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Summary: Here, we present a protocol for conducting bibliometric analysis in biomedicine using CiteSpace and VOSviewer. We describe the steps for extracting data from Web of Science, data cleaning, and preprocessing. We then detail procedures for identifying research trends and collaboration networks by visualizing data with CiteSpace; mapping co-authorship, co-citation, and keyword co-occurrence using VOSviewer; and analyzing highly cited literature to identify key publications and trends. Finally, we outline techniques for interpreting the visualizations to draw meaningful conclusions about the research landscape.For complete details on the use and execution of this protocol, please refer to Li et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background There were controversies for the association between computed tomography (CT)‐determined low skeletal muscle mass (SMM) and overall survival (OS) in gastric cancer (GC). In this study, we investigated whether cachexia could be a potential confounding variable for this issue. Methods We retrospectively collected the patients of GC in our institution between July 2016 and January 2021. Preoperative SMM was determined by analyzing the skeletal muscle index of L3 with abdominal CT, and the cut‐offs for low SMM were defined as

Abstract Introduction The main emphasis of the research about adjuvant imatinib for high‐risk gastrointestinal stromal tumors (GISTs) is prolonging the treatment duration and ignores the heterogeneous that 10‐year recurrence rates ranged from about 20%–100%. Thus, this study evaluated the effect of different durations of adjuvant imatinib on outcomes in high‐risk GISTs to explore the feasibility of individual treatment. Methods We analyzed 855 high‐risk GIST patients from three centers who underwent macroscopically complete resection between December 2007 and September 2020. The patients were divided into training (n =564) and two validation cohorts (n = 238 and53) based on their source. Recurrence‐free survival (RFS) was the primary point. Cox multivariate analysis was used to develop the nomogram. C‐index, time‐dependent area under the curves, and calibration plots were used to assess the performance of the nomogram. Results Univariate analysis showed that longer adjuvant imatinib was significantly associated with better 5‐year RFS (p

BackgroundFew studies have investigated the correlation between visceral fat area (VFA) and early postoperative complications in patients with obesity undergoing bariatric surgery. This study aimed to investigate the relationship between VFA and early postoperative complications in patients with obesity following bariatric surgery.MethodsThe study was conducted at a tertiary university hospital. Patients with obesity who underwent laparoscopic sleeve gastrectomy between June 2016 and October 2020 were divided into two groups based on umbilical level VFA: high-VFA group (umbilical level VFA ≥ 100 cm2) and low-VFA group (umbilical level VFA < 100 cm2). Baseline characteristics, intraoperative and postoperative conditions, and early postoperative complications were compared between the groups. The primary outcome was early postoperative complications, and the secondary outcome was postoperative hospital stay.ResultsThe study included 152 patients, with 82 patients in the low-VFA group and 70 patients in the high-VFA group. The high-VFA group had a higher incidence of early postoperative complications (14.29% vs. 2.44%, P = 0.013) than the low-VFA group. The length of postoperative hospital stay did not differ significantly between the groups.ConclusionsOur study suggests that excess VFA is an independent risk factor for early postoperative complications following bariatric surgery, and VFA may be used in preoperative evaluations.

Background. Both low skeletal muscle mass and delirium are prevalent in older hospitalized patients, while their associations are unclear. This systematic review and meta-analysis aim to investigate the associations between low skeletal muscle mass and the incidence of delirium in hospitalized patients. Methods. The PubMed, Web of Science, and Embase were searched for relevant studies published before May 2022, and we conducted this systematic review and meta-analysis according to the PRISMA and MOOSE guidelines. The summary odds ratios (OR) and 95% confidence intervals (CI) were estimated, and subgroup analyses were also conducted according to the age and major surgeries. Results. Finally, nine studies with 3 828 patients were included. The pooled result showed no significant association between low skeletal muscle mass and the incidence of delirium (OR 1.69, 95% CI 0.85 to 2.52). However, sensitivity analysis suggested that one study caused a significant alteration of the summary result, and the meta-analysis of the remaining 8 studies showed that low skeletal muscle mass was significantly associated with an 88% increased incidence of delirium (OR 1.88, 95% CI 1.43 to 2.33). Furthermore, subgroup analyses indicated that low skeletal muscle mass was associated with a higher incidence of delirium in patients ≥75 years old or undergoing major surgeries instead of those

BackgroundFew studies have investigated the relationship between sarcopenia and postoperative pulmonary complications (PPCs) after gastric cancer surgery. This study aimed to explore the impact of sarcopenia on PPCs in patients who had undergone gastric cancer surgery.MethodsWe included patients who underwent a transabdominal radical gastrectomy between June 2016 and October 2020. Patients were divided into two groups according to the median prevalence rate of lumbar triplane skeletal muscle index (L3 SMI): sarcopenia group (≤37.5% percentile in male and female group) and non-sarcopenia group (>37.5% percentile in male and female group). Baseline characteristics, intraoperative and postoperative conditions, pulmonary complications, and overall complications were compared between the two groups. The primary outcome was the incidence of PPCs. The secondary outcomes were overall postoperative complications and length of stay (LOS).ResultsAmong the 143 patients included, 50 had sarcopenia and 93 had not. Compared to the non-sarcopenia group, the sarcopenia group had a higher the incidence of PPCs (22.0% vs. 8.6%, P = 0.024). The incidence of overall postoperative complications in the sarcopenia group was higher than that in the non-sarcopenia group (36.00% vs. 20.43%, P = 0.043). There was no significant difference in the LOS between the two groups.ConclusionsOur research indicates that sarcopenia, preoperative comorbidities, and longer duration of intraoperative oxygen saturation

Abstract Background Most previous studies compared the risk for non-melanoma skin cancer (NMSC) in biologic-treated common inflammatory diseases with the general population. Whether the increased NMSC risk is caused by the disease itself, the biologics, or both remains unknown. Methods We systematically searched PubMed, Embase, Medline, Web of Science, and Cochrane Library from inception to May 2021. Studies were included if they assessed the risk of NMSC for rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis patients treated with biologics compared with patients not receiving biologics. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the fixed- or random-effects model. Results The current meta-analysis included 12 studies. Compared with patients with the inflammatory disease without biologics, patients receiving biological therapy were associated with an increased risk for NMSC (RR 1.25, 95% CI 1.14 to 1.37), especially in patients with RA (RR 1.24, 95% CI 1.13 to 1.36) and psoriasis (RR 1.28, 95% CI 1.07 to 1.52), but not in patients with IBD (RR 1.49, 95% CI 0.46 to 4.91). The risks for squamous cell skin cancer and basal cell skin cancer were both increased for patients receiving biologics. However, the risk of NMSC did not increase in patients treated with biologics less than 2 years. Conclusions Current evidence suggests that increased risk of NMSC was identified in RA and psoriasis treated with biologics compared with patients not receiving biologics, but not in patients with IBD. The inner cause for the increased risk of NMSC in IBD patients should be further discussed.

