Plasma Metabolite Profiling Identifies Nondiabetic Chronic Pancreatitis Patients With Metabolic Alterations Progressing to Prediabetes Before HbA1c.

INTRODUCTION: Diabetes (T3cDM) secondary to chronic pancreatitis (CP) arises due to endocrine dysfunction and metabolic dysregulations. Currently, diagnostic tests are not available to identify patients who may progress from normoglycemia to hyperglycemia in CP. We conducted plasma metabolomic profiling to diagnose glycemic alterations early in the course of disease. METHODS: Liquid chromatography-tandem mass spectrometry was used to generate untargeted, targeted plasma metabolomic profiles in patients with CP, controls (n = 445) following TRIPOD guidelines. Patients were stratified based on glucose tolerance tests following ADA guidelines. Multivariate analysis was performed using partial least squares discriminant analysis to assess discriminatory ability of metabolites among stratified groups. COMBIROC and logistic regression were used to derive biomarker signatures. AI-ML tool (Rapidminer) was used to verify these preliminary results. RESULTS: Ceramide, lysophosphatidylethanolamine, phosphatidylcholine, lysophosphatidic acid (LPA), phosphatidylethanolamine, carnitine, and lysophosphatidylcholine discriminated T3cDM CP patients from healthy controls with AUC 93% (95% CI 0.81-0.98, P < 0.0001), and integration with pancreatic morphology improved AUC to 100% (95% CI 0.93-1.00, P < 0.0001). LPA, phosphatidylinositol, and ceramide discriminated nondiabetic CP with glycemic alterations (pre-diabetic CP); AUC 66% (95% CI 0.55-0.76, P = 0.1), and integration enhanced AUC to 74% (95% CI 0.55-0.88, P = 0.86). T3cDM was distinguished from prediabetic by LPA, phosphatidylinositol, and sphinganine (AUC 70%; 95% CI 0.54-0.83, P = 0.08), and integration improved AUC to 83% (95% CI 0.68-0.93, P = 0.05). CombiROC cutoff identified 75% and 78% prediabetes in validation 1 and 2 cohorts. Random forest algorithm assessed performance of integrated panel demonstrating AUC of 72% in predicting glycemic alterations. DISCUSSION: We report for the first time that a panel of metabolites integrated with pancreatic morphology detects glycemia progression before HbA1c in patients with CP.

Antibiotics With or Without Rifaximin for Acute Hepatic Encephalopathy in Critically Ill Patients With Cirrhosis: A Double-Blind, Randomized Controlled (ARiE) Trial.

INTRODUCTION: Critically ill patients with cirrhosis admitted to the intensive care unit (ICU) are usually on broad-spectrum antibiotics because of suspected infection or as a hospital protocol. It is unclear if additional rifaximin has any synergistic effect with broad-spectrum antibiotics in ICU patients with acute overt hepatic encephalopathy (HE). METHODS: In this double-blind trial, patients with overt HE admitted to ICU were randomized to receive antibiotics (ab) alone or antibiotics with rifaximin (ab + r). Resolution (or 2 grade reduction) of HE, time to resolution of HE, in-hospital mortality, nosocomial infection, and changes in endotoxin levels were compared between the 2 groups. A subgroup analysis of patients with decompensated cirrhosis and acute-on-chronic liver failure was performed. RESULTS: Baseline characteristics and severity scores were similar among both groups (92 in each group). Carbapenems and cephalosporin with beta-lactamase inhibitors were the most commonly used ab. On Kaplan-Meier analysis, 44.6% (41/92; 95% confidence interval [CI], 32-70.5) in ab-only arm and 46.7% (43/92; 95% CI, 33.8-63) in ab + r arm achieved the primary objective ( P = 0.84).Time to achieve the primary objective (3.65 ± 1.82 days and 4.11 ± 2.01 days; P = 0.27) and in-hospital mortality were similar among both groups (62% vs 50%; P = 0.13). Seven percent and 13% in the ab and ab + r groups developed nosocomial infections ( P = 0.21). Endotoxin levels were unaffected by rifaximin. Rifaximin led to lower in-hospital mortality (hazard ratio: 0.39 [95% CI, 0.2-0.76]) in patients with decompensated cirrhosis but not in patients with acute-on-chronic liver failure (hazard ratio: 0.99 [95% CI, 0.6-1.63]) because of reduced nosocomial infections. DISCUSSION: Reversal of overt HE in those on ab was comparable with those on ab + r.

