Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis.

The genetic association of primary biliary cholangitis with major histocompatibility complex (MHC) has been widely confirmed among different ethnicities. To map specific MHC region variants associated with PBC in a Han Chinese cohort, we imputed HLA antigens and amino acids (AA) in 1126 PBC cases and 1770 healthy control subjects using a Han-MHC reference database. We demonstrate that HLA-DRB1 and/or HLA-DQB1 contributed the strongest signals, and that HLA-DPB1 was a separate independent locus. Regression analyses with classical HLA alleles indicate that HLA-DQB1*03:01 or HLA-DQß1-Pro55, HLA-DPB1*17:01 or HLA-DPß1-Asp84 and HLA-DRB1*08:03 could largely explain MHC association with PBC. Forward stepwise regression analyses with HLA amino acid variants localize the major signals to HLA-DRß1-Ala74, HLA-DQß1-Pro55 and HLA-DPß1-Asp84. Electrostatic potential calculations implicated AA variations at HLA-DQß1 position 55 and HLA-DPß1 position 84 as critical to peptide binding properties. Furthermore, although several critical Han Chinese AA variants differed from those shown in European populations, the predicted effects on antigen binding are likely to be very similar or identical and underlie the major component of MHC association with PBC.

Genome-wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis.

Anti-nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome-wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single-nucleotide polymorphisms rs492899 (P = 3.27 × 10-22 ; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34-3.66) and rs1794280 (P = 5.78 × 10-28 ; OR, 3.89; 95% CI, 3.05-4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti-sp100-positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA-DRß1-Asn77/Arg74, DRß1-Ser37, and DPß1-Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10-9 ; OR, 2.97; 95% CI, 2.06-4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

[Value of preoperative pulmonary artery diastolic pressure on predicting primary graft dysfunction after bilateral lung transplantation for patients with idiopathic pulmonary fibrosis].

OBJECTIVE: To analyze the value of the potential risk factors on predicting primary graft dysfunction (PGD) after bilateral lung transplantation for the patients with idiopathic pulmonary fibrosis (IPF). METHODS: A retrospective study was conducted. Fifty-eight patients with IPF who underwent the bilateral lung transplantation admitted to Wuxi People's Hospital Affiliated to Nanjing Medical University from June 2014 to March 2017 were enrolled. The grade 3 PGD happened within 72 hours after transplantation was taken as the outcome event, and these patients were divided into PGD and non-PGD groups. The age, gender, body mass index (BMI), underlying disease, and N-terminal-probrain natriuretic peptide (NT-proBNP) before operation, pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), and mean pulmonary artery pressure (mPAP) before and after operation, duration of operation, the volume of blood transfusion during operation and postoperation, the use of extracorporeal membrane oxygenation (ECMO) during the operation, blood purification treatment after operation, and shock within 3 days after operation were recorded. The differences of parameters mentioned above between the two groups were compared. The predictive factors of PGD were searched by binary logistic regression analysis, and the receiver operating characteristic curve (ROC) was plotted to analyze the predictive value of preoperative PADP for grade 3 PGD after transplantation. RESULTS: Among 58 patients who underwent the bilateral lung transplantation, 52 patients were enrolled. The rest patients were excluded because of incomplete clinical data. There were 17 patients in the PGD group, with a mortality rate of 47.06%. The non-PGD group included 35 patients with a mortality rate of 8.57%. PADP and mPAP ahead of operation, the dosage of red cells suspension after the operation, and the total amount of blood transfusion during and after the operation in PGD group were significantly higher than those in non-PGD group [PADP ahead of operation (mmHg, 1 mmHg = 0.133 kPa): 33.7±10.5 vs. 25.3±10.1, mPAP ahead of operation (mmHg): 40.4±14.1 vs. 32.8±11.1, the dosage of red cells suspension after the operation (mL): 700 (300, 1 500) vs. 300 (300, 500), the total amount of blood transfusion during and after the operation (mL): 2 250 (1 850, 4 275) vs. 1 800 (1 550, 2 800)], with statistically significant differences (all P < 0.05). There were no significant differences in age, gender, BMI, underlying disease, NT-proBNP before operation, PASP before and after operation, PADP and mPAP after operation, duration of operation, amount of plasma and red cells suspension as well as total amount of blood transfusion during operation, plasma amount and total amount of blood transfusion after operation, amount of plasma and red cells suspension during and after operation, use of ECMO during operation, blood purification treatment after operation, and shock after operation between the two groups (all P > 0.05). It was shown by binary logistic regression analysis that the preoperative PADP was the independent risk factor of grade 3 PGD after lung transplantation [odds ratio (OR) = 1.084, 95% confidence interval (95%CI) = 1.016-1.156, P = 0.015]. It was shown by ROC curve that the area under the ROC curve (AUC) of the PADP before operation for predicting the grade 3 PGD after lung transplantation was 0.728. When the cut-off value was 36 mmHg, the sensitivity was 47.1%, and the specificity was 91.4%. CONCLUSIONS: Compared with the non-PGD group, the patients with higher preoperative PADP were more common in the PGD group, and the patients in the PGD group were more likely to be characterized by grade 3 PGD after lung transplantation. The preoperative PADP was an effective predictor of grade 3 PGD after lung transplantation.

