Aspartate aminotransferase to platelet ratio at admission can predict the prognosis of patients with hemorrhagic fever with renal syndrome.

Early indicators are needed to predict the prognosis of patients with hemorrhagic fever with renal syndrome (HFRS). Aspartate aminotransferase to platelet ratio index (APRI) has been shown to be related to mortality risk of patients with various diseases. This study evaluated the prognostic value of APRI and other inflammatory scores in HFRS patients. Data of hospitalized HFRS patients from a tertiary hospital in northwest China were collected and the inflammatory scores such as APRI and neutrophil to lymphocyte count ratio (NLR) were calculated at the day of patient admission. Independent factors related to the survival of patients were determined by multivariate logistic regression. Receiver operating characteristic curve was used to analyze the predictive value, and area under the curve (AUC) and 95% confidence interval (CI) were calculated for quantification. Of the 317 HFRS patients included in study, 15 patients died. Age (OR: 1.10, 95% CI: 1.04-1.16, p = 0.001), NLR (OR: 1.11, 95% CI: 1.02-1.19, p = 0.01), and APRI (OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were quantitative objective factors independently associated with the survival of patients. APRI had an AUC of 0.95 (95% CI: 0.91-1.00, p < 0.001) for predicting the prognosis of patients, with a sensitivity of 93.3% and a specificity of 86.8%. The performance of APRI was better than that of age or NLR. Patients with an APRI ≥ 6.15 had significantly decreased survival compared with those with an APRI < 6.15. In conclusion, this simple index APRI calculated at admission can serve as a biomarker to identify HFRS patients at risk of poor prognosis.

A Case Report of Cutaneous Anthrax Diagnosed by Using a Metagenomic Next-Generation Sequencing (mNGS) Approach.

Anthrax is caused by Bacillus anthracis. Humans are mainly infected through contact with the fur and meat of livestock. The cutaneous form is the most common form. The skin lesions of typical cutaneous anthrax are characterized by shallow ulcers with black crusts, surrounded by small blisters and nonpitting edema of nearby tissues. Metagenomic next-generation sequencing (mNGS) is a new pathogenic detection method which is rapid and unbiased. We reported the first case of cutaneous anthrax diagnosed by mNGS. Ultimately, the man received prompt antibiotic therapy and had a good prognosis. In conclusion, mNGS is proved to be a good method for etiological diagnosis, especially for rare infectious diseases.

Clinical and laboratory features and factors predicting disease severity in pediatric patients with hemorrhagic fever with renal syndrome caused by Hantaan virus.

The clinical features and factors associated with disease severity in children with hemorrhagic fever with renal syndrome (HFRS) have not been well characterized. This study analyzed the clinical and laboratory factors associated with disease severity in children with HFRS caused by Hantaan virus. Data in pediatric patients with HFRS were retrospectively collected from Xi'an Children's Hospital over a 9-year period. Independent factors associated with disease severity were identified. Nomogram predicting disease severity was constructed based on variables filtered by feature selection. In total, 206 children with HFRS were studied. Fever, digestive tract symptoms, headache, backache, bleeding, and renal injury signs were the common symptoms. Elevated white blood cell, reduced platelet, hematuria, proteinuria, coagulation abnormalities, increased blood urea nitrogen (BUN) and procalcitonin (PCT), decreased estimated glomerular filtration rate and low serum Na+ , Cl- , and Ca2+ were the common laboratory findings. In the 206 patients, 21 patients had critical type disease and 4 patients (1.9%) died. Hydrothorax, hypotension and cerebral edema/cerebral herniation at hospital admission were independent clinical characteristics, and neutrophil %, prothrombin activity, PCT, BUN, and Ca2+ at hospital admission were independent laboratory factors associated with critical disease. Feature selection identified BUN, PCT and prothrombin time as independent factors related to critical disease. A nomogram integrating BUN and PCT at admission was constructed and calibration showed high accuracy for the probability prediction of critical disease. In conclusion, this study characterized the clinical and laboratory features and constructed a nomogram predicting disease severity in pediatric HFRS, providing references for disease severity evaluation in managing children HFRS.

Alterations in circadian rhythms aggravate Acetaminophen-induced liver injury in mice by influencing Acetaminophen metabolization and increasing intestinal permeability.

