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Objective. This systematic review and meta-analysis aimed to compare the diagnostic performance of transient elastography (TE) and two-dimensional shear wave elastography (2D-SWE) for staging liver fibrosis in patients with chronic viral hepatitis (CVH). Methods. Pubmed, Embase, Web of Science, and Cochrane Library were searched (-01/08/2021) for studies comparing TE with 2D-SWE in patients with CVH. Other etiologies of chronic liver disease (CLD) and articles not published in SCI journals were excluded. The bivariate random-effects model was used to pool the performance of the TE and 2D-SWE. Results. Eight articles with a total of 1301 CVH patients were included. The prevalence of significant fibrosis ( fibrosis stage ≥ 2 ), advanced fibrosis ( fibrosis stage ≥ 3 ), and cirrhosis was 50.8%, 44.8%, and 34.7%, respectively. 2D-SWE expressed higher overall accuracy than TE in detecting significant fibrosis (0.93 vs. 0.85, P = 0.04 ). No significant difference among the overall diagnostic accuracy of TE and 2D-SWE in staging advanced fibrosis and cirrhosis was found. Conclusion. TE and 2D-SWE express good to excellent diagnostic accuracies to stage fibrosis in CVH patients. 2D-SWE compares favorably with TE especially for predicting significant fibrosis.

Lumbar transforaminal epidural block (LTEB) is a minimally invasive interventional method, and the interventional effect of LTEB on the treatment of low back pain with radicular pain is not yet clear; therefore, a total of 100 patients with low back pain with radicular pain treated in our hospital from January 2021 to December 2021 were included in this study, and they were divided into two groups of 50 each using a digital double-blind method. The control group was treated conservatively, and the study group was treated with LTEB. Patients’ pain was assessed using the numerical rating scale (NRS), and the degree of functional impairment was assessed using the Oswestry disability index (ODI). The results of the study showed comparable differences in NRS scores for low back pain, NRS scores for lower extremities, and ODI scores of patients before treatment ( t = 0.071 , 0.035 , 0.007 , P > 0.05 ). After treatment, patients in the control group had a low back pain NRS score ( 4.00 ± 0.85 ), lower extremity NRS score ( 3.87 ± 0.78 ), ODI score ( 58.25 ± 2.53 ), and low back pain NRS score ( 2.00 ± 0.54 ), while the study group had a lower extremity NRS score ( 2.00 ± 0.50 ) and ODI score ( 58.25 ± 2.53 ) that were statistical significance ( t = 0.071 , 0.035 , 24.218 , P < 0.001 ). In conclusion, treatment with LTEB can effectively reduce the pain and improve the functional impairment of patients with low back pain with radicular pain, which is clinically important.

Pneumonia infection is the leading cause of death in young children. The commonly used pneumonia detection method is that doctors diagnose through chest X-ray, and external factors easily interfere with the results. Assisting doctors in diagnosing pneumonia in patients based on deep learning methods can effectively eliminate similar problems. However, the complex network structure and redundant parameters of deep neural networks and the limited storage and computing resources of clinical medical hardware devices make it difficult for this method to use widely in clinical practice. Therefore, this paper studies a lightweight pneumonia classification network, CPGResNet50 (ResNet50 with custom channel pruning and ghost methods), based on ResNet50 pruning and compression to better meet the application requirements of clinical pneumonia auxiliary diagnosis with high precision and low memory. First, based on the hierarchical channel pruning method, the channel after the convolutional layer in the bottleneck part of the backbone network layer is used as the pruning object, and the pruning operation is performed after its normalization to obtain a network model with a high compression ratio. Second, the pruned convolutional layers are decomposed into original convolutions and cheap convolutions using the optimized convolution method. The feature maps generated by the two convolution parts are combined as the input to the next convolutional layer. Further, we conducted many experiments using pneumonia X-ray medical image data. The results show that the proposed method reduces the number of parameters of the ResNet50 network model from 23.7 M to 3.455 M when the pruning rate is 90%, a reduction is more than 85%, FIOPs dropped from 4.12G to 523.09 M, and the speed increased by more than 85%. The model training accuracy error remained within 1%. Therefore, the proposed method has a good performance in the auxiliary diagnosis of pneumonia and obtained good experimental results.

Once the sludge was directly used in the farmland, it will have a negative impact on human health through the food chain because sludge contains pollutants. Sewage sludge pyrolysis into biochar is an effective way to realize sludge harmless and resourceful utilization. This research used hydrothermal carbonization method to convert sludge into sludge biochar (SLBC) to reduce the types and contents of pharmaceuticals and personal care products (PPCPs) and available heavy metals. Furthermore, migration of the residual caffeine (Caf), acetaminophen (Ace), and heavy metals (Cr, Pb, Cu, Zn) released from the SLBC in the wheat was assessed. The results showed that the levels of Caf, Ace, Pb, Cu, and Zn accumulated in the shoots were lower than the limit regulated by Drug and Food Additive Use Standard in China (Caf: 150 mg/kg; Ace: 2.5 ~ 5 mg/kg; Pb: 0.3 mg/kg; Cu: 10 mg/kg; Zn: 20 mg/kg). The migration of Cr from roots to shoots was also significantly controlled by SBLC. SBLC delayed the germination time of wheat seeds with increasing in hydrothermal temperature, the germination rate and root length showed a decreasing trend. Evans blue and O

Background: Animal models demonstrate circulating aldosterone leads to aortic dissection and aneurysm, whereas data from humans are lacking. Therefore, we aimed to examine the associations of plasma aldosterone concentrations (PAC) with aortic dissection and aneurysm. Methods: We identified patients with aortic dissection and aneurysm with assessed PAC before disease onset from hospital-based electronic database and set as case group. Simultaneously, age and gender-matched cohort with PAC measurement whereas without aortic dissection and aneurysm were selected as control group using ratio of 1:4. Multi-variable logistic regression analysis was used to assess the relationship of PAC with aortic dissection and aneurysm. Results: Totally, 133 cases and 531 controls (all hypertensive) were enrolled between 2004 and 2021, with 77.9% men, mean age of 55.5 years and PAC of 13.9 ng/dL. Case group showed significantly higher PAC(14.51 versus 13.65 ng/dL, P =0.012) than did control group. In logistic regression analysis, higher PAC exhibited 1.68-fold higher odds (95% CI, 1.14–2.48, P =0.008) for presence of aortic dissection and aneurysm, significant in adjusted model (odds ratio, 1.69 [95% CI, 1.11–2.57], P =0.015). In stratified analysis, the association between the two was observed in women of all ages and in men with coronary artery disease. Sensitivity analysis by excluding those under interfering agents at PAC measurement and those with primary aldosteronism did not change the relationship of the two. Conclusions: Higher PAC is associated with the increased odd for aortic dissection and aneurysm in patients with hypertension, even in the absence of primary aldosteronism, implying that PAC might be a target for prevention.

