Beijing Friendship Hospital

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.

OBJECTIVE: To estimate systematic and anatomic site-specific age-standardized prevalence rates (ASRs) and analyze the secular trends of osteoarthritis (OA) at global, regional, and national levels. METHODS: Data were derived from the Global Burden of Disease Study 2019. ASRs and their estimated annual percentage changes (EAPCs) were used to describe the secular trends of OA according to age group, sex, region, country, and territory, as well as the joints involved. RESULTS: Globally, prevalent cases of OA increased by 113.25%, from 247.51 million in 1990 to 527.81 million in 2019. ASRs were 6,173.38 per 100,000 in 1990 and 6,348.25 per 100,000 in 2019, with an average annual increase of 0.12% (95% confidence interval [95% CI] 0.11%, 0.14%). The ASR of OA increased for the knee, hip, and other joints, but decreased for the hand, with EAPCs of 0.32 (95% CI 0.29, 0.34), 0.28 (95% CI 0.26, 0.31), 0.18 (95% CI 0.18, 0.19), and -0.36 (95% CI -0.38, -0.33), respectively. OA prevalence increased with age and revealed female preponderance, geographic diversity, and disparity with regard to anatomic site. OA of the knee contributed the most to the overall burden, while OA of the hip had the highest EAPC in most regions. CONCLUSION: OA has remained a major public health concern worldwide over the past decades. The prevalence of OA has increased and diversified by geographic location and affected joint. Prevention and early treatment are pivotal to mitigating the growing burden of OA.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

Immunotherapies have led to substantial changes in cancer treatment and have been a persistently popular topic in cancer research because they tremendously improve the efficacy of treatment and survival of individuals with various cancer types. However, only a small proportion of patients are sensitive to immunotherapy, and specific biomarkers are urgently needed to separate responders from nonresponders. Mismatch repair pathways play a vital role in identifying and repairing mismatched bases during DNA replication and genetic recombination in normal and cancer cells. Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host. Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis. Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors. To date, the anti-programmed cell death-1 inhibitor pembrolizumab has been approved for mismatch repair deficiency/microsatellite instability-high refractory or metastatic solid tumors, and nivolumab has been approved for colorectal cancer patients with mismatch repair deficiency/microsatellite instability-high. This is the first time in the history of cancer therapy that the same biomarker has been used to guide immune therapy regardless of tumor type. This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death-ligand 1/programmed cell death-1, and the recent advances in predicting immunotherapy efficacy.

Resting-state fMRI was first described by Biswal et al in 1995 and has since then been widely used in both healthy subjects and patients with various neurologic, neurosurgical, and psychiatric disorders. As opposed to paradigm- or task-based functional MR imaging, resting-state fMRI does not require subjects to perform any specific task. The low-frequency oscillations of the resting-state fMRI signal have been shown to relate to the spontaneous neural activity. There are many ways to analyze resting-state fMRI data. In this review article, we will briefly describe a few of these and highlight the advantages and limitations of each. This description is to facilitate the adoption and use of resting-state fMRI in the clinical setting, helping neuroradiologists become familiar with these techniques and applying them for the care of patients with neurologic and psychiatric diseases.

Hepatic myofibroblasts are activated in response to chronic liver injury of any etiology to produce a fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of fibrotic liver diseases is unresolved. To identify distinct populations of myofibroblasts and quantify their contribution to hepatic fibrosis of two different etiologies, collagen-α1(I)-GFP mice were subjected to hepatotoxic (carbon tetrachloride; CCl4) or cholestatic (bile duct ligation; BDL) liver injury. All myofibroblasts were purified by flow cytometry of GFP(+) cells and then different subsets identified by phenotyping. Liver resident activated hepatic stellate cells (aHSCs) and activated portal fibroblasts (aPFs) are the major source (>95%) of fibrogenic myofibroblasts in these models of liver fibrosis in mice. As previously reported using other methodologies, hepatic stellate cells (HSCs) are the major source of myofibroblasts (>87%) in CCl4 liver injury. However, aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of injury (5 d BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and contribute to the myofibroblast population (14 and 20 d BDL). Unlike aHSCs, aPFs respond to stimulation with taurocholic acid and IL-25 by induction of collagen-α1(I) and IL-13, respectively. Furthermore, BDL-activated PFs express high levels of collagen type I and provide stimulatory signals to HSCs. Gene expression analysis identified several novel markers of aPFs, including a mesothelial-specific marker mesothelin. PFs may play a critical role in the pathogenesis of cholestatic liver fibrosis and, therefore, serve as an attractive target for antifibrotic therapy.

