The mode and timing of administrating nutritional treatment of critically ill elderly patients in intensive care units: a multicenter prospective study.

Introduction: Critically ill patients are more susceptible to malnutrition due to their severe illness. Moreover, elderly patients who are critically ill lack specific nutrition recommendations, with nutritional care in the intensive care units (ICUs) deplorable for the elderly. This study aims to investigate nutrition treatment and its correlation to mortality in elderly patients who are critically ill in intensive care units. Method: A multiple-center prospective cohort study was conducted in China from 128 intensive care units (ICUs). A total of 1,238 elderly patients were included in the study from 26 April 2017. We analyzed the nutrition characteristics of elderly patients who are critically ill, including initiated timing, route, ways of enteral nutrition (EN), and feeding complications, including the adverse aspects of feeding, acute gastrointestinal injury (AGI), and feeding interruption. Multivariate logistic regression analysis was used to screen out the impact of nutrition treatment on a 28-day survival prognosis of elderly patients in the ICU. Result: A total of 1,238 patients with a median age of 76 (IQR 70-83) were enrolled in the study. The Sequential Organ Failure (SOFA) median score was 7 (interquartile range: IQR 5-10) and the median Acute Physiology and Chronic Health Evaluation (APACHE) II was 21 (IQR 16-25). The all-cause mortality score was 11.6%. The percentage of nutritional treatment initiated 24 h after ICU admission was 58%, with an EN of 34.2% and a parenteral nutrition (PN) of 16.0% in elderly patients who are critically ill. Patients who had gastrointestinal dysfunction with AGI stage from 2 to 4 were 25.2%. Compared to the survivors' group, the non-survivors group had a lower ratio of EN delivery (57% vs. 71%; p = 0.015), a higher ratio of post-pyloric feeding (9% vs. 2%; p = 0.027), and higher frequency of feeding interrupt (24% vs. 17%, p = 0.048). Multivariable logistics regression analysis showed that patients above 76 years old with OR (odds ratio) 2.576 (95% CI, 1.127-5.889), respiratory rate > 22 beats/min, and ICU admission for 24 h were independent risk predictors of the 28-day mortality study in elderly patients who are critically ill. Similarly, other independent risk predictors of the 28-day mortality study were those with an OR of 2.385 (95%CI, 1.101-5.168), lactate >1.5 mmol/L, and ICU admission for 24 h, those with an OR of 7.004 (95%CI, 2.395-20.717) and early PN delivery within 24 h of ICU admission, and finally those with an OR of 5.401 (95%CI, 1.175-24.821) with EN delivery as reference. Conclusion: This multi-center prospective study describes clinical characteristics, the mode and timing of nutrition treatment, frequency of AGI, and adverse effects of nutrition in elderly ICU patients. According to this survey, ICU patients with early PN delivery, older age, faster respiratory rate, and higher lactate level may experience poor prognosis.

Decoding molecular signature on heart of septic mice with distinct left ventricular ejection fraction.

Dysregulated cardiac function after sepsis in intensive care unit is known to predict poor long-term outcome and increase mortality. Their pathological feature and molecular mechanism remain unclear. We observed that septic patients with depressed left ventricular ejection fraction (LVEF) have the highest in-hospital and 28 days mortality comparing to patients with hyperdynamic LVEF or with heart failure with preserved LVEF. Echocardiograms reveal that survivors post cecum ligation and puncture (CLP) on rodents have stable LVEF and non-survivors have fluctuated LVEF at CLP early phase. CLP-induced mice fall into three groups based on LVEF 24 h post-surgery: high-, low-, and normal-LVEF. Transcriptomic and proteomic analyses identify jointly and distinctively changed genes, proteins and biologically essential pathways in left ventricles from three CLP groups. Notably, transmission electron microscopy shows different mitochondrial and sarcomere defects associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury.

Development of a nomogram model for the early prediction of sepsis-associated acute kidney injury in critically ill patients.

