A Combination of Biocatalysis and Fenton-Like Reaction Induced OH• Burst for Cascade Amplification of Cancer Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a novel antitumor strategy that employs Fenton or Fenton-like reactions to generate highly toxic hydroxyl radical (OH•) from hydrogen peroxide (H2O2) for inducing tumor cell death. However, the antitumor efficacy of the CDT strategy is harshly limited by the redox homeostasis of tumor cells; especially the OH • is easily scavenged by glutathione (GSH) and the intracellular H2O2 level is insufficient in the tumor cells. Herein, we propose the Mn2+-menadione (also known as vitamin K3, MK3) cascade biocatalysis strategy to disrupt the redox homeostasis of tumor cells and induce a OH• storm, resulting in enhanced CDT effect. A nanoliposome encapsulating Mn-MK3 (Mn-MK3@LP) was prepared for the treatment of hepatic tumors in this study. After Mn-MK3@LPs were taken up by tumor cells, menadione could facilitate the production of intracellular H2O2 via redox cycling, and further the cytotoxic OH • burst was induced by Mn2+-mediated Fenton-like reaction. Moreover, high-valent manganese ions were reduced by GSH and the depletion of GSH further disrupted the redox homeostasis of tumor cells, thus achieving synergistically enhanced CDT. Overall, both cellular and animal experiments confirmed that the Mn-MK3@LP cascade biocatalysis nanoliposome exhibited excellent biosafety and tumor suppression efficacy. This study may provide deep insights for developing novel CDT-based strategies for tumor therapy.

Risk factors and mortality of carbapenem-resistant Pseudomonas aeruginosa bloodstream infection in haematology department: A 10-year retrospective study.

OBJECTIVES: This study aims to investigate the risk factors for carbapenem-resistant Pseudomonas aeruginosa bloodstream infection (CRPA-BSI) and identify predictors of outcomes among patients with P. aeruginosa bloodstream infection (PA-BSI). METHODS: A retrospective cohort study was conducted on patients with PA-BSI at Henan Cancer Hospital from 2013 to 2022. RESULTS: Among the 503 incidences analysed, 15.1% of them were CRPA strains. Age, ANC < 100/mmc, receiving antifungal prophylaxis, exposure to carbapenems within the previous 90 days to onset of BSI, and allogeneic HSCT (allo-HSCT) were associated with the development of CRPA-BSI. CRPA-BSI patients experienced significantly higher 28-day mortality rates compared to those with carbapenem-susceptible P. aeruginosa bloodstream infection. Multivariate logistic regression analysis identified age at BSI, active stage of haematological disease, procalcitonin levels, prior corticosteroid treatment, isolation of CRPA, and septic shock as independent predictors of 28-day mortality. CONCLUSIONS: Risk factors for CRPA-BSI include age, ANC < 100/mmc, antifungal prophylaxis, exposure to carbapenems, and allo-HSCT. Additionally, age at BSI, active haematological disease, procalcitonin levels, prior corticosteroid treatment, CRPA isolation, and septic shock contribute to increased mortality rates among patients with PA-BSI.

Modulating Intracellular Dynamics for Optimized Intracellular Release and Transcytosis Equilibrium.

Active transcytosis-mediated nanomedicine transport presents considerable potential in overcoming diverse delivery barriers, thereby facilitating tumor accumulation and penetration. Nevertheless, the persistent challenge lies in achieving a nuanced equilibrium between intracellular interception for drug release and transcytosis for tumor penetration. In this study, a comprehensive exploration is conducted involving a series of polyglutamine-paclitaxel conjugates featuring distinct hydrophilic/hydrophobic ratios (HHR) and tertiary amine-oxide proportions (TP) (OPGA-PTX). The screening process, meticulously focused on delineating their subcellular distribution, transcytosis capability, and tumor penetration, unveils a particularly promising candidate denoted as OPPX, characterized by an HHR of 10:1 and a TP of 100%. OPPX, distinguished by its rapid cellular internalization through multiple endocytic pathways, selectively engages in trafficking to the Golgi apparatus for transcytosis to facilitate accumulation within and penetration throughout tumor tissues and simultaneously sorted to lysosomes for cathepsin B-activated drug release. This study not only identifies OPPX as an exemplary nanomedicine but also underscores the feasibility of modulating subcellular distribution to optimize the active transport capabilities and intracellular release mechanisms of nanomedicines, providing an alternative approach to designing efficient anticancer nanomedicines.

