The exposome refers to all environmental exposures (internal and specific/general external) that humans experience from conception through to death. This article examines the importance of both fundamental biological and public health perspectives within the context of the exposome, dealing with novel and well recognized concepts that include exposotype, issues of life stage/aging, and both short (epigenetic) and long-term (evolutionary) biological effects. The problem of scale, use of omics technology and database resources are also discussed. A special focus is also placed on the role of the ultraviolet light exposome in regard to the photolysis of folate and biosynthesis of vitamin D as important molecular mechanisms within human health and biology. Specifically, this includes critical nutrigenomic interactions. High-dimensional biology will permit extremely large scale initiatives in the future that will shed new light on the exposome by better characterizing a plethora of new and established biomarkers. However, smaller, delimited studies should not be ignored, as they can still help define aspects of the human exposome that remain unclear. Still, overall trends in the field are moving inexorably towards multiplexing metabolite and other omic analyses within large population studies. This article aims to reinforce the importance of exposomics via the idea, a fundamental tenet of biology, that human phenotype results from an amalgamation of genes and environment. What needs to be recognized is that phenotypes can be either adaptive or maladaptive. Within our phenome this process propagates disease or provides evolutionary advantage. In other words, the exposome is about more than simply public health.

Patients with cirrhosis are immunocompromised and at higher risk of developing infections compared to the general population. The aim of this study was to assess the incidence of infections in cirrhotic patients in a large academic liver center and investigate potential associations between infections, bacteria isolated, therapeutic regimens used, and mortality.

This was a retrospective chart review study, including 192 patients. All patients had a diagnosis of cirrhosis and were admitted to University Hospital. Information collected included demographics, etiology of cirrhosis, identification of bacteria from cultures, multidrug-resistant (MDR) status, antibiotics administered, intensive care unit (ICU) admission, and patient mortality.

Infections were present in 105 (54.6%) patients, and 60 (31.2%) patients had multiple infections during a hospitalization(s) for infections. A total of 201 infections were identified. Urinary tract infections (UTIs) were the most common infection (37.8%), followed by bacteremia (20.4%), pneumonia (12.9%), spontaneous bacterial peritonitis (SBP) (11.9%), abscess/cellulitis (6.0%), infectious diarrhea (6.0%), and other (5.0%). Escherichia coli was the most common bacteria isolated (13.4%), both among sensitive and MDR infections. MDR bacteria were the cause for 41.3% of all infections isolated. Fungi accounted for 9.5% of infections. 21.9% of patients had decompensation from their infection(s) that required ICU care, and 14.6% of patients died during hospitalization or soon after discharge.

The incidence of infections in cirrhotic patients is much higher than in their non-cirrhotic counterparts (54.6%), even higher than prior studies suggest. As many of these infections are caused by MDR bacteria and fungal organisms, stronger empiric antibiotics and antifungals should be considered when initially treating this immunocompromised population. However, once organism sensitivities are discovered, narrowing of antibiotic regimens must occur to maintain good antibiotic stewardship.

The noncanonical NF-κB signaling pathway is an important branch of NF-κB signaling. It is involved in regulating multiple important biological processes, including inflammation and host immune response. A central adaptor protein of the noncanonical NF-κB pathway is NF-κB-inducing kinase (NIK), which activates the downstream kinase IKKα to process p100 to p52, thereby forming the RelB/p52 heterodimer to initiate the expression of target genes. Currently, many specific inhibitors and monoclonal antibodies targeting or triggering this pathway are being developed and tested for various diseases, including cancers, autoimmune diseases, and virus infection. Given that aberrant activation of the noncanonical NF-κB pathway is frequently observed in various liver diseases, targeting this pathway may be a promising therapeutic strategy to alleviate liver inflammation. Moreover, activation of this pathway may contribute to the antiviral immune response and promote the clearance of persistent hepatotropic virus infection. Here, we review the role of the noncanonical NF-κB pathway in the occurrence and development of different liver diseases, and discuss the potency and application of modulating the noncanonical NF-κB pathway for treatment of these liver diseases.

In our previous review published in 2017 on the Zika virus pandemic sweeping the Western World, we mentioned that understanding viral pandemics and vaccine preparedness is vital to combating new outbreaks. In this review, we discuss key updated aspects of the Zika virus in terms of its origin, present status, and prognosis. We also discuss developments in the preventive measure of designing a vaccine to limit the fatal effects of the virus in its current or mutated form. By summarizing updated knowledge of the Zika virus and its effects, we aim to understand how modern technology may help in this objective and how we can apply our knowledge to help mitigate the crises caused by other deadly viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background and Aims: To better understand nonalcoholic steatohepatitis (NASH) disease progression and to evaluate drug targets and compound activity, we undertook the development of an in vitro 3D model to mimic liver architecture and the NASH environment.

