Home-based intensive nutrition therapy improves frailty and sarcopenia in patients with decompensated cirrhosis: A randomized clinical trial.

BACKGROUND AND AIM: The majority of patients with decompensated cirrhosis suffer from malnutrition, a potentially modifiable contributor to frailty and sarcopenia. The present study investigated the impact of a 6-month dietician-supported home-based intensive nutrition therapy (HINT) intervention on objective frailty and sarcopenia metrics in patients with decompensated cirrhosis. METHODS: One hundred adult patients with decompensated cirrhosis, frailty, and sarcopenia at baseline were randomized 1:1 to receive standard medical therapy (SMT) plus HINT (intervention) versus SMT (control) alone. The primary outcome was an improvement in frailty as measured by the liver frailty index (LFI). Secondary outcome measures included sarcopenia metrics, liver disease severity scores, hospitalization, and death. RESULTS: The LFI improved more in the intervention arm as compared with controls (0.8 vs 0.4; P < 0.001). Baseline and end-of-study skeletal muscle index (SMI) was available in a subset of 32 male patients, with greater improvements seen in the intervention arm compared with controls (6.36 vs 0.80; P = 0.02). Patients in the intervention arm had less hospitalizations over the 6-month follow-up (19 [38%] vs 29 [58%]; P = 0.04). On subgroup analysis, in the 64% of patients who were adherent to calorie and protein intake targets at 6 months, significant improvement was seen in liver disease severity scores and survival (P < 0.05). CONCLUSION: In patients with decompensated cirrhosis, frailty, and sarcopenia, a 6-month dietitian-supported home-based intensive outpatient nutrition therapy was associated with statistically and clinically relevant improvement in frailty. The subgroup of adherent patients showed improvement in their liver disease scores and reduction in mortality. These findings support the key role of food as medicine in the management of cirrhosis.

Improvement of chronic HCV infection-related depression, anxiety, and neurocognitive performance in persons achieving SVR-12: A real-world cohort study.

Chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric changes. Also, patients with cirrhosis may develop overt or minimal hepatic encephalopathy. Sustained virological response (SVR) with direct-acting antiviral agents (DAAs) may improve the neuropsychiatric manifestations and quality of life (QoL). Consecutive patients (with and without cirrhosis, all genders and aged 18-65 years) with hepatitis C were assessed at enrolment and at 12 weeks after therapy completion for mood (Beck's Depression Inventory [BDI]), anxiety (generalized anxiety disorder [GAD-7]), QoL (SF-36 ver.2) and computer-based tests for number connection (NCT), visual memory, Stroop test and reaction times. We recruited 385 viraemic chronic HCV patients (76.1% male, 21.0% cirrhotic, mean age 39.4 ± 14.2 years, 59.3% genotype 3, mean HCV RNA load 5.8 log). Overall SVR-12 rates were 90.6%, with cure rates 87.6% and 91.4% in patients with and without cirrhosis, respectively. Patients who achieved SVR-12 had mean percentage reduction in BDI (11.3%, p = .000), GAD (8.6%, p = .001) and Stroop test (58.4%, p = .001), with improved NCT (1.7%, p = .001), visual memory (13.7%, p = .001) and digit span (23.8%, p = .002). On multivariate logistic regression, adherence (OR, 17.5 [95% CI 2.80-110.50], p = .000), high ALT (OR 1.02 [95% CI 1.00-1.05]), and BDI score (OR 1.73 [95% CI 1.42-3.26] p = .039) predicted cure. SVR-12 was associated with improved visual memory ≥5.5 (AUC-0.708; sensitivity 62.5%, specificity 63%, p = .000) and % correct Stroop test responses >26.6% (AUC-0.918, sensitivity 94.4% specificity 80.4%, p = .000). In conclusion, given the cumulative evidence of the safety of DAAs and efficacy of improving cognitive and neuropsychological and quality-of-life outcomes irrespective of age and gender, as shown in our study, future recommendations should focus on integrated universal HCV care to enable HCV elimination.