The Asia-Pacific region is home to more than half of the global population and accounted for 62·6% of global deaths due to liver diseases in 2015. 54·3% of global deaths due to cirrhosis, 72·7% of global deaths due to hepatocellular carcinoma, and more than two-thirds of the global burden of acute viral hepatitis occurred in this region in 2015. Chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to cirrhosis in the region, followed by alcohol consumption (20·8%), non-alcoholic fatty liver disease (NAFLD; 12·1%), and chronic infection with hepatitis C virus (HCV; 15·7%). In 2015, HBV accounted for about half the cases of hepatocellular carcinoma in the region. Preventive strategies for viral hepatitis-related liver disease include increasing access to clean drinking water and sanitation. HBV vaccination programmes for neonates have been implemented by all countries, although birth-dose coverage is extremely suboptimal in some. Availability of screening tests for blood and tissue, donor recall policies, and harm reduction strategies are in their initial stages in most countries. Many governments have put HBV and HCV drugs on their essential medicines lists and the availability of generic versions of these drugs has reduced costs. Efforts to eliminate viral hepatitis as a public health threat, together with the rapid increase in per-capita alcohol consumption in countries and the epidemic of obesity, are expected to change the spectrum of liver diseases in the Asia-Pacific region in the near future. The increasing burden of alcohol-related liver diseases can be contained through government policies to limit consumption and promote less harmful patterns of alcohol use, which are in place in some countries but need to be enforced more strictly. Steps are needed to control obesity and NAFLD, including policies to promote healthy lifestyles and regulate the food industry. Inadequate infrastructure and insufficient health-care personnel trained in liver diseases are issues that also need to be addressed in the Asia-Pacific region. The policy response of most governments to liver diseases has thus far been inadequate and poorly funded. There must be a renewed focus on prevention, early detection, timely referral, and research into the best means to introduce and improve health interventions to reduce the burden of liver diseases in the Asia-Pacific region.

The gut microbiota have long been recognized to play a key role in human health and disease. Currently, several lines of evidence from preclinical to clinical research have gradually established that the gut microbiota can modulate antitumor immunity and affect the efficacy of cancer immunotherapies, especially immune checkpoint inhibitors (ICIs). Deciphering the underlying mechanisms reveals that the gut microbiota reprogram the immunity of the tumor microenvironment (TME) by engaging innate and/or adaptive immune cells. Notably, one of the primary modes by which the gut microbiota modulate antitumor immunity is by means of metabolites, which are small molecules that could spread from their initial location of the gut and impact local and systemic antitumor immune response to promote ICI efficiency. Mechanistic exploration provides novel insights for developing rational microbiota-based therapeutic strategies by manipulating gut microbiota, such as fecal microbiota transplantation (FMT), probiotics, engineered microbiomes, and specific microbial metabolites, to augment the efficacy of ICI and advance the age utilization of microbiota precision medicine.

Abstract Introduction Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapies. Human platelet lysate represents an efficient alternative to fetal bovine serum for clinical-scale expansion of MSCs. Different media used in culture processes should maintain the biological characteristics of MSCs during multiple passages. However, bone marrow-derived MSCs and adipose tissue-derived MSCs have not yet been directly compared with each other under human platelet lysate conditions. This study aims to conduct a direct head-to-head comparison of the biological characteristics of the two types of MSCs under human platelet lysate-supplemented culture conditions for their ability to be used in regenerative medicine applications. Methods The bone marrow- and adipose tissue-derived MSCs were cultured under human platelet lysate conditions and their biological characteristics evaluated for cell therapy (morphology, immunophenotype, colony-forming unit-fibroblast efficiency, proliferation capacity, potential for mesodermal differentiation, secreted proteins, and immunomodulatory effects). Results Under human platelet lysate-supplemented culture conditions, bone marrow- and adipose tissue-derived MSCs exhibited similar fibroblast-like morphology and expression patterns of surface markers. Adipose tissue-derived MSCs had greater proliferative potential than bone marrow-derived MSCs, while no significantly difference in colony efficiency were observed between the two types of cells. However, bone marrow-derived MSCs possessed higher capacity toward osteogenic and chondrogenic differentiation compared with adipose tissue-derived MSCs, while similar adipogenic differentiation potential wase observed between the two types of cells. There were some differences between bone marrow- and adipose tissue-derived MSCs for several secreted proteins, such as cytokine (interferon-γ), growth factors (basic fibroblast growth factor, hepatocyte growth factor, and insulin-like growth factor-1), and chemokine (stem cell-derived factor-1). Adipose tissue-derived MSCs had more potent immunomodulatory effects than bone marrow-derived MSCs. Conclusions Adipose tissue-derived MSCs have biological advantages in the proliferative capacity, secreted proteins (basic fibroblast growth factor, interferon-γ, and insulin-like growth factor-1), and immunomodulatory effects, but bone marrow-derived MSCs have advantages in osteogenic and chondrogenic differentiation potential and secreted proteins (stem cell-derived factor-1 and hepatocyte growth factor); these biological advantages should be considered systematically when choosing the MSC source for specific clinical application.

