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Abstract Here, this study reports single-band red upconversion emission in β-Ba2ScAlO5: Yb3+/Er3+ phosphor by doping Mn2+. The optimum concentration of Mn2+ ions in β-Ba2ScAlO5: Yb3+/Er3+ phosphor was 0.20. The intensity of red and green emissions is increased by 27.4 and 19.3 times, respectively. Compared with the samples without Mn2+ ions, the red-green integral strength ratio of β-Ba2ScAlO5: Yb3+/Er3+/Mn2+ sample was significantly increased by 28.4 times, reaching 110.9. The UCL mechanism was explored by analyzing the down-conversion luminescence spectra, absorption spectra, UCL spectra, and upconversion fluorescence lifetime decay curves of Yb3+/Er3+/Mn2+ co-doped β-Ba2ScAlO5. The enhancement of upconversion red light is achieved through energy transfer between defect bands and Er3+ ions, as well as energy transfer between Mn2+ ions and Er3+ ions. In addition, the Mn2+ doped β-Ba2ScAlO5: Yb3+/Er3+ red UCL phosphors have great potential for ambient temperature sensing in the 298–523 K temperature range. The maximum sensitivity of β-Ba2ScAlO5: Yb3+/Er3+/Mn2+ phosphor as a temperature sensor at 523 K is 0.0247 K−1.

Abstract With the rapid advancements in spatial transcriptome sequencing, multiple tissue slices are now available, enabling the integration and interpretation of spatial cellular landscapes. Herein, we introduce SpaDo, a tool for multi-slice spatial domain analysis, including modules for multi-slice spatial domain detection, reference-based annotation, and multiple slice clustering at both single-cell and spot resolutions. We demonstrate SpaDo’s effectiveness with over 40 multi-slice spatial transcriptome datasets from 7 sequencing platforms. Our findings highlight SpaDo’s potential to reveal novel biological insights in multi-slice spatial transcriptomes.

Abstract Background The precise characterization of individual tumors and immune microenvironments using transcriptome sequencing has provided a great opportunity for successful personalized cancer treatment. However, the cancer treatment response is often characterized by in vitro assays or bulk transcriptomes that neglect the heterogeneity of malignant tumors in vivo and the immune microenvironment, motivating the need to use single-cell transcriptomes for personalized cancer treatment. Methods Here, we present comboSC, a computational proof-of-concept study to explore the feasibility of personalized cancer combination therapy optimization using single-cell transcriptomes. ComboSC provides a workable solution to stratify individual patient samples based on quantitative evaluation of their personalized immune microenvironment with single-cell RNA sequencing and maximize the translational potential of in vitro cellular response to unify the identification of synergistic drug/small molecule combinations or small molecules that can be paired with immune checkpoint inhibitors to boost immunotherapy from a large collection of small molecules and drugs, and finally prioritize them for personalized clinical use based on bipartition graph optimization. Results We apply comboSC to publicly available 119 single-cell transcriptome data from a comprehensive set of 119 tumor samples from 15 cancer types and validate the predicted drug combination with literature evidence, mining clinical trial data, perturbation of patient-derived cell line data, and finally in-vivo samples. Conclusions Overall, comboSC provides a feasible and one-stop computational prototype and a proof-of-concept study to predict potential drug combinations for further experimental validation and clinical usage using the single-cell transcriptome, which will facilitate and accelerate personalized tumor treatment by reducing screening time from a large drug combination space and saving valuable treatment time for individual patients. A user-friendly web server of comboSC for both clinical and research users is available at www.combosc.top . The source code is also available on GitHub at https://github.com/bm2-lab/comboSC .

