Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Objectives:Using data from the heart transplant patient dataset of our center,we aimed to develop a preoperative risk scoring model specifically suitable for the Chinese population undergoing heart transplantation.This model was established to predict the likelihood of graft failure within the first year post-surgery and classify recipients according to their risk level.Methods:A retrospective study was conducted at a single center on 1 210 consecutive heart transplant recipients between June 2004 and December 2022.Risk factor screening was performed using univariate and multivariate logistic regression analyses.Variable selection was carried out through a stepwise backward procedure based on the Akaike Information Criterion(AIC).The regression coefficients obtained from the final model were employed as weighting factors in the multifactor analysis.The study utilized the area under the receiver operating characteristic(ROC)area under curve(AUC)as a metric to evaluate the performance of the model.Patients were stratified into low,medium,and high-risk groups based on the distribution of the calculated scores.Survival analysis was conducted on the various risk groups using the Kaplan-Meier method,with statistical comparisons performed using the log-rank test.A significance level of P<0.05 was deemed statistically significant.Results:A risk scoring model,denoted as the heart transplant(HTx)score,was developed,comprising 11 variables and yielding a total score of 20.6 points.In comparison to the low-risk group,the OR for 1-year graft failure in the medium-risk group was 2.0(95%CI:1.1-3.6,P=0.02),while the high-risk group had an OR of 9.8(95%CI:5.4-17.7,P<0.01).The risk scoring model exhibited strong discriminative ability with an AUC of 0.712(95%CI:0.646-0.778)and an internally validated bias-corrected AUC of 0.713.The results of the Hosmer-Lemeshow goodness-of-fit test indicated that the predictive model demonstrated a strong calibration ability(Hosmer-Lemeshow χ2=2.92,P=0.71).Within the cohort,the AUC values for the IMPACT score,UNOS score,RSS score,Mayo score,BO score,and TRS score models were 0.645,0.651,0.632,0.589,0.610,and 0.604,respectively.These findings suggest that the HTx scoring model exhibited superior predictive performance compared to the aforementioned models in forecasting outcomes within our cohort.The Kaplan-Meier survival analysis revealed statistically significant differences in long-term survival rates between the three risk groups,a noticeable decrease in long-term survival rates were observed with increasing levels of HTx risk stratification(P<0.05).Conclusions:Present results indicate a significant association between the developed HTx risk scores and graft failure within the initial year post-surgery,present model effectively categorizes the heart transplant recipients into low,medium,and high-risk groups and is valuable for risk stratification.

Objectives:Using data from the heart transplant patient dataset of our center,we aimed to develop a preoperative risk scoring model specifically suitable for the Chinese population undergoing heart transplantation.This model was established to predict the likelihood of graft failure within the first year post-surgery and classify recipients according to their risk level.Methods:A retrospective study was conducted at a single center on 1 210 consecutive heart transplant recipients between June 2004 and December 2022.Risk factor screening was performed using univariate and multivariate logistic regression analyses.Variable selection was carried out through a stepwise backward procedure based on the Akaike Information Criterion(AIC).The regression coefficients obtained from the final model were employed as weighting factors in the multifactor analysis.The study utilized the area under the receiver operating characteristic(ROC)area under curve(AUC)as a metric to evaluate the performance of the model.Patients were stratified into low,medium,and high-risk groups based on the distribution of the calculated scores.Survival analysis was conducted on the various risk groups using the Kaplan-Meier method,with statistical comparisons performed using the log-rank test.A significance level of P<0.05 was deemed statistically significant.Results:A risk scoring model,denoted as the heart transplant(HTx)score,was developed,comprising 11 variables and yielding a total score of 20.6 points.In comparison to the low-risk group,the OR for 1-year graft failure in the medium-risk group was 2.0(95%CI:1.1-3.6,P=0.02),while the high-risk group had an OR of 9.8(95%CI:5.4-17.7,P<0.01).The risk scoring model exhibited strong discriminative ability with an AUC of 0.712(95%CI:0.646-0.778)and an internally validated bias-corrected AUC of 0.713.The results of the Hosmer-Lemeshow goodness-of-fit test indicated that the predictive model demonstrated a strong calibration ability(Hosmer-Lemeshow χ2=2.92,P=0.71).Within the cohort,the AUC values for the IMPACT score,UNOS score,RSS score,Mayo score,BO score,and TRS score models were 0.645,0.651,0.632,0.589,0.610,and 0.604,respectively.These findings suggest that the HTx scoring model exhibited superior predictive performance compared to the aforementioned models in forecasting outcomes within our cohort.The Kaplan-Meier survival analysis revealed statistically significant differences in long-term survival rates between the three risk groups,a noticeable decrease in long-term survival rates were observed with increasing levels of HTx risk stratification(P<0.05).Conclusions:Present results indicate a significant association between the developed HTx risk scores and graft failure within the initial year post-surgery,present model effectively categorizes the heart transplant recipients into low,medium,and high-risk groups and is valuable for risk stratification.

