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Background To apply CBCT to investigate the anatomical relationship between the mandibular molar and alveolar bone, aimed to provide clinical guidelines for the design of implant restoration. Methods 201 CBCT data were reevaluated to measure height of the alveolar process (EF), width of the alveolar process (GH), width of the basal bone (IJ), the angle between the long axis of the first molar and the alveolar bone (∠a) and the angle between the long axis of the alveolar bone and basal bone (∠b). The angle and width were measured to determine the implant-prosthodontic classification of the morphology in the left lower first molar (36) and right lower first molar (46). All measurements were performed on the improved cross-sectional images. Results EF, GH and IJ were measured as (10.83 ± 1.31) mm, (13.93 ± 2.00) mm and (12.68 ± 1.96) mm for 36, respectively; and (10.87 ± 1.24) mm, (13.86 ± 1.93) mm and (12.60 ± 1.90) mm for 46, respectively. No statistical significance was observed in EF, GH, IJ, ∠a and ∠b between 36 and 46 (all P > 0.05). The morphology was divided into three categories including the straight (68.7–69.2%), oblique (19.9–20.4%) and concave types (11%). Each type was consisted of two subcategories. Conclusions The proposed classification could provide evidence for appropriate selection and direction design of the mandibular molar implant in clinical. The concave type was the most difficult to implant with the highest risk of lingual perforation. The implant length, width, direction required more attention.

Problem: The novel coronavirus disease 2019 (COVID-19) pandemic adversely affected the preparation of Malaysia’s National Health and Morbidity Survey for 2020 because conducting it would expose data collectors and participants to an increased risk of infection. Context: The survey is nationally representative and community based and is conducted by the Institute for Public Health, part of the National Institutes of Health, to generate health-related evidence and to support the Malaysian Ministry of Health in policymaking. Its planned scope for 2020 was the seroprevalence of communicable diseases such as hepatitis B and C. Action: Additional components were added to the survey to increase its usefulness, including COVID-19 seroprevalence and facial anthropometric studies to ensure respirator fit. The survey’s scale was reduced, and data collection was changed from including only face-to-face interviews to mainly self-administered and telephone interviews. The transmission risk to participants was reduced by screening data collectors before the survey and fortnightly thereafter, using standard droplet and contact precautions, ensuring proper training and monitoring of data collectors, and implementing other administrative infection prevention measures. Outcome: Data were collected from 7 August to 11 October 2020, with 5957 participants recruited. Only 4 out of 12 components of the survey were conducted via face-to-face interview. No COVID-19 cases were reported among data collectors and participants. All participants were given their hepatitis and COVID-19 laboratory test results; 73 participants with hepatitis B and 14 with hepatitis C who had been previously undiagnosed were referred for further case management. Discussion: Preparing and conducting the National Health and Morbidity Survey during the COVID-19 pandemic required careful consideration of the risks and benefits, multiple infection prevention measures, strong leadership and strong stakeholder support to ensure there were no adverse events.

Introduction: The rapid spread of the COVID-19 worldwide has led the World Health Organization (WHO) to declare COVID-19 outbreak as a pandemic on March 11, 2020. This study aims to determine the factors associated with asymptomatic COVID-19 patients in Petaling District, Selangor, Malaysia. Methods: Data on COVID-19 patients were extracted from the database of confirmed cases in Petaling District Health Office, Selangor, Malaysia from 3rd February 2020 to 30th April 2020. An asymptomatic laboratory-confirmed case is a person infected with COVID-19 who does not develop any symptoms. The study included socio-demographic variables, the detailed information on clinical manifestations and co-morbidity of the patients. Descriptive and multivariable logistic regression analyses were conducted to determine the factors associated with asymptomatic patients. Results: The overall COVID-19 patients in Petaling District were 434. Approximately 70% (N = 292) of the patients were symptomatic while 32.7% (N = 142) were asymptomatic. Multivariable logistic regression analyses revealed that factors significantly associated with asymptomatic patients were age below 40 years old (aOR: 1.79, 95% CI 1.11, 2.86), non-Malaysians (aOR: 3.22, 95% CI 1.44, 7.19) and local cases (aOR: 2.51, 95% CI 1.42, 4.42). Gender, ethnicity, co-morbidity and township were not significantly associated with asymptomatic patients. Conclusion: Approximately one-third of COVID-19 patients were asymptomatic and the risk factors identified were younger age, non-Malaysians and local cases. Rigorous epidemiological investigation and laboratory examinations are helpful in identifying COVID-19 cases among these group of people who are asymptomatic. Keywords: COVID-19 - asymptomatic - pandemic - Malaysia

Immunity plays an important role in tumor development. In this study, we aimed to investigate molecular classification and its prognostic value in hepatocellular carcinoma (HCC) based on immune signature. Gene set enrichment analysis (GSEA) was used to calculate scores of immune pathways for HCC and hierarchical clustering in two databases (The Cancer Genome Atlas [TCGA], Liver Cancer-RIKEN, JP [LIRI_JP]). The scores of the immune microenvironment and the proportions of 22 immune cells were also calculated. Single-sample GSEA (ssGSEA) was used to screen survival prognosis-related immune pathways and calculate the hazard radio of differentially expressed immune-related genes (IRGs), which were validated in clinical samples and multiple datasets. Based on the immune characteristics, we identified three HCC subtypes, namely immunity high (Immunity_H), immunity medium (Immunity_M), and immunity low (Immunity_L), and confirmed that the classification was reliable and predictable. Immunity_H with a higher immune and stromal score indicated better survival rate. Cox regression analysis showed that IL18RAP and IL7R were the protective genes. Immune risk score was the independent risk factor of overall survival in HCC patients. These results indicated that immunogenomic classification could distinguish HCC patients with different immune status, which could impact the prognosis of the patients with HCC., Graphical abstract, Weiwei et al. provided an immunogenomic classification based on immune characteristics to distinguish hepatocellular carcinoma (HCC) patients with different immune status, and the prediction model can be used for individual immunotherapy of HCC patients.

Jingyi Du,* Yifan Deng,* Zhuolin Qiu, Guoliang Sun, Yue Guo, Ziqing Hei, Xiang Li Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiang LiDepartment of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Number 600, Tianhe Road, Guangzhou, 510630, People’s Republic of ChinaTel/ Fax +86 20 8525 3132Email lixiang27@mail.sysu.edu.cnPurpose: Cognitive impairment is a complication that most frequently happens in patients with chronic neuropathic pain and has limited effective therapy. The aim of this study was to explore the effects of curcumin on the cognitive deficit in rats with peripheral nerve injury induced-neuropathic pain.Methods: The neuropathic pain rat model was constructed using chronic constriction injury (CCI). The curcumin (60 mg/kg) or vehicle was intraperitoneally administered once a day, beginning at 14th day after surgery and continued for 14 consecutive days. The nociceptive threshold tests were measured by paw mechanical withdraw threshold (PMWT) and paw thermal withdrawal latency (PTWL), while the spatial memory abilities were evaluated by the Morris water maze test. The mean counts of bromodeoxyuridine (Brdu)/neuronal nuclei (NeuN) as well as Brdu/doublecortin (DCX) co-labeled cells were used to evaluate neurogenesis in the dentate gyrus of hippocampus. The ultrastructure of the synapse in hippocampal region was visualized using transmission electron microscopy (TEM).Results: Increased PMWT and PTWL, as well as relieved memory deficits, were found in CCI rats under curcumin administration. Moreover, curcumin treatment increased the number of newly born immature (BrdU/NeuN) and newly generated mature neurons (BrdU/DCX). The TEM examination revealed increased PSD thickness and shorter active zone length as well as narrowed synaptic cleft width in the hippocampal region of CCI rats after curcumin injection.Conclusion: Curcumin can alleviate CCI induced nociceptive behaviors and memory deficit. This effect might be associated with hippocampal neurogenesis and synaptic plasticity improvements, which indicated curcumin as a potential strategy for the cognitive impairment restoration under prolonged neuropathic pain condition.Keywords: curcumin, peripheral nerve injury, cognitive impairment, hippocampus neurogenesis

