CD2AP is a potential prognostic biomarker of renal clear cell carcinoma.

BACKGROUND: CD2-associated protein (CD2AP) is a podocyte-associated gene and its reduced expression is associated with the development of proteinuria and glomerulosclerosis. However, few studies have focused on the correlation between the expression and prognosis of CD2AP in renal clear cell carcinoma (ccRCC). Therefore, we aimed to assess the regulation of CD2AP expression and prognostic value in ccRCC. METHODS: Multiple databases were employed to examine the expression of CD2AP in ccRCC. RT-qPCR, Western Blot and immunohistochemistry were used to validate CD2AP expression in different cell lines and tissue samples. Kaplan-Meier analysis and ROC curve analysis were performed on the predictive prognostic performance of CD2AP. COX regression was used to construct CD2AP-related prognostic models. The TIMER and TISIDB databases were used to analyze the correlation of tumor-infiltrating immune cells with gene expression, mutations, somatic copy number variation, and immune molecules. Mass spectrometry was used to detect methylation status of the promoter CpG site of CD2AP in multiple cells. RESULTS: We found that CD2AP expression was downregulated in ccRCC and its lower expression level was correlation with worse patient prognosis, higher tumor stage and grade and distant metastasis through analysis of databases, ccRCC cell lines and clinical tissue samples. Moreover, database and mass spectrometry techniques identified and validated cg12968598 hypermethylation as one of the key reasons for the downregulation of CD2AP expression. CD2AP expression was also associated with macrophage and neutrophil infiltration. CONCLUSIONS: Taken together, our results suggest that CD2AP can be used as a diagnostic and prognostic biomarker in ccRCC patients and that DNA hypermethylation plays an important role in reducing CD2AP expression.

Pan-cancer analysis identifies the IRF family as a biomarker for survival prognosis and immunotherapy.

IRF family genes have been shown to be crucial in tumorigenesis and tumour immunity. However, information about the role of IRF in the systematic assessment of pan-cancer and in predicting the efficacy of tumour therapy is still unknown. In this work, we performed a systematic analysis of IRF family genes in 33 tumour samples, including expression profiles, genomics and clinical characteristics. We then applied Single-Sample Gene-Set Enrichment Analysis (ssGSEA) to calculate IRF-scores and analysed the impact of IRF-scores on tumour progression, immune infiltration and treatment efficacy. Our results showed that genomic alterations, including SNPs, CNVs and DNA methylation, can lead to dysregulation of IRFs expression in tumours and participate in regulating multiple tumorigenesis. IRF-score expression differed significantly between 12 normal and tumour samples and the impact on tumour prognosis and immune infiltration depended on tumour type. IRF expression was correlated to drug sensitivity and to the expression of immune checkpoints and immune cell infiltration, suggesting that dysregulation of IRF family expression may be a critical factor affecting tumour drug response. Our study comprehensively characterizes the genomic and clinical profile of IRFs in pan-cancer and highlights their reliability and potential value as predictive markers of oncology drug efficacy. This may provide new ideas for future personalized oncology treatment.

Preoperative alpha fetoprotein, total bilirubin, fibrinogen, albumin, and lymphocytes predict postoperative survival in hepatocellular carcinoma.

AIMS: Our study focused on exploring the feasible prognostic laboratory parameters of HCC and establishing a score model to estimate individualized overall survival (OS) in HCC after resection. METHODS: Four hundred and sixty-one patients with HCC who underwent hepatectomy between January 2010 and December 2017 was enrolled in this investigation. Cox proportional hazards model was conducted to analyze the prognostic value of laboratory parameters. The score model construction was based on the forest plot results. Overall survival was evaluated by Kaplan-Meier method and the log-rank test. The novel score model was validated in an external validation cohort from a different medical institution. RESULTS: We identified that alpha fetoprotein (AFP), total bilirubin (TB), fibrinogen (FIB), albumin (ALB), and lymphocyte (LY) were independent prognostic factors. High AFP, TB, FIB (HR > 1, p < 0.05), and low ALB, LY (HR < 1, p < 0.05) were associated with the survival of HCC. The novel score model of OS based on these five independent prognostic factors achieved high C-index of 0.773 (95% confidence interval [CI]: 0.738-0.808), which was significantly higher than those of the single five independent factors (0.572-0.738). The score model was validated in the external cohort whose C-index was 0.7268 (95% CI: 0.6744-0.7792). CONCLUSION: The novel score model we established was an easy-to-use tool which could enable individualized estimation of OS in patients with HCC who underwent curative hepatectomy.