Acetaminophen (APAP) is the most common antipyretic and analgesic drug causing drug-induced liver injury (DILI). Alterations in circadian rhythms can adversely affect liver health, especially metabolic and detoxification functions. However, the effect of circadian rhythm alterations induced by environmental factors on APAP-induced liver injury and the underlying mechanisms are not well known. In this study, a mouse model of circadian rhythm alterations was established by light/dark cycle shift and then treated with excessive APAP. The liver injury indexes, APAP-related metabolic enzymes, and intestinal permeability in mice were evaluated by biochemical analysis, quantitative real-time PCR, enzyme-linked immunosorbent assays, and histopathology. Results showed that circadian rhythm alterations resulted in increased reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased liver superoxide dismutase (SOD), glutathione, and CYP1A2 and CYP3A11 mRNA expression, and increased serum diamine oxidase, lipopolysaccharide, and D-lactate in the mice. Compared with control mice, APAP induced higher serum alanine aminotransferase and aspartate aminotransferase, liver interleukin-1ß and tumor necrosis factor-α mRNA, ROS and MDA, lower SOD, glutathione, and UDP-glucuronosyltransferases /sulfotransferases mRNA and more severe liver necrosis and intestinal damage in mice with alterations in circadian rhythms. In conclusion, circadian rhythm alterations by light/dark cycle shift resulted in increased oxidative stress and intestinal permeability in the mice and exacerbated APAP-induced liver injury by influencing APAP metabolization and increasing intestinal permeability.

Case report: Brucellosis with rare multiple pulmonary nodules in a depressed patient.

Background: Brucellosis is a zoonotic disease that threatens public health and creates an economic burden. Unfortunately, it is often overlooked in developing countries, with misdiagnosis causing negative impacts on those with low income. Although the symptoms of brucellosis are commonly reported as fever and fatigue, rare pulmonary, and psychiatric involvements should also be considered. We present the first brucellosis patient in China with multiple pulmonary nodules and depression. Furthermore, this report highlights the importance of collecting patient history in epidemic areas of brucellosis. Case presentation: We report the case of a 40-year-old woman with intermittent fever for 2 months and gradually accompanied by chills, dry cough, arthralgia, and fatigue. The patient was also diagnosed with depression after fever. She received symptomatic treatment at a regional hospital; however, there was no significant symptom relief. She suddenly developed hemoptysis 1 day prior to arrival at our hospital, where we discovered that her liver, spleen, neck, and axillary lymph nodes were enlarged, and there were multiple nodules in both lungs. The patient was eventually diagnosed with brucellosis after the serum agglutination test and received antibiotic therapy, which provided symptom relief. Conclusion: This report describes a case of brucellosis with uncommon multipulmonary nodules and depression in China. This study has widened the evidence of respiratory involvement due to brucellosis. Second, it demonstrates the importance of collecting a comprehensive medical history, especially in epidemic areas. In conclusion, for febrile patients with pulmonary nodules and depression, especially in endemic areas, brucellosis should be considered.

Case Report: Use of Liposomal Amphotericin B in Low Doses in Patients With Visceral Leishmaniasis.

Background: No consensus has been reached regarding the optimal therapy for visceral leishmaniasis (VL), which affects ~12 million people worldwide. Case Presentation: This report described four cases of VL encountered in the First Affiliated Hospital of Xi'an Jiaotong University between October 2019 and December 2020. Of the four patients, one patient experienced relapse after antimonial treatment, and the remaining patients had primary VL (including one patient with impaired kidney function and one patient with hemophagocytic syndrome). All patients received a novel treatment protocol, namely the low-dose L-AmB therapy, which was characterized by a low initial dose, cautious dose escalation, and low-dose therapy as maintenance. All patients were cured without severe complications, and there was no further recurrence during follow-up. Conclusions: This case series demonstrated the safety and efficacy of the low-dose L-AmB therapy for VL patients, providing novel treatment protocol for the VL.