Vascular remodeling contributes to the development of a variety of vascular diseases including hypertension and atherosclerosis. Phenotypic transformation of vascular cells, oxidative stress, inflammation and vascular calcification are closely associated with vascular remodeling. Extracellular vesicles (EVs) are naturally released from almost all types of cells and can be detected in nearly all body fluids including blood and urine. EVs affect vascular oxidative stress, inflammation, calcification, and lipid plaque formation; and thereby impact vascular remodeling in a variety of cardiovascular diseases. EVs may be used as biomarkers for diagnosis and prognosis, and therapeutic strategies for vascular remodeling and cardiovascular diseases. This review includes a comprehensive analysis of the roles of EVs in the vascular remodeling in vascular diseases, and the prospects of EVs in the diagnosis and treatment of vascular diseases.

Abnormal changes in intracellular viscosity and cysteine are both associated with several important biological processes such as reversible redox reaction, which plays a pivotal role in the process of inflammation. However, it remains unclear how cysteine and viscosity alter in inflammation. Herein, we firstly report a high sensitivity and selectivity near-infrared imaging probe (FCV) for tracking intracellular viscosity and endogenous cysteine. This dual-functional probe displays excellent photostability and large Stokes shifts. FCV exhibites a 54-fold enhancement in fluorescence emission at 560 nm with the increasing of Cys (λex =420 nm), and increases about 63-fold at 660 nm (λex = 460 nm) with the viscosity from 1.0 cP to 952.5 cP. Moreover, FCV reveals the synergistic relationship between viscosity and cysteine in the inflammation model of living cells and zebrafish for the first time. Thus, FCV is a promising vehicle to identify the alternation of Cys and viscosity in associated diseases.

Background Resting-state functional magnetic resonance imaging has been widely used for the assessment of brain functional network, yet with inconsistent results. The present study aimed to investigate intranetwork and internetwork connectivity differences between patients with major depressive disorder (MDD) and healthy controls at the integrity, network and edge levels of 8 well-defined resting state networks. Methods Thirty patients with MDD and sixty-three healthy control subjects were recruited in this study. Results Compared with healthy controls, patients with MDD showed increased node degree in the right amygdala and putamen, increased connectivity strength in the deep gray matter network (DGN) and increased functional connectivity in intranetwork and internetwork. Meanwhile, MDD showed decreased connectivity strength in visual network-DGN pair. Limitations The sample size was small, and all patients in this study were of Asian ethnicity, especially Han individuals. Conclusions These findings demonstrate that MDD cases and healthy controls may have divergent intranetwork and internetwork connectivity at an early stage without confounding influence of medication. These differences may underlie cognitive and behavioral alterations in patients with MDD. And these differences may help with the discrimination of patients and healthy people at an early stage of MDD. More studies in the future are warranted to assist in the diagnosis of this burdensome disease.

Cardiac fibrosis is an essential pathological process in pressure overload (PO)-induced heart failure. Recently, myocyte-fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs-containing exosomes (Exos). Peli1 regulates the activation of NF-κB and AP-1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNA-mediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM-conditional deletion of Peli1 improved PO-induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)-induced WT CMs (WT MS-Exos) promote activation of CFs, Peli1

BackgroundThe current status of the dose-response relationship between the metabolic score for insulin resistance (METS-IR) and new-onset stroke in hypertensive patients and its subtypes is unclear. This study aimed to determine the association between METS-IR and incident stroke and its subtypes within a cohort of Chinese hypertensive patients.MethodsA total of 14032 hospitalized patients with hypertension from January 1, 2010, to December 31, 2021, were included in this retrospective cohort study. Cox models and restricted cubic splines were applied to determine the association between METS-IR and the risk of stroke.ResultsDuring a median follow-up of 4.80 years, 1067 incident stroke cases occurred. Patients in the highest quartile group of METS-IR levels exhibited a higher risk of stroke (HR, 1.80; 95% CI, 1.50-2.17) and ischemic stroke (HR, 1.96; 95% CI, 1.60–2.42) than those in the lowest quartile group. However, no significant associations were observed between METS-IR and the risk of hemorrhagic stroke. Restricted cubic spline analysis suggested a nearly J-shaped association between METS-IR and risk of stroke and ischemic stroke (P for nonlinearity < 0.001). METS-IR did produce a significant improvement in the C statistic when added to the basic model (from 0.637 to 0.664, P < 0.001). Notably, the addition of METS-IR to the basic model resulted in a significant improvement in predicting incident total stroke and ischemic stroke.ConclusionsThis cohort study suggests a relationship between METS-IR and the risk of stroke and ischemic stroke. Further studies are required to elucidate the underlying mechanisms.

OBJECTIVES/HYPOTHESIS To develop a deep-learning-based automatic diagnosis system for identifying nasopharyngeal carcinoma (NPC) from noncancer (inflammation and hyperplasia), using both white light imaging (WLI) and narrow-band imaging (NBI) nasopharyngoscopy images. STUDY DESIGN Retrospective study. METHODS A total of 4,783 nasopharyngoscopy images (2,898 WLI and 1,885 NBI) of 671 patients were collected and a novel deep convolutional neural network (DCNN) framework was developed named Siamese deep convolutional neural network (S-DCNN), which can simultaneously utilize WLI and NBI images to improve the classification performance. To verify the effectiveness of combining the above-mentioned two modal images for prediction, we compared the proposed S-DCNN with two baseline models, namely DCNN-1 (only considering WLI images) and DCNN-2 (only considering NBI images). RESULTS In the threefold cross-validation, an overall accuracy and area under the curve of the three DCNNs achieved 94.9% (95% confidence interval [CI] 93.3%-96.5%) and 0.986 (95% CI 0.982-0.992), 87.0% (95% CI 84.2%-89.7%) and 0.930 (95% CI 0.906-0.961), and 92.8% (95% CI 90.4%-95.3%) and 0.971 (95% CI 0.953-0.992), respectively. The accuracy of S-DCNN is significantly improved compared with DCNN-1 (P-value

Background There are few reports regarding the influence of varying illumination on the compensation effect before and after corneal refractive surgery. We aimed to evaluate the changes in refraction, higher-order aberrations, and aberration compensation between mesopic and photopic illumination before and after small incision lenticule extraction. Methods In this prospective cohort study, only the right eyes of patients who underwent small incision lenticule extraction for the correction of myopia and myopic astigmatism at the Tianjin Eye Hospital were included. Wavefront refraction and higher-order aberrations were measured preoperatively and 3 months postoperatively under mesopic and photopic illumination. Compensation factors were calculated as 1 − (aberration of the whole eye/aberration of the anterior corneal surface). Results Forty patients undergoing small incision lenticule extraction were enrolled. All surgeries were completed without postoperative complications. Preoperatively, the eyes only had a statistically significantly higher (t = − 4.589, p t = − 3.013, p = .005) astigmatism (− 0.608 [0.414] vs. − 0.382 [0.319] D). Differences in spherical refraction between the two illuminations were the highest in postoperative eyes (Δ > 0.5 D). Only postoperative eyes exhibited statistically significant elevations (t ≥ 4.081, p < .001) in higher-order aberrations under mesopic illumination, and only preoperative eyes exhibited statistically significantly enhanced (χ2 = 6.373, p = .01 for fourth-order and χ2 = 11.850, p = .001 for primary spherical aberrations) and decreased (χ2 = 13.653, p = .001 for horizontal trefoil) compensation factors under mesopic illumination. Conclusions Exaggerations in higher-order aberrations and myopic shift after small incision lenticule extraction became apparent under mesopic illumination. Slight undercorrection may have an enhanced effect under low illumination and may reduce night vision. The specific changes in compensation effects in preoperative eyes may improve optical quality under mesopic illumination. Postoperative eyes have reduced compensation ability, specifically for spherical aberrations, under mesopic illumination, which may diminish night vision. Further studies that include the measurement of subjective night vision parameters should be conducted.

