Effect of Ursodeoxycholic Acid on Preventing SARS-CoV-2 Infection in Patients With Liver Transplantation: a multicenter retrospective cohort study.

BACKGROUND: Immunosuppressed recipients of liver transplantation (LT) are more likely to develop coronavirus disease 2019 (COVID-19) and may have an increased risk of developing worse outcomes. AIM: To assess the effect of ursodeoxycholic acid (UDCA) on preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients. DESIGN: Adult patients (aged ≥ 18 years) who underwent LT between January 1st, 2015, and December 31st, 2022, were included and categorized into two groups according to their use of UDCA. METHODS: The prevalence and severity of COVID-19 among transplantation patients between the UDCA and non-UDCA groups were estimated and compared. RESULTS: Among the 897 LT patients who met the inclusion criteria, infection rate of SARS-CoV-2 was 78.4%, and the rate of severe illness was 5.1% from January 2022 to January 2023 in China. In the multivariate analysis, only UDCA treatment (P = 0.006) was found to be a protective factor against SARS-CoV-2 infection. After propensity score matching, the SARS-CoV-2 infection rate in the UDCA group was lower than that in the non-UDCA group (74.1% vs. 84.6%, P = 0.002). This rate was further reduced to 62.1% (P = 0.002) when the oral administration dose was greater than 15 mg/kg/d. There was no difference in the rates of severe COVID-19 illness, ICU admission, or ventilation rate or length of hospital stay with or without UDCA treatment (all P > 0.05). CONCLUSIONS: The use of UDCA in LT patients significantly reduced the SARS-CoV-2 infection rate and showed a dose-dependent protective effect.

Multifunctional antibacterial bioactive nanoglass hydrogel for normal and MRSA infected wound repair.

Large-scale skin damage brings potential risk to patients, such as imbalance of skin homeostasis, inflammation, fluid loss and bacterial infection. Moreover, multidrug resistant bacteria (MDRB) infection is still a great challenge for skin damage repair. Herein, we developed an injectable self-healing bioactive nanoglass hydrogel (FABA) with robust antibacterial and anti-inflammatory ability for normal and Methicillin-resistant Staphylococcus aureus (MRSA) infected skin wound repair. FABA hydrogel was fabricated facilely by the self-crosslinking of F127-CHO (FA) and alendronate sodium (AL)-decorated Si-Ca-Cu nanoglass (BA). FABA hydrogel could significantly inhibit the growth of Staphylococcus aureus, Escherichia coli and MRSA in vitro, while showing good cytocompatibility and hemocompatibility. In addition, FABA hydrogel could inhibit the expression of proinflammatory factor TNF-α and enhance the expression of anti-inflammatory factor IL-4/ IL-10. Based on its versatility, FABA hydrogel could complete wound closure efficiently (75% at day 3 for normal wound, 70% at day 3 for MRSA wound), which was almost 3 times higher than control wound, which was related with the decrease of inflammatory factor in early wound. This work suggested that FABA hydrogel could be a promising dressing for acute and MRSA-infected wound repair.

A bionic "Trojan horse"-like gene delivery system hybridized with tumor and macrophage cell membrane for cancer therapy.

MiRNA-based gene therapy as a novel targeted therapy has yielded promising results in experimental cancer treatment, however, the inefficient delivery of miRNA to target tissues has limited its application in vivo. Here a unique dual-membrane-camouflaged miRNA21 antagomir delivery nanoplatform (M@NPs/miR21) with immune escape and homologous targeting properties was constructed by cancer cell membrane and macrophage membrane. Different from the single-cell membrane camouflage strategy, the dual-membrane camouflage miRNA21 antagomir delivery nanoplatform based on modification of CD47 protein with immune escape signal and galectin-3 protein with tumor cell aggregation enables efficient, safe and targeted therapy for colon cancer and lung metastases. Camouflaged with the dual-cell membrane, the "Trojan horse" like "pseudo-tumor cell" and/or "pseudo-macrophage" (M@NPs/miR21) carried the target gene miR21 antagomir to the tumor site and showed significant anti-tumor properties at the periphery and the core of subcutaneous tumor tissues. In addition, M@NPs/miR21 was more likely to penetrate dense tumor tissues and function within the tumor mass than NPs/miR21 without membrane coating. M@NPs/miR21 can deliver miR21 antagomir into MC38 cancer cells and tumor tissues, promote tumor apoptosis, and regulate the expression of Bcl2 and Ki67. Moreover, the M@NPs/miR21 gene delivery system not only can effectively inhibit the progression of subcutaneous tumors and lung metastases, but also showed minimal toxicity and good biosafety, making this delivery system particularly attractive for future translational research.