BackgroundCurrent diagnostic criteria for cancer cachexia are inconsistent, and arguments still exist about the impact of cachexia on the survival of patients with colorectal cancer. In this study, we aim to investigate the prognostic value of a novel cachexia indicator, the cachexia index (CXI), in patients with colorectal cancer.MethodsThe CXI was calculated as skeletal muscle index (SMI) × serum albumin/neutrophil-lymphocyte ratio. The cut-off value of CXI was determined by the receiver operating characteristic (ROC) curves and Youden’s index. The major outcomes were major complications, overall survival (OS), and recurrence-free survival (RFS).ResultsA total of 379 patients (234 men and 145 women) were included. The ROC curves indicated that CXI had a significantly diagnostic capacity for the detection of major complications. Based on Youden’s index, there were 231 and 148 patients in the low and high CXI groups, respectively. Patients in the low CXI group had significantly older age, lower BMI, and a higher percentage of cachexia and TNM stage II+III. Besides, Patients in low CXI group were associated with a significantly higher rate of major complications, blood transfusion, and longer length of stay. Logistic regression analysis indicated that low CXI, cachexia, and coronary heart disease were independent risk factors for the major complications. Kaplan Meier survival curves indicated that patients with high CXI had a significantly more favorable OS than those with low CXI, while no significant difference was found in RFS between the two groups. Besides, there were no significant differences in OS or RFS between patients with and without cachexia. The univariate and multivariate Cox regression analysis indicated that older age, low CXI, and coronary heart disease instead of cachexia were associated with a decreased OS.ConclusionCXI was better than cachexia in predicting OS and could be a useful prognostic indicator in patients with colorectal cancer, and greater attention should be paid to patients with low CXI.

Soy is rich in plant protein, isoflavones, and polyunsaturated fatty acids. To clarify the associations between soy intake and type 2 diabetes (T2D) and cardiovascular diseases (CVDs) events, we performed a meta-analysis and review. A total of 1963 studies met the inclusion criteria, and 29 articles with 16,521 T2D and 54,213 CVDs events were identified by the eligibility criteria. During a follow-up of 2.5–24 years, the risk of T2D, CVDs, coronary heart disease, and stroke in participants with the highest soy consumption decreased by 17% (total relative risk (TRR) = 0.83, 95% CI: 0.74–0.93), 13% (TRR = 0.87, 95% CI: 0.81–0.94), 21% (TRR = 0.79, 95% CI: 0.71–0.88), and 12% (TRR = 0.88, 95% CI: 0.79–0.99), respectively, compared to the lowest sot consumption. A daily intake of 26.7 g of tofu reduced CVDs risk by 18% (TRR = 0.82, 95% CI: 0.74–0.92) and 11.1 g of natto lowered the risk of CVDs by 17% (TRR = 0.83, 95% CI: 0.78–0.89), especially stroke. This meta-analysis demonstrated that soy consumption was negatively associated with the risks of T2D and CVDs and a specific quantity of soy products was the most beneficial for the prevention of T2D and CVDs. This study has been registered on PROSPERO (registration number: CRD42022360504).

Abstract Objective The purpose of this umbrella review was to assess the associations between sarcopenia and adverse health‐related outcomes. Design An umbrella review of meta‐analyses of observational studies. Setting and Participants Patients with sarcopenia and controls without sarcopenia were included. Measures The PubMed, Web of Science and Embase were searched for relevant systematic review and meta‐analysis. AMSTAR and GRADE system were used for methodological quality and evidence quality assessments, respectively. Results Totally 54 outcomes extracted from 30 meta‐analyses were analyzed. Twenty out of 21 prognostic outcomes indicated that sarcopenia was significantly associated with poorer prognosis of gastric cancer, hepatocellular cancer, urothelial cancer, head and neck cancer, hematological malignancy, pancreatic cancer, breast cancer, colorectal cancer, lung cancer, esophageal cancer, and ovarian cancer. Besides, 10 out of 16 postoperative outcomes suggested that sarcopenia significantly increased the risk of multiple postoperative complications and prolonged the length of hospitalization of patients with digestive cancer. In age‐related outcomes, sarcopenia significantly increased the risk of dysphagia, cognitive impairment, fractures, falls, hospitalization, and all‐cause mortality of elderly populations. Moreover, sarcopenia was also associated with higher level of albuminuria, risk of depression, and several metabolic diseases. Conclusions and Implications Sarcopenia significantly affected a wide range of adverse health‐related outcomes, particularly in patients of tumor and elderly populations. Because evidences of most outcomes were rated as “low” and “very low,” more prospective cohort studies are required in the future.

The current diagnostic criteria for cancer cachexia are inconsistent, and the prognostic value of cachexia in gastric cancer (GC) is controversial. This study aimed to investigate the prognostic value of the cachexia index (CXI) in patients with GC. We calculated the CXI as skeletal muscle index (SMI) × serum albumin/neutrophil-lymphocyte ratio (NLR), and a total of 161 and 163 patients were included in the high and low CXI groups, respectively. Low CXI was significantly associated with a more advanced tumor–node–metastasis (TNM) stage, a higher level of serum C-reactive protein, serum interleukin-6, and NLR, but also a decreased level of serum prealbumin and albumin. In addition, patients in the low CXI group were more likely to have postoperative pulmonary infections (9.8% vs. 3.7%, p = 0.03). Cox proportional analyses indicated that patients with low CXI (HR 0.45, 95% CI 0.29 to 0.69; p < 0.001) or TNM stage III+IV (HR 4.38, 95% CI 2.54 to 7.55; p < 0.001) had a significantly poorer overall survival (OS). Kaplan–Meier survival curves suggested that patients with low CXI had a significantly decreased OS, which was not affected by subgroup analyses of different sex, age, cachexia, body mass index (BMI), and TNM stage. Furthermore, low CXI combined with cachexia, low BMI, or TNM stage III+IV caused the worst OS in each subgroup analysis, respectively. Our study demonstrated that CXI had a good prognostic value in GC. Greater attention should be paid to patients with low CXI, particularly those combined with cachexia, low BMI, or TNM stage III+IV.

Abstract Previously, our meta‐analysis and other studies have suggested that allium vegetable consumption is beneficial for health, but no umbrella review has been conducted to assess the evidence of the various health benefits of allium vegetable consumption. Therefore, we conducted this umbrella review on this topic. This umbrella review included a total of 16 meta‐analyses with 50 unique outcomes. The most beneficial cancer‐related outcome was shown for gastric cancer (risk ratio 0.78; 95% confidence interval [CI] 0.67–0.91). In addition, only 8 weeks of garlic consumption significantly decreased serum total cholesterol (weighted mean differences −17.20 mg/dl; 95% CI −23.10 to −11.30), and patients with dyslipidemia who consumed garlic experienced more benefits than the whole population. Diabetic patients with longer durations of garlic intake experienced more benefits in terms of fasting blood glucose (FBG), HbA1c, and serum fructosamine than healthy participants, and garlic intake was associated with blood pressure reduction in hypertensive patients but not in normotensive participants. Limited side effects of garlic, such as garlic odor and gastrointestinal complaints, were reported among the included meta‐analyses. Our results suggested that allium vegetables might be beneficial for cancer prevention. In particular, garlic was comparatively safe and is recommended as a long‐term dietary component for patients with dyslipidemia, diabetes, and hypertension.