We here showed that ADCK1 (AarF domain-containing kinase 1), a mitochondrial protein, is upregulated in human osteosarcoma (OS) tissues and OS cells. In primary and established OS cells, ADCK1 shRNA or CRISPR/Cas9-induced ADCK1 knockout (KO) remarkably inhibited cell viability, proliferation and migration, and provoked apoptosis activation. Conversely, ectopic ADCK1 overexpression exerted pro-cancerous activity by promoting OS cell proliferation and migration. ADCK1 depletion disrupted mitochondrial functions in OS cells and induced mitochondrial membrane potential reduction, ATP depletion, reactive oxygen species production. Significantly, ADCK1 silencing augmented doxorubicin-induced apoptosis in primary OS cells. mTOR activation is important for ADCK1 expression in OS cells. The mTOR inhibitors, rapamycin and AZD2014, as well as mTOR shRNA, potently decreased ADCK1 expression in primary OS cells. In nude mice, the growth of subcutaneous pOS-1 xenografts was largely inhibited when bearing ADCK1 shRNA or ADCK1 KO construct. Moreover, ADCK1 KO largely inhibited pOS-1 xenograft in situ growth in proximal tibia of nude mice. ADCK1 depletion, apoptosis activation and ATP reduction were detected in pOS-1 xenografts bearing ADCK1 shRNA or ADCK1 KO construct. Together, the mitochondrial protein ADCK1 is required for OS cell growth and is a novel therapeutic target of OS.

Background The aim was to evaluate the causes of death for patients with localized, regional and metastatic penile cancer (PeCa) after diagnosis. Methods PeCa patients diagnosed during 2004-2018 in the Surveillance, Epidemiology, and End Results program database were identified. Causes of deaths including PeCa, second malignant tumors (SMTs) and non-tumor diseases were analyzed, as well as the standardized mortality ratio (SMR) of each cause. Results For localized PeCa, 800 of 2155 patients died during the follow-up. 24.9% of all deaths were due to PeCa. 18.0% and 57.1% deaths were due to SMTs and non-tumor causes. Main SMTs included cancers of lung and bronchus (n = 40) and skin (n = 11) with significantly increased SMRs of 1.71 (1.22-2.33) and 4.82 (2.41-8.63). Mortality risks of other SMTs were mostly similar with the general populations. Main causes of non-tumor diseases included diseases of heart [n = 172, SMR: 1.66 (1.42-1.93)], COPD and allied cond [n = 38, SMR: 1.63 (1.15-2.24)], and cerebrovascular diseases [n = 33, SMR: 1.71 (1.17-2.4)]. For regional PeCa, 679 of 1310 patients died including 43.5% PeCa, 14.8% SMTs and 26.6% non-tumor causes. The mortality risks of cancers from lung and bronchus [SMR: 2.41 (1.53-3.62)], skin [SMR: 6.41 (2.35-13.95)] and testis [SMR: 149.35 (18.09-539.5)] were significantly increased. Main non-tumor causes of death included diseases of heart [n = 71, SMR: 1.77 (1.38-2.23)], COPD and allied cond [n = 17, SMR: 1.85 (1.08-2.95)] and diabetes mellitus [n = 16, SMR: 3.62 (2.07-5.88)]. For distant diseases, 109 of 132 patients died including 76 (69.7%) died for PeCa itself, 24 (22.0%) died for SMTs and 9 (8.3%) died for non-tumor diseases. The majority of PeCa deaths (67.1%) and SMTs deaths (79.2%) occurred within 1 year after the diagnosis of PeCa. Conclusions We firstly analyzed the SMTs and non-tumor causes of death and morality risks of each cause for PeCa patients, which provided valuable information for PeCa patients on disease prevention and health care during their survivorship.

Based on the self-determination theory, to explore the relationship between motivation quality and college studentsapos; physical fitness and the mediating role of physical activities from the perspective of the coexistence of autonomous motivation(AM) and controlled motivation(CM).From October to November 2019, a total of 682 freshmen and sophomores(252 males and 430 females) were recruited with cluster-sampling method from 4 colleges and universities in Wuhu City, filled with questionnaires of Perceived Locus of Causality scale and Godinapos;s leisure-time physical activity questionnaire, and tested physical fitness according to China National Fitness Test Program after 6 weeks. The data were analyzed by polynomial regression combined with response surface analysis and mediation effect test.Physical fitness presented a "convex" curve increase with the consistency of AM and CM(a1=1.547, a2=1.254, Plt;0.01). The physical fitness of high AM-high CM combination was higher than that of low AM-low CM combination(Z_(hat)=3.111, 95% CI 0.446-5.896). Under the condition of AM and CM differentiation, physical fitness was higher when the discrepancy was such that AM was higher than CM(a3=5.280, Plt;0.01; a4=0.232, Pgt;0.05). AM positively predicted physical activity in a nonlinear form(β_( AM)=1.605, β_(AM)~2=1.602, Plt;0.01). Physical activity showed a "convex" change with the consistency of AM-CM(a1=0.811, Pgt; 0.05; a2=1.618, Plt;0.01), but there was no significant difference in the level of physical activity between high and low AM-CM combination(Z_(hat)=1.407, 95% CI-0.084-3.391). Physical activity was higher in high AM-low CM combination than that in high CM-low AM combination(Z_(hat)=5.008, 95% CI 2.348-7.113). Matching of AM and CM influenced college studentsapos; physical fitness directly(β=0.453, Plt;0.01) and indirectly through physical activity(β=0.184, 95% CI 0.145-0.240).The coexistence of AM and CM effects physical fitness through their consistency and inconsistency matching.

Small non-coding RNAs are widespread in the biological world and have been extensively explored over the past decades. Their fundamental roles in human health and disease are increasingly appreciated. Furthermore, a growing number of studies have investigated the functions of small non-coding RNAs in cancer initiation and progression. In this review, we provide an overview of the biogenesis of small non-coding RNAs with a focus on microRNAs, PIWI-interacting RNAs, and a new class of tRNA-derived small RNAs. We discuss their biological functions in human cancer and highlight their clinical application as molecular biomarkers or therapeutic targets.