Prognostic value of estimated plasma volume in patients with chronic systolic heart failure.

Assessing congestion is challenging but important to patients with chronic heart failure (CHF). However, there are limited data regarding the association between estimated plasma volume status (ePVS) determined using hemoglobin/hematocrit data and outcomes in patients with stable CHF. We prospectively analyzed 231 patients; the median follow-up period was 35.6 months. We calculated ePVS at admission using the Duarte and Strauss formula, derived from hemoglobin and hematocrit ratios and divided patients into three groups. The primary outcome was a composite of all-cause mortality or heart failure rehospitalization. Among 274 patients (61.98 years of age, 2.3% male), the mean ePVS was 3.98±0.90 dL/g. The third ePVS tertile had a higher proportion of primary outcome (71.4%) than the first or second tertile (48.1% and 59.7%, respectively; p=0.013). On multivariable Cox analysis, after adjusting for potential confounders, higher ePVS remained significantly associated with increased rate of primary outcome (adjusted HR 1.567, 95% CI 1.267 to 1.936; p<0.001). Kaplan-Meier survival analyses showed that the occurrence of primary outcome, all-cause mortality and rehospitalization increased progressively from first to third tertiles (p=0.006, 0.014 and 0.001; respectively). In receiver operating characteristic analysis, the area under the curve of ePVS for primary outcome was 0.645. ePVS determined using hemoglobin and hematocrit was independently associated with clinical outcomes for patients with stable CHF. Our study thus further strengthens the evidence that ePVS has important prognostic value in patients with stable CHF. Trial registration number ChiCTR-ONC-14004463.

Xenogeneic-free generation of vascular smooth muscle cells from human induced pluripotent stem cells for vascular tissue engineering.

Development of mechanically advanced tissue-engineered vascular grafts (TEVGs) from human induced pluripotent stem cell (hiPSC)-derived vascular smooth muscle cells (hiPSC-VSMCs) offers an innovative approach to replace or bypass diseased blood vessels. To move current hiPSC-TEVGs toward clinical application, it is essential to obtain hiPSC-VSMC-derived tissues under xenogeneic-free conditions, meaning without the use of any animal-derived reagents. Many approaches in VSMC differentiation of hiPSCs have been reported, although a xenogeneic-free method for generating hiPSC-VSMCs suitable for vascular tissue engineering has yet to be established. Based on our previously established standard method of xenogeneic VSMC differentiation, we have replaced all animal-derived reagents with functional counterparts of human origin and successfully derived functional xenogeneic-free hiPSC-VSMCs (XF-hiPSC-VSMCs). Next, our group developed tissue rings via cellular self-assembly from XF-hiPSC-VSMCs, which exhibited comparable mechanical strength to those developed from xenogeneic hiPSC-VSMCs. Moreover, by seeding XF-hiPSC-VSMCs onto biodegradable polyglycolic acid (PGA) scaffolds, we generated engineered vascular tissues presenting effective collagen deposition which were suitable for implantation into an immunodeficient mice model. In conclusion, our xenogeneic-free conditions for generating hiPSC-VSMCs produce cells with the comparable capacity for vascular tissue engineering as standard xenogeneic protocols, thereby moving the hiPSC-TEVG technology one step closer to safe and efficacious clinical translation.

Efficient Differentiation of Human Induced Pluripotent Stem Cells into Endothelial Cells under Xenogeneic-free Conditions for Vascular Tissue Engineering.