While yes-associated protein (YAP) is now recognized as a potent mechanosensitive transcriptional regulator to affect cell growth and differentiation including the osteogenic transcription of mesenchymal stem cells (MSCs), most studies have reported the YAP mechanosensing of static mechanophysical cues such as substrate stiffness. We tested MSC response to dynamic loading, i.e., cyclic mechanical stretching, and assessed YAP mechanosensing and resultant MSC osteogenesis. We showed that cyclic stretching at 10% strain and 1 Hz frequency triggered YAP nuclear import in MSCs. YAP phosphorylation at S127 and S397, which is required for YAP cytoplasmic retention, was suppressed by cyclic stretch. We also observed that anti-YAP-regulatory Hippo pathway, LATS phosphorylation, was significantly decreased by stretch. We confirmed the stretch induction of MSC osteogenic transcription and differentiation, and this was impaired under YAP siRNA suggesting a key role of YAP dynamic mechanosensing in MSC osteogenesis. As an underlying mechanism, we showed that the YAP nuclear transport by cyclic stretch was abrogated by ROCK inhibitor, Y27632. ROCK inhibitor also impaired the stretch induction of F-actin formation and MSC osteogenesis, thus implicating the role of the ROCK-F-actin cascade in stretch-YAP dynamic mechanosensing-MSC osteogenesis. Our results provide insight into bone tissue engineering and skeletal regenerative capacity of MSCs especially as regards the role of dynamic mechanical loading control of YAP-mediated MSC osteogenic transcription.

Little is known about whether preventative practices for post-contrast acute kidney injury (PC-AKI) recommended in guidelines have been adopted in clinical practice and translated into a lower incidence of PC-AKI. The aim of this study was to examine the yearly trends in the incidence of PC-AKI, and comorbidities and care practices associated with PC-AKI in hospitalized patients who received intravenous administration of iodinated contrast medium (ICM). Adult patients receiving intravenous ICM at the Second Xiangya Hospital of Central South University in China between 2015 and 2021 were included. Temporal trends in the incidence and risk factors for PC-AKI were evaluated using logistic regression analyses with adjustments for relevant variables. The incidence of PC-AKI has declined significantly from 5.3% in 2015 to 4.1% in 2021 (p 1000 mL on the day of ICM administration or using iso-osmolar ICM increased. In conclusion, a declining trend in PC-AKI incidence was observed in patients receiving intravenous ICM between 2015 and 2021, which may be related to increased awareness and efforts to prevent PC-AKI.

AbstractContrast-induced acute kidney injury (CI-AKI), which occurs after the use of iodinated contrast media, has become the third leading cause of hospital-acquired acute kidney injury (AKI). It is associated with prolonged hospitalization and increased risks of end-stage renal disease and mortality. The pathogenesis of CI-AKI is unclear and effective treatments are lacking. By comparing different post-nephrectomy times and dehydration times, we constructed a new, short-course CI-AKI model using dehydration for 24 h two weeks after unilateral nephrectomy. We found that the low-osmolality contrast media iohexol caused more severe renal function decline, renal morphological damage, and mitochondrial ultrastructural alterations compared to the iso-osmolality contrast media iodixanol. The shotgun proteomics based on Tandem Mass Tag (TMT) was used to conduct proteomics research on renal tissue in the new CI-AKI model, and 604 distinct proteins were identified, mainly involving complement and coagulation cascade, COVID-19, PPAR signalling pathway, mineral absorption, cholesterol metabolism, ferroptosis, staphylococcus aureus infection, systemic lupus erythematosus, folate biosynthesis, and proximal tubule bicarbonate reclamation. Then, using parallel reaction monitoring (PRM), we validate 16 candidate proteins, of which five were novel candidates (Serpina1, Apoa1, F2, Plg, Hrg) previously unrelated to AKI and associated with an acute response as well as fibrinolysis. The pathway analysis and 16 candidate proteins may help to discover new mechanisms in the pathogenesis of CI-AKI, allowing for early diagnosis and outcome prediction.

