Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

A tempo-spatial controllable microfluidic shear-stress generator for in-vitro mimicking of the thrombus.

Pathological conditions linked to shear stress have been identified in hematological diseases, cardiovascular diseases, and cancer. These conditions often exhibit significantly elevated shear stress levels, surpassing 1000 dyn/cm2 in severely stenotic arteries. Heightened shear stress can induce mechanical harm to endothelial cells, potentially leading to bleeding and fatal consequences. However, current technology still grapples with limitations, including inadequate flexibility in simulating bodily shear stress environments, limited range of shear stress generation, and spatial and temporal adaptability. Consequently, a comprehensive understanding of the mechanisms underlying the impact of shear stress on physiological and pathological conditions, like thrombosis, remains inadequate. To address these limitations, this study presents a microfluidic-based shear stress generation chip as a proposed solution. The chip achieves a substantial 929-fold variation in shear stress solely by adjusting the degree of constriction in branch channels after PDMS fabrication. Experiments demonstrated that a rapid increase in shear stress up to 1000 dyn/cm2 significantly detached 88.2% cells from the substrate. Long-term exposure (24 h) to shear stress levels below 8.3 dyn/cm2 did not significantly impact cell growth. Furthermore, cells exposed to shear stress levels equal to or greater than 8.3 dyn/cm2 exhibited significant alterations in aspect ratio and orientation, following a normal distribution. This microfluidic chip provides a reliable tool for investigating cellular responses to the wide-ranging shear stress existing in both physiological and pathological flow conditions.

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy.

Backgrounds and Aim: Chronic hepatitis C (CHC) patients who fail antiviral therapy have a high risk of developing hepatocellular carcinoma (HCC). We investigated the effects of metformin and statins, commonly used to treat diabetes mellitus (DM) and hyperlipidemia (HLP), on HCC risk in CHC patients who failed antiviral therapy. Methods: CHC patients with failed interferon-based therapy were enrolled in a large-scale multicenter cohort study in Taiwan (T-COACH). HCC occurrence 1.5 years after the end of antiviral therapy was identified by linking to the cancer registry databases from 2003 to 2019. After considering death and liver transplantation as competing risks, Gray's cumulative incidence and Cox sub-distribution hazards for HCC development were used. Results: Among the 2,779 CHC patients, 480 (17.3%) developed new-onset HCC and 238 (8.6%) died after antiviral therapy. Metformin non-users with DM had a 51% higher risk of liver cancer than patients without DM, while statin users with HLP had a 50% lower risk of liver cancer than patients without HLP. The 5-year cumulative incidence of HCC was 16.5% in metformin non-users, significantly higher in metformin non-users than in patients without DM (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Conversely, HLP statin users had a significantly lower HCC risk than patients without HLP (3.8% vs. 12.5%; aSHR=0.50; P<0.001). Notably, the unfavorable effect of non-metformin use on increased HCC risk was mainly observed among patients without cirrhosis but not in patients with cirrhosis. In contrast, a favorable effect of statins reduced the risk of HCC in both cirrhotic and non-cirrhotic patients. Conclusion: Metformin for DM and statins for HLP have chemopreventive effects on HCC risk in CHC patients who failed antiviral therapy. These findings emphasize the importance of personalized preventive strategies for managing patients with these clinical profiles.

Autologous liver transplantation for unresectable hepatobiliary malignancies in enhanced recovery after surgery model.

Ex vivo liver resection combined with autologous liver transplantation offers the opportunity to treat otherwise unresectable hepatobiliary malignancies and has been applied in clinic. The implementation of enhanced recovery after surgery (ERAS) program improves the outcome of surgical procedures. This is a retrospective single-center study including 11 cases of patients with liver cancer that underwent autologous liver transplantation and received ERAS: cholangiocarcinoma of the hilar region (n = 5), intrahepatic cholangiocarcinoma (n = 3), gallbladder cancer (n = 1), liver metastasis from colorectal cancer (n = 1), and liver metastasis from gastrointestinal mesenchymal tumor (n = 1). There were no deaths within 30 days and major complications occurred in two patients, and four patients were readmitted upon the first month after the surgery. Median hospital stay was 20 days (range 13-44) and median open diet was Day 4 (range 2-9) after surgery and median early post-operative activity was Day 5 (range 2-9) after surgery. In conclusion, autologous liver transplantation is feasible in the treatment of otherwise unresectable hepatobiliary malignancies, and our study showed favorable results with autologous liver transplantation in ERAS modality. ERAS modality provides a good option for some patients whose tumors cannot be resected in situ and offers a chance for rapid recovery.

