BAN) logic and Scyther simulation tool to prove that the proposed scheme can achieve user anonymity, untraceability, and session key forward security. Meanwhile, mutual authentication is performed, and the scheme is resistant to all known attacks described in this article. Finally, a performance comparison is made in terms of efficiency, which shows that our scheme can have certain advantages with those newly designed schemes, achieve a delicate balance in performance and safety, and is more practical for the real smart home environment.

Objective To investigate the expressions of miR-135a-5p, GATA3 and STAT3 in different pathological types of cervical tissues and cervical cancer cell lines and their correlation in cervical cancer. Methods Real-time PCR was performed to determine the expression of miR-135a-5p in cervical carcinoma tissue and cell lines. Immunohistochemistry SP and Western blot methods were used to determine the expression of GATA3 and STAT3 in cervical tissues and cells. The effect of miR-135a-5p on GATA3 3'UTR was verified by dual-luciferase reporter assay system. The correlation of miR-135a-5p and GATA3 mRNA expression with the clinical pathological parameters of cervical squamous cell carcinoma patients was analyzed. Results The miR-135a-5p expression was up-regulated in CSCC tissues and cell lines(all P < 0.05). With the increasing stage of carcinoma, the mRNA levels of GATA3 was reduced(P < 0.05), whereas the mRNA levels of STAT3 was increased(P < 0.05). miR-135a-5p could target GATA3 3'UTR. The expression of GATA3 mRNA was negatively correlated with STAT3 mRNA expression(r=-0.4534) and miR-135a-5p expression(r=-0.6656). Moreover, the miR-135a-5p expression was related to clinical stages and lymph node metastasis(P < 0.05), and the GATA3 mRNA expression was related to clinical stage, depth of invasion and lymph node metastasis in cervical squamous cell carcinoma(P < 0.05). Conclusion In cervical cancer, the expression of miR-135a-5p and STAT3 mRNA are up-regulated, the expression of GATA3 mRNA is down-regulated, suggesting that they may be involved in the occurrence and development of cervical cancer through interaction.

Educational decentralisation has been implemented globally. However, few studies have compared the effects of different decentralisation strategies on students' academic achievement in diverse cultural contexts. Using data from 49 countries participating in the Programme for International Student Assessment (PISA) 2015, this study attempts to fill this research gap by examining the relationship between three delegation strategies (school autonomy, teacher participation and parental involvement), student achievement and societal culture. Our findings suggest that teacher participation in school management is the most effective educational decentralisation strategy for enhancing students' mathematics, reading and science performance. This strategy is particularly effective in countries with high power distance. The findings indicate that parental involvement does not have a significant effect on student academic achievement and that its effect is suppressed by a culture of uncertainty avoidance. Furthermore, school autonomy does not have a significant effect on students' academic achievement in any of the societal cultures examined.