Background: Pleuropterus multiflorum Thunb. cv. “Heshouwu”(HSW) has been used as a classical material for both medicine and food in China for millennia. Recently, the cultivation region of HSW has shifted from Guangdong to Sichuan, Guizhou, and other regions. The investigation of geographic variation in bioactive metabolite contents and their relationship with soil mineral elements holds academic significance. Objective: This study aimed to investigate the variations in the distribution of active components in HSW across diverse planting regions and their relationship with soil mineral elements. Methods: A reliable quantitative analysis based on ultrahigh-performance liquid chromatography with triple-quadrupole mass spectrometry (UPLC-QQQ-MS) was developed to assess the levels of 15 bioactive metabolites in 60 HSW samples collected from 4 distinct regions. A total of 43 soil mineral elements in corresponding 60 soil samples were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Orthogonal partial least squares-discriminant analysis (OPLS-DA), heatmap analysis, Pearson correlation analysis, and random forest (RF) regression were conducted based on the above quantitative data. Results: The content of stilbene glycosides displayed a wider range of variation compared with emodin and physcion among different regions. Eight compounds were screened as the differential metabolites in HSW samples from various sources using the supervised OPLS-DA analysis. Among these, 2 important functional compounds including physcion and 2, 3, 5, 4′-tetrahydroxystilbene-2-O-(6″-O-ace-tyl)-glucoside (THSG-5) are the most abundant in HSW samples from Deqing, a geographical indicative production region. Pearson correlation analysis indicated that the impact of soil mineral elements on the levels of stilbene glycosides is greater compared to that on anthraquinones. A negative correlation was observed between the levels of elements Na, Zn, Ba, Ti, and 2, 3, 5, 4′-tetrahydroxysilbene 2-O-glucoside (THSG-1). Conversely, a positive correlation was found between the contents of elements Na, Ce, Ti, and physcion and THSG-5, 2 components that exhibited higher levels in Deqing. Furthermore, an RF algorithm was employed to establish an interrelationship model, effectively forecasting the abundance of the majority of differential metabolites in HSW samples based on the content data of soil mineral elements. Conclusions: The variation of stilbene glycosides is wider than emodin and physcion in HSW. The levels of metabolites in HSW samples are influenced by soil mineral elements, with stilbene glycosides being more susceptible to such influences compared to anthraquinones. Specifically, THSG-1 shows a negative association withmost soil mineral elements, notably Na, Zn, Ba, and Ti, whereas the content of physcion displays a positive correlation.