The efficacy of PD-1/PD-L1 blockades is heterogeneous in different molecular subtypes of gastric cancer (GC). In this study, we analyzed relevant clinical trials to identify the molecular subtypes associated with the efficacy of PD-1/PD-L1 blockades, and public datasets, patient samples, and GC cell lines were used for investigating potential mechanisms. We found that GC with EBV-positive, MSI-H/dMMR, TMB-H or PIK3CA mutant subtype had enhanced efficacy of PD-L1/PD-1 blockades. Also, differentially expressed genes of these molecular subtypes shared the same gene signature and functional annotations related to immunity. Meanwhile, CIBERSORT identified that the overlapping landscapes of tumor-infiltrating immune cells in the four molecular subtypes were mainly M1-like macrophages (M1). The relationships between M1 and clinical characteristics, M1, and gene signatures associated with PD-1/PD-L1 blockades also revealed that M1 was associated with improved prognosis and required for the efficacy of PD-L1/PD-1 blockades in GC. We identified that tumor-infiltrating CD68+CD163− macrophages could represent M1 calculated by CIBERSORT in clinical application, and CXCL9, 10, 11/CXCR3 axis was involved in the mechanism of CD68+CD163− macrophages in the enhanced efficacy of PD-L1/PD-1 blockades. In conclusion, CD68+CD163− macrophages are required for the efficacy of PD-L1/PD-1 blockades and expand the applicable candidates in GC patients without the molecular subtypes.

Abstract Background The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. Methods Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. Results Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). Conclusions Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

Abstract Phospholipase A2(PLA2) superfamily is recognized as being involved in the pathogenesis of schizophrenia by affecting lipid homeostasis in cell membranes. We hypothesized that PLA2 gene copy number variation (CNV) may affect PLA2 enzyme expression and be associated with schizophrenia risk. This study indicated that in the discovery stage, an increased copy number of PLA2G6 and the deletion of PLA2G3, PLA2G4A, PLA2G4F and PLA2G12F was associated with increased risk of schizophrenia. CNV segments involving six PLA2 genes were detected in publicly available datasets, including two deletion segments specific to the PLA2G4A gene. The relationship between the deletion of PLA2G4A and susceptibility to schizophrenia was then reaffirmed in the validation group of 806 individuals. There was a significant correlation between PLA2G4A deletion and the symptoms of poverty of thought in male patients and erotomanic delusion in females. Furthermore, ELISA results demonstrate a significant decrease in peripheral blood cytosolic PLA2(cPLA2) levels in patients with the PLA2G4A deletion genotype compared to those with normal and copy number duplicate genotypes. These data suggest that the functional copy number deletion in the PLA2G4A gene is associated with the risk of schizophrenia and clinical phenotypes by reducing the expression of cPLA2, which may be an indicator of susceptibility to schizophrenia.

Abstract Background The role of thyroid health in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder, such as hypothyroidism or hyperthyroidism, is destructive in TMDs. This study aims to investigate the overall and specific causal effects of various thyroid conditions on TMDs. Methods Mendelian randomization (MR) studies were performed using genetic instruments for thyrotropin (TSH, N = 119,715), free thyroxine (fT4, N = 49,269), hypothyroidism (N = 410,141), hyperthyroidism (N = 460,499), and TMDs (N = 211,023). We assessed the overall effect of each thyroid factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct or indirect effects of hypothyroidism on TMDs whilst accounting for TSH, fT4 and hyperthyroidism, and vice versa. Results Univariable MR analyses revealed a causal effect of hypothyroidism on an increased risk of TMDs (IVW OR: 1.12, 95% CI: 1.05–1.20, p = 0.001). No significant association between genetically predicted hyperthyroidism, TSH, or fT4 and TMDs. In the multivariable MR analyses, the effects of hypothyroidism on TMDs occurrence remained significant even after adjSusting for TSH, fT4 and hyperthyroidism (multivariable IVW OR: 1.10, 95% CI: 1.03–1.17, p = 0.006). No pleiotropy and heterogeneity were detected in the analyses (p > 0.05). Conclusions Hypothyroidism might causally increase the risk of TMDs through a direct pathway, highlighting the critical role of managing thyroid health in the prevention of TMDs. Clinicians should give heightened attention to patients with hypothyroidism when seeking medical advice for temporomandibular discomfort. However, caution is warranted due to the potential confounders, pleiotropy, and selection bias in the MR study.

BackgroundThe role of autoimmune diseases (ADs) in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder is destructive in TMDs. This Mendelian randomization (MR) study aims to estimate the causal effect of common ADs on TMDs.MethodsGenetic data from published genome-wide association studies for fourteen common ADs, specifically multiple sclerosis (MS, N = 15,283), ankylosing spondylitis (AS, N = 22,647), asthma (N = 408,422), celiac disease (N = 15,283), Graves’ disease (N = 458,620), Hashimoto thyroiditis (N = 395,640), primary biliary cirrhosis (PBC, N = 11,375), primary sclerosing cholangitis (PSC, N = 14,890), psoriasis vulgaris (N = 483,174), rheumatoid arthritis (RA, N = 417,256), systemic lupus erythematosus (SLE, N = 23,210), Type 1 diabetes (T1D, N = 520,580), inflammatory bowel disease (IBD, N = 34,652), and Sjogren’s syndrome (SS, N = 407,746) were collected. Additionally, the latest summary-level data for TMDs (N = 228,812) were extracted from the FinnGen database. The overall effects of each immune traits were assessed via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Finally, 731 immune cell phenotypes (N = 3,757) were analyzed for their mediating role in the significant causality.ResultsUnivariable MR analyses revealed that genetically predicted RA (IVW OR: 1.12, 95% CI: 1.05-1.19, p < 0.001) and MS (IVW OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were associated with increased risk of TMDs. Two out of 731 immune cell phenotypes were identified as causal mediators in the associations of RA with TMDs, including “CD25++ CD8+ T cell % CD8+ T cell” (mediation proportion: 6.2%) and “CD3 on activated CD4 regulatory T cell” (5.4%). Additionally, “CD127 on granulocyte” mediated 10.6% of the total effect of MS on TMDs. No reverse directions, heterogeneity, and pleiotropy were detected in the analyses (p > 0.05).ConclusionThis MR study provides new evidence regarding the causal impact of genetic predisposition to RA or MS on the increased risk of TMDs, potentially mediated by the modulation of immune cells. These findings highlight the importance for clinicians to pay more attention to patients with RA or MS when consulting for temporomandibular discomfort. The mediating role of specific immune cells is proposed but needs further investigation.

