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BackgroundThe association between dietary zinc intake and epilepsy remains unclear. This study aimed to investigate the relationship between zinc intake from the diet and epilepsy, employing Mendelian randomization (MR) to explore potential causal links between zinc and epilepsy.MethodsThe cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2018. Among the 4,434 participants included, 1.5% (67/4,434) reported having epilepsy. Restricted cubic spline models and logistic regression models were employed to examine the relationships between dietary zinc intakes and epilepsy. Subsequently, a 2-sample Mendelian randomization (MR) analysis was conducted using the inverse variance weighted (IVW) approach as the primary analysis.ResultsIn the restricted cubic spline (RCS) analysis, the relationship between dietary zinc consumption and epilepsy displayed an L-shaped curve (nonlinear, p = 0.049). After multivariate adjustments, the adjusted odds ratios for epilepsy in T2 (5.0–11.0 mg/day) and T3 (≥11.0 mg/day) were 0.49 (95% confidence interval [CI]: 0.26–0.92, p = 0.026) and 0.60 (95% CI: 0.31–1.17, p = 0.132), respectively, compared to the lowest dietary zinc consumption tertile (T1, ≤5.0 mg/day). The IVW method indicated that genetically predicted zinc intake per standard-deviation increase was inversely associated with three types of epilepsy, including all types of epilepsy (OR = 1.06, 95% CI: 1.02–1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01–1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00–1.02, p = 0.025).ConclusionOur findings suggest that a daily zinc intake ranging from 5.0 to 11.0 mg is associated with the lowest risk of epilepsy. Furthermore, Mendelian randomization (MR) studies provide additional support for the existence of a causal relationship between zinc and epilepsy.

BackgroundPrevious observational studies have indicated a potential association between the gut microbiota and multiple myeloma (MM). However, the relationship between the gut microbiota and MM remains unclear. This study aimed to ascertain the existence of a causal link between the gut microbiota and MM.MethodsTo investigate the potential causal relationship between gut microbiota and MM, a two-sample Mendelian randomization (MR) analysis was conducted. Exposure data was obtained from the MiBioGen consortium, which provided genetic variants associated with 211 bacterial traits. MM outcome data was obtained from the FinnGen consortium. The selection of Single nucleotide polymorphisms estimates was performed through meta-analysis using inverse-variance weighting, and sensitivity analyses were conducted using weighted median, MR Egger, Simple mode, and MR-PRESSO.ResultsThe results of the study demonstrated a significant positive correlation between the genus Eubacterium ruminantium group and the risk of MM (OR 1.71, 95% CI 1.21 to 2.39). Conversely, the genus: Dorea (OR 0.46, 95% CI 0.24 to 0.86), Coprococcus1 (OR 0.47, 95% CI 0.22 to 1.00), RuminococcaceaeUCG014 (OR 0.57, 95% CI 0.33 to 0.99), Eubacterium rectale group (OR 0.37, 95% CI 0.18 to 0.77), and order: Victivallales (OR 0.62, 95% CI 0.41–0.94), class: Lentisphaeria (OR 0.62, 95% CI 0.41 to 0.94), exhibited a negative association with MM. The inverse variance weighting analysis provided additional support for these findings.ConclusionThis study represents an inaugural exploration of MR to investigate the connections between gut microbiota and MM, thereby suggesting potential significance for the prevention and treatment of MM.

BackgroundThe preoperative inflammatory condition significantly influences the prognosis of malignancies. We aimed to investigate the potential significance of preoperative inflammatory biomarkers in forecasting the long-term results of lung carcinoma after microwave ablation (MWA).MethodThis study included patients who received MWA treatment for lung carcinoma from Jan. 2012 to Dec. 2020. We collected demographic, clinical, laboratory, and outcome information. To assess the predictive capacity of inflammatory biomarkers, we utilized the area under the receiver operating characteristic curve (AUC-ROC) and assessed the predictive potential of inflammatory biomarkers in forecasting outcomes through both univariate and multivariate Cox proportional hazard analyses.ResultsA total of 354 individuals underwent MWA treatment, of which 265 cases were included in this study, whose average age was 69.1 ± 9.7 years. The AUC values for the Systemic Inflammatory Response Index (SIRI) to overall survival (OS) and disease-free survival (DFS) were 0.796 and 0.716, respectively. The Cox proportional hazards model demonstrated a significant independent association between a high SIRI and a decreased overall survival (hazard ratio [HR]=2.583, P

BackgroundSeveral studies have pointed to the critical role of gut microbiota (GM) and their metabolites in Hirschsprung disease (HSCR) pathogenesis. However, the detailed causal relationship between GM and HSCR remains unknown.MethodsIn this study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between GM and HSCR, based on the MiBioGen Consortium’s genome-wide association study (GWAS) and the GWAS Catalog’s HSCR data. Reverse MR analysis was performed subsequently, and the sensitivity analysis, Cochran’s Q-test, MR pleiotropy residual sum, outlier (MR-PRESSO), and the MR-Egger intercept were used to analyze heterogeneity or horizontal pleiotropy. 16S rDNA sequencing and targeted mass spectrometry were developed for initial validation.ResultsIn the forward MR analysis, inverse-variance weighted (IVW) estimates suggested that Eggerthella (OR: 2.66, 95%CI: 1.23–5.74, p = 0.01) was a risk factor for HSCR, while Peptococcus (OR: 0.37, 95%CI: 0.18–0.73, p = 0.004), Ruminococcus2 (OR: 0.32, 95%CI: 0.11–0.91, p = 0.03), Clostridiaceae1 (OR: 0.22, 95%CI: 0.06–0.78, p = 0.02), Mollicutes RF9 (OR: 0.27, 95%CI: 0.09–0.8, p = 0.02), Ruminococcaceae (OR: 0.16, 95%CI: 0.04–0.66, p = 0.01), and Paraprevotella (OR: 0.45, 95%CI: 0.21–0.98, p = 0.04) were protective factors for HSCR, which had no heterogeneity or horizontal pleiotropy. However, reverse MR analysis showed that HSCR (OR: 1.02, 95%CI: 1–1.03, p = 0.049) is the risk factor for Eggerthella. Furthermore, some of the above microbiota and short-chain fatty acids (SCFAs) were altered in HSCR, showing a correlation.ConclusionOur analysis established the relationship between specific GM and HSCR, identifying specific bacteria as protective or risk factors. Significant microbiota and SCFAs were altered in HSCR, underlining the importance of further study and providing new insights into the pathogenesis and treatment.

BackgroundPrevious research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics.MethodsWe used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy.ResultsThe analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available.ConclusionThe drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.