BACKGROUND:Traditional scoliosis orthosis has some disadvantages,such as complex manufacturing process,long processing cycle,poor fit and so on.Three-dimensional printed scoliosis orthosis has the advantages of high manufacturing precision and personalization. OBJECTIVE:To evaluate the efficacy of three-dimensional printed scoliosis orthosis for scoliosis based on multi-criteria decision model. METHODS:Clinical data of 72 patients with scoliosis admitted to Chen Xinghai Hospital of Integrated Traditional Chinese and Western Medicine from January 2019 to October 2022 were retrospectively collected and divided into two groups according to the treatment of orthosis.Study group(n=23)received three-dimensional printed scoliosis orthosis.Traditional group(n=49)received the traditional polypropylene spine brace treatment.The clinical efficacy and complications were compared between the two groups.A multi-criteria decision model for the treatment of scoliosis with three-dimensional printed scoliosis orthosis was established,and the stability of the benefit value,risk value and decision model of the two groups were evaluated. RESULTS AND CONCLUSION:(1)Compared with the traditional group,there were significant differences in the top vertebral offset distance,Cobb angle,top vertebral rotation,Functional Movement Screen score,visual analog scale score and total effective rate in the study group at 6 months after surgery(P<0.05).(2)Among the benefit indexes,Cobb angle had the greatest impact on the condition of patients,while the risk indexes had the greatest impact on dyspnea.(3)The benefit values of the study group and the traditional group for scoliosis were 79 and 64,and the risk values were 74 and 57,respectively.The combined benefit and risk values found that the benefit-risk value of the study group was 16 higher than that of the traditional group.(4)In the range of 0-100%relative risk weight,the benefit-risk value of the study group was always higher than that of the traditional group,which proved that the multi-criteria decision-making model had good stability.(5)It is indicated that three-dimensional printed scoliosis orthosis can better restore the physiological curvature of scoliosis and improve the efficiency of treatment.

Objective To evaluate the effect of extracorporeal membrane oxygenation (ECMO) on early allograft dysfunction (EAD) after heart transplantation. Methods Clinical data of 614 heart transplant recipients were retrospectively analyzed. All recipients were divided into the ECMO group (n=43) and non-ECMO group (n=571) according to postoperative application of ECMO. In the ECMO group, the conditions of recipients undergoing ECMO after heart transplantation were summarized. Perioperative status and long-term prognosis of recipients were compared between two groups. Results Among 43 recipients undergoing ECMO, 17 cases underwent thoracotomy due to bleeding, 10 cases of infection, 4 cases of venous thrombosis of the lower limbs, and 1 case of stroke, respectively. Twenty-six recipients were recovered and discharged after successful weaning from ECMO, six died during ECMO support, six died after weaning from ECMO, five received retransplantation due to unsuccessful weaning from ECMO, and only one survived after retransplantation. Compared with the non-ECMO group, intraoperative cardiopulmonary bypass duration was significantly longer, the proportion of recipients requiring postoperative intra-aortic balloon pump (IABP), dialysis due to renal insufficiency, reoperation for hemostasis, infection, mechanical ventilation time≥96 h and tracheotomy was significantly higher, and the length of postoperative intensive care unit (ICU) stay was significantly longer in the ECMO group (all P < 0.05). The survival rate after discharge and 90-d survival rate in the ECMO group were 63% and 96%, significantly lower than 97% and 100% in the non-ECMO group (both P < 0.05). Survival analysis showed that the long-term survival rate in the ECMO group was significantly lower than that in the non-ECMO group (P < 0.05). After excluding the recipients who died within 90 d after heart transplantation, no significant difference was observed in the long-term survival rate (P > 0.05). Conclusions ECMO is an effective treatment of EAD after heart transplantation. The short-term survival rate of recipients using ECMO after heart transplantation is lower than that of those who do not use ECMO, and there is no significant difference in long-term survival of recipients surviving 90 d after heart transplantation.

Human pluripotent stem cells provide an inexhaustible model to study human embryogenesis in vitro. Recent studies have provided diverse models to generate human blastoids by self-organization of different pluripotent stem cells or somatic reprogramming intermediates. However, whether blastoids can be generated from other cell types or whether they can recapitulate postimplantation development in vitro is unknown. Here, we develop a strategy to generate human blastoids from heterogeneous intermediates with epiblast, trophectoderm, and primitive endoderm signatures of the primed-to-naïve conversion process, which resemble natural blastocysts in morphological architecture, composition of cell lineages, transcriptome, and lineage differentiation potential. In addition, these blastoids reflect many features of human peri-implantation and pregastrulation development when further cultured in an in vitro 3D culture system. In summary, our study provides an alternative strategy to generate human blastoids and offers insights into human early embryogenesis by modeling peri- and postimplantation development in vitro.
Humans ; Pluripotent Stem Cells/metabolism* ; Embryo, Mammalian/metabolism* ; Cell Differentiation ; Blastocyst ; Cell Lineage ; Embryonic Development