Photocatalytic Bicyclization of Indole-Tethered 1,6-Enynes for Diastereoselective Synthesis of Pyrrolo[3,2,1-jk]carbazoles.

A visible-light-driven photocatalytic protocol is established for the diastereoselective synthesis of pyrrolo[3,2,1-jk]carbazoles via a radical-triggered multicomponent bicyclization reaction starting from readily available indole-tethered 1,6-enynes and α-benzyl-α-bromomalonates under mild conditions. This photocatalytic approach exhibits a wide substrate compatibility and excellent tolerability toward various functional groups and boasts the benefit of efficient ring formation and chemical bond creation.

Photocatalytic Thio/Selenosulfonylation-Bicyclization of Indole-Tethered 1,6-Enynes Leading to Substituted Benzo[c]pyrrolo[1,2,3-lm]carbazoles.

The photocatalyzed radical-triggered thio/selenosulfonylation-bicyclization of indole-tethered 1,6-enynes has been established for the first time, enabling the synthesis of various previously unreported thio/selenosulfonylated benzo[c]pyrrolo[1,2,3-lm]carbazoles with moderate to good yields under mild conditions. The reaction pathway was proposed, consisting of energy transfer, homolytic cleavage, radical addition, 5-exo-dig, radical coupling, and a Mallory reaction cascade. This approach exhibits a wide substrate compatibility and excellent tolerability toward various functional groups and is characterized by its remarkable efficiency in both bond formation and annulation.

Merge-and-Split Graph Convolutional Network for Skeleton-Based Interaction Recognition.

We introduce an innovative approach to address a significant challenge in interaction recognition, specifically the capture of correlation features between different interaction body parts. These features are often overlooked by traditional graph convolution networks commonly used in interaction recognition tasks. Our solution, the Merge-and-Split Graph Convolutional Network, takes a unique perspective, treating interaction recognition as a global problem. It leverages a Merge-and-Split Graph structure to effectively capture dependencies between interaction body parts. To extract the essential interaction features, we introduce the Merge-and-Split Graph Convolution module, which seamlessly combines the Merge-and-Split Graph with Graph Convolutional Networks. This fusion enables the extraction of rich semantic information between adjacent joint points. In addition, we introduce a Short-term Dependence module designed to extract joint and motion characteristics specific to each type of interaction. Furthermore, to extract correlation features between different hierarchical sets, we present the Hierarchical Guided Attention Module. This module plays a crucial role in highlighting the relevant hierarchical sets that contain essential interaction information. The effectiveness of our proposed model is demonstrated by achieving state-of-the-art performance on 2 widely recognized datasets, namely, the NTU60 and NTU120 interaction datasets. Our model's efficacy is rigorously validated through extensive experiments, and we have made the code available for the research community at https://github.com/wanghq05/MS-GCN/.

Multi-step validation of a deep learning-based system with visual explanations for optical diagnosis of polyps with advanced features.

Artificial intelligence (AI) has been found to assist in optical differentiation of hyperplastic and adenomatous colorectal polyps. We investigated whether AI can improve the accuracy of endoscopists' optical diagnosis of polyps with advanced features. We introduced our AI system distinguishing polyps with advanced features with more than 0.870 of accuracy in the internal and external validation datasets. All 19 endoscopists with different levels showed significantly lower diagnostic accuracy (0.410-0.580) than the AI. Prospective randomized controlled study involving 120 endoscopists into optical diagnosis of polyps with advanced features with or without AI demonstration identified that AI improved endoscopists' proportion of polyps with advanced features correctly sent for histological examination (0.960 versus 0.840, p < 0.001), and the proportion of polyps without advanced features resected and discarded (0.490 versus 0.380, p = 0.007). We thus developed an AI technique that significantly increases the accuracy of colorectal polyps with advanced features.

Primary hepatic malignant triton tumor mimicking hepatocellular carcinoma by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging: a case report and literature review.

Background: Malignant Triton tumor (MTT) is a relatively rare subtype of malignant peripheral nerve sheath tumor (MPNST) characterized by rhabdomyosarcoma differentiation. There are no distinct features of MTT, and it is easy to misdiagnose preoperatively. Case presentation: Here, we describe a rare case of primary hepatic MTT in a 56-year-old male who presented with nonspecific abdominal pain for 1 day. Magnetic resonance imaging and abdominal computed tomography revealed an extremely large mass located in the right liver with intratumoral hemorrhage, arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging and the possibility of intrahepatic metastasis. Tumor marker levels revealed only an elevated level of alpha-fetoprotein (AFP: 5304.0 ng/mL). Then, he received transcatheter arterial chemoembolization combined with lenvatinib and pembrolizumab, and he was diagnosed with hepatocellular carcinoma. After 3 months of neoadjuvant therapy, we resected the hepatic cancer and adherent diaphragmatic pleura. MTT was confirmed by postoperative pathology and immunohistochemistry. Conclusion: Despite the preoperative diagnosis of hepatocellular carcinoma with a rising serum AFP level, typical CT and MRI findings, histopathology assessment showing MPNST with rhabdomyosarcoma differentiation confirms the diagnosis of primary hepatic MTT.

