Repurposing cyclovirobuxine D as a novel inhibitor of colorectal cancer progression via modulating the CCT3/YAP axis.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) ranks second in mortality worldwide and requires effective and affordable remedies. Cyclovirobuxine D (CVB-D) is the main effective component of Huangyangning tablet, an approved traditional patent medicine, which is mainly used for cardiovascular treatment. As a multibioactive natural compound, CVB-D possesses underlying anticancer activities. EXPERIMENTAL APPROACH: Cell viability and clone-forming ability were determined in human CRC lines. Western blot, immunofluorescence assay, transmission electron microscopy and senescence-associated ß-galactosidase (SA-ß-Gal) staining were utilized to investigate cell autophagy and senescence. The molecular mechanisms were explored by virtual prediction and experimental validation. Patient-derived xenograft (PDX), dextran sulfate sodium salt (DSS), and azomethane (AOM)/DSS mouse models were employed for in vivo studies. KEY RESULTS: CVB-D inhibited the growth and development of advanced CRC cells / mice by inducing autophagic and senescent activities through the chaperonin containing TCP1 subunit 3 (CCT3)/yes-associated protein (YAP) axis. CVB-D acted as a promising inhibitor of CCT3 by interacting with its ATP site. In PDX tumours, CVB-D showed potential therapeutic effects by targeting CCT3. Treatment with CVB-D alleviated the mouse model of colitis induced by DSS and attenuated AOM/DSS-induced formation of adenomatous polyps by its action on CCT3. CONCLUSIONS AND IMPLICATIONS: Our study has provided a scientific basis for the suggestion that CVB-D may be recognized as a prospective drug candidate for the therapy of CRC in patients.

Assessment of Early Glaucomatous Optic Neuropathy in the Dog by Spectral Domain Optical Coherence Tomography (SD-OCT).

BACKGROUND: Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the ADAMTS10 gene. Using this model, the study describes early clinical disease markers for canine glaucoma. METHODS: Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, ADAMTS10-mutant (median age 45.6 months, range 28.8-52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/- SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/- SEM 0.53 mmHg). RESULTS: Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/- SEM 38.4 µm to 9.3 +/- SEM 22.1 µm; p < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: -0.78; p < 0.003). There were no significant differences in the thickness of any retinal layers evaluated. CONCLUSIONS: SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin.

Pathogenesis-Related 1 (PR1) Protein Family Genes Involved in Sugarcane Responses to Ustilago scitaminea Stress.

Plant resistance against biotic stressors is significantly influenced by pathogenesis-related 1 (PR1) proteins. This study examines the systematic identification and characterization of PR1 family genes in sugarcane (Saccharum spontaneum Np-X) and the transcript expression of selected genes in two sugarcane cultivars (ROC22 and Zhongtang3) in response to Ustilago scitaminea pathogen infection. A total of 18 SsnpPR1 genes were identified at the whole-genome level and further categorized into four groups. Notably, tandem and segmental duplication occurrences were detected in one and five SsnpPR1 gene pairs, respectively. The SsnpPR1 genes exhibited diverse physio-chemical attributes and variations in introns/exons and conserved motifs. Notably, four SsnpPR1 (SsnpPR1.02/05/09/19) proteins displayed a strong protein-protein interaction network. The transcript expression of three SsnpPR1 (SsnpPR1.04/06/09) genes was upregulated by 1.2-2.6 folds in the resistant cultivar (Zhongtang3) but downregulated in the susceptible cultivar (ROC22) across different time points as compared to the control in response to pathogen infection. Additionally, SsnpPR1.11 was specifically upregulated by 1.2-3.5 folds at 24-72 h post inoculation (hpi) in ROC22, suggesting that this gene may play an important negative regulatory role in defense responses to pathogen infection. The genetic improvement of sugarcane can be facilitated by our results, which also establish the basis for additional functional characterization of SsnpPR1 genes in response to pathogenic stress.

The readiness of malaria services and uptake of intermittent preventive treatment in pregnancy in six sub-Saharan countries.