Effects of centrifugation prior to pneumatic tube system transport on routine biochemical and immunological tests of susceptibility to hemolysis.

BACKGROUND: Pneumatic tube system (PTS) may be associated with preanalytical hemolysis. The objective of this study was to evaluate the effects of PTS on biochemical and immunological tests susceptible to hemolysis and try to find ways to reduce the result bias caused by PTS. METHODS: Laboratory parameters were compared between PTS without centrifuging group, PTS after centrifuging group, PTS with serum group, and hand-delivered (HD) group. Studies were performed to access the influence of different PTS transport frequencies on laboratory assays. RESULTS: PTS transportation resulted in obviously increase in LDH (lactate dehydrogenase) and NSE (neuron-specific enolase) results (LDH: Bias = 17.95%, 95% confidence interval (CI) = -3.13-39.02; p < 0.001; NSE: Bias = 64.26%, 95% CI = -21.29-149.82; p < 0.001; respectively). After pre-centrifugation, no statistical difference was observed in LDH results (Bias = 2.83%, 95% CI = -13.00-18.65; p = 0.737). However, the bias of NSE still reach 19.16% (95% CI = -41.78-80.11), which exceeded the clinical acceptable range (p = 0.017). Both LDH(p = 0.931) and NSE(p > 0.999) show no statistical difference between PTS with serum group and HD group (LDH: Bias = -1.60%, 95% CI = -6.00-2.81; NSE: Bias = -3.68%, 95% CI = -11.35-3.99). CONCLUSION: PTS can lead to falsely increased LDH and NSE test results. Only loading the centrifuged upper serum in new tubes during PTS transport can eliminate the results bias of NSE.

Diagnostic Accuracy of Fecal Calprotectin for Predicting Relapse in Inflammatory Bowel Disease: A Meta-Analysis.

Fecal calprotectin (FC) levels correlate with the disease activity of inflammatory bowel diseases (IBD); however, the utility of FC in predicting IBD relapse remains to be determined. We aim to evaluate the efficacy of fecal calprotectin in predicting the relapse of inflammatory bowel disease. We searched Pubmed (MEDLINE), Embase, Web of Science, and the Cochrane library databases up to 7 July 2021. Our study estimated the pooled sensitivity and specificity, summary receiver operating characteristic (SROC) curve, and the optimal cut-off value for predicting IBD relapse using a multiple threshold model. A total of 24 prospective studies were included in the meta-analysis. The optimal FC cut-off value was 152 µg/g. The pooled sensitivity and specificity of FC was 0.720 (0.528 to 0.856) and 0.740 (0.618 to 0.834), respectively. FC is a useful, non-invasive, and inexpensive biomarker for the early prediction of IBD relapse. An FC value of 152 µg/g is an ideal threshold to identify patients with a high relapse probability.

NF-κB regulates the expression of STING via alternative promoter usage.