Background Pre-existing comorbidities can predict severe disease requiring intensive care unit (ICU) admission among COVID-19 cases. We compared comorbidities, clinical features and other predictive factors between COVID-19 patients requiring ICU admission for intubation/mechanical ventilation and all other COVID-19 cases in Selangor, Malaysia. Method Field data collected during the COVID-19 outbreak in Selangor, Malaysia, up to 13 April 2020 were used, comprising socio-demographic characteristics, comorbidities and presenting symptoms of COVID-19 cases. ICU admission was determined from medical records. Multiple logistic regression analysis was performed to identify factors associated with ICU admission requiring intubation/mechanical ventilation among COVID-19 cases. Results A total of 1287 COVID-19-positive cases were included for analysis. The most common comorbidities were hypertension (15.5%) and diabetes (11.0%). More than one third of cases presented with fever (43.8%) or cough (37.1%). Of the 25 cases that required intubation/mechanical ventilation, 68.0% had hypertension, 88.0% had fever, 40.0% had dyspnoea and 44.0% were lethargic. Multivariate regression showed that cases that required intubation/mechanical ventilation had significantly higher odds of being older (aged 360 years) [adjusted odds ratio (aOR) = 3.9] and having hypertension (aOR = 5.7), fever (aOR = 9.8), dyspnoea (aOR = 9.6) or lethargy (aOR = 7.9) than cases that did not require intubation/mechanical ventilation. Conclusion The COVID-19 cases in Selangor, Malaysia requiring intubation/mechanical ventilation were significantly older, with a higher proportion of hypertension and symptoms of fever, dyspnoea and lethargy. These risk factors have been reported previously for severe COVID-19 cases, and highlight the role that ageing and underlying comorbidities play in severe outcomes to respiratory disease.

Background: Huangqi Guizhi Wuwu decoction (HQGZWW) exhibits good effects when administered to treat multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Understanding the precise mechanism of this decoction is thus important. Based on the findings of our previous study, the aim of the present study was to understand the role of antigen-specific CD8+ T-cells on the pathogenesis of MS/EAE when HQGZWW is administered as treatment. Methods: Myelin oligodendrocyte glycoprotein (MOG) 35-55-induced mice were administered distilled water, prednisone, and high dose or low dose HQGZWW. After purified CD4+ and CD8+ T-cells were stimulated with the MOG35-55 peptide, proliferation and cytokine secretion assays were performed. To establish the adoptive transfer EAE model, naive mice were injected with MOG35-55 -CD8+ or CD4+ T-cells. Results: Significant improvements in EAE score and pathology were observed in the high dose HQGZWW and prednisone groups. Compared to the low dose HQGZWW and distilled water groups, lower antigen-specific responses, lower levels of interferon-gamma, and higher levels of interleukin (IL)-4 and IL-10 from CD8+ and CD4+ T cells were observed in the high dose HQGZWW and prednisone groups. Finally, the EAE score was observed to be similar between the high dose HQGZWW group and prednisone group; however, this finding was not observed in the low dose HQGZWW group. Conclusion: Our findings suggest that high dose HQGZWW has similar effects on cell proliferation, cytokine secretion, and EAE score to prednisone, while low dose HQGZWW does not have such effect. The protective role of HQGZWW against EAE might thus depend on the Th2 cytokine secretion profile induced by either MOG35-55 specific CD8+ or CD4+ T-cells.

A number of studies have suggested that coronavirus disease 2019 (COVID-19) can cause liver damage. However, clinical features and outcome of COVID-19 in patients with liver injury remain to be further investigated. In this study, the clinical data of 265 COVID-19 patients admitted to seven tertiary hospitals were collected. Based on a threshold for transaminase or total bilirubin levels at two times the normal upper limit, patients were divided into mild or moderate/severe liver injury groups. Among the 265 patients, 183 patients showed liver injury within 48 hours of admission. Aspartate aminotransferase levels were predominantly elevated in the liver injury group, but albumin levels were reduced. Moreover, fibrinogen and D-dimer were significantly increased. Furthermore, 68% of the patients with moderate/severe liver injury had one or more underlying diseases. Almost half of these patients developed acute respiratory distress syndrome (44%) and secondary infections (46%). These patients showed increased interleukin-6 and interleukin-10 levels and a decrease in PaO2 and the oxygenation index. In addition, levels of alanine aminotransferase, aspartate aminotransferase, and albumin were correlated with the oxygenation index, D-dimer and lymphocyte counts. Furthermore, a novel prognostic assessment model based on liver function was established, which accuracy reached 88% and was able to accurately assess the prognosis of COVID-19 patients.

Background Emerging evidence suggests that competing endogenous RNAs plays a crucial role in the development and progress of pancreatic adenocarcinoma (PAAD). The objective was to identify a new lncRNA-miRNA-mRNA network as prognostic markers, and develop and validate a multi-mRNAs-based classifier for predicting overall survival (OS) in PAAD. Methods Data on pancreatic RNA expression and clinical information of 445 PAAD patients and 328 normal subjects were downloaded from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype-Tissue Expression (GTEx). The weighted correlation network analysis (WGCNA) was used to analyze long non-coding RNA (lncRNA) and mRNA, clustering genes with similar expression patterns. MiRcode was used to predict the sponge microRNAs (miRNAs) corresponding to lncRNAs. The downstream targeted mRNAs of miRNAs were identified by starBase, miRDB, miRTarBase and Targetscan. A multi-mRNAs-based classifier was develop using least absolute shrinkage and selection operator method (LASSO) COX regression model, which was tested in an independent validation cohort. Results A lncRNA-miRNA-mRNA co-expression network which consisted of 60 lncRNAs, 3 miRNAs and 3 mRNAs associated with the prognosis of patients with PAAD was established. In addition, we constructed a 14-mRNAs-based classifier based on a training cohort composed of 178 PAAD patients, of which the area under receiver operating characteristic (AUC) in predicting 1-year, 3-year, and 5-year OS was 0.719, 0.806 and 0.794, respectively. The classifier also shown good prediction function in independent verification cohorts, with the AUC of 0.604, 0.639 and 0.607, respectively. Conclusions A novel competitive endogenous RNA (ceRNA) network associated with progression of PAAD could be used as a reference for future molecular biology research.