Increased Serum Pentraxin 3 Levels are Associated with Poor Prognosis of Hepatitis B Virus-Related Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of liver-related mortality. Serum pentraxin 3 (PTX3) has been revealed to be associated with the development of hepatitis B virus (HBV)-related HCC. This study evaluated whether serum PTX3 is related to the survival of HBV-related HCC patients. METHODS: One hundred and seven patients with HBV-related HCC were included. Baseline serum PTX3 levels were quantified using quantitative immunoassay. The HCC patients were followed-up for a median of 24 months and divided into high serum PTX3 level and low PTX3 level groups according to the baseline serum PTX3 levels. The overall survivals of the HBV-related HCC patients according to the serum PTX3 levels were compared. Factors potentially influencing the prognosis of the patients with HBV-related HCC were analyzed. RESULTS: HCC patients with high serum PTX3 levels [PTX3 > 9.25ng/mL (n=85)] had a shorter overall survival time than HCC patients with low serum PTX3 levels [PTX3 ≤ 9.25ng/mL (n=22)] (P = 0.049). HCC patients with serum PTX3 levels between >9.25ng/mL and ≤9.25ng/mL had significant difference in HCC histology grade. Multivariate analysis showed that PTX3 level was an independent risk factor related to the overall survival of HCC patients (hazard ratio: 1.058, 95% confidence interval: 1.031-1.085, P <0.001). CONCLUSION: These results support the involvement of PTX3 in the disease progression of HCC and suggest the potential of using serum PTX3 levels as a biomarker for the prognostic prediction of HBV-related HCC patients.

Metagenomic Next-Generation Sequencing in the Diagnosis of HHV-1 Reactivation in a Critically Ill COVID-19 Patient: A Case Report.

Background: Secondary infections pose tremendous challenges in Coronavirus disease 2019 (COVID-19) treatment and are associated with higher mortality rates. Clinicians face of the challenge of diagnosing viral infections because of low sensitivity of available laboratory tests. Case Presentation: A 66-year-old woman initially manifested fever and shortness of breath. She was diagnosed as critically ill with COVID-19 using quantitative reverse transcription PCR (RT-qPCR) and treated with antiviral therapy, ventilator and extracorporeal membrane oxygenation (ECMO). However, after the condition was relatively stabled for a few days, the patient deteriorated with fever, frequent cough, increased airway secretions, and increased exudative lesions in the lower right lung on chest X-rays, showing the possibility of a newly acquired infection, though sputum bacterial and fungal cultures and smears showed negative results. Using metagenomic next-generation sequencing (mNGS), we identified a reactivation of latent human herpes virus type 1 (HHV-1) in the respiratory tract, blood and gastrointestinal tract, resulting in a worsened clinical course in a critically ill COVID-19 patient on ECMO. Anti-HHV-1 therapy guided by these sequencing results effectively decreased HHV-1 levels, and improved the patient's clinical condition. After 49 days on ECMO and 67 days on the ventilator, the 66-year-old patient recovered and was discharged. Conclusions: This case report demonstrates the potential value of mNGS for evidence-based treatment, and suggests that potential reactivation of latent viruses should be considered in critically ill COVID-19 patients.

Association of 5-Hydroxytryptamine 3 Receptor Antagonists With the Prognosis of Liver Failure.

Liver failure is a severe clinical syndrome with high mortality. 5-Hydroxytryptamine 3 receptor antagonists (5-HT3RAs) can reduce liver damage in animal models. We investigated whether 5-HT3RAs may improve the prognosis of liver failure. We analyzed the 28 and 90 days mortality of liver failure patients in relation to the use of 5-HT3RAs using data from a tertiary hospital in northwest China. According to the use of 5-HT3RAs, 419 patients with liver failure (46 acute, 93 sub-acute, 44 chronic, 236 acute on chronic) were divided into 5-HT3RA group (n = 105) and control group (n = 314). 5-HT3RAs were associated with decreased 28 days (HR 0.18, 95% CI 0.10-0.34, p < 0.001) and 90 days (HR 0.21, 95% CI 0.13-0.33, p < 0.001) mortality. After propensity score matching (PSM) (n = 67 in each group), 5-HT3RAs were still significantly associated with reduced 28 days (HR 0.10, 95%CI 0.04-0.26, p < 0.001) and 90 days (HR 0.16, 95%CI 0.08-0.31, p < 0.001) mortality. 5-HT3RA group patients had significantly higher 28 and 90 days survivals than controls both before and after PSM (all p < 0.001). This study shows that 5-HT3RAs are associated with increased survival of liver failure patients and thus may be used to treat liver failure if the findings are confirmed by additional studies.

