Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.

BACKGROUND & AIMS: Whether non-selective ß-blockers can prevent decompensation of cirrhosis warrants clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, a major mechanism of portal hypertension in early cirrhosis. We assessed whether carvedilol may prevent decompensation and improve survival in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH). METHODS: By systematic review we identified randomized-controlled trials (RCTs) comparing carvedilol vs. control therapy (no-active treatment or endoscopic variceal ligation [EVL]) in patients with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs. Only compensated patients were included. Primary outcomes were prevention of decompensation (liver transplantation and death were competing events) and death (liver transplantation was a competing event). Models were adjusted using propensity scores for baseline covariates with the inverse probability of treatment weighting (IPTW) approach. RESULTS: Among 125 full-text studies evaluated, 4 RCTs were eligible. The 4 provided IPD and were included, comprising 352 patients with compensated cirrhosis, 181 treated with carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics were similar between groups. Standardized differences were <10% by IPTW. The risk of developing decompensation of cirrhosis was lower with carvedilol than in controls (subdistribution hazard ratio [SHR] 0.506; 95% CI 0.289-0.887; p = 0.017; I2 = 0.0%, Q-statistic-p = 0.880), mainly due to a reduced risk of ascites (SHR 0.491; 95% CI 0.247-0.974; p = 0.042; I2 = 0.0%, Q-statistic-p = 0.384). The risk of death was also lower with carvedilol (SHR 0.417; 95% CI 0.194-0.896; p = 0.025; I2 = 0.0%, Q-statistic-p = 0.989). CONCLUSIONS: Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly improved survival in compensated patients with CSPH. This suggests that screening patients with compensated cirrhosis for CSPH to enable the prompt initiation of carvedilol could improve outcomes. PROSPERO REGISTRATION NUMBER: CRD42019144786. LAY SUMMARY: The transition from compensated cirrhosis to decompensated cirrhosis is associated with markedly reduced life expectancy. Therefore, preventing decompensation in patients with compensated cirrhosis would be associated with greatly improved patient outcomes. There has been controversy regarding the use of non-selective ß-blockers (portal pressure-lowering medications) in patients with cirrhosis and elevated portal blood pressure (portal hypertension). Herein, using a competing-risk meta-analysis to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events, we show that carvedilol (a non-selective ß-blocker) is associated with a reduced risk of decompensating events and improved survival in patients with cirrhosis and portal hypertension.

Comparison of safety and efficacy of convalescent plasma with fresh frozen plasma in severe covid-19 patients.

BACKGROUND: Role of Convalescent plasma (COPLA) to treat severe COVID-19 is under investigation. We compared efficacy and safety of COPLA with fresh frozen plasma (FFP) in severe COVID-19 patients. METHODS: One group received COPLA with standard medical care (n = 14), and another group received random donor FFP, as control with standard medical care (n = 15) in severe COVID-19 disease. RESULTS: The proportion of patients free of ventilation at day seven were 78.5% in COPLA group, and 93.3 % in control group were not significant (p= 0.258). However, improved respiratory rate, O2 saturation, SOFA score, and Ct value were observed in the COPLA group. No serious adverse events were noticed by plasma transfusion in both groups.

Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial.

Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet [PLT] count), and its use may avoid unnecessary blood component transfusion in patients with advanced cirrhosis and significant coagulopathy who have nonvariceal upper gastrointestinal (GI) bleeding. A total of 96 patients with significant coagulopathy (defined in this study as INR >1.8 and/or PLT count < 50 × 109 /L) and nonvariceal upper GI bleed (diagnosed after doing upper gastrointestinal endoscopy, which showed ongoing bleed from a nonvariceal source) were randomly allocated to TEG-guided transfusion strategy (TEG group; n = 49) or standard-of-care (SOC) group (n = 47). In the TEG group, only 26.5% patients were transfused with all three blood components (fresh frozen plasma [FFP], PLTs, and cryoprecipitate) versus 87.2% in the SOC group (P < 0.001). Although 7 (14.3%) patients in the TEG group received no blood component transfusion, there were no such patients in the SOC group (P = 0.012). Also, there was a significantly lower use of blood components (FFP, PLTs, and cryoprecipitate) in the TEG group compared with the SOC group. Failure to control bleed, failure to prevent rebleeds, and mortality between the two groups were similar. Conclusion: In patients with advanced cirrhosis with coagulopathy and nonvariceal upper GI bleeding, TEG-guided transfusion strategy leads to a significantly lower use of blood components compared with SOC (transfusion guided by INR and PLT count), without an increase in failure to control bleed, failure to prevent rebleed, and mortality.