IntroductionAs of 3rdJune 2021, Malaysia is experiencing a resurgence of COVID-19 cases. In response, the federal government has implemented various non-pharmaceutical interventions (NPIs) under a series of Movement Control Orders and, more recently, a vaccination campaign to regain epidemic control. In this study, we assessed the potential for the vaccination campaign to control the epidemic in Malaysia and four high-burden regions of interest, under various public health response scenarios.MethodsA modified susceptible-exposed-infectious-recovered compartmental model was developed that included two sequential incubation and infectious periods, with stratification by clinical state. The model was further stratified by age and incorporated population mobility to capture NPIs and micro-distancing (behaviour changes not captured through population mobility). Emerging variants of concern (VoC) were included as an additional strain competing with the existing wild-type strain. Several scenarios that included different vaccination strategies (i.e. vaccines that reduce disease severity and/or prevent infection, vaccination coverage) and mobility restrictions were implemented.ResultsThe national model and the regional models all fit well to notification data but underestimated ICU occupancy and deaths in recent weeks, which may be attributable to increased severity of VoC or saturation of case detection. However, the true case detection proportion showed wide credible intervals, highlighting incomplete understanding of the true epidemic size. The scenario projections suggested that under current vaccination rates complete relaxation of all NPIs would trigger a major epidemic. The results emphasise the importance of micro-distancing, maintaining mobility restrictions during vaccination roll-out and accelerating the pace of vaccination for future control. Malaysia is particularly susceptible to a major COVID-19 resurgence resulting from its limited population immunity due to the country’s historical success in maintaining control throughout much of 2020.

An amendment to this paper has been published and can be accessed via the original article.

Background: The Von Hippel-Lindau ( VHL ) p.Tyr98His ( Y98H ) mutation is designated as the “Black Forest” founder mutation and has been previously reported in Western countries. This study reports the first recorded Chinese VHL family with the “Black Forest” mutation in Asia. Methods: Paired whole-exome sequencing (WES), Sanger sequencing and immunohistochemistry (IHC) were performed on samples from a large Chinese family to confirm the causative mutation and mutation carriers in the family. Clinical manifestations of the family were summarized and compared with those reported from other patients with the VHL Y98H mutation. Results: The Chinese pheochromocytoma (PCC) family was identified as a VHL type 2 family with a Y98H mutation. There were 4 VHL patients and 11 currently healthy individuals with the mutation. Copy number analysis and SDHB IHC were performed to exclude interference from other pathogenic genes of PCC or paraganglioma (PGL). Conclusions: We report the first recorded instance of a Chinese VHL type 2 family with the “Black Forest” mutation by using WES and Sanger sequencing, which widens the currently recorded presence of the “Black Forest” mutation to China and potentially elsewhere in Asia and indicates that the “Black Forest” mutation does not uniquely evolve in occidental countries. A personalized surveillance approach, which may be more appropriate for affected families, has been recommended to improve quality of life.

Cryptococcal meningitis (CM) is found to occur in immunosuppressed patients and those who are immunocompetent. This study aimed to compare the presentation and outcome of CM in patients who are human immunodeficiency virus (HIV) negative with and without immunosuppression. We reviewed 255 clinical records from patients with CM who are HIV negative. The demographic and clinical characteristics, cerebrospinal fluid profiles, brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. Among the 255 patients with CM, 91 (35.7%) appeared immunocompetent. CM was present in a younger population in the immunocompetent group (above 50 y, 19.8% vs. 32.3%, P=0.026), with higher initial complaints of visual and auditory symptoms (45.1% vs. 27.4%, P=0.004; 19.8% vs. 9.1%, P=0.016; respectively) and higher cerebrospinal fluid white blood cell counts (30.8% vs. 45.1%, P=0.009) compared with the immunocompromised patients. In addition, the immunocompetent patients had a higher proportion of normal brain images than did the immunocompromised patients (10% vs. 2%, P=0.028). There were no differences in hospital mortality and satisfactory outcomes between the groups (mortality: 10.9% vs. 7.0%, P=0.416; satisfactory outcomes: 76.4% vs. 80.2%, P=0.585). We found significant differences between the immunocompetent and HIV-negative immunocompromised patients; however, there were fewer differences between the groups than expected. Further studies assessing the immune responses in both groups should be performed.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. Pyroptosis can influence the proliferation, invasion and metastasis of tumors. However, the prognostic value of pyroptosis-related genes in HCC remains to be further elucidated.Methods: In this study, univariate Cox regression analysis and the least absolute shrinkage and selection operator Cox regression were performed to construct a four-gene signature. Kaplan-Meier curve, time-dependent receiver operating characteristic curve and univariate/multivariate Cox analysis were used to evaluate the prognostic model. Single-sample gene set enrichment analysis was performed to calculate the enrichment scores of diverse immune cell subpopulations and related functions. The correlation of the prognostic model with immune infiltrate types and drug chemosensitivity were analyzed by Analysis of variance and Pearson correlation respectively. Spearman correlation was carried out to analyze the associations between the risk score and immune checkpoint-related genes, cell cycle-related genes, and multidrug resistance-related genes. Gene set enrichment analysis was conducted to further explore the underlying molecular mechanisms. Finally, real-time quantitative polymerase chain reaction and immunohistochemistry were applied to analyze the mRNA and protein expression levels between HCC tissues and adjacent non-tumorous tissues in an independent sample cohort.Results: A pyroptosis-related gene signature was constructed to classify patients into two risk groups. Compared with the low-risk group, patients in the high-risk group showed significantly reduced overall survival (OS). The risk score was an independent predictor of OS. Tumor-related pathways were enriched in the high-risk group and patients with different risk scores showed different immune status. Immune checkpoint-related genes, cell cycle-related genes, and multidrug resistance-related genes were overexpressed in the high-risk group compared with the low-risk group. The expression level of each prognostic gene was negatively related to the anti-tumor drug sensitivity. Furthermore, the expression level of each prognostic gene in HCC tissues was higher than that in adjacent non-tumorous tissues in an independent sample cohort and similar results were found in most cancer types.Conclusions: A novel pyroptosis-related gene signature is a promising biomarker for estimating the OS and immune status of HCC, which is beneficial to the realization of individualized treatment.

What is known and objective The benefits of local infiltration analgesia (LIA) in knee arthroplasty (KA) have been well-documented. However, it is unknown whether adding a corticosteroid to the composition of the LIA is beneficial. This study aimed to investigate the efficacy and safety of administering periarticular steroids intraoperatively in patients who underwent KA through a systematic review and meta-analysis. Methods A systematic search was conducted to identify relevant randomized controlled trials in the PubMed, Embase, Web of Science and Cochrane databases up to January 19th, 2021 to perform a meta-analysis. Outcome variables included pain scores, total opioid consumption, knee range of motion (ROM) and postoperative complications. Results Corticosteroid injections did not reduce pain scores at 6, 12, 24 or 72 h postoperatively, although a minimal degree of transient pain relief was achieved at 48 h postoperatively compared with those in the placebo group, nor was there a significant difference in total opioid consumption. However, patients receiving corticosteroids did exhibit a transient ROM increase on postoperative days 1, 2 and 3. Since the minimal clinically important difference (MCID) for ROM is unclear, it is unknown if the improvement in ROM is clinically significant. What is new and conclusion Our specific end-point analysis demonstrated that corticosteroid administration did not provide pain relief or reduce opioid consumption compared with placebo. However, corticosteroids might provide a statistically significant, though transient and minimal improvement in knee ROM after KA, although no firm conclusions about the benefits of administering corticosteroids in KA can be made based on the available evidence.