AIMS: Stimulator of interferon genes (STING) is a transmembrane protein in endoplasmic reticulum and plays crucial roles in autophagy, antiviral and anti-tumor responses. However, there are few studies on the transcriptional regulation mechanism of STING. MAIN METHODS: The 5' RACE experiment was used to determine the location of STING promoters. Luciferase reporting assay confirmed the activity and core region of STING internal promoter. Site-directed mutagenesis confirmed that NF-κB regulates the activity of STING promoters. The regulation of NF-κB on STING was investigated by real-time quantitative PCR, western blot, chromatin immunoprecipitation assay and lipopolysaccharide (LPS) inflammatory cell model. KEY FINDINGS: There was also a transcription start site at the 17 bp sequence upstream of STING second exon. STING-285 was the core region of the internal promoter. After NF-κB binding site mutation, the activity of STING internal promoter decreased significantly. In addition, we found that NF-κB can bind to the promoter region of wild-type STING. Overexpression of NF-κB significantly increased the activity of STING internal promoter and wild-type promoter, while knockdown of endogenous NF-κB significantly inhibited the activity of STING promoters. The binding of NF-κB to STING promoters in vivo were confirmed by chromatin immunoprecipitation assay. Meanwhile, we stimulated HeLa cells with LPS to activate the NF-κB pathway and found that STING expression was up-regulated. SIGNIFICANCE: These results suggest that transcription factor NF-κB positively regulates the expression of STING via alternative promoter usage. This provides a new basis and potential drug targets for the clinical treatment of STING related diseases.

Nomogram for preoperative estimation of histologic grade in gastrointestinal neuroendocrine tumors.

Background: The treatment strategies and prognosis for gastroenteropancreatic neuroendocrine tumors were associated with tumor grade. Preoperative predictive grading could be of great benefit in the selection of treatment options for patients. However, there is still a lack of effective non-invasive strategies to detect gastrointestinal neuroendocrine tumors (GI-NETs) grading preoperatively. Methods: The data on 147 consecutive GI-NETs patients was retrospectively collected from January 1, 2012, to December 31, 2019. Logistic regression was used to construct a predictive model of gastrointestinal neuroendocrine tumor grading using preoperative laboratory and imaging parameters.The validity of the model was assessed by area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). Results: The factors associated with GI-NETs grading were age, tumor size, lymph nodes, neuron-specific enolase (NSE), hemoglobin (HGB) and sex, and two models were constructed by logistic regression for prediction. Combining these 6 factors, the nomogram was constructed for model 1 to distinguish between G3 and G1/2, achieving a good AUC of 0.921 (95% CI: 0.884-0.965), and the sensitivity, specificity, accuracy were 0.9167, 0.8256, 0.8630, respectively. The model 2 was to distinguish between G1 and G2/3, and the variables were age, tumor size, lymph nodes, NSE, with an AUC of 0.847 (95% CI: 0.799-0.915), and the sensitivity, specificity, accuracy were 0.7882, 0.8710, 0.8231, respectively. Two online web servers were established on the basis of the proposed nomogram to facilitate clinical use. Both models showed an excellent calibration curve through 1000 times bootstrapped dataset and the clinical usefulness were confirmed using decision curve analysis. Conclusion: The model served as a valuable non-invasive tool for differentiating between different grades of GI-NETs, personalizing the calculation which can lead to a rational treatment choice.

Diagnostic Utility of Non-invasive Tests for Inflammatory Bowel Disease: An Umbrella Review.

Background: This study aims to consolidate evidence from published systematic reviews and meta-analyses evaluating the diagnostic performances of non-invasive tests for inflammatory bowel disease (IBD) in various clinical conditions and age groups. Methods: Two independent reviewers systematically identified and appraised systematic reviews and meta-analyses assessing the diagnostic utility of non-invasive tests for IBD. Each association was categorized as adults, children, and mixed population, based on the age ranges of patients included in the primary studies. We classified clinical scenarios into diagnosis, activity assessment, and predicting recurrence. Results: In total, 106 assessments from 43 reviews were included, with 17 non-invasive tests. Fecal calprotectin (FC) and fecal lactoferrin (FL) were the most sensitive for distinguishing IBD from non-IBD. However, anti-neutrophil cytoplasmic antibodies (ANCA) and FL were the most specific for it. FC and FL were the most sensitive and specific tests, respectively, to distinguish IBD from irritable bowel syndrome (IBS). Anti-Saccharomyces cerevisiae antibodies (ASCA), IgA, were the best test to distinguish Crohn's disease (CD) from ulcerative colitis (UC). Interferon-γ release assay was the best test to distinguish CD from intestinal tuberculosis (ITB). Ultrasound (US) and magnetic resonance enterography (MRE) were both sensitive and specific for disease activity, along with the high sensitivity of FC. Small intestine contrast ultrasonography (SICUS) had the highest sensitivity, and FC had the highest specificity for operative CD recurrence. Conclusion: In this umbrella review, we summarized the diagnostic performance of non-invasive tests for IBD in various clinical conditions and age groups. Clinicians can use the suggested non-invasive test depending on the appropriate clinical situation in IBD patients.