Development of a machine learning model to predict bleed in esophageal varices in compensated advanced chronic liver disease: A proof of concept.

BACKGROUND AND AIM: Risk stratification beyond the endoscopic classification of esophageal varices (EVs) to predict first episode of variceal bleeding (VB) is currently limited in patients with compensated advanced chronic liver disease (cACLD). We aimed to assess if machine learning (ML) could be used for predicting future VB more accurately. METHODS: In this retrospective analysis, data from patients of cACLD with EVs, laboratory parameters and liver stiffness measurement (LSM) were used to generate an extreme-gradient boosting (XGBoost) algorithm to predict the risk of VB. The performance characteristics of ML and endoscopic classification were compared in internal and external validation cohorts. Bleeding rates were estimated in subgroups identified upon risk stratification with combination of model and endoscopic classification. RESULTS: Eight hundred twenty-eight patients of cACLD with EVs, predominantly related to non-alcoholic fatty liver disease (28.6%), alcohol (23.7%) and hepatitis B (23.1%) were included, with 455 (55%) having the high-risk varices. Over a median follow-up of 24 (12-43) months, 163 patients developed VB. The accuracy of machine learning (ML) based model to predict future VB was 98.7 (97.4-99.5)%, 93.7 (88.8-97.2)%, and 85.7 (82.1-90.5)% in derivation (n = 497), internal validation (n = 149), and external validation (n = 182) cohorts, respectively, which was better than endoscopic classification [58.9 (55.5-62.3)%] alone. Patients stratified high risk on both endoscopy and model had 1-year and 3-year bleeding rates of 31-43% and 64-85%, respectively, whereas those stratified as low risk on both had 1-year and 3-year bleeding rates of 0-1.6% and 0-3.4%, respectively. Endoscopic classification and LSM were the major determinants of model's performance. CONCLUSION: Application of ML model improved the performance of endoscopic stratification to predict VB in patients with cACLD with EVs.

Clinical Decompensation and Outcomes in Patients With Compensated Cirrhosis and a Hepatic Venous Pressure Gradient ≥20 mm Hg.