Sepsis-associated acute kidney injury is a common complication of sepsis, but it is difficult to predict sepsis-associated acute kidney injury. In this retrospective observational study, adult septic patients were recruited from the MIMIC-III database as the training cohort (n = 4764) and from Xiangya Hospital (n = 1568) and Zhang's database as validation cohorts. We identified eleven predictors with seven independent risk predictors of sepsis-associated acute kidney injury [fluid input_day1 ≥ 3390 ml (HR hazard ratio 1.42), fluid input_day2 ≥ 2734 ml (HR 1.64), platelet_min_day5 ≤ 224.2 × 109/l (HR 0.86), length of ICU stay ≥ 2.5 days (HR 1.24), length of hospital stay ≥ 5.8 days (HR 1.18), Bun_max_day1 ≥ 20 mmol/l (HR 1.20), and mechanical ventilation time ≥ 96 h (HR 1.11)] by multivariate Cox regression analysis, and the eleven predictors were entered into the nomogram. The nomogram model showed a discriminative ability for estimating sepsis-associated acute kidney injury. These results indicated that clinical parameters such as excess input fluid on the first and second days after admission and longer mechanical ventilation time could increase the risk of developing sepsis-associated acute kidney injury. With our study, we built a real-time prediction model for potentially forecasting acute kidney injury in septic patients that can help clinicians make decisions as early as possible to avoid sepsis-associated acute kidney injury.

Ferroptosis-mediated immune responses in cancer.

Cell death is a universal biological process in almost every physiological and pathological condition, including development, degeneration, inflammation, and cancer. In addition to apoptosis, increasing numbers of cell death types have been discovered in recent years. The biological significance of cell death has long been a subject of interest and exploration and meaningful discoveries continue to be made. Ferroptosis is a newfound form of programmed cell death and has been implicated intensively in various pathological conditions and cancer therapy. A few studies show that ferroptosis has the direct capacity to kill cancer cells and has a potential antitumor effect. As the rising role of immune cells function in the tumor microenvironment (TME), ferroptosis may have additional impact on the immune cells, though this remains unclear. In this study we focus on the ferroptosis molecular network and the ferroptosis-mediated immune response, mainly in the TME, and put forward novel insights and directions for cancer research in the near future.

The Hyperbilirubinemia and Potential Predictors Influence on Long-Term Outcomes in Sepsis: A Population-Based Propensity Score-Matched Study.

Objective: Although hyperbilirubinemia has been associated with mortality in patients who are critically ill, yet no clinical studies dissect the effect of dynamic change of hyperbilirubinemia on long-term septic prognosis. The study aims to investigate the specific stages of hyperbilirubinemia and potential risk factors on long-term outcomes in patients with sepsis. Methods: In this retrospective observational cohort study, patients with sepsis, without previous chronic liver diseases, were identified from the Medical Information Mart for the Intensive Care III MIMIC-III database. We used propensity scores (PS) to adjust the baseline differences in septic patients with hyperbilirubinemia or not. The multivariate Cox was employed to investigate the predictors that influence a clinical outcome in sepsis. Results: Of 2,784 patients with sepsis, hyperbilirubinemia occurred in 544 patients (19.5%). After PS matching, a survival curve demonstrated that patients with sepsis with the new onset of total bilirubin (TBIL) levels more than or equal to 5 mg/dl survived at significantly lower rates than those with TBIL levels <5 mg/dl. Multivariate Cox hazard analysis showed that patients with TBIL at more than or equal to 5 mg/dl during sepsis exhibit 1.608 times (95% CI: 1.228-2.106) higher risk of 1-year mortality than those with TBIL levels <5 mg/dl. Also, age above 65 years old, preexisting malignancy, a respiratory rate above 30 beats/min at admission, serum parameters levels within 24-h admission, containing international normalized ratio (INR) above 1.5, platelet <50*10∧9/L, lactate above 4 mmol/L, and bicarbonate <22 or above 29 mmol/L are the independent risk factors for long-term mortality of patients with sepsis. Conclusions: After PS matching, serum TBIL levels at more than or equal to 5 mg/dl during hospitality are associated with increased long-term mortality for patients with sepsis. This study may provide clinicians with some cutoff values for early intervention, which may improve the prognosis of patients with sepsis.