Scores based on neutrophil percentage and lactate dehydrogenase with or without oxygen saturation predict hospital mortality risk in severe COVID-19 patients.

BACKGROUND: Risk scores are needed to predict the risk of death in severe coronavirus disease 2019 (COVID-19) patients in the context of rapid disease progression. METHODS: Using data from China (training dataset, n = 96), prediction models were developed by logistic regression and then risk scores were established. Leave-one-out cross validation was used for internal validation and data from Iran (test dataset, n = 43) was used for external validation. RESULTS: A NSL model (area under the curve (AUC) 0.932) and a NL model (AUC 0.903) were developed based on neutrophil percentage and lactate dehydrogenase with and without oxygen saturation (SaO2) using the training dataset. AUCs of the NSL and NL models in the test dataset were 0.910 and 0.871, respectively. The risk scoring systems corresponding to these two models were established. The AUCs of the NSL and NL scores in the training dataset were 0.928 and 0.901, respectively. At the optimal cut-off value of NSL score, the sensitivity and specificity were 94% and 82%, respectively. The sensitivity and specificity of NL score were 94% and 75%, respectively. CONCLUSIONS: These scores may be used to predict the risk of death in severe COVID-19 patients and the NL score could be used in regions where patients' SaO2 cannot be tested.

Sleep disorders are associated with acetaminophen-induced adverse reactions and liver injury.

Risk factors related to the development of acetaminophen (APAP)-induced adverse reactions and liver injury remain uncertain. Sleep disorders have been linked to some health outcomes. This study examined the associations of sleep disorders with APAP-induced adverse reactions or liver injury and the possible mechanisms. From NIS database, adverse reactions, liver injury and sleep disorders were identified. Factors associated with the risk of the total adverse effects or liver injury were examined with logistic regression. From Gene Expression Omnibus database, datasets GSE111828, containing transcriptome data based on RNA-seq analysis from liver samples extracted from mice post APAP administration, and GSE92913, containing transcriptome data based on microarray analysis from liver samples extracted from mice with sleep deprivation, were analyzed. A total of 4372754 patients without and 91314 patients with sleep disorders were eligible for analyses. Both before and after propensity score matching, APAP-induced adverse reactions were higher in patients with sleep disorders than in patients without. In multivariate regression, sleep disorders were associated with higher odds of APAP-induced adverse reactions (adjusted OR [aOR] 2.005, 95 % CI 1.343-2.995) and liver injury (aOR 2.788, 95 % CI 1.310-5.932). Genes that were enriched in bile secretion and retinol metabolism and PPAR signaling pathways were basically down-regulated in livers of mice after APAP administration and livers of mice with sleep deprivation. This study shows that sleep disorders may be novel independent risk factors for APAP-associated adverse reactions and liver injury and provides bioinformation linking sleep disorders to increased risk of APAP-induced liver injury.

A nomogram for discrimination of non-alcoholic fatty liver disease in patients with chronic hepatitis B.

OBJECTIVES: Comorbid of non-alcoholic fatty liver disease (NAFLD) in chronic hepatitis B (CHB) patients is common but no simple noninvasive diagnostic methods are available for the identification. This study aims to develop a noninvasive nomogram for accurate detection of NAFLD in CHB patients. PATIENTS AND METHODS: This study included 535 liver biopsy-proven CHB patients with or without comorbid NAFLD. Independent risk factors of NAFLD were identified by multivariate logistic regression analysis. The risk factors identified were then incorporated into the nomogram. Performance of the nomogram was assessed by calibration, receiver operating characteristic (ROC) curve and decision curve analysis. RESULTS: Of the 535 patients, 100 patients (18.69%) were diagnosed as CHB/NAFLD and 435 patients (81.31%) as simple CHB. Body mass index, serum uric acid and low-density lipoprotein cholesterol levels and diabetes mellitus were independent risk factors of NAFLD. The nomogram incorporating these 4 factors had an area under ROC curve (AUC) of 0.864, achieved good concordance index of 0.864 (95% confidence interval: 0.832-0.892) for predicting NAFLD in the patients and had well-fitted calibration curves. The nomogram had a significantly higher AUC than some previously reported models. The decision curve analysis yielded larger net benefit. CONCLUSION: This study developed a simple, noninvasive, effective and convenient nomogram that achieved an optimal detection of NAFLD in CHB patients. Using this nomogram, the risk for an individual patient to have NAFLD could be discriminated, leading to a rational clinical management.