Nonalcoholic fatty liver disease is the most common hepatic disease in western countries and is even more ubiquitous in Asian countries. Our study determined that TH17/Treg cells were imbalanced in animal models. Based on our interest in the mechanism underlying TH17/Treg cell imbalance in nonalcoholic fatty liver mice, we conducted a joint bioinformatics analysis to further investigate this process. Common gene sequencing analysis was based on one trial from one sequencing platform, where gene expression analysis and enrichment analysis were the only analyses performed. We compared different sequencing results from different trials performed using different sequencing platforms, and we utilized the intersection of these analytical results to perform joint analysis. We used a bioinformatics analysis method to perform enrichment analysis and map interaction network analysis and predict potential microRNA sites. Animal experiments were also designed to validate the results of the data analysis based on quantitative polymerase chain reaction (qPCR) and western blotting. Our results revealed 8 coexisting differentially expressed genes (DEGs) and 7 hinge genes. The identified DEGs may influence nonalcoholic steatosis hepatitis through the interleukin-17 pathway. We found that microRNA-29c interacts with FOS and IGFBP1. Polymerase chain reaction analyses revealed both FOS and microRNA-29c expression in NASH mice, and western blot analyses indicated the same trend with regard to FOS protein levels. Based on these results, we suggest that microRNA-29c acts on FOS via the interleukin-17 signaling pathway to regulate TH17/Treg cells in NASH patients.

Dengue is a major threat to public health globally. While point-of-care diagnosis of acute/recent dengue is available to reduce its mortality, a lack of rapid and accurate testing for the detection of previous dengue remains a hurdle in expanding dengue seroepidemiological surveys to inform its prevention, especially vaccination, to reduce dengue morbidity. This study evaluated ViroTrack Dengue Serostate, a biosensors-based semi-quantitative anti-dengue IgG (immunoglobulin G) immuno-magnetic agglutination assay for the diagnosis of previous and recent dengue in a single test. Blood samples were obtained from 484 healthy participants recruited randomly from two communities in Petaling district, Selangor, Malaysia. The reference tests were Panbio Dengue IgG indirect and capture enzyme-linked immunosorbent assays, in-house hemagglutination inhibition assay, and focus reduction neutralization test. Dengue Serostate had a sensitivity and specificity of 91.1% (95%CI 87.8–93.8) and 91.1% (95%CI 83.8–95.8) for the diagnosis of previous dengue, and 90.2% (95%CI 76.9–97.3) and 93.2% (95%CI 90.5–95.4) for the diagnosis of recent dengue, respectively. Its positive predictive value of 97.5% (95%CI 95.3–98.8) would prevent most dengue-naïve individuals from being vaccinated. ViroTrack Dengue Serostate’s good point-of-care diagnostic accuracy can ease the conduct of dengue serosurveys to inform dengue vaccination strategy and facilitate pre-vaccination screening to ensure safety.

The inflammatory response of endothelial cells accelerates various vascular diseases. MicroRNAs (miRNAs) participate in diverse cellular processes during inflammation. In the present study, we found that miR-302a is an effective suppressor of vascular inflammation in endothelial cells. It was revealed that miR-302a exhibited a lower level in a lipopolysaccharide (LPS)-induced mouse model and in patients with vascular inflammatory disease. Genetic haploinsufficiency of miR-302 aggravated the LPS-induced vascular inflammatory response in mice, and overexpression of miR-302a attenuated vascular inflammation in mice. Furthermore, overexpression of miR-302a inhibited the synthesis and secretion of adhesion factors in endothelial cells, and suppressed the adhesion of monocytes to endothelium. In the study of molecular mechanism, we found that miR-302a relieved vascular inflammation mainly by regulating the nuclear factor kappa-B (NF-κB) pathway in endothelial cells. The results showed that interleukin-1 receptor-associated kinase4 (IRAK4) and zinc finger protein 91 (ZFP91) were the binding targets of miR-302a. MiR-302a prevented the nuclear translocation of NF-κB by inhibiting phosphorylation of IκB kinase complex β (IKKβ) and inhibitors of κBα (IκBα) via targeting IRAK4. In addition, miR-302a downregulated the expression of NF-κB by directly binding with ZFP91. These findings indicate that miR-302a negatively regulates inflammatory responses in the endothelium via the NF-κB pathway and it may be a novel target for relieving vascular inflammation.

BackgroundHepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. As part of the active cross-talk between the tumor and the host, inflammatory response in the tumor or its microenvironment could affect prognosis. However, the prognostic value of inflammatory response-related genes in HCC remains to be further elucidated.MethodsIn this study, the mRNA expression profiles and corresponding clinical data of HCC patients were downloaded from the public database. The least absolute shrinkage and selection operator Cox analysis was utilized to construct a multigene prognostic signature in the TCGA cohort. HCC patients from the ICGC cohort were used for validation. Kaplan Meier analysis was used to compare the overall survival (OS) between high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors for OS. Single-sample gene set enrichment analysis was utilized to calculate the immune cell infiltration score and immune related pathway activity. Gene set enrichment analysis was implemented to conduct GO terms and KEGG pathways. The qRT-PCR and immunohistochemistry were utilized to perform the mRNA and protein expression of prognostic genes between HCC tissues and normal liver tissues respectively.ResultsAn inflammatory response-related gene signature model was constructed by LASSO Cox regression analysis. Compared with the low-risk group, patients in the high-risk group showed significantly reduced OS. Receiver operating characteristic curve analysis confirmed the predictive capacity of the prognostic gene signature. Multivariate Cox analysis revealed that the risk score was an independent predictor for OS. Functional analysis indicated that immune status was definitely different between two risk groups, and cancer-related pathways were enriched in high-risk group. The risk score was significantly correlated with tumor grade, tumor stage and immune infiltrate types. The expression levels of prognostic genes were significantly correlated with sensitivity of cancer cells to anti-tumor drugs. Furthermore, the expression of prognostic genes showed significant difference between HCC tissues and adjacent non-tumorous tissues in the separate sample cohort.ConclusionA novel signature constructed with eight inflammatory response-related genes can be used for prognostic prediction and impact the immune status in HCC. Moreover, inhibition of these genes may be a therapeutic alternative.

