Background and Aims: Coronavirus disease 2019 (COVID-19) is a new respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (commonly known as SARS-CoV-2) with multiple organ injuries. The aim of this study was to analyze COVID-19-associated liver dysfunction (LD), its association with the risk of death and prognosis after discharge.

Methods: Three-hundred and fifty-five COVID-19 patients were recruited. Clinical data were collected from electronic medical records. LD was evaluated and its prognosis was tracked. The association between LD and the risk of death was analyzed.

Results: Of the 355 COVID-19 patients, 211 had mild disease, 88 had severe disease, and 51 had critically ill disease. On admission, 223 (62.8%) patients presented with hypoproteinemia, 151(42.5%) with cholestasis, and 101 (28.5%) with hepatocellular injury. As expected, LD was more common in critically ill patients. By multivariate logistic regression, male sex, older age and lymphopenia were three important independent risk factors predicting LD among COVID-19 patients. Risk of death analysis showed that the fatality rate was higher in patients with hypoproteinemia than in those without hypoproteinemia (relative risk=9.471, p<0.01). Moreover, the fatality rate was higher in patients with cholestasis than those without cholestasis (relative risk=2.182, p<0.05). Follow-up observation found that more than one hepatic functional index of two-third patients remained abnormal at 14 days after discharge.

Conclusions: LD at early disease stage elevates the risk of death of COVID-19 patients. COVID-19-associated LD does not recover completely by 14 days after discharge.

Background and Aims: To investigate the impact of MR bias field correction on response determination and survival prediction using volumetric tumor enhancement analysis in patients with infiltrative hepatocellular carcinoma, after transcatheter arterial chemoembolization (TACE).

Methods: This study included 101 patients treated with conventional or drug-eluting beads TACE between the years of 2001 and 2013. Semi-automated 3D quantification software was used to segment and calculate the enhancing tumor volume (ETV) of the liver with and without bias-field correction on multi-phasic contrast-enhanced MRI before and 1-month after initial TACE. ETV (expressed as cm3) at baseline imaging and the relative change in ETV (as % change, ETV%) before and after TACE were used to predict response and survival, respectively. Statistical survival analyses included Kaplan-Meier curve generation and Cox proportional hazards modeling. Q statistics were calculated and used to identify the best cut-off value for ETV to separate responders and non-responders (ETV cm3). The difference in survival was evaluated between responders and non-responders using Kaplan-Meier and Cox models.

Results: MR bias field correction correlated with improved response calculation from baseline MR as well as survival after TACE; using a 415 cm3 cut-off for ETV at baseline (hazard ratio: 2.00, 95% confidence interval: 1.23-3.26, p=0.01) resulted in significantly improved response prediction (median survival in patients with baseline ETV <415 cm3: 19.66 months vs. ≥415 cm3: 9.21 months, p<0.001, log-rank test). A ≥41% relative decrease in ETV (hazard ratio: 0.58, 95%confidence interval: 0.37-0.93, p=0.02) was significant in predicting survival (ETV ≥41%: 19.20 months vs. ETV <41%: 8.71 months, p=0.008, log-rank test). Without MR bias field correction, response from baseline ETV could be predicted but survival after TACE could not.

Conclusions: MR bias field correction improves both response assessment and accuracy of survival prediction using whole liver tumor enhancement analysis from baseline MR after initial TACE in patients with infiltrative hepatocellular carcinoma.

L-theanine (L-THE) is a green tea-derived amino acid, consumed for its many benefits, including improved cardiovascular health, anxiolytic effects, antioxidant properties, and its effect on instigating a state of relaxed alertness. The aim of this clinical trial is to evaluate the effectiveness of the amino acid L-THE embedded in functional food whey protein mango sorbet, its related stress effects on physiological responses, state of alertness, and focus, and the accuracy of eye movements post-consumption.

Twenty-one healthy males, aged 18–65, will be recruited for this study. Participants will be required to consume a mango sorbet (without L-THE) and mango sorbet containing 0.2 g of L-THE and a placebo or 0.2 g pure L-THE within a capsule, after an overnight fast. L-THE exerts its effects 30–50 minutes post consumption, lasting up to 90 minutes. Participants will perform a series of visual functional tests, including habitual visual acuity, contrast sensitivity and measurements of saccadic eye movements after the consumption of the food products at 15-minute intervals to measure their state of alertness and fatigue. Salivary cortisol will be measured every 30 minutes; blood pressure, heart rate and heart rate variability responses will also be measured every 10 minutes.