Summary: Maternal-to-zygotic transition (MZT) is central to early embryogenesis. However, its underlying molecular mechanisms are still not well described. Here, we revealed the expression dynamics of 5,000 proteins across four stages of zebrafish embryos during MZT, representing one of the most systematic surveys of proteome landscape of the zebrafish embryos during MZT. Nearly 700 proteins were differentially expressed and were divided into six clusters according to their expression patterns. The proteome expression profiles accurately reflect the main events that happen during the MZT, i.e., zygotic genome activation (ZGA), clearance of maternal mRNAs, and initiation of cellular differentiation and organogenesis. MZT is modulated by many proteins at multiple levels in a collaborative fashion, i.e., transcription factors, histones, histone-modifying enzymes, RNA helicases, and P-body proteins. Significant discrepancies were discovered between zebrafish proteome and transcriptome profiles during the MZT. The proteome dynamics database will be a valuable resource for bettering our understanding of MZT.

Background: Though anterior cruciate ligament (ACL) tear has been widely accepted as an important accelerator for knee osteoarthritis (KOA), the role of intrinsic ACL degeneration in developing KOA has not been fully investigated. Purpose: To determine whether ACL degeneration, in the absence of ACL tear, is associated with incident KOA over 4 years. Study design: Cohort study; Level of evidence, 2. Methods: Participants’ knees in this nested case–control study were selected from the Osteoarthritis Initiative (OAI) study, with Kellgren–Lawrence grading (KLG) of 0 or 1 ​at baseline (BL). Case knees which had incident KOA (KLG ≥2) over 4 years, were matched 1:1 with control knees by gender, age and radiographic status. ACL signal intensity alteration (0–3 scale) and volume were assessed as compositional feature and morphology of ACL degeneration, using knee MRI at P0 (time of onset of incident KOA), P-1 (1 year prior to P0) and baseline. Conditional logistic regression was applied to analyze the association between measures of ACL degeneration and incident KOA. Results: 337 case knees with incident KOA were matched to 337 control knees. Participants were mostly female (68.5%), with an average age of 59.9 years old. ACL signal intensity alterations at BL, P-1 and P0 were significantly associated with an increased odds of incident KOA respectively (all P for trend ≤0.001). In contrast, ACL volumes were not significantly associated with incident KOA at any time points. Conclusions: ACL signal intensity alteration is associated with increased incident KOA over 4 years, whereas ACL volume is not.The translational potential of this article: This paper focused on ACL signal intensity alteration which could better reflect ACL degeneration rather than ACL tear during the progression of KOA and explored this topic in a nested case–control study. Utilizing MR images from KOA participants, we extracted the imaging features of ACL. In addition, we established a semi-quantitative score for ACL signal intensity alteration and found a significant correlation between it and KOA incidence. Our findings confirmed that the more severe the ACL signal intensity alteration, the stronger relationship with the occurrence of KOA. This suggests that more emphasis should be placed on ACL degeneration rather than ACL integrity in the future.

The development of appropriate and effective periodate (PI) activation technology is currently a popular research area. This study presents a novel efficient photocatalytic activation approach of PI for pollutant degradation based on carbon nitride (g-C3N4) and visible light (Vis). The results show that the system can remove 92.3% of acid orange 7 (AO7) within 60 min under the g-C3N4/PI/Vis reaction system. The degradation rate constant (kobs) reached 4.08 × 10−2 min−1, which is 4.21, 5.16 times, and 51.3 times higher than that of the g-C3N4/Vis system (9.7 × 10−3 min−1), PI/Vis system (7.9 × 10−3 min−1) and the g-C3N4/PI system (7.96 × 10−4 min−1), respectively. Clearly, the addition of PI significantly enhances the degradation efficiency of AO7 in the system. Additionally, under the same reaction conditions, the presence of PI showed excellent oxidation capacity in the photoactivation process compared with other common oxidants, such as peroxymonosulfate, peroxydisulfate, and H2O2. Moreover, the g-C3N4/PI/Vis system showed excellent removal of AO7 across a wide range of pH levels and in the presence of various anions. Electron paramagnetic resonance (EPR) and quenching experiments suggested that the superoxide anions (•O2−) and singlet oxygen (1O2) dominated in the oxidation of pollutants in the g-C3N4/PI/Vis system. In addition, the catalyst showed relative stability during cyclic testing, although a slight reduction in degradation efficiency was observed. In brief, the g-C3N4/PI/Vis system is highly efficient and environmentally friendly, with significant application potential in wastewater treatment.

Abstract Objective This study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA). Methods BMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles. Results A total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The “has-miR-424-5p/lncRNA PVT1” was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes. Conclusion IL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.

Objectives: To evaluate the efficacy and image processing time of the dynamic contrast-enhanced MRI (DCE-MRI) exchange model in liver fibrosis staging and compare it to the efficacy of magnetic resonance elastography (MRE). Methods: The subjects were 45 patients with nonalcoholic fatty liver disease (NAFLD) who underwent MRE and DCE-MRI in our hospital. Liver biopsy results were available for all patients. Spearman rank correlation coefficients were used to compare the correlations among MRE, DCE-MRI and liver fibrosis parameters. Quantitative DCE-MRI parameters, MRE-derived liver stiffness measurement (LSM), and the results of a combined DCE-MRI + MRE logistic regression model were compared in terms of the area under the receiver operating characteristic curve (AUC). We also compared the scanning and postprocessing times of the MRE and DCE-MRI techniques. Results: The correlation coefficients between the following parameters of interest and liver fibrosis were as follows: capillary permeability–surface area product (PS; DCE-MRI parameter), −0.761; portal blood flow (Fp; DCE-MRI parameter), −0.754; MRE-LSM, 0.835. Some DCE-MRI parameters (PS, Fp) had slightly greater AUC values than MRE-LSM for diagnosing the presence or absence of liver fibrosis, and the combined model had the highest AUC value for all stages except F4, but there was no significant difference in the diagnostic efficacy of the DCE-MRI, MRE, and combined models for any stage of fibrosis. The average scanning times for MRE and DCE-MRI were 17 s and 330 s, respectively, and the average postprocessing times were 45.5 s and 342.7 s, respectively. Conclusions: In the absence of MRE equipment, DCE-MRI represents an alternative technique. However, MRE is a quicker and simpler method for assessing fibrosis than DCE-MRI in the clinic.