Aim: To develop a trans-omics-based molecular clinicopathological algorithm for predicting pancreatic adenocarcinoma prognosis, we performed a comprehensive analysis of the expression levels of mRNA, DNA methylation and DNA copy number in The Cancer Genome Atlas dataset. Materials & methods: Based on the least absolute shrinkage and selection operator method – COX regression analysis, a trans-omics-based classifier was established to predict overall survival. Nomogram was constructed by combining the classifier band clinical pathological characterization. Results: Based on trans-omics, we developed a 10-gene-based classifier and a molecular-clinicopathologic nomogram for predicting overall survival with satisfactory accuracy. Conclusion: Trans-omics-based classifier and molecule-clinicopathological nomogram based on the classifier can accurately predict the prognosis of pancreatic adenocarcinoma patients

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease. Reduced expression of focal adhesion is considered as an important prerequisite for tumor cell invasion and metastasis. However, the prognostic value of focal adhesion related genes in HCC remains to be further determined. In this study, RNA expression profiles were downloaded from public databases. A five focal adhesion related gene signature model was established by the least absolute shrinkage and selection operator Cox regression analysis, which categorized patients into high- and low-risk groups. Multivariate Cox regression analysis showed that the risk score was an independent predictor for overall survival. Single-sample gene set enrichment analysis revealed that immune status was different between the two risk groups, and tumor-related pathways were enriched in high-risk group. The risk score was significantly associated with tumor grade, tumor stage, immune scores, and immune infiltrate types. Pearson correlation showed that the expression level of prognostic genes was associated with anti-tumor drug sensitivity. Besides, the mRNA and protein expression of prognostic genes was significantly different between HCC tissues and adjacent non-tumorous tissues in our separate cohort. Taken together, a novel focal adhesion related gene signature can be used for prognostic prediction in HCC, which may be a therapeutic alternative.

Background: To analyze the clinical features and the possible risk factors of secondary infection, and explore their impact on prognosis of COVID-19. Methods: A total of 165 severe and critical hospitalized patients diagnosed with COVID-19 were included. The clinical characteristics, laboratory tests, imaging data, secondary infections and outcomes were analyzed. Results: The mean age of total patients was (57.3±15.2) years, of which 111 were males (67.3%). 108 cases were with basic diseases (65.5%), and 1 death (0.6%). The secondary infection rate in critical patients was significantly higher than in severe patients (P p < 0.001).The utilization rate and usage time of invasive ventilator, and deep vein catheterization, catheter indwelling and ECMO were the risk factors for the secondary infected patients.Conclusion: Secondary infection is an extremely common complication in critically ill patients and a trigger point for exacerbation of the disease. An effective control on the secondary infection will do good to the prognosis of COVID-19 patients.

Objective: Hepatic encephalopathy (HE) characterized by neuropsychiatric abnormalities is a major complication of cirrhosis with high mortality. However, the pathogenesis of HE has not been fully elucidated. This study aimed to determine endogenous hydrogen sulfide (H2S) in the blood of HE patients and investigate the role of H2S in an astrocytic model of HE. Methods: Patients with and without HE were recruited to determine plasma H2S levels and blood microbial 16S rRNA gene. Rat astrocytes were employed as a model of HE by treatment of NH4Cl. Exogenous H2S was preadded. Cell viability was measured by Cell Counting Kit-8 (CCK-8) assay, and cell death was evaluated by lactate dehydrogenase (LDH) release. Apoptosis was determined by Hoechst 33342/Propidium Iodide (PI) Double Staining and Western blot analysis of apoptosis-related protein expression. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometer. Expressions of Nrf2 and its downstream regulated genes were examined by immunofluorescence staining and Western blot, respectively. Nrf2 gene knockdown was performed by antisense shRNA of Nrf2 gene. Results: There was a significant decrease in H2S levels in cirrhotic patients with HE compared with without HE. Blood microbiota analyses revealed that certain strains associated with H2S production were negatively correlated with HE. In vitro, H2S markedly attenuated NH4Cl-induced cytotoxicity, oxidative stress, and apoptosis. This effect was mediated by Nrf2/ARE signaling, and knockdown of Nrf2 expression abolished the antagonistic effect of H2S on NH4Cl-induced neurotoxicity in astrocytes. Conclusion: Levels of H2S and bacteria associated with H2S production are decreased in HE, and H2S functions as the neuroprotector against NH4Cl-induced HE by activating Nrf2/ARE signaling of astrocytes.

Temporomandibular disorder (TMD) is commonly comorbid with fibromyalgia syndrome (FMS). The incidence of these pain conditions is prevalent in women and prone to mental stress. Chronic pain symptoms in patients with FMS and myofascial TMD (mTMD) are severe and debilitating. In the present study, we developed a new animal model to mimic the comorbidity of TMD and FMS. In ovariectomized female rats, repeated forced swim (FS) stress induced mechanical allodynia and thermal hyperalgesia in the hindpaws of the 17β-estradiol (E2) treated rats with orofacial inflammation. Subcutaneous injection of E2, injection of complete Freund’s adjuvant (CFA) into masseter muscles or FS alone did not induce somatic hyperalgesia. We also found that the somatic hyperalgesia was accompanied by upregulation of GluN1 receptor and serotonin (5-hydroxytryptamine, 5-HT)3A receptor expression in the dorsal horn of spinal cord at L4-L5 segments. Intrathecal injection of N-methyl-D-aspartic acid receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid (APV) or 5-HT3 receptor antagonist Y-25130 blocked stress-induced wide-spreading hyperalgesia. These results suggest that NMDAR-dependent central sensitization in the spinal dorsal horn and 5-HT-dependent descending facilitation contribute to the development of wide-spreading hyperalgesia in this comorbid pain model.

Background Long noncoding ribonucleic acid (lncRNA) promoter methylation is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Thus, we aim to screen and verify the lncRNA promoter methylation sites associated with overall survival (OS), vascular invasion, pathological grade, and clinical stage in HCC. Methods Methylation-related data including clinical characteristic, transcriptome, methylation, and messenger RNA (mRNA) expression were taken from the Cancer Genome Atlas (TCGA) database. The OS, vascular invasion, pathological grade, and clinical stage-related lncRNA promoter methylation models were developed by the least absolute shrinkage and selection operator (LASSO) algorithm based on the lncRNA promoter methylation sites screened via R software. The Kaplan–Meier analysis, the area under the receiver operating characteristic (ROC) curve (AUC), the calibration curve (C-index) were performed to evaluate the performance of these models. Finally, the methylation-specific polymerase chain reaction (MS-PCR) was performed to verify the accuracy of these models based on 146 HCC tissues from our hospital. Results A total of 10 methylation sites were included in the OS-related lncRNA promoter methylation model that could effectively divide HCC patients into high-risk and low-risk groups (P Conclusion The lncRNA promoter methylation sites are closely correlated with the process of HCC and can be utilized to improve the therapy and prognosis of HCC.

Aim: The aim of our study was to describe the characteristics of postinfectious inflammatory response syndrome (PIIRS) in HIV-uninfected and nontransplant men after cryptococcal meningitis (CM). Patients & methods: A case-control study was designed to compare HIV-uninfected and nontransplant male CM patients with and without PIIRS. Results: CM-PIIRS patients had increased rates of hearing loss, V-P shunt placement, amphotericin B treatment, higher cerebrospinal fluid pressures and Cryptococcus counts in the first CM episode. CM-PIIRS episode was characterized by higher frequencies of headache and fever, higher C-reactive protein, erythrocyte sedimentation rate, cerebrospinal fluid white blood cell (WBC) counts and modified Rankin Score. Brain MRI scans revealed the high signal lesions on axial flair imaging. Receipt of corticosteroid therapy was associated with lower rates of fever and better modified Rankin Score scores at 1 month after treatment. Conclusion: CM-PIIRS episode differs to the initial presentation, may help to identify which patients are at risk to develop PIIRS. Steroids therapy could be beneficial.