Heterologous Booster Dose with CORBEVAX following Primary Vaccination with COVISHIELD Enhances Protection against SARS-CoV-2.

Despite effective vaccination programs, waning immunity in the vaccinated populations and the emergence of variants of concern posed a risk of breakthrough infections. A booster dose was demonstrated to provide substantially increased protection against symptomatic disease and hospitalization. We aimed to evaluate immune memory and the efficacy of reducing the rate of SARS-CoV-2 infection post heterologous booster with CORBEVAX after primary vaccination with two doses of COVISHIELD. SARS-CoV-2 S1/S2 spike IgG and RBD-specific antibody responses were elicited with both booster vaccines, with a greater response in individuals receiving heterologous booster. T and B memory responses were increased with booster dose, whereas B memory needed a longer duration to develop in individuals who received a homologous booster (90 days) in comparison to a heterologous booster (30 days). RBD-specific B memory and antibody-secreting (non-memory) B lymphocytes were enhanced with both boosters; however, the duration of response was longer with the heterologous booster compared to the homologous, indicating greater protection with the heterologous booster. The rate of infection 14 days after administration of the heterologous booster was comparatively lower than that of the homologous booster, with the symptoms being much less or asymptomatic.

Poor immune response to coronavirus disease vaccines in decompensated cirrhosis patients and liver transplant recipients.

BACKGROUND AND AIMS: Recent studies have reported poor humoral immune response to mRNA vaccines in patients with chronic liver disease (CLD). However, the immunogenicity of ChAdOx1 (vector-based) and BBV152 (inactivated virus) vaccines in patients with CLD and liver transplant recipients (LTRs) is unknown. Therefore, we aimed to assess the immunogenicity of ChAdOx1 and BBV152 vaccines in patients with CLD (including cirrhosis patients) and LTRs. METHODS: In this single-center prospective study, consecutive completely vaccinated (ChAdOx1 or BBV152) non-cirrhosis CLD patients, those with cirrhosis, and LTRs were compared with matched healthy controls for anti-spike antibody and cellular response. RESULTS: Sixty healthy individuals, 50 NCCLD patients, 63 compensated and 50 decompensated cirrhosis, and 17 LTRs were included. The proportion of non-responders was similar among the healthy control (8 %), non-cirrhosis CLD (16 %), and compensated cirrhosis groups (17.5 %;p = 0.3). However, a higher proportion of patients with decompensated cirrhosis (34 %) and LTRs (59 %) were non-responders than the healthy controls (p = 0.001). Cluster of differentiation (CD) 4-effector cells were lower in patients with non-cirrhosis CLD and compensated cirrhosis. CD4-naïve, CD4-effector, B, and B-memory cells were lower in the decompensated cirrhosis group. Although the central memory cells were higher in the decompensated cirrhosis group, they could not differentiate into effector cells. CD4- and CD8-naïve cells were higher in the marrow in the LTRs, while the CD4-effector memory cells and CD4- and CD8-effector cells were lower in the LTRs. Furthermore, B cells were more deficient in the LTRs, suggesting poor antibody response. CONCLUSION: Patients with decompensated cirrhosis and LTRs demonstrated suboptimal humoral and cellular immune responses against recombinant and inactivated COVID-19 vaccines.

Primary Norfloxacin Prophylaxis for APASL-Defined Acute-on-Chronic Liver Failure: A Placebo-Controlled Double-Blind Randomized Trial.