The use of L-THE as a functional additive may provide potential therapeutic stress benefits when consumed alongside food products. The results of this protocol study will ultimately determine whether L-THE embedded within mango sorbet at physiologically relevant levels can alter the stress response and exhibit its effect on eye fatigue and concentration.

Background and Aims: This study was designed to analyze the effects of age and clinicopathological characteristics on prognosis of Chinese patients with hepatocellular carcinoma (HCC).

Methods: The clinical data of 2032 HCC patients who were first diagnosed with HCC and underwent curative hepatectomy in our hospital between January 2006 and January 2011 were retrospectively analyzed.

Results: Younger HCC patients (age <40 years, n=465) had a significantly higher hepatitis B infection rate, larger tumors, higher alpha-fetoprotein levels, higher preoperative liver function, and more frequent vascular invasions than older patients. Most younger patients were suitable for anatomical hepatectomy, and their tumors were found to be at a highly advanced stage. The recurrence-free survival and overall survival rates of younger HCC patients were significantly worse than those of older patients but this difference disappeared after propensity score matching. Multivariate analysis of pre-matched samples showed that age ≤40 years was one of the independent risk factors associated with poor overall survival.

Conclusions: Younger patients showed different clinicopathological characteristics than older patients, such as higher rates of hepatitis B infection and advanced tumors. The recurrence-free survival and overall survival rates of younger HCC patients after hepatectomy may be similar to those of older patients.

Background and Aims: With the availability of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection and changing liver disease etiology for liver transplantation (LT), data on the changes in LT recipient population in the DAA era are scanty.

Methods: The United Network for Organ Sharing (UNOS) registry (01/2007 to 06/2018) was used to develop a retrospective cohort of LT recipients for HCV, alcohol-associated liver disease (ALD), and non-alcoholic steatohepatitis (NASH). LT recipients in the DAA era (2013-2018) were compared with those in the pre-DAA era (2007-2012) era for recipient characteristics. Chi-square and analysis of variance were the statistical tests used for categorical and continuous variables, respectively.

Results: Of 40,309 LT recipients (21,110 HCV, 7586 NASH, and 11,713 ALD), the 21,790 in the DAA era (9432 HCV, 7240 ALD, and 5118 NASH) were more likely to be older, female, obese, diabetic, have acute-on-chronic liver failure with a higher model for end-stage liver disease score, receive grafts with a lower donor risk index, and have waited on the LT list for a shorter period compared with their pre-DAA era counterparts. Specific to ALD, LT recipients with alcohol hepatitis were more likely to be younger at the time of LT. Of 9895 LT recipients with hepatocellular carcinoma, recipients in the DAA era were observed to have a higher proportion of HCV (43% vs. 32%, p<0.001), a lower proportion of ALD (9% vs. 12%, p<0.001), and no change for NASH (13% vs. 13%, p=0.9) compared with the pre-DAA era. Within the hepatocellular carcinoma population, LT recipients in the DAA era were older, diabetic, and waited on the LT list longer compared with their pre-DAA counterparts.

Conclusions: Along with changing liver disease etiology in the DAA era, the LT recipient population demographics, comorbidities, liver disease severity, and graft quality are changing. These changes are relevant for future studies, immunosuppression, and post-transplant follow-up.

In this review, we examine the pharmacokinetics and clinically relevant drug interactions of the newer generation direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C, specifically sofosbuvir/velpatasvir (Epclusa®), sofosbuvir/velpatasvir/voxilaprevir (Vosevi®), glecaprevir/pibrentasvir (Maviret®), and elbasvir/grazoprevir (Zepatier®). We searched MEDLINE (1948-January 2020), Embase (1964-January 2020), Google, and GoogleScholar using the terms pharmacokinetics, drug interaction, drug metabolism, sofosbuvir, velpatasvir, Epclusa, voxilaprevir, Vosevi, glecaprevir, pibrentasvir, Maviret, elbasvir, grazoprevir, and Zepatier, from inception to January 13, 2020. The search was limited to randomized controlled trials, in vitro studies, prospective and retrospective human studies, drug monographs, abstracts, and conference proceedings. All relevant published literature on pharmacokinetic and pharmacodynamic interactions involving DAAs were reviewed and the data extracted. Numerous clinically relevant drug-drug interactions (DDIs) were identified with the newer generation DAAs and commonly prescribed drugs. NS3/4A protease inhibitors are more likely to be involved in DDIs, followed by NS5A inhibitors and NS5B polymerase inhibitor. The majority of clinically relevant DDIs are predictable, according to known pharmacokinetic, pharmacodynamics, and physicochemical properties of DAAs; however, in select cases, unpredictable DDIs do occur. As expected, many drug interactions exist between newer generation DAAs and commonly prescribed medications. While the majority of clinically relevant interactions are predictable, many require therapeutic dose adjustment or careful selection of non-interacting drugs. In select cases, severe and unpredictable drug interactions can occur. Clinicians should consult hepatitis C virus pharmacotherapy experts and tertiary drug interaction resources when initiating DAA therapy in patients taking other medications.

Perioperative neurocognitive disorder is a decline in cognitive function of patients after anesthesia and surgery. It seems to be a comprehensive effect of the combination of psychological state before the operation, neurotoxicity of narcotic drugs, inflammation caused by the operation, and sleep deprivation after surgery. The glymphatic pathway is a newly discovered system that clears metabolic waste from the brain. The clearing efficiency of the glymphatic pathway can be influenced by sleep deprivation, some narcotic drugs (like dexmedetomidine and ketamine), and neuroinflammation. We hypothesize that the glymphatic system may play a pivotal role in the occurrence and development of perioperative neurocognitive disorder.

Nonalcoholic fatty liver disease (NAFLD) is a complex clinical entity which can be secondary to many other diseases including hypothyroidism, characterized by lowering of thyroid hormones and increased thyroid stimulating hormone (TSH). A lot of emerging data published recently advocates the hypothesis that hypothyroid induced NAFLD could be a separate clinical entity, even suggesting possible treatment options for NAFLD involving substitution therapy for hypothyroidism along with lifestyle modifications. In addition, a whole new field of research is focused on thyromimetics in NAFLD/NASH treatment, currently in phase 3 clinical trials. In this critical review we summarized epidemiological and pathophysiological evidence linking these two clinical entities and described specific treatment options with the accent on promising new agents in NAFLD treatment, specifically thyroid hormone receptor (THR) agonist and its metabolites.

Background and Aims: To evaluate the efficacy of Fuzheng Huayu (FZHY), a Chinese herbal formula, plus entecavir (ETV) in regression of liver fibrosis in chronic hepatitis B (CHB) patients with significant fibrosis/cirrhosis.

Methods: The current study was a two-center, randomized, double-blind and placebo-controlled pilot study. Fifty-two currently untreated chronic hepatitis B patients with Ishak fibrosis score ≥3 points were identified and 1:1 randomized into FZHY plus ETV combination and placebo plus ETV groups. The second liver biopsy was performed after 48-week treatment. Necroinflammatory improvement and regression of fibrosis were assessed. Fine changes in different collagen features in paired liver biopsies were evaluated by dual-photon microscopy for both groups.

Results: Forty-nine patients completed the full course of treatment; forty-six of them underwent second liver biopsy (for which twenty-two were in the combination group and twenty-four were in the control group). Compared to those in the control group, patients in the combination group had significantly higher rate of fibrosis regression (82% vs. 54%) (p<0.05). Furthermore, the necroinflammatory improvement was greater in the combination group than in the control group (59% vs. 25%, p<0.05). Among the more than 80 collagen parameters in the dual-photon analysis, 5 decreased significantly in the combination group compared to the control group (p<0.05). However, no significant improvement was detected in either biochemical, virologic or serologic responses between these two groups at week 48.

Conclusions: The combination therapy of FZHY plus ETV for 48 weeks resulted in a higher rate of necroinflammatory improvement and fibrosis regression than ETV alone in chronic hepatitis B patients with significant fibrosis/cirrhosis. The clinical trial number is ChiCTR-TRC-11001377.

Background and Aims: Recent accumulating evidence indicates the biological actions of autotaxin (ATX) in liver disease. However, the relationship between ATX and liver failure has not been reported. The present study aimed to examine alterations of serum ATX in acute-on-chronic liver failure (ACLF) and evaluate whether serum ATX could be useful as an early warning biomarker of ACLF.