Background: Mildly elevated levels of transaminase and/or immunoglobulin G (IgG) are common in patients with primary biliary cholangitis (PBC). It is still unclear whether adding immunosuppressive therapy to ursodeoxycholic acid (UDCA) benefits those patients who are not fulfilling the diagnostic criteria of PBC with autoimmune hepatitis (AIH) features. Objectives: To assess the efficacy of adding immunosuppressive therapy to UDCA for patients with PBC and autoimmune phenomena but not fulfilling the diagnostic criteria of PBC with AIH features. Design: This is a retrospective–prospective cohort study in a tertiary medical center. Methods: Patients with PBC and autoimmune phenomena were defined by the elevation of IgG and/or transaminase but did not fulfill the diagnostic criteria of PBC with AIH features. We grouped these patients based on with and without add-on immunosuppressive therapy and balanced their baseline characteristics using inverse probability treatment weighting (IPTW). Results: A total of 652 patients with PBC and autoimmune phenomena were included, with a median follow-up of 4.08 years. After IPTW, the pseudo sample size in the add-on therapy and monotherapy groups was 558 and 655, respectively. After 1 year of observation, patients in the add-on therapy group had a higher biochemical response rate (normalization of transaminase and IgG levels) (49% versus 17%, p

Abstract Background Non-alcoholic steatohepatitis (NASH) had not yet been approved therapy. Electro-acupuncture (EA) has been reported to have potential efficacy. However, high-quality clinical evidence was still lacking. Methods NASH patients were randomized and allocated to either sham acupuncture (SA) or EA group in a 1:1 ratio, with the patient blinded. Each patient received 36 sessions of SA or EA treatment over 12 weeks, followed by additional 4 weeks. The primary outcome was the changes in relative liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Results A total of 60 patients were enrolled. From baseline to week 12, the reduction of relative liver fat content measured by MRI-PDFF in the EA group (− 33.6%, quantile range: − 52.9%, − 22.7%) was significantly more significant than that in the SA group (− 15.8%, quantile range: − 36.1%, − 2.7%) (p = 0.022). Furthermore, the EA group had more patients who achieved MRI-PDFF to 30% reduction at week 12 (53.3% vs. 25.9%, p = 0.035). EA treatment also significantly reduced body weight (− 3.0 vs. + 0.1 kg, p = 0.034) and BMI (− 1.5 vs. − 0.2 kg/m2, p = 0.013) at week 16. Except for AST (− 27.4 vs. − 16.2 U/L, p = 0.015), other biochemical varieties, including ALT, fasting-glucose, cholesterol, and triglyceride, showed no statistically significant difference. Both groups measured no significant changes in liver stiffness by magnetic resonance elastography (MRE). There were no serious adverse events in either group. Conclusions Twelve weeks of EA effectively and safely reduces relative liver fat content in NASH patients. Further multicenter randomized controlled studies are needed. Trial registration Chinese Clinical Trial Registry, ChiCTR2100046617. Registered 23 May 2021, http://www.chictr.org.cn/edit.aspx?pid=127023&htm=4

Abstract Aims To investigate whether the associations between cartilage defects and cartilage volumes with changes in knee symptoms were mediated by osteophytes. Methods Data from the Vitamin D Effects on Osteoarthritis (VIDEO) study were analyzed as a cohort. The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess knee symptoms at baseline and follow-up. Osteophytes, cartilage defects, and cartilage volumes were measured using magnetic resonance imaging at baseline. Associations between cartilage morphology and changes in knee symptoms were assessed using linear regression models, and mediation analysis was used to test whether these associations were mediated by osteophytes. Results A total of 334 participants (aged 50 to 79 years) with symptomatic knee osteoarthritis were included in the analysis. Cartilage defects were significantly associated with change in total knee pain, change in weight-bearing pain, and change in non-weight-bearing pain after adjustment for age, sex, body mass index, and intervention. Cartilage volume was significantly associated with change in weight-bearing pain and change in physical dysfunction after adjustment. Lateral tibiofemoral and patellar osteophyte mediated the associations of cartilage defects with change in total knee pain (49–55%) and change in weight-bearing pain (61–62%) and the association of cartilage volume with change in weight-bearing pain (27–30%) and dysfunction (24–25%). Both cartilage defects and cartilage volume had no direct effects on change in knee symptoms. Conclusions The significant associations between cartilage morphology and changes in knee symptoms were indirect and were partly mediated by osteophytes.

Abstract Background and aims Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. The aim of the present study was to characterize the clinical features and therapeutic response of patients with IgG4-RD and identify risk factors for disease relapse. Methods We collected baseline data of eligible patients with IgG4-RD and analyzed clinical features by interview and review of medical records. The patients who received glucocorticoids (GC) therapy with at least 3 months follow-up were used to characterize the therapeutic response and identify risk factors for relapse. Result Totally 127 IgG4-RD patients, including 92 males and 35 females, were enrolled in the present study. The median age of onset was 63.0 years, ranging from 23 to 86. The pancreas, bile duct and lymph nodes were the most frequently involved organs. The serum IgG4 level was elevated in 94.5% of the patients and was correlated with the number of organs involved. Patients classified as head and neck limited group were more likely to be female. Compared to Mikulicz syndrome and systemic involvement group, pancreato-hepatobiliary group had higher aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin and lower IgG4 level. Mikulicz syndrome and systemic involvement group had the highest IgG4-RD RI score, IgG level. Among 92 patients who received medical therapy with at least 3 months follow-up, 76 received GC alone or in combination with immunomodulator (IM) and 16 patients did not take GC. 74 out of the 76 patients (97.3%) achieved remission, with 59 of them remained in remission and 15 of them relapsed. Whereas 16 patients did not take GC, among them, 6 patients achieved remission with one relapsed. On multivariate analysis, higher initial score of ACR/EULAR IgG4-RD Classification Criteria and GC withdrawal were independent predictors for relapse. Conclusion Four phenotypes of IgG4-RD showed different demographic and serological features. GC + IM therapy was safe and effective and might protect patients from relapse. The independent risk factors of relapse were GC withdrawal and higher score of ACR/EULAR IgG4-RD Classification Criteria.

In this study, waterborne polyurethane acrylate (WPUA)/MXene nanocomposite films with varying MXene loadings were fabricated using UV-curing technology, where MXene (Ti3C2Tx) was employed as a nanofiller. The microstructure and chemical structure of the WPUA/MXene nanocomposite films were examined by XRD and FTIR, respectively. The water contact angle testing demonstrated that the incorporation of MXene into the nanocomposite films led to an increase in their hydrophilic properties. The tensile strength, the elongation at break, and Young’s modulus of the WPUA/MXene nanocomposite coatings exhibited an initial increase followed by a decrease with increasing MXene loadings. Compared to the pure WPUA film, the tensile strength and elongation at break of nanocomposites with 0.077 wt% MXene loading reached their maximum values, which increased by 39.9% and 38.5%, respectively. Furthermore, the glass transition temperature and the thermal stability were both enhanced by MXene to some extent. This study introduces a novel method for utilizing MXene in UV-curable waterborne coatings.

Abstract Acute respiratory distress syndrome (ARDS), caused by noncardiogenic pulmonary edema (PE), contributes significantly to Coronavirus 2019 (COVID-19)-associated morbidity and mortality. We explored the effect of transmembrane osmotic pressure (OP) gradients in PE using a fluorescence resonance energy transfer-based Intermediate filament (IF) tension optical probe. Angiotensin-II- and bradykinin-induced increases in intracellular protein nanoparticle (PN)-OP were associated with inflammasome production and cytoskeletal depolymerization. Intracellular protein nanoparticle production also resulted in cytomembrane hyperpolarization and L-VGCC-induced calcium signals, which differed from diacylglycerol-induced calcium increment via TRPC6 activation. Both pathways involve voltage-dependent cation influx and OP upregulation via SUR1-TRPM4 channels. Meanwhile, intra/extracellular PN-induced OP gradients across membranes upregulated pulmonary endothelial and alveolar barrier permeability. Attenuation of intracellular PN, calcium signals, and cation influx by drug combinations effectively relieved intracellular OP and pulmonary endothelial nonselective permeability, and improved epithelial fluid absorption and PE. Thus, PN-OP is pivotal in pulmonary edema in ARDS and COVID-19, and transmembrane OP recovery could be used to treat pulmonary edema and develop new drug targets in pulmonary injury. Graphical Abstract

Abstract Backgrounds Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload. Methods Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro. Results Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level. Conclusions Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload.