Abstract Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m 6 A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.

Esophageal cancer is a familiar malignancy with high incidence and mortality, and the overall prognosis is poor. The numbers of cases of and deaths from esophageal cancer have risen rapidly in recent decades. It is one of the most malignant cancers, with more than 0.6 million new cases and 0.54 million deaths worldwide in 2020. Here, we present the global epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040 at different geographical levels of continents, regions and countries, and analyze them by gender, race, geographic region and human development index. We summarize the prospects for the esophageal cancer burden and risk factors in different areas, which will be useful for global esophageal cancer clinical therapy and cancer control planning.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis. METHODS: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686). RESULTS: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%. CONCLUSIONS: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide. LAY SUMMARY: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.

Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000 IU/ml), HBsAg <1000 IU/ml in genotype D HBV infection and HBsAg <100 IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100 IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA. Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000 IU/ml), HBsAg <1000 IU/ml in genotype D HBV infection and HBsAg <100 IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100 IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.

Community-acquired pneumonia (CAP) in adults is an infectious disease with high morbidity in China and the rest of the world. With the changing pattern in the etiological profile of CAP and advances in medical techniques in diagnosis and treatment over time, Chinese Thoracic Society of Chinese Medical Association updated its CAP guideline in 2016 to address the standard management of CAP in Chinese adults. Extensive and comprehensive literature search was made to collect the data and evidence for experts to review and evaluate the level of evidence. Corresponding recommendations are provided appropriately based on the level of evidence. This updated guideline covers comprehensive topics on CAP, including aetiology, antimicrobial resistance profile, diagnosis, empirical and targeted treatments, adjunctive and supportive therapies, as well as prophylaxis. The recommendations may help clinicians manage CAP patients more effectively and efficiently. CAP in pediatric patients and immunocompromised adults is beyond the scope of this guideline. This guideline is only applicable for the immunocompetent CAP patients aged 18 years and older. The recommendations on selection of antimicrobial agents and the dosing regimens are not mandatory. The clinicians are recommended to prescribe and adjust antimicrobial therapies primarily based on their local etiological profile and results of susceptibility testing, with reference to this guideline.

Early diagnosis of colon cancer (CC) is clinically important, as it can significantly improve patients' survival rate and quality of life. Although the potential role for small extracellular vesicles (sEVs) in early detection of many diseases has been repeatedly mentioned, systematic screening of plasma sEVs derived early CC specific biomarkers has not yet been reported. In this work, plasma sEVs enriched fractions were derived from 15 early-stage (TisN0M0) CC patients and 10 normal controls (NC). RNA sequencing identified a total number of 95 sEVs enriched fraction derived miRNAs with differential expression between CC and NC, most of which (60/95) was in well accordance with tissue results in the Cancer Genome Atlas (TCGA) dataset. Among those miRNAs, we selected let-7b-3p, miR-139-3p, miR-145-3p, and miR-150-3p for further validation in an independent cohort consisting of 134 participants (58 CC and 76 NC). In the validation cohort, the AUC of 4 individual miRNAs ranged from 0.680 to 0.792. A logistic model combining two miRNAs (i.e. let-7b-3p and miR-145-3p) achieved an AUC of 0.901. Adding the 3rd miRNA into this model can further increase the AUC to 0.927. Side by side comparison revealed that sEVs miRNA profile outperformed cell-free plasma miRNA in the diagnosis of early CC. In conclusion, we suggested that circulating sEVs enriched fractions have a distinct miRNA profile in CC patients, and sEVs derived miRNA could be used as a promising biomarker to detect CC at an early stage.