Combined PEG3350 Plus Lactulose Results in Early Resolution of Hepatic Encephalopathy and Improved 28-Day Survival in Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label-randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥2 for efficacy and outcome. PATIENTS AND METHODS: Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit. RESULTS: Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%); P=0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d; P=0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13); P=0.03], HESA score [HR, 6.01 (1.27 to 28.5); P=0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53); P=0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P=0.010) and at 90 days was 68.9% versus 48.3% (P=0.940), respectively, with fewer persons relapsing with HE in the PEG arm. CONCLUSIONS: PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.

Sofosbuvir and Velpatasvir combination is safe and effective in treating chronic hepatitis C in end-stage renal disease on maintenance haemodialysis.

BACKGROUND & AIMS: There is emerging data on the use of Sofosbuvir-based directly acting antiviral (DAA) drug regimens in chronic hepatitis C (CHC) patients with end-stage renal disease (ESRD) on maintenance haemodialysis (MHD). We evaluated the safety and efficacy of Sofosbuvir plus Velpatasvir fixed-dose combination in CHC patients with ESRD on MHD. METHODS: Fifty-one CHC patients with ESRD on MHD were included in a real-life prospective study. All patients irrespective of genotype; presence of cirrhosis; treatment naive or experienced status were treated with full-dose Sofosbuvir (400 mg) plus Velpatasvir (100 mg) fixed-dosed combination given daily for 12 weeks. The efficacy was assessed by the sustained virological response (SVR12) with negative HCV RNA 12 weeks after the end of treatment (ETR). Side effects if any were recorded in all patients. RESULTS: The median HCV RNA level in 51 CHC patients [Males 41 (80.4%), mean age 42.8 ± 14.6 years] was 2.0 × 106 IU/mL. HCV genotype was available in 19 patients with predominant genotype 1 in 15 (79%) patients. Ten (19.6%) patients had evidence of cirrhosis (defined as LSM ≥ 12.5 kPa on Transient Elastography), and 8 (15.6%) patients were treatment experienced. Testing for ETR was done in 36 patients and all 36 (100%) patients achieved ETR, and 49 patients (96%) achieved SVR 12. All 51 patients tolerated the Sofosbuvir + Velpatasvir combination, with none of the patients reporting any serious adverse event. CONCLUSION: Sofosbuvir plus Velpatasvir fixed-dose combination is safe and effective in treating CHC in patients with ESRD on MHD.

Impact of metabolic risk factors on the severity and outcome of patients with alcohol-associated acute-on-chronic liver failure.

BACKGROUND: Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY: One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS: Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P < .001), independent of age, CTP, MELD and AARC scores. CONCLUSION: Overweight/obesity and dyslipidaemia increase the severity of alcohol-associated ACLF, and the former also increases the short-term mortality in these patients.

Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: We aimed to synthesize evidence for most effective treatments for minimal hepatic encephalopathy (HE) and prevention of overt HE in patients with cirrhosis. METHODS: We performed a systematic search of the PubMed, EMBASE, OvidSP, and Cochrane Central Register of Controlled Trials databases through July 26, 2018, for randomized controlled trials evaluating treatments for minimal HE in patients with cirrhosis, with primary outcomes of reversal of minimal HE or prevention of overt HE. We conducted a meta-analysis and then used network meta-analysis and surface under cumulated ranking (SUCRA) to pool the direct and indirect estimates and rank the different treatments. We appraised study quality using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Our meta-analysis and network meta-analysis included 25 trials, comprising 1563 participants. Agents found to be effective in reversing minimal HE compared with placebo or no treatment included rifaximin (odds ratio [OR], 7.53; 95% predictive interval [PrI], 4.45-12.73; SUCRA, 89.2%; moderate quality), lactulose (OR, 5.39; 95% PrI, 3.60-8.0; SUCRA, 67.2%; moderate quality), the combination of probiotics and lactulose (OR, 4.66; 95% PrI, 1.90-11.39; SUCRA, 52.4%; low quality), L-ornithine L-aspartate (OR, 4.45; 95% PrI, 2.67-7.42; SUCRA, 47.2%; low moderate quality), and probiotics (OR, 3.89; 95% PrI, 2.52-6.02; SUCRA, 34.1%; low quality). Agents found to be effective in preventing episodes of overt HE compared with placebo or no treatment included L-ornithine L-aspartate (OR, 0.19; 95% PrI, 0.04-0.91; SUCRA, 75.1%; high moderate quality), lactulose (OR, 0.22; 95% PrI, 0.09-0.52; SUCRA, 73.9%; moderate quality), and probiotics (OR, 0.27; 95% PrI, 0.11-0.62; SUCRA, 59.6%; low quality). CONCLUSIONS: In a meta-analysis of data from 25 trials, we found rifaximin and lactulose to be most effective for reversal of minimal HE in patients with cirrhosis. L-ornithine L-aspartate and lactulose are most effective in the prevention of overt HE. Lactulose was the only agent that was effective in reversing minimal HE, preventing overt HE, reducing ammonia, and improving quality of life, with tolerable adverse effects. International prospective register of systematic reviews ID: 107003.

Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus.

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy.

Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.

Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria.

BACKGROUND: Emergence of anti-malarial drug resistance and perpetual increase in malaria incidence necessitates the development of novel anti-malarials. Histone deacetylases (HDAC) has been shown to be a promising target for malaria, despite this, there are no HDAC inhibitors in clinical trials for malaria treatment. This can be attributed to the poor pharmacokinetics, bioavailability and selectivity of the HDAC inhibitors. METHODS: A collection of HDAC inhibitors were screened for anti-malarial activity, and the best candidate was profiled in parasite-killing kinetics, growth inhibition of sensitive and multi-drug resistant (MDR) strains and against gametocytes. Absorption, distribution, metabolism and excretion pharmacokinetics (ADME-PK) parameters of FNDR-20123 were determined, and in vivo efficacy was studied in a mouse model for Plasmodium falciparum infection. RESULTS: A compound library of HDAC inhibitors (180 in number) was screened for anti-malarial activity, of which FNDR-20123 was the most potent candidate. The compound had been shown to inhibit Plasmodium HDAC with IC50 of 31 nM and human HDAC with IC50 of 3 nM. The IC50 obtained for P. falciparum in asexual blood-stage assay was 42 nM. When compared to atovaquone and pyrimethamine, the killing profiles of FNDR-20123 were better than atovaquone and comparable to pyrimethamine. The IC50 values for the growth inhibition of sensitive and MDR strains were similar, indicating that there is no cross-resistance and a low risk of resistance development. The selected compound was also active against gametocytes, indicating a potential for transmission control: IC50 values being 190 nM for male and > 5 µM for female gametocytes. FNDR-20123 is a stable candidate in human/mouse/rat liver microsomes (> 75% remaining post 2-h incubation), exhibits low plasma protein binding (57% in humans) with no human Ether-à-go-go-Related Gene (hERG) liability (> 100 µM), and does not inhibit any of the cytochrome P450 (CYP) isoforms tested (IC50 > 25 µM). It also shows negligible cytotoxicity to HepG-2 and THP-1 cell lines. The oral pharmacokinetics in rats at 100 mg/kg body weight shows good exposures (Cmax = 1.1 µM) and half-life (T1/2 = 5.5 h). Furthermore, a 14-day toxicokinetic study at 100 mg/kg daily dose did not show any abnormality in body weight or gross organ pathology. FNDR-20123 is also able to reduce parasitaemia significantly in a mouse model for P. falciparum infection when dosed orally and subcutaneously. CONCLUSION: FNDR-20123 may be a suitable candidate for the treatment of malaria, which can be further developed.

Prediction of 28-day mortality in acute decompensation of cirrhosis through the presence of multidrug-resistant infections at admission.

BACKGROUND AND AIM: The aim of this study is to evaluate the epidemiology and impact of bacterial infections at admission in patients with acute decompensation (AD) of cirrhosis. METHODS: A cohort with AD of cirrhosis (European Association for the Study of the Liver criteria) admitted at a tertiary center was evaluated between 2013 and 2014 for the presence of bacterial infections at admission. Clinical, demographic, and microbiological data were collected prospectively till death, transplant, or 90 days. RESULTS: Of 179 patients with AD, 102 (56.9%) had bacterial infections at admission. The commonest infections were spontaneous bacterial peritonitis (SBP) (n = 65; 63.7%), spontaneous bacteremia (n = 10; 9.8%), pneumonia (n = 9; 8.8%), urinary tract infection (n = 8; 7.8%), spontaneous bacterial empyema (n = 4; 3.9%), and cellulitis (n = 2; 1.9%). The commonest source was community acquired (n = 85; 83.3%). Serum albumin and sodium levels were lower in infected as compared with non-infected cohort (P = 0.015; for both). Escherichia coli was the commonest organism isolated from SBP (n = 14; 21.5%), urinary tract infection (n = 5; 45.5%), and bacteremia (n = 3; 20%). There was a trend toward higher 28-day mortality in infected cohort as compared with non-infected cohort (48 [52.7%] vs 28 [32%]; P = 0.152). Multidrug-resistant organisms (MDROs) were isolated in 63% of all culture-positive infections. The presence of MDRO was an independent predictor of 28-day mortality. CONCLUSIONS: Infections are the leading reason for the occurrence of AD; SBP is the most common infection, and E. coli is the commonest microorganism based on this single-center study of Indian patients with AD of cirrhosis. There is a high prevalence of MDROs among culture-positive infections that independently predict 28-day mortality in AD of cirrhosis.

Effectiveness of Paraffin and Sustained Stretch in Treatment of Shoulder Contractures Following a Burn Injury.

OBJECTIVE: To examine if range of motion of the shoulder treated with paraffin will be better than that of the shoulder treated with sustained stretch alone. DESIGN: Pilot randomized controlled trial. SETTING: Regional burn center. PARTICIPANTS: Patients (N=23) who sustained a burn injury, with a shoulder active abduction and/or flexion in the +70° to +150° degree range, who were 14 years or older, were receiving follow-up physical therapy after discharge from hospital, and provided a signed consent to participate. INTERVENTIONS: Group A received sustained stretch and paraffin, and group B received sustained stretch only. Both groups had 6 sessions of treatment over 2 weeks. MAIN OUTCOME MEASURES: Active range of motion (AROM) and active-assisted range of motion (AAROM) for shoulder flexion (SF) and shoulder abduction (SA) were measured before and after each treatment session. RESULTS: For pretreatment measurements, only the results for SF AAROM had significant time effects. For posttreatment measurements, SF AROM and SF AAROM had significant effects for time. Session 1 was significantly lower than sessions 2, 3, 4, and 6 for both measures, and additionally, session 1 was significantly lower than session 5 for SF AAROM. For SA AROM, a group-by-time interaction effect was significant, with scores for the paraffin group relatively stable across sessions, and the nonparaffin group had peaks at sessions 3 and 6. There were no significant effects for (1) within-session changes to examine improvement during a session or (2) presession scores across the 6 sessions showing maintenance of motion. Total change from the first session presession measurement to the sixth session postsession measurement for the 2 treatment groups were nonsignificantly different. CONCLUSIONS: As shown in this study, sustained stretching with paraffin may be a valuable adjunct to range of motion intervention for the shoulder after burn injury.

Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public health care setting.