The economic and health significance of quinoa is steadily growing on a global scale. Nevertheless, the primary obstacle to achieving high yields in quinoa cultivation is pre-harvest sprouting (PHS), which is intricately linked to seed dormancy. However, there exists a dearth of research concerning the regulatory mechanisms governing PHS. The regulation of seed germination by various plant hormones has been extensively studied. Consequently, understanding the mechanisms underlying the role of endogenous hormones in the germination process of quinoa seeds and developing strategies to mitigate PHS in quinoa cultivation are of significant research importance. This study employed the HPLC-ESI-MS/MS internal standard and ELISA method to quantify 8 endogenous hormones. The investigation of gene expression changes before and after germination was conducted using RNA-seq analysis, leading to the discovery of 280 differentially expressed genes associated with the regulatory pathway of endogenous hormones. Additionally, a correlation analysis of 99 genes with significant differences identified 14 potential genes that may act as crucial “transportation hubs” in hormonal interactions. Through the performance of an analysis on the modifications in hormone composition and the expression of associated regulatory genes, we posit a prediction that implies the presence of a negative feedback regulatory mechanism of endogenous hormones during the germination of quinoa seeds. This mechanism is potentially influenced by the unique structure of quinoa seeds. To shed light on the involvement of endogenous hormones in the process of quinoa seed germination, we have established a regulatory network. This study aims to offer innovative perspectives on the breeding of quinoa varieties that exhibit resistance to PHS, as well as strategies for preventing PHS.

IntroductionAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-β peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear.MethodsDepressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS.ResultsWe found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ–mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice.ConclusionThese results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer’s disease.

ObjectTo investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs: sorafenib and lenvatinib) plus PD-1 inhibitor (camrelizumab) versus TKIs alone in transarterial chemoembolization-refractory (TACE-refractory) hepatocellular carcinoma (HCC).Materials and methodsData of TACE-refractory HCC patients treated with TACE+TKIs+PD-1 inhibitor (TACE+TKIs+PD-1group) (n=57) or TACE+TKIs (TACE+TKIs group) (n=50) from January 2019 to January 2022 were retrospectively collected and analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were evaluated by univariate and multivariate analyses.ResultsCompared with the TKIs group, both PFS and OS were prolonged in the TACE+TKIs+PD-1 group (median PFS: 7 months vs. 5 months, P=0.007; median OS: 17 months vs. 11 months, P=0.002). In multivariate analysis, tumor size and treatment were independent prognostic factors for PFS and OS. The incidence and severity of AEs related to the treatment between the two groups showed no significant difference.ConclusionThe treatment of TACE combined with TKIs plus camrelizumab demonstrated promising efficacy and safety in TACE-refractory HCC.

BackgroundHepatoblastoma (HB) is the most common liver tumor in children with easy metastasis. The emergence of ferroptosis as a novel form of cell death has gained increased attention in various human cancers. However, the roles of ferroptosis-related (FR) genes in HB remain elusiveMethodsThe GSE133039, GSE131329, and GSE81928 datasets were utilized for screening core FR genes in HB. Through Lasso regression analysis and using the support vector machine recursive feature elimination (SVM-RFE) algorithm, three candidate FR genes were obtained for characterizing HB. Their expression patterns and their clinical associations were explored through the ‘Limma’ R package, and their diagnostic potential was evaluated using ROC curves. Nitric oxide synthase 2 (NOS2) emerged as a candidate for further analyses. The CIBERSORT algorithm and GSEA dataset were used to respectively investigate the immune and metabolism effects of NOS2; the former was validated through immunofluorescence. The GSDC database was employed to analyze the correlation between NOS2 expression and the therapeutic efficacy of multiple drugs. PCR, Western blotting, colony formation assays, and Transwell experiments, were used to determine biological functions of NOS2 in HB cells. Potential upstream transcription factors of NOS2 were predicted through the TRRUST, hTFtarget, GeneCards, and JASPAR databases.ResultsNQO1, SLC1A4, and NOS2 were identified as potential genes in HB and found to be significantly upregulated in tumor samples. Nevertheless, only NOS2 was closely associated with HB clinicopathological characteristics; high NOS2 expression indicated poor prognosis, metastatic tendency, and late clinical stage. Immune analyses indicated that high NOS2 expression was concomitant with decreased infiltration levels of CD8+ T cells but increased infiltration levels of macrophages. GSEA revealed that NOS2 failed to affect the enrichments of glycolysis, fatty acid metabolism, and cholesterol biosynthesis in HB. Moreover, NOS2 was positively correlated with the IC50 values of trametinib, lapatinib, and cisplatin. NOS2 overexpression promoted the proliferation, migration and invasion of HepG2 and HuH-6 cells. JUND was identified as a potential transcriptional regulator of NOS2 by binding to its promoter (5’-TTCTGACTCTTTT-3’).ConclusionNOS2 plays a significant role in HB clinical assessments and holds promise as a novel therapeutic target.

This study mapped the dynamic interaction of narratives regarding Nigeria's pursuit of rice self-sufficiency and related trade policies since the 1970s to explore whether agricultural protectionist policies can help achieve food security in Nigeria. Developing agricultural trade policies that simultaneously secure imported food supplies and protect domestic agricultural development is a challenging task. Nigeria's protectionist policies have a controversial agenda. Few studies have investigated the dynamic process of rice production and trade policy from a historical viewpoint; our study fills this gap. Through mapping Nigeria's pursuit of rice self-sufficiency over the past 50 years, we found that seesawed trade policy parallels complex rice development, leaving imported rice dependence unchanged. Regardless of when policies switch to trade protection or liberalization, the procedure does not directly lead to increased rice production. Since much exploration is needed regarding how to achieve food security in Nigeria, we also identify three new dimensions for future food security research based on our findings' optimal recommendations.

A well-known milk-derived bioactive tripeptide, VPP (Val-Pro-Pro) has good anti-inflammatory, anti-hypertension, and anti-hydrolysis properties. However, whether VPP can alleviate calf intestinal inflammation is unclear. In this experiment, the effects of VPP on growth, diarrhea incidence, serum biochemical indices, short-chain fatty acids, and fecal microorganisms were examined in pre-weaning Holstein calves. Eighteen calves with similar birth date, body weight, and genetic background were randomly assigned equally to two groups (n = 9). The control group was given 50 mL of phosphate buffer saline before morning feeding, whereas the VPP group received 50 mL of VPP solution (100 mg/kg body weight/d). The study lasted for 17 days, with the first 3 days used for adaptation. Initial and final body weights were determined, and daily dry matter intake and fecal score were recorded throughout the study. Serum hormone levels and antioxidant and immune indices were measured on day 14. Fecal microorganisms were collected on days 0, 7, and 14, and 16S rDNA sequencing was performed. Oral administration of VPP did not significantly affect calf average daily feed intake and body weight, but the growth rate in body weight was significantly higher in the VPP group than in the control group on day 7 (P < 0.05). Compared with the control, VPP significantly decreased serum TNF-α and IL-6 contents (P < 0.05), and concentrations of nitric oxide and IL-1β also decreased but not significantly (0.05 < P < 0.1). After seven days of VPP, relative abundances of g_Lachnoclostridium, uncultured_bacterium_, and g_Streptococcus in fecal samples increased significantly (P < 0.05). Compared with the control, VPP significantly increased concentrations of the fecal short-chain fatty acids n-butyric acid and isovaleric acid (P < 0.05). In conclusion, VPP can relieve intestinal inflammation and alleviate the degree of diarrhea in pre-weaning calves.