Depressive and Anxiety Symptoms of Healthcare Workers in Intensive Care Unit Under the COVID-19 Epidemic: An Online Cross-Sectional Study in China.

Background: Since the coronavirus disease-2019 (COVID-19) outbreak, intensive care unit (ICU) healthcare workers were responsible for the critical infected patients. However, few studies focused on the mental health of ICU healthcare workers. This study aimed to investigate the psychological impact of COVID-19 on ICU healthcare workers in China. Methods: We distributed the nine-item Patient Health Questionnaire (PHQ-9) and seven-item General Anxiety Disorder questionnaire (GAD-7) online to ICU healthcare workers in China. Respondents were divided into frontline and second-line according to whether they have contact with COVID-19 patients. Depressive and anxiety symptoms of all respondents were evaluated based on their questionnaire scores. Results: There were 731 ICU healthcare workers finally enrolled in our study, including 303 (41.5%) male, 383 (52.4%) doctors, and 617 (84.4%) aged 26-45 years. All in all, 482 (65.9%) ICU healthcare workers reported symptoms of depression, while 429 (58.7%) reported anxiety. There was no significant difference between frontline (n = 325) and second-line (n = 406) respondents in depression (P = 0.15) and anxiety severity (P = 0.56). Logistic regression analysis showed that being female, ICU work time >5 years, and night duty number ≥10 were risk factors of developing depressive and anxiety symptoms. Income reduction was separately identified as risk of anxiety. Additionally, ICU work time >5 years was also identified as risk of developing moderate-severe depressive and anxiety symptoms. Conclusions: Frontline ICU work was not associated with higher risk of depressive and anxiety symptoms during COVID-19 pandemic remission period in China. Actions like controlling night duty number, ensuring vacation, and increasing income should be taken to relieve mental health problem. Furthermore, we should pay close attention to those who had worked long years in ICU.

Candidemia indicates poor outcome in patients with infected pancreatic necrosis.

BACKGROUND: Intra-abdominal fungal infection (AFI) and candidemia are common in patients with acute pancreatitis (AP), but with limited and conflicting reports on their clinical impacts. This study aims to evaluate the clinical impacts of AFI and candidemia in infected pancreatic necrosis (IPN). METHODS: A single-centre, prospective cohort including 235 consecutive patients with IPN between January 2010 and September 2020 was analysed to study the clinical impacts of AFI and candidemia. RESULTS: Of the 235 patients with IPN, 69 patients (29.4%) developed AFI and 13 patients (5.5%) developed candidemia. AFI was associated with higher intestinal leakage rate (27.5% vs 12.7%, P = .006), higher pancreatic fistula rate (53.6% vs 34.3%, P = .006) and longer hospital stays (72 vs 58 days, P = .003), but with similar mortality rate compared with patients without AFI (23.2% vs 24.7%, P = .806). However, candidemia was associated with significantly higher mortality rate compared with patients without candidemia (69.2% vs 21.6%, P < .001). Patients with candidemia had higher rate of multiple organ failure and AFI (69.2% vs 36.5%, P = .018; 69.2% vs 27.0%, P = .001, respectively). Multivariable analysis showed that age ≥ 50 years (OR = 2.8; 95% CI, 1.3-5.8; P = .007), severe category (OR = 11.2; 95% CI, 3.5-35.7; P < .001), multidrug-resistant organisms infection (OR = 2.5; 95% CI, 1.0-6.2; P = .039), candidemia (OR = 11.8; 95% CI, 2.5-56.5; P = .002), step-down surgical approach (OR = 3.2; 95% CI, 1.5-7.0; P = .004) were the independent predictors associated with higher mortality in IPN patients. CONCLUSION: Although AFI did not increase the mortality of IPN, patients with candidemia carried significantly higher mortality.

Early Hemoglobin Status as a Predictor of Long-Term Mortality for Sepsis Patients in Intensive Care Units.

