A Strategy based on Bioinformatics and Machine Learning Algorithms Reveals Potential Mechanisms of Shelian Capsule against Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent and life-threatening form of cancer, with Shelian Capsule (SLC), a traditional Chinese medicine (TCM) formulation, being recommended for clinical treatment. However, the mechanisms underlying its efficacy remain elusive. This study sought to uncover the potential mechanisms of SLC in HCC treatment using bioinformatics methods. METHODS: Bioactive components of SLC were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and HCC-related microarray chip data were sourced from the Gene Expression Omnibus (GEO) database. The selection criteria for components included OB ≧ 30% and DL ≧ 0.18. By integrating the results of differential expression analysis and weighted gene co-expression network analysis (WGCNA), disease-related genes were identified. Therapeutic targets were determined as shared items between candidate targets and disease genes. Protein-protein interaction (PPI) network analysis was conducted for concatenated genes, with core protein clusters identified using the MCODE plugin. Machine learning algorithms were applied to identify signature genes within therapeutic targets. Subsequently, immune cell infiltration analysis, single-cell RNA sequencing (sc-RNA seq) analysis, molecular docking, and ADME analysis were performed for the screened genes. RESULTS: A total of 153 SLC ingredients and 170 candidate targets were identified, along with 494 HCCrelated disease genes. Overlapping items between disease genes and drug candidates represented therapeutic genes, and PPI network analysis was conducted using concatenated genes. MCODE1 and MCODE2 cluster genes underwent Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Four signature genes (TOP2A, CYP1A2, CYP2B6, and IGFBP3) were identified from 28 therapeutic genes using 3 machine learning algorithms, with ROC curves plotted. Molecular docking validated the interaction modes and binding abilities between signature genes and corresponding compounds, with free binding energy all <-7 kcal/mol. Finally, ADME analysis revealed similarities between certain SLC components and the clinical drugs Sorafenib and Lenvatinib. CONCLUSION: In summary, our study revealed that the mechanism underlying the anti-HCC effects of SLC involves interactions at three levels: components (quercetin, beta-sitosterol, kaempferol, baicalein, stigmasterol, and luteolin), pathways (PI3K-Akt signaling pathway, TNF signaling pathway, and IL-17 signaling pathway), and targets (TOP2A, CYP1A2, CYP2B6, and IGFBP3). This study provides preliminary insights into the potential pharmacological mechanisms of SLC in HCC treatment, aiming to support its clinical application and serve as a reference for future laboratory investigations.

Pressure-Modulated Structural and Magnetic Phase Transitions in Two-Dimensional FeTe: Tetragonal and Hexagonal Polymorphs.

Two-dimensional (2D) Fe chalcogenides with their rich structures and properties are highly desirable for revealing the torturous transition mechanism of Fe chalcogenides and exploring their potential applications in spintronics and nanoelectronics. Hydrostatic pressure can effectively stimulate phase transitions between various ordered states, allowing one to successfully plot a phase diagram for a given material. Herein, the structural evolution and transport characteristics of 2D FeTe were systematically investigated under extreme conditions by comparing two distinct symmetries, i.e., tetragonal (t) and hexagonal (h) FeTe. We found that t-FeTe presented a pressure-induced transition from an antiferromagnetic state to a ferromagnetic state at ∼3 GPa, corresponding to the tetragonal collapse of the layered structure. Contrarily, the ferromagnetic order of h-FeTe was retained up to 15 GPa, which was evidently confirmed by electrical transport and Raman measurements. Furthermore, T-P phase diagrams for t-FeTe and h-FeTe were mapped under delicate critical conditions. Our results can provide a unique platform to elaborate the extraordinary properties of Fe chalcogenides and further develop their applications.

Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report.

BACKGROUND: Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3' end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR). CASE PRESENTATION: This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient's mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown). CONCLUSIONS: In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.

Combining single-cell RNA sequencing data and transcriptomic data to unravel potential mechanisms and signature genes of the progression of idiopathic pulmonary fibrosis to lung adenocarcinoma and predict therapeutic agents.