Animal medicine is an important part of traditional Chinese medicine(TCM). Bear bile is one of the rare animal-derived medicinal materials with the functions of clearing the liver, promoting bile secretion, calming the liver, relieving convulsions, clearing heat, and removing toxins. From the Jin Dynasty to the Tang Dynasty, bear bile was mainly used to treat internal diseases, surgical diseases, and pediatric diseases with limitations. At present, bear bile has been used to treat various diseases in pediatrics, gynecology, internal medicine, and surgery. Studies on the chemical constituents and pharmacological effects of bear bile mostly focused on bile acids. Although the non-bile acids also showed certain pharmacological effects, their mechanism of action was less investigated. At present, the source animals of bear bile are national second-class protected animals. Obtaining transformed bear bile powder through biotransformation is expected to alleviate the shortage of bear bile resources to a certain extent. Although related research on bear bile substitutes has protected bear bile resources, there are problems in functional quantification and modern interpretation. It is necessary to sort out the functions and indications of bear bile recorded in ancient books according to related modern research. This study firstly reviewed the evolution of bear bile functions and indications, analyzed the chemical components of bear bile, sorted out the relevant records of the efficacy and clinical application of bear bile in ancient books, and summarized the research progress in the safety of bear bile based on the modern pharmacological effects and clinical applications of bear bile, which is conducive to the clarification of modern efficacy and functional quantification of bear bile and the tentative exploration of the modern interpretation of bear bile.

Ultra-high-performance liquid chromatography-Q exactive orbitrap tandem mass spectrometry(UHPLC-QEOrbitrap-MS/MS) was used to explore the inhibitory effect and mechanism of ginkgo flavone aglycone(GA) combined with doxorubicin(DOX) on H22 cells. The effects of different concentrations of GA and DOX on the viability of H22 cells were investigated, and combination index(CI) was used to evaluate the effects. In the experiments, control(CON) group, DOX group, GA group, and combined GA and DOX(GDOX) group were constructed. Then the metabolomics strategy was employed to explore the metabolic markers that were significantly changed after combination therapy on the basis of single medication treatment, and by analyzing their biological significance, the effect and mechanism of the anti-tumor effect of GA combined with DOX were explained. The results revealed that when 30 μg·mL~(-1) GA and 0.5 μmol·L~(-1) DOX was determined as the co-administration concentration, the CI value was 0.808, indicating that the combination of GA and DOX had a synergistic anti-tumor effect. Metabolomics analysis identified 23 metabolic markers, including L-arginine, L-tyrosine and L-valine, mostly amino acids. Compared with the CON group, 22 and 17 metabolic markers were significantly down-regulated after DOX treatment and GA treatment, respectively. Compared with the DOX and GA groups, the treatment of GA combined with DOX further down-regulated the levels of these metabolic markers in liver cancer, which might contribute to the synergistic effect of the two. Five key metabolic pathways were found in pathway enrichment analysis, including glutathione metabolism, phenylalanine metabolism, arginine and proline metabolism, β-alanine metabolism, and valine, leucine and isoleucine degradation. These findings demonstrated that the combination of GA and DOX remarkably inhibited the viability of H22 cells and exerted a synergistic anti-tumor effect. The mechanism might be related to the influence of the energy supply of tumor cells by interfering with the metabolism of various amino acids.

Under some unexpected conditions, drive rods and control-rod assemblies may not be disconnected. If this situation is not detected, the control rod will be lifted out of the reactor core together with the upper reactor internals. This situation will seriously affect the follow-up work and reduce the economy and safety protection of the nuclear power plant. To ensure safety, the tripping status must be checked after tripping. Follow-up work can be carried out after checking and confirming that all drive rods are in the tripping status. There are many problems for traditional inspection methods, such as misjudgment, low accuracy, and labor consumption. This paper proposes a visual inspection system for the uncoupling state of the control-rod drive rod of the nuclear reactor. The proposed method is based on the fitting model of the ellipse parameter of the drive-rod head and the height of the drive rod. The ellipse of the drive-rod head is firstly accurately detected. Then, a mathematical model between the ellipse parameter and the height of the drive rod is established. The measurement error caused by the swing of the head of the drive rod is eliminated. The accurate measurement of the height difference before and after the tripping of the drive rod is computed. Finally, the status of the uncoupling of the drive rod is judged according to the difference. Many experiments are carried out with our developed system. The experimental results show that the proposed system realizes remote operation, ensures the quality of trip-status inspection, improves work efficiency, and reduces the workload of staff.

Monoclonal antibodies (mAbs) targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have demonstrated clinical efficacy in preventing or treating coronavirus disease 2019 (COVID-19), resulting in the emergency use authorization (EUA) for several SARS-CoV-2 targeting mAb by regulatory authority. However, the continuous virus evolution requires diverse mAb options to combat variants. Here we describe two fully human mAbs, amubarvimab (BRII-196) and romlusevimab (BRII-198) that bind to non-competing epitopes on the receptor binding domain (RBD) of spike protein and effectively neutralize SARS-CoV-2 variants. A YTE modification was introduced to the fragment crystallizable (Fc) region of both mAbs to prolong serum half-life and reduce effector function. The amubarvimab and romlusevimab combination retained activity against most mutations associated with reduced susceptibility to previously authorized mAbs and against variants containing amino acid substitutions in their epitope regions. Consistently, the combination of amubarvimab and romlusevimab effectively neutralized a wide range of viruses including most variants of concern and interest in vitro. In a Syrian golden hamster model of SARS-CoV-2 infection, animals receiving combination of amubarvimab and romlusevimab either pre- or post-infection demonstrated less weight loss, significantly decreased viral load in the lungs, and reduced lung pathology compared to controls. These preclinical findings support their development as an antibody cocktail therapeutic option against COVID-19 in the clinic.

Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is a cullin 3-based E3 ubiquitin ligase adaptor protein that plays a crucial role in ubiquitin-mediated protein degradation. Recently, SPOP has attracted major research attention as it is frequently mutated in a range of cancers, highlighting pleiotropic tumorigenic effects and associations with treatment resistance. Structurally, SPOP contains a functionally critical N-terminal meprin and TRAF homology (MATH) domain for many SPOP substrates. SPOP has two other domains, including the internal Bric-a-brac-Tramtrack/Broad (BTB) domain, which is linked with SPOP dimerization and binding to cullin3, and a C-terminal nuclear localization sequence (NLS). The dysregulation of SPOP-mediated proteolysis is associated with the development and progression of different cancers since abnormalities in SPOP function dysregulate cellular signaling pathways by targeting oncoproteins or tumor suppressors in a tumor-specific manner. SPOP is also involved in genome stability through its role in the DNA damage response and DNA replication. More recently, studies have shown that the expression of SPOP can be modulated in various ways. In this review, we summarize the current understanding of SPOP’s functions in cancer and discuss how to design a rational therapeutic target.

Background and aims Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases. Approach and results We evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose-dependently decreased the elevated levels of serum aminotransferases in mice with diet-induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation-dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin-induced hepatoprotection in hepatocytes and mice with NASH. Conclusion Cordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.

The diagnosis of vocal cord leukoplakia mainly relies on laryngoscopy. The morphology of vocal cord leukoplakia under laryngoscope is closely related to the pathological nature of leukoplakia. The specific manifestations associated with high-risk vocal cord leukoplakia remain to be explored.To investigate the characteristics of low-risk and high-risk vocal cord leukoplakia under conventional white light imaging (WLI) laryngoscopy and its correlations with narrow band imaging (NBI) laryngoscopy.One hundred and seventy-five cases of vocal cord leukoplakia were divided into low-risk and high-risk groups. The characteristics of low-risk and high-risk vocal cord leukoplakia under WLI laryngoscopy and its correlations with NBI laryngoscopy were analyzed.Logistic regression analysis showed that thickness and hyperemia were independent factors (The sign of hyperemia under WLI laryngoscopy is significantly correlated with the visualized spots under NBI laryngoscopy. Hyperemia is an important feature for predicting malignant potential of vocal cord leukoplakia.