Serum pentraxin 3 as a biomarker of hepatocellular carcinoma in chronic hepatitis B virus infection.

Biomarkers for early diagnosis of hepatocellular carcinoma (HCC) are needed in chronic hepatitis B virus (HBV) infection, a leading cause of HCC. We evaluated whether measurement of serum pentraxin 3 (PTX3) could improve diagnosis of HCC in chronic HBV infection. Data from patients with HBV-related chronic hepatitis (n = 159), cirrhosis (n = 99) and HCC (n = 107), and healthy controls (n = 151) were analyzed. Serum PTX3 concentration was measured by immunoassay. Area under the receiver operating characteristic curve (AUC) was applied to assess diagnostic accuracy. PTX3 levels were significantly higher in HBV patients than in healthy controls (P < 0.001) and in HCC than in chronic hepatitis (P < 0.001) or cirrhosis patients (P < 0.001). PTX3 was an independent risk factor of HCC [odds ratio (OR) 1.617, P < 0.001] and could distinguish HCC in chronic HBV infection [cutoff 9.231 ng/mL, AUC 0.929 with 95% confidence interval (CI) of 0.898-0.953], including α-fetoprotein (AFP) negative [cutoff 8.985 ng/mL, AUC (95%CI) 0.947 (0.908-0.973)] and early-stage HCC [cutoff 9.359 ng/mL, AUC (95%CI) 0.920 (0.885-0.947)]. Combination of PTX3 with AFP improved the discrimination of early HCC from chronic HBV infection [AUC (95%CI) 0.948 (0.918-0.970)]. In short, PTX3 measurement could identify HCC, including AFP-negative and early-stage HCC, in chronic HBV infection.

Quarantine at home may not enough!-from the epidemiological data in Shaanxi Province of China.

OBJECTIVES: A pneumonia associated with 2019 novel coronavirus (2019-nCoV, subsequently named SARS-CoV2) emerged worldwide since December, 2019. We aimed to describe the epidemiological characteristics of 2019 coronavirus disease (COVID-19) in Shaanxi province of China. RESULTS: 1. Among the 245 patients, 132 (53.9%) were males and 113 (46.1%) were females. The average age was 46.15 ± 16.43 years, ranging from 3 to 89 years. 2. For the clinical type, 1.63% (4/245) patients were mild type, 84.90% (208/245) were moderate type, 7.76% (19/245) were severe type, 5.31% (13/245) were critical type and only 0.41% (1/245) was asymptomatic. 3. Of the 245 patients, 116 (47.35%) were input case, 114 (46.53%) were non-input case, and 15 (6.12%) were unknown exposure. 4. 48.57% (119/245) cases were family cluster, involving 42 families. The most common pattern of COVID-19 family cluster was between husband and wife or between parents and children.

Involvement of NEK2 and its interaction with NDC80 and CEP250 in hepatocellular carcinoma.

BACKGROUND: NEK2 has an established involvement in hepatocellular carcinoma (HCC) but the roles of NEK2 and its interacting proteins in HCC have not been systematically explored. METHODS: This study examined NEK2 and its interacting proteins in HCC based on multiple databases. RESULTS: NEK2 mRNA was highly expressed in HCC tissues compared with normal liver tissues. The survival of HCC patients with high NEK2 mRNA expression was shorter than those with low expression. MAD1L1, CEP250, MAPK1, NDC80, PPP1CA, PPP1R2 and NEK11 were the interacting proteins of NEK2. Among them, NDC80 and CEP250 were the key interacting proteins of NEK2. Mitotic prometaphase may be the key pathway that NEK2 and its interacting proteins contributed to HCC pathogenesis. NEK2, NDC80 and CEP250 mRNAs were highly expressed in HCC tissues compared with normal liver tissues. The mRNA levels of NEK2 were positively correlated with those of NDC80 or CEP250. Univariate regression showed that NEK2, NDC80 and CEP250 mRNA expressions were significantly associated with HCC patients' survival. Multivariate regression showed that NDC80 mRNA expression was an independent predictor for HCC patients' survival. Methylations and genetic alterations of NEK2, NDC80 and CEP250 were observed in HCC samples. The alterations of NEK2, NDC80 and CEP250 genes were co-occurrence. Patients with high mRNA expression and genetic alterations of NEK2, NDC80 and CEP250 had poor prognosis. CONCLUSIONS: NEK2 and its interacting proteins NDC80 and CEP250 play important roles in HCC development and progression and thus may be potentially used as biomarkers and therapeutic targets of HCC.