Co-transplantation of umbilical cord mesenchymal stem cells and peripheral blood stem cells in children and adolescents with refractory or relapsed severe aplastic anemia.

To evaluate the co-transplantation efficacy of umbilical cord mesenchymal stem cells (UC-MSCs) and peripheral blood stem cells (PBSCs) as a novel approach for refractory or relapsed severe aplastic anemia (R/R SAA) in children and adolescents, thirty-two children and adolescents diagnosed with R/R SAA underwent a retrospective chart review. The patients were categorized into two groups based on the source of PBSCs: the matched sibling donor (MSD) group and the unrelated donor (UD) group. No adverse events related to UC-MSC infusion occurred in any of the patients. The median time for neutrophil engraftment was 13 days (range: 10-23 days), and for platelets, it was 15 days (range: 11-28 days). Acute GVHD of Grade I-II and moderate chronic GVHD were observed in 21.8 and 12.5% of cases, respectively. No statistically significant differences were found between the MSD and UD groups in terms of engraftment, GVHD, and complications, including infection and hemorrhagic cystitis. The median follow-up time was 38.6 months (range: 1.4-140.8 months). As of October 31, 2021, five patients had succumbed, while 27 (84.4%) survived. The 5-year OS rate showed no statistically significant difference between the MSD and UD groups (84.8 ± 10.0 vs. 82.4 ± 9.2%, p = 0.674). In conclusion, the application of UC-MSCs in the treatment of R/R SAA in PBSC transplantation is reliable and safe, they had no graft rejection, low incidence of severe GVHD which may have been contributed by the co-infusion of MSC.

High-pressure microfluidization enhanced the stability of sodium caseinate-EGCG complex-stabilized fish oil emulsion.

Improving the emulsion-stabilizing effect of protein by chemical or physical modification has been paid much attention recently. Here, sodium caseinate (CS) was treated by high-pressure-microfluidization (HPM) under 0-100 MPa, and was further complexed with (-)-epigallocatechin-3-gallate (EGCG) to form an excellent emulsifier that stabilized fish oil emulsions. Results showed that HPM treatment (especially 80 MPa) significantly changed the secondary structure of CS, and 80 MPa-PCS-EGCG had the best emulsifying and antioxidant activities. In addition, after HPM treatment and EGCG bonding, CS formed a thicker interface layer on the surface of oil droplets, which could better protect the fish oil from the influence by oxygen, temperature and ion concentration. Moreover, the fish oil emulsion stabilized by PCS-EGCG complex significantly delayed the release of free fatty acids subjected to in vitro digestion. Conclusively, HPM-treated CS-EGCG complex could be a potential emulsifier to improve the stability of fish oil emulsions.

Characteristics of non-carbapenemase producing carbapenem-resistant Klebsiella pneumoniae from a tertiary hospital in China.

INTRODUCTION: The spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a substantial severe global public health burden. Non-carbapenemase-producing CRKP (non-CP-CRKP) is increasingly recognized as the source of severe infections. METHODOLOGY: We analyzed the genotypic, and phenotypic profiles of non-CP-CRKP strains with the whole-genome sequences isolated between 2017 and 2019 and the clinical characterization of non-CP-CRKP infection. RESULTS: A total of 91 CRKP strains were collected, of which 5 (5.49%) strains were non-CP-CRKP. Four strains were from male patients; three strains were isolated from the bile of patients who underwent biliary interventional surgery and four had a history of antibiotic exposure. Three strains were sequence type (ST)11, one was ST1, and one was ST5523. The non-CP-CRKP strains were insusceptible to ertapenem. Three strains were susceptible to amikacin. All the strains were susceptible to imipenem, meropenem, tigecycline, ceftazidime/avibatam and polymyxin B. The ß-lactamases of non-CP-CRKP predominantly included blaCTX-M, blaSHV, and blaTEM subtypes. Two site mutations in ompK36 (p.A217S and p.N218H) and four in ompK37 (p.I70M, p.I128M, p.N230G, and m233_None234insQ) were detected accounting for carbapenem resistance. Plasmids IncFI and IncFII were found in most strains. Genes encoding aerobactin, yersiniabactin and allantoin utilization were not detected in several isolates, and all non-CP-CRKP strains did not carry rmpA gene. CONCLUSIONS: Non-CP-CRKP infected patients had a history of previous antibiotic exposure or invasive procedures. Non-CP-CRKP strains were insusceptible to ertapenem. The mechanism of resistance includes ß-lactamases production and the site mutations in ompK36 and ompK37. Several virulence genes were not detected in non-CP-CRKP.