OBJECTIVES: It is still not clear what influences hemoglobin has on the outcomes of patients with sepsis. The intention of this research is to investigate the impact of early hemoglobin levels on clinical outcomes for sepsis. METHODS: In this single-center, cohort study, each patient was put into one of four groups dependent on hemoglobin levels of 70 g/L, 80 g/L, or 90 g/L in the first 48 h of being admitted to intensive care unit (ICU). Adjustments for baseline/confounding factors were made using the multiple Cox regression model. RESULTS: In all, 235 septic patients were examined in this research. The non-survivors exhibited significantly higher levels for early hemoglobin status at or below 80 g/L (33.7% vs. 19.4%, P = 0.016) than survivors. Survival curve demonstrated that septic patients with early hemoglobin levels at or below 80 g/L survived at significantly lower rates than those with hemoglobin above 80 g/L. Multivariate Cox analysis demonstrated that levels of 1-year mortality rose as early hemoglobin levels fell in the first 48 h after ICU admission, with relative risks for 80 g/L to 90 g/L, 70 g/L to 80 g/L, and at or below 70 g/L being respectively 1.11 (95% CI: 0.654-1.882), 1.742 (95% CI: 0.969-3.133), 1.981 (95% CI: 1.124-3.492) times higher than those for hemoglobin levels above 90 g/L. CONCLUSIONS: Hemoglobin levels at or below 80 g/L in the first 48 h after ICU admission are an alternative indicator for predicting long-term mortality of sepsis. Awareness should be encouraged of the importance of targeting early hemoglobin levels when treating sepsis to improve prognosis.

Care for Critical Ill Patients With COVID-19: Establishment of a Temporary Intensive Care Unit in an Isolated Hospital.

The current global spread of COVID-19, a highly contagious disease, has challenged healthcare systems, and placed immense burdens on medical staff globally. With a sharp increase in the number of newly confirmed cases and the rapid progression of the disease into a critically ill state, overstretched critical care units have had to contend with a shortage of beds, specialist personnel, and medical resources. Temporary intensive care units (ICUs) were therefore set up in isolated hospitals to provide the required standardized care for all severe cases. The current paper describes the authors' experience of setting up and managing such an ICU in Wuhan, Hubei Province, China, from the identification of critically ill COVID-19 patients through to the arranging and equipping of the unit, providing training and protection for staff, and standardizing all aspects of care.

Nomogram to predict the risk of septic acute kidney injury in the first 24 h of admission: an analysis of intensive care unit data.

Background: Acute kidney injury (AKI) is a significant cause of morbidity and mortality, especially in sepsis patients. Early prediction of AKI can help physicians determine the appropriate intervention, and thus, improve the outcome. This study aimed to develop a nomogram to predict the risk of AKI in sepsis patients (S-AKI) in the initial 24 h following admission.Methods: Sepsis patients with AKI who met the Sepsis 3.0 criteria and Kidney Disease: Improving Global Outcomes criteria in the Massachusetts Institute of Technology critical care database, Medical Information Mart for Intensive Care (MIMIC-III), were identified for analysis. Data were analyzed using multiple logistic regression, and the performance of the proposed nomogram was evaluated based on Harrell's concordance index (C-index) and the area under the receiver operating characteristic curve.Results: We included 2917 patients in the analysis; 1167 of 2042 patients (57.14%) and 469 of 875 patients (53.6%) had AKI in the training and validation cohorts, respectively. The predictive factors identified by multivariate logistic regression were blood urea nitrogen level, infusion volume, lactate level, weight, blood chloride level, body temperature, and age. With the incorporation of these factors, our model had well-fitted calibration curves and achieved good C-indexes of 0.80 [95% confidence interval (CI): 0.78-0.82] and 0.79 (95% CI: 0.76-0.82) in predicting S-AKI in the training and validation cohorts, respectively.Conclusion: The proposed nomogram effectively predicted AKI risk in sepsis patients admitted to the intensive care unit in the first 24 h.

[Clinical analysis of sepsis with extensively drug resistant Gram-negative bacteria in intensive care unit treated with polymyxin B-based combination therapy].