INTRODUCTION: This study aimed to evaluate the role of prophylactic norfloxacin in preventing bacterial infections and its effect on transplant-free survival (TFS) in patients with acute-on-chronic liver failure (ACLF) identified by the Asian Pacific Association for the Study of the Liver criteria. METHODS: Patients with ACLF included in the study were randomly assigned to receive oral norfloxacin 400 mg or matched placebo once daily for 30 days. The incidence of bacterial infections at days 30 and 90 was the primary outcome, whereas TFS at days 30 and 90 was the secondary outcome. RESULTS: A total of 143 patients were included (72 in the norfloxacin and 71 in the placebo groups). Baseline demographics, biochemical variables, and severity scores were similar between the 2 groups. On Kaplan-Meier analysis, the incidence of bacterial infections at day 30 was 18.1% (95% confidence interval [CI], 10-28.9) and 33.8% (95% CI, 23-46) (P = 0.03); and the incidence of bacterial infections at day 90 was 46% (95% CI, 34-58) and 62% (95% CI, 49.67-73.23) in the norfloxacin and placebo groups, respectively (P = 0.02). On Kaplan-Meier analysis, TFS at day 30 was 77.8% (95% CI, 66.43-86.73) and 64.8% (95% CI, 52.54-75.75) in the norfloxacin and placebo groups, respectively (P = 0.084). Similarly, TFS at day 90 was 58.3% (95% CI, 46.11-69.84) and 43.7% (95% CI, 31.91-55.95), respectively (P = 0.058). Thirty percent of infections were caused by multidrug-resistant organisms. More patients developed concomitant candiduria in the norfloxacin group (25%) than in the placebo group (2.63%). DISCUSSION: Primary norfloxacin prophylaxis effectively prevents bacterial infections in patients with ACLF.

Adipocyte Fatty Acid-Binding Protein as a Predictor of Outcome in Alcohol-induced Acute-On-Chronic Liver Failure.

BACKGROUND: Alcohol is the leading cause of acute-on-chronic liver failure (ACLF). Several severity scores predict the outcome of ACLF. However, there is a lack of simple biomarkers in predicting the outcome of these sick patients. Fatty acid-binding proteins (FABPs) are small cytosolic proteins that play a major role in lipid metabolism, energy homeostasis, and inflammation, but, have not been investigated in alcohol-induced ACLF (A-ACLF). OBJECTIVES: The primary objective was to assess the correlation between serum adipocyte-FABP (A-FABP) and liver-FABP (L-FABP) levels on mortality at day 90. Secondary objectives were to compare the levels between controls and A-ACLF, correlate L-FABP, and A-FABP levels on the development of organ failure/sepsis at day 90. METHODS: In this prospective observational pilot study, we included patients with A-ACLF and age-matched healthy controls. FABP's were analyzed by enzyme-linked immunosorbent assay method. The patients were followed up for 90 days. RESULTS: Twenty-five patients with A-ACLF (mean age: 40years; mean model for end-stage liver disease NA: 29.8; median Modified Maddrey's discriminant function [mDF]: 95) and 12 controls (mean age: 36.83yrs) were included in the study. A-FABP and L-FABP levels were significantly high in patients with A-ACLF than controls. Forty-four percent of patients with A-ACLF developed sepsis, 48% developed organ failure, and 44% expired by day 90. On multivariate Cox regression analysis, A-FABP (hazard ratio [HR]: 1.27 [1.08-1.5]; P = 0.003), Asian Pacific Association for the Study of Liver ACLF research consortium score (HR: 3.3[1.15-9.54]; P = 0.02), L-FABP (HR: 0.69 [0.52-0.91]; P = 0.009), and serum protein levels (HR: 0.03 [0.003-0.36]; P = 0.005) predicted mortality. A-FABP (1.17 [1.07-1.29]; P = 0.001), and serum bilirubin (1.05 [0.99-1.12]; P = 0.06) predicted development of organ failure, and only mDF (HR: 1.04 [1.01-1.07]; P = 0.009) predicted the development of sepsis on multivariate analysis. Fifteen patients received steroid therapy, of which 13.34% were nonresponders. CONCLUSIONS: In a selected group of patients with A-ACLF, A-FABP is highly sensitive at predicting mortality and outcome. If validated in a large, diverse sample, A-FABP can be used as a simple biomarker for prognostication in A-ACLF.