Presenilin 1 Is a Therapeutic Target in Pulmonary Hypertension and Promotes Vascular Remodeling.

Small muscular pulmonary artery remodeling is a dominant feature of PAH. PSEN1 affects angiogenesis, cancer and Alzheimer's disease. We aimed to determine the role of PSEN1 in the pathogenesis of vascular remodeling in PH. Haemodynamics and vascular remodeling in the Psen1-knockin and smooth muscle-specific Psen1-knockout mice were assessed. The functional partners of PSEN1 were predicted by bioinformatics analysis and biochemical experiments. The therapeutic effect of PH was evaluated by administration of the PSEN1-specific inhibitor ELN318463. We discovered that both the mRNA and protein levels of PSEN1 were increased over time in hypoxic rats, monocrotaline (MCT) rats and Su5416/hypoxia (SuHx) mice. Psen1 transgenic mice were highly susceptible to PH, whereas smooth muscle-specific Psen1-knockout mice were resistant to hypoxic PH. STRING analysis showed that the Notch1/2/3, ß-catenin, Cadherin-1, DNER, TMP10 and ERBB4 appeared to be highly correlated with PSEN1. Immunoprecipitation confirmed that PSEN1 interacts with ß-catenin and DNER, and these interactions were suppressed by the catalytic PSEN1 mutations D257A, D385A and C410Y. PSEN1 was found to mediate the nuclear translocation of the Notch1 intracellular domains and activated RBP-Jκ. Octaarginine-coated liposome-mediated pharmacological inhibition of PSEN1 significantly prevented and reversed the pathological process of in hypoxic and MCT induced PH. PSEN1 essentially drives the pathogenesis of PAH and interacted with the non-canonical Notch ligand DNER. PSEN1 can be used as a promising molecular target for treating PAH. PSEN1 inhibitor ELN318463 can prevent and reverse the progression of PH and be developed as a potential anti-PAH drug.

ZNF460-mediated circRPPH1 promotes TNBC progression through ITGA5-induced FAK/PI3K/AKT activation in a ceRNA manner.

BACKGROUND: Circular RNAs are highly stable regulatory RNAs that have been increasingly associated with tumorigenesis and progression. However, the role of many circRNAs in triple-negative breast cancer (TNBC) and the related mechanisms have not been elucidated. METHODS: In this study, we screened circRNAs with significant expression differences in the RNA sequencing datasets of TNBC and normal breast tissues and then detected the expression level of circRPPH1 by qRT‒PCR. The biological role of circRPPH1 in TNBC was then verified by in vivo and in vitro experiments. Mechanistically, we verified the regulatory effects between circRPPH1 and ZNF460 and between circRPPH1 and miR-326 by chromatin immunoprecipitation (ChIP), fluorescence in situ hybridization assay, dual luciferase reporter gene assay and RNA pull-down assay. In addition, to determine the expression of associated proteins, we performed immunohistochemistry, immunofluorescence, and western blotting. RESULTS: The upregulation of circRPPH1 in TNBC was positively linked with a poor prognosis. Additionally, both in vivo and in vitro, circRPPH1 promoted the biologically malignant behavior of TNBC cells. Additionally, circRPPH1 may function as a molecular sponge for miR-326 to control integrin subunit alpha 5 (ITGA5) expression and activate the focal adhesion kinase (FAK)/PI3K/AKT pathway. CONCLUSION: Our research showed that ZNF460 could promote circRPPH1 expression and that the circRPPH1/miR-326/ITGA5 axis could activate the FAK/PI3K/AKT pathway to promote the progression of TNBC. Therefore, circRPPH1 can be used as a therapeutic or diagnostic target for TNBC.

Boosting synergism of chemo- and immuno-therapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules.