Skin fibrosis is a physiopathological process featuring the excessive deposition of extracellular matrix (ECM), which is the main architecture that provides structural support and constitutes the microenvironment for various cellular behaviors. Recently, increasing interest has been drawn to the relationship between the mechanical properties of the ECM and the initiation and modulation of skin fibrosis, with the engagement of a complex network of signaling pathways, the activation of mechanosensitive proteins, and changes in immunoregulation and metabolism. Simultaneous with the progression of skin fibrosis, the stiffness of ECM increases, which in turn perturbs mechanical and humoral homeostasis to drive cell fate toward an outcome that maintains and enhances the fibrosis process, thus forming a pro-fibrotic “positive feedback loop”. In this review, we highlighted the central role of the ECM and its dynamic changes at both the molecular and cellular levels in skin fibrosis. We paid special attention to signaling pathways regulated by mechanical cues in ECM remodeling. We also systematically summarized antifibrotic interventions targeting the ECM, hopefully enlightening new strategies for fibrotic diseases.

Background: Several clinical trials have demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) reduce the incidence of non-fatal myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unclear. In this study, we applied a network pharmacology method to investigate the mechanisms by which GLP-1RAs reduce MI occurrence in patients with T2DM.Methods: Targets of three GLP-1RAs (liraglutide, semaglutide, and albiglutide), T2DM, and MI were retrieved from online databases. The intersection process and associated targets retrieval were employed to obtain the related targets of GLP-1RAs against T2DM and MI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) enrichment analyses were performed. The STRING database was used to obtain the protein-protein interaction (PPI) network, and Cytoscape was used to identify core targets, transcription factors, and modules.Results: A total of 198 targets were retrieved for the three drugs and 511 targets for T2DM with MI. Finally, 51 related targets, including 31 intersection targets and 20 associated targets, were predicted to interfere with the progression of T2DM and MI on using GLP-1RAs. The STRING database was used to establish a PPI network comprising 46 nodes and 175 edges. The PPI network was analyzed using Cytoscape, and seven core targets were screened: AGT, TGFB1, STAT3, TIMP1, MMP9, MMP1, and MMP2. The transcription factor MAFB regulates all seven core targets. The cluster analysis generated three modules. The GO analysis for 51 targets indicated that the terms were mainly enriched in the extracellular matrix, angiotensin, platelets, and endopeptidase. The results of KEGG analysis revealed that the 51 targets primarily participated in the renin-angiotensin system, complement and coagulation cascades, hypertrophic cardiomyopathy, and AGE-RAGE signaling pathway in diabetic complications.Conclusion: GLP-1RAs exert multi-dimensional effects on reducing the occurrence of MI in T2DM patients by interfering with targets, biological processes, and cellular signaling pathways related to atheromatous plaque, myocardial remodeling, and thrombosis.

Here, capacitive deionization technology (CDI) using modified activated carbon fiber felt (ACF) electrodes was proposed to provide a new strategy for the challenge of simultaneous phosphorus and fluoride wastewater treatment. The acid-modified iron-loaded ACF (A@Fe-ACF) was obtained by modifying ACF through a two-step impregnation method. After the modification, the oxygen-containing functional groups on ACF increased and provided more adsorption sites. The electron transfer efficiency on the A@Fe-ACF was increased by introducing Fe and synergistically promoted the adsorption of phosphorus and fluorine. Results showed that the removal efficiencies of total phosphorus (TP) and total fluorine (TF) in wastewater reached 89.4% and 85% under optimal conditions (voltage intensity 1.5 V, pH 7, plate spacing 1 cm), while the adsorption mechanism of phosphorus and fluorine was dominated by chemical adsorption. Meanwhile, A@Fe-ACF electrode has good recyclability and stability after five cycles.

About 70% of non-small cell lung cancer (NSCLC) patients require radiotherapy. However, due to the difference in radiation sensitivity, the treatment outcome may differ for the same pathology and choice of treatment. Poly (ADP-ribose) polymerase 1 (PARP-1) is a key gene responsible for DNA repair and is involved in base excision repair as well as repair of single strand break induced by ionizing radiation and oxidative damage. In order to investigate the relationship between PARP-1 gene polymorphism and radiation sensitivity in NSCLC, we collected 141 primary NSCLC patients undergoing three-dimensional conformal radiotherapy. For each case, the gross tumor volumes (GTV) before radiation and that after 40 Gy radiation were measured to calculate the tumor regression rate. TaqMan real-time polymerase chain reaction was performed to genotype the single-nucleotide polymorphisms (SNPs). Genotype frequencies for PARP-1 genotypes were 14.2% for C/C, 44.7% for C/G and 41.1% for G/G. The average tumor regression rate after 40 Gy radiation therapy was 35.1% ± 0.192. Tumor regression rate of mid-term RT of C/C genotype was 44.6% ± 0.170, which was higher than that of genotype C/G and G/G (32.4% ± 0.196 and 34.8% ± 0.188, respectively) with statistical significance (F = 3.169 p = 0.045). The higher tumor regression rate in patients with C/C genotype suggested that G allele was a protective factor against radiation therapy. Using the median tumor regression rate of 34%, we divided the entire cohort into two groups, and found that the frequency distribution of PARP-1 gene rs3219073 had significant difference between these two groups (p < 0.05). These results showed that PARP-1 gene polymorphism may affect patient radiation sensitivity and predict the efficacy of radiotherapy. It therefore presents an opportunity for developing new therapeutic targets to improve radiotherapy outcome.

The placenta is important for fetal development in mammals, and spatial transcriptomic profiling of placenta helps to resolve its structure and function. In this study, we described the landscape of spatial transcriptome of human placental villi obtained from two pregnant women at the first trimester using the modified Stereo-seq method applied for paraformaldehyde (PFA) fixation samples. The PFA fixation of human placenta villi was better than fresh villi embedded in optimum cutting temperature (OCT) compound, since it greatly improved tissue morphology and the specificity of RNA signals. The main cell types in chorionic villi such as syncytiotrophoblasts (SCT), villous cytotrophoblasts (VCT), fibroblasts (FB), and extravillous trophoblasts (EVT) were identified with the spatial transcriptome data, whereas the minor cell types of Hofbauer cells (HB) and endothelial cells (Endo) were spatially located by deconvolution of scRNA-seq data. We demonstrated that the Stereo-seq data of human villi could be used for sophisticated analyses such as spatial cell-communication and regulatory activity. We found that the SCT and VCT exhibited the most ligand-receptor pairs that could increase differentiation of the SCT, and that the spatial localization of specific regulons in different cell types was associated with the pathways related to hormones transport and secretion, regulation of mitotic cell cycle, and nutrient transport pathway in SCT. In EVT, regulatory pathways such as the epithelial to mesenchyme transition, epithelial development and differentiation, and extracellular matrix organization were identified. Finally, viral receptors and drug transporters were identified in villi according to the pathway analysis, which could help to explain the vertical transmission of several infectious diseases and drug metabolism efficacy. Our study provides a valuable resource for further investigation of the placenta development, physiology and pathology in a spatial context.