INTRODUCTION: Hepatic venous pressure gradient (HVPG) of ≥10 mm Hg predicts clinical decompensation (CD) in compensated cirrhosis. A proportion of cirrhotic patients at presentation have high HVPG (≥20 mm Hg) and are compensated. The natural history, spectrum of CD, and mortality in this group is largely unknown. METHODS: Consecutive compensated cirrhotic patients with HVPG ≥6 mm Hg (n = 741) were followed up for 3-6 months for the development of any CD. Patients were classified based on the baseline HVPG (6 to <12 mm Hg [low HVPG, Gr.A, n = 163], 12 to <20 mm Hg [intermediate HVPG, Gr.B, n = 437] and ≥20 mm Hg [high HVPG, Gr.C, n = 141]). We analyzed the predictors of first CD, HVPG response to carvedilol, and mortality in these groups. RESULTS: CD developed in 217 (29.3%) patients during a mean follow-up of 1.6 ± 0.4 years, and those who developed CD had higher baseline HVPG (17.02 ± 4.79 vs 14.28 ± 4.86; P < 0.001). First CD was seen earlier (1.3 ± 0.7 years vs 1.5 ± 0.6 years and 1.6 ± 0.5 years, P = 0.02) and more frequently (44.7% vs 11% and 31.1%, P < 0.01) in high HVPG groups compared with low and intermediate HVPG groups, with higher mortality rates. Patients in the high HVPG group compared with the low HVPG group more often had NASH-cirrhosis (35.5% vs 19.6%; P 0.001), higher liver stiffness values (45.06 ± 20.46 vs 20.09 ± 5.47 kPa, P < 0.001), and lower platelet counts (113.37 ± 72.57 vs 151.7 ± 87.30/cmm, P < 0.001). Patients with HVPG ≥12 mm Hg received carvedilol, and a repeat HVPG performed in a proportion after 9.3 ± 2.4 months showed response (≥20% reduction in HVPG or <12 mm Hg) in 31.6% patients (Gr. B, 44.9% > Gr. C, 22.2%, P < 0.05). Baseline HVPG (HVPG ≥12 to <20 mm Hg [Hazard ratio: 2.73] and HVPG ≥20 mm Hg [Hazard ratio: 4.48], P < 0.001) independently predicted CD. DISCUSSION: HVPG ≥20 mm Hg in patients with compensated cirrhosis independently predicts early and more frequent CD and poor outcomes. These patients should be labeled as "high-risk compensated cirrhosis," and early and effective interventions to reduce portal pressure should be initiated to improve long-term outcomes.

Global microRNA expression profiling in the liver biopsies of hepatitis B virus-infected patients suggests specific microRNA signatures for viral persistence and hepatocellular injury.

Hepatitis B virus (HBV) can manipulate the microRNA (miRNA) regulatory networks in infected cells to create a permissive environment for viral replication, cellular injury, disease onset, and its progression. The aim of the present study was to understand the miRNA networks and their target genes in the liver of hepatitis B patients involved in HBV replication, liver injury, and liver fibrosis. We investigated differentially expressed miRNAs by microarray in liver biopsy samples from different stages of HBV infection and liver disease (immune-tolerant [n = 8], acute viral hepatitis [n = 8], no fibrosis [n = 16], early [F1+F2, n = 19] or late [F3+F4, n = 14] fibrosis, and healthy controls [n = 7]). miRNA expression levels were analyzed by unsupervised principal component analysis and hierarchical clustering. Analysis of miRNA-mRNA regulatory networks identified 17 miRNAs and 18 target gene interactions with four distinct nodes, each representing a stage-specific gene regulation during disease progression. The immune-tolerant group showed elevated miR-199a-5p, miR-221-3p, and Let-7a-3p levels, which could target genes involved in innate immune response and viral replication. In the acute viral hepatitis group, miR-125b-5p and miR-3613-3p were up, whereas miR-940 was down, which might affect cell proliferation through the signal transducer and activator of transcription 3 pathway. In early fibrosis, miR-34b-3p, miR-1224-3p, and miR-1227-3p were up, while miR-499a-5p was down, which together possibly mediate chronic inflammation. In advanced fibrosis, miR-1, miR-10b-5p, miR-96-5p, miR-133b, and miR-671-5p were up, while miR-20b-5p and miR-455-3p were down, possibly allowing chronic disease progression. Interestingly, only 8 of 17 liver-specific miRNAs exhibited a similar expression pattern in patient sera. CONCLUSION: miRNA signatures identified in this study corroborate previous findings and provide fresh insight into the understanding of HBV-associated liver diseases which may be helpful in developing early-stage disease diagnostics and targeted therapeutics. (Hepatology 2018;67:1695-1709).

Positive familial history for metabolic traits predisposes to early and more severe alcoholic cirrhosis: A cross-sectional study.