BACKGROUND This meta-analysis aims to determine the association between antibodies including anti-citrullinated protein antibodies (ACPA) and rheumatoid factors (RF) and risk of rheumatoid arthritis-related interstitial lung disease (RA-ILD). METHODS PubMed, Embase, and Cochrane were searched up to September 13, 2020, for studies investigating the risk of RA-ILD in ACPA-positive patients. The statistical meta-analysis and sensitivity analysis were performed using the Review Manager 5.4 and Stata16.0 software, respectively. RESULTS Total 1 double-blind randomized controlled study and 16 observational studies, including 992 RA-ILD patients and 2223 RA-non ILD patients, met the inclusion criteria of the meta-analysis. Compared with ACPA-negative patients, positive serum ACPA increased the risk of RA-ILD (OR = 2.51; 95% CI: 1.35-4.68; P = 0.004) and serum ACPA titer was significantly correlated with risk of RA-ILD (SMD = 0.39; 95% CI: 0.17-0.62; P = 0.0006). In a region-based subgroup analysis, ACPA titer in Asian, European, and African populations was significantly related to the risk of RA-ILD, while there was no significant correlation in the Americans (SMD = - 0.03; 95% CI: - 0.89-0.83; P = 0.95), especially in the USA (SMD = 0.37; 95% CI: - 0.26-0.99; P = 0.25). In addition, serum positive RF increased the risk of RA-ILD (OR = 2.85; 95% CI: 2.19-3.71; P

Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated.Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters.The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 hOur results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

ObjectiveTo evaluate the association of plasma aldosterone concentration (PAC) with incident cardiovascular disease (CVD) and all-cause mortality in hypertensive patients with suspected obstructive sleep apnea (OSA) and calculate the optimal cut-off value of PAC for this specific population.Patients and methodsParticipants with PAC at baseline in UROSAH in 2011-2013 were enrolled and followed up till 2021. Composite outcome included CVD and all-cause mortality. Cox proportional hazards model was used to evaluate the relationship between PAC and the composite outcome. Time-dependent ROC curve was used to determine the optimal cut-off value of PAC. Besides, we conducted subgroup analyses and sensitivity analyses.Results3173 hypertensive participants aged 18-84 years comprised analytical sample. During a median follow-up of 7.3 years and 22640 person-years, 69 deaths and 343 cases of incident CVD occurred. The incidence of composite outcome was increased with elevation in tertile of PAC. Compared with the first tertile, the risk of CVD and all-cause death was higher in third tertile (HR=1.81, 95%CI: 1.39-2.35, P0.5ng/ml per h), elevated PAC was associated with an increased risk of CVD. Our results remained stable and consistent in sensitivity analyses.ConclusionHigher PAC was associated with increased risk of CVD and all-cause mortality in hypertensives with suspected OSA, even in the absence of primary aldosteronism (PA). Hypertensives with PAC≥12.5ng/dl showed a significantly increased risk of CVD, indicating that special attention and treatment were required in this specific population.

New insecticidal genes and approaches for pest control are a hot research area. In the present study, we explored a novel strategy for the generation of insecticidal proteins. The midgut cadherin of

To observe the effects of electroacupuncture at bilateral Zusanli(ST36), Shangjuxu(ST37), and Sanyinjiao (SP6) acupoints on gastrointestinal function after laparoscopic cholecystectomy under general anesthesia.A total of 150 patients(American Society of Anesthesiologists［ASA］ grades Ⅰ and Ⅱ) undergoing laparoscopic cholecystectomy in the Department of Hepatobiliary Surgery of the First Affiliated Hospital of Guangzhou University of Chinese Medicine were randomly assigned into three groups: electroacupuncture group (Compared with the control group, the electroacupuncture group and the simple acupuncture group showed shortened time of bowel sound recovery, shortened time to the first postoperative exhaust and defecation, and shortened time of postoperative liquid diet recovery (Both electroacupuncture and simple acupuncture can promote the recovery of gastrointestinal function in patients after laparoscopic cholecystectomy under general anesthesia, and electroacupuncture is superior to simple acupuncture,but they have no significant difference in alleviating postoperative abdominal pain and gastrointestinal reactions.

Background Recurrent retinal detachment (Re-RD) usually affects the prognosis of surgery for rhegmatogenous retinal detachment (RRD). Previous clinical studies of Re-RD were not specific. This study aimed to analyze the clinical characteristics of Re-RD in post-vitrectomy eyes with RRD and surgical outcomes after revitrectomy without combining it with retinectomy or scleral buckling. Methods This is a retrospective case series analyzed the ocular characteristics of 20 recurrent and contralateral eyes, evaluated the significance of the associations between variables before reoperation and the final best-corrected visual acuity (BCVA), and calculated the outcome of revitrectomy. Results Patients with phakic eyes, those undergoing only one surgery, and those with more than one break had better final BCVA. The final BCVA was negatively correlated with the axial length and positively correlated with the preoperative BCVA. Among the 12 eyes with no break detected before surgery, 11 (92%) were found to have a small crevice-like break beside the pigment scar of a large number of original laser spots. The single-operation complete retinal reattachment rate was 75%, the complete retinal reattachment rate was 80%, and the final incomplete retinal reattachment rate was 90%. The BCVA improved from 1.2 ± 0.6LogMAR (0.06 ± 0.25) before surgery to 0.8 ± 0.7LogMAR (0.15 ± 0.2) at the last follow-up. The BCVA of 16 patients with complete retinal reattachment improved from 1.0 ± 0.5LogMAR (0.1 ± 0.3) to 0.6 ± 0.4LogMAR (0.25 ± 0.4). In the contralateral eyes, 15% already had vision-damaging disease, and the incidence of eyesight-threating lesions was 5.9% during follow-up. Conclusions Revitrectomy without retinectomy or scleral buckling can effectively treat Re-RD in post-vitrectomy eyes. In Re-RD patients with no definite retinal break detected preoperatively, the retinal hole usually shows small crevice-like changes alongside a large number of original laser pigment scars.