Review on Layered Manganese-Based Metal Oxides Cathode Materials for Potassium-Ion Batteries: From Preparation to Modification.

Potassium-ion battery is rich in resources and cheap in price, in the era of lithium-ion battery commercialization, potassium-ion battery is the most likely to replace it. Based on the classification and summary of electrode materials for potassium-ion batteries, this paper focuses on the introduction of manganese-based oxide KxMnO2. The layered KxMnO2 has a large layer spacing and can be embedded with large size potassium-ions. This paper focuses on the preparation and doping of manganese-based cathode materials for potassium-ion batteries, summarizes the main challenges of KxMnO2-based cathode materials in the current stage of research and further looks into its future development direction.

L-shaped association of triglyceride glucose index and sensorineural hearing loss: results from a cross-sectional study and Mendelian randomization analysis.

Background: The association between the sensorineural hearing loss (SNHL) and triglyceride-glucose (TyG) index remains inadequately understood. This investigation seeks to elucidate the connection between the TyG index and SNHL. Methods: In this cross-sectional study, we utilized datasets sourced from the National Health and Nutrition Examination Survey (NHANES). A comprehensive analysis was conducted on 1,851 participants aged 20 to 69, utilizing complete audiometry data from the NHANES database spanning from 2007 to 2018. All enrolled participants had accessible hearing data, and the average thresholds were measured and calculated as both low-frequency pure-tone average and high-frequency pure-tone average. Sensorineural hearing loss (SNHL) was defined as an average pure tone of 20 dB or higher in at least one better ear. Our analysis involved the application of multivariate linear regression models to examine the linear relationship between the TyG index and SNHL. To delineate any non-linear associations, we utilized fitted smoothing curves and conducted threshold effect analysis. Furthermore, we conducted a two-sample Mendelian randomization (MR) study, leveraging genetic data from genome-wide association studies (GWAS) on circulating lipids, blood glucose, and SNHL. The primary analytical method for the MR study was the application of the inverse-variance-weighted (IVW) approach. Results: In our multivariate linear regression analysis, a substantial positive correlation emerged between the TyG index and SNHL [2.10 (1.80-2.44), p < 0.0001]. Furthermore, using a two-segment linear regression model, we found an L-shaped relationship between TyG index, fasting blood glucose and SNHL with an inflection point of 9.07 and 94 mg/dL, respectively. Specifically, TyG index [3.60, (1.42-9.14)] and blood glucose [1.01, (1.00-1.01)] concentration higher than the threshold values was positively associated with SNHL risk. Genetically determined triglyceride levels demonstrated a causal impact on SNHL (OR = 1.092, p = 8.006 × 10-4). In addition, blood glucose was found to have a protective effect on SNHL (OR = 0.886, p = 1.012 × 10-2). Conclusions: An L-shaped association was identified among the TyG index, fasting blood glucose, and SNHL in the American population. TyG index of more than 9.07 and blood glucose of more than 94 mg/dL were significantly and positively associated with SNHL risk, respectively.

Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

BACKGROUND: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood. METHODS: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT‒PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions. RESULTS: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression. CONCLUSIONS: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

Differences in the perceptions of patients with primary biliary cholangitis and physicians from various hospital departments: An online survey.

OBJECTIVES: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that affects the quality of life (QoL) of patients. This study aimed to evaluate the differences in perceptions of PBC among physicians from different hospital departments and patients with PBC. METHODS: An online survey regarding the general knowledge, diagnosis, and management of PBC was completed by physicians and patients. RESULTS: A total of 239 patients with PBC and 239 physicians from eight hospital departments (gastroenterology, infectious diseases, rheumatology, hepatobiliary surgery, pathology, clinical laboratory, ultrasound, and radiology) completed the survey. The results showed that physicians from departments other than gastroenterologists and rheumatologists lacked knowledge of PBC, and that junior gastroenterologists were uncertain about the diagnostic and treatment pathways of PBC. Importantly, the lack of knowledge significantly impacted the QoL of patients, especially the emotional scores of PBC-40 (odds ratio -2.556, 95% confidence interval -3.852 to -1.260, P < 0.001). In addition, there was a perceived knowledge gap between patients and gastroenterologists. CONCLUSIONS: Physicians must improve their awareness of PBC. Patient education and patient-physician communication are important for improving the patient's QoL.