ObjectiveThe prevention of hypertension in primary care requires an effective and suitable hypertension risk assessment model. The aim of this study was to develop and compare the performances of three machine learning algorithms in predicting the risk of hypertension for residents in primary care in Shanghai, China.MethodsA dataset of 40,261 subjects over the age of 35 years was extracted from Electronic Healthcare Records of 47 community health centers from 2017 to 2019 in the Pudong district of Shanghai. Embedded methods were applied for feature selection. Machine learning algorithms, XGBoost, random forest, and logistic regression analyses were adopted in the process of model construction. The performance of models was evaluated by calculating the area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, accuracy and F1-score.ResultsThe XGBoost model outperformed the other two models and achieved an AUC of 0.765 in the testing set. Twenty features were selected to construct the model, including age, diabetes status, urinary protein level, BMI, elderly health self-assessment, creatinine level, systolic blood pressure measured on the upper right arm, waist circumference, smoking status, low-density lipoprotein cholesterol level, high-density lipoprotein cholesterol level, frequency of drinking, glucose level, urea nitrogen level, total cholesterol level, diastolic blood pressure measured on the upper right arm, exercise frequency, time spent engaged in exercise, high salt consumption, and triglyceride level.ConclusionsXGBoost outperformed random forest and logistic regression in predicting the risk of hypertension in primary care. The integration of this risk assessment model into primary care facilities may improve the prevention and management of hypertension in residents.

Background: Preimplantation genetic test for monogenic disorders (PGT-M) has been used to select genetic disease-free embryos for implantation during in vitro fertilization (IVF) treatment. However, embryos tested by PGT-M have risks of harboring chromosomal aneuploidy. Hence, a universal method to detect monogenic diseases and genomic imbalances is required.Methods: Here, we report a novel PGT-A/M procedure allowing simultaneous detection of monogenic diseases and genomic imbalances in one experiment. Library was prepared in a special way that multiplex polymerase chain reaction (PCR) was integrated into the process of whole genome amplification. The resulting library was used for one-step low-pass whole genome sequencing (WGS) and high-depth target enrichment sequencing (TES).Results: The TAGs-seq PGT-A/M was first validated with genomic DNA (gDNA) and the multiple displacement amplification (MDA) products of a cell line. Over 90% of sequencing reads covered the whole-genome region with around 0.3–0.4 × depth, while around 5.4%–7.3% of reads covered target genes with >10000 × depth. Then, for clinical validation, 54 embryos from 8 women receiving PGT-M of β-thalassemia were tested by the TAGs-seq PGT-A/M. In each embryo, an average of 20.0 million reads with 0.3 × depth of the whole-genome region was analyzed for genomic imbalance, while an average of 0.9 million reads with 11260.0 × depth of the target gene HBB were analyzed for β-thalassemia. Eventually, 18 embryos were identified with genomic imbalance with 81.1% consistency to karyomapping results. 10 embryos contained β-thalassemia with 100% consistency to conventional PGT-M method.Conclusion: TAGs-seq PGT-A/M simultaneously detected genomic imbalance and monogenic disease in embryos without dramatic increase of sequencing data output.

Scoparone (SCO) is known to have curative effect of alleviating liver injury. The purpose of this study was to observe the therapeutic effect and possible mechanism of SCO against high-fat diet (HFD) induced non-alcoholic liver disease (NAFLD) through in vivo experiments and RNA sequencing. Male Kunming mice were fed with HFD for 8 weeks to establish a mouse model of NAFLD, and SCO was used to treat NAFLD. Histopathology and biochemical indicators were used to evaluate the liver injury and the efficacy of SCO. RNA sequencing analysis was performed to elucidate the hepatoprotective mechanism of SCO. Finally, the differentially expressed genes of cholesterol synthesis and fatty acid (triglyceride) synthesis pathways were verified by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The histopathological results showed that HFD could lead to significant steatosis in mice, while SCO could alleviate liver steatosis remarkably in NAFLD mice. The determination of biochemical indicators showed that SCO could inhibit the increased serum transaminase activity and liver lipid level induced by HFD. RNA sequencing analysis of liver tissues found that 2742 and 3663 genes were significantly changed by HFD and SCO, respectively. SCO reversed the most of genes involved in cholesterol synthesis and fatty acid (triglyceride) metabolism induced by HFD. the results of the validation experiment were mostly consistent with the RNA sequencing. SCO alleviated liver injury and steatosis in NAFLD mice, which may be closely related to the regulation of cholesterol and fatty acid (triglyceride) metabolism.

Purposes: We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD.Methods: We designed a retrospective study wherein a total of 1,334 patients diagnosed with IRD were included as a study cohort, namely 1,278 RP and 56 USH patients, as well as other types of IEDs patients and healthy family members as a control cohort. The genotype-phenotype correlation of all participants with USH2A variant was evaluated.Results: Etiological mutations in USH2A, the most common cause of RP and USH, were found in 16.34% (n = 218) genetically solved IRD patients, with prevalences of 14.87% (190/1,278) and 50% (28/56). After bioinformatics and QC processing, 768 distinct USH2A variants were detected in all participants, including 136 disease-causing mutations present in 665 alleles, distributed in 5.81% of all participants. Of these 136 mutations, 43 were novel, nine were founder mutations, and two hot spot mutations with allele count ≥10. Furthermore, 38.5% (84/218) of genetically solved USH2A-IRD patients were caused by at least one of both c.2802T>G and c.8559–2 A>G mutations, and 36.9% and 69.6% of the alleles in the RP and USH groups were truncating, respectively.Conclusion: USH2A-related East Asian-specific founder and hot spot mutations were the major causes for Chinese RP and USH patients. Our study systematically delineated the genotype spectrum of USH2A-IRD, enabled accurate genetic diagnosis, and provided East Asian and other ethnicities with baseline data of a Chinese origin, which would better serve genetic counseling and therapeutic targets selection.

Background: Non-invasive prenatal diagnosis (NIPD) can identify monogenic diseases early during pregnancy with negligible risk to fetus or mother, but the haplotyping methods involved sometimes cannot infer parental inheritance at heterozygous maternal or paternal loci or at loci for which haplotype or genome phasing data are missing. This study was performed to establish a method that can effectively recover the whole fetal genome using maternal plasma cell-free DNA (cfDNA) and parental genomic DNA sequencing data, and validate the method’s effectiveness in noninvasively detecting single nucleotide variations (SNVs), insertions and deletions (indels).Methods: A Bayesian model was developed to determine fetal genotypes using the plasma cfDNA and parental genomic DNA from five couples of healthy pregnancy. The Bayesian model was further integrated with a haplotype-based method to improve the inference accuracy of fetal genome and prediction outcomes of fetal genotypes. Five pregnancies with high risks of monogenic diseases were used to validate the effectiveness of this haplotype-assisted Bayesian approach for noninvasively detecting indels and pathogenic SNVs in fetus.Results: Analysis of healthy fetuses led to the following accuracies of prediction: maternal homozygous and paternal heterozygous loci, 96.2 ± 5.8%; maternal heterozygous and paternal homozygous loci, 96.2 ± 1.4%; and maternal heterozygous and paternal heterozygous loci, 87.2 ± 4.7%. The respective accuracies of predicting insertions and deletions at these types of loci were 94.6 ± 1.9%, 80.2 ± 4.3%, and 79.3 ± 3.3%. This approach detected pathogenic single nucleotide variations and deletions with an accuracy of 87.5% in five fetuses with monogenic diseases.Conclusions: This approach was more accurate than methods based only on Bayesian inference. Our method may pave the way to accurate and reliable NIPD.

The education level and social participation of contemporary Chinese women have reached their historical peak; work is fast becoming the dominant theme of their lives. However, influenced by traditional attitudes, women are still expected to undertake the main family care tasks, thus, facing dual constraints of family and work, which seriously affect their life happiness. Based on the theory of subjective well-being and feminist geography, this study used the questionnaire survey and in-depth interview results of professional females in Dalian High-tech Industrial Zone as basic data to explore the life satisfaction and emotional cognition in intra- and extra-household life of professional females (Professional females: In this study, they are the women who have received formal education and currently have full-time and steady job (including regular employees in the national systems and those who have signed labor contracts with labor units).). The following results were obtained: (1) Most professional females reported higher life satisfaction in intra- rather than extra-household life, and it varied with individual attributes, reflecting the internal differences among them. (2) The positive emotions of professional females came from the company of family and friends in intra-household life, and satisfaction with the working environment and treatment in extra-household life. (3) The negative emotions came from the pressure of “marriage,” “birth,” and other traditional concepts in intra-household life. In extra-household life, it came from the health problems caused by working stress, interpersonal problems and gender inequality in the workplace, and the anxiety of age and future career development. Therefore, this study committed to revealing the living status and subjective feelings of contemporary professional females in China, hoping to improve women’s life quality and enhance their life happiness from a theoretical and realistic perspective.

BackgroundDecreased serum albumin level (SAL) is associated with adverse clinical outcomes. We designed the present study to further assess the prognostic value of SAL in critically ill patients based on data from large intensive care unit (ICU) databases.MethodsThis retrospective cohort study recruited 18,353 patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Restricted cubic splines (RCS) were performed to visualize the association of SAL at admission with ICU and hospital mortalities. The prognostic value of SAL was analyzed using logistic regression models and receiver operating characteristic (ROC) curves in overall patients and subgroups.ResultsRestricted cubic splines revealed rapid increasing risks in ICU and hospital mortalities when SAL declined to below 30 g/l. Patients with SAL

Fibrosis, a pathologic process featured by the excessive deposition of connective tissue components, can affect virtually every organ and has no satisfactory therapy yet. Fibrotic diseases are often associated with organ dysfunction which leads to high morbidity and mortality. Biomechanical stmuli and the corresponding cellular response havebeen identified in fibrogenesis, as the fibrotic remodeling could be seen as the incapacity to reestablish mechanical homeostasis: along with extracellular matrix accumulating, the physical property became more “stiff” and could in turn induce fibrosis. In this review, we provide a comprehensive overview of mechanoregulation in fibrosis, from initialing cellular mechanosensing to intracellular mechanotransduction and processing, and ends up in mechanoeffecting. Our contents are not limited to the cellular mechanism, but further expand to the disorders involved and current clinical trials, providing an insight into the disease and hopefully inspiring new approaches for the treatment of tissue fibrosis.

This study empirically demonstrates significant regional peer effects due to tax avoidance. We used peer companies’ idiosyncratic stock returns as an instrumental variable to address potential endogeneity problems. The heterogeneity analysis indicates that for companies with a stronger intensity of regional tax collection and management, a higher degree of informatization, and companies with a low management shareholding ratio, the regional peer effects of enterprise tax avoidance are more significant. Finally, we determined that the managers’ information learning, reputation consideration, and information communication are key mechanisms propagating peer effects. The conclusions of this paper enrich and expand the peer effect theory of corporate tax avoidance, thereby providing a theoretical basis and empirical evidence for tax authorities in supervising corporate tax avoidance.

Risperidone is an efficacious second-generation antipsychotic (SGA) to treat a wide spectrum of psychiatric diseases, whereas its active moiety (risperidone and 9-hydroxyrisperidone) concentration without a therapeutic reference range may increase the risk of adverse drug reactions. We aimed to establish a prediction model of risperidone active moiety concentration in the next therapeutic drug monitoring (TDM) based on the initial TDM information using machine learning methods. A total of 983 patients treated with risperidone between May 2017 and May 2018 in Beijing Anding Hospital were collected as the data set. Sixteen predictors (the initial TDM value, dosage, age, WBC, PLT, BUN, weight, BMI, prolactin, ALT, MECT, Cr, AST, Ccr, TDM interval, and RBC) were screened from 26 variables through univariate analysis (p < 0.05) and XGBoost (importance score >0). Ten algorithms (XGBoost, LightGBM, CatBoost, AdaBoost, Random Forest, support vector machine, lasso regression, ridge regression, linear regression, and k-nearest neighbor) compared the model performance, and ultimately, XGBoost was chosen to establish the prediction model. A cohort of 210 patients treated with risperidone between March 1, 2019, and May 31, 2019, in Beijing Anding Hospital was used to validate the model. Finally, the prediction model was evaluated, obtaining R2 (0.512 in test cohort; 0.374 in validation cohort), MAE (10.97 in test cohort; 12.07 in validation cohort), MSE (198.55 in test cohort; 324.15 in validation cohort), RMSE (14.09 in test cohort; 18.00 in validation cohort), and accuracy of the predicted TDM within ±30% of the actual TDM (54.82% in test cohort; 60.95% in validation cohort). The prediction model has promising performance to facilitate rational risperidone regimen on an individualized level and provide reference for other antipsychotic drugs' risk prediction.

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic neoplasm with poor survival outcomes. However, the routine clinical features are not sufficient to accurately predict the prognosis of AML. The expression of hypoxia-related genes was associated with survival outcomes of a variety of hematologic and lymphoid neoplasms. We established an 18-gene signature-based hypoxia-related prognosis model (HPM) and a complex model that consisted of the HPM and clinical risk factors using machine learning methods. Both two models were able to effectively predict the survival of AML patients, which might contribute to improving risk classification. Differentially expressed genes analysis, Gene Ontology (GO) categories, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to reveal the underlying functions and pathways implicated in AML development. To explore hypoxia-related changes in the bone marrow immune microenvironment, we used CIBERSORT to calculate and compare the proportion of 22 immune cells between the two groups with high and low hypoxia-risk scores. Enrichment analysis and immune cell composition analysis indicated that the biological processes and molecular functions of drug metabolism, angiogenesis, and immune cell infiltration of bone marrow play a role in the occurrence and development of AML, which might help us to evaluate several hypoxia-related metabolic and immune targets for AML therapy.

Aim: To reconstruct the ancestral sequence of human adenoviral hexon protein by combining sequence variations and structural information. And to provide a candidate hexon protein for developing new adenoviral vector capable of escaping the pre-existing immunity in healthy populations.Methods: The sequences of 74 adenovirus-type strains were used to predict the ancestral sequence of human adenovirus hexon protein using FastML and MEGA software. The three-dimensional structure model was built using homology modeling methods. The immunological features of ancestral loop 1 and loop 2 regions of sequences were tested using protein segments expressed in a prokaryotic expression system and polypeptides synthesized with human serum samples.Results: The tower region of the hexon protein had the highest sequence variability, while the neck and base regions remained constant among different types. The modern strains successfully predicted the common ancestral sequence of the human adenovirus hexon. The positive sera against neutralizing epitopes on the common ancestor of adenoviral hexon were relatively rare among healthy adults.Conclusion: The existing strains inferred the common ancestor of human adenoviruses, with epitopes never observed in the current human strains. The predicted common ancestor hexon is a good prospect in the improvement of adenovirus vectors.

Ruminants are mostly herbivorous animals that employ rumen fermentation for the digestion of feed materials, including dairy cows. Ruminants consume plant fibre as their regular diet, but lack the machinery for their digestion. For this reason, ruminants maintain a symbiotic relation with microorganisms that are capable of producing enzymes to degrade plant polymers. Various species of microflora including bacteria, protozoa, fungi, archaea, and bacteriophages are hosted at distinct concentrations for accomplishing complete digestion. The ingested feed is digested at a defined stratum. The polysaccharic plant fibrils are degraded by cellulolytic bacteria, and the substrate formed is acted upon by other bacteria. This sequential degradative mechanism forms the base of complete digestion as well as harvesting energy from the ingested feed. The composition of microbiota readily gets tuned to the changes in the feed habits of the dairy cow. The overall energy production as well as digestion is decided by the intactness of the resident communal flora. Disturbances in the homogeneity gastrointestinal microflora has severe effects on the digestive system and various other organs. This disharmony in communal relationship also causes various metabolic disorders. The dominance of methanogens sometimes lead to bloating, and high sugar feed culminates in ruminal acidosis. Likewise, disruptive microfloral constitution also ignites reticuloperitonitis, ulcers, diarrhoea, etc. The role of symbiotic microflora in the occurrence and progress of a few important metabolic diseases are discussed in this review. Future studies in multiomics provides platform to determine the physiological and phenotypical upgradation of dairy cow for milk production.

Background: It remains unclear whether the mean vancomycin trough concentration (VTC) derived from the entire course of therapy is of potential benefit for critically ill patients. This study was conducted to explore the association between mean serum VTC and mortality in intensive care units (ICUs).Methods: 3,603 adult patients with two or more VTC records after receiving vancomycin treatment in the eICU Collaborative Research Database were included in this multicenter retrospective cohort study. Mean VTC was estimated using all measured VTCs and investigated as a continuous and categorical variable. Patients were categorised into four groups according to mean VTC: 20 mg/L. Multivariable logistic regression and subgroup analyses were performed to investigate the relationship of mean VTC with mortality.Results: After adjusting for a series of covariates, logistic regression analyses indicated that mean VTC, as a continuous variable, was positively correlated with ICU (odds ratio, 1.038, 95% confidence interval, [1.014–1.063]) and hospital (1.025 [1.005–1.046]) mortalities. As a categorical variable, mean VTC of 10–15 mg/L was not associated with reduced ICU (1.705 [0.975–2.981]) and hospital (1.235 [0.829–1.841]) mortalities. Mean VTC of 15–20 mg/L was not correlated with a lower risk of hospital mortality (1.370 [0.924–2.029]). Moreover, mean VTCs of 15–20 and >20 mg/L were significantly associated with higher ICU mortality (1.924 [1.111–3.332]; 2.428 [1.385–4.258]), and mean VTC of >20 mg/L with higher hospital mortality (1.585 [1.053–2.387]) than mean VTC of

Alzheimer disease (AD) is the most common cause of dementia in geriatric population. At present, no effective treatments exist to reverse the progress of AD, however, early diagnosis and intervention might delay its progression. The search for biomarkers with good safety, repeatable detection, reliable sensitivity and community application is necessary for AD screening and early diagnosis and timely intervention. Electroencephalogram (EEG) examination is a non-invasive, quantitative, reproducible, and cost-effective technique which is suitable for screening large population for possible AD. The power spectrum, complexity and synchronization characteristics of EEG waveforms in AD patients have distinct deviation from normal elderly, indicating these EEG features can be a promising candidate biomarker of AD. However, current reported deviation results are inconsistent, possibly due to multiple factors such as diagnostic criteria, sample sizes and the use of different computational measures. In this study, we collected two neurological tests scores (MMSE and MoCA) and the resting-state EEG of 30 normal control elderly subjects (NC group) and 30 probable AD patients confirmed by Pittsburgh compound B positron emission tomography (PiB-PET) inspection (AD group). We calculated the power spectrum, spectral entropy and phase synchronization index features of these two groups’ EEG at left/right frontal, temporal, central and occipital brain regions in 4 frequency bands: δ oscillation (1–4 Hz), θ oscillation (4–8 Hz), α oscillation (8–13 Hz), and β oscillation (13–30 Hz). In most brain areas, we found that the AD group had significant differences compared to NC group: (1) decreased α oscillation power and increased θ oscillation power; (2) decreased spectral entropy in α oscillation and elevated spectral entropy in β oscillation; and (3) decrease phase synchronization index in δ, θ, and β oscillation. We also found that α oscillation spectral power and β oscillation phase synchronization index correlated well with the MMSE/MoCA test scores in AD groups. Our study suggests that these two EEG features might be useful metrics for population screening of probable AD patients.

Pseudomonas aeruginosa is a Gram-negative pathogen that causes a variety of infections in humans and animals. Due to the inappropriate use of antibiotics, multi-drug resistant (MDR) P. aeruginosa strains have emerged and are prevailing. In recent years, cow mastitis caused by MDR P. aeruginosa has attracted attention. In this study, a microbial community analysis revealed that P. aeruginosa could be a cause of pathogen-induced cow mastitis. Five MDR P. aeruginosa strains were isolated from milk diagnosed as mastitis positive. To seek an alternative antibacterial agent against MDR, P. aeruginosa, a lytic phage, designated vB_PaeS_PAJD-1 (PAJD-1), was isolated from dairy farm sewage. PAJD-1 was morphologically classified as Siphoviridae and was estimated to be about 57.9 kb. Phage PAJD-1 showed broad host ranges and a strong lytic ability. A one-step growth curve analysis showed a relatively short latency period (20 min) and a relatively high burst size (223 PFU per infected cell). Phage PAJD-1 remained stable over wide temperature and pH ranges. Intramammary-administered PAJD-1 reduced bacterial concentrations and repaired mammary glands in mice with mastitis induced by MDR P. aeruginosa. Furthermore, the cell wall hydrolase (termed endolysin) from phage PAJD-1 exhibited a strong bacteriolytic and a wide antibacterial spectrum against MDR P. aeruginosa. These findings present phage PAJD-1 as a candidate for phagotherapy against MDR P. aeruginosa infection.