BACKGROUND & AIMS: Familial aggregation of metabolic traits in NAFLD is well documented. However, relevance of these traits in alcoholic cirrhosis is not well studied. We aimed to explore the association of family history of metabolic traits with age at diagnosis, severity and complications of alcoholic cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with alcoholic cirrhosis presenting to our tertiary care centre were included. Family and personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. The amount and duration of alcohol consumption were also carefully recorded. RESULTS: Out of 1084 alcoholic cirrhotics (age 48.5 ± 10.1 years, all males), family history for metabolic traits was documented in 688 (63.5%) patients. These patients had younger age at diagnosis, increased incidence of jaundice, ascites, variceal bleed and hepatic encephalopathy with consequently higher MELD and CTP score. These patients developed cirrhosis despite shorter median duration (13 years, IQR 7-20 vs 21, IQR 18-25) and lesser amount of alcohol consumption (74 g/d, IQR 24-96 vs 144, IQR 100-148). Patients with both family and personal history of metabolic traits had a higher risk by 3.3 times (95% CI 2.2-4.8) of an early age at diagnosis, 13.2 times (95% CI 8.7-20.1) of progression to cirrhosis with lesser amount of alcohol consumption and 4.6 times (95% CI 3.1-6.9) with lesser duration of alcohol consumption. CONCLUSIONS: Positive family and personal history of metabolic traits predispose to alcoholic cirrhosis with an earlier age at onset and more severity despite lesser exposure to alcohol.

A double-blind randomized controlled trial to assess efficacy of bromocriptine in cirrhotic patients with hepatic parkinsonism.

BACKGROUND: Parkinsonism like features can be seen in cirrhotics, possibly related to alterations in brain dopamine metabolism, transport and receptor integrity at basal ganglia. Hepatic parkinsonism is often not suspected and only ammonia-reducing therapies are given to such patients. We investigated the efficacy and safety of bromocriptine, a dopaminergic agent, in patients with hepatic parkinsonism. PATIENTS AND METHODS: Cirrhotics were screened for the presence of extrapyramidal symptoms and were diagnosed as hepatic parkinsonism if any two of tremor, bradykinesia and/or rigidity were present, supported by MRI brain showing T1 hyperintensities in basal ganglia and substantia nigra. Patients were randomized to receive placebo (Gr A, n = 22) or bromocriptine (Gr B, n = 24) for 12 weeks. Complete, partial and non-response were defined as 30%, 10%-30% and <10% reduction,respectively, in Unified Parkinson's Disease Rating Scale motor score. RESULTS: Of 1016 cirrhotics, 50 (4.9%) had hepatic parkinsonism. Patients in two treatment groups were comparable for MELD score, arterial NH3 and frequency of portosystemic shunts. Bromocriptine therapy for 12 weeks resulted in improvement in rigidity, tremors, bradykinesia and gait compared to placebo with complete and partial response in seven vs none (29.1%, 0%, P < 0.01) and 12 vs one (50%, 4.5%, P < 0.01) patients. Prolonged and more severe motor symptoms were associated with non-response to bromocriptine therapy. There were no major side effects in either treatment group. CONCLUSIONS: Hepatic parkinsonism is seen in ~5% cirrhotics. Bromocriptine is a safe and effective therapy for these patients and is more effective in mild to moderate hepatic parkinsonism.

Cystatin C predicts acute kidney injury and mortality in cirrhotics: A prospective cohort study.

BACKGROUND & AIMS: Acute kidney injury is a frequent and ominous complication in cirrhosis. An episode of AKI damages the functional nephron mass, compromising the renal functional reserve. We aimed to study the incidence of AKI, probability of subsequent episodes, whether AKI itself predisposes to future AKI and the reliability of serum cystatin C(sCyC) as a biomarker in a prospective cohort of cirrhotics. PATIENTS AND METHODS: Five hundred and thirty-one cirrhotics without ongoing AKI were followed for development/resolution of AKI. Predictive models for AKI and mortality were developed and validated (Gr. A, Derivative cohort [n = 273], Gr. B, Validation Cohort [n = 258]). RESULTS: 365 episodes of AKI occurred in 233 patients; yielding a mean of 1.56 episodes of AKI per patient. In Gr. A and B, 97 (35.5%) and 78 (30%) patients had prior AKI episodes and were predisposed to further attacks (Gr. A, HR 3.9, 95% CI 2.7-5.6, Gr. B, HR 3.6, 95% CI 2.5-5.4). AKI was thus an independent predictor of the development of new AKI(P < .05) and this risk increased significantly with increase in the number of AKI episodes (P < .001). S.CysC but not s.Cr was an independent predictor of new AKI on multivariate analysis. "AKI-Score" incorporating CysC; and the addition of Cyst into components of MELD, that is the "MELD-Cystatin" score predicted the development of AKI and mortality, respectively, and performed significantly better than the MELD and CTP scores. CONCLUSIONS: An episode of AKI itself predisposes to subsequent attacks of AKI in cirrhotics. Scores incorporating CysC can accurately predict the development of AKI and mortality in these patients.

SX-Ella Stent Danis Effectively Controls Refractory Variceal Bleed in Patients with Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Almost 10% of bleeding episodes are refractory to combination of vasoactive agent and endotherapy, and are associated with a mortality up to 50%. Severity of liver disease and high portal pressure are mainly responsible for it. TIPS cannot be used in these patients due to high MELD score. We aimed to evaluate the efficacy of self-expandable DE stents for control of refractory variceal bleeds in patients with ACLF. METHODS: Acute-on-chronic liver failure patients (n = 88, mean age 47.3 ± 10.9 years) with refractory variceal bleeds received either DE stent (Gr. A, n = 35) or continued with repeat endotherapy and vasoactive drug (Gr.B, n = 53). Matching by propensity risk score (PRS) was done to avoid selection bias. Competing risk Cox regression analysis was done to identify event-specific, i.e., gastrointestinal bleed-related death. RESULTS: Majority (78.4%) of patients were alcoholic with MELD score of 45.9 ± 20.1. Control of initial bleeding was significantly more in the DE stent group as compared to controls in both pre-match (89 vs. 37%; p < 0.001) and PRS-matched cohorts (73 vs. 32%; 0.007). Further, bleed-related death was also significantly lower in DE group as compared to controls in both pre-match (14 vs. 64%; p = 0.001) and PRS-matched cohorts (6 vs. 56%; p = 0.001). In a multivariate competing risk Cox model, patients who underwent DE stenting had reduced mortality in both pre-match (p = 0.04, HR 0.36, 95% CI 0.13-0.96) and PRS-matched cohorts (p < 0.001, HR 0.21, 95% CI 0.08-0.51). CONCLUSIONS: Self-expandable DE stents are very effective in control of refractory variceal bleeding and reduced mortality in patients with severe liver failure.

Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial.

BACKGROUND AND AIMS: Carvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices. METHODS: Consecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices. RESULTS: Baseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (-8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group. CONCLUSIONS: Carvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis. TRIAL REGISTRATION NUMBER: NCT01196507; post-results.

Impact of family history of metabolic traits on severity of non-alcoholic steatohepatitis related cirrhosis: A cross-sectional study.

BACKGROUND & AIMS: Familial aggregation of metabolic traits with fatty liver disease is well documented. However, there is scarcity of data regarding such association with non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study was aimed to explore the association of family history of metabolic traits with severity of cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with NASH-related cirrhosis presenting to our tertiary care centre were included. Family history, personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. RESULTS: Of the 1133 cirrhotics (68.1% males, age 51.4±10.9 years); 779 (68.8%) had family history for metabolic traits. These patients had lower age at diagnosis (45.4±10.6 vs 49.6±11.2 years), higher Child-Turcotte-Pugh (CTP) score (7.8±1.9 vs 6.6±1.5), higher model for end stage liver disease (MELD) score (12.9±6.1 vs 10.9±4.1) and more incidence of decompensation in the form of ascites (46.3% vs 25.7%), jaundice (12.1% vs 6.2%) and hepatic encephalopathy (26.1% vs 11.0%). Patients with family and personal history of metabolic traits, had an increased risk of an early diagnosis of cirrhosis at<45 years of age (OR: 3.1, 95% CI 2.1-4.4), CTP≥10 (OR: 4.6, 95% CI 2.3-9.1), MELD>15 (OR: 6.6, 95% CI 3.8-11.5) with ≥1 features of decompensation (OR: 4.2, 95% CI 2.9-6.1). Family history of diabetes alone, also had higher risk of cirrhosis with MELD>15 (OR: 4.3, 95% CI 2.4-5.3, P<.001). CONCLUSION: Family and personal history of metabolic traits are associated with early age at diagnosis of cirrhosis with more severity and decompensation and so, has a prognostic importance in NASH-related cirrhotics.