Cryoballoon ablation (CBA) is recommended for patients with symptomatic drug refractory paroxysmal atrial fibrillation (pAF). However, substantial atrial fibrillation (AF) recurrence is common during follow-up. Searching for a potential biomarker representing both myocardial injury and inflammation to identify patients at high risk of AF recurrence after CBA is very meaningful for postoperative management of AF patients.To evaluate the clinical efficacy of high-mobility group box 1 (HMGB1) protein released from the left atrium to predict AF recurrence in pAF patients after CBA at 1-year follow-up.We included 72 pAF patients who underwent CBA. To determine the expression levels of HMGB1, left atrial blood samples were collected from the patients before CBA and after the procedure through the transseptal sheath. Patients were followed up for AF recurrence for 1 year.A total of 19 patients of the 72 experienced AF recurrence. The level of postoperative HMGB1 (HMGB1post) was higher in the AF recurrence group than in the AF non recurrence group (p = .03). However, no differences were noted in the levels of other biomarkers such as preoperative high-sensitivity C-reactive protein (hs-CRP), postoperativehs-CRP, and preoperative HMGB1 between the two groups. Multiple logistic regression analysis revealed that a higher level of serum HMGB1post was associated with AF recurrence (odds ratio: 5.29 [1.17-23.92], p = .04). Receiver operating characteristic analysis revealed that HMGB1post had a moderate predictive power for AF recurrence (area under the curve: 0.68; sensitivity: 72%; and specificity: 68%). The 1-year AF-free survival was significantly lower in patients with a high HMGB1post level than in those with a low HMGB1post level (hazard ratio: 3.81 [1.49-9.75], p = .005).In pAF patients who under went CBA, the level of HMGB1 after CBA was associated with AF recurrence and demonstrated a moderate predictive power. Thus, we offer a potential biomarker to identify pAF patients at high risk of AF recurrence.

Background. The prevention of type 2 diabetes (T2D) and its associated complications has become a major priority of global public health. In addition, there is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of diabetes. Therefore, the purpose of this study was to develop and validate a nomogram based on independent predictors to better assess the 8-year risk of T2D in Japanese patients with NAFLD. Methods. This is a historical cohort study from a collection of databases that included 2741 Japanese participants with NAFLD without T2D at baseline. All participants were randomized to a training cohort ( n = 2058 ) and a validation cohort ( n = 683 ). The data of the training cohort were analyzed using the least absolute shrinkage and selection operator method to screen the suitable and effective risk factors for Japanese patients with NAFLD. A cox regression analysis was applied to build a nomogram incorporating the selected features. The C-index, receiver operating characteristic curve (ROC), calibration plot, decision curve analysis, and Kaplan-Meier analysis were used to validate the discrimination, calibration, and clinical usefulness of the model. The results were reevaluated by internal validation in the validation cohort. Results. We developed a simple nomogram that predicts the risk of T2D for Japanese patients with NAFLD by using the parameters of smoking status, waist circumference, hemoglobin A1c, and fasting blood glucose. For the prediction model, the C-index of training cohort and validation cohort was 0.839 (95% confidence interval (CI), 0.804-0.874) and 0.822 (95% CI, 0.777-0.868), respectively. The pooled area under the ROC of 8-year T2D risk in the training cohort and validation cohort was 0.811 and 0.805, respectively. The calibration curve indicated a good agreement between the probability predicted by the nomogram and the actual probability. The decision curve analysis demonstrated that the nomogram was clinically useful. Conclusions. We developed and validated a nomogram for the 8-year risk of incident T2D among Japanese patients with NAFLD. Our nomogram can effectively predict the 8-year incidence of T2D in Japanese patients with NAFLD and helps to identify people at high risk of T2D early, thus contributing to effective prevention programs for T2D.

Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George’s Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62–128]; P

Background Co‐infections, secondary bacterial or fungal infections, are important risk factors for poor outcomes in viral infections. The prevalence of co‐infection and secondary infection in patients infected with SARS‐CoV‐2 is not well understood. Aims To investigate the role of co‐infections and secondary infections in disease severity of hospitalized individuals with COVID‐19. Materials and Methods A retrospective study was carried out between 11 January 2020 and 1 March 2020 among 408 laboratory confirmed COVID‐19 patients in China. These patients were divided into three groups based on disease severity: mild or moderate, severe, or critically ill. Microbiological pathogens in blood, urine, and respiratory tract specimens were detected by the combination of culture, serology, polymerase chain reaction, and metagenomic next‐generation sequencing (mNGS). Results The median age of participants was 48 years (IQR 34–60 years). Fifty‐two patients (12.7%) had at least one additional pathogen, 8.1% were co‐infected, and 5.1% had a secondary infection. There were 13 Mycoplasma pneumoniae cases, 8 Haemophilus influenzae cases, 8 respiratory viruses, and 3 Streptococcus pneumoniae cases, primarily detected in mild and moderate COVID‐19 patients. Hospital‐acquired infection pathogens were more common in critically ill patients. Compared to those without additional pathogens, patients with co‐infections and/or secondary infections were more likely to receive antibiotics (p < 0.001) and have elevated levels of d‐dimer (p = 0.0012), interleukin‐6 (p = 0.0027), and procalcitonin (p = 0.0002). The performance of conventional culture was comparable with that of mNGS in diagnosis of secondary infections. Conclusion Co‐infections and secondary infections existed in hospitalized COVID‐19 patients and were relevant to the disease severity. Screening of common respiratory pathogens and hospital infection control should be strengthened.

Martin Anderson,1 Kathryn Collison,2 M Bradley Drummond,3 Melanie Hamilton,4 Renu Jain,2 Neil Martin,5,6 Richard A Mularski,7 Mike Thomas,8 Chang-Qing Zhu,9 Gary T Ferguson10 1Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 2Respiratory Therapy Area, GSK, Research Triangle Park, NC, USA; 3Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4R&D, GSK, Ware, Hertfordshire, UK; 5Global Medical Affairs, GSK, Brentford, Middlesex, UK; 6Institute for Lung Health, University of Leicester, Leicester, Leicestershire, UK; 7Department of Pulmonary and Critical Care Medicine, Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA; 8Primary Care Research, University of Southampton, Southampton, UK; 9Biostatistics, GSK, Stockley Park West, Uxbridge, Middlesex, UK; 10Pulmonary Research, Institute of Southeast Michigan, Farmington Hills, MI, USACorrespondence: Gary T FergusonPulmonary Research, Institute of Southeast Michigan, Farmington Hills, MI, USATel +1 248-478-6561Email garytferguson@msn.comBackground: The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has not been fully determined. In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥ 30 L/min. This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials.Methods: The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients. This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population. Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations.Results: A total of 1460 (207608/207609) and 3282 (KPNW) patients were included. There was considerable overlap between spirometric PIF distributions for both populations. Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥ 50 L/min, estimated as equivalent to ELLIPTA PIFR ≥ 30 L/min. In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF.Conclusion: Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥ 30 L/min through the ELLIPTA DPI. Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities.Keywords: COPD, inhaled triple therapy, patient outcomes, real-world studies, peak inspiratory flow rate, DPI

Objective To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. Methods We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. Results Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. Significance Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease.This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium.This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 mThe primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment.A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group.SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone.NCT02063100 on ClinicalTrials.gov.