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

The high incidence of restenosis after angioplasty has been the leading reason for the recurrence of coronary heart disease, substantially increasing the mortality risk for patients. However, current anti-stenosis drug-eluting stents face challenges due to their limited functions and long-term safety concerns, significantly compromising their therapeutic effect. Herein, a stent-free anti-stenosis drug coating (denoted as Cur-NO-Gel) based on a peptide hydrogel is proposed. This hydrogel is formed by assembling a nitric oxide (NO) donor-peptide conjugate as a hydrogelator and encapsulating curcumin (Cur) during the assembly process. Cur-NO-Gel has the capability to release NO upon ß-galactosidase stimulation and gradually release Cur through hydrogel hydrolysis. The in vitro experiments confirmed that Cur-NO-Gel protects vascular endothelial cells against oxidative stress injury, inhibits cellular activation of vascular smooth muscle cells, and suppresses adventitial fibroblasts. Moreover, periadventitial administration of Cur-NO-Gel in the angioplasty model demonstrate its ability to inhibit vascular stenosis by promoting reendothelialization, suppressing neointima hyperplasia, and preventing constrictive remodeling. Therefore, the study provides proof of concept for designing a new generation of clinical drugs in angioplasty.

A virtual phantom for patient-specific QA On A 1.5T MR-linac.

Create a virtual ArcCHECK-MR phantom, customized for a 1.5T MR-linac, with consideration of the different density regions within the quality assurance (QA) phantom, aiming to streamline the utilization of this specialized QA device. A virtual phantom was constructed in the treatment planning system (TPS) to replicate the ArcCHECK-MR's composition, consisting of five distinct layers: "Outer" (representing the outer PMMA ring), "Complex" (simulating the printed circuit boards), "Detectors" (encompassing the detector area), "Inner" (signifying the inner PMMA ring) and "Insert" (representing the PMMA insert). These layers were defined based on geometric data and represented as contour points on a set of dummy CT images. Additionally, a setup platform was integrated as contoured structures. To determine the relative electron density (RED) values of the external and internal PMMA components, measurements were taken at 25 points in the insert using an ion chamber. A novel method for establishing the exit/entrance dose ratio (EEDR) for ArcCHECK-MR was introduced. The RED of higher density region was derived by evaluating the local gamma index passing rate results with criteria of 2% dose difference and 2 mm distance-to-agreement. The performance of the virtual phantom was assessed for Unity 7 FFF beams with a 1.5T magnetic field. The radii of the five ring structures within the virtual phantom measured 133.0 mm, 110.0 mm, 103.4 mm, 100.0 mm, and 75.0 mm for the "Outer," "Complex," "Detectors," "Inner" and "Insert" regions, respectively. The RED values were as follows: ArcCHECK-MR PMMA had a RED of 1.130, "Detectors" were assumed to have a RED of 1.000, "Complex" had a RED of 1.200, and the setup QA phantom justified a RED of 1.350. Early validation results demonstrate that the 5-layer virtual phantom, when compared to the commonly used bulk overridden phantom, offers improved capability in MR-linac environments. This enhancement led to an increase in passing rates for the local gamma index by approximately 5 ∼ 6%, when applying the criteria of 2%, 2 mm. We have successfully generated a virtual representation of the distinct regions within the ArcCHECK-MR using a TPS, addressing the challenges associated with its use in conjunction with a 1.5T MR-linac. We consistently observed favorable local gamma index passing rates across two 1.5T MR-linac and ArcCHECK-MR unit combinations. This approach has the potential to minimize uncertainties in the creation of the QA phantom for ArcCHECK-MR across various institutions.

A surgical mouse model of neonatal right ventricular outflow tract obstruction by pulmonary artery banding.

BACKGROUD: Diseased animal models play an extremely important role in preclinical research. Lacking the corresponding animal models, many basic research studies cannot be carried out, and the conclusions obtained are incomplete or even incorrect. Right ventricular (RV) outflow tract (RVOT) obstruction leads to RV pressure overload (PO) and reduced pulmonary blood flow (RPF), which are 2 of the most important pathophysiological characteristics in pediatric cardiovascular diseases and seriously affect the survival rate and long-term quality of life of many children. Due to the lack of a neonatal mouse model for RVOT obstruction, it is largely unknown how RV PO and RPF regulate postnatal RV and pulmonary development. The aim of this study was to construct a neonatal RVOT obstruction mouse model. METHODS AND RESULTS: Here, we first introduced a neonatal mouse model of RVOT obstruction by pulmonary artery banding (PAB) on postnatal day 1. PAB induced neonatal RVOT obstruction, RV PO, and RPF. Neonatal RV PO induced cardiomyocyte proliferation, and neonatal RPF induced pulmonary dysplasia, the 2 features that are not observed in adult RVOT obstruction. As a result, PAB neonates exhibited overall developmental dysplasia, a sign similar to that of children with RVOT obstruction. CONCLUSIONS: Because many pediatric cardiovascular diseases are associated with RV PO and RPF, the introduction of a neonatal mouse model of RVOT obstruction may greatly enhance our understanding of these diseases and eventually improve or save the lives of many children.