Methods: We have developed an in vitro preclinical 3D NASH model by coculturing primary human hepatocytes, human stellate cells, liver endothelial cells and Kupffer cells embedded in a hydrogel of rat collagen on a 96-well plate. A NASH-like environment was induced by addition of medium containing free fatty acids and tumor necrosis factor-α. This model was then characterized by biochemical, imaging and transcriptomics analyses.

Results: We succeeded in defining suitable culture conditions to maintain the 3D coculture for up to 10 days in vitro, with the lowest level of steatosis and reproducible low level of inflammation and fibrosis. NASH disease was induced with a custom medium mimicking NASH features. The cell model exhibited the key NASH disease phenotypes of hepatocyte injury, steatosis, inflammation, and fibrosis. Hepatocyte injury was highlighted by a decrease of CYP3A4 expression and activity, without loss of viability up to day 10. Moreover, the model was able to stimulate a stable inflammatory and early fibrotic environment, with expression and secretion of several cytokines. A global gene expression analysis confirmed the NASH induction.

Conclusions: This is a new in vitro model of NASH disease consisting of four human primary cell-types that exhibits most features of the disease. The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

To develop the evidence-based guidelines for managing mother-to-child transmission of hepatitis B virus in China, a multidisciplinary guideline development group was established. Clinical questions were identified from two rounds of surveys on the concerns of first-line clinicians. We conducted a comprehensive search and review of the literature. A grading of recommendations’ assessment, development, and evaluation system was adopted to rate the quality of evidence and the strength of recommendations. Recommendations were formulated based on the evidence, overall balance of benefits and harms (at individual and population levels), patient/health worker values and preferences, resources available, cost-effectiveness, and feasibility. Eventually, recommendations related to 13 main clinical concerns were developed, covering diagnostic criteria, treatment indications, antiviral therapy choice, timing to initiate and discontinue treatment, immunoprophylaxis strategy at birth, and how to deal with special situations, such as unintended pregnancy, assisted reproduction, and breastfeeding. The guidelines are intended to serve as guidance for clinicians and patients, to optimize the management of majority of pregnant women who are positive for hepatitis B surface antigen. Guideline registration: International Practice Guide Registration Platform (IPGRP-2018CN040).

The association between the pathogenesis and natural course of nonalcoholic fatty liver disease (NAFLD) and skeletal muscle dysfunction is increasingly recognized. These obesity-associated disorders originate primarily from sustained caloric excess, gradually disrupting cellular and molecular mechanisms of the adipose–muscle–liver axis resulting in end-stage tissue injury exemplified by cirrhosis and sarcopenia. These major clinical phenotypes develop through complex organ–tissue interactions from the earliest stages of NAFLD. While the role of adipose tissue expansion and remodeling is well established in the development of NAFLD, less is known about the specific interplay between skeletal muscle and the liver in this process. Here, the relationship between skeletal muscle and liver in various stages of NAFLD progression is reviewed. Current knowledge of the pathophysiology is summarized with the goal of better understanding the natural history, risk stratification, and management of NAFLD.

Globally, the rise in prevalence of obesity and metabolic syndrome as a whole has been linked to increased access to processed foods, such as refined sugars and saturated fats. Consequently, nonalcoholic fatty liver disease (NAFLD) is on the rise in both developed and developing nations. However, much is still unknown on the NAFLD phenotype with regards to the effect of ethnic diversity. Despite similarities in dietary habits, it appears that certain ethnicities are more protected against NAFLD than others. However, manifestations of the same genetic polymorphisms in different groups of people increase those individuals’ predisposition to NAFLD. Diets from different regions have been associated with a lower prevalence of NAFLD and have even been linked to regression of hepatic steatosis. Socioeconomic variations amongst different regions of the world also contribute to NAFLD prevalence and associated complications. Thus, a thorough understanding of ethnic variability in NAFLD is essential to tailoring treatment recommendations to patients of different backgrounds.

Some genetic association studies have investigated the potential role of patatin-like phospholipase domain-containing-3 (PNPLA3) polymorphisms in chronic liver disease, retrieving inconsistent results. Therefore, we performed a meta-analysis to further explore PNPLA3 rs738409 in a large pooled population with chronic liver disease.