Characterization of body composition and definition of sarcopenia in patients with alcoholic cirrhosis: A computed tomography based study.

BACKGROUND: Alterations in body composition (BC) as loss of fat and muscle mass (sarcopenia) are associated with poor outcome in alcoholic cirrhosis (ALC). Prevalence of sarcopenia depends upon the method of assessment. Computed Tomography (CT) is a gold standard tool for assessing BC. AIM: To characterize BC and define sarcopenia in ALC patients using CT. METHODS: Single slice CT images at L3 vertebrae of healthy controls (HC) - organ transplant donors and ALC patients were analysed to give cross-sectional area of five skeletal muscles normalized for height -skeletal muscle index (SMI; cm2 /m2 ), area of subcutaneous (SAT;cm2 ) and visceral adipose tissue (VAT;cm2 ). Cut-offs for defining sarcopenia was established at 2SD below the mean of HC. HC were compared with Child A-compensated (C) and Child B+C-decompensated (DC) patients. RESULTS: Cut-offs of SMI derived from HC (n = 275; M: 50%; age 32.2 ± 9.8 years; BMI 24.2 ± 3.2 Kg/m2 ) were 36.54 in males and 30.21 in females. Sarcopenia was found in 12.8% of ALC patients [n = 148; C (31.8%): DC (68.2%); M: 100%; age 46.6 ± 9.7 years; BMI 24.5 ± 4.4]. Compared to HC, compensated patients had higher adiposity and comparable muscularity; decompensated patients had significantly lower muscle and also fat mass compared to both HC and compensated patients. HC vs C vs DC: SAT (140 ± 82 vs 177.3 ± 11 vs 112 ± 8.2); VAT (96.5 ± 6.5 vs 154.9 ± 8.7 vs 87.5 ± 6.5) and SMI (52.1 ± 0.9 vs 49.6 ± 1.2 vs 46 ± 0.9). CONCLUSIONS: Compensated ALC have increased adiposity and relatively preserved muscularity but decompensation leads to loss of both muscle and fat mass. Prevalence of sarcopenia, based on derived ethnic cut-offs was 12.8%.

Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts. CONCLUSIONS: The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.

Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis.

BACKGROUND & AIMS: Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis. METHODS: In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 µg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months. RESULTS: Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group. CONCLUSIONS: In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.

Fabrication of angstrom-scale two-dimensional channels for mass transport.

Fluidic channels at atomic scales regulate cellular trafficking and molecular filtration across membranes, and thus play crucial roles in the functioning of living systems. However, constructing synthetic channels experimentally at these scales has been a significant challenge due to the limitations in nanofabrication techniques and the surface roughness of the commonly used materials. Angstrom (Å)-scale slit-like channels overcome such challenges as these are made with precise control over their dimensions and can be used to study the fluidic properties of gases, ions and water at unprecedented scales. Here we provide a detailed fabrication method of the two-dimensional Å-scale channel devices that can be assembled to contain a desired number of channels, a single channel or up to hundreds of channels, made with atomic-scale precision using layered crystals. The procedure includes the fabrication of the substrate, flake, spacer layer, flake transfers, van der Waals assembly and postprocessing. We further explain how to perform molecular transport measurements with the Å-channels to directly probe the intriguing and anomalous phenomena that help shed light on the physics governing ultra-confined transport. The procedure requires a total of 1-2 weeks for the fabrication of the two-dimensional channel device and is suitable for users with prior experience in clean room working environments and nanofabrication.