Background: Malaria infection during pregnancy is associated with an increased risk of maternal death, as well as adverse birth outcomes. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is known to improve pregnancy outcomes. However, the coverage of IPTp-SP in antenatal care (ANC) in sub-Saharan Africa remains well below the target. This study aims to estimate to what extent malaria service readiness affects the uptake of IPTp-SP during ANC visits in sub-Saharan African countries. Methods: This study included 3267 pregnant women attending ANC for the first time and 2797 pregnant women who had attended ANC more than a month ago in six sub-Saharan African countries. The readiness of malaria services at each institution includes four indicators: the presence of IPTp-SP guidelines, SP availability, integration of IPTp-SP service into ANC, and provider training on IPTp-SP. The outcome variable indicates whether a pregnant woman received IPTp-SP at her current ANC visit. A modified Poisson regression model estimated the associations between malaria service readiness and IPTp-SP uptake for women eligible for the first and subsequent doses. Results: For women eligible for their first dose, visiting an institution with available SP was associated with an increased probability of receiving IPTp-SP (risk ratio (RR) = 1.43; 95% confidence interval (CI) = 1.22 to 1.67, P < 0.001). For women who were eligible for their next dose, the availability of SP (RR = 1.17; 95% CI = 1.04 to 1.32, P = 0.008) and integration of IPTp-SP service into ANC (RR = 1.82; 95% CI = 1.21 to 2.74, P = 0.004) in the institution were associated with increased likelihood of IPTp-SP uptake. Counterfactual predictions indicated that enhanced provider training could boost IPTp-SP uptake in high-uptake countries, while better SP availability and IPTp-SP integration into ANC would significantly impact low-uptake countries. Conclusions: For better IPTp-SP coverage, strategies should be customised. High uptake countries should focus on provider training, while low uptake ones should ensure IPTp-SP availability and service integration.

Identification of proteins related to SIS3 by iTRAQ and PRM-based comparative proteomic analysis in cisplatin-induced acute kidney injury.

Background: Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. Methods: The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Results: Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. Conclusion: SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.

Impact evaluation of invisible intimate partner violence on maternal healthcare utilization in Pakistan.

INTRODUCTION: Existing research has shown that intimate partner violence (IPV) may hinder maternal access to healthcare services, thereby affecting maternal and child health. However, current studies have ignored whether emotional intimate partner violence (EV) could negatively affect maternal healthcare use. This study aims to evaluate the impact of invisible IPV on maternal healthcare utilization in Pakistan. METHODS: We analyzed nationally representative data from the Pakistan Demographic and Health Survey database from 2012-2013 and 2017-2018. Exposure to physical intimate partner violence (PV) and EV was the primary predictor. Based on women's last birth records, outcomes included three binary variables indicating whether women had inadequate antenatal care (ANC) visits, non-institutional delivery, and lack of postnatal health check-ups. A logistic regression model was established on weighted samples. RESULTS: Exposure to EV during pregnancy was significantly associated with having inadequate ANC visits (aOR = 2.16, 95% CI: 1.06 to 4.38, p = 0.033) and non-institutional delivery (aOR = 2.24, 95% CI: 1.41 to 3.57, p = 0.001). Lifetime exposure to EV was associated with increased risks of inadequate ANC visits (aOR = 1.48, 95% CI: 1.00 to 2.19, p = 0.049). Lifetime exposure to low-scale physical intimate partner violence (LSPV) (adjusted OR (aOR) = 1.73, 95% CI: 1.29 to 2.31, p < 0.001) was associated with increased risks of having no postnatal health check-ups. CONCLUSIONS: Pregnant women who experienced EV and LSPV are at greater risk of missing maternal healthcare, even if the violence occurred before pregnancy. Therefore, in countries with high levels of IPV, early screening for invisible violence needs to be integrated into policy development, and healthcare providers need to be trained to identify EV and LSPV.

Nanodrug Delivery Systems for Myasthenia Gravis: Advances and Perspectives.

Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by the production of autoantibodies against the postsynaptic membrane receptors present at the neuromuscular junction. This condition is characterized by fatigue and muscle weakness, including diplopia, ptosis, and systemic impairment. Emerging evidence suggests that in addition to immune dysregulation, the pathogenesis of MG may involve mitochondrial damage and ferroptosis. Mitochondria are the primary site of energy production, and the reactive oxygen species (ROS) generated due to mitochondrial dysfunction can induce ferroptosis. Nanomedicines have been extensively employed to treat various disorders due to their modifiability and good biocompatibility, but their application in MG management has been rather limited. Nevertheless, nanodrug delivery systems that carry immunomodulatory agents, anti-oxidants, or ferroptosis inhibitors could be effective for the treatment of MG. Therefore, this review focuses on various nanoplatforms aimed at attenuating immune dysregulation, restoring mitochondrial function, and inhibiting ferroptosis that could potentially serve as promising agents for targeted MG therapy.

Astragaloside IV protects against autoimmune myasthenia gravis in rats via regulation of mitophagy and apoptosis.

Astragaloside IV (AS­IV) has various pharmacological effects, including antioxidant and immunoregulatory properties, which can improve myasthenia gravis (MG) symptoms. However, the potential mechanism underlying the effects of AS­IV on MG remains to be elucidated. The present study aimed to investigate whether AS­IV has a therapeutic effect on MG and its potential mechanism of action. By subcutaneously immunizing rats with R97­116 peptide, an experimental autoimmune (EA) MG rat model was established. AS­IV (40 or 80 mg/kg/day) treatment was then applied for 28 days after modeling. The results demonstrated that AS­IV significantly ameliorated the weight loss, Lennon score and pathological changes in the gastrocnemius muscle of EAMG rats compared with the model group. Additionally, the levels of acetylcholine receptor antibody (AChR­Ab) were significantly decreased, whereas mitochondrial function [ATPase and cytochrome c (Cyt­C) oxidase activities] and ultrastructure were improved in the AS­IV treated rats. Moreover, the mRNA and protein expression levels of phosphatase and tensin homolog­induced putative kinase 1, Parkin, LC3II and Bcl­2, key signaling molecules for mitophagy and apoptosis, were upregulated, whereas the mRNA and protein expression levels of p62, Cyt­C, Bax, caspase 3 and caspase 9 were downregulated following AS­IV intervention. In conclusion, AS­IV may protect against EAMG in a rat model by modulating mitophagy and apoptosis. These findings indicated the potential mechanism underlying the effects of AS­IV on MG and provided novel insights into treatment strategies for MG.

Comparison contrast-enhanced CT with contrast-enhanced US in diagnosing combined hepatocellular-cholangiocarcinoma: a propensity score-matched study.

OBJECTIVES: To develop and compare noninvasive models for differentiating between combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and HCC based on serum tumor markers, contrast-enhanced ultrasound (CEUS), and computed tomography (CECT). METHODS: From January 2010 to December 2021, patients with pathologically confirmed cHCC-CCA or HCC who underwent both preoperative CEUS and CECT were retrospectively enrolled. Propensity scores were calculated to match cHCC-CCA and HCC patients with a near-neighbor ratio of 1:2. Two predicted models, a CEUS-predominant (CEUS features plus tumor markers) and a CECT-predominant model (CECT features plus tumor markers), were constructed using logistic regression analyses. Model performance was evaluated by the area under the curve (AUC), sensitivity, specificity, and accuracy. RESULTS: A total of 135 patients (mean age, 51.3 years ± 10.9; 122 men) with 135 tumors (45 cHCC-CCA and 90 HCC) were included. By logistic regression analysis, unclear boundary in the intratumoral nonenhanced area, partial washout on CEUS, CA 19-9 > 100 U/mL, lack of cirrhosis, incomplete tumor capsule, and nonrim arterial phase hyperenhancement (APHE) volume < 50% on CECT were independent factors for a diagnosis of cHCC-CCA. The CECT-predominant model showed almost perfect sensitivity for cHCC-CCA, unlike the CEUS-predominant model (93.3% vs. 55.6%, p < 0.001). The CEUS-predominant model showed higher diagnostic specificity than the CECT-predominant model (80.0% vs. 63.3%; p = 0.020), especially in the ≤ 5 cm subgroup (92.0% vs. 70.0%; p = 0.013). CONCLUSIONS: The CECT-predominant model provides higher diagnostic sensitivity than the CEUS-predominant model for CHCC-CCA. Combining CECT features with serum CA 19-9 > 100 U/mL shows excellent sensitivity. CRITICAL RELEVANCE STATEMENT: Combining lack of cirrhosis, incomplete tumor capsule, and nonrim arterial phase hyperenhancement (APHE) volume < 50% on CECT with serum CA 19-9 > 100 U/mL shows excellent sensitivity in differentiating cHCC-CCA from HCC. KEY POINTS: 1. Accurate differentiation between cHCC-CCA and HCC is essential for treatment decisions. 2. The CECT-predominant model provides higher accuracy than the CEUS-predominant model for CHCC-CCA. 3. Combining CECT features and CA 19-9 levels shows a sensitivity of 93.3% in diagnosing cHCC-CCA.