Association of LIN28B polymorphisms with chronic hepatitis B virus infection.

BACKGROUND: LIN28B is involved in multiple cellular developmental processes, tissue inflammatory response and tumourigenesis. The association of LIN28B polymorphisms with hepatitis B virus (HBV) infection remains unknown. METHODS: This study investigated the association of LIN28B rs314277, rs314280, rs369065 and rs7759938 polymorphisms in patients with chronic HBV infection, a major cause of liver disease including hepatocellular carcinoma (HCC). A total of 781 individuals including 515 cases of chronic HBV infection (91 asymptomatic carrier status, 128 chronic hepatitis, 127 cirrhosis and 169 HCC), 97 HBV infection resolvers and 169 healthy controls were investigated. RESULTS: LIN28 rs314280 genotypes GA + AA were higher in resolver and controls than patients (P = 0.011). Patients had significantly lower rs314280 allele A than resolvers (P = 0.031, OR 0.689, 95%CI 0.491-0.969) or controls (P = 0.034, OR 0.741, 95%CI 0.561-0.978). In dominant model, patients had significantly lower rs314280 genotypes AA+GA than controls (P = 0.008, OR 0.623, 95%CI 0.439-0.884). LIN28 rs7759938 genotypes TC + CC were higher in resolvers and controls than patients (P = 0.015). Patients had significantly lower rs7759938 allele C than resolvers (P = 0.048, OR 0.708, 95%CI 0.503-0.999). In dominant model, patients had significantly lower rs7759938 genotypes TC + CC than controls (P = 0.010, OR 0.632, 95%CI 0.445-0.897). Chronic hepatitis patients had lower frequency of rs369065 genotype TC than asymptomatic carriers, cirrhosis and HCC (P = 0.019). CONCLUSIONS: These results suggest that LIN28 rs314280 and rs7759938 may be related to the susceptibility of chronic HBV infection. Further studies are warranted to examine the association of LIN28B polymorphisms with HBV-related diseases, especially HCC.

Advances in the use of chloroquine and hydroxychloroquine for the treatment of COVID-19.

Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading worldwide. Antiviral therapy is the most important treatment for COVID-19. Among the drugs under investigation, anti-malarials, chloroquine (CQ) and hydroxychloroquine (HCQ), are being repurposed as treatment for COVID-19. CQ/HCQ were shown to prevent receptor recognition by coronaviruses, inhibit endosome acidification, which interferes with membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. A number of in vitro studies revealed inhibitory effects of CQ/HCQ on various coronaviruses, including SARS-CoV-2 although conflicting results exist. Several clinical studies showed that CQ/HCQ alone or in combination with a macrolide may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay disease progression, with less serious adverse effects. However, recent studies indicated that the use of CQ/HCQ, alone or in combination with a macrolide, did not show any favorable effect on patients with COVID-19. Adverse effects, including prolonged QT interval after taking CQ/HCQ, may develop in COVID-19 patients. Therefore, current data are not sufficient enough to support the use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken about the application of CQ/HCQ in COVID-19 before conclusive findings are obtained by well-designed, multi-center, randomized, controlled studies.

Circulating CTLA-4 levels and CTLA4 polymorphisms associate with disease condition and progression and hepatocellular carcinoma patients' survival in chronic hepatitis B virus infection.