AbstractMajor adverse kidney events within 30 d (MAKE30) implicates poor outcomes for elderly patients in the intensive care unit (ICU). This study aimed to predict the occurrence of MAKE30 in elderly ICU patients using machine learning. The study cohort comprised 2366 elderly ICU patients admitted to the Second Xiangya Hospital of Central South University between January 2020 and December 2021. Variables including demographic information, laboratory values, physiological parameters, and medical interventions were used to construct an extreme gradient boosting (XGBoost) -based prediction model. Out of the 2366 patients, 1656 were used for model derivation and 710 for testing. The incidence of MAKE30 was 13.8% in the derivation cohort and 13.2% in the test cohort. The average area under the receiver operating characteristic curve of the XGBoost model was 0.930 (95% CI: 0.912–0.946) in the training set and 0.851 (95% CI: 0.810–0.890) in the test set. The top 8 predictors of MAKE30 tentatively identified by the Shapley additive explanations method were Acute Physiology and Chronic Health Evaluation II score, serum creatinine, blood urea nitrogen, Simplified Acute Physiology Score II score, Sequential Organ Failure Assessment score, aspartate aminotransferase, arterial blood bicarbonate, and albumin. The XGBoost model accurately predicted the occurrence of MAKE30 in elderly ICU patients, and the findings of this study provide valuable information to clinicians for making informed clinical decisions.

AbstractContrast-induced acute kidney injury (CI-AKI) is a severe complication associated with significant morbidity and mortality, and effective therapeutic strategies are still lacking. Apelin is an endogenous physiological regulator with antioxidative, anti-inflammatory and antiapoptotic properties. However, the role of apelin-13 in CI-AKI remains unclear. In our study, we found that the protein expression levels of apelin were significantly downregulated in rat kidney tissues and HK-2 cells during contrast media treatment. Moreover, we explored the protective effect of apelin-13 on renal tubule damage using in vitro and in vivo models of CI-AKI. Exogenous apelin-13 ameliorated endoplasmic reticulum stress, reactive oxygen species and apoptosis protein expression in contrast media-treated cells and rat kidney tissues. Mechanistically, the downregulation of endoplasmic reticulum stress contributed critically to the antiapoptotic effect of apelin-13. Collectively, our findings reveal the inherent mechanisms by which apelin-13 regulates CI-AKI and provide a prospective target for the prevention of CI-AKI.

Abstract Background Treatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused by Staphylococcus aureus (S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival. Methods A mouse model of S. aureus craniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1 Cre IL-10 fl/fl ) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8 Cre IL-10 fl/fl ), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined. Results Granulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+ and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response. S. aureus burden was reduced in Mrp8 Cre IL-10 fl/fl but not CX3CR1 Cre IL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production. Conclusion Collectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.

Recent studies have shown that astronauts experience altered immune response behavior during spaceflight, resulting in heightened susceptibility to illness. Resources and resupply shuttles will become scarcer with longer duration spaceflight, limiting access to potentially necessary medical treatment and facilities. Thus, there is a need for preventative health countermeasures that can exploit in situ resource utilization technologies during spaceflight, such as additive manufacturing (i.e., 3D printing). The purpose of the current study was to test and validate recyclable antimicrobial materials compatible with additive manufacturing. Antimicrobial poly(lactic acid)- and polyurethane-based materials compatible with 3D printing were assessed for antimicrobial, mechanical, and chemical characteristics before and after one closed-loop recycling cycle. Our results show high biocidal efficacy (>90%) of both poly(lactic acid) and polyurethane materials while retaining efficacy post recycling, except for recycled-state polyurethane which dropped from 98.91% to 0% efficacy post 1-year accelerated aging. Significant differences in tensile and compression characteristics were observed post recycling, although no significant changes to functional chemical groups were found. Proof-of-concept medical devices developed show the potential for the on-demand manufacturing and recyclability of typically single-use medical devices using antimicrobial materials that could serve as preventative health countermeasures for immunocompromised populations, such as astronauts during spaceflight.

Transplanting cell cultured brown adipocytes (BAs) represents a promising approach to prevent and treat obesity (OB) and its associated metabolic disorders, including type 2 diabetes mellitus (T2DM). However, transplanted BAs have a very low survival rate in vivo. The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells. There is a critical need for novel methods that can avoid cell death during cell preparation, transplantation, and in vivo. Here, we reported that preparing BAs as injectable microtissues could overcome the problem. We found that 3D culture promoted BA differentiation and UCP-1 expression, and the optimal initial cell aggregate size was 100 μm. The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved. Fabricated microtissues could survive in vivo for long term. They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet (HFD)-induced OB and T2DM mice. Transplanted microtissues impacted multiple organs, secreted protein factors, and influenced the secretion of endogenous adipokines. To our best knowledge, this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice. The proposal of transplanting fabricated BA microtissues, the microtissue fabrication method, and the demonstration of efficacy in T2DM mice are all new. Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability, storage, purity, safety, dosage, survival, and efficacy.