BACKGROUND & AIMS: The prevalence of anti-hepatitis C virus antibody in Punjab, India is 3.6%, with 728,000 people estimated to have viremic chronic hepatitis C (CHC). The Mukh-Mantri Punjab Hepatitis C Relief Fund, launched on 18th June 2016, provides no-cost generic direct-acting antivirals (DAAs) with sofosbuvir + ledipasvir ±â€¯ribavirin or sofosbuvir + daclatasvir ±â€¯ribavirin with the goal of eliminating CHC from Punjab. We assessed the safety and efficacy of decentralized treatment of CHC in a public health care setting. METHODS: Primary care providers from 3 university and 22 district hospitals were trained to provide algorithm-based DAA treatment and supervised by telehealth clinics conducted fortnightly. The diagnosis of cirrhosis was based on clinical and radiological evidence, including aspartate aminotransferase-to-platelet ratio index (APRI ≥2.0) and FIB-4 score (>3.25), or on liver stiffness measurement ≥12.5 kPa on Fibroscan®. RESULTS: We enrolled 48,088 individuals with CHC (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhosis; 69.9% genotype [GT] 3) between 18th June 2016 to 31st July 2018. While 36,250 (75.4%) patients completed treatment, 5,497 (11.4%) had treatment interruptions and 6,341 (13.2%) patients are currently ongoing treatment. Sustained virological response at 12 weeks after treatment completion (SVR12) was achieved in 91.6% of patients per protocol, 67.6% in intention-to-treat (ITT) analysis, where all interruptions were treated as failures, and 91.2% in a modified ITT analysis where all patients with successful SVR12 in the interruptions arm were included as cured. SVR12 rates in patients with and without cirrhosis and GT3 versus non-GT3 were comparable. The SVR12 rate was 84.4% in patients who had treatment interruptions. CONCLUSION: Decentralized care of patients with CHC using generic all-oral DAA regimens is safe and effective regardless of genotype or presence of cirrhosis. ClinicalTrials.gov number: NCT01110447. LAY SUMMARY: We assessed the safety and efficacy of public health care using no-cost all-oral generic direct-acting antiviral drugs against hepatitis C in the state of Punjab, India. The goal is elimination of chronic hepatitis C (CHC) by 2030 and involves primary care providers at 25 sites in the state. We enrolled 48,088 individuals (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhotic; 69.9% genotype 3) between 18th June 2016 to 31st July 2018. Cure was achieved in 91.6% of patients, demonstrating that decentralized care of CHC with generic all-oral regimens is safe and effective.

Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

OBJECTIVES: Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS: We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS: Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION: Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

Invasive fungal infections amongst patients with acute-on-chronic liver failure at high risk for fungal infections.

AIMS: To study the prevalence, risk factors, role of serum biomarkers for diagnosis and impact of invasive fungal infections (IFIs) in patients with acute-on-chronic liver failure (ACLF). METHODS: An analysis of IFI in patients with ACLF (EASL criteria) was conducted retrospectively. The diagnosis of IFI in clinically suspected patients was based on EORTC/MSG criteria. The demographical, clinical, laboratory details and outcomes were analysed. RESULTS: Out of 264 patients with ACLF, 54 (20.4%) patients with suspicion of IFI were evaluated and IFI was diagnosed in 39 (14.7%). Invasive candidiasis was documented in 25 (64.1%) and invasive aspergillosis in 14 (35.8%). The most common source of infection was respiratory (n = 13) followed by renal (n = 7) and spontaneous fungal peritonitis (n = 6). On univariate analysis, diabetes mellitus, hemodialysis, prior antibiotic use, cerebral and respiratory organ failures, Chronic Liver Failure Consortium (CLIF-OF and CLIF-C ACLF) scores were predictors for development of IFI (P < 0.05). On multivariate analysis, hemodialysis and prior antibiotics use predicted the development of IFI (P < 0.05). Non-survivors were more likely to have IFI (P = 0.029), high CLIF-OF and CLIF-C ACLF scores (P < 0.001; for both) and higher 1,3-ß D Glucan (BDG) levels (P = 0.009). The sensitivity, specificity, and AUROC of BDG (80 pg/mL) and Galactomannan index (GMI [0.5]) for diagnosing IFI were 97.4%, 60%, 0.770% and 43.6%, 100%, 0.745 respectively. CONCLUSIONS: Invasive fungal infections constitutes an important cause of mortality in ACLF patients. BDG and GMI can be useful markers to guide antifungal therapy in patients at high risk for IFI.