BACKGROUND: Extracellular communication within the tumor microenvironment plays a critical role in tumor progression. Although exosomes can package into long non-coding RNAs (lncRNAs) to mediate extracellular communication, the role of exosomal lncRNA PTENP1 in bladder cancer (BC) remains unclear. METHOD: We detected PTENP1 expression between patients with BC and healthy controls; the expression occurred in tissues and exosomes from plasma. We assessed the diagnostic accuracy by the receiver operating characteristic curve (ROC) and the area under curve (AUC). Cell phenotypes and animal experiments were performed to determine the effect of exosomal PTENP1. RESULTS: PTENP1 was significantly reduced in BC tissues and in exosomes from plasma of patients with BC (P < 0.05). We found that PTENP1 was mainly wrapped by exosomes. Exosomal PTENP1 could distinguish patients with BC from healthy controls (AUC = 0.743; 95% confidence interval (CI) = 0.645-0.840). Normal cells secreted exosomal PTENP1 and transmitted it to BC cells, thus inhibiting the biological malignant behavior of BC cells by increasing cell apoptosis and reducing the ability to invade and migrate (P < 0.05). Exosomal PTENP1 could suppress tumor growth in vivo. Furthermore, exosomal PTENP1 mediated the expression of PTEN by competitively binding to microRNA-17. CONCLUSION: Exosomal PTENP1 is a promising novel biomarker that can be used for the clinical detection of BC. Exosomes derived from normal cells transfer PTENP1 to BC cells, which reduce the progression of BC both in vitro and in vivo and suggest that exosomal PTENP1 participates in normal-cell-to-bladder-cell communication during the carcinogenesis of BC.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is a new short-acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy. METHODS: This positive-controlled, non-inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety. RESULTS: The success rate of sedation in the RT group was non-inferior to that in the propofol group (97.34% vs 100.00%; difference in rate -2.66%, 95% CI -4.96 to -0.36, meeting criteria for non-inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment-related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001). CONCLUSION: This trial established non-inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.