CLCN2-related leukoencephalopathy (CC2L) is a rare disease due to autosomal recessive loss-of-function mutations in CLCN2 gene. We generated an induced pluripotent stem cell (iPSC) line (SKLOi001-A) from urine cells isolated from a CC2L patient carrying a homozygotic mutation: c.2257C>T (p.Arg753*) in CLCN2 gene via an integration-free methods. The established iPSC line kept the CLCN2 mutation and displayed a normal karyotype, expressed pluripotency markers, showed differentiation potential. This newly iPSC line could be served as a possible tool to unravel the mechanisms underlying CLCN2-associated diseases and screen drugs for the treatment.

Impaired intestinal barrier function and oxidative stress injury play critical roles in the pathogenesis of alcoholic liver disease (ALD), and recent investigations have revealed a role for dietary copper in the liver and intestinal barrier function. Therefore, the current study investigates the mechanisms and role of dietary copper in alcohol induced liver diseases. C57BL/6 mice were used to create an alcoholic liver disease model with a Lieber-DeCarli diet containing 5% alcohol and were fed with different concentrations of dietary copper of adequate (6 ppm, CuA), marginal (1.5 ppm, CuM), or supplemental (20 ppm, CuS) amounts. Caco-2 cells were also exposed to ethanol and different concentrations of copper. Damages of the liver and intestine were evaluated by transaminases, histology staining, and protein and mRNA level, as well as cell proliferation, oxidative stress, and mitochondrial membrane potential. In animal experiments, the results indicate that an alcohol diet causes liver injury and disruption of intestinal barrier function as well as decreasing the expression of genes such as HIF-1α, occludin, SOD1, and GPX1. Supplemental dietary copper can revert these changes except for SOD1, but marginal dietary copper can worsen these changes. The in vitro cell experiments showed that proper copper supplementation can promote cell growth and reduce reactive oxygen species (ROS) production. In conclusion, supplemental dietary copper has beneficial effects on alcohol-induced intestine and liver injury, and marginal dietary copper shows detrimental effects on these parameters.

There has been an increase in morbidity and mortality related to coronary heart disease (CHD) in China in recent years. Numerous clinical experiences and studies have shown that traditional Chinese medicine (TCM) plays an important role in the prevention, treatment, and prognosis of CHD. However, the mechanism of TCM in the treatment of CHD has not yet been elucidated. The circRNA-miRNA-mRNA network consists of miRNA that is competitively bound by circRNA, and miRNA regulates the transcription level of mRNA. Through literature review, we found that the circRNA-miRNA-mRNA network acts to contribute to certain effects to CHD such as myocardial hypertrophy, myocardial fibrosis, and heart failure. TCM contains constituents that act against CHD by antiatherosclerosis and apoptosis inhibition action, cardiac and cardiomyocyte protection, and these components also promote cell growth and protection of the vascular system by regulating miRNAs. Therefore, we consider that the circRNA-miRNA-mRNA network may be a new regulatory mechanism for the effective treatment of CHD by TCM.

Background: Coronavirus Disease (COVID-19) has spread rapidly across the globe, since it was first discovered in late December 2019 We are still learning about

Background The present survey evaluated the incidence of perioperative cardiac arrests in a Chinese tertiary general teaching hospital over ten years. Methods The incidence of cardiac arrest that occurred within 24 h of anaesthesia administration was retrospectively identified in the Third Affiliated Hospital of Sun Yat-Sen University between August 2007 and October 2017. Overall, 152,513 anaesthetics were included in the study period. Data collected included patient characteristics, American Society of Anaesthesiologists (ASA) physical status score, surgical specialty and anaesthesia technique. Cardiac arrests were assigned to one of three groups: “anaesthesia-related”, “anaesthesia-contributing” or “anaesthesia-unrelated”. Results In total, 104 cardiac arrests (6.8:10,000) and 34 deaths (2.2:10,000) were obtained. Among them, eleven cardiac arrests events were anaesthesia-related, resulting in an incidence of 0.7 per 10,000 anaesthetics. Sixteen cardiac arrests events were found to be anaesthesia-contributing, resulting in an incidence of 1.0 per 10,000 anaesthetics. Cardiovascular adverse events were the major events that contributed to anaesthesia-related cardiac arrest. Differences were found between events related and unrelated to anaesthesia with regard to ASA physical status and anaesthesia technique (P

BACKGROUND Alpha-fetoprotein (AFP) has been shown to predict the prognosis of liver disease in several studies. This study aimed to evaluate the prognostic value of stratified AFP in patients with acute-on-chronic hepatitis B liver failure (ACHBLF). METHODS A total of 192 patients were included and AFP were categorized into quartiles. The prognostic value was determined for overall survival (OS) and assessed by Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazard regression analyses studied the association of all independent parameters with disease prognosis. RESULTS The optimal cut-off points of AFP were: (Q1) 252.3-4800.0 ng/ml, (Q2) 76.0-252.2 ng/ml, (Q3) 18.6-75.9 ng/ml, and (Q4) 0.7-18.5 ng/ml. Based on the Kaplan-Meier analysis of the OS, each AFP quartile revealed a progressively worse OS and apparent separation (log-rank P = 0.006). The second-highest quartiles of AFP (Q2) always demonstrated an extremely favorable short-term survival. Combining the lowest AFP quartiles with a serum sodium < 131mmol/L or an INR ≥ 3.3 showed a poor outcome (90-days survival of 25.0% and 11.9% respectively). CONCLUSIONS Stratified AFP could strengthen the predictive power for short-term survival of patients with ACHBLF. Combining AFP quartiles with low serum sodium and high INR may better predict poor outcome in ACHBLF patients.

Background and aim Recent investigation revealed that dysbiosis in the gut flora and disruption of permeability of intestinal barrier are possible causes for the development of autoimmune hepatitis. Supplementation of sodium butyrate has been suggested to protect liver injury from disrupted permeability of small intestine. In current study, we employed S100/Freund's complete adjuvant induced autoimmune hepatitis to investigate therapeutic efficacy of sodium butyrate and its mechanism in the liver and upper small intestine. Methods C57BL/6 mice were employed and divided into three groups – control group (n = 8), autoimmune hepatitis group (n = 12) and autoimmune hepatitis with treatment of sodium butyrate group (n = 12). Histological staining and western blot analyses were employed to evaluate liver and upper small intestine morphology and gene expression respectively. Results The findings revealed that S100/Freund’s complete adjuvant caused liver injury and disruption of upper small intestine villi. Sodium butyrate attenuated the injuries and prevented migration of Escherichia coli into the liver. Moreover, the effect of sodium butyrate on protection of injuries of the liver and upper small intestine could be due to inhibition of toll-like receptor 4 signaling pathway, as well as its down-regulation of inflammatory cytokines – interleukin-6 and tumor necrosis factor-a. Conclusions Sodium butyrate can prevent liver injury by maintaining the integrity of small intestine and inhibiting inflammatory response in S100/Freund’s complete adjuvant induced autoimmune hepatitis.