A Trinity Nano-Vaccine System with Spatiotemporal Immune Effect for the Adjuvant Cancer Therapy after Radiofrequency Ablation.

Cancer vaccine gains great attention with the advances in tumor immunology and nanotechnology, but its long-term efficacy is restricted by the unsustainable immune activity after vaccination. Here, we demonstrate the vaccine efficacy is negatively correlated with the tumor burden. To maximum the vaccine-induced immunity and prolong the time-effectiveness, we design a priming-boosting vaccination strategy by combining with radiofrequency ablation (RFA), and construct a bisphosphonate nanovaccine (BNV) system. BNV system consists of nanoparticulated bisphosphonates with dual electric potentials (BNV(+&-)), where bisphosphonates act as the immune adjuvant by blocking mevalonate metabolism. BNV(+&-) exhibits the spatial and temporal heterogeneity in lymphatic delivery and immune activity. As the independent components of BNV(+&-), BNV(-) is drained to the lymph nodes, and BNV(+) is retained at the injection site. The alternately induced immune responses extend the time-effectiveness of antitumor immunity and suppress the recurrence and metastasis of colorectal cancer liver metastases after RFA. As a result, this trinity system integrated with RFA therapy, bisphosphonate adjuvant, and spatiotemporal immune effect provides an orientation for the sustainable regulation and precise delivery of cancer vaccines.

Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study.

BACKGROUND: Spread of SARS-CoV-2 led to a global pandemic, and there remains unmet medical needs in the treatment of Omicron infections. VV116, an oral antiviral agent that has potent activity against SARS-CoV-2, was compared with a placebo in this phase 3 study to investigate its efficacy and safety in patients with mild-to-moderate COVID-19. METHODS: This multicentre, double-blind, phase 3, randomised controlled study enrolled adults in hospitals for infectious diseases and tertiary general hospitals in China. Eligible patients were randomly assigned in a 1:1 ratio using permuted block randomisation to receive oral VV116 (0·6 g every 12 h on day 1 and 0·3 g every 12 h on days 2-5) or oral placebo (on the same schedule as VV116) for 5 days. Randomisation stratification factors included SARS-CoV-2 vaccination status and the presence of high-risk factors for progression to severe COVID-19. Inclusion criteria were a positive SARS-CoV-2 test, an initial onset of COVID-19 symptoms 3 days or less before the first study dose, and a score of 2 or more for any target COVID-19-related symptoms in the 24 h before the first dose. Patients who had severe or critical COVID-19 or who had taken any antiviral drugs were excluded from the study. The primary endpoint was the time to clinical symptom resolution for 2 consecutive days. Efficacy analyses were performed on a modified intention-to-treat population, comprising all patients who received at least one dose of VV116 or placebo, tested positive for SARS-CoV-2 nucleic acid, and did not test positive for influenza virus before the first dose. Safety analyses were done on all participants who received at least one dose of VV116 or placebo. This study was registered with ClinicalTrials.gov, NCT05582629, and has been completed. FINDINGS: A total of 1369 patients were randomly assigned to treatment groups and 1347 received either VV116 (n=674) or placebo (n=673). At the interim analysis, VV116 was superior to placebo in reducing the time to sustained clinical symptom resolution among 1229 patients (hazard ratio [HR] 1·21, 95% CI 1·04-1·40; p=0·0023). At the final analysis, a substantial reduction in time to sustained clinical symptom resolution was observed for VV116 compared with placebo among 1296 patients (HR 1·17, 95% CI 1·04-1·33; p=0·0009), consistent with the interim analysis. The incidence of adverse events was similar between groups (242 [35·9%] of 674 patients vs 283 [42·1%] of 673 patients). INTERPRETATION: Among patients with mild-to-moderate COVID-19, VV116 significantly reduced the time to sustained clinical symptom resolution compared with placebo, with no observed safety concerns. FUNDING: Shanghai Vinnerna Biosciences, Shanghai Science and Technology Commission, and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Smart Physical-Based Transdermal Drug Delivery System:Towards Intelligence and Controlled Release.