The City of Wuwei was the first place in Gansu province to cultivate grapes for wine production and is representative of wine grape growing in arid areas across China. In the interest of advancing green agricultural development and in order to cope with a changing climate, viticulture in China is experiencing a shift towards greener production methods. In order to do this, a better understanding of the environmental impacts associated with production at the farm level is needed. This study assessed three different wine grape production chains (one organic and two conventional) using life cycle assessment (LCA) in the Wuwei wine region of Gansu Province. Results show that non-renewable energy (NR) consumption is higher at the pre-farm stage compared to on-farm consumption. In addition, nitrogen fertilizer (N) and electricity production, account for 32.5% and 30% respectively in conventional production, whilst in organic farming, electricity generation and pesticide production account for 62% and 22% respectively. Pre-farm activities were found to have a higher impact on global warming potential (GWP) than on-farm operations. The average contribution of N and electricity production was 36% and 32% respectively in conventional production during the pre-farm stage, while in organic farming, the contribution of electricity generation dominated at 68%. Organic fertilizer, N and electricity production are the major contributors to acidification potential (AP) and pesticide production contributes the most to eutrophication potential (EP) in the pre-farm phase·NH3 and NO3--N emissions are dominant contributors to on-farm AP and EP respectively. N2O, NH3, and NO3--N emissions are the top 3 contributors to GWP, AP and EP in the on-farm stage are mainly caused by overuse of N. In general, organic production has a lower environmental impact index than conventional farming. Options for minimizing environmental burdens include: the use of biotic materials in vineyard infrastructure; soil testing-based fertilization; deficit irrigation, policy innovation and strengthening the enabling environment for laws and regulations.

The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived exosomes (Exos) have gained widespread attention as biocompatible vehicles for therapeutics in clinical applications. However, engineering targeted Exos for the peripheral nervous system (PNS) is still challenging. This study aims to develop a targeted Exo delivery system specifically designed for presynaptic terminals of peripheral nerve tissue. The clostridium neurotoxin, tetanus toxin-C fragment (TTC), was tethered to the surface of red blood cell (RBC)-derived Exos via a facile and efficient bio-orthogonal click chemistry method without a catalyst. Additionally, Cyanine5 (Cy5), a reactive fluorescent tag, was also conjugated to track Exo movement in both in vitro and in vivo models. Subsequently, Neuro-2a, a mouse neuronal cell line, was treated with dye-labeled Exos with/without TTC in vitro, and the results indicated that TTC-Exos exhibited more efficient accumulation along the soma and axonal circumference, compared to their unmodified counterparts. Further investigation, using a mouse model, revealed that within 72 h of intramuscular administration, engineered TTC-Exos were successfully transported into the neuromuscular junction and sciatic nerve tissues. These results indicated that TTC played a crucial role in the Exo delivery system, improving the affinity to peripheral nerves. These promising results underscore the potential of using targeted Exo carriers to deliver therapeutics for treating peripheral neuropathies.

Background Hemodialysis (HD) and peritoneal dialysis (PD) are effective ways to treat end-stage renal disease (ERSD). This study aimed to investigate the differences in survival and the factors that influence it in patients with end-stage renal disease treated with HD or PD.Methods We retrospectively analyzed factors related to all-cause death with renal replacement therapy and compared the long-term mortality between HD and PD strategies in patients with ESRD who started HD or PD treatment in our renal HD center between January 1, 2008, and December 1, 2021.Results Overall, 1,319 patients were included, comprising 690 and 629 patients in the HD and PD groups, respectively, according to the inclusion criteria. After propensity matching, 922 patients remained, with 461 (50%) patients each in the two groups. There were no significant differences in the 1-, 2-, 3-, and 4-year mortality rates between the HD and PD groups (all p > .05). However, the 5- and 10-year mortality rates of the matched patients were 15.8%. 17.6% in the HD group and 21.0%. 27.3% in the PD group, respectively. The 5- and 10-year mortality rates were significantly lower in the HD group (all p

Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as connectivity map (CMap) and library of integrated network-based cellular signatures (LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed. Among them, the fundamental issue is to define the proper similarity between transcriptional profiles. Traditionally, such similarity has been defined in an unsupervised way. However, due to the high dimensionality and the existence of high noise in high-throughput data, similarity defined in the traditional way lacks robustness and has limited performance. To this end, we present DrSim, which is a learning-based framework that automatically infers similarity rather than defining it. We evaluated DrSim on publicly available in vitro and in vivo datasets in drug annotation and repositioning. The results indicated that DrSim outperforms the existing methods. In conclusion, by learning transcriptional similarity, DrSim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery. The source code and manual of DrSim are available at https://github.com/bm2-lab/DrSim/.

Abstract Renal artery stenosis (RAS) causes severe renovascular hypertension, worsening kidney function, and increased cardiovascular morbidity. According to recent studies, mesenchymal stem cells (MSCs) administration is a promising therapy for the improvement of RAS outcomes. The meta-analysis aims to evaluate the therapeutic effects of MSC therapy on RAS. We performed a search in MEDLINE, Web of Science, Embase, and Cochrane Library from inception to 5, October 2022. We included 16 preclinical and 3 clinical studies in this meta-analysis. In preclinical studies, the pooled results indicated that animals treated with MSCs had lower levels of systolic blood pressure (SBP) (SMD = − 1.019, 95% CI − 1.434 to − 0.604, I2 = 37.2%, P = 0.000), serum creatinine (Scr) (SMD = − 1.112, 95% CI − 1.932 to − 0.293, I2 = 72.0%, P = 0.008), and plasma renin activity (PRA) (SMD = − 0.477, 95% CI − 0.913 to 0.042, I2 = 43.4%, P = 0.032). The studies also revealed increased levels of renal blood flow (RBF) in stenotic kidney (STK) (SMD = 0.774, 95% CI − 0.351 to 1.197, I2 = 0%, P = 0.000) and the glomerular filtration rate (GFR) of STK (SMD = 1.825, 95% CI 0.963 to 2.688, I2 = 72.6%, P = 0.000). In clinical studies, the cortical perfusion and fractional hypoxia of the contralateral kidney (CLK) were alleviated by MSC therapy. Taken together, this meta-analysis revealed that MSCs therapy might be a promising treatment for RAS. However, due to the discrepancy between preclinical studies and early clinical trials outcomes, MSC therapy couldn’t be recommended in clinical care for the moment, more high-quality randomized controlled clinical trials are needed to validate our conclusions and standardize MSCs protocols.

Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health burden. Exosomes, especially those derived from mesenchymal stem cells (MSCs), are promising as potential cell-free therapeutics and gene therapy vehicles for promoting neural regeneration. In this study, we reported the differentiation of human adipose derived MSCs (hADMSCs) towards the Schwann cell (SC) phenotype (hADMSC-SCs) and then isolated exosomes from hADMSCs with and without differentiation (i.e., dExo vs uExo). We assessed and compared the effects of uExo and dExo on antioxidative, angiogenic, anti-inflammatory, and axon growth promoting properties by using various peripheral nerve-related cells. Our results demonstrated that hADMSC-SCs secreted more neurotrophic factors and other growth factors, compared to hADMSCs without differentiation. The dExo isolated from hADMSC-SCs protected rat SCs from oxidative stress and enhanced HUVEC migration and angiogenesis. Compared to uExo, dExo also had improved performances in downregulating pro-inflammatory gene expressions and cytokine secretions and promoting axonal growth of sensory neurons differentiated from human induced pluripotent stem cells. Furthermore, microRNA (miRNA) sequencing analysis revealed that exosomes and their parent cells shared some similarities in their miRNA profiles and exosomes displayed a distinct miRNA signature. Many more miRNAs were identified in dExo than in uExo. Several upregulated miRNAs, like miRNA-132-3p and miRNA-199b-5p, were highly related to neuroprotection, anti-inflammation, and angiogenesis. The dExo can effectively modulate various peripheral nerve-related cellular functions and is promising for cell-free biological therapeutics to enhance neural regeneration.