Background The treatment for displaced Salter-Harris II (S-H II) distal tibia fractures remains controversial. The purpose of this study was to review S-H II distal tibia fractures and evaluate the rate of premature physeal closure (PPC) treated by open reduction and internal fixation (ORIF). Methods We reviewed the charts and radiographs of S-H II fractures of the distal tibia with displacement > 3 mm between 2012 and 2019 treated by ORIF. Patients were followed up for a minimum of 6 months. CT scans of injured side or contralateral ankle radiograph were obtained if there was any evidence of PPC. Any angular deformity or shortening of the involved leg was documented. Multivariable logistic regression was performed to identify risk factors for the occurrence of PPC. Results A total of 65 patients with a mean age of 11.8 years were included in this study. The mean initial displacement was 8.0 mm. All patients but one were treated within 7 days after injury and the mean interval was 3.7 days. Supination-external rotation injuries occurred in 50 patients, pronation-eversion external rotation in 13, and supination-plantar flexion in two. The residual gap was less than 1 mm in all patients following ORIF and all fractures healed within 4–6 weeks. Superficial skin infection developed in one patient. Ten patients complained of the cosmetic scar. The rate of PPC was 29.2% and two patients with PPC developed a varus deformity of the ankle. Patients with associated fibular fracture had 7 times greater odds of developing PPC. Age, gender, injured side, mechanism of injury, amount of initial displacement, interval from injury to surgery, or energy of injury did not significantly affect the rate of PPC. Conclusions ORIF was an effective choice of treatment for S-H II distal tibia fractures with displacement > 3 mm to obtain a satisfactory reduction. PPC is a common complication following ORIF. The presence of concomitant fibula fracture was associated with PPC.

Programmed cell death protein 1 (PD‐1), an immune checkpoint receptor expressed by activated T, B, and NK cells, is a well‐known target for cancer immunotherapy. Tislelizumab (BGB‐A317) is an anti‐PD‐1 antibody that has recently been approved for treatment of Hodgkin's lymphoma and urothelial carcinoma. Here, we show that tislelizumab displayed remarkable antitumor efficacy in a B16F10/GM‐CSF mouse model. Structural biology and Surface plasmon resonance (SPR) analyses revealed unique epitopes of tislelizumab, and demonstrated that the CC′ loop of PD‐1, a region considered to be essential for binding to PD‐1 ligand 1 (PD‐L1) but not reported as targeted by other therapeutic antibodies, significantly contributes to the binding of tislelizumab. The binding surface of tislelizumab on PD‐1 overlaps largely with that of the PD‐L1. SPR analysis revealed the extremely slow dissociation rate of tislelizumab from PD‐1. Both structural and functional analyses align with the observed ability of tislelizumab to completely block PD‐1/PD‐L1 interaction, broadening our understanding of the mechanism of action of anti‐PD‐1 antibodies., We evaluated the antitumor efficacy of tislelizumab (BGB‐A317), an approved anti‐PD‐1 antibody. Its critical epitopes were investigated by both structural biology and SPR studies, and the CC′ loop of PD‐1 was discovered to be a novel targetable region for anti‐PD‐1 antibodies. The unique epitopes and slow dissociation rate of tislelizumab contribute to its complete blocking activity to PD‐L1.

To explore the molecular epidemiological status of human immunodeficiency virus type 1 (HIV-1) in Ganzhou, China, eight HIV-1-positive outpatients were recruited from July 5 to 21, 2018. Six HIV-1 near-full-length sequences were amplified and sequenced from the plasma samples that were collected before the patients' antiretroviral treatments. Phylogenetic and bootscan analyses revealed that one of the sequences was CRF01_AE, one was CRF55_01B, and two were CRF07_BC. Notably, one of the sequences was a unique recombinant form, and one of them was a second-generation recombinant form of CRF07_BC and subtype C. These results revealed that multiple HIV-1 subtypes are circulating in Ganzhou, China. Systematic surveys with large sample sizes are urgently needed to explore the exact molecular epidemiological characteristics and to trace the origins of HIV-1 in Ganzhou, China.

The Notch1-mediated inflammatory response participates in the development of abdominal aortic aneurysm (AAA). The vascular endogenous bioactive peptide intermedin (IMD) plays an important role in maintaining vascular homeostasis. However, whether IMD inhibits AAA by inhibiting Notch1-mediated inflammation is unclear. In this study, we found Notch intracellular domain (NICD) and hes1 expression were higher in AAA patients’ aortas than in healthy controls. In angiotensin II (AngII)-induced AAA mouse model, IMD treatment significantly reduced AAA incidence and maximal aortic diameter. IMD inhibited AngII-enlarged aortas and -degraded elastic lamina, reduced NICD, hes1 and inflammatory factors expression, decreased infiltration of CD68 positive macrophages and the NOD-like receptor family pyrin domain containing 3 protein level. IMD inhibited lipopolysaccharide-induced macrophage migration in vitro and regulated macrophage polarization. Moreover, IMD overexpression significantly reduced CaCl2-induced AAA incidence and down-regulated NICD and hes1 expression. However, IMD deficiency showed opposite results. Mechanically, IMD treatment significantly decreased cleavage enzyme-a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) level. Pre-incubation with IMD17-47 (IMD receptors blocking peptide) and the phosphatidylinositol 3-kinase/protein kinase b (PI3K/Akt) inhibitor LY294002 reversed ADAM10 level. In conclusion, exogenous and endogenous IMD could inhibit the development of AAA by inhibiting Notch1 signaling-mediated inflammation via reducing ADAM10 through IMD receptor and PI3K/Akt pathway.

Serum pepsinogens (PGs) are biomarkers for gastric mucosal damage and have been reported to be associated with atherosclerosis. Its correlation with atherosclerotic cardiovascular disease (ASCVD) is still unknown. This study aimed to explore the association between serum PGs and ASCVD for providing physicians with an integrative picture to make rational plans in the diagnosis and treatment of ASCVD.The concentrations of serum PGs and their distributions between ASCVD and non-ASCVD were compared by non-parametric test, Chi-squared test and Fisher exact test. The correlation between variables was analyzed by Spearman's correlation test. The association of serum PGs with ASCVD was analyzed by the binary logistic regression and two-piecewise linear regression. A total of 8355 recruited cases were eligible for the study. The concentrations of serum PGs were significantly different between the ASCVD and non-ASCVD groups (P = 0.025, P0.001). The lower PGI and PGR levels were significantly correlated with a high risk of ASCVD presence after adjustment for 26 potential covariates. Moreover, there was a linear relationship between the high level of PGII and the high risk of ASCVD [adjusted OR = 1.16 (1.00, 1.37), P = 0.07]. A nonlinear relationship of PGI/PGR and ASCVD (P = 0.08/0.001) was also revealed. The risk of ASCVD increased with a range of log PGI ≥2.13 (PGI≥131 ng/mL) [adjusted OR = 4.67 (1.00, 23.17)], and decreased with a range of log PGR ≥0.22 (1.65) [adjusted OR = 0.59 (0.48, 0.74), P0.001].Serum PGI and PGR are nonlinearly correlated with ASCVD, while PGII is linearly correlated with ASCVD. Among all PGs, PGR may serve as a reliable biomarker for ASCVD.