OBJECTIVE: To investigate the clinical efficacy and safety of polymyxin B in the treatment of sepsis caused by extensively-drug resistant (XDR) Gram-negative bacteria. METHODS: A retrospective analysis of 39 septic patients with XDR Gram-negative bacterial infection treated with polymyxin B in the department of critical care medicine of Xiangya Hospital of Central South University from June 2018 to September 2019 were enrolled. The clinical characteristics, bacterial culture, the sensitivity antibacterial drugs, types and courses of antibiotics, biochemical indexes, and acute physiology and chronic health evaluation II (APACHE II) before and after polymyxin B treatment were collected, to assess microbial clearance and efficacy, drug related adverse effects, and 28-day mortality in septic patients with XDR. RESULTS: Of the 39 septic patients with XDR, 32 (82.1%) were male, with the mean age of (53.6±12.6) years old. The main infection site was pulmonary infection (51.2%), and the treatment courses of polymyxin B were ≥ 5 days. A total of 66 pathogenic bacteria were detected from 39 patients. Among them, with the high estrate of detecting Acinetobacter baumannii of 51.5% (34/66). After treatment with polymyxin B, the results showed that the clearance rate of microorganisms was 65.2% (43/66), the overall effective rate was 59.0% (23/39), and the 28-day all-cause mortality was 41.0% (16/39). There were no significant differences in clinical efficacy and microbial clearance among patients with different treatment groups of polymyxin B [< 10 days, 10-15 days, and > 15 days groups: effective rates were 56.5% (13/23), 54.5% (6/11), 80.0% (4/5), χ 2 = 0.999, P = 0.728; the microbial clearance rates were 43.5% (10/23), 54.5% (6/11), and 80.0% (4/5), χ 2 = 2.141, P = 0.393]. The effective and microbial clearance rates of the polymyxin B daily doses of 150 mg and 200 mg groups were significantly higher than those of the daily dose of 100 mg [effectiveness: 85.7% (6/7), 87.5% (7/8) vs. 41.7% (10/24); microbial clearance rate: 71.4% (5/7), 87.5% (7/8) vs. 33.3% (8/24), all P < 0.05], however, there were no significant differences in the length of intensive care unit (ICU) stay and mechanical ventilation time among different daily dose groups. The APACHE II score after polymyxin B administration was significantly lower than before administration (all patients: 16.20±9.24 vs. 24.40±4.73, effective patients: 11.30±4.08 vs. 23.00±4.56, both P < 0.05). Four patients with renal injury had an increase in serum creatinine during the administration of polymyxin B, and recovered after discontinuation of the drug without other adverse reactions. CONCLUSIONS: Polymyxin B can be used as an effective treatment option for patients with severe infection of XDR Gram-negative bacteria.

Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: A meta-analysis.

OBJECTIVE: Compelling evidence has shown that aggressive resuscitation bundles are one of the cornerstones of the successful treatment of patients with sepsis. Recent studies suggest that lactate normalization during resuscitation is a more powerful indicator of resuscitative adequacy; however, early lactate clearance-guided therapy is still not recommended. We performed this meta-analysis to evaluate the effect of early lactate clearance-directed therapy as a potentially more effective resuscitation target. METHODS: Studies were identified using PubMed, Embase, and the Cochrane Library without region, publication type, or language restrictions. Randomized trials were included when they compared the efficacy and safety of lactate clearance-guided resuscitation versus central venous oxygen saturation (ScvO2)-guided therapy. The primary outcome was mortality, and the secondary outcomes were intensive care unit (ICU) stay, length of hospital stay, mechanical ventilation time, Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score, and Sepsis-related Organ Failure Assessment (SOFA) score. RESULTS: Seven randomized controlled trials encompassing 1301 cases were reviewed. Compared with guided ScvO2 therapy, early lactate clearance-directed therapy was associated with decreased in-hospital mortality (relative ratio [RR] 0.68, 95% confidence interval [CI] 0.56 to 0.82), shorter ICU stay (mean difference [MD] -1.64 days, 95% CI -3.23 to -0.05), shorter mechanical ventilation time (MD -10.22 hours, 95% CI -15.94 to -4.5), and lower APACHE-II scores (MD -4.47, 95% CI -7.25 to -1.69). However, patients undergoing early lactate clearance-guided therapy had similar lengths of hospital stay and similar SOFA scores. CONCLUSIONS: As a specific indicator of resuscitation outcome, lactate clearance alone is superior to ScvO2 alone during a standard resuscitation paradigm. The optimal or desired rate of lactate clearance is still a contentious area. To guide resuscitation and normalize lactate levels in patients, repeating lactate measurements every 2 hours until the patient has met a lactate clearance of 10% or greater may be helpful. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018100515.