Abstract Background Hereditary hemochromatosis (HH) is widely recognized and clinical manifestations of hemochromatosis-related (HFE-related) HH is well studied in European populations. Less is known about the clinical and laboratory characteristics of non-HFE related HH in Asian population. We aimed to explore the relationship between genotype and clinical phenotype in Chinese patients with non-HFE related hereditary hemochromatosis. Methods Peripheral blood samples and clinical data of patients with primary iron overload were collected from the China Registry of Genetic/Metabolic Liver Diseases. Sanger sequencing was performed in cases with primary iron overload, for 5 known HH related genes (HFE, HJV, HAMP, TFR2 and SLC40A1) and 2 novel iron homeostasis-related genes (DENND3 and SUGP2). The correlation of genotype and clinical phenotype in these patients was analyzed. Results Of the 32 patients with primary iron overload (23 were males and 9 were females), non-HFE variants were detected in 31 (31/32, 97%), including 8 pathogenic variants in HJV, 7 pathogenic variants in SLC40A1, 8 likely pathogenic variants in SUGP2 and 5 likely pathogenic variants in DENND3 cases. Among these 31 cases, 4 cases harbored homozygous variants, 2 cases harbored homozygous + heterozygous variants, 19 cases harbored heterozygous or combined heterozygous variants, and 6 cases harbored no any damaging variants. None of investigated cases carried damaging HAMP and TFR2 variants were found. 8 cases were classified as type 2A HH and 6 cases as type 4 HH, 10 cases as non-classical genotype, and 6 cases had no pathogenic variants from 31 cases. During the statistical analysis, we excluded one case (SLC40A1 IVS3 + 10delGTT + SUGP2 p. R639Q(homo)) with difficulty in grouping due to combined damaging variants. Cases with type 2A HH have an earlier age at diagnosis (p = 0.007). The iron index of cases in type 2A HH and type 4 HH was higher than that in other groups (p = 0.01). Arthropathy was relatively rare in all groups. None of cases with type 2A HH developed cirrhosis. Cirrhosis and diabetes are more prevalent in type 4 HH. The incidence of cirrhosis (p = 0.011), cardiac involvement (p = 0.042), diabetes (p = 0.035) and hypogonadism (p = 0.020) was statistically significant in the four groups. However, due to the limited sample size, the pairwise comparison showed no significant difference. Conclusions This is the first comprehensive analysis about the gene variant spectrum and phenotypic aspects of non-HFE HH in China. The results will be useful to the identification, diagnosis and management of HH in China.

Melatonin application has obvious improving effects on alleviating the drought-induced inhibition of plant growth. However, the root phenotypic dynamics in wheat treated with melatonin remain unknown. This study was conducted using RhizoPot, a novel and improvised in situ root observation device, with three treatments, including normal water condition (CK), drought condition (Ds, relative water content 45–50%), and 100 µM melatonin treatment under drought condition (MT). Results showed that MT application effectively improves root morphological indicators, including root (specific root) length, surface area, and volume; root length density; and the average root diameter of wheat plants. Also, the inhibitory effect of drought on shoot morphology, including plant height, dry weight, net photosynthesis, and stomatal aperture of leaves, were improved significantly through MT under drought condition. Life span and percent survival of fine root, lateral root, and root hair at different segments were also effectively improved under MT treatment. Compared with those shown under CK and Ds, the melatonin contents in leaves and roots were increased, and the expression levels of melatonin-synthesis-related genes (TaCOMT and TaTDC) were upregulated significantly under MT treatment. The findings of this study may clarify the drought resistance mechanism of wheat treated with melatonin under drought stress.

Context Naoxintong (NXT), a prescribed traditional Chinese medicine, widely used in cerebrovascular and cardiovascular diseases, could be effective in diabetic wounds. Objective This study evaluates the wound healing activity of NXT by employing an excisional wound splinting model. Materials and methods NXT was dissolved in saline and given daily by gavage. Wounds were induced at the dorsum of non-diabetic (db/+) and diabetic (db/db) mice and treated with saline or 700 mg/kg/d NXT for 16 days. Wound closure was measured every four days. Extracellular matrix (ECM) remodelling, collagen deposition, leukocyte infiltration and expression of Col-3, CK14, CXCL1, CXCL2, MPO, Ly6G, CD68, CCR7, CD206, p-JAK1, p-STAT3 and p-STAT6 was analysed. Results NXT significantly accelerated rate of wound closure increased from 70% to 84%, accompanied by up-regulation of collagen deposition and ECM at days 16 post-injury. Moreover, NXT alleviated neutrophil infiltration, accompanied by down-regulation of CXCL1 and CXCL2 mRNA expression. In addition, NXT markedly augmented neutrophil efferocytosis. In diabetic wounds, the levels of M1 marker gene (CCR7) increased, while M2 marker gene (CD206) decreased, demonstrating a pro-inflammatory shift. Application of NXT increased M2 macrophage phenotype in db/db mice. Mechanistically, NXT treatment increased expression level of p-STAT3 and p-STAT6 at days 3 post-injury, indicating NXT mediated macrophages towards M2 phenotype and alleviated inflammation in diabetic wounds by activation of STAT3 and STAT6. Conclusions Our study provides evidence that NXT accelerates diabetic wound healing by attenuating inflammatory response, which provides an important basis for use of NXT in the treatment of chronic diabetic wound healing.

Image segmentation is a key technology in the field of computer image processing. Among them, segmentation methods based on active contour models have been developed rapidly in recent years due to their effective processing of complex images such as medical images. These methods have achieved significant results in medical, military, and industrial fields. Present research work mainly introduces the training of computer graphics and image processing technology and the method of active contour image segmentation. It focuses on the study of image segmentation methods and focuses on the segmentation methods based on active contour models. Firstly, it summarizes two types of segmentation methods based on edge and region and summarizes their advantages and disadvantages. Then, the segmentation method based on the active contour model is studied, and several typical active contour models are comprehensively compared. Finally, the local binary fitting model and the local Gaussian distribution fitting energy model are improved and simulated. Furthermore, from the development of computer graphics and image processing technology to analyze some methods and means of training this professional talent. The experimental results of this article show that the active contour image segmentation algorithm can not only ensure the image segmentation algorithm but also reduce the number of iterations and shorten the image segmentation time. Compared with the CV, LBF, and LGIF models computational efficiency of Segmentation method is increased by 9.2 times, 2.64 times, and 1.44 times, respectively.