Sono-activated materials for enhancing focused ultrasound ablation: Design and application in biomedicine.

The ablation effect of focused ultrasound (FUS) has played an increasingly important role in the biomedical field over the past decades, and its non-invasive features have great advantages, especially for clinical diseases where surgical treatment is not available or appropriate. Recently, rapid advances in the adjustable morphology, enzyme-mimetic activity, and biostability of sono-activated materials have significantly promoted the medical application of FUS ablation. However, a systematic review of sono-activated materials based on FUS ablation is not yet available. This progress review focuses on the recent design, fundamental principles, and applications of sono-activated materials in the FUS ablation biomedical field. First, the different ablation mechanisms and the key factors affecting ablation are carefully determined. Then, the design of sono-activated materials with high FUS ablation efficiencies is comprehensively discussed. Subsequently, the representative biological applications are summarized in detail. Finally, the primary challenges and future perspectives are also outlined. We believe this timely review will provide key information and insights for further exploration of focused ultrasound ablation and new inspiration for designing future sono-activated materials. STATEMENT OF SIGNIFICANCE: The ablation effect of focused ultrasound (FUS) has played an increasingly important role in the biomedical field over the past decades. However, there are also some challenges of FUS ablation, such as skin burns, tumour recurrence after thermal ablation, and difficulty in controlling cavitation ablation. The rapid advance in adjustable morphology, enzyme-mimetic activity, and biostability of sono-activated materials has significantly promoted the medical application of FUS ablation. However, the systematic review of sono-activated materials based on FUS ablation is not yet available. This progress review focuses on the recent design, fundamental principles, and applications in the FUS ablation biomedical field of sono-activated materials. We believe this timely review will provide key information and insights for further exploration of FUS ablation.

Pomegranate (Punica granatum L.) and Its Rich Ellagitannins as Potential Inhibitors in Ulcerative Colitis.

Ulcerative colitis, an immune-mediated inflammatory disease of the gastrointestinal tract, places a significant financial burden on patients and the healthcare system. Recently, reviews of the pomegranate and the abundant medicinal applications of its ellagitannins, as well as its pharmacological action, phytochemicals, metabolism, and pharmacokinetics, have been completed. However, summaries on their anti-ulcerative colitis effects are lacking. Numerous preclinical animal investigations and clinical human trial reports demonstrated the specific therapeutic effects of pomegranate and the effect of its ellagitannins against ulcerative colitis. According to the literature collected by Sci-finder and PubMed databases over the past 20 years, this is the first review that has compiled references regarding how the rich ellagitannins found in pomegranate have altered the ulcerative colitis. It was suggested that the various parts of pomegranates and their rich ellagitannins (especially their primary components, punicalagin, and ellagic acid) can inhibit oxidant and inflammatory processes, regulate the intestinal barrier and flora, and provide an anti-ulcerative colitis resource through dietary management.

Relationship between diabetic knowledge, attitudes and practices among patients with diabetes in China: a structural equation model.