Meta-Analysis of Early Enteral Nutrition Provided Within 24 Hours of Admission on Clinical Outcomes in Acute Pancreatitis.

BACKGROUND: Enteral nutrition (EN) is more beneficial than parenteral nutrition (PN) in reducing organ failure, infectious complications, and mortality of acute pancreatitis (AP), but its timing is controversial. We attempted to evaluate the safety and clinical outcomes of early EN within 24 hours of admission in patients with AP, especially in predicted severe or severe acute pancreatitis (SAP). METHODS: We searched PubMed, EMBASE Databases, Web of Science, and the Cochrane Library for relevant articles before June 2016 using RevMan 5.2 software. RESULTS: Eight studies containing 727 patients with AP were analyzed in the meta-analysis. Comparing early EN to late EN or total parental nutrition in AP, the odds ratios (OR) were 0.56 (95% CI 0.23 -1.34) for the risk of mortality, 0.40 (95% CI 0.20-0.79) for multiple organ failure, 0.57 (95% CI 0.23-1.42) for infectious complications, 0.45 (95% CI 0.17-1.21) for adverse events, and 0.83 (95% CI 0.59-1.18) for pancreatic-related infections. Furthermore, subgroup analysis for early EN in predicted severe or SAP showed a significant reduction in multiple organ failure (OR 0.30; 95% CI 0.09-0.96) and pancreatic-related infections (OR 0.51, 95% CI 0.29-0.88). Early EN provided no benefits for mild to moderate AP. CONCLUSION: Early EN within 24 hours of admission is safe and provides benefits for predicted severe or SAP, but not for mild to moderate pancreatitis.

Differences in IP­10, TLR4 and IRF5/3 between SVR and non­SVR HCV­1 patients treated with PEG­IFN and ribavirin.

The present study aimed to investigate alterations in Toll­like receptor 4 (TLR4), interferon regulatory factor 5 (IRF5) and interferon­Î³­inducible protein­10 (IP­10), and evaluate whether these factors may be associated with a sustained virological response (SVR) among patients with hepatitis C virus genotype­1 (HCV­1) who were treated with peginterferon plus ribavirin (PEG­IFN­RBV). A total of 31 Chinese patients infected with HCV­1 were enrolled in the present study and 25 patients obtained SVR. The expression levels of IP­10 declined significantly during PEG­IFN­RBV therapy at the 24 and 48 week time­points, compared with the baseline (P<0.005, 0.001 and 0.001, respectively). In addition, it was observed that IRF5 mRNA expression and the number of TLR4+ peripheral blood mononuclear cells exhibited similar correlations with IP­10 concentration (R2=0.0726, P=0.001, R2=0.1634, P<0.0001, respectively) in the SVR group patients; however, these correlations were not observed to be present in the non­SVR group patients. In conclusion, the results of the present study suggest that marked alterations in IP­10, TLR4 and IRF5 expression may serve as indicators for the development of SVR in patients with HCV­1 treated with PEG­IFN­RBV.

HIV Vpr protein upregulates microRNA-122 expression and stimulates hepatitis C virus replication.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection is characterized by higher serum HCV RNA loads compared with HCV mono-infection. However, the relationship between HIV and HCV replication remains to be clarified. HIV Vpr has been shown to play an essential role in HIV replication. In this study, we aimed to explore the role of Vpr in HCV replication and pathogenesis. We therefore used the genotype 2a full-length HCV strain JFH1 infection system and the genotype 1b full-length HCV replicon OR6 cell line to analyse the effects of Vpr on HCV replication. We found that Vpr promoted HCV 5' UTR activity, HCV RNA replication and HCV protein expression in two HCV infection cell models. Additionally, lymphocyte-produced Vpr significantly induced HCV 5' UTR activity and HCV replication in hepatocytes. We also found that Vpr upregulated the expression of miR-122 by stimulating its promoter activity. Furthermore, an miR-122 inhibitor suppressed the Vpr-mediated enhancement of both HCV 5' UTR activity and HCV replication. In summary, our results revealed that the Vpr-upregulated expression of miR-122 is closely related to the stimulation of HCV 5' UTR activity and HCV replication by Vpr, providing new evidence for how HIV interacts with HCV during HIV/HCV co-infection.