Context Astragali Radix (AR) and Angelica sinensis Radix (ASR) combinations are used to treat cardiovascular disorders. Objectives This study investigates the protective effects of different compatibility proportions of AR and ASR on cardiac dysfunction in a C57BL/6 mouse model of myocardial infarction (MI). Materials and methods MI mice were induced by ligation of the left coronary artery and divided into six groups: sham, vehicle, 10 mg/kg/d simvastatin and combinations of AR and ASR at different ratios, including 1:1 (AR 2.5 g/kg + ASR 2.5 g/kg), 3:1 (AR 3.75 g/kg + ASR 1.25 g/kg) and 5:1 (AR 4.17 g/kg + ASR 0.83 g/kg). Both AR–ASR combinations and simvastatin were dissolved in saline solution and given daily by gavage. The left ventricle function, infarct size, heart tissue injury, apoptosis of cardiomyocytes, leukocyte infiltrates, capillary density and expression of cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, Bad, IL-1β, IL-6, VEGF, p-Akt and p-eNOS were analysed. Results Different combinations of AR and ASR improve cardiac function and reduce infarct size (61.15% vs. 39.3%, 42.65% and 45.5%) and tissue injury through different mechanisms. When AR was combined with ASR at ratio of 1:1, the inflammation and cardiomyocyte apoptosis were suppressed (p

Liver fibrosis is a pathological result of liver injury that usually leads to a pathophysiological wound healing response. The total alkaloids of Corydalis saxicola Bunting (TACS) have been used for hepatoprotective effects on the liver. However, its exact therapeutic mechanisms of liver fibrosis are not yet well understood. To explore the potential anti-fibrosis mechanism of TACS, metabolomics coupled with network pharmacology were applied to reveal the underlying mechanisms. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) combined with multivariate statistical analyses were performed to estimate changes in metabolic profiles. As a result, a total of 23 metabolites in rats with liver fibrosis were altered; of these, 11 had been downregulated and 12 had been upregulated compared with the control group. After TACS treatment, the levels of 13 metabolites were significantly restored compared with the CCl4-treated group, of which 4 metabolites were up-regulated and 9 metabolites were down-regulated. Many of these metabolites are involved in the bile acid metabolism, glutathione metabolism, tryptophan metabolism and purine metabolism. Then, three key targets, including cytochrome P450 family1 subfamily A member 1 (CYP1A1), ornithine decarboxylase 1 (OCD1) and monoamine oxidase Type B (MAOB) were predicted as potential therapeutic targets of TACS against liver fibrosis through network pharmacology analysis. Finally, palmatine, tetrahydropalmatine and dehydrocavidine were screened as potential active compounds responsible for the anti-fibrosis effect of TACS by molecular docking analysis. This study reveals that TACS exerted anti-fibrosis effects by regulating the liver metabolic pathway with multiple components and multiple targets, which is helpful to further clarify the hepatoprotective mechanisms of natural plant extracts.

Oroxylin A (OA) has been shown to simultaneously increase coronary flow and provide a strong anti-inflammatory effect. In this study, we described the angiogenic properties of OA. OA treatment accelerated perfusion recovery, reduced tissue injury, and promoted angiogenesis after hindlimb ischemia (HLI). In addition, OA regulated the secretion of multiple cytokines, including vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANG-2), fibroblast growth factor-basic (FGF-2), and platelet derived growth factor BB (PDGF-BB). Specifically, those multiple cytokines were involved in cell migration, cell population proliferation, and angiogenesis. These effects were observed at 3, 7, and 14 days after HLI. In skeletal muscle cells, OA promoted the release of VEGFA and ANG-2. After OA treatment, the conditioned medium derived from skeletal muscle cells was found to significantly induce endothelial cell (EC) proliferation. OA also induced EC migration by activating the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil kinase 2 (ROCK-II) signaling pathway and the T-box20 (TBX20)/prokineticin 2 (PROK2) signaling pathway. In addition, OA was able to downregulate the number of macrophages and neutrophils, along with the secretion of interleukin-1β, at 3 days after HLI. These results expanded current knowledge about the beneficial effects of OA in angiogenesis and blood flow recovery. This research could open new directions for the development of novel therapeutic intervention for patients with peripheral artery disease (PAD).

Introduction Heart failure (HF) is an end-stage of numerous heart diseases including hypertension, coronary heart disease and arrhythmia, in which the heart is unable to perform its circulatory function with sufficient efficiency due to structural or functional dysfunction (systolic or diastolic alterations). Strategies such as exercise rehabilitation may improve cardiac function, exercise capacity and health-related quality of life and reduce anxiety and depression in patients with HF. However, the relative effectiveness as well as the hierarchy of exercise interventions have not been well established, although various exercise options are available. Therefore, this protocol proposes to conduct a network meta-analysis (NMA) aiming to compare the effectiveness of different types of exercise training in patients with HF.Methods and analysis PubMed, Embase and the Cochrane Library will be searched from inception to March 2021 for relevant randomised controlled trials. Other resources, such as Google Scholar and Clinical Trials.gov will also be considered. Studies assessing exercise rehabilitation in patients with HF will be selected. Two independent reviewers will identify eligible trials. The PEDro risk of bias assessment tool will be used to assess the quality of the included studies. Bayesian NMA will be used when possible to determine the comparative effectiveness of the different exercise interventions. The mean ranks and surface will estimate the ranking probabilities for the optimal intervention of various treatments under the cumulative ranking curve. Subgroup, sensitivity and meta-regression will be conducted to explain the included studies’ heterogeneity if possible. We will also use the Grading of Recommendations, Assessment, Development, and Evaluation system to assess the strength of evidence.Ethics and dissemination This systematic review and NMA will synthesise evidence on the effectiveness of the different exercises in patients with HF. The results will be submitted to a peer-reviewed journal. No ethical approval will be required because the data used for the review will be exclusively extracted from published studies.PROSPERO registration number CRD42020165870.

Compositing with metal oxides is proved to be an efficient strategy to improve electrochemical performance of anode material Li4Ti5O12 for lithium-ion batteries. Herein, spherical Li4Ti5O12/NiO composite powders have been successfully prepared via a spray drying method. X-ray diffraction and high-resolution transmission electron microscopy results demonstrate that crystal structure of the powders is spinel. Scanning electron microscopy results show that NiO uniformly distributes throughout Li4Ti5O12 matrix. It is found that compositing with NiO increases both discharge platform capacity and rate stability of Li4Ti5O12. The as-prepared Li4Ti5O12/NiO (5%) exhibits a high initial discharge capacity of 381.3 mAh g−1 at 0.1 C, and a discharge capacity of 194.7 mAh g−1 at an ultrahigh rate of 20 C.

Summary: Ultra-high-molecular-weight (UHMW) polymers can display outstanding properties; however, it is challenging to synthesize UHMW polymers by using external free radical initiators. To address this, here, we report the ration design and adoption of B-alkylcatecholborane (RBCat) as a radical initiator in controlled radical polymerization in the presence of a chain-transfer agent. The autoxidation of RBCat with one alkyl substituent generates only one alkyl radical. The oxygen is incorporated and stored in the oxidized form (ROOB-Cat) that slowly releases the alkyl radical. The rationally designed alkyl radical is proposed to preferentially activate the chain-transfer agent (CTA) and grow the polymer chain from CTA, so limited free polymer chains are formed from the initiating alkyl radicals. Polymerizations of (meth)acrylates are achieved with narrow molecular weight distribution (Ð = 1.10) and predetermined molecular weights even in a UHMW range (up to 3 million). The successful chain extension of UHMW indicates the high degree of control of the polymerization.