Fabrication of chitosan-bis (4-formyl-2 methoxy phenyl carbonate) Schiff base nanoparticles and evaluation of their antioxidant and anticancer properties.

The present study details on the mechanism of synthesis of bis (4-formyl-2 methoxy phenyl carbonate), using two green reagents dimethyl carbonate and vanillin for application as therapeutic agent. The synthesized FMPC was identified from the 13C nuclear magnetic resonance spectra. The novel modified Schiff base nanoparticles resulted from the crosslinking of FMPC with chitosan were confirmed by cross-polarization magic angle spinning carbon-13 nuclear magnetic resonance spectroscopy. The incorporation of the FMPC was identified from the amorphous X-ray diffraction patterns of C-FMPC-Nps. The thermal stability of the formed nanoparticles was predicted using thermogravimetric analysis. The morphology of the nanoparticles as observed from HRTEM was found to be smooth and spherical in nature. Both FMPC and C-FMPC-Nps showed significant radical scavenging potential and anticancer property. The carbonate ester backbone and the moiety present in chitosan-FMPC-nanoparticles, underwent hydrolysis at the targeted cancer causing microenvironment to release vanillin and chitosan and enhance the anticancer activity. Both FMPC and C-FMPC-Nps exhibits a dose dependent cytotoxicity towards the different cell lines and it was tested with a commercial drug for application studies. Effective synthesis of FMPC, successful incorporation onto chitosan nanoparticles for the formation of C-FMPC-Nps. The formed Schiff base compound proves to have enhanced antioxidant and anticancer efficacy.

Direct-acting antiviral Therapy Is Safe and Effective in Pediatric Chronic Hepatitis C: The Public Health Perspective.

OBJECTIVES: We assessed the efficacy of decentralized public health services and safety of direct-acting antiviral agents (DAAs) in the treatment of pediatric chronic hepatitis C (CHC) in the Mukh-Mantri Punjab Hepatitis C Relief Fund, a public-health initiative for prevention and control of CHC in Punjab, India. METHODS: Consecutive children with CHC [age ≥12 to <18 years; both treatment-naïve (TN) and treatment-experienced (TE)] were enrolled. Genotyping was not recommended for non-cirrhotic patients and were treated with sofosbuvir (SOF)+ daclatasvir (DCV) for 12 weeks, while genotyping was recommended for patients with cirrhosis. Patients with cirrhosis and genotype (G2) were treated with SOF+DCV+ribavirin (RBV) for 12 weeks, G3 with SOF+DCV+RBV for 24 weeks and G1, 4, 5, and 6 patients were treated with SOF+ledipasvir (LDV)+RBV for 12 weeks. Treatment duration was increased to 24 weeks if RBV was not tolerated. RESULTS: In the first 16 months (June 18, 2016-October 31, 2017), 88 children (mean age 15.8 years; 69.3.3% boys, 72.3% rural) were enrolled. The mean baseline hepatitis C virus RNA log10 IU/mL was 6.0 (range 4.2-7.5 log10 IU/mL), 65.5% with G3, and 2 (2.5%) with cirrhosis. Of 57 with completed treatment, sustained virological response (SVR) 12 was achieved in 56 (98.2%). Unsafe medical practices (55.5%), IV drug abuse (11.1%), and prior surgery (2.7%) were risk-factors for transmission (n = 36). Comparable results were noted in G3 (SVR at 12 weeks [SVR12], 94.3%) versus non-G3 (SVR12, 100%; P = 0.073). No serious adverse effects like anemia and decompensation were reported. CONCLUSIONS: The study demonstrates that the decentralized algorithm-based public-health program can ensure high efficacy (SVR12, 98.2%) and low-cost DAA-based treatment of pediatric patients with CHC.

Introduction to the NIDILRR Burn Model System (BMS) Program: Selected Findings II.

A special supplement to the Archives of Physical Medicine and Rehabilitation in 2007 reported selected findings of research from the first 13 years of the BMS Centers and Database Coordinating Center. This special supplement is the second such effort and reports on the growth of the BMS National Longitudinal Database (BMS NDB) since that time and select new research findings from the BMS centers.