Transdermal drug delivery systems based on physical principles have provided a stable, efficient, and safe strategy for disease therapy. However, the intelligent device with real-time control and precise drug release is required to enhance treatment efficacy and improve patient compliance. This review summarizes the recent developments, application scenarios, and drug release characteristics of smart transdermal drug delivery systems fabricated with physical principle. Special attention is paid to the progress of intelligent design and concepts in of physical-based transdermal drug delivery technologies for real-time monitoring and precise drug release. In addition, facing with the needs of clinical treatment and personalized medicine, the recent progress and trend of physical enhancement are further highlighted for transdermal drug delivery systems in combination with pharmaceutical dosage forms to achieve better transdermal effects and facilitate the development of smart medical devices. Finally, the next generation and future application scenarios of smart physical-based transdermal drug delivery systems are discussed, a particular focus in vaccine delivery and tumor treatment.

Carvedilol Plus NUC for Patients With HBV-Compensated Cirrhosis Under Virological Suppression: A Randomized Open-Label Trial.

INTRODUCTION: Portal hypertension progression can be relieved after controlling the etiology of liver cirrhosis. Whether beta-blockers could additionally enhance the effects during treatment, particularly for small esophageal varices (EV), was unclear. This study aims to assess the efficacy of add-on carvedilol to delay EV progression during anti-hepatitis B virus (HBV) treatment in HBV-related cirrhosis. METHODS: This randomized controlled trial enrolled patients with virologically suppressed HBV-compensated cirrhosis and small/medium EV. The participants were randomly assigned to receive nucleos(t)ide analog (NUC) or carvedilol 12.5 mg plus NUC (1:1 allocation ratio). The primary end point was the progression rate of EV at 2 years of follow-up. RESULTS: A total of 238 patients (small EV, 77.3%) were randomized into 119 NUC and 119 carvedilol plus NUC (carvedilol [CARV] combination group). Among them, 205 patients (86.1%) completed paired endoscopies. EV progression rate was 15.5% (16/103) in the NUC group and 12.7% (13/102) in the CARV combination group (relative risk = 0.79, 95% confidence interval 0.36-1.75, P = 0.567). Subgroup analysis on medium EV showed the CARV combination group had a more favorable effect in promoting EV regression (43.5% vs 13.1%, P = 0.022) than NUC alone, but not in small cases ( P = 0.534). The incidence of liver-related events (decompensation, hepatocellular carcinoma, or death/liver transplantation) within 2 years was similar between the 2 groups (11.2% vs 10.4%, P = 0.881). DISCUSSION: The overall results did not show statistically significant differences between the added carvedilol strategy and NUC monotherapy in preventing EV progression in patients with virologically suppressed HBV-compensated cirrhosis. However, the carvedilol-added approach might offer improved outcomes specifically for patients with medium EV (NCT03736265).

Identification of risk factors for disseminated cryptococcosis in non-hiv patients: a retrospective analysis.

OBJECTIVE: This study aimed to investigate the potential risk factors associated with disseminated cryptococcosis in HIV-negative individuals. METHODS: A total of 106 HIV-negative patients with cryptococcal disease were enrolled. The observation group consisted of patients with disseminated cryptococcosis (DC), whereas the control groups included patients with pulmonary cryptococcosis (PC) and cryptococcal meningitis (CM). Univariate and multivariate logistic regression algorithms were used to explore the significant clinical and laboratory characteristics that affect the progression of cryptococcal infections. Finally, receiver operating characteristics (ROC) curves are applied to assess the diagnostic value of identified risk factors.LE: Kindly check the edit made in the title.I agree RESULTS: Of the 106 patients, 57 were diagnosed with pulmonary cryptococcosis, 22 with cryptococcal meningitis, and 27 with disseminated cryptococcosis. The logistic regression equation included five variables: diabetes, decompensated liver cirrhosis, long-term use of immunosuppressive agents, decreased serum albumin level, and elevated plasma cytokine IL-10 level. The ROC curves showed that albumin (AUC > 0.7), IL-10 (AUC > 0.7) and decompensated liver cirrhosis (AUC > 0.6) have relatively high diagnostic capacity in predicting the progression of Cryptococcus. CONCLUSION: This study identified elevated IL-10 levels as an independent risk factor for developing disseminated cryptococcosis in the control groups. Furthermore, decompensated liver cirrhosis and decreased serum albumin independently affected the progression of cryptococcosis in the CM and PC groups, respectively.