ABSTRACT Background: primary biliary cholangitis (PBC) patients with a suboptimal response to ursodeoxycholic acid (UDCA) have a significantly worse survival rate. Fenofibrate has been shown to improve the short-term biochemical response in this group of patients. However, there is limited data available on the safety and efficacy of its long-term use, especially in patients with cirrhosis. Methods: in this retrospective cohort study, fenofibrate was given to PBC patients with a suboptimal response to at least 12 months of UDCA (13-15 mg/kg/d) therapy. Biochemistry data, GLOBE score and UK-PBC risk score at baseline and at different time points of treatment were compared. The safety profiles were also compared between cirrhotic and non-cirrhotic patient groups. Results: fenofibrate (200 mg/day) was given to 39 PBC patients with a suboptimal response to UDCA (15 cirrhotic and 24 non-cirrhotic patients). In the 26 patients who completed more than one year of combination therapy, the alkaline phosphatase (ALP) levels were 215 (185, 326) U/l, 122 (110, 202) U/l, 128 (106, 194) U/l, 124 (100, 181) U/l and 120 (82, 168) U/l, at baseline, three months, six months, 12 months and 24 months, respectively. All p values were < 0.01 when compared to baseline values. After two years of combination therapy, the UK-PBC risk score and GLOBE score did not significantly improve. The overall rates of adverse events were not significantly different between the cirrhotic and non-cirrhotic group. The elevation of liver enzymes was the most frequent side effect (n = 7), leading to a discontinuation in four patients. Furthermore, after two years of combination therapy, the serum creatinine levels and estimated glomerular filtration rates (eGFR) were significantly worse in both groups. Conclusion: fenofibrate add-on therapy could improve ALP and -GT levels in both non-cirrhotic and cirrhotic PBC patients with a suboptimal response to UDCA. However, patients need to be monitored carefully for a potential liver injury and nephrotoxicity.

Traditional methods of stripe noise removal based on space domain or transformation domain generally cannot handle the case where the noise is extremely sparse. To solve this problem, we propose a novel approach to accurately detect and remove the stripe noise by analyzing the directional and structural information of the stripe noise. First, we build a preselected stripe noise lines set by using local progressive probabilistic Hough transform. Subsequently, the real stripe noise lines are screened out from this set according to the feature of grayscale discontinuities. Finally, our approach uses the strategy of neighborhood grayscale weighted replacement and a local Gaussian filter to perform image destriping. Extensive experiments demonstrate that our approach proposed in this paper outperforms other recent promising methods in terms of quantitative assessments, qualitative assessments, and computing time.

Summary: Both innate and adaptive immune cells are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the crosstalk between innate and adaptive immunity is largely unknown. Here we show that compared with WT mice, OX40−/− mice exhibit decreased liver fat accumulation, lobular inflammation, and focal necrosis after feeding with diets that induce NASH. Mechanistically, OX40 deficiency suppresses Th1 and Th17 differentiation, and OX40 deficiency in T cells inhibits monocyte migration, antigen presentation, and M1 polarization. Soluble OX40 stimulation alone upregulates antigen presentation, chemokine receptor expression, and proinflammatory cytokine secretion by liver monocytes. Furthermore, plasma soluble OX40 levels are positively associated with NASH in humans, suggesting clinical relevance of the findings. In conclusion, we show a mechanism for T cell regulation of innate immune cells. OX40 is a key regulator of both intrahepatic innate and adaptive immunity, generates two-way signals, and promotes both proinflammatory monocyte and macrophage and T cell function, resulting in NASH development. : Sun et al. show that OX40 is a key molecule in the regulation of both intrahepatic innate and adaptive immunity. OX40 promotes both proinflammatory monocyte and macrophage and T cell function, resulting in NASH development and progression. These findings suggest that OX40 could serve as a diagnostic index and therapeutic target in NASH. Keywords: OX40, NAFLD, inflammation, monocyte, T cell

The modeling and design of multi-agent systems is imperative for applications in the evolving intelligence of unmanned systems. In this paper, we propose a multi-agent system design that is used to build a system for training a team of unmanned surface vehicles (USVs) where no historical data concerning the behavior is available. In this approach, agents are built as the physical controller of each USV and their cooperative decisions used for the USVs’ group coordination. To make our multi-agent system intelligently coordinate USVs, we built a multi-agent-based learning system. First, an agent-based data collection platform is deployed to gather competition data from agents’ observation for on-line learning tasks. Second, we design a genetic-based fuzzy rule training algorithm that is capable of optimizing agents’ coordination decisions in an accumulated manner. The simulation results of this study demonstrate that our proposed training approach is feasible and able to converge to a stable action selection policy towards efficient multi-USVs’ cooperative decision making.

BackgroundSaturated fat (SFA), ω‐6 (n‐6) polyunsaturated fat (PUFA), and trans fat (TFA) influence risk of coronary heart disease (CHD), but attributable CHD mortalities by country, age, sex, and time are unclear. Methods and ResultsNational intakes of SFA, n‐6 PUFA, and TFA were estimated using a Bayesian hierarchical model based on country‐specific dietary surveys; food availability data; and, for TFA, industry reports on fats/oils and packaged foods. Etiologic effects of dietary fats on CHD mortality were derived from meta‐analyses of prospective cohorts and CHD mortality rates from the 2010 Global Burden of Diseases study. Absolute and proportional attributable CHD mortality were computed using a comparative risk assessment framework. In 2010, nonoptimal intakes of n‐6 PUFA, SFA, and TFA were estimated to result in 711 800 (95% uncertainty interval [UI] 680 700–745 000), 250 900 (95% UI 236 900–265 800), and 537 200 (95% UI 517 600–557 000) CHD deaths per year worldwide, accounting for 10.3% (95% UI 9.9%–10.6%), 3.6%, (95% UI 3.5%–3.6%) and 7.7% (95% UI 7.6%–7.9%) of global CHD mortality. Tropical oil–consuming countries were estimated to have the highest proportional n‐6 PUFA– and SFA‐attributable CHD mortality, whereas Egypt, Pakistan, and Canada were estimated to have the highest proportional TFA‐attributable CHD mortality. From 1990 to 2010 globally, the estimated proportional CHD mortality decreased by 9% for insufficient n‐6 PUFA and by 21% for higher SFA, whereas it increased by 4% for higher TFA, with the latter driven by increases in low‐ and middle‐income countries. ConclusionsNonoptimal intakes of n‐6 PUFA, TFA, and SFA each contribute to significant estimated CHD mortality, with important heterogeneity across countries that informs nation‐specific clinical, public health, and policy priorities.