Colorectal cancer (CRC) is one of the most common tumors, ranking second in the global cause of death from cancer. The prognosis of advanced patients is still very poor. In this study, hub modules with the highest association with tumor-infiltrating immune cells were identified by weighted gene co-expression network analysis based on CRC expression data from the Gene Expression Omnibus database. Next, three hub genes (ADAM8, IL-1A, VAV3) related to infiltrating immune cells were identified by co-expression network and prognostic analysis. After analysis and verification of the TIMER database, ADAM8 was selected as a prognostic biomarker. Finally, the result of functional test showed that ADAM8 gene expression down-regulation partially reversed the immune tolerance of CRC cells to TILs. By bioinformatics analysis methods and the experimental techniques, we identified ADAM8 as a prognostic biomarker and clinical therapeutic target related to tumor-infiltrating immune cells in CRC., Graphical abstract

Plant exosome-like nanovesicles, being innately replete with bioactive lipids, proteins, RNA, and other pharmacologically active molecules, offer unique morphological and compositional characteristics as natural nanocarriers. Furthermore, their compelling physicochemical traits underpin their modulative role in physiological processes, all of which have fostered the concept that these nanovesicles may be highly proficient in the development of next-generation biotherapeutic and drug delivery nanoplatforms to meet the ever-stringent demands of current clinical challenges. This review systemically deals with various facets of plant exosome-like nanovesicles ranging from their origin and isolation to identification of morphological composition, biological functions, and cargo-loading mechanisms. Efforts are made to encompass their biotherapeutic roles by elucidating their immunological modulating, anti-tumor, regenerative, and anti-inflammatory roles. We also shed light on re-engineering these nanovesicles into robust, innocuous, and non-immunogenic nanovectors for drug delivery through multiple stringent biological hindrances to various targeted organs such as intestine and brain. Finally, recent advances centered around plant exosome-like nanovesicles along with new insights into transdermal, transmembrane and targeting mechanisms of these vesicles are also elucidated. We expect that the continuing development of plant exosome-like nanovesicle-based therapeutic and delivery nanoplatforms will promote their clinical applications.

A novel mitochondria-targeting molecular rotator FD was designed to visualize changes in viscosity under hypoxic conditions in vitro and in vivo. Importantly, FD can be used to detect changes in the blood viscosity of liver cancer and liver cirrhosis patients, and also rehabilitation of liver disease.

Precartilaginous stem cells (PCSCs) are able to initiate chondrocyte and bone development. The present study aimed to investigate the role of miR-143 and the underlying mechanisms involved in PCSC proliferation. In a rat growth plate injury model, tissue from the injury site was collected and the expression of miR-143 and its potential targets was determined. PCSCs were isolated from the rabbits' distal epiphyseal growth plate. Cell viability, DNA synthesis, and apoptosis were determined with MTT, BrdU, and flow cytometric analysis, respectively. Real time PCR and western blot were performed to detect the mRNA and protein expression of the indicated genes. Indian hedgehog (IHH) was identified as a target gene for miR-143 with luciferase reporter assay. Decreased expression of miR-143 and increased expression of IHH gene were observed in the growth plate after injury. miR-143 mimics decreased cell viability and DNA synthesis and promoted apoptosis of PCSCs. Conversely, siRNA-mediated inhibition of miR-143 led to increased growth and suppressed apoptosis of PCSCs. Transfection of miR-143 decreased luciferase activity of wild-type IHH but had no effect when the 3'-UTR of IHH was mutated. Furthermore, the effect of miR-143 overexpression was neutralized by overexpression of IHH. Our study showed that miR-143 is involved in growth plate behavior and regulates PCSC growth by targeting IHH, suggesting that miR-143 may serve as a novel target for PCSC-related diseases.

Lung adenocarcinoma (LUAD) accounts for a frequently seen non-small cell lung cancer (NSCLC) histological subtype, and it is associated with dismal prognostic outcome. However, the benefits of traditional treatment are still limited, and the efficacies of immunotherapy are quite different. Therefore, it is of great significance to identify novel immune-related therapeutic targets in lung adenocarcinoma. In this study, we identified a set of immune-related biomarkers for prognosis of lung adenocarcinoma, which could provide new ideas for immunotherapy of lung adenocarcinoma. Datasets related to LUAD were filtered from the GEO database. The appropriate packages were used to identify differentially expressed genes (DEGs) and to carry out enrichment analysis, followed by the construction of prognostic biomarkers. The Kaplan-Meier (K-M) curves were plotted to analyze patient survival based on hub genes. Associations between the expression of selected biomarkers and six types of tumor-infiltrating immune cells were evaluated based on the online tool TIMER. After analyzing five GEO datasets(GSE32867, GSE46539, GSE63459, GSE75037 and GSE116959), we discovered altogether 67 DEGs, among which, 15 showed up-regulation while 52 showed down-regulation. Enrichments of integrated DEGs were identified in the ontology categories. CAV1, CFD, FMO2 and CLEC3B were eventually selected as independent prognostic biomarkers, they were correlated with clinical outcomes of LUAD patients. Moreover, a positive correlation was observed between biomarker expression and all different types of immune infiltration, and the expression level of the four biomarkers was all positively related to macrophage., Graphical abstract

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy., We conducted a pilot study to assess the feasibility of the sequential infusion of CD19 and B‐cell maturation antigen (BCMA)‐specific chimeric antigen receptor T‐cell (CART) for relapsed and/or refractory multiple myeloma treatment with a similar 3 + 3 dose escalation design. Translational Significance: The favorable and persistent responses against RRMM were observed in those patients with a combined infusion of autologous CD19‐CART and BCMA‐CART. The emergence of intolerant adverse event (neurotoxicity and sever CRS) was associated with increased dose level of BCMA‐CARTs infusion.

Objective Several COVID-19 patients have overlapping comorbidities. The independent role of each component contributing to the risk of COVID-19 is unknown, and how some non-cardiometabolic comorbidities affect the risk of COVID-19 remains unclear. Methods A retrospective follow-up design was adopted. A total of 1,160 laboratory-confirmed patients were enrolled from nine provinces in China. Data on comorbidities were obtained from the patients’ medical records. Multivariable logistic regression models were used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of the associations between comorbidities (cardiometabolic or non-cardiometabolic diseases), clinical severity, and treatment outcomes of COVID-19. Results Overall, 158 (13.6%) patients were diagnosed with severe illness and 32 (2.7%) had unfavorable outcomes. Hypertension (2.87, 1.30–6.32), type 2 diabetes (T2DM) (3.57, 2.32–5.49), cardiovascular disease (CVD) (3.78, 1.81–7.89), fatty liver disease (7.53, 1.96–28.96), hyperlipidemia (2.15, 1.26–3.67), other lung diseases (6.00, 3.01–11.96), and electrolyte imbalance (10.40, 3.00–26.10) were independently linked to increased odds of being severely ill. T2DM (6.07, 2.89–12.75), CVD (8.47, 6.03–11.89), and electrolyte imbalance (19.44, 11.47–32.96) were also strong predictors of unfavorable outcomes. Women with comorbidities were more likely to have severe disease on admission (5.46, 3.25–9.19), while men with comorbidities were more likely to have unfavorable treatment outcomes (6.58, 1.46–29.64) within two weeks. Conclusion Besides hypertension, diabetes, and CVD, fatty liver disease, hyperlipidemia, other lung diseases, and electrolyte imbalance were independent risk factors for COVID-19 severity and poor treatment outcome. Women with comorbidities were more likely to have severe disease, while men with comorbidities were more likely to have unfavorable treatment outcomes.