OBJECTIVES: Whether the routine delivery of diabetes-related knowledge can change patients' attitudes and hence influence their self-management activities remains unknown in primary healthcare settings in China. Thus, this study aims to explore the complex transformation process between knowledge, attitude and practice (KAP) among patients with diabetes in a city in China. DESIGN: A cross-sectional study. SETTING: Yuhuan City, Zhejiang Province, China. PARTICIPANTS: A total of 803 patients with diabetes were invited to attend a questionnaire survey and 782 patients with type 2 diabetes completed the survey. The average age of participants was 58.47 years old, 48.21% of whom only attended primary school or below. PRIMARY AND SECONDARY OUTCOME MEASURES: A questionnaire based on existing scales and expert consultation was applied to assess patients' socio-demographic information (SI), disease progression risk and diabetes-related KAP. A structural equation model was built to analyse the relationships between patients' characteristics and KAP. RESULTS: No significant association was found between patients' knowledge and attitude (ß=0.01, p=0.43). Better knowledge and attitude were both found to be associated with better diet and physical activities (ß=0.58, p<0.001; ß=0.46, p=0.01). However, patients with a more positive attitude toward diabetic care showed worse foot care practice (ß=-0.13, p=0.02), while better knowledge was associated with better foot care practice (ß=0.29, p<0.001). In addition, patients with higher SI (ß=0.88, p<0.001) and/or disease progression risk (ß=0.42, p<0.001) tended to present higher levels of disease knowledge. CONCLUSIONS: While successful KAP transformation has been achieved in practice for diet and physical activities, there is a need to improve foot care practice. Health education should also prioritise the prevention, detection and care of diabetic foot. Also, appropriate methods should be adopted to deliver health education to vulnerable patients, such as the elderly, those living in rural areas, those with minimal education, the unemployed and low-income patients.

Overlooked impact of less severe physical violence on antenatal care visits: Findings from South Asia.

Background: In South Asia, women often experience intimate partner violence (IPV) and have limited access to maternal health services (MHS). However, the effects of IPV on antenatal care (ANC) visits remain unclear. This study aimed to examine the impact of IPV of different forms and severities on ANC visits in South Asia. Methods: This cross-sectional study used the latest available data from demographic and health surveys conducted in Bangladesh, India, Afghanistan, Nepal, Maldives, and Pakistan. The study sampled 4467 women who had given birth within the past 12 months and were interviewed for IPV. IPV was measured by binary variables indicating the presence of physical violence (PV), categorised into less severe (LSPV) and severe physical violence (SPV), emotional violence (EV), and sexual violence (SV). ANC utilization was measured using binary variables indicating whether respondents had any, at least four, or at least eight ANC visits, as recommended by World Health Organization (WHO). Logistic regressions adjusted for survey weights were used to assess associations between ANC utilization and exposure to IPV during pregnancy and lifetime. Results: The prevalence of LSPV, SPV, EV, and SV during pregnancy were 14.5%, 4.4%, 11.6%, and 4.1%. LSPV experience during pregnancy was associated with decreased likelihoods of at least four ANC visits (odds ratio (OR) = 0.55; 95% confidence interval (CI) = 0.40-0.76) and eight ANC visits (OR = 0.53; 95% CI = 0.31-0.90). Results of lifetime exposure to IPV followed similar patterns. Lifetime exposure to LSPV was associated with decreased likelihoods of at least four ANC visits (OR = 0.55; 95% CI = 0.41-0.74) and eight ANC visits (OR = 0.47; 95% CI = 0.29-0.77). Conclusion: This study highlights the negativities of LSPV on the frequency of women seeking ANC visits. Policies are necessary to identify women at risk of the often-overlooked LSPV early and provide protective interventions to promote maternal health in South Asia.

A nomogram based on ultrasonographic features and clinical indicators for differentiating mass-forming intrahepatic cholangiocarcinoma and liver metastatic colorectal adenocarcinoma.