HBx down-regulated Gld2 plays a critical role in HBV-related dysregulation of miR-122.

miR-122 is a liver-rich-specific microRNA that plays an important role in hepatic gene expression via post-transcription regulation, and it is potentially associated with the development of hepatocellular carcinoma. It has been confirmed that miR-122 is down-regulated during HBV infection; however, how HBV affects miR-122 is still debated. One research provided evidence that HBx could reduce the miR-122 transcription level, but the other insisted that HBV had no significant effect on miR-122 transcription level but reduce miR-122 level via binding and sequestering endogenous miR-122. It is determinate that Gld2 could increase the specific miRNA stabilization by monoadenylation which was a post-transcription regulation. In this study, we aimed to investigate the mechanism of HBV-induced reduction of miR-122 and examine whether Gld2 is involved in it. According to the results of a microRNA microarray, we found miR-122 was the most down-regulated microRNA in HepG2.2.15 compared to HepG2. As revealed by qRT-PCR and western blotting analyses, both miR-122 and Gld2 levels were reduced in hepatic cell lines with expression of HBV or HBx but not other proteins of HBV, and over-expression of Gld2 could abolish the effect of HBV and HBx on the miR-122 level. What's more, both HBV and HBx have no significant effect on pre-miR-122 levels. And the dual-luciferase assay implicated that HBx could reduce the Gld2 promoter activity but had no significant effect on miR-122 promoter activity. In conclusion, HBx is a critical protein derived from HBV, which regulates miR-122 via down-regulating Gld2.

Evaluation of the revised versus the simplified scoring system in patients with autoimmune hepatitis.

The aim of this study was to evaluate the simplified and revised scoring systems for the diagnosis of autoimmune hepatitis (AIH). Seventy-seven patients diagnosed with AIH via the revised scoring system were enrolled in this study. Statistical analysis was performed by means of the χ2 test and logistic regression analysis. A total of 39 patients with definite AIH and 38 patients with probable AIH were diagnosed by the revised scoring system, whereas among these 77 patients, the simplified scoring system classified nine cases as definite AIH, 39 as probable AIH and 29 without AIH. In this study, the parameters contributing to the discrepant diagnosis of AIH were compared using the revised and simplified systems. A χ2 test showed that antinuclear antibody (ANA) or smooth muscle antibody (SMA) titers were significantly lower in the patients with discrepant diagnoses (χ2=15.0, P=0.001). Logistic regression with backward selection revealed that for the discrepant diagnosis of patients, the presence of other concurrent autoimmune diseases [odds ratio (OR)=7.25; P=0.018; 95% confidence interval (CI), 1.41-37.29] was the only independent risk factor. In addition, the presence of anti-soluble liver antigen/liver-pancreas antigen (SLA/LP) or perinuclear antineutrophil cytoplasmic antibody (pANCA) (OR=0.12; P=0.022; 95% CI, 0.02-0.74), the level of immunoglobulin G (IgG) with 1-1.1 × Normal (N) (OR=0.02; P=0.044; 95% CI, 0.00-0.89) and ANA or SMA titers ≥1:80 (OR=0.04; P=<0.001; 95% CI, 0.01-0.23) were three independent protective factors. In conclusion, the revised scoring system has a superior performance in the diagnosis of patients with AIH compared with the simplified scoring system. According to the simplified scoring system, other concurrent autoimmune diseases are the risk factor for the AIH diagnosis.

Clinical features in different age groups of patients with autoimmune hepatitis.