Eligible studies were selected from PubMed, Embase, and CNKI databases. Studies heterogeneity was assessed using I2 statistics: when I2 >50% the random effects model was used to pool the data; otherwise, a fixed effects model was used.

In total, 36 studies were selected, comprising 14,855 cases and 12,510 controls. The analysis showed that rs738409 was significantly associated with chronic liver disease in the general population (dominant model: P < 0.0001, OR=1.62, 95% CI=1.43–1.83, I2=81.2%; recessive model: p<0.0001, OR=2.01, 95% CI=1.75–2.30, I2=74.1%; allele model: P=0.001, OR=1.53, 95% CI=1.39–1.68, I2=84.8%). These significant correlations were further confirmed in Asian and Caucasian populations. A stratified analysis also showed a positive correlation between rs738409 and hepatocellular carcinoma (HCC), cirrhosis, and non-alcoholic fatty liver disease (NAFLD), but not with chronic hepatitis B infection or alcoholic liver disease.

Altogether, PNPLA3 rs738409 may help identify individuals at higher susceptibility to chronic liver disease, in particular for HCC, cirrhosis, and NAFLD.

To explore the characteristics of traditional Chinese medicine (TCM) and the efficacy of traditional Chinese materia medica in patients with positive results in virus retests in the recovery period of the Coronavirus Disease 2019 (COVID-19). The clinical symptoms, tongue features, and lung computed tomography (CT) findings before and after treatment were recorded in detail by case series observation. The clinical symptoms of three patients with moderate COVID-19 who retested positive improved after combined TCM and symptomatic treatment. Lung CT showed that the inflammation resolved or improved progressively. Two patients continuously showed negative results in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid retests, and were in complete remission and discharged. There was a persistence of positive results in SARS-CoV-2 nucleic acid tests in one patient. Our experience is that the TCM treatment approaches of strengthening body resistance and eliminating pathogenic factors, cultivating earth, and generating metal, as well as eliminating dampness and resolving phlegm achieved good clinical effects in patients with COVID-19 who retested positive.

Increasing evidence has shown that epigenetics is closely related to the pathogenesis of nonalcoholic fatty pancreatic disease. Epigenetic modification processes, such as DNA methylation and protein acetylation and methylation, have been extensively studied. The epigenetic state of cells regulates nutrients as well as the proliferation and development of beta cells. Decreases in the mass of beta cells are likely to cause diabetes. Recent studies have shown that epigenetic modifications play important roles in the development and progression of cancer. Although DNA methylation, histone modification, microRNAs, and long noncoding RNAs have been preliminarily confirmed to participate in the development of pancreatic cancer, their roles in the pathogenesis of this disease need further study. In this paper, the roles of the various epigenetic modification processes in the pathogenesis of nonalcoholic fatty pancreatic disease and pancreatic cancer are reviewed.

Hepatitis B core antigen (HBcAg) reflects viral replication and is the target of T cells which can reflect the progression of liver disease. We aim to evaluate the relationship between Peginterferon alfa-2a (Peg-IFNα-2a) and the expression intensity of hepatitis B core antigen in chronic hepatitis B (CHB) patients in this study. 207 patients were enrolled with HBeAg-positive CHB and performed liver biopsy to determine the expression intensity of HBcAg detected by immunocytochemistry. All patients received 180μg of Peg-IFNα-2a once weekly for 48 weeks. We evaluated therapy response after 48 weeks of Peg-IFNα-2a therapy. All patients were divided into four groups (0 point group, 1 point group,2 point group,3 point group)by the expression intensity of HBcAg. Statistics on 207 patients, 118 (57.00%) had over 66% HBcAg expression (3 point group), 30 (14.49%) had 34%-66% HBcAg expression (2 point group), 45(21.74%) cases had 5%-33% HBcAg expression (1 point group), while only 14 (6.76%) had less than 5% HBcAg (0 point group). 0 point group has the lowest baseline HBV DNA among the four groups (P < 0.01). The degrees of baseline Liver tissue inflammation and fibrosis among the four groups have no difference(P > 0.05). The combination response was significantly higher in the 0 point group than in the 3 point group (57.1 % and 18.6 %, P < 0.01) after 48 weeks of Peg-IFNα-2a therapy. In conclusion, CHB patients at lower expression intensity of HBcAg have a better response to Peg-IFNα-2a therapy than at higher expression intensity of HBcAg.