Background The presence of vascular invasion (VI) in pathology specimens is a well-known unfavorable prognostic factor of hepatocellular carcinoma (HCC) recurrence and overall survival (OS). We investigated the vascular invasion related microRNA (miRNA) expression profiles and potential of prognostic value in HCC. Methods MiRNA and mRNA expression data for HCC were accessed from The Cancer Genome Atlas (TCGA). LASSO logistic regression models were used to develop a miRNA-based classifier for predicting VI. The predictive capability was accessed by area under receiver operating characteristics (AUC). Concordance index (C-index) and time-dependent receiver operating characteristic (td-ROC) were used to determine its prognostic value. We validated the predictive and prognostic accuracy of this classifier in an external independent cohort of 127 patients. Functionally relevant targets of miRNAs were determined using miRNA target prediction, experimental validation and correlation of miRNA and mRNA expression data. Results A 16-miRNA-based classifier was developed which identified VI accurately, with AUC of 0.731 and 0.727 in TCGA set and validation cohort, respectively. C-index and td-ROC showed that the classifier was able to stratify patients into risk groups strongly associated with OS. When stratified by tumor characteristics, the classifier was still a clinically and statistically significant prognostic model. The predictive and prognostic accuracy of the classifier was confirmed in validation cohort. Vascular invasion related miRNA/target pairs were identified by integrating expression patterns of predicted targets, which were validated in cell lines. Conclusions A multi-miRNA-based classifier developed based on the presence of VI, which could effectively predict OS in HCC.

Background Acute-on-chronic hepatitis B liver failure (ACHBLF) is associated with poor short-term prognosis. The aim of the present study was to construct and validate a model for end-stage liver disease (MELD)-based nomogram for the 3-month mortality estimation for patients with ACHBLF. Methods A total of 551 patients with ACHBLF were prospectively enrolled from 2 independent medical centers and divided into 2 cohorts of training and validation, respectively. The 3-month mortality was recorded as the outcome. The MELD-based nomogram was constructed to predict the 3-month mortality for ACHBLF using the training group of 335 patients and validated using an independent cohort of 216 patients. The predictive capability of MELD-based nomogram was compared with the MELD score system by calibration analysis, receiver operating characteristics (ROC) and decision curve analysis in both training cohort and validation cohort. Results Multivariate analysis suggested that age, serum sodium, and MELD score were independent prognostic indicators associated with the 3-month mortality for ACHBLF, and therefore used for developing the nomogram. In terms of calibration, the predicted survival by the MELD-based nomogram was found to be extremely in line with the observed 3-month mortality both in training cohort and validation cohort. Additionally, both ROC and decision curve analyses showed that the MELD-based nomogram was better than MELD, MELD-Na, MELDNa, and iMELD for ACHBLF prognosis prediction. The results were confirmed in the external cohort of validation. Conclusions The MELD-based nomogram provided a user-friendly, accurate and reproducible tool for predicting 3-month mortality of patients with ACHBLF.

Hepatitis B virus (HBV) infection remains a major health problem and HBV-related-decompensated cirrhosis (HBV-DC) usually leads to a poor prognosis. Our aim was to determine the utility of inflammatory biomarkers in predicting mortality of HBV-DC.A total of 329 HBV-DC patients were enrolled. Survival estimates for the entire study population were generated using the Kaplan-Meier method. The prognostic values for model for end-stage liver disease (MELD) score, Child-Pugh score, and inflammatory biomarkers neutrophil/lymphocyte ratio, C-reactive protein-to-albumin ratio (CAR), and lymphocyte-to-monocyte ratio (LMR) for HBV-DC were compared using time-dependent receiver operating characteristic curves and time-dependent decision curves.The survival time was 23.1±15.8 months. Multivariate analysis identified age, CAR, LMR, and platelet count as prognostic independent risk factors. Kaplan-Meier analysis indicated that CAR of at least 1.0 (hazard ratio, 7.19; 95% confidence interval, 4.69-11.03), and LMR less than 1.9 (hazard ratio, 2.40; 95% confidence interval, 1.69-3.41) were independently associated with mortality of HBV-DC. The time-dependent receiver operating characteristic indicated that CAR showed the best performance in predicting mortality of HBV-DC compared with LMR, MELD score, and Child-Pugh score. The results were also confirmed by time-dependent decision curves.CAR and LMR were associated with the prognosis of HBV-DC. CAR was superior to LMR, MELD score, and Child-Pugh score in HBV-DC mortality prediction.

SummaryBackground Inflammation plays a vital role in liver cirrhosis progression and prognosis. Aim To investigate the prognostic significance of inflammatory response markers in decompensated cirrhotic patients without acute-on-chronic liver failure (ACLF). Methods Independent predictors were identified using multivariate Cox model and then assembled into a nomogram to predict survival. Concordance index (C-index) and time-dependent receiver operating characteristics (td-ROC) analysis were adopted to evaluate and compare the performance of nomogram, model for end-stage liver disease (MELD) scores, MELD-Na and Chronic Liver Failure-consortium score for acute decompensated (CLIF-C ADs). Results A total of 902 decompensated cirrhotic patients with different aetiologies were enrolled, with 6-month, 1-year and 3-year mortality of 18.6%, 24.4% and 34.8%, respectively. The cut-off values for neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) determined by X-tile program were 5.7 and 1.1 respectively. Patients with NLR>5.7 or LMR≤1.1 had significantly higher mortality (P

Background and Aim Determining individual risk of short-term mortality in patients with acute-on-chronic hepatitis B liver failure (ACHBLF) is a difficult task. We aimed to develop and externally validate a prognostic nomogram for ACHBLF patients. Methods The nomogram was built to estimate the probability of 30-day, 60-day, 90-day, and 60-month survival based on an internal cohort of 246 patients with ACHBLF. The predictive accuracy and discriminative ability of nomogram were determined by a concordance index (C-index), calibration curve, and time-dependent receiver operating characteristics (tdROC), comparing with model for end-stage liver disease (MELD) score. The results were validated using bootstrap resampling and an external cohort of 138 patients. Furthermore, we plotted decision curves to evaluate the clinical usefulness of nomogram. Results Independent factors derived from multivariable Cox analysis of training cohort to predict mortality were age, total bilirubin, serum sodium, and prothrombin activity, which were all assembled into nomogram. The calibration curves for probability of survival showed optimal agreement between nomogram prediction and actual observation. The C-index of nomogram was higher than that of MELD score for predicting survival (30-day, 0.809 vs 0.717, P