Abstract Acute kidney injury (AKI) is common among hospitalized children and is associated with a poor prognosis. The study sought to develop machine learning-based models for predicting adverse outcomes among hospitalized AKI children. We performed a retrospective study of hospitalized AKI patients aged 1 month to 18 years in the Second Xiangya Hospital of Central South University in China from 2015 to 2020. The primary outcomes included major adverse kidney events within 30 days (MAKE30) (death, new renal replacement therapy, and persistent renal dysfunction) and 90-day adverse outcomes (chronic dialysis and death). The state-of-the-art machine learning algorithm, eXtreme Gradient Boosting (XGBoost), and the traditional logistic regression were used to establish prediction models for MAKE30 and 90-day adverse outcomes. The models’ performance was evaluated by split-set test. A total of 1394 pediatric AKI patients were included in the study. The incidence of MAKE30 and 90-day adverse outcomes was 24.1% and 8.1%, respectively. In the test set, the area under the receiver operating characteristic curve (AUC) of the XGBoost model was 0.810 (95% CI 0.763–0.857) for MAKE30 and 0.851 (95% CI 0.785–0.916) for 90-day adverse outcomes, The AUC of the logistic regression model was 0.786 (95% CI 0.731–0.841) for MAKE30 and 0.759 (95% CI 0.654–0.864) for 90-day adverse outcomes. A web-based risk calculator can facilitate the application of the XGBoost models in daily clinical practice. In conclusion, XGBoost showed good performance in predicting MAKE30 and 90-day adverse outcomes, which provided clinicians with useful tools for prognostic assessment in hospitalized AKI children.

Abstract Coronary artery disease (CAD) is one of the major cardiovascular diseases and represents the leading causes of global mortality. Developing new diagnostic and therapeutic approaches for CAD treatment are critically needed, especially for an early accurate CAD detection and further timely intervention. In this study, we successfully isolated human plasma small extracellular vesicles (sEVs) from four stages of CAD patients, that is, healthy control, stable plaque, non‐ST‐elevation myocardial infarction, and ST‐elevation myocardial infarction. Surface‐enhanced Raman scattering (SERS) measurement in conjunction with five machine learning approaches, including Quadratic Discriminant Analysis, Support Vector Machine (SVM), K‐Nearest Neighbor, Artificial Neural network, were then applied for the classification and prediction of the sEV samples. Among these five approaches, the overall accuracy of SVM shows the best predication results on both early CAD detection (86.4%) and overall prediction (92.3%). SVM also possesses the highest sensitivity (97.69%) and specificity (95.7%). Thus, our study demonstrates a promising strategy for noninvasive, safe, and high accurate diagnosis for CAD early detection.

Summary: Background: The evidence of radiofrequency ablation (RFA) following transarterial chemoembolisation (TACE) combined with sorafenib for intermediate-stage recurrent hepatocellular carcinoma (RHCC) is limited. Patient responses to this treatment vary because of the heterogeneous nature of RHCC, making it important to identify patients who are most likely to benefit from this combination therapy. The aim of this study was to evaluate the efficacy of RFA following TACE and sorafenib for the intermediate-stage RHCC. Methods: This retrospective, multicentre, cohort study included 363 patients with intermediate-stage RHCC underwent TACE combined with sorafenib (TACE-sorafenib group) or RFA following TACE and sorafenib (TACE-sorafenib + RFA group) between January 01, 2009 to December 31, 2015 from four institutions in China. Overall survival (OS), progression-free survival (PFS) and efficacy of patients were compared between the two groups by propensity score–matching (PSM). Findings: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% in TACE-sorafenib + RFA group, and 93.3%, 57.0%, 32.7% in TACE-sorafenib group. The 1-, 2-, and 3-year PFS rates were 85.3%, 58.0%, 26.9% in TACE-sorafenib + RFA group, and 55.3%, 30.7%, 15.3% in TACE-sorafenib group. Compared with the TACE-sorafenib group, the TACE-sorafenib + RFA group had significantly longer OS (HR, 0.54; 95%CI, 0.40–0.73; P