Long Term HBsAg Responses to Peg-Interferon Alpha-2b in HBeAg Negative Chronic Hepatitis B Patients Developing Clinical Relapse after Stopping Long-Term Nucleos(t)ide Analogue Therapy.

Background and aims: A high proportion of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients develop clinical relapse after stopping long-term nucleotide analogues (NAs). The aim of this study was to assess the efficacy of pegylated interferon (PEG-IFN) alpha 2b in inducing hepatitis B surface antigen (HBsAg) loss in such patients. Methods: NAs were stopped in 118 HBeAg-negative CHB patients fulfilling the Asian Pacific Association for the Study of Liver (APASL) 2015 criteria for stopping NAs; they had received NAs for a median interquartile range (IQR) of 60 (48-84) months. Results: Overall, 82 of 118 (69.5%) patients developed clinical relapse after stopping NAs; 44 within 12 months (and treated with PEG-IFN alpha 2b 1.5 mcg/kg weekly subcutaneous injections for 48 weeks); and 38 after 12 months [and treated with tenofovir alafenamide fumarate (TAF) 25 mg daily] of follow-up. The decision to treat with either PEG-IFN or TAF was not a time-bound decision but was due to logistical problems.During the median IQR follow-up of 48 (43.5-52.5) months after the start of PEG-IFN, 14 of 44 (31.8%) patients developed clinical relapse after stopping PEG-IFN and were started on TAF. At the last follow-up visit, HBsAg was found to be negative in 7/44 (15.9%) of patients receiving PEG-IFN.Among 38 patients treated with TAF for clinical relapse, during the median IQR follow-up of 18 (12-30) months after start of TAF, no patient became HBsAg negative.36 patients did not develop clinical relapse during the follow-up, and after a median IQR follow-up of 60 (60-60) months after stopping NAs, HBsAg negative was found in 1/36 (2.8%) of patient at the last follow-up. Conclusions: Among patients with HBeAg-negative chronic hepatitis B who developed clinical relapse after stopping long-term NAs therapy and were subsequently treated with PEG-IFN alpha 2b, 15.9% achieved HBsAg loss on long-term follow-up.

COVID-19 - a potential trigger for MOGAD-associated optic neuritis: a case report and literature review.

SARS-CoV-2 affects the nervous system directly by neurotoxic action, by binding to angiotensin-converting enzyme-2 (ACE2) receptors or indirectly by inducing cytokine storm leading to disruption of the blood-brain barrier, immunological mediation, increasing blood coagulation and as a trigger for autoimmune-mediated demyelinating injuries in the central nervous system. In COVID-19 neuro-ophthalmological manifestations are not so common. Optic neuritis is the result of optic nerve inflammation and has varied causes. In many patients, signs of inflammation are not visible on the fundus, and it usually manifests as papillitis-anterior neuritis, retrobulbar neuritis or visible optic nerve oedema. We are reporting a case of a middle-aged adult diagnosed with myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis of the right eye post-COVID-19 disease. Routine biochemical and haematological investigations, including electrolytes and hepatic and renal functions, were normal. In cerebrospinal fluid (CSF) - glucose 63.8 mg/dL, protein 39.1 mg/dL and ADA - 1 µ/L. No oligoclonal bands of immunoglobulin G (IgG) were seen on high-resolution electrophoresis. Serum Anti-MOG-antibodies were positive. A gadolinium-contrast magnetic resonance imaging (MRI) of the brain and orbits shows post-contrast enhancement in the superior aspect of the right intraconal soft tissue. The right optic nerve appears bulky and heterogeneous with peripheral post-contrast enhancement along its entire length suggestive of neuritis. A diagnosis of MOG antibody-positive optic neuritis was made, and the patient was treated with an injection of Methylprednisolone with intravenous immunoglobulin. Each day, the evaluation of the right eye showed remarkable improvement from finger counting to 6/6 vision. The patient was discharged on the 9th day of admission. We can conclude that early diagnosis was essential for improving the long-term outcome of the patient.