Nonalcoholic fatty liver disease (NAFLD) is an acquired metabolic stress-induced liver disease associated with insulin resistance (IR) and genetic susceptibility, sharing histological similarities with alcoholic liver disease (ALD) in the absence of substantial alcohol consumption or other causes of liver disease. The spectrum of NAFLD is from simple steatosis to nonalcoholic steatohepatitis (NASH) and eventually cirrhosis and hepatocellular carcinoma.1, 2 NAFLD is one of the important public health problems worldwide in the 21st century and is also becoming more and more important in China.3 In order to further normalize the diagnosis and management of NAFLD, the Chinese National Consensus Workshop on NAFLD organized experts in this field to update the Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases formulated in 2006 with reference to the latest worldwide research findings and related diagnosis and treatment consensus and in line with the principles of evidence-based medicine.4-9 The evidence bases are categorized into three grades and five levels,11 presented as roman digits in parentheses (Table 1). The aim of this guideline is to help physicians to make correct decision in diagnosing and treating NAFLD. This guideline is not a mandatory standard and cannot involve or resolve all issues in the diagnosis and treatment program of NAFLD. Clinicians facing a specific patient should be able to make a reasonable diagnostic and therapeutic scheme based on the full understanding of the best clinical evidence and available medical resources and the comprehensive consideration of patient's specific condition and wishes, and in accordance with their own knowledge and experience. The research work on NAFLD has been advancing rapidly, so the guidelines should be updated and improved continually based on the progress of the discipline and clinical requirements in near future. NAFLD is now recognized as one of the most common causes of minor serum aminotransferase elevations and chronic liver diseases in developed countries such as Europe and America, and the prevalence of NAFLD is 20–33% in adults in the general population, among which NASH and cirrhosis account for 10–20% and 2–3%, respectively.1, 2, 12 The prevalence of simple steatosis, NASH and cirrhosis in obese patients was 60–90%, 20–25% and 2–8%, respectively. The prevalence of NASH in patients with type 2 diabetes mellitus (T2DM) and hyperlipidemia were 28–55% and 27–92%, respectively.1, 2, 12, 13 In parallel with the epidemic of obesity and metabolic syndrome worldwide, the prevalence of NAFLD in Asian countries has increased rapidly with a trend to younger patients during the last two decades. The prevalence of NAFLD was about 15% in adults in Shanghai, Guangzhou and Hong Kong.3 The risk factors for NAFLD include a high-fat diet, a high-calorific diet, a sedentary lifestyle, insulin resistance, metabolic syndrome and its components (obesity, hypertension, dyslipidemia and T2DM).3, 12, 13 Although alcohol abuse and hepatitis C virus (HCV) infection are closely associated with steatosis, the global epidemic of fatty liver is mainly correlated with the rapid increase in the epidemic of obesity.3, 12, 14 NAFLD patients with normal body mass index (BMI) or a normal waist circumference, or both, are not uncommon in Asia–Pacific regions, even when the criteria put forth by the World Health Organization regional office for the western Pacific region were used to diagnose obesity.3, 12, 13 A recent short-term weight gain and an increased waist circumference may be a cause of NAFLD and waist circumference predicts the presence of a fatty liver more accurately than BMI.3, 12, 13 Steatosis in patients with chronic HCV genotype 1 and 4 infection and hepatitis B virus (HBV) infection is highly likely to be related to insulin resistance and metabolic disorders and NAFLD is a common cause of minor serum aminotransferase elevation in hepatitis B surface antigen (HBsAg)-positive patients with serum HBV DNA level below 104 IU/mL.3, 4, 16 The long-term liver-related prognosis of patients with NAFLD depends mainly on its histological type as shown by a liver biopsy at presentation. Simple steatosis develops slowly and the incidence of cirrhosis is low (0.6–3%) after 10 to 20 years follow up; however, the rate of cirrhosis reaches 15–25% within 10 to 15 years in NASH patients.1, 2 Some markers, including age over 50 years, obesity (especially visceral obesity), hypertension, T2DM, alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST)/ALT ratio greater than 1, and a decrease of platelet count are risk factors for NASH and advanced fibrosis.1, 2, 9, 17 During the chronic protracted course of NAFLD, NASH is an inevitable stage in the development of simple steatosis into cirrhosis.1, 2 Compared to chronic hepatic C and alcoholic hepatitis, the liver fibrosis of patients with NASH progresses relatively slowly and decompensated cirrhosis and hepatocellular carcinoma usually occur in elderly people.1, 2, 13, 17 For individuals with IR, simple steatosis is a precondition of the development of NASH and cirrhosis, and a fatty liver decreases tolerance to hepatic toxins, ischemia and hypoxia. A liver with steatosis that is used for transplantation may easily cause the primary non-function of a liver graft.13, 16 Furthermore, in