Construction and validation of a prognostic model for kidney renal clear cell carcinoma based on podocyte-associated genes.

BACKGROUND: As the most common renal malignancy, kidney renal clear cell carcinoma (KIRC) has a high prevalence and death rate as well as a poor response to treatment. Developing an efficient prognostic model is essential for accurately predicting the outcome and therapeutic benefit of KIRC patients. METHODS: Gene expression profiles of podocyte-associated genes (PAGs) were obtained from The Cancer Genome Atlas and GEO datasets. Cox regression and Lasso regression analyses were then used for filtering prognosis-associated PAGs. Risk score (RS) was computed from these genetic characteristics. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were applied for ascertaining the prognostic value. Stratified analysis was used to sufficiently validate model performance. Concordance index was used to compare the predictive ability of different models. Immuno-infiltration analysis and immunophenoscore were utilized for the prediction of patient reaction to immune checkpoint inhibitors (ICIs). RESULTS: WT1, ANLN, CUBN, OSGEP, and RHOA were significantly associated with KIRC prognosis. Prognostic analysis indicated that high-RS patients have a significantly poorer outcome. Cox regression analysis demonstrated a potential for RS to be an independent prognostic factor. Pathway enrichment results indicated a lower enrichment of cancer-related biological pathways in the low-RS subgroup. Immune infiltration analysis and IPS demonstrated greater responsiveness to ICIs in the high RS group. CONCLUSIONS: This podocyte-associated KIRC prognostic model can effectively predict KIRC prognosis and immunotherapy response, which may help to provide clinicians with more effective treatment strategies.

Development of Laboratory Parameters-Based Formulas in Predicting Short Outcomes for Adult Hemophagocytic Lymphohistiocytosis Patients with Different Underlying Diseases.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a severe disease with high mortality. The purpose of this investigation was to build models to predict 30-day death in total and subgroup HLH patients based on available and cheap laboratory parameters. METHOD: The research contained 431 adults HLH patients from January 2015 to September 2021 in the hospital. Logistic regression and receiver operating characteristic (ROC) were utilized to build models. RESULTS: Results suggested that age, ferritin, lymphocyte (LY), international normalized ratio (INR), thrombin time (TT), globulin, uric acid (UA), chloride, activated partial thromboplastin time (APTT), aspartate aminotransferase (AST), triglycerides (TG), total bilirubin (TB), and indirect bilirubin (IB) were independent factors in HLH and subgroups. Then, models adapted to patients with different underlying diseases were established based on these factors. Area under curve (AUC) of these models was excellent: HLH patients: 0.838 (p < 0.001); infection-associated HLH (I-HLH) patients: 0.913 (p < 0.001); malignancy-associated HLH (M-HLH): 0.921 (p < 0.001) and 0.809 (p < 0.001) for two or more different etiologies-associated HLH (Mix-HLH patients). In addition, UA, TT, and chloride were firstly confirmed as independent factors in adult HLH. CONCLUSION: Four models depending on biomarkers that available and affordable in clinical practice were built. With these models, high-risk patients with different underlying diseases could be easily identified.

Global prevalence of occult hepatitis B: A systematic review and meta-analysis.

The study aimed to investigate the prevalence and risk factors associated with occult hepatitis B virus (HBV) infection (OBI) in the global population. We searched PubMed, Embase, CINAHL, Cochrane and Web of Science from database inception through 27 Dec, 2018. Studies reporting HBV-DNA serological data in previously undiagnosed hepatitis B patients were included. The data were further categorized according to the presence of risk factors. After an initial screening of 2,325 records, we finally included 98 articles about the prevalence of OBI from 34 countries and regions. The OBI prevalence was 0.82% (95% CI:0.69-0.96) in the general population, 16.26% (95% CI:10.97-22.34) in HIV patients, 13.99% (95% CI:8.33-20.79) in patients with other liver diseases, 4.25% (95% CI:1.64-7.87) in haemodialysis patients and 5.14% (95% CI:2.26-9.01) patients with other risk factors. In conclusion, OBI prevalence varies significantly across different populations and nations, which deserve attention from the public health authorities. Our results generate further epidemiological data to identify the population with OBI, which has important clinical implications in finding these high-risk populations to design preventive and management strategies.

Identification of IRF-associated molecular subtypes in clear cell renal cell carcinoma to characterize immunological characteristics and guide therapy.

Background: Recently studies have identified a critical role for interferon regulatory factor (IRF) in modulating tumour immune microenvironment (TME) infiltration and tumorigenesis. Methods: Based on IRF1-9 expression profiles, we classified all ccRCC samples into three molecular subtypes (clusters A-C) and characterized the prognosis and immune infiltration of these clusters. IRFscore constructed by principal component analysis was performed to quantify IRF-related subtypes in individual patients. Results: We proved that IRFscore predicted multiple patient characteristics, with high IRFscore group having poorer prognosis, suppressed TME, increased T-cell exhaustion, increased TMB and greater sensitivity to anti- PD-1/CTLA-4 therapies. Furthermore, analysis of metastatic ccRCC (mccRCC) molecular subtypes and drug sensitivity proved that low IRFscore was more sensitive to targeted therapies. Moreover, IRFscore grouping can be well matched to the immunological and molecular typing of ccRCC. qRT-PCR showed differential expression of IRFs in different cell lines. Conclusions: Evaluating IRF-related molecular subtypes in individual ccRCC patients not only facilitates our understanding of tumour immune infiltration, but also provides more effective clinical ideas for personalised treatment.

Clinical utility of procalcitonin and its association with pathogenic microorganisms.

In this review, we summarize the relationship of PCT with pathogens, evaluate the clinical utility of PCT in the diagnosis of clinical diseases, condition monitoring and evaluation, and guiding medical decision-making, and explore current knowledge on the mechanisms by which pathogens cause changes in PCT levels. The lipopolysaccharides of the microorganisms stimulate cytokine production in host cells, which in turn stimulates production of serum PCT. Pathogens have different virulence mechanisms that lead to variable host inflammatory responses, and differences in the specific signal transduction pathways result in variable serum PCT concentrations. The mechanisms of signal transduction have not been fully elucidated. Further studies are necessary to ascertain the PCT fluctuation range of each pathogen. PCT levels are helpful in distinguishing between certain pathogens, in deciding if antibiotics are indicated, and in monitoring response to antibiotics.

5-Methylcytosine (m5C) Modification Patterns and Tumor Immune Infiltration Characteristics in Clear Cell Renal Cell Carcinoma.