Patients with idiopathic pulmonary fibrosis (IPF) have a significantly higher prevalence of lung adenocarcinoma (LUAD) than normal subjects, although the underlying association is unclear. The raw data involved were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis were used to screen for differentially expressed genes (DEGs) and modular signature genes (MSGs). Genes intersecting DEGs and MSGs were considered hub genes for IPF and LUAD. Machine learning algorithms were applied to capture epithelial cell-derived signature genes (EDSGs) shared. External cohort data were exploited to validate the robustness of EDSGs. Immunohistochemical staining and K-M plots were used to denote the prognostic value of EDSGs in LUAD. Based on EDSGs, we constructed a TF-gene-miRNA regulatory network. Molecular docking can validate the strength of action between candidate drugs and EDSGs. Epithelial cells, 650 DEGs, and 1773 MSGs were shared by IPF and LUAD. As for 379 hub genes, we performed pathway and functional enrichment analysis. By analyzing sc-RNA seq data, we identified 1234 marker genes of IPF epithelial cell-derived and 1481 of LUAD. And these genes shared 8 items with 379 hub genes. Through the machine learning algorithms, we further fished TRIM2, S100A14, CYP4B1, LMO7, and SFN. The ROC curves emphasized the significance of EDSGs in predicting the onset of LUAD and IPF. The TF-gene-miRNA network revealed regulatory relationships behind EDSGs. Finally, we predicted appropriate therapeutic agents. Our study preliminarily identified potential mechanisms between IPF and LUAD, which will inform subsequent studies.

Deciphering the underlying mechanisms of Sanleng-Ezhu for the treatment of idiopathic pulmonary fibrosis based on network pharmacology and single-cell RNA sequencing data.

AIMS: To decipher the underlying mechanisms of Sanleng-Ezhu for the treatment of idiopathic pulmonary fibrosis based on network pharmacology and single-cell RNA sequencing data. BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease. Although the combination of herbs Sanleng (SL) and Ezhu (EZ) has shown reliable efficacy in the management of IPF, its underlying mechanisms remain unknown. OBJECTIVE: To decipher the pathogenesis of IPF and achieve personalized clinical management of IPF patients Method: Based on LC-MS/MS analysis and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, we identified the bioactive components of SL-EZ. After obtaining the IPF-related dataset GSE53845 from the Gene Expression Omnibus (GEO) database, we performed the differential expression analysis and the weighted gene co-expression network analysis (WGCNA), respectively. We obtained lowly and highly expressed IPF subtype gene sets by comparing differentially expressed genes (DEGs) with the most significantly negatively and positively related IPF modules in WGCNA. Subsequently, we performed Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on IPF subtype gene sets. The low- and high-expression MCODE subgroup feature genes were identified by the MCODE plug-in and were adopted for Disease Ontology (DO), GO, and KEGG enrichment analyses. Next, we performed the immune cell infiltration analysis of the MCODE subgroup feature genes. Single-cell RNA sequencing analysis demonstrated the cell types which expressed different MCODE subgroup feature genes. Molecular docking and animal experiments validated the effectiveness of SL-EZ in delaying the progression of pulmonary fibrosis. RESULT: We obtained 5 bioactive components of SL-EZ as well as their corresponding 66 candidate targets. After normalizing the samples of the GSE53845 dataset from the GEO database source, we obtained 1907 DEGs of IPF. Next, we performed a WGCNA analysis on the dataset and got 11 modules. Notably, we obtained 2 IPF subgroups by contrasting the most significantly up- and down-regulated modular genes in IPF with DEGs, respectively. The different IPF subgroups were compared with drug-candidate targets to obtain direct targets of action. After constructing the protein interaction networks between IPF subgroup genes and drug candidate targets, we applied the MCODE plug-in to filter the highest-scoring MCODE components. DO, GO, and KEGG enrichment analyses were applied to drug targets, IPF subgroup genes, and MCODE component signature genes. In addition, we downloaded the single-cell dataset GSE157376 from the GEO database. By performing quality control and dimensionality reduction, we clustered the scattered primary sample cells into 11 clusters and annotated them into 2 cell subtypes. Drug sensitivity analysis suggested that SL-EZ acts on different cell subtypes in IPF subgroups. Molecular docking revealed the mode of interaction between targets and their corresponding components. Animal experiments confirmed the efficacy of SL-EZ. CONCLUSION: We found SL-EZ acted on epithelial cells mainly through the calcium signaling pathway in the lowly-expressed IPF subtype, while in the highly-expressed IPF subtype, SL-EZ acted on smooth muscle cells mainly through the viral infection, apoptosis, and p53 signaling pathway.