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

[Prognostic significance of early lactate clearance rate for severe acute respiratory failure patients on extracorporeal membrane oxygenation].

OBJECTIVE: To investigate the prognostic significance of early lactate clearance rate for severe acute respiratory failure patients on extracorporeal membrane oxygenation (ECMO). METHODS: Forty-three patients with severe acute respiratory failure supported by venous-venous (v-v) ECMO were enrolled from January 2007 to January 2013. Arterial blood lactate at pre-ECMO support(0 h) and at post-ECMO 6 hours (6 h) were measured and then 6 h lactate clearance rate was calculated. The acute physiology and chronic health evaluation II (APACHEII) score was evaluated on the first day of ECMO support. Survival at 90 d after admission was the study endpoint. Patients were divided into the survival group (n = 24) and the death group (n = 19) . The 0 h blood lactate, 6 h lactate clearance rate and APACHE II score were compared between groups. The value of 0 h blood lactate, 6 h lactate clearance rate and APACHE II score for predicting death was evaluated by receiver operating characteristic (ROC) curves. The surviving curve was drawn using the Kaplan-Meier method, and the survival of the patients was analyzed by the Log-rank test. Factors influencing the prognosis were analyzed by the multiple logistic regression analysis. RESULTS: (1) The 0 h blood lactate and APACHE II score were lower in survivors than in nonsurvivors [(3.8 ± 2.1) mmol/L vs. (5.9 ± 2.3) mmol/L, (18 ± 7) vs. (25 ± 7) , t = 7.924, 8.446, respectively, both P < 0.05], while the 6 h lactate clearance rate was higher in survivors than in nonsurvivors [(35.7 ± 20.4) % vs. (10.7 ± 18.2) %, t = 8.607, P < 0.05]. (2) The areas under the ROC curve of 0 h blood lactate, 6 h lactate clearance rate and APACHE II score for predicting death were 0.699 ± 0.083 (95%CI:0.567∼0.892, P < 0.05) , 0.871 ± 0.119 (95%CI:0.724∼0.980, P < 0.05) and 0.836 ± 0.063 (95%CI: 0.713∼0.958, P < 0.05) . The best cutoff point was 17.5% for 6 h lactate clearance with a sensitivity of 87.5% and specificity of 84.2%. (3) Kaplan-Meier survival analysis showed that 90 d survival rate of the high lactate clearance rate group and the low lactate clearance rate group were 78.3% and 30%, with significant difference between the two groups (χ² = 10.103, P < 0.05). (4) Multivariate logistic regression analysis showed that 0 h blood lactate (OR = 1.318, 95%CI:1.159∼6.882, P < 0.05) , 6 h lactate clearance rate (OR = 6.921, 95%CI:4.469∼15.036, P < 0.05) and APACHEII score (OR = 4.417, 95%CI:3.058∼10.356, P < 0.05) were independent risk factors associated with mortality of patients on ECMO. CONCLUSION: Early lactate clearance rate could be used as an important variable for evaluating the prognosis of severe acute respiratory failure patients on ECMO.

[The value of changes in end-tidal carbon dioxide pressure induced by passive leg raising test in predicting fluid responsiveness in mechanically ventilated patients with septic shock].