Background This study aimed to investigate whether human periodontal ligament (PDL) cells secrete pro-angiogenic factors that induce the vascularization of surrounding bone tissue under tensile stress. Methods Quantitative real-time PCR and Western blotting were used to analyze the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), Angiopoietin-I (Ang-I), connective tissue growth factor （CTGF）, and macrophage colony-stimulating factor (M-CSF) in PDL cells after tensile force treatments of different durations. Enzyme-linked immunosorbent assay was used to measure the VEGF concentration in the supernatants of cell cultures. Cell viability assay, wound healing assay, and tube formation assay were performed to evaluate the angiogenic behaviors of human umbilical vein endothelial cells (HUVECs). Results The mRNA expression and protein expression of VEGF, bFGF, Ang-I, and M-CSF was increased in the cells that received 6 to 48 hours of tensile force treatment. And, the VEGF level in the supernatant significantly increased in the human PDL cell cultures stressed for 6 to 48 hours. The abilities of HUVECs to proliferate, migrate, and form tubes were enhanced in media conditioned with tensile-stressed human PDL cells. Hence, tensile force induced human PDL cells to express and release pro-angiogenic factors enhancing the proliferation, migration, and angiogenic capacity of HUVECs. Conclusion Tensile stress induced human PDL cells to express and release pro-angiogenic factors, including VEGF, bFGF, Ang-I, and M-CSF, thereby enhancing the proliferation, migration, and angiogenic capacity of HUVECs.

BACKGROUND Postictal delirium (PID) is a relatively common complication following electroconvulsive therapy (ECT). OBJECTIVE We investigated whether prophylactic dexmedetomidine administration would safely decrease the incidence of PID in psychiatric patients after ECT. DESIGN A randomised, double-blind, placebo-controlled trial. PATIENTS A total of 223 patients undergoing ECT were randomly allocated to two groups. INTERVENTIONS Patients received 0.5 μg kg dexmedetomidine (Dex group, n=111) or 0.9% sodium chloride (Con group, n=112) before ECT. Propofol was used for anaesthesia and succinylcholine for muscle relaxation. The incidence of PID was measured using the Confusion Assessment Method for the Intensive Care Unit. MAIN OUTCOME MEASURES The percentage of patients who were diagnosed with PID at any ECT session during the whole treatment. RESULTS PID occurred in 76 (67.9%) of 112 patients given saline (0.9% sodium chloride), and in 49 (44.1%) of 111 patients given dexmedetomidine during the whole treatment. There was a significant difference in the incidence of PID between two groups (P

Neuropathic pain is a common, debilitating clinical issue. Here, the weighted gene co-expression network analysis (WGCNA) was used to identify the specific modules and hub genes that are related to neuropathic pain. The microarray dataset of a neuropathic rat model induced by tibial nerve transection (TNT), including dorsal root ganglion (DRG) tissues from TNT model (n=7) and sham (n=8) rats, was downloaded from the ArrayExpress database (E-MTAB-2260). The co-expression network modules were identified by the WGCNA package. The protein–protein interaction (PPI) network was constructed, and the node with highest level of connectivity in the network were identified as the hub gene. A total of 1739 genes and seven modules were identified. The most significant module was the brown module, which contained 215 genes that were primarily associated with the biological process (BP) of the defense response and molecular function of calcium ion binding. Furthermore, C–C motif chemokine ligand 2 (Ccl2), Fos and tissue inhibitor of metalloproteinase 1 (Timp1) which were identified as the hub genes in the PPI network and two subnetworks separately. The in vivo studies validated that mRNA and protein levels of Ccl2, Fos and Timp1 were up-regulated in DRG and spinal cord tissues after TNT. The present study offers novel insights into the molecular mechanisms of neuropathic pain in the context of peripheral nerve injury.

There is a lack of precise and clinical accessible model to predict the prognosis of hepatocellular carcinoma (HCC) in clinic practice currently. Here, an inclusive nomogram was developed by integrating genomic markers and clinicopathologic factors for predicting the outcome of patients with HCC. A total of 365 samples of HCC were obtained from the Cancer Genome Atlas (TCGA) database. The LASSO analysis was carried out to identify HCC-related mRNAs, and the multivariate Cox regression analysis was used to construct a genomic-clinicopathologic nomogram. As results, 9 mRNAs were finally identified as prognostic indicators, including RGCC, CDH15, XRN2, RAB3IL1, THEM4, PIF1, MANBA, FKTN and GABARAPL1, and used to establish a 9-mRNA classifier. Additionally, an inclusive nomogram was built up by combining the 9-mRNA classifier (P 0.001) and clinicopathologic factors including age (P = 0.006) and metastasis (P 0.001) to predict the mortality of HCC patients. Time-dependent receiver operating characteristic, index of concordance and calibration analyses indicated favorable accuracy of the model. Decision curve analysis suggested that appropriate intervention according to the established nomogram will bring net benefit when threshold probability was above 25%. The genomic-clinicopathologic model could be a reliable tool for predicting the mortality, helping determining the individualized treatment and probably improving HCC survival.

Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA‐143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir‐143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1‐mediated miRNA‐143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA‐143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA‐143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis.

Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in many autoimmune diseases. However, few studies have focused on the effects of MSCs on autoimmune hepatitis. In our study, we investigated the therapeutic effects of BMSCs (bone mesenchymal stem cells) transplantation in mouse experimental autoimmune hepatitis (EAH) and explored the potential mechanism. BMSCs were injected intravenously into EAH mice. Then, serum levels of ALT and AST, and pathologic alteration of liver tissue were measured to evaluate the liver function and inflammation degree. The expressions of programmed death ligand 1, IL-17 and IL-23 were detected by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting. Upon serum biochemical levels and pathological examination, the BMSCs-treated mice especially with multiple dosing administration showed significantly reduction of liver damage. Moreover, the expression of IL-17 was down-regulated by BMSCs intervention as compared to the model group, whereas the PD-L1 and IL-23 were up-regulated following the administration of MSCs. In conclusion, the results of this study suggest that BMSCs transplantation, especially on multiple dosing, may exert immunosuppression effect to ameliorate EAH through the inhibition of IL-17 and up-regulation of PD-L1.

Background Persistent and uncontrollable intracranial hypertension (ICH) and difficulty in reducing Cryptococcus count are severe problems in cryptococcal meningitis (CM) patients. The therapeutic effects of ventriculoperitoneal shunts (VPS) in non-HIV CM patients are not fully known, and the procedure is somewhat unusual. Here, our study offers a review to investigate the role of VPS in non-HIV CM. Methods We retrospectively collected data on 23 non-HIV CM patients with and without ventriculomegaly from 2010 to 2016. Their demographic data, clinical manifestations, cerebrospinal fluid (CSF) features and outcomes were analysed. Results We found that non-HIV CM patients without ventriculomegaly were older, had earlier treatment times and had shorter symptom durations than CM patients with ventriculomegaly. In both groups, headache, vomiting, fever and loss of vision were the most common clinical features. CSF pressure and Cryptococcus count were significantly decreased after operation. VPS could provide sustained relief from ICH symptoms such as headache. 13% of patients had poor outcomes because of serious underlying disease, while 87% of patients had good outcomes. Conclusions The use of a VPS is helpful in decreasing ICH and fungal overload in non-HIV CM patients, and VPS should be performed before CM patients present with symptoms of severe neurological deficit.