Objective: This study aimed to develop and validate a nomogram based on ultrasonographic features and clinical indicators to differentiate mass-forming intrahepatic cholangiocarcinoma (MF-ICC) from hepatic metastatic colorectal adenocarcinoma. Materials and methods: A total of 343 patients with pathologically confirmed MF-ICC or metastatic colorectal adenocarcinoma were enrolled between October 2018 and July 2022. Patients were randomly assigned to training and validation sets at a ratio of 7:3. Preoperative ultrasound features and clinical indicators were retrieved. Univariate logistic regression analysis was employed to select relevant features. Multivariate logistic regression analysis was used to establish a predictive model, which was presented as a nomogram in training sets. The model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: The study included 169 patients with MF-ICC and 174 with liver metastatic colorectal adenocarcinoma, assigned to training (n=238) and validation (n=105) cohorts. The nomogram incorporated ultrasound features (tumor size, lesion number, echogenicity, tumor necrosis, and rim arterial phase hyperenhancement) and clinical information (serum levels of CEA, CA19-9, CA125). The nomogram demonstrated promising performance in differentiating these two entities in both training and validation sets, with an AUC value of 0.937 (95%CI: 0.907,0.969) and 0.916 (95%CI: 0.863,0.968), respectively. The Hosmer-Lemeshow test and calibration curves confirmed good consistency between predictions and observations. Additionally, decision curve analysis confirmed the nomogram's high clinical practicability. Conclusion: The nomogram based on ultrasound features and clinical indicators demonstrated good discrimination performance in differentiating MF-ICC from metastatic colorectal adenocarcinoma, which may enhance clinical decision-making process in managing these challenging diagnostic scenarios.

Efficiency trends of essential public health services and possible influencing factors since the new round health reform in China: a case study from Hainan Province.

Objective: This article aimed to evaluate the efficiency trends and influencing factors of essential public health services in Hainan Province after the healthcare reform launched in 2009 in China. Methods: The efficiency of essential public health services (EPHS) at primary health institutions was assessed using data envelopment analysis (DEA), and the efficiency change was analyzed by employing the Malmquist productivity index (MPI). We used Tobit regression to identify the influence of environmental factors on the efficiency of public health services. The bootstrap method was adopted to reduce the impact of random errors on the result. Results: The bootstrapping bias-corrected efficiency revealed that the average values of technical efficiency, pure technical efficiency, and scale efficiency were 0.7582, 0.8439, and 0.8997, respectively, which meant that the EPHS in Hainan Province were not at the most effective state. The average bias-corrected MPI was 1.0407 between 2010 and 2011 and 1.7404 between 2011 and 2012. MPIs were less than 1.0000 during other periods investigated, ranging from 0.8948 to 0.9714, indicating that the efficiency of EPHS has been decreasing since 2013. The Tobit regression showed that the regression coefficients of per capita GDP, population density, the proportion of older people aged over 65, and the proportion of ethnic minority population were 0.0286, -0.0003, -0.0316, and - 0.0041 respectively, which were statistically significant (p < 0.05). Conclusion: There was a short-term improvement in the efficiency of EPHS in Hainan after the launch of the new round of health reform. However, this trend has not been sustained after 2013. In particular, equalized financial investment in essential public health could not fulfill the needs of poor counties. This has resulted in the inability to improve scale efficiency in some counties, which in turn has affected the improvement of overall EPHS efficiency. Therefore, to promote EPHS efficiency sustainably, it is suggested that under this model of provincial control of counties, the equity of resource allocation should be effectively improved while further advancing the technology of service delivery.

Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.

Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.

Contrast-enhanced ultrasound studies registered on ClinicalTrials.gov: A cross-sectional analysis of characteristics, early discontinuation, and reporting results.