Causal associations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. METHODS: For data on infections, we used the genome-wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti-aquaporin-4 antibody [AQP4-ab]-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls. Single-nucleotide polymorphism (SNP) identification and two-sample Mendelian randomization (MR) analyses were then performed. RESULTS: In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA-B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA-B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4-ab-positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [p < 0.001, Q < 0.001]). The association between shingles and AQP4-ab-positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4-ab-positive or AQP4-ab-negative NMOSD. CONCLUSION: These findings suggest there are positive associations between cold sores and shingles and AQP4-ab-positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella-zoster virus infection and AQP4-ab-positive NMOSD.

Global and regional prevalence of vitamin D deficiency in population-based studies from 2000 to 2022: A pooled analysis of 7.9 million participants.

Background: Vitamin D deficiency causes the bone hypomineralization disorder osteomalacia in humans and is associated with many non-skeletal disorders. We aim to estimate the global and regional prevalence of vitamin D deficiency in people aged 1 year or older from 2000 to 2022. Methods: We systematically searched Web of Science, PubMed (MEDLINE), Embase, Scopus, and Google databases on December 31, 2021, and updated them on August 20, 2022, without language and time restrictions. Meanwhile, we identified references of relevant system reviews and eligible articles and included the latest and unpublished data from the National Health and Nutrition Examination Survey (NHANES, 2015-2016 and 2017-2018) database. The studies investigating the prevalence of vitamin D deficiency in population-based studies were included. A standardized data extraction form was used to collect information from eligible studies. We used a random-effects meta-analysis to estimate the global and regional prevalence of vitamin D deficiency. We stratified meta-analyses by latitude, season, six WHO regions, the World Bank income groups, gender, and age groups. This study was registered with PROSPERO (CRD42021292586). Findings: Out of 67,340 records searched, 308 studies with 7,947,359 participants from 81 countries were eligible for this study, 202 (7,634,261 participants), 284 (1,475,339 participants), and 165 (561,978 participants) studies for the prevalence of serum 25(OH)D <30, <50, and <75 nmol/L, respectively. We found that globally, 15.7% (95% CrI 13.7-17.8), 47.9% (95% CrI 44.9-50.9), and 76·6% (95% CrI 74.0-79.1) of participants had serum 25-hydroxyvitamin D levels less than 30, 50, and 75 nmol/l, respectively; the prevalence slightly decreased from 2000-2010 to 2011-2022, but it was still at a high level; people living in high latitude areas had a higher prevalence; the prevalence in winter-spring was 1.7 (95% CrI 1.4-2.0) times that in summer-autumn; the Eastern Mediterranean region and Lower-middle-income countries had a higher prevalence; females were vulnerable to vitamin D deficiency; gender, sampling frame, detection assays, sampling region, time of data collection, season, and other factors contributed to heterogeneity between the included studies. Interpretation: Globally, vitamin D deficiency remained prevalent from 2000 to 2022. The high prevalence of vitamin D deficiency would increase the global burden of disease. Therefore, governments, policymakers, health workers, and individuals should attach importance to the high prevalence of vitamin D deficiency and take its prevention as a public health priority. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021292586, PROSPERO CRD42021292586.

Identification of immune-related signature for the prognosis and benefit of immunotherapy in triple-negative breast cancer.