OBJECTIVE: To test whether the changes of partial end-tidal carbon dioxide pressure (PETCO2) during passive leg raising (PLR) predict fluid responsiveness in mechanically ventilated patients with septic shock. METHODS: Forty-two mechanically ventilated patients with septic shock admitted from January 2012 to November 2012 were prospectively recruited.Hemodynamic parameters monitored by a pulse indicator continuous cardiac output (PiCCO) device and PETCO2 monitored by an expiratory-CO2 device were studied at baseline, after PLR, and after volume expansion. Fluid responsiveness was defined as an increase in cardiac index (CI) of 15% or greater after volume expansion. The correlation between PLR-induced CI change (ΔCIPLR) and PETCO2 (ΔPETCO2-PLR) was analyzed. The value of ΔPETCO2-PLR to predict fluid responsiveness was evaluated by receiver operating characteristic (ROC) curves. RESULTS: A total of 42 patients were enrolled in this study, of whom, 24 had a CI increase of ≥ 15% after volume expansion (responders). After PLR, CI and PETCO2 were both significantly increased in the response group compared with baseline [(21.4 ± 12.9)% of CI and (9.6 ± 4.7)% of PETCO2, P < 0.05], while no significant changes were observed (P > 0.05) in the non-response group. Both ΔCIPLR and ΔPETCO2-PLR were significantly higher in responder group than in the non-responder group (both P < 0.05). ΔCI and ΔPETCO2 after PLR were strongly correlated (r = 0.64, P < 0.05). In responders after PLR, the area under ROC curve of ΔPETCO2-PLR was 0.900 ± 0.056 (95%CI 0.775-1.000, P < 0.05). An increase of ≥ 5% in ΔPETCO2-PLR predicted fluid responsiveness with a sensitivity of 88.0% and specificity of 88.2%. CONCLUSIONS: The change of PETCO2 induced by passive leg raising is a non-invasive and easy way to predict fluid responsiveness in mechanically ventilated patients with septic shock.

[Supplemental Fuzhenghuayu capsule therapy for improving liver fibrosis markers in patients with chronic hepatitis B following unsatisfactory outcome of nucleos(t)ide analogue monotherapy].

OBJECTIVE: To investigate the ability of Fuzhenghuayu capsule to improve markers of liver fibrosis when provided as supplemental therapy in patients with chronic hepatitis B (CHB) who achieved complete virological response but unsatisfactory resolution of fibrosis markers with nucleos(t)ide analog (NAs) monotherapy. METHODS: One-hundred-and-ten patients with CHB-related liver fibrosis who had received NA for more than or equal to 2 years and achieved sustained virological response (SVR) but no improvement in liver fibrosis index were randomly divided into two equal groups: experimental group, continued oral NAs (one tablet, 1 time/day) with simultaneous Fuzhenghuayu capsule (1.5 g, 3 times/day) for 48 weeks; control group, continued oral NAs only for 48 weeks. Serum fibrosis markers (hyaluronic acid (HA), laminin (LN), amino terminal propeptide of type III procollagen (PIIIP) and IV collagen (IV-C)), liver fibrosis stages, B ultrasonic wave, and liver function were observed before (baseline) and after treatment and compared by statistical analysis. RESULTS: The baseline levels of fibrosis markers were not significantly different between the experimental and control groups. After treatment, the levels of all of the fibrosis markers were lower in the experimental group (P less than 0.05 vs. control group; HA t = 19.548, LN t = 2.264, PIIIP t = 2.230, and IV-C t = 6.649) and lower than the baseline levels (P less than 0.01; HA t = 12.458, LN t = 7.402, PIIIP t = 4.620, IV-C t = 8.937). The control group also showed a significant reduction in HA and LN levels after treatment (P less than 0.01 vs. baseline; t = 5.202 and 3.444), but PIIIP and IV-C were unaffected. The baseline liver fibrosis stages were not significantly different between the experimental and control groups. After treatment, only the experimental group showed significant improvement in liver fibrosis stages (P less than 0.01). The rates of excellent therapeutic outcome, effectiveness, and non-effectiveness were significantly different between the experimental group (11.3%, 43.4%, and 45.3%) and the control group (1.0%, 22.2%, and 75.6%) (x2 = 9.408, P less than 0.01). Similar trends were observed for improvements in B ultrasonic wave for liver and spleen and in markers of liver function. Finally, neither treatment group experienced adverse effects. CONCLUSION: For CHB patients who achieve SVR by antiviral treatment with NAs, but unsatifactory improvement in liver fibrosis indices, administration of supplemental Fuzhenghuayu capsule with continued NAs therapy may represent a safe and effective treatment.

[An analysis of clinical characteristics of septic acute kidney injury by using criteria of Kidney Disease: Improving Global Outcomes].