Anti-virulence strategy has been considered as one of the most promising approaches to combat drug-resistant bacterial infections. Pore-forming toxins (PFTs) are the largest class of bacterial toxins, inflicting their virulence effect through creating pores on the cell membrane. However, current solutions for eliminating PFTs are mostly designed based on their molecular structure, requiring customized design for different interactions. In the present study, we employed erythroliposome (denoted as RM-PL), a biomimetic platform constructed by artificial lipid membranes and natural erythrocyte membranes, to neutralize different hemolytic PFTs regardless of their molecular structure. When tested with model PFTs, including α-hemolysin, listeriolysin O, and streptolysin O, RM-PL could completely inhibit toxin-induced hemolysis in a concentration-dependent manner. In vivo studies further confirmed that RM-PL could efficiently neutralize various toxins and save animals' lives without causing damage to organs or tissues. In addition, we explored the underlying mechanisms of this efficient detoxification ability and found that it was mainly macrophages in the spleen and the liver that took up RM-PL-absorbed toxins through a variety of endocytosis pathways and digested them in lysosomes. In summary, the biomimetic RM-PL presented a promising system for broad-spectrum and powerful toxin neutralization with a mechanism of lysosome-mediated toxin degradation.

In this article, a case for random signal interference in resolver (or encoder) of carousel on Varian VitalBeam medical linear accelerator was illustrated. This case was considered as a rare failure of the technology platform (including TrueBeam) by Chinese, European and American technical experts in Varian. In this article, the differences of the carousel in the structure and control system between VitalBeam and traditional accelerator were comparatively analyzed to enable the peers to have a deeper understanding of resolver. The logic and methods to solve the fault were summarized, providing reference experience for analyzing the problems related to carousel. It is found that the interlocking system is imperfect, which provides a factual and technological basis for Varian to optimize the system.

Objective To analyze the early outcomes of heart transplantation in critical patients and its significance in donor allocation decision. Methods Clinical data of 449 recipients undergoing heart transplantation were retrospectively analyzed. According to preoperative status, all patients were divided into the critical status group (n=64) and general status group (n=385). The incidence of critical status was summarized. Clinical data of recipients were statistically compared between two groups. Postoperative survival and causes of death in recipients between two groups were analyzed. Perioperative results of critical recipients undergoing different mechanical circulation support as a bridge to heart transplantation were compared. Results Critical patients accounted for 14.3% of the total number of transplant recipients. The proportion of critical patients gradually increased in recent 5 years. Compared with the general status group, the recipients in critical status group had a lower proportion of smoking history, a higher proportion of cardiac surgery history, a higher serum level of creatinine, and a higher proportion of primary diseases of heart failure before heart transplantation(all P≤0.01). The proportion of undergoing mechanical circulation support was higher, the incidence of complications was higher, the stay time in intensive care unit (ICU) was longer and the in-hospital fatality was higher after heart transplantation in the critical status group (all P≤0.01). The 1-year survival rate of recipients in critical status group was significantly lower than that in general status group (83% vs. 95%, P < 0.01). The fatality of recipients due to infection and multiple organ failure in critical status group was higher than that in general status group. Among 64 critical recipients, 1 recipient received ventilator alone, and 63 recipients underwent mechanical circulation support devices as a bridge to heart transplantation. Among them, intra-aortic balloon pump (IABP) alone was applied in 49 cases (77%), 8 cases (13%) of extracorporeal membrane oxygenation (ECMO) combined with IABP, 4 cases (6%) of ECMO alone, and 2 cases (3%) of left ventricular assist device (LVAD) alone. Critical patients who received preoperative ECMO and ECMO combined with IABP bridging to heart transplantation have a higher proportion of postoperative complications, a longer ICU stay time, a longer mechanical ventilation time, and a higher proportion of hospital deaths. Conclusions The overall prognosis of critical patients undergoing heart transplantation is relatively poor. Effective preoperative management may reverse the high-risk status of critical patients in a certain extent. The limited quantity of donor heart should be allocated to the most urgent patients who can obtain the greatest benefit from heart transplantation.