Magnetophoresis-Enhanced Elasto-Inertial Migration of Microparticles and Cells in Microfluidics.

Microfluidic particle and cell manipulation techniques possess many potentials for biomedicine and healthcare. Many techniques have been developed based on active (e.g., electrical, magnetic, acoustic, and thermal) force fields and passive hydrodynamic forces (e.g., inertial and elastic lift forces). However, techniques based on a single active or passive manipulating physics cannot always meet the demands, and combining multiple physics becomes a promising strategy to promote technique flexibility and versatility. In this work, we explored the physical coupling of magnetophoresis with the elastic and inertial (i.e., elasto-inertial) lift forces for the manipulation of microparticles. Particle lateral migration was studied in a coflowing configuration of viscoelastic ferrofluid/water (sample/sheath). The particles were suspended in the viscoelastic ferrofluid and confined near the channel sidewall by a sheath flow. The coordination of magnetophoresis and elasto-inertial lift forces promoted the cross-stream migration of particles. Besides, we investigated the effect of the flow rate ratio and total flow rate on the migration of particles. Furthermore, we also investigated the effects of fluid elasticity in sample and sheath flows on particle migration using different combinations of sample and sheath flows, including Newtonian ferrofluid/water, Newtonian ferrofluid/viscoelastic fluid, and viscoelastic ferrofluid/viscoelastic coflows. Experimental results demonstrated and ascertained the promoted particle lateral migration in the PEO-based ferrofluid/water coflow. Finally, we demonstrate the proof-of-concept application of the physical coupling strategy for cell cross-stream migration and solution exchange. We envisage that this novel multiphysical coupling scheme has great potential for the flexible and versatile manipulation of microparticles and cells.

Understanding the role of red blood cells in venous thromboembolism: A comprehensive review.

Traditionally, red blood cells (RBCs) have been perceived as passive entities within the fibrin network, without any significant role in the pathophysiology of venous thromboembolism (VTE). This review explores the involvement of RBCs in the VTE process, summarizing previous study findings and providing a comprehensive review of the latest theories. At first, it explores the influence of abnormal RBC counts (as seen in polycythemia vera and with erythropoietin use) and the exposure of RBCs to phosphatidylserine (Ptd-L-Ser) in the pathophysiology of VTE. The mechanisms of endothelial injury induced by RBCs and their adhesion to the endothelium under different disease models are then demonstrated. We explore the role of physical and chemical interactions between RBCs and platelets, as well as the interactions between RBCs and neutrophils - particularly the neutrophil extracellular traps (NETs) released by neutrophils - in the process of VTE. Additionally, we investigate the effect of RBCs on thrombin activation through two pathways, namely, the FXIIa-FXI-FIX pathway and the prekallikrein-dependent pathway. Lastly, we discuss the impact of RBCs on clot volume. In conclusion, we propose several potential methods aimed at unraveling the role of RBCs and their interaction with other components in the vascular system in the pathogenesis of VTE.

Microgels for bioprinting: recent advancements and challenges.

Microgels have become a popular and powerful structural unit in the bioprinting field due to their advanced properties, ranging from the tiny size and well-connected hydrogel (nutrient) network to special rheological properties. Different microgels can be fabricated by a variety of fabrication methods including bulk crushing, auxiliary dripping, multiphase emulsion, and lithography technology. Traditionally, microgels can encapsulate specific cells and are used for in vitro disease models and in vivo organ regeneration. Furthermore, microgels can serve as a drug carrier to realize controlled release of drug molecules. Apart from being used as an independent application unit, recently, these microgels are widely applied as a specific bioink component in 3D bioprinting for in situ tissue repair or building special 3D structures. In this review, we introduce different methods used to generate microgels and the microgel-based bioink for bioprinting. Besides, the further tendency of microgel development in future is introduced and predicted to provide guidance for related researchers in exploring more effective ways to fabricate microgels and more potential bioprinting application cases as multifunctional bioink components.

A modified Blumgart method using a homemade crochet needle facilitates pancreaticojejunostomy in laparoscopic pancreaticoduodenectomy: a retrospective cohort study.