Objective Contrast-enhanced ultrasound offers numerous potential applications in diagnostic and interventional radiology. However, systematic studies on the status of clinical studies are limited. Hence, the aim of this study was to analyze the characteristics of registered contrast-enhanced ultrasound studies on ClinicalTrials.gov and identify features associated with early discontinuation and results reporting. METHODS: A data set containing all contrast-enhanced ultrasound clinical studies from ClinicalTrials.gov registered was downloaded. Then, a cross-sectional descriptive study of clinical contrast-enhanced ultrasound studies was conducted. Cox and logistic regression of early discontinuation and reported results, respectively, were also performed. RESULTS: A total of 225 studies were identified; 174 were interventional and 51 were observational. Regarding the outcomes measure, 175 (77.78%) were diagnosis-oriented, and the remaining 50 (22.22%) were interventional radiology studies. The most common regions of interest were abdominal (56%), superficial (14.22%), or vascular (7.11%) organs. As of the contrast agents, SonoVue/Lumason (39.11%) was most frequently used, followed by Definity (20.89%) and Sonazoid (8.89%). Of all contrast-enhanced ultrasound studies, 32 (14.22%) were discontinued early, and 29 (12.89%) completed studies reported their results. Cox regression analysis revealed that a large sample size and US registration were factors reducing early discontinuation risk. Among completed studies, factors associated with reported results were industry funding and US registration. CONCLUSION: The findings suggest that the number of contrast-enhanced ultrasound studies has grown over time, but is still small. Developing new advancements in contrast-enhanced ultrasound will require a concerted effort to increase the quality and quantity of clinical studies in this field.

Non-invasive evaluation of liver steatosis with imaging modalities: New techniques and applications.

In the world, nonalcoholic fatty liver disease (NAFLD) accounts for majority of diffuse hepatic diseases. Notably, substantial liver fat accumulation can trigger and accelerate hepatic fibrosis, thus contributing to disease progression. Moreover, the presence of NAFLD not only puts adverse influences for liver but is also associated with an increased risk of type 2 diabetes and cardiovascular diseases. Therefore, early detection and quantified measurement of hepatic fat content are of great importance. Liver biopsy is currently the most accurate method for the evaluation of hepatic steatosis. However, liver biopsy has several limitations, namely, its invasiveness, sampling error, high cost and moderate intraobserver and interobserver reproducibility. Recently, various quantitative imaging techniques have been developed for the diagnosis and quantified measurement of hepatic fat content, including ultrasound- or magnetic resonance-based methods. These quantitative imaging techniques can provide objective continuous metrics associated with liver fat content and be recorded for comparison when patients receive check-ups to evaluate changes in liver fat content, which is useful for longitudinal follow-up. In this review, we introduce several imaging techniques and describe their diagnostic performance for the diagnosis and quantified measurement of hepatic fat content.

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Head-to-head comparison of Sonazoid and SonoVue in the diagnosis of hepatocellular carcinoma for patients at high risk.

Objectives: To compare the diagnostic efficacy of SonoVue-enhanced and Sonazoid-enhanced ultrasound (US) for hepatocellular carcinoma (HCC) in patients at high risk. Methods: Between August 2021 and February 2022, participants at high risk for HCC with focal liver lesions were enrolled and underwent both SonoVue- and Sonazoid-enhanced US. Vascular-phase and Kupffer phase (KP) imaging features of contrast-enhanced US (CEUS) were analyzed. The diagnostic performance of both contrast agent-enhanced US according to the CEUS liver imaging reporting and data system (LI-RADS) and the modified criteria (using KP defect instead of late and mild washout) were compared. Histopathology and contrast-enhanced MRI/CT were used as reference standards. Results: In total, 62 nodules, namely, 55 HCCs, 3 non-HCC malignancies and 4 hemangiomas, from 59 participants were included. SonoVue-enhanced US had comparable sensitivity to Sonazoid-enhanced US for diagnosing HCC [80% (95% confidential interval (CI): 67%, 89.6%) versus 74.6% (95% CI: 61%, 85.3%), p = 0.25]. Both SonoVue and Sonazoid-enhanced US achieved a specificity of 100%. Compared with CEUS LI-RADS, the modified criteria with Sonazoid did not improve sensitivity for HCC diagnosis [74.6% (95% CI: 61%, 85.3%) versus 76.4% (95% CI: 63%, 86.8%), p = 0.99]. Conclusions: Sonazoid-enhanced US had comparable diagnostic performance to SonoVue-enhanced US for patients with HCC risk. KP did not considerably improve the diagnostic efficacy, whereas KP defects in atypical hemangioma may be pitfalls in diagnosing HCC. Further studies with larger sample sizes are needed to further validate the conclusions in the present study.