Background: There is a lack of biomarkers for predicting the efficacy of immunotherapy in triple-negative breast cancer (TNBC). Hence, we constructed an immune risk score (IRS) model to predict the prognosis of patients with TNBC and evaluate those who are sensitive to immunotherapy. Methods: The ribonucleic acid (RNA) sequencing data, mutation data, and clinical information of TNBC patients were obtained from The Cancer Genome Atlas database. Data of immune-related genes were obtained from the Import and InnateDB databases. The IRS model was constructed using univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, and the predictive ability of the prognostic model was evaluated. Further external validation was performed using the Gene Expression Omnibus (GEO) databases GSE58812 and GSE135565. Data on the clinical characteristics, immune landscape, and immune checkpoint inhibitors used in different risk groups were analyzed. Finally, the drug sensitivity of the patients in the high- and low-risk groups was predicted. Results: The prognostic risk score model comprised six genes: HSPA6, LCN1, ARTN, IL36G, BCL2A1, and CASP12. The area under the curve values at 1 year, 3 years, and 5 years were 0.835, 0.852, and 0.843, respectively, indicating that the model has a good potential for predicting the long-term survival of TNBC patients, which is consistent with the results of the GEO cohort. Compared with the high-risk group, the low-risk group had a better prognosis; more abundant immune-activated cell infiltrates, such as CD8+ T cells and CD4 memory-activated T cells, and a higher enrichment of immune-related signaling pathways, such as the cytokine receptor interaction, nucleotide oligomerization domain-like receptor signal pathway, T-cell receptor signal pathway, and B-cell receptor signaling pathway, were observed. In addition, the immune checkpoint encoding genes, such as CD274, CTLA4, PDCD1, and PDCD1LG2 were highly expressed in the low-risk group, which showed that this group was more likely to benefit from immunotherapy. Conclusion: A new IRS gene feature was established to predict the patients' prognosis and guide immunotherapy. Moreover, it was revealed that several potential therapeutic drugs can be used in high-risk patients who are unresponsive to immunotherapy.

Analysis of Pregnancy-Related Attacks in Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Meta-Analysis.

Importance: Risk of relapse may be increased in the postpartum period of neuromyelitis optica spectrum disorder (NMOSD). Information regarding factors associated with pregnancy-related attacks is still lacking. Objectives: To identify factors associated with pregnancy-related NMOSD attacks, investigate the integrated annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score in each phase of pregnancy, and summarize pregnancy outcomes and complications in patients with NMOSD. Data Sources: An electronic search was performed in the MEDLINE, PubMed in-process and non-MEDLINE, EMBASE, Web of Science, and Cochrane databases using the OvidSP search platform, updated through December 30, 2021. Study Selection: All published and unpublished studies in English were considered, covering all patients with NMOSD with an informative pregnancy. Data Extraction and Synthesis: Two independent reviewers extracted the published data with a standardized procedure following MOOSE and PRISMA guidelines. The end points were calculated with the DerSimonian and Laird inverse variance (for random effects) method. Main Outcomes and Measures: The primary outcome was the rate of pregnancies with pregnancy-related NMOSD attacks, measured by risk ratios (RRs). The mean differences (MDs) in ARR and EDSS scores between each phase of pregnancy, pregnancy outcomes, and complications were defined as the secondary outcomes. Results: A total of 15 studies were analyzed, including 443 patients with NMOSD with 639 informative pregnancies. Patients receiving immunosuppressive treatment during pregnancy (RR, 0.43; 95% CI, 0.32-0.57; P < .001) and with older age at conception (RR, 0.67; 95% CI, 0.47-0.95; P = .02) had lower rates of pregnancy with pregnancy-related attacks. The increase in the ARR was highest in the first trimester after delivery compared with before pregnancy (MD, 1.28; 95% CI, 0.94-1.62; P < .001). The EDSS scores increased significantly both during pregnancy (MD, 0.44; 95% CI, 0.20-0.69; P < .001) and in the postpartum period (MD, 0.88; 95% CI, 0.51-1.26; P < .001) compared with before pregnancy. Conclusions and Relevance: This systematic review and meta-analysis found that receiving immunosuppressive treatment during pregnancy and older age at conception were associated with reduced risk of pregnancy-related NMOSD attacks, which mostly occurred in the first trimester of the postpartum period, although more high-quality prospective studies are needed.

H3K27ac-activated lncRNA KTN1-AS1 aggravates tumor progression by miR-505-3p/ZNF326 axis in ovarian cancer.