patients with other chronic liver diseases, coexisting steatosis and its underlying disease may contribute to the development of cirrhosis and hepatocellular carcinoma and reduce the response to interferon-based anti viral treatment in patients with non-genotype 3 hepatitis C.1, 2, 9, 13, 14 A few prospective cohort studies have found that the expected life span of patients with NAFLD, including patients with cryptogenic elevation of serum ALT or gamma-glutamyl transferase (GGT), or both, is shortened and the causes of death are mainly malignancy, atherosclerotic cardiovascular disease and cirrhosis.1, 2, 9 The all-cause mortality of patients with simple steatosis is not significantly lower than that of patients with NASH, but for the latter, liver-related mortality is markedly higher than that of a control group.1, 2, 9 NAFLD (including simple steatosis) and metabolic syndrome could be of reciprocal causation and NAFLD might be a better predictor of risk factor clusters when compared with the overall obesity reflected by BMI and the visceral obesity indicated by waist circumference.3, 13, 18, 19 Even if the patients with NAFLD have normal body weight, the incidence of T2DM and cardiovascular disease still increase significantly after 6 to 15 years follow up.2, 3, 9, 13, 18, 19 NAFLD can be diagnosed by the presence of three findings:3-5, 9, 10 (i) the histological findings of liver biopsy are in accord with the pathological diagnostic criteria of fatty liver disease; (ii) there is no history of alcohol drinking habit or the ethanol intake per week was less than 140 g in men (70 g in women) in the past 12 months; and (iii) specific diseases that could lead to steatosis, such as viral hepatitis, drug-induced liver disease, total parenteral nutrition, Wilson's disease and autoimmune liver disease, can be excluded. For epidemiological studies and in clinical settings, an operational definition of NAFLD is usually required because the histopathological diagnosis is usually difficult to obtain. The working definition is: (i) results of liver imaging study meet the diagnostic criteria of diffuse fatty liver and cannot be explained by other reasons;4 or (ii) patients with metabolic syndrome-related components show a persistent elevation of serum ALT or AST and GGT of unknown causes for more than 6 months, or both.4, 5, 9 NAFLD can be definitely diagnosed if an abnormal zymogram and fatty liver imaging has improved and even returned to normal after successful body weight reduction and the improvement of IR.4, 5, 9 Histologically, fatty liver disease can be diagnosed by the presence of parenchymal macrovesicular steatosis or mixed hepatocellular steatosis, with or without hepatocellular balloon-like degeneration, mixed inflammatory cell infiltration in the lobules and peri-sinus fibrosis in zone 3 of the liver acinus.4, 5, 9, 20 NAFLD includes a spectrum of abnormalities from hepatic steatosis alone to steatosis associated with necroinflammatory changes and varying degrees of fibrosis. NASH in children is different from that in adults; the histology usually is characterized by more severe pathological changes such as inflammation and fibrosis in the portal area rather than in the lobules.21 It is recommended that the NAFLD activity score (NAS) and liver fibrosis stage should be assessed routinely to make a pathological diagnosis, and the effect of therapeutic in patients with NASH should be evaluated by referring to the National Institutes of Health NASH Clinical Research Website criteria.4, 20 NAS is a semi-quantitative grading system but not a diagnosis procedure. NAS < 3 were largely considered not to be diagnostic of NASH; patients with scores of >4 were diagnosed as having NASH; patients with scores between 3 and 4 were diagnosed as probably having NASH.20 It is stipulated that patients without lobular inflammation, ballooning and fibrosis but with more than 30% hepatic steatosis are diagnosed as having simple fatty liver, and with steatosis less than 30% as having hepatocellular steatosis.10 NASH-related cirrhosis includes NASH combined with cirrhosis, fatty cirrhosis and cryptogenic cirrhosis (due to liver steatosis and the alleviation of steatosis and inflammation with the progression of fibrosis). Cryptogenic cirrhosis without the histological features of steatohepatitis should not be rashly attributed to NAFLD and other likely causes that lead to cirrhosis must be sought.4, 20 Diffuse fatty liver can be defined by the presence of at least two of three abnormal findings on abdominal ultrasonography: diffusely increased liver near field ultrasound echo (‘bright liver’), liver echo greater than kidney; vascular blurring and the gradual attenuation of far field ultrasound echo.4 The typical findings of fatty liver in computed tomography (CT) include a diffuse decrease of liver density. Portal and hepatic vein branches appear prominent in a scan unenhanced with contrast. A liver-to-spleen CT ratio less than 1 is defined as fatty liver: a mild degree of fatty liver has a liver: spleen CT ratio of less than 1 but more than 0.7; a moderate degree of fatty liver has a ratio of less than or equal to 0.7 but more than 0.5, and a severe degree of fatty liver has a ratio less than or equal to 0.5.10 A diagnosis of metabolic syndrome components is recommended to adopt