Recently, studies have revealed the prognostic value of 5-methylcytosine (m5C) in clear cell renal cell carcinoma (ccRCC). However, the role of m5C methylation in ccRCC immune infiltration and the immunotherapeutic response remains unknown. Based on the mRNA expressions of 14 m5C regulators, we evaluated the m5C modification patterns of 530 tumor samples from the TCGA-ccRCC database. We used the principal component analysis (PCA) algorithm to construct individual patient m5Cscores to facilitate individual analysis of m5C modification patterns in ccRCC patients. We finally defined three different m5C modification patterns. Different clinical features and immune heterogeneity existed among the three patterns, and their immune infiltration characteristics could correspond to different immune phenotypes, including the immune-inflamed, immune-excluded, and immune-desert phenotype. We designed the m5Cscore calculated by the PCA algorithm to measure individual patients' m5C modification patterns. The low m5Cscore group presented with a positive prognosis, increased TMB, and immune activation. Additionally, low m5Cscore patients showed an increased response to immune checkpoint inhibitors. We further the value of the m5Cscore in predicting OS verified in four other tumor cohorts. Our findings revealed that m5C methylation modifications are essential in regulating ccRCC immune infiltration. Assessing single ccRCC patients' m5C modification patterns can fully improve our comprehension of tumor immune characteristics and be used to provide effective personalized immunotherapy strategies for clinical use.

Hepatitis D: challenges in the estimation of true prevalence and laboratory diagnosis.

Hepatitis delta virus (HDV) is a defective single negative chain RNA virus, as its envelope protein synthesis is dependent on hepatitis B virus (HBV). Studies have consistently shown that coinfection of HBV and HDV is the most serious form of viral hepatitis, with accelerated progression to liver cirrhosis and hepatocellular carcinoma. About 74 million of HBV surface antigen (HBsAg) positive patients worldwide are also co-infected with HDV. Besides, patients with intravenous drug use and high-risk sexual behavior are at higher risk of HDV infection. Therapeutic schedules for HDV are limited, and relapse of HDV has been observed after treatment with pegylated interferon alpha. To reduce the transmission of HDV, all people infected with HBV should be screened for HDV. At present, several serological and molecular detection methods are widely used in the diagnosis of HDV. However, due to the lack of international standards diagnostic results from different laboratories are often not comparable. Therefore, the true prevalence of HDV is still unclear. In this manuscript, we have analyzed various factors influencing the estimation of HDV prevalence. We have also discussed about the advantages and disadvantages of currently available HDV laboratory diagnostic methods, in order to provide some ideas for improving the detection of HDV.

Association of Serum Neuron-Specific Enolase and C-Reactive Protein With Disease Location and Endoscopic Inflammation Degree in Patients With Crohn's Disease.

Objective: The objective of this study was to explore the association between serum markers neuron-specific enolase (NSE) and C-reactive protein (CRP) with intestinal lesion location and degree of inflammation in patients with Crohn's disease (CD). Design: The levels of serum NSE, CRP, and fecal calprotectin (FC) in patients with CD were analyzed retrospectively. The severity of inflammatory lesions in the intestinal wall was accessed using the Simple Endoscopic Score for Crohn's disease (SES-CD). Results: The levels of NSE in patients with CD were higher than those of healthy individuals (14.87 vs. 12.68 ng/ml, P < 0.001). The levels of CRP in patients with CD were higher than those of healthy individuals (12.30 vs. 3.40 mg/l, P < 0.001). The FC levels in patients with CD were higher than those of patients with non-inflammatory bowel disease (1,143.90 vs. 114.21 µg/g, P < 0.05). The levels of NSE in CD with ileal lesions and simultaneous ileal and colon lesions were significantly higher than those in patients with CD with colonic lesions. However, the CRP was higher in patients with colonic lesions than those with ileal lesions. The levels of NSE in patients with severe inflammation were higher than those in patients with moderate inflammation (15.95 vs. 13.89 ng/ml, P < 0.05). Similarly, the NSE levels in patients with CD with severe inflammation were higher than those in patients with CD with mild inflammation (15.95 vs. 13.53 ng/mL, P < 0.05). The levels of CRP in severe inflammation were higher than those in moderate inflammation (29.80 vs. 19.60 mg/l, P < 0.05). In addition, the CRP levels in severe inflammation were higher than those in mild inflammation (29.80 vs. 5.86 mg/l, P < 0.05). ROC curve analysis showed that when NSE was combined with CRP for distinguishing between patients with CD and those without CD, sensitivity increased to 80.41%, specificity increased to 74.66%, and a highest AUC was equal to 0.843. Conclusion: Our study shows that serum NSE and CRP can be used to assess the severity of CD as well as the location of intestinal involvement. Therefore, NSE and CRP could be used as the non-invasive tests in detecting the location and severity of disease in patients with CD in daily routine practice.