BACKGROUND: Among the safest procedures for anastomosis in pancreaticoduodenectomy, Blumgart pancreaticojejunostomy is associated with low rates of postoperative pancreatic fistula (POPF) and postoperative complications. However, this technique is difficult to perform during laparoscopic pancreaticoduodenectomy (LPD). This study presents a modified Blumgart method using a homemade crochet needle to facilitate laparoscopic pancreaticojejunostomy and evaluates its safety and reliability. METHODS: From February 2019 to October 2022, 96 LPD surgeries with the new technique were performed by the same surgeons in the Second Affiliated Hospital of Zhejiang University School of Medicine. The operative details (operative time, pancreaticojejunostomy time, POPF rate, postoperative complication rate, mortality rate) were analyzed along with clinical and pathological indicators (pancreatic duct diameter, pancreatic texture, and histopathological findings). RESULTS: There were 54 men and 42 women with a mean age of 63.38 ± 10.41 years. The intraoperative bleeding volume, operative time and postoperative length of hospital stay were 198.43 ± 132.97 mL, 445.30 ± 87.05 min and 13.68 ± 4.02 days, respectively. The operation time of pancreaticojejunostomy was 66.28 ± 10.17 min. Clinically relevant POPFs (grades B and C) occurred in 14.6% of patients. Only one patient had postoperative abdominal hemorrhage and was cured after reoperation. There were no operative or in-hospital deaths. With our proposed modification, the pancreatic duct and jejunal orifice are aligned correctly during duct-to-mucosa (DTM) after the application of external traction through the homemade crochet needle. The space between the posterior wall of pancreatic remnant and jejunal loop can be exposed by adjusting the tension of the external threads, which can facilitate DTM. CONCLUSIONS: A modified Blumgart method using a homemade crochet needle could be technically feasible and safe during LPD. A randomized control trial is needed to confirm these findings.

Ba4B14O25: A Deep Ultraviolet Transparent Nonlinear Optical Crystal with Strong Second Harmonic Generation Response Achieved by a Boron-Rich Closed-Loop Strategy.

Discovering new deep ultraviolet (DUV) nonlinear optical (NLO) materials is the current research hotspot. However, how to perfectly integrate several stringent performances into a crystal is a great challenge because of the natural incompatibility among them, particularly wide band gap and large NLO coefficient. To tackle the challenge, a boron-rich closed-loop strategy is supposed, based on which a new barium borate, Ba4B14O25, is designed and synthesized successfully via the high-temperature solid-state melting method. It features a highly polymeric 3D geometry with the closed-loop anionic framework [B14O25]8- constructed by the fundamental building blocks [B14O33]24-. The high-density π-conjugated [BO3]3- groups and the fully closed-loop B-O-B connections make Ba4B14O25 possess excellent NLO properties, including short UV cutoff edge (<200 nm), large second harmonic generation response (3.0 × KDP) and phase-matching capability, being a promising DUV-transparent NLO candidate material. The work provides a creative design strategy for the exploration of DUV NLO crystals.

Prevalence of hypertension among type 2 diabetes mellitus patients in China: a systematic review and meta-analysis.

This study aimed to estimate the prevalence of hypertension in Chinese patients with type 2 diabetes mellitus (T2DM) using the results of a regional study. The studies were reviewed using PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, Wan Fang Data and Chinese Science Citation Database. After screening articles and data extraction, Stata V.16 was used for statistical analysis. This study was registered in the Prospective Register Systematic Reviews (CRD42020170649). A total of 2126 articles were identified, and nine papers were finally included. Random-effects modelling showed that the pooled prevalence of hypertension among Chinese patients with T2DM was 54% (95% CI 47 to 61%). Subgroup analysis showed that the prevalence in men (59.8%; 95% CI 49.0 to 70.7%) was higher than that in women (40.2%; 95% CI 29.3 to 59.2%). The prevalence in North China was higher than that in East China. The prevalence in institution-based settings (56%; 95% CI 48 to 64%) was higher than that in community-based settings (51%; 95% CI 34 to 69%). Appropriate preventive measures should be undertaken, such as health education, to control and reduce the risk of hypertension in diabetic patients and reduce the burden of cardiovascular disease.

Endothelial extracellular vesicles induce acute lung injury via follistatin-like protein 1.

Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles (eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of eEVs after cardiopulmonary bypass, remains unclear. Plasma plasminogen-activated inhibitor-1 (PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice (C57BL/6, Toll-like receptor 4 knockout (TLR4-/-) and inducible nitric oxide synthase knockout (iNOS-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3 (JAK2/3)-signal transducer and activator of transcription 3 (STAT3)-interferon regulatory factor 1 (IRF-1) pathway, along with iNOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors (AG490 or S3I-201, respectively), and was relieved in TLR4-/- and iNOS-/- mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1 (FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.