improved International Diabetes Federation (2005) criteria. Metabolic syndrome can be diagnosed if any three of the following five items coexist: (i) obesity: waist circumference >90 cm in male (>80 cm in female) or BMI > 25 kg/m2 in both sexes, or both; (ii) elevated triglycerides: serum triglycerides ≥ 1.7 mmol/L or previously diagnosed as having hypertriglyceridemia; (iii) decreased high-density lipoprotein cholesterol (HDL-C): HDL-C < 1.03 mmol/L in males and <1.29 mmol/L in females; (iv) elevated blood pressure: blood pressure ≥130/85 mm mercury (1 mm Hg = 0.133 kPa) or having confirmed hypertension before; and (v) elevated fasting plasma glucose (FPG): FPG ≥ 5.6 mmol/L or previously diagnosed as having T2DM.4, 22 2.1 Before ascribing fatty liver diagnosed by imaging or pathology to NAFLD, some specific liver diseases that can cause fatty liver such as ALD, chronic hepatitis C, autoimmune liver disease and Wilson's disease should be excluded, together with some special conditions known to cause fatty liver such as intake of drugs (i.e., tamoxifen, amiodarone, valproate, methotrexate and glucocorticoid), total parenteral nutrition, inflammatory bowel disease, hypothyroidism, Cushing's syndrome, hypo-β-lipoproteinemia and some IR-related syndromes (lipoatrophic diabetes and Mauriac syndrome) should also be excluded.4-10, 16 2.2 Before ascribing raised ALT or GGT, or both, to NAFLD, other types of liver diseases including virus hepatitis, ALD, autoimmune liver disease, Wilson's disease and alpha-1-antitrypsin deficiency should be excluded; patients with hepatic malignancies, infections and biliary tract disease and those who are receiving or have recently received drugs (Chinese traditional and western medicines) known to raise liver enzymes should not be regarded as NAFLD.4-10 2.3 For chronic HBV and HCV genotype 1 and 4 infection patients without excess alcohol intake, coexisting diffuse steatosis usually belongs to NAFLD.14-16 In HBsAg-positive patients with persistent abnormal serum transaminase, the abnormal liver function tests may be due to NAFLD if a serum HBV DNA level below 104 IU/mL and metabolic risk factors are present.4, 15, 16 2.4 In patients whose alcohol consumption lies between mild (less than 140 g/week in men and less than 70 g/week in women) and excessive, the causes of abnormal serum enzymes and fatty liver are usually difficult to determine and individual management should consider the potential of coexistence of alcohol abuse and metabolic factors.4, 16 In patients with metabolic syndrome complicated by hepatotropic virus infection or alcohol abuse, or both, the diagnostician needs to be on the alert for the possibility of a coexistence of virus hepatitis and fatty liver disease and a coexistence of ALD and NAFLD.16 3.1 For patients with metabolic risk factors (i.e., visceral obesity, dyslipidemia, hypertension, T2DM, metabolic syndrome and a recent increase or rapid decrease of bodyweight), besides the need to evaluate heart, brain and kidney damage, liver function tests and the ultrasound scanning of the liver should also be routinely performed.4-10, 13, 23, 24 3.2 For patients with asymptomatic hepatomegaly, a persistent and unexplained increase of serum transaminases or GGT, or both, and imaging findings of diffuse fatty liver denotes the need to take further medical history and related examinations to identify the existence of other liver-damaging factors, NAFLD and potential metabolic factors.4-10, 17, 23, 24 Besides the detailed collection of data including recent changes of bodyweight and waist circumference, history of drinking alcohol, history of contacting drugs and hepatotoxic agents, family history of diabetes and coronary heart disease, the following routine examinations should also be undertaken: (i) anthropometry (height, bodyweight, waist circumference) and arterial blood pressure; (ii) complete blood count; (iii) serum enzymes, such as ALT, AST, GGT and alkaline phosphatase; (iv) serum HBsAg (also testing positive for HBV DNA), anti-HCV (also testing positive for HCV RNA), anti-nuclear antibody; (v) serum lipids profile including triglyceride, HDL-C, low-density lipoprotein cholesterol (LDL-C) and (vi) fasting plasma glucose (FPG) and glycated hemoglobin (HbA1C), and 75 g oral glucose tolerance test (OGTT) (in patients without a previous diagnosis of T2DM when their FPG is between 5.6 and 7.0 mmol/L or their HbA1C was between 6% and 6.5%, or both). 3.3 For patients with NAFLD established by clinical diagnosis, optional reference tests include:4-10, 17, 23, 24 (i) their homeostatic model assessment IR may be calculated according to their FPG and fasting serum insulin; their postprandial blood glucose regulating capacity and insulin sensitivity should be estimated on the basis of OGTT; (ii) their whole blood viscosity, serum high sensitive C-reactive protein, serum uric acid and uric micro-albumin should be measured for the detection of metabolic syndrome relevant components; (iii) their serum total bilirubin, albumin and prothrombin time should be measured to reflect the liver reserve function. In patients with suspected cirrhosis gastroscopy should be considered to screen gastroesophageal varices and an alpha fetoprotein assay should be done for screening hepatocellular carcinoma; (iv) a carotid artery color Doppