Background Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). Methods We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. Results Of the 978 patients in our cohort, 867 patients (mean age 56.9±14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. Conclusions The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19.

Background Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplant (LT) recipients with COVID-19 is not defined. Approach and Results We conducted a multicenter study in the US of 112 adult LT recipients with COVID-19. The median age was 61 years (IQR 20), 54.5% (n=61) were male, and 39.3% (n=44) Hispanic. The mortality rate was 22.3% (n=25); 72.3% (n=81) were hospitalized and 26.8% (n=30) admitted to the ICU. Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5x ULN) in 22.2% (n= 18) and severe liver injury (ALT > 5x ULN) in 12.3% (n= 10). Compared to age and gender matched non-transplant patients with CLD and COVID-19 (n=375), the incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; p=0.037). Variables associated with liver injury in LT recipients were younger age (p= 0.009, odds ratio (OR) 2.06 [1.20-3.54]), Hispanic ethnicity (p= 0.011; OR 6.01 [1.51-23.9]), metabolic syndrome (p= 0.016; OR 5.87 [1.38-24.99]), vasopressor use (p= 0.018; OR 7.34 [1.39-38.52]) and antibiotic use (p= 0.046; OR 6.93 [1.04-46.26]). Reduction in immunosuppression (49.4%) was not associated with liver injury (p= 0.156) or mortality (p= 0.084). Liver injury during COVID-19 was significantly associated with mortality (p= 0.007; OR 6.91 [95% CI: 1.68-28.48]) and ICU admission (p=0.007; OR 7.93[1.75-35.69]) in LT recipients. Conclusion Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

The COVID‐19 pandemic forced medical schools to rapidly transform their curricula using online learning approaches. At our institution, the preclinical Practice of Medicine (POM) course was transitioned to large‐group, synchronous, video‐conference sessions. The aim of this study is to assess whether there were differences in learner engagement, as evidenced by student question‐asking behaviors between in‐person and videoconferenced sessions in one preclinical medical student course. In Spring, 2020, large‐group didactic sessions in POM were converted to video‐conference sessions. During these sessions, student microphones were muted, and video capabilities were turned off. Students submitted typed questions via a Q&A box, which was monitored by a senior student teaching assistant. We compared student question asking behavior in recorded video‐conference course sessions from POM in Spring, 2020 to matched, recorded, in‐person sessions from the same course in Spring, 2019. We found that, on average, the instructors answered a greater number of student questions and spent a greater percentage of time on Q&A in the online sessions compared with the in‐person sessions. We also found that students asked a greater number of higher complexity questions in the online version of the course compared with the in‐person course. The video‐conference learning environment can promote higher student engagement when compared with the in‐person learning environment, as measured by student question‐asking behavior. Developing an understanding of the specific elements of the online learning environment that foster student engagement has important implications for instructional design in both the online and in‐person setting.

Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 predict poor survival (p=4.3×10−10), CCL2/IL13 expression (p<10−109) and TAM infiltration (p<10−96). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, MYC and TWIST1 generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Early detection of HCC enables patients to avail curative therapies that can improve patient survival. Current international guidelines advocate for the enrollment of patients at high risk for HCC, like those with cirrhosis, in surveillance programs that perform ultrasound every 6 months. In recent years, many studies have further characterized the utility of established screening strategies and have introduced new promising tools for HCC surveillance. In this review, we provide an overview of the most promising new imaging modalities and biomarkers for the detection of HCC. We discuss the role of imaging tools like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) in the early detection of HCC, and describe recent innovations which can potentially enhance their applicability, including contrast enhanced ultrasound, low-dose CT scans, and abbreviated MRI. Next, we outline the data supporting the use of three circulating biomarkers (i.e., alpha-fetoprotein [AFP], AFP lens culinaris agglutinin-reactive fraction, and des-gamma-carboxy prothrombin) in HCC surveillance, and expand on multiple emerging liquid biopsy biomarkers, including methylated cell-free DNA (cfDNA), cfDNA mutations, extracellular vesicles, and circulating tumor cells. These promising new imaging modalities and biomarkers have the potential to improve early detection, and thus improve survival, in patients with HCC. (Hepatology Communications 2021;5:1972-1986).L iver cancer is the sixth most common cancer worldwide and is now the third-leading cause of cancer-related death, behind lung cancer and colorectal cancer. (1) In 2020, more than 900,000 cases of liver cancer were diagnosed globally, with more than 830,000 liver cancer-related deaths, underscoring the high mortality index of this cancer. (1) Hepatocellular carcinoma (HCC) accounts for 75%-85% of primary liver cancers. The global incidence of HCC has increased by more than 75% in the last 30 years, especially in Western countries, (2)(3)(4) and is expected to continue to grow in the near future. Unfortunately, survival rates for patients with HCC in the United States remain dismally low and essentially unchanged over the past 30 years, (5) with only 3%-34% of patients with HCC surviving 5 years after diagnosis. (6) The high HCC mortality rates can be attributed to several factors, with delayed diagnosis of cancer at more advanced stages of disease being an important reason. (2,7,8) HCC typically arises in the background of the cirrhotic liver, where chronic inflammation and fibrosis induce genomic alterations that render the hepatocytes vulnerable to malignant transformation. (9)(10)(11) The presence of cirrhosis is the strongest risk factor for HCC, with 90% of HCCs arising in cirrhotic livers. The