Mastitis caused by Escherichia coli (E. coli) remains a threat to dairy animals and impacts animal welfare and causes great economic loss. Furthermore, antibiotic resistance and the lagged development of novel antibacterial drugs greatly challenge the livestock industry. Phage therapy has regained attention. In this study, three lytic phages, termed vB_EcoM_SYGD1 (SYGD1), vB_EcoP_SYGE1 (SYGE1), and vB_EcoM_SYGMH1 (SYGMH1), were isolated from sewage of dairy farm. The three phages showed a broad host range and high bacteriolytic efficiency against E. coli from different sources. Genome sequence and transmission electron microscope analysis revealed that SYGD1 and SYGMH1 belong to the Myoviridae, and SYGE1 belong to the Autographiviridae of the order Caudovirales. All three phages remained stable under a wide range of temperatures or pH and were almost unaffected in chloroform. Specially, a mastitis infected cow model, which challenged by a drug resistant E. coli, was used to evaluate the efficacy of phages. The results showed that the cocktails consists of three phages significantly reduced the number of bacteria, somatic cells, and inflammatory factors, alleviated the symptoms of mastitis in cattle, and achieved the same effect as antibiotic treatment. Overall, our study demonstrated that phage cocktail may be a promising alternative therapy against mastitis caused by drug resistant E. coli.

Taxifolin is a natural antioxidant polyphenol with various bioactivities and has many beneficial effects on human gut health. However, little is known of its function on colitis. In this study, the protective effects of taxifolin on colitis symptoms, inflammation, signaling pathways, and colon microbiota were investigated using dextran sulfate sodium (DSS)-induced colitis mice. Intriguingly, pre-administration of taxifolin alleviated the colitis symptoms and histological changes of the DSS-challenged mice. Supplementation of taxifolin significantly inhibited the secretions of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 and significantly increased the secretions of IL-10, secretory immunoglobulin A, superoxide dismutase, and immunoglobulins (IgA, IgG, and IgM) in DSS-induced colitis mice. In addition, the activation of nuclear factor kappa B (NF-κB; p65 and IκBα) signaling was significantly suppressed by taxifolin supplementation. The expression of tight junction proteins (claudin-1 and occludin) was significantly increased by taxifolin. Moreover, 16S rDNA sequencing revealed that the DSS-induced changes of colon microbiota composition and microbial functions (amino acid metabolism and MAPK signaling) were restored by taxifolin, including the decreases of the abundances of Bacteroides, Clostridium ramosum, Clostridium saccharogumia, Sphingobacterium multivorum, and the ratio of Bacteroidetes/Firmicutes, and the increases of the abundances of Desulfovibrio C21 c20 and Gemmiger formicilis at species level. In conclusion, these results revealed that dietary taxifolin has a great potential to prevent colitis by inhibiting the NF-κB signaling pathway, enhancing intestinal barrier, and modulating gut microbiota.

Background: Research collaboration of registered clinical trials for Coronavirus Disease 2019 (COVID-19) remains unclear. This study aimed to analyze research collaboration and distribution of outcome measures in registered interventional clinical trials (ICTs) of COVID-19 conducted in China.Methods: The International Clinical Trials Registry Platform, China Clinical Trials Registry, and Clinicaltrials.gov were searched to obtain COVID-19-registered ICTs up to May 25, 2020. Excel 2016 was used to perform a descriptive statistical analysis of the extracted information. VOSviewer 1.6.14 software was used to generate network maps for provinces and institutions and create density maps for outcomes.Results: A total of 390 ICTs were included, and the number of daily registrations fluctuated greatly. From 29 provinces in China, 430 institutions contributed to the registration of ICTs. The top three productive provinces were Hubei (160/390, 41.03%), Shanghai (60/390, 15.38%), and Beijing (59/390, 15.13%). The top three productive institutions were Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (30/390, 7.69%), Zhongnan Hospital of Wuhan University (18/390, 4.62%), and Wuhan Jinyintan Hospital (18/390, 4.62%). Collaborations between provinces and institutions were not close enough. There were many interventions, but many trials did not provide specific drugs and their dosage and treatment duration. The most frequently used primary outcome was Chest/lung CT (53/390, 13.59%), and the most frequently used secondary outcome was hospital stay (33/390, 8.46%). There was a large difference in the number of outcomes, the expression of some outcomes was not standardized, the measurement time and tools for some outcomes were not clear, and there was a lack of special outcomes for trials of traditional Chinese medicine.Conclusions: Although there were some collaborations between provinces and institutions of the current COVID-19 ICT protocols in China, cooperation between regions should be further strengthened. The identified deficiencies in interventions and outcome measures should be given more attention by future researchers of COVID-19.

AimBiologic interfaces play important roles in tissue function. The vascular lumen-blood interface represents a surface where dynamic interactions between the endothelium and circulating blood cells are critical in preventing thrombosis. The arterial lumen possesses a uniform wrinkled surface determined by the underlying internal elastic lamina. The function of this structure is not known, but computational analyses of artificial surfaces with dynamic topography, oscillating between smooth and wrinkled configurations, support the ability of this surface structure to shed adherent material (Genzer and Groenewold, 2006; Bixler and Bhushan, 2012; Li et al., 2014). We hypothesized that incorporating a luminal surface capable of cyclical wrinkling/flattening during the cardiac cycle into vascular graft technology may represent a novel mechanism of resisting platelet adhesion and thrombosis.Methods and ResultsBilayer silicone grafts possessing luminal corrugations that cyclically wrinkle and flatten during pulsatile flow were fabricated based on material strain mismatch. When placed into a pulsatile flow circuit with activated platelets, these grafts exhibited significantly reduced platelet deposition compared to grafts with smooth luminal surfaces. Constrained wrinkled grafts with static topography during pulsatile flow were more susceptible to platelet accumulation than dynamic wrinkled grafts and behaved similar to the smooth grafts under pulsatile flow. Wrinkled grafts under continuous flow conditions also exhibited marked increases in platelet accumulation.ConclusionThese findings provide evidence that grafts with dynamic luminal topography resist platelet accumulation and support the application of this structure in vascular graft technology to improve the performance of prosthetic grafts. They also suggest that this corrugated structure in arteries may represent an inherent, self-cleaning mechanism in the vasculature.