Quantitative evaluation of colorectal tumour vasculature using contrast-enhanced ultrasound: Correlation with angiogenesis and prognostic significance.

BACKGROUND: Ultrasound is a vital tool for the diagnosis and management of colorectal cancer (CRC). Contrast-enhanced ultrasound (CEUS) is a non-invasive, safe, and cost-effective method for evaluating tumour blood vessels, that play a crucial role in tumour growth and progression. AIM: To explore CEUS's role in the quantitative evaluation of CRC blood vessels and their correlation with angiogenesis markers and prognosis. METHODS: This study prospectively enrolled 100 patients with CRC confirmed by histopathology. All patients received preoperative CEUS examinations. Quantitative parameters, such as peak intensity (PI), time to peak (TTP), and area under the curve (AUC), were derived from time-intensity curve (TIC) analysis. Tumour tissue samples were obtained during surgery and examined immunohistochemically to assess the expression of angiogenesis markers, including vascular endothelial growth factor (VEGF) and microvessel density (MVD). The correlation between CEUS parameters, angiogenesis markers, and clinicopathological features was evaluated using appropriate statistical tests. RESULTS: Quantitative CEUS parameters (PI, TTP, and AUC) showed significant correlations with VEGF expression (P < 0.001) and MVD (P < 0.001), indicating a strong link between tumour blood vessels and angiogenesis. Increased PI, reduced TTP, and expanded AUC values were significantly related to higher tumour stage (P < 0.001), lymph node metastasis (P < 0.001), and distant metastasis (P < 0.001). Furthermore, these parameters were recognized as independent predictors of overall survival and disease-free survival in multivariate analysis (P < 0.001). CONCLUSION: CEUS has a high potential in guiding treatment planning and predicting patient outcomes. However, more comprehensive, multicentre studies are required to validate the clinical utility of CEUS in CRC management.

Haploidentical Cord Blood Transplantation with 8 mg/kg Antithymocyte Globulin as Graft-versus-Host Disease Prophylaxis Compared to Haploidentical Transplantation with 10 mg/kg Antithymocyte Globulin in the Treatment of Acute Leukemia.

Clinical outcomes of the transplantation strategy combined with a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) with low-dose antithymocyte globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis for the treatment of acute leukemia remains unclear. This study aimed to explore the clinical outcomes of haplo-cord HSCT in acute leukemia patients with the GVHD prevention strategy of 8 mg/kg ATG compared with haploidentical transplantation with 10 mg/kg ATG. A total of 130 patients with acute leukemia who underwent allogeneic HSCT between January 2016 and December 2020 were included in this study, including 70 patients who received haploidentical stem cell grafts and unrelated umbilical cord blood units (haplo-cord HSCT) with 8 mg/kg ATG (haplo-cord-ATG8 group) and haploidentical HSCT with 10 mg/kg ATG (haplo-ATG10 group) in 60 patients. Clinical data were collected and analyzed retrospectively. Patients in the haplo-cord-ATG8 group were significantly older compared with the haplo-ATG10 group (P = .000). Haplo-cord HSCT with reduced ATG to 8 mg/kg results in more rapid neutrophil recovery (P = .036). No between-group differences were observed in platelet recovery or the incidences of Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis. The rate of grade II-IV acute GVHD by day 100 post-transplantation was higher in the haplo-ATG10 group (27.16% versus 11.48%; P = .033), as was the rate of chronic GVHD at 1 year (14.60% versus 3.36%; P = .048). The rate of cytomegalovirus reaction was higher in the haplo-ATG10 group (48.31% versus 26.30%; P = .022). With a median follow-up of 27.4 months for the haplo-cord-ATG8 group and 27.5 months for the haplo-ATG10 group, overall survival (OS) at 2 years was 79.4% versus 62.8% (P = .005), event-free survival (EFS) was 76.3% versus 55.9% (P = .001), the cumulative incidence of relapse was 10.11% versus 25.97% (P = .164), and nonrelapse mortality (NRM) was 14.33% versus 24.43% (P = .0040). Multivariate analysis identified Center for International Blood and Marrow Transplant Research Disease Risk Index was the sole significant predictor of relapse, NRM, OS, and EFS. Haplo-cord HSCT supported by cord blood with 8 mg/kg ATG as GVHD prophylaxis results in better outcomes compared with haplo-HSCT with 10 mg/kg ATG.