STING and liver disease.

STING (stimulator of interferon genes) also known as transmembrane protein 173 (TMEM173) is a cytoplasmic DNA sensor which can be activated by the upstream cyclic dinucleotides (CDNs). This activation produces cytokines such as interferons and pro-inflammatory factors via the downstream IRF3 and NF-κB pathways, triggering an innate immune response and adaptive immunity to maintain homeostasis. STING is mainly expressed and activated in non-parenchymal cells, thus exerting a corresponding effect to maintain the homeostasis of the liver. In viral hepatitis, interferons and pro-inflammatory factors produced after STING activation initiate the immune response to inhibit virus replication and assembly. In the case of metabolic diseases of the liver, the activation of STING in kupffer cells and hepatic stellate cells leads to inflammation, the proliferation of connective tissue, and metabolic disorders in the hepatocytes, promoting the occurrence and development of the disease. In hepatocellular carcinoma, STING has two contradictory roles. When STING is activated in dendritic cells and macrophages, a large number of cytokines can be produced to initiate innate immune effects directly and to exert adaptive immunity through the recruitment and activation of T cells; however, aberrant activation of the STING pathway leads to a weakening of immune function and promotes oncogenesis and metastasis. Here, we summarize the interactions between STING and liver disease that have currently been identified and how to achieve therapeutic goals by modulating the activity of the STING pathway.

Development and Validation of Novel Nomograms Using Serum Tumor Markers for the Prediction of Preoperative Histologic Grades in Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: To develop and validate nomogram models for the preoperatively prediction of the histologic grade of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to provide appropriate treatments. METHODS: A total of 1014 participants, including 211 healthy controls, 293 patients with benign diseases, 299 patients with cancers, and 211 patients with GEP-NETs were included in the final analysis. Their sociodemographic and laboratory information, including serum tumor markers such as AFP, CEA, CA19-9, CA72-4, Cyfra21-1 and NSE were collected. Nomogram models were developed to preoperatively predict histologic grades of GEP-NETs. RESULTS: Among six serum tumor markers, only NSE was found to have a statistically significant association with the histologic grades in GEP-NETs (G1 vs. G2: p < 0.05; G2 vs. G3: p < 0.001; G1 vs. G3: p < 0.0001), which was combined with sex and age to develop the nomogram models. The first nomogram (to differentiate grade 1(G1) and grade 2/3 tumor (G2/G3)) showed a strong association to differentiate with an AUC of 0.747 (95% CI: 0.663-0.832) and 0.735 (95% CI: 0.624-0.847) in the training and validation datasets, respectively. The second nomogram (to differentiate G1/G2 and G3 tumors) showed a strong association to differentiate with an AUC of 0.827 (95% CI: 0.744-0.911) and 0.847 (95% CI: 0.744-0.950) in the training and validation datasets, respectively. The ROC, area under ROC curve (AUC), calibration curve and decision curve analysis (DCA) demonstrated the clinical usefulness of both models. CONCLUSIONS: We proposed two novel nomogram models based on sex, age and serum NSE levels to preoperatively predict the histologic grades in GEP-NETs to assist the clinical decision-making.

Association of Rotavirus Vaccines With Reduction in Rotavirus Gastroenteritis in Children Younger Than 5 Years: A Systematic Review and Meta-analysis of Randomized Clinical Trials and Observational Studies.