Background: Numerous studies indicate that long noncoding RNA (lncRNA) is aberrantly expressed in ovarian cancer (OC). Our research investigated the regulatory role of lncRNA KTN1 antisense RNA1 (KTN1-AS1) in the progression of OC through the miR-505-3p/ZNF326 axis. Methods: Expression of KTN1-AS1, microRNA-505-3p (miR-505-3p), and zinc-finger protein-326 (ZNF326) in OC was evaluated by using RT-qPCR analysis. The biological function of KTN1-AS1 was inspected using the loss-of-function assay. Luciferase reporter assay and RIP assay were performed to determine the competitive endogenous RNA (ceRNA) network of KTN1-AS1/miR-505-3p/ZNF326. Results: The data showed that KTN1-AS1 and ZNF326 had a high expression in OC than in the normal tissue, and miR-505-3p exhibited a low expression in OC than in the normal tissue. The knockdown of KTN1-AS1 caused an inhibition in OC cell proliferation, migration, and invasion, and promoted cell apoptosis. In terms of mechanical exploration, KTN1-AS1 was transcriptionally activated by histone H3 on lysine 27 acetylation (H3K27ac) at the promoter region, and KTN1-AS1 increased ZNF326 expression by competitively adsorbing miR-505-3p. Conclusions: This study indicated that H3K27ac-induced lncRNA KTN1-AS1 expression, and facilitated proliferation, migration, and invasion of OC cells by the KTN1-AS1/miR-505-3p/ZNF326 axis.

Progress and challenges of network meta-analysis.

In the past years, network meta-analysis (NMA) has been widely used among clinicians, guideline makers, and health technology assessment agencies and has played an important role in clinical decision-making and guideline development. To inform further development of NMAs, we conducted a bibliometric analysis to assess the current status of published NMA methodological studies, summarized the methodological progress of seven types of NMAs, and discussed the current challenges of NMAs.

Investigation on the contour and bone mineral density of the distal tibial cutting surface used for total ankle arthroplasty.

PURPOSE: This study was designed to investigate (1) the contour of the distal tibial cutting surface, and (2) the bone mineral density (BMD) of the distal tibial cutting surface used during total ankle arthroplasty (TAA). METHODS: Eight-four distal tibial models were created using foot and ankle computerized tomographic (CT) images taken from normal people. The distal tibial cutting surface for TAA was determined to be 10 mm proximal to the tibial plafond. The bony contour and BMD values were determined from the CT image at that level. A bounding box was made on the contour and the width and length of the contour was measured. Regional BMD was evaluated by Hounsfield units (HU) value measurement, with 7 regions of interest (ROI) on 8 different directions for all the 84 CT images. Two different observers made independent measurements and mean HU values for all the 56 ROIs were calculated. RESULTS: Great variations were found among the contours of the cutting surface especially in term of the shape of the anterior and posterior tibial tubercle, and the fibular notch. These variations could be grouped into six categories. For the BMD of the cutting surface, the medial border of the cutting surface did not included cortical bone. The HU value of seven ROIs, which included cortical bone, were significantly greater than all the other ROIs. Few statistical differences were found by multiple comparisons among HU value of all the 49 ROIs without cortex. CONCLUSIONS: Great variability existed in the shape and the BMD of the distal tibial cutting surface.

Risk factors for mortality of coronavirus disease 2019 (COVID-19) patients during the early outbreak of COVID-19: a systematic review and meta-analysis.

BACKGROUND: Identification of risk factors for poor prognosis of patients with coronavirus disease 2019 (COVID-19) is necessary to enable the risk stratification and modify the patient's management. Thus, we performed a systematic review and meta-analysis to evaluate the in-hospital mortality and risk factors of death in COVID-19 patients. METHODS: All studies were searched via the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases. The in-hospital mortality of COVID-19 patients was pooled. Odds ratios (ORs) or mean difference (MD) with 95% confidence intervals (CIs) were calculated for evaluation of risk factors. RESULTS: A total of 80 studies were included with a pooled in-hospital mortality of 14% (95% CI: 12.2-15.9%). Older age (MD =13.32, 95% CI: 10.87-15.77; P<0.00001), male (OR =1.66, 95% CI: 1.37-2.01; P<0.00001), hypertension (OR =2.67, 95% CI: 2.08-3.43; P<0.00001), diabetes (OR =2.14, 95% CI: 1.76-2.6; P<0.00001), chronic respiratory disease (OR =3.55, 95% CI: 2.65-4.76; P<0.00001), chronic heart disease/cardiovascular disease (OR =3.15, 95% CI: 2.43-4.09; P<0.00001), elevated levels of high-sensitive cardiac troponin I (MD =66.65, 95% CI: 16.94-116.36; P=0.009), D-dimer (MD =4.33, 95% CI: 2.97-5.68; P<0.00001), C-reactive protein (MD =48.03, 95% CI: 27.79-68.27; P<0.00001), and a decreased level of albumin at admission (MD =-3.98, 95% CI: -5.75 to -2.22; P<0.0001) are associated with higher risk of death. Patients who developed acute respiratory distress syndrome (OR =62.85, 95% CI: 29.45-134.15; P<0.00001), acute cardiac injury (OR =25.16, 95% CI: 6.56-96.44; P<0.00001), acute kidney injury (OR =22.86, 95% CI: 4.60-113.66; P=0.0001), and septic shock (OR =24.09, 95% CI: 4.26-136.35; P=0.0003) might have a higher in-hospital mortality. CONCLUSIONS: Advanced age, male, comorbidities, increased levels of acute inflammation or organ damage indicators, and complications are associated with the risk of mortality in COVID-19 patients, and should be integrated into the risk stratification system.