OBJECTIVE: To evaluate the value of Kidney Disease: Improving Global Outcomes (KDIGO) criteria in investigating clinical feature and prognosis of acute kidney injury (AKI) patients with sepsis in ICU. METHODS: Clinical data of patients with AKI defined by KDIGO criteria in ICU of Wuxi People's Hospital from June 2007 to June 2012 were collected. Clinical characteristics, prognosis and major risk factors of death of septic AKI patients were retrospectively analyzed. RESULTS: Of the enrolled 703 AKI patients, 395 (56.2%) were caused by sepsis (septic AKI), which indicated that sepsis mainly contributed to the causes of AKI. For septic AKI stratified by KDIGO classification, 146 (37.0%) patients belonged to AKI I, 154 (39.0%) to AKI II, and 95 (24.1%) to AKI III. Compared with the patients with non-septic AKI, septic AKI patients had greater APACHE II and SOFA score (25.1 ± 4.9 vs 20.5 ± 6.4, 12.9 ± 2.6 vs 10.4 ± 4.5; all P values < 0.05). Although there was no significant difference in baseline serum creatinine [(82.9 ± 22.2) µmol/L vs (83.1 ± 30.0) µmol/L, P > 0.05] between the two groups, patients with sepsis had higher serum creatinine [(143.5 ± 21.6) µmol/L vs (96.2 ± 15.5)µmol/L; P < 0.05], a higher proportion fulfilled KDIGO categories for both AKI II and III (63.0% vs 33.1%; P < 0.05), a higher renal replacement therapy (RRT) rate (22.3% vs 6.2%; P < 0.05) and a lower proportion of complete renal recovery (74.4% vs 82.8%) (all P values < 0.05). The 90-day mortality of septic AKI patients was higher than that of non-septic AKI patients (52.2% vs 34.1%; P < 0.05). Septic AKI, graded by KDIGO, was associated with an increased mortality. Logistic regression analysis showed that APACHEII score (OR = 5.451, 95%CI: 3.095 - 9.416), SOFA score (OR = 2.166, 95%CI: 1.964 - 4.515) and RRT (OR = 4.021, 95%CI: 2.975 - 6.324) were independent risk factors for mortality of septic AKI patients. CONCLUSION: Septic AKI patients have a higher burden of illness, worse renal function and higher mortality. APACHEII score, SOFA score and RRT are independent risk factors to septic AKI mortality.

[Urinary neutrophil gelatinase-associated lipocalin and urinary interleukin-18 in early diagnosis of acute kidney injury in critically ill patients].

OBJECTIVE: To determine whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) and urinary interleukin-18 (uIL-18) are early markers of acute kidney injury (AKI) in critically ill patients. METHODS: Ninety-two critically ill patients were studied for one week after their enrollment into our hospital. During the study, 46 patients who met the RIFLE criteria were selected as AKI group and the remaining 46 patients without AKI taken as a control group. The two groups were matched for age, gender and illness severity. Urine samples were collected daily for one week. The receiver operating characteristic curve was used to evaluate the early diagnostic value of uNGAL, uIL-18 and serum creatinine (SCr). RESULTS: As compared with the levels obtained 3 days before the diagnosis of AKI, the uNGAL levels in the AKI group increased significantly (P < 0.05), while uIL-18 and SCr levels did not change 2 days prior to the diagnosis of AKI (all P > 0.05). uNGAL and uIL-18 levels increased significantly (all P < 0.05), while SCr levels did not change 1 day prior to the diagnosis of AKI in the AKI group (P > 0.05). The levels of uNGAL, uIL-18 and SCr did not change significantly in the control group during the study period (all P > 0.05). Three days before the diagnosis of AKI, concentrations of uNGAL, uIL-18 and SCr were not the predictive of AKI. Two days before the diagnosis of AKI, the area under the curve (AUC) of uNGAL was 0.840 (95%CI 0.672 - 1.009, P < 0.05), which indicated that uNGAL was the predictive of AKI while uIL-18 and SCr were not. One day before the diagnosis of AKI, the AUC of uNGAL and uIL-18 were 0.830 (95%CI 0.711 - 0.950, P < 0.05) and 0.818 (95%CI 0.697 - 0.938, P < 0.05), indicating that uNGAL and uIL-18 were the predictive of AKI while SCr was not. CONCLUSION: uNGAL and uIL-18 may be the early predictive markers of AKI in critically ill patients.