BackgroundSeveral clinical trials investigated the effects of enteral lactoferrin supplementation on the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm infants, but the efficacy and safety remain disputed. Therefore, we systematically evaluated the effect of enteral lactoferrin supplementation in preterm infants through a meta‑analysis with trial sequential analysis (TSA).MethodsWe searched six databases to identify randomized controlled trials (RCTs) that evaluated the effects of lactoferrin supplementation compared with placebo or no intervention in preterm infants. RevMan version 5.3 software was used to estimate pooled relative risks (RRs) with the random-effects model. TSA, subgroup analyses, and meta-regression analyses were also performed.ResultsNine RCTs with 3515 samples were included. With low to moderate quality of evidence, compared with placebo, enteral lactoferrin supplementation did not significantly decrease the incidences of late-onset sepsis (RR = 0.63, 95% CI: 0.38 to 1.02, P = 0.06), NEC stage II or III (RR = 0.68, 95% CI: 0.30 to 1.52, P = 0.35), all-cause mortality (RR = 0.89, 95% CI: 0.51 to 1.57, P = 0.69), bronchopulmonary dysplasia (RR = 1.01, 95% CI: 0.90 to 1.13, P = 0.92), retinopathy of prematurity (RR = 0.80, 95% CI: 0.49 to 1.32, P = 0.38), invasive fungal infection (RR = 0.27, 95% CI: 0.02 to 3.94, P = 0.34), intraventricular hemorrhage (RR = 1.40, 95% CI: 0.39 to 5.08, P = 0.61), and urinary tract infection (RR = 0.35, 95% CI: 0.11 to 1.06, P = 0.06). Subgroup analysis revealed that lactoferrin significantly reduced the incidence of sepsis in infants with a birth weight below 1500 g (RR = 0.43, 95% CI: 0.22 to 0.84, P = 0.01). TSAs of the primary outcomes showed that the evidence is insufficient and further data is required.ConclusionsLimited evidence suggested that enteral lactoferrin supplementation was associated with a reduction of late-onset sepsis in infants with a birth weight below 1500g, however, did not decrease the incidence of NEC stage II or III, all-cause mortality, and other adverse events in preterm infants. The present evidence was insufficient to inform clinical practice.

Background: As an emerging infectious disease, COVID-19 has garnered great research interest. We aimed to explore the differences between English language and Chinese language Medical/Scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in English and Chinese in relation to the outcomes of management and characterization of COVID-19 during the early stage of COVID-19 pandemic.Methods: Publications on COVID-19 research were retrieved from both English and Chinese databases. Bibliometric analyses were performed using VOSviewer 1.6.14, and CiteSpace V software. Network maps were generated to evaluate the collaborations between different authors, countries/provinces, and institutions.Results: A total of 143 English and 721 Chinese original research articles and reviews on COVID-19 were included in our study. Most of the authors and institutions of the papers were from China before March 1st, 2020, however, the distribution of authors and institutions were mainly in developed countries or more wealthy areas of China. The range of the keywords in English publications was more extensive than those in Chinese. Traditional Chinese Medicine was seen more frequently in Chinese papers than in English. Of the 143 articles published in English, 54 articles were published by Chinese authors only and 21 articles were published jointly by Chinese and other overseas authors.Conclusions: The publications in English have enabled medical practitioners and scientists to share/exchange information, while on the other hand, the publications in the Chinese language have provided complementary educational approaches for the local medical practitioners to understand the essential and key information to manage COVID-19 in the relatively remote regions of China, for the general population with a general level of education.

Alzheimer disease (AD) has an insidious onset and heterogeneous clinical symptoms. The well-accepted biomarkers for clinical diagnosis of AD include β-amyloid (Aβ) deposition and pathologic tau level within cerebral spinal fluid (CSF) and imaging AD pathology such as positive emission tomography (PET) imaging of the amyloid-binding agent Pittsburgh compound B (PET-PiB). However, the high expense and invasive nature of these methods highly limit their wide usage in clinic practice. Therefore, it is imperious to develop less expensive and invasive methods, and plasma biomarkers are the premium targets. In the current study, we utilized a single-blind comparison method; all the probable AD cases met the core clinical National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria and validated by PET-PiB. We used ultrasensitive immunomagnetic reduction (IMR) assays to measure plasma Aβ42 and total-tau (t-tau) levels, in combination with different variables including Aβ42 × t-tau value, Montreal Cognitive Assessment (MoCA), and Mini Mental State Examination (MMSE). We used logistic regression to analyze the effect of all these variables in the algorism. Our results showed that (1) plasma Aβ42 and t-tau are efficient biomarkers for AD diagnosis using IMR platform, whereas Aβ42 × t-tau value is more efficient for discriminating control and AD; (2) in the control group, Aβ42 level and age demonstrated strong negative correlation; Aβ42 × t-tau value and age demonstrated significant negative correlation; (3) in the AD group, t-tau level and MMSE score demonstrated strong negative correlation; (4) using the model that Aβ42, Aβ42 × t-tau, and MoCA as the variable to generate receiver operating characteristic (ROC) curve, cutoff value = 0.48, sensitivity = 0.973, specificity = 0.982, area under the curve (AUC) = 0.986, offered better categorical efficacy, sensitivity, specificity, and AUC. The multifactor model of plasma Aβ42 and t-tau in combination with MoCA can be a viable model separate health and AD subjects in clinical practice.

A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic in silico study was performed on 52 DHPYs using three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q2, R2, and rpred2 of the optimal comparative molecular similarity indices analysis model were 0.647, 0.970, and 0.751, respectively. The docking results indicated that residues Lys101, Tyr181, Tyr188, Trp229, and Phe227 played important roles for the DHPY binding. Nine lead compounds were obtained by the virtual screening based on the docking and pharmacophore model, and three new compounds with higher docking scores and better ADME properties were subsequently designed based on the screening and 3D-QSAR results. The MD simulation studies further demonstrated that the newly designed compounds could stably bind with the HIV-1 RT. These hit compounds were supposed to be novel potential anti-HIV-1 inhibitors, and these findings could provide significant information for designing and developing novel HIV-1 NNRTIs.

Brain-derived neurotrophic factor (BDNF) is essential for cognitive and memory functions. Abnormal BDNF expression in the central nervous system may impair these functions. Anaesthesia and surgery can induce perioperative neurocognitive disorders (PND). Clinical studies show that BDNF expression is decreased in patients presenting with cognitive impairment after anaesthesia and surgery. However, the molecular mechanism is still unclear. Epigenetic regulation plays an important role in cognition. The hypermethylation of H3K9 is crucial for transcriptional silencing and the onset of cognitive disorders. Here, we hypothesised that H3K9 trimethylation repressed BDNF expression and impaired memory formation or recall during anaesthesia and surgery. Laparotomy under isoflurane inhalation anaesthesia, behavioural tests, Western blotting, quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation (ChIP), and immunohistochemistry were used in this study. BDNF expression was decreased in the hippocampus after anaesthesia and surgery. Cognitive impairment affected memory formation but not recall. The trimethylation of H3K9 downregulated BDNF expression. The overexpression of BDNF or use of exogenous BDNF improved the impairment of memory formation caused by anaesthesia and surgery. Therefore, inhibiting H3K9 trimethylation and increasing the expression of BDNF may help prevent PND in the clinical setting.