Splanchnic Vein Thrombosis in Liver Cirrhosis After Splenectomy or Splenic Artery Embolization: A Systematic Review and Meta-Analysis.

INTRODUCTION: Splenectomy and splenic artery embolization are major treatment options for hypersplenism and portal hypertension in liver cirrhosis, but may lead to splanchnic vein thrombosis (SVT), which is potentially lethal. We conducted a systematic review and meta-analysis to explore the incidence of SVT in liver cirrhosis after splenectomy or splenic artery embolization and the risk factors for SVT. METHODS: All relevant studies were searched through the PubMed, EMBASE, and Cochrane Library databases. The incidence of SVT in liver cirrhosis after splenectomy or splenic artery embolization was pooled. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Sixty-six studies with 5632 patients with cirrhosis were included. The pooled incidence of SVT after splenectomy and splenic artery embolization was 24.6% (95% CI 20.2-29.3%) and 11.7% (95% CI 7.1-17.3%), respectively. A meta-analysis of three comparative studies demonstrated that the incidence of SVT after splenectomy was statistically similar to that after splenic artery embolization (OR 3.15, P = 0.290). Platelet count, mean platelet volume, preoperative splenic or portal vein diameter, preoperative or postoperative portal blood velocity, splenic volume and weight, and periesophagogastric devascularization were significant risk factors for SVT after splenectomy. Postoperative use of preventive antithrombotic therapy was a significant protective factor against SVT after splenectomy. CONCLUSIONS: SVT is common in liver cirrhosis after splenectomy and splenic artery embolization. Coagulation and hemostasis factors, anatomical factors, and surgery-related factors have been widely identified for the assessment of high risk of SVT after splenectomy. Prophylactic strategy after splenectomy, such as antithrombotic therapy, might be considered in such high-risk patients. STUDY REGISTRATION: This study was registered in PROSPERO with a registration number of CRD42019129673.

Role of Blood Pressure Management in Stroke Prevention: A Systematic Review and Network Meta-Analysis of 93 Randomized Controlled Trials.

BACKGROUND AND PURPOSE: The present study aimed to compare the efficacy and tolerability of different blood pressure (BP)-lowering strategies. METHODS: Randomized controlled trials that compared various antihypertensive treatments and stroke outcomes were included. Eligible trials were categorized into three scenarios: single or combination antihypertensive agents against placebos; single or combination agents against other agents; and different BP-lowering targets. The primary efficacy outcome was the risk reduction pertaining to strokes. The tolerability outcome was the withdrawal of drugs, owing to drug-related side effects (PROSPERO registration number CRD42018118454 [20/12/2018]). RESULTS: The present study included 93 trials (average follow-up duration, 3.3 years). In the pairwise analysis, angiotensin-converting enzyme inhibitors (ACEis) and beta-blockers (BBs) were inferior to calcium channel blockers (CCBs) (odds ratio [OR], 1.123; 95% confidence interval [CI], 1.008 to 1.252) (OR, 1.261; 95% CI, 1.116 to 1.425) for stroke prevention, BB was inferior to angiotensin II receptor blockers (ARB) (OR, 1.361; 95% CI, 1.142 to 1.622), and diuretics were superior to ACEi (OR, 0.871; 95% CI, 0.771 to 0.984). The combination of ACEi+CCB was superior to ACEi+diuretic (OR, 0.892; 95% CI, 0.823 to 0.966). The network meta-analysis confirmed that diuretics were superior to BB (OR, 1.34; 95% CI, 1.11 to 1.58), ACEi+diuretic (OR, 1.47; 95% CI, 1.02 to 2.08), BB+CCB (OR, 2.05; 95% CI, 1.05 to 3.79), and renin inhibitors (OR, 1.87; 95% CI, 1.25 to 2.75) for stroke prevention. Regarding the tolerability profile, the pairwise analysis revealed that ACEi was inferior to CCB and less tolerable, compared to the other treatments. CONCLUSIONS: Monotherapy using diuretics, CCB, or ARB, and their combinations could be employed as first-line treatments for stroke prevention in terms of efficacy and tolerability.