Patency Rates and Outcomes of Renal Access Arteriovenous Fistulas for Hemodialysis in Patients with Chronic Kidney Disease.

Hemodialysis remains the most popular modality of renal replacement therapy for end-stage renal disease patients with chronic kidney disease. Various factors such as a radial artery, cephalic vein diameter, age, hypertension, and diabetes mellitus can affect the fistula maturation. This study was carried out to know the patency rates and factors affecting fistula maturation in the Indian population. This is a prospective observational study which aimed to study the patency rate of arteriovenous (AV) fistulas. On the day of surgery, patients were shifted inside the operation theater. Under all aseptic precautions, an AV fistula was formed using the radial artery and cephalic vein. All patients were followed up for 6 months. The data were analyzed using IBM SPSS version 22. To see the change over a period of time, McNemar test for categorical data and repeated measure for continuous data followed by post hoc comparison by Bonferroni method were used. The mean age of the patients was 46.98 ± 13.33 years. The mean diameter of the cephalic vein, ulnar artery, and radial artery at the wrist was 1.733 ± 0.528, 1.700 ± 0.364, and 1.908 ± 0.420, respectively, whereas the mean diameter of the cephalic vein, ulnar artery, and radial artery at the forearm was 1.952 ± 0.488, 1.910 ± 0.421, and 2.058 ± 0.458, respectively. Immediate thrill after the surgery was present in 36/52 (69.2%) of the patients. The radial artery diameter at the wrist was significantly less in the patients with primary failure in whom immediate thrill was not present (P = 0.016). At 1-month follow-up, 30/49 (61.2%) and, at 6 months, 29/48 (60.4%) fistulas were functional. Radiocephalic AV fistulas have a reasonable success rate and minimal morbidity, and radial artery diameter is a good predictor of the outcome.

Safety and Efficacy of Endoscopic Retrograde Cholangio-Pancreatography in Patients of Liver Cirrhosis: A Case-Control Study.

Background With the improvement in noninvasive diagnostic imaging modalities, Endoscopic Retrograde Cholangio-Pancreatography (ERCP) has evolved into a primarily therapeutic procedure. Besides being efficacious and one of the most commonly done procedures, ERCP is also associated with a high risk of complications. However, there is a lack of studies analyzing the safety and success of ERCP in patients with liver cirrhosis. We retrospectively evaluated the outcome of ERCP in patients with cirrhosis of the liver compared to non-cirrhotic patients using the database from our institute. Methods Patients with liver cirrhosis who underwent ERCP from January 2010 to March 2020 were analyzed. This was a matched case-control study in which one cirrhotic patient undergoing ERCP was age and gender-matched randomly to one non-cirrhotic patient. We compared adverse events and the success rate of ERCP between cirrhotic patients and non-cirrhotic patients. The primary outcome of the study was analyzing the prevalence of procedure-related adverse events and their independent risk factors in patients of cirrhosis compared to the non-cirrhotic population. Results Two hundred patients were analyzed in both groups. Choledocholithiasis was the most common reason for ERCP in both groups. Mean Child-Turcotte-Pugh (CTP) score and Model for End-stage Liver Disease (MELD) score in the cirrhosis group were 9.16 ±1.78 and 19.09 ±7.06 respectively. Patients in the cirrhosis group had a significantly higher frequency of complications compared to the controls: 41 (20.5 %) versus 15 (7.5%), p < 0.01. Bleeding was the most common adverse event in both groups: 19 (9.5%) vs 6(3%). High International Normalised Ratio (INR), low platelets, and cholangitis at presentation were independently predictive of post-ERCP complications. Despite a similar technical success rate, the clinical success rate was lower in the cirrhotic than in the noncirrhotic group (83.9% versus 97.9%, p=0.006). Conclusion The prevalence of complications following ERCP was nearly three-fold higher in patients with cirrhosis than in non-cirrhotic patients. These events were related primarily to cholangitis, coagulopathy, and the advanced status of chronic liver disease.