The Chinese population are at an increased risk of autoimmune hepatitis (AIH). The aims of this study were to determine the demographic and clinical features of AIH in China. A total of 83 patients with AIH diagnosed by the revised scoring system were re-analyzed, and the clinical presentations among the different ages were compared. The patients were classified according to age at presentation. AIH occurred in patients aged ≤30 years (9.6%), 31-39 years (10.8%), 40-49 years (16.9%), 50-59 years (31.3%) and ≥60 years (31.3%). There were no differences in the form of the clinical presentation, concurrent autoimmune diseases, cirrhosis distribution and autoantibodies among the groups. However, patients aged ≥60 years presented with higher levels of alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GT) compared with patients aged ≤30 years (P=0.034, P=0.043, respectively), and patients aged 31-39 years had a significantly lower immunoglobulin G (IgG) level compared with those aged 50-59 years (P=0.049) and those aged ≥60 years (P=0.012). By contrast, patients aged ≤30 years had a significantly higher total bilirubin (TBIL) level compared with those aged 31-39 years (P=0.007), 50-59 years (P=0.002) and ≥60 years (P=0.013). A substantial portion of patients with AIH were aged >60 years, indicating a poor liver-associated outcome under current management strategies. Elderly patients appeared to be more asymptomatic compared with the younger patients.

[Dynamic changes in PD-1, TLR3, and TLR4 surface expression on peripheral blood mononuclear cells in chronic hepatitis C patients undergoing peg-IFNalpha-2a plus ribavirin combination therapy].

OBJECTIVE: To investigate the dynamic changes in expression of programmed death (PD)-1, Toll-like receptor (TLR)3, and TLR4 on the surface of peripheral blood mononuclear cells (PBMCs) in patients with chronic hepatitis C (CHC) that occur in response to pegylated-interferon alpha-2a (peg-IFNalpha-2a) plus ribavirin (RBV) combination therapy, and to analyze the relation to achievement of sustained virological response (SVR). METHODS Twenty-three CHC patients and 10 healthy controls were enrolled in the study. All CHC patients underwent 48 weeks of combination therapy with peg-IFNalpha-2a (180 microg, subcutaneous injection, once weekly) plus RBV (15 microg/kg, oral, once daily). Total PBMCs were isolated from both groups (CHC patients at treatment week 0, 12, 24, and 48 and post-treatment week 24; controls at enrollment) and subjected to flow cytometric analysis of PD-1, TLR3, and TLR4 surface expression. In addition, serum levels of alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels were analyzed by enzymatic assay and the AmpliPrep/COBAS (Roche) nucleic acid amplification test, respectively. SVR was defined as undetectable levels of HCV RNA at post-treatment week 24. Intergroup differences were assessed by one-way ANOVA. RESULTS: The expression ratios of PD-1, TLR4 and PD-1: TLR4 on PBMCs were significantly higher in CHC patients before therapy than in the healthy controls (45.20 +/- 7.12% vs. 16.82 +/- 4.13%, 58.45 +/- 15.13% vs. 21.09 +/- 2.89%, and 35.54 +/- 7.69% vs. 14.12 +/- 2.89%; all P < 0.05). In contrast, the expression ratios of TLR3 and PD-1:TLR3 were slightly, but not significantly, higher in CHC patients before therapy than in the healthy controls (P > 0.05). During the course of peg-IFNalpha-2a plus RBV combination therapy, the expression ratios of PD-1 and TLR4 on PBMCs showed a decreasing trend, while TLR3 expression showed an increasing trend. Furthermore, CHB patients who achieved SVR at post-treatment week 24 had a significantly different expression ratio of PD-1 and TLR3 than those who did not achieve SVR (P < 0.05). CONCLUSION: Surface expression of PD-1, TLR4, and PD-1:TLR4 is up-regulated in the total PBMCs of CHC patients. Peg-IFNalpha-2a plus RBV treatment-induced suppression of HCV replication results in a significant reduction in PD-1 and TLR4 expression on the surface of PBMCs, but a remarkably elevated level of TLR3 expression. The dynamic change in PD-1 and TLR3 expression on PBMCs that occurs during antiviral therapy may be related to achievement of SVR.