Efficacy and safety of erythropoietin for traumatic brain injury.

BACKGROUND: Recent studies regarding the effects of erythropoietin (EPO) for treating traumatic brain injury (TBI) have been inconsistent. This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess the safety and efficacy of EPO for TBI patients at various follow-up time points. METHODS: A literature search was performed using PubMed, Web of Science, MEDLINE, Embase, Google Scholar and the Cochrane Library for RCTs studying EPO in TBI patients published through March 2019. Non-English manuscripts and non-human studies were excluded. The assessed outcomes include mortality, neurological recovery and associated adverse effects. Dichotomous variables are presented as risk ratios (RR) with a 95% confidence interval (CI). RESULTS: A total of seven RCTs involving 1197 TBI patients (611 treated with EPO, 586 treated with placebo) were included in this study. Compared to the placebo arm, treatment with EPO did not improve acute hospital mortality or short-term mortality. However, there was a significant improvement in mid-term (6 months) follow-up survival rates. EPO administration was not associated with neurological function improvement. Regarding adverse effects, EPO treatment did not increase the incidence of thromboembolic events or other associated adverse events. CONCLUSIONS: This meta-analysis indicates a slight mortality benefit for TBI patients treated with EPO at mid-term follow-up. EPO does not improve in-hospital mortality, nor does it increase adverse events including thrombotic, cardiovascular and other associated complications. Our analysis did not demonstrate a significant beneficial effect of EPO intervention on the recovery of neurological function. Future RCTs are required to further characterize the use of EPO in TBI.

Positive and negative factors for the treatment outcomes following total ankle arthroplasty? A systematic review.

BACKGROUND: Patient selection, surgeon's experience and implant design play an integral role and affect the treatment outcomes of total ankle arthroplasty (TAA). The aims of this study were to investigate the positive and negative attributes that correlate with different clinical and radiographic outcomes. METHODS: Eight-nine studies matched the inclusion criteria: (1) studies of primary TAA with uncemented prosthesis; (2) mean follow-up of no less than 2-year; (3) reports of clinical and radiographic outcomes, and exclusion criteria: (1) non-English study; (2) more than one type of prosthesis without separated data; (3) kin studies with shorter follow-up or smaller cohort. Age, etiology, preoperative deformity, surgeon's experience, follow-up duration and prosthetic type were studied with respect to different outcomes by mixed-effects logistic regression analysis. RESULTS: Patients factor: older patients reported less pain or stiffness and demonstrated less radiographic loosening which did not require additional surgical intervention. More traumatic arthritis experienced adjacent joints degeneration after TAA. Surgeon factor: less experienced surgeons had more intraoperative complications. Lack of experience for complications management without implant retrieval during early period might result in more revisions or fusion was done. Prosthetic factor: updated instrumentation decreased malalignment. If the polyethylene (PE) insert was significantly narrower than the metal components more implant instability and subsequent severe particulate wear was seen. Designs with flat-on-flat articulation and ridge at the center of the talar component associated with more PE fracture. Minimal bone resection reduced postoperative fractures. A flat cut of the tibial component and a flat undersurface with press-fit by two screws or pegs of the talar component demonstrated less postoperative fractures, whereas a syndesmosis fusion and a small triangular shape with one central fin of the talar component experienced more loosening which did not require additional surgery. Anatomic conical shape of the talar component seemed to reduce adjacent joint degeneration. Finally, fewer failures were found in patients who received HINTEGRA and Salto Talaris. CONCLUSIONS: Based on our investigation, some positive and negative factors for different clinical and radiographic outcomes were found, which should be taken into consideration in clinical practice and ankle implant design.