Methods: Serum ATX was measured in 50 patients with hepatitis B-related ACLF, 14 patients with alcohol-related ACLF, 11 patients with hepatitis B-related pre-ACLF, 11 patients with alcohol-related Child-Pugh A cirrhosis, 39 patients with hepatitis B-related Child-Pugh A cirrhosis, 26 patients with chronic hepatitis B, and 38 healthy volunteers by enzyme-linked immunosorbent assay.

Results: Serum ATX level was significantly higher in the pre-ACLF group than in the Child-Pugh A cirrhosis and chronic hepatitis B groups but lower than in the ACLF group; furthermore, patients with pre-ACLF deteriorated to ACLF had significantly higher serum ATX levels than pre-ACLF patients that did not progress to ACLF. Serum ATX levels were significantly higher among male ACLF patients with preclinical infection, spontaneous bacterial peritonitis or pneumonia, as compared to patients with ACLF but no spontaneous bacterial peritonitis or pneumonia. Serum ATX levels were well correlated with serum biochemical parameters of liver function and model for end-stage liver disease score. Serum ATX ≥ 584.1 ng/mL was a poor prognostic factor for ACLF (hazard ratio of 4.750, 95% confidence interval of 1.106-20.392, p=0.036).

Conclusions: Serum ATX level may be a useful early warning biomarker for ACLF.

Background and Aims: This study serves to revisit the effects of liver transplantation (LT) on employment in an era of improving survival outcomes post-transplant, and to identify areas of improvement in the transplant process to better optimize post-LT employment and patient satisfaction.

Methods: Prospectively, patients who had undergone LT at a single tertiary LT center were surveyed in person and by e-mail. Primary outcomes included employment rate pre- and post-LT, annual salary, weekly hours worked, barriers to re-employment, and patient satisfaction.

Results: Responses were collected and analyzed from 121 patients who underwent LT. Pre-LT, 68 (56.1%) reported full-time employment, 13 (10.7%) part-time employment, and 40 (33.1%) unemployment. Post-LT, 26 (21.4%) reported continued full-time employment, 18 (14.9%) part-time employment, and 77 (63.6%) unemployment. Average weekly work hours decreased post-LT (16.1 h/week vs. 39.9 h/week). Mean annual salaries decreased post-LT (17 earning salary ≥$40,000 vs. 56 earning salary ≥$40,000). These outcomes differed from patient pre-LT expectations, with 81.0% of previously employed patients believing they would return to employment, resulting in decreased patient satisfaction. Patients working physically demanding jobs pre-LT were less likely to return to work. Reasons cited for lack of return to full employment included early fatigue and difficulty regaining physical strength.

Conclusions: Re-employment rates remain low post-LT, which is particularly true for patients working physically active jobs. Fatigue is a significant barrier to re-employment and increased physical rehabilitation post-LT may prove to be beneficial. Patients should be given realistic expectations about return to employment prior to their LT.

Public health interventions have reduced coronavirus disease 2019 (COVID-19) transmission in several countries, but their impacts on COVID-19 epidemics in the USA are unclear. We examined associations of stay-at-home order (SAHO) and face-masking recommendation with COVID-19 epidemics in the USA.

In this quasi-experimental interrupted time-series study, we modeled temporal trends in daily new cases and deaths of laboratory-confirmed COVID-19 cases, and COVID-19 time-varying reproduction numbers in the USA between March 1 and April 20, 2020. In addition, we conducted simulation analyses.

The number of residents under SAHO increased since March 19 and plateaued at 290,829,980 (88.6% of the U.S. population) on April 7. Trends in COVID-19 time-varying reproduction numbers peaked on March 23, further reduced on April 3, and fell below/around 1.0 on April 13. Early-implementation and early-lift of SAHO would reduce and increase COVID-19 epidemics, respectively. Multivariable piecewise log-linear regression revealed the states’ neighboring relationship with New York was linked to COVID-19 daily new cases and deaths. There were two turning points in daily new-case trend, being March 28 (slope-changes = −0.09) and April 3 (slope-changes = −0.09), which appeared to be associated with implementation of SAHO on March 28 (affecting 48.5% of the US population in 22 states and District of Columbia), and face-masking recommendation on April 3, respectively. There were also two turning points in daily new-death trend, being April 9 (slope-changes = −0.06) and April 19 (slope-changes = −0.90).