Identification of T cell and B cell epitopes against Indian HCV-genotype-3a for vaccine development- An in silico analysis.

Hepatitis C virus (HCV) infects almost 150 million people and is a leading cause of liver disease worldwide. It has been classified into seven genotypes; the most common genotype affecting Indian population is genotype 3 (60-70%). Currently there is no vaccine for any genotype of HCV. In order to develop peptide based vaccine against HCV, it is important to identify the conservancy in the circulating genotypes, along with the Human Leucocyte Antigen (HLA) alleles in the target population. The present study aims to identify conserved CD4 and CD8 T cells and B cell epitopes against Indian HCV-genotype-3a using an in silico analysis. In the present study, 28 promiscuous CD4 T cell epitopes and some CD8 epitopes were identified. The NS4 region was predicted to be the most antigenic with maximum number of conserved and promiscuous CD4 T cell epitopes and CD8 T cell epitopes having strong and intermediate affinity towards a number of HLA alleles prevalent in Indian population. Additionally, some linear B cell epitopes were also identified, which could generate neutralizing antibodies. In order to ascertain the binding pattern of the identified epitopes with HLA alleles, molecular docking analysis was carried out. The authors suggest further experimental validation to investigate the immunogenicity of the identified epitopes.

Successful treatment of chronic hepatitis C infection with directly acting antivirals in renal transplant recipients.

AIMS: The data regarding the treatment of chronic hepatitis C (CHC) in renal transplant recipients is lacking from the Asia-Pacific region. The aim of the present study was to assess the safety and efficacy of directly acting antivirals (DAAs) in the treatment of CHC infection in renal transplant recipients. METHODS: A total of 47 CHC infected renal transplant recipients were enrolled in this real life observational cohort analysis between March 2015 and September 2016. Presence of hepatic fibrosis/cirrhosis was assessed on transient elastography (Fibroscan). Fourteen patients were treated with Sofosbuvir and Ribavirin for 24 weeks. Twenty-two patients received Sofosbuvir and Ledipasvir and 12 patients received Sofosbuvir and Daclatasvir with (n = 3) or without (n = 31) Ribavirin for 12 or 24 weeks depending on genotype and underlying cirrhosis. Data were analyzed for safety and treatment efficacy [sustained virological response at 12 weeks (SVR12)]. RESULTS: The median baseline HCV RNA concentration in the whole group was 7.38 × 106 IU/mL (1.23 × 104 -6.36 × 107 ). The SVR12 rates were 100% in all groups except in the Sofosbuvir and Ribavirin group (86%). Transient Elastography revealed minimal or no fibrosis (F0-F1) in 31 (65.96%) patients, moderate fibrosis (F2) in 11 (23.4%) patients and cirrhosis in five (10.64%) patients. The only serious adverse effect was anaemia observed in eight (57%) patients in the Sofosbuvir and Ribavirin group. CONCLUSION: DAAs including Sofosbuvir, Daclatasvir and Ledipasvir with or without ribavirin are safe and effective for the treatment of chronic hepatitis C in renal transplant recipients.

Factors associated with maternal near miss: A study from Kerala.

Severe life-threatening situations leading to a "near-miss" event may arise unexpectedly in pregnancy. Delay in seeking help, delayed access to care, and poor quality of emergency obstetric services can lead to undesirable outcomes. Women meeting the WHO "near-miss" criteria were assessed using a cross-sectional study design. These women were interviewed to evaluate the circumstances leading to a near-miss event. Reasons for delays in getting proper care were studied using the "3 delays' model." Thirty-two women met the criteria for "near miss" during the 15-month study period, with a maternal near-miss incidence ratio of 9.27/1000 live births. One or more delays were identified in 21 (65.6%) near-miss cases. Delayed access to care was the most important factor for delay. A review of near-miss cases can be used to improve and optimize the existing obstetric services.