BACKGROUND: CTLA-4 is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating CTLA-4 levels and CTLA4 polymorphisms with disease condition and progression in chronic HBV infection. METHODS: Serum CTLA-4 levels and CTLA4 rs231775 and rs5742909 polymorphisms were determined in patients with various HBV-related diseases [53 asymptomatic HBV carrier status (ASC), 147 chronic hepatitis, 130 cirrhosis and 102 HCC] and nearly a 10-year follow-up. RESULTS: Serum CTLA-4 levels were stepwisely increased from ASC, chronic hepatitis, cirrhosis to HCC and independently associated with HCC (OR 2.628, P < 0.001). HCC patients had lower frequencies of rs231775 genotype GA, genotype AA and allele A than ASC, chronic hepatitis and cirrhosis patients. Rs231775 genotype GG was independently associated with HCC (OR 2.324, P = 0.010) and higher CTLA-4 levels in patients with HBV infection. In the follow-up, higher baseline CTLA-4 levels and CTLA4 rs231775 genotype GG significantly associated with disease progression from chronic hepatitis to cirrhosis (OR 2.561, P = 0.011 and OR 2.799, P = 0.015, respectively) or from cirrhosis to HCC (OR 2.673, P = 0.008 and OR 2.097, P = 0.023, respectively) and with a shorter overall survival in HCC patients (HR 0.317, P = 0.018 and HR 0.682, P = 0.026, respectively). Rs5742909 had no significant association with CTLA-4 levels and disease progression. CONCLUSION: CTLA-4 levels and CTLA4 rs231775 polymorphism associate with the disease condition and progression and HCC development in chronic HBV infection and their determination may be used for monitoring disease progression and predicting patient prognosis.

Genetic association of polymorphisms at the intergenic region between PRDM1 and ATG5 with hepatitis B virus infection in Han Chinese patients.

Chronic hepatitis B virus (HBV) infection is related to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC), and the interplay between the virus and host immune response leads to different outcomes of the infection. PR domain zinc finger protein 1 (PRDM1) and autophagy-related protein 5 (ATG5) are involved in immune response and HBV infection. An intergenic region between PRDM1 and ATG5 (PRDM1-ATG5 region) has been identified, and single-nucleotide polymorphisms (SNPs) in this region were shown to be involved in immune regulation. This study investigated the functionally relevant rs548234, rs6937876, and rs6568431 polymorphisms at the PRDM1-ATG5 region in a Han Chinese population (403 patients with chronic HBV infection [171 chronic hepatitis, 119 cirrhosis, and 113 HCC], 70 infection resolvers, and 196 healthy controls). The frequencies of the rs6568431 allele A in HBV patients (P = .005) and genotype CA in infection resolvers (P = .005) were significantly higher than in healthy controls. In the dominant model, HCC patients had significantly higher frequencies of rs548234 genotypes CC + TC than cirrhosis patients (P = .009). Rs548234 was an independent factor for HCC in comparison with either cirrhosis (P = .005) or all chronic HBV infection without HCC (P = .018). Functional annotation showed evidence of the role of the SNPs in gene regulation. In conclusion, through this study it is revealed for the first time that rs6568431 may be associated with susceptibility to HBV infection and that rs548234 may be associated with HCC risk in chronic HBV infection, supporting the presence of HBV-related disease-causing regulatory polymorphisms in the PRDM1-ATG5 intergenic region.

PRDM1 rs1010273 polymorphism is associated with overall survival of patients with hepatitis B virus-related hepatocellular carcinoma.

T cell exhaustion is involved in the pathogenesis of chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). B lymphocyte-induced maturation protein 1 (BLIMP-1), encoded by the PRDM1 gene, plays a crucial role in T cell exhaustion. This study investigated PRDM1 rs1010273 and rs2185379 polymorphisms in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 liver cirrhosis and 113 HCC), 70 spontaneous HBV infection resolvers and 196 healthy controls. The results showed that the rs1010273 and rs2185379 polymorphisms had no significant differences between patients with chronic HBV infection and healthy controls or between patients with different clinical diseases. However, PRDM1 rs1010273 polymorphism was shown to be significantly associated with the overall survival of patients with HBV-related HCC. The 1-, 3-, and 5-year survival rates of HCC patients were 70.5%, 34.6%, and 11.5%, respectively, in genotype GG carriers and 91.4%, 51.4% and 31.4%, respectively, in genotypes AA + GA carriers (p =  0.008). Multivariate analysis showed that PRDM1 rs1010273 polymorphism was an independent factor associated with the overall survival of patients with HCC (odds ratio, 0.529; 95% confidence interval, 0.126-0.862; p =  0.002). These results provide novel evidence for a role of PRDM1 rs1010273 in the pathogenesis of HBV-related HCC. Additional studies are needed to replicate and extend the findings of this study and to elucidate the underlying mechanisms.