Chronic hepatitis B (CHB) affects more than 257 million individuals with high liver-related morbidity and mortality worldwide. This review summarizes research progress and reflection on new drugs for the treatment of CHB. Some available HBV therapeutic strategies and their corresponding stages of development from preclinical to various clinical phases are indicated in this article. Through this review, the author aims to give us a comprehensive understanding of the global research trends and the latest progress of new drugs for treating chronic hepatitis B, so as to gain useful enlightenment.

Coronavirus disease 2019 (COVID-19) is a global epidemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many digestive symptoms have been reported in patients infected with this virus, however, the relationship between the intestinal microbiota and SARS-CoV-2 remains unknown. This review aims to elucidate the interaction between intestinal microbiota and SARS-CoV-2, and review the mechanism of interaction between these two items as well as the effects of probiotics. This review further discusses various studies on gastrointestinal symptoms and changes in intestinal microbiota in COVID-19 patients. To further understand the mechanism, we focused on the role of angiotensin converting enzyme 2 and transmembrane protease serine 2 in this viral infection. There is a correlation between many diseases and dysbiosis of intestinal microbiota. SARS-CoV-2 can lead to dysbiosis of intestinal microbiota through a variety of mechanisms, with a decrease in the abundance and diversity of probiotics and an increase in that of pathogenic bacteria. Dysbiosis of intestinal microbiota results in the translocation of intestinal flora, aggravation of systemic inflammation, and lung injury. Modulating the intestinal microbiota ameliorates digestive symptoms and pathology in infectious respiratory diseases. Intestinal microbiota and SARS-CoV-2 interact through a variety of mechanisms; SARS-CoV-2 can cause dysbiosis of the intestinal microbiota, while dysbiosis of intestinal microbiota, in turn, aggravates COVID-19.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH; moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or ‘Holy Grail’ within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.

Accumulated studies have reported the key role of circulating fetuin-A in the development and progression of nonalcoholic fatty liver disease (NAFLD) but the results have not been consistent. In this study, we performed a systematic review and meta-analysis to explore the relationship between circulating fetuin-A level and the development and classification of NAFLD.

The PubMed, EMBASE, and Cochrane Library databases were searched to obtain the potentially relevant studies up to May 2020. Standardized mean differences (SMD) and 95% confidence intervals of circulating fetuin-A levels were extracted and summarized. Sensitivity, subgroup analysis and meta-regression analysis were performed to investigate the potential heterogeneity. Association of circulating fetuin-A level with classification of NAFLD was also reviewed.

A total of 17 studies were included, composed of 1,755 NAFLD patients and 2,010 healthy controls. Meta-analysis results showed that NAFLD patients had higher circulating fetuin-A level (SMD=0.43, 95% confidence interval [CI]: 0.22–0.63, p<0.001) than controls. Subgroup analysis indicated that circulating fetuin-A level was markedly increased in adult NAFLD patients (SMD=0.48, 95% CI: 0.24–0.72, p<0.001) and not in pediatric/adolescent patients compared to controls. Circulating fetuin-A level was markedly increased in ultrasound-proven NAFLD pediatric/adolescent patients (SMD=0.42, 95% CI: 0.12–0.72, p=0.007), other than in the liver biopsy-proven NAFLD pediatric/adolescent patients. Body mass index might be the influencing factor to the heterogeneity in adult patients. Circulating fetuin-A level was not associated with the classification of NAFL vs. nonalcoholic steatohepatitis (NASH). Whether the circulating fetuin-A level was associated with the development of fibrosis remains controversial.

Circulating fetuin-A level was significantly higher in NAFLD patients and was not associated with the classification of NAFL vs. NASH. Whether the circulating fetuin-A level was associated with the development of fibrosis remains controversial.

Aminotransferases are commonly found to be elevated in patients with celiac disease in association with two different types of liver dysfunction: cryptogenic liver disorders and autoimmune disorders. The purpose of this review is to discuss the mechanisms by which aminotransferases become elevated in celiac disease, clinical manifestations, and response to gluten-free diet. Many studies have shown that celiac patients with cryptogenic liver disease have normalization in aminotransferases, intestinal histologic improvement and serologic resolution after 6–12 months of strict gluten-free diet. In patients with an underlying autoimmune liver disease, simultaneous treatment for both conditions resulted in normalized elevated aminotransferases. The literature suggests that intestinal permeability may be at least one of the mechanisms by which liver damage occurs. Patients with celiac disease should have liver enzymes routinely checked and treated with a strict gluten-free diet if found to be abnormal. Lack of improvement in patients who have strictly adhered to gluten-free diet should prompt further workup for other causes of liver disease.