Importance: Rotavirus vaccines have been introduced worldwide, and the clinical association of different rotavirus vaccines with reduction in rotavirus gastroenteritis (RVGE) after introduction are noteworthy. Objective: To evaluate the comparative benefit, risk, and immunogenicity of different rotavirus vaccines by synthesizing randomized clinical trials (RCTs) and observational studies. Data Sources: Relevant studies published in 4 databases: Embase, PubMed, the Cochrane Library, and Web of Science were searched until July 1, 2020, using search terms including "rotavirus" and "vaccin*." Study Selection: Randomized clinical trials and cohort and case-control studies involving more than 100 children younger than 5 years that reported the effectiveness, safety, or immunogenicity of rotavirus vaccines were included. Data Extraction and Synthesis: A random-effects model was used to calculate relative risks (RRs), odds ratios (ORs), risk differences, and 95% CIs. Adjusted indirect treatment comparison was performed to assess the differences in the protection of Rotarix and RotaTeq. Main Outcomes and Measures: The primary outcomes were RVGE, severe RVGE, and RVGE hospitalization. Safety-associated outcomes involved serious adverse events, intussusception, and mortality. Results: A meta-analysis of 20 RCTs and 38 case-control studies revealed that Rotarix (RV1) significantly reduced RVGE (RR, 0.316 [95% CI, 0.224-0.345]) and RVGE hospitalization risk (OR, 0.347 [95% CI, 0.279-0.432]) among children fully vaccinated; RotaTeq (RV5) had similar outcomes (RVGE: RR, 0.350 [95% CI, 0.275-0.445]; RVGE hospitalization risk: OR, 0.272 [95% CI, 0.197-0.376]). Rotavirus vaccines also demonstrated higher protection against severe RVGE. Additionally, no significant differences in the protection of RV1 and RV5 against rotavirus disease were noted in adjusted indirect comparisons. Moderate associations were found between reduced RVGE risk and Rotavac (RR, 0.664 [95% CI, 0.548-0.804]), Rotasiil (RR, 0.705 [95% CI, 0.605-0.821]), and Lanzhou lamb rotavirus vaccine (RR, 0.407 [95% CI, 0.332-0.499]). All rotavirus vaccines demonstrated no risk of serious adverse events. A positive correlation was also found between immunogenicity and vaccine protection (eg, association of RVGE with RV1: coefficient, -1.599; adjusted R2, 99.7%). Conclusions and Relevance: The high protection and low risk of serious adverse events for rotavirus vaccines in children who were fully vaccinated emphasized the importance of worldwide introduction of rotavirus vaccination. Similar protection provided by Rotarix and RotaTeq relieves the pressure of vaccines selection for health care authorities.

Epidemiology estimates of hepatitis D in individuals co-infected with human immunodeficiency virus and hepatitis B virus, 2002-2018: A systematic review and meta-analysis.

Hepatitis delta virus (HDV) is an obligate satellite of hepatitis B virus (HBV). HIV/HDV co-infection is associated with a high rate of hepatic decompensation events and death. We aimed to characterize the epidemiology of HDV infection in HIV/HBV co-infected individuals. We systematically searched PubMed, Embase, Cochrane Library, Web of Science, CINAHL and Scopus for studies published from 1 Jan 2002 to 7 May 2018 measuring prevalence of HDV among the HIV population. Pooled seroprevalence was calculated with the DerSimonian-Laird random-effects model. Our search returned 4624 records, 38 of which met the inclusion and exclusion criteria. These studies included data for 63 cohorts from 18 countries and regions. The overall HDV seroprevalence of HIV-infected individuals was 1.03% (95% CI 0.43-1.85) in 2002-2018 globally. Moreover, the estimated pooled HDV seroprevalence among the general population was 1.07% (95% CI 0.65-1.59) in 2002-2018, which was not significantly different from the HDV seroprevalence of individuals living with HIV (p = 0.951). The overall HDV seroprevalence of the HBsAg positive population was 12.15% (95% CI 10.22-14.20), p = 0.434 when compared with the corresponding data of HIV/HBV co-infected individuals. This meta-analysis suggested that there was no difference between the HDV seroprevalence in HIV-infected individuals and the general population.