We identified two turning points of COVID-19 daily new cases or deaths in the USA, which seem to be linked to implementation of SAHO and the Center for Disease Control’s face-masking recommendation.

Diabetes is among the most frequently reported comorbidities in patients with coronavirus disease 2019 (COVID-19) and it represents a strong risk factor for developing severe, critical and fatal forms of COVID-19. The association between diabetes and worse outcome in viral infections is not unexpected, as hyperglycemia is detrimental to the control of viremia and inflammation, and very often linked to accelerated morbidity and mortality in a majority of patients. Understanding the pathophysiological mechanisms underlying the impact of diabetes on COVID-19 progression is now under critical scrutiny in several ongoing investigations, with the ultimate aim of maximizing therapeutic outcomes. On the other hand, there is a new school of thought that COVOD-19 and its devastating ravage on multiple organs could be causally linked to new-onset diabetes. Thus, the threatening new lesson is that there might be a bidirectional relationship between COVID-19 and diabetes. This review is unique in that it summarizes the very recent literature that supports why we should revisit studying virus-induced diabetes in the context of COVID-19.

Background and Aims: Hepatocellular iron accumulation in patients with chronic liver disease has been linked to adverse outcomes. The objective of this study was to identify clinical factors associated with hemosiderosis.

Methods: A total of 103 consecutive liver transplant recipients were identified, in whom liver biopsy had been performed prior to transplantation. Laboratory and clinical data at biopsy and transplant were abstracted from the medical records and hepatocyte iron was graded in the biopsy and explant. The association of change in iron score from biopsy to transplant, with the time interval between these two events, was examined using linear mixed model analysis for repeated measures.

Results: Most subjects had advanced fibrosis (F3-F4) at liver biopsy, which was performed on average about 2.5 years before transplant. Over 80% of patients had no or 1+ hepatocyte iron at biopsy; iron increased between biopsy and transplant in about 40%. The only demographic or clinical feature that correlated with increased iron was the presence of a transjugular intrahepatic portosystemic shunt. Increased iron at transplant was associated with higher serum iron and transferrin saturation at biopsy, and with lower hemoglobin level, greater mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, higher ferritin and model for end-stage liver disease score at transplant.

Conclusions: The development of hemosiderosis in end-stage liver disease is associated with lower hemoglobin levels and alterations in red blood cell indices that are suggestive of hemolysis. These observations suggest that extravascular hemolysis may play a role in the development of secondary iron overload.

Type 1 diabetes mellitus is a chronic autoimmune disease, requiring glucose monitoring and intensive insulin therapy. Its therapeutic management aims to restore normal HbA1C and stabilize prandial and postprandial glucose levels. The burden of self-management of diabetes is high, and the growing requirement for blood glucose measuring devices presents a challenge. Such devices can continuously monitor glucose concentrations and automatically adjust insulin delivery rates, which in turn help to maintain blood glucose within a healthy range. The artificial pancreas system (so-called APS) technology has evolved rapidly over the past few years, capable of providing effective management of diabetes to improve quality of life of the type 1 diabetes mellitus patients. This review discusses the evolution of the APS technology and its progress in the various components: continuous subcutaneous insulin infusion, mathematical model, real-time continuous glucose monitoring, and control algorithms driving closed-loop control systems. The limitations and the proposed future directives are also discussed.

Hepatitis E virus (HEV) is a global health problem, affecting about 20 million people worldwide. There is significant overlap of hepatitis B virus (HBV) and HEV endemicity in many Asian countries where dual infections with HEV and HBV can occur. Though the clinical course of HEV is largely self-limited, HEV superinfection in patients with chronic hepatitis B (CHB) can result in acute exacerbation of underlying CHB. HEV superinfection in patients with CHB-related cirrhosis has been identified as a risk factor for decompensated cirrhosis and an independent predictor of mortality. Whereas acute HEV infection in pregnancy can cause fulminant liver failure, the few studies on pregnant patients with dual HBV and HEV infection have shown a subclinical course. Immunosuppression is a risk factor for the development of chronic HEV infection, which can be managed by decreasing the dose of immune-suppressants and administering ribavirin. Vaccination for HEV has been developed and is in use in China but its efficacy in patients with CHB has yet to be established in the USA. In this review, we appraise studies on dual infection with HEV and HBV, including the effect of HEV superinfection and coinfection in CHB, management strategies used and the role of active vaccination in the prevention of HEV.