Tissue engineered vascular grafts (TEVGs) represent a promising therapeutic option for emergency vascular intervention. Although the application of small-diameter TEVGs using patient-specific primary endothelial cells (ECs) to prevent thrombosis and occlusion prior to implantation could be hindered by the long time course required for in vitro endothelialization, human induced pluripotent stem cells (hiPSCs) provide a robust source to derive immunocompatible ECs (hiPSC-ECs) for immediate TEVG endothelialization. To achieve clinical application, hiPSC-ECs should be derived under culture conditions without the use of animal-derived reagents (xenogeneic-free conditions), to avoid unwanted host immune responses from xenogeneic reagents. However, a completely xenogeneic-free method of hiPSC-EC generation has not previously been established. Herein, we substituted animal-derived reagents used in a standard method of xenogeneic hiPSC-EC differentiation with functional counterparts of human origin. As a result, we generated xenogeneic-free hiPSC-ECs (XF-hiPSC-ECs) with similar marker expression and function to those of human primary ECs. Furthermore, XF-hiPSC-ECs functionally responded to shear stress with typical cell alignment and gene expression. Finally, we successfully endothelialized decellularized human vessels with XF-hiPSC-ECs in a dynamic bioreactor system. In conclusion, we developed xenogeneic-free conditions for generating functional hiPSC-ECs suitable for vascular tissue engineering, which will further move TEVG therapy toward clinical application.

U-shaped association between plasma sphingosine-1-phosphate levels and mortality in patients with chronic systolic heart failure: a prospective cohort study.

BACKGROUND: The endogenous lipid molecule sphingosine-1-phosphate (S1P) has received attention in the cardiovascular field due to its significant cardioprotective effects, as revealed in animal studies. The purpose of our study was to identify the distribution characteristics of S1P in systolic heart failure patients and the prognostic value of S1P for long-term prognosis. METHODS: We recruited 210 chronic systolic heart failure patients from June 2014 to December 2015. Meanwhile 54 healthy people in the same area were selected as controls. Plasma S1P was measured by liquid chromatography-tandem mass spectrometry. Patients were grouped according to the baseline S1P level quartiles, and restricted cubic spline plots described the association between S1P and all-cause death. Cox proportional hazard analysis was used to determine the relationship between category of S1P and all-cause death. RESULTS: Compared with the control group, the plasma S1P in chronic heart failure patients demonstrated a higher mean level (1.269 µmol/L vs 1.122 µmol/L, P = 0.006) and a larger standard deviation (0.441 vs 0.316, P = 0.022). Based on multivariable Cox regression with restricted cubic spline analysis, a non-linear and U-shaped association between S1P levels and the risk of all-cause death was observed. After a follow-up period of 31.7 ± 10.3 months, the second quartile (0.967-1.192 µml/L) with largely normal S1P levels had the lowest all-cause mortality and either an increase (adjusted HR = 2.368, 95%CI 1.006-5.572, P = 0.048) or a decrease (adjusted HR = 0.041, 95%CI 0.002-0.808, P = 0.036) predicted a worse prognosis. The survival curves showed that patients in the lowest quartile and highest quartile were at a higher risk of death. CONCLUSIONS: Plasma S1P levels in systolic heart failure patients are related to the long-term all-cause mortality with a U-shaped correlation. TRIAL REGISTRATION: CHiCTR, ChiCTR-ONC-14004463. Registered 20 March 2014.

Author Correction: Community Detection on Networks with Ricci Flow.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Community Detection on Networks with Ricci Flow.

Many complex networks in the real world have community structures - groups of well-connected nodes with important functional roles. It has been well recognized that the identification of communities bears numerous practical applications. While existing approaches mainly apply statistical or graph theoretical/combinatorial methods for community detection, in this paper, we present a novel geometric approach which  enables us to borrow powerful classical geometric methods and properties. By considering networks as geometric objects and communities in a network as a geometric decomposition, we apply curvature and discrete Ricci flow, which have been used to decompose smooth manifolds with astonishing successes in mathematics, to break down communities in networks. We  tested our method on networks with ground-truth community structures, and experimentally confirmed the effectiveness of this geometric approach.