Role of cardioprotective agents on chemotherapy-induced heart failure: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Although previous clinical randomized controlled trials (RCTs) have tested the effect of a variety of cardioprotective agents on cancer therapy-induced cardiotoxicity, the number of included patients was limited, and the results remained controversial. In this study, we aimed to evaluate the preventive or therapeutic effects of cardioprotective agents on heart failure (HF) caused by cardiotoxicity induced by cancer therapy. METHODS: We included trials of the following cardioprotective drugs: Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists and stains. We extracted the relevant information with predefined data extraction forms, and assessed the risk of bias in randomized controlled trials with the Cochrane risk of bias tool. The primary outcome was the left ventricular ejection fraction of patients after chemotherapy. We used the random-effects model to carry out pair-wise meta-analysis, and then carry out the random-effects network meta-analysis within the Bayesian framework. RESULTS: Twenty-two relevant RCTs, including 1 916 patients (79.6 % women) with a mean age of 48.4 years, were included. Based on the evaluation of all drug species from 20 studies (26 comparisons), the analysis found that 4 therapies, aldosterone antagonists (MD, 12.78 [95 % CI, 2.87-22.69] and MD, 13.75 [95 % CI, 2.21-25.30]), ACEIs (MD, 6.79 [95 % CI, 2.11-11.48] and MD, 7.76 [95 % CI, 2.64-12.88]), statin (MD, 8.35 [95 % CI, 1.11-15.59]), and beta-blockers (MD, 4.00 [95 % CI, 0.87-7.14]), had a higher efficacy than placebo and/or control, suggesting an LVEF protective effect of cardioprotective therapy. In the analysis classified by single drug or drug combination, based on 22 studies (31 comparisons), spironolactone (MD, 12.77 [95 % CI, 1.76-23.79] and MD, 14.62 [95 % CI, 1.70-27.55]), a combination of candesartan and carvedilol (MD, 12.40 [95 % CI, 0.99-23.81]), enalapril (MD, 7.35 [95 % CI, 1.16-13.54] and MD, 9.20 [95 % CI, 2.61-15.79]), and statin (MD, 8.36 [95 % CI, 0.36-16.36]) showed significant benefits in protecting left ventricular (LV) systolic function compared with the placebo and/or control. CONCLUSION: When classified according to drug type, aldosterone antagonists, ACEIs, statins, and beta-blockers could substantially improve the LV systolic function. In the analysis classified by single drug or drug combination, spironolactone, enalapril, and statin have a significant cardioprotective effect. However, ARBs have no cardioprotective effect and fail to improve the LVEF.

A Network Meta-Analysis of Efficacy of Different Interventions in the Prevention of Postoperative Intrauterine Adhesions.

This network meta-analysis was conducted to compare the efficacy of six interventions, including anti-blocking agents, intrauterine contraceptive devices (IUDs), estrogens, intrauterine balloon, Foley catheter, and amnion graft for the prevention of intrauterine adhesions (IUAs). We searched PubMed, Embase, and Cochrane Library from inception to December 2016. Cohort studies meeting these six interventions in the prevention of IUAs were included. The combination of direct and indirect evidence was conducted to assess the odds ratio (OR) or weighted mean differences and surface under the cumulative ranking curves of the six interventions in the prevention of postoperative IUAs. Finally, 12 eligible cohort studies were included in this network meta-analysis. The results of this network meta-analysis demonstrated that during 1 to 2 months after operation, compared with the surgical group, anti-blocking agent, and estrogens presented with relatively low ratios of postoperative IUAs (OR = 0.30 95% confidence interval (CI) = 0.10-0.67; OR = 0.12, 95% CI = 0.01-0.78, respectively). Compared with IUDs, estrogens exerted comparatively low ratio of postoperative IUAs (OR = 0.10, 95% CI = 0.01-0.90), which indicated that anti-blocking agent and estrogens had relatively better prevention efficacy. The cluster analysis showed that estrogens had relatively better efficacy in the prevention postoperative IUAs. Overall, our findings support that estrogens had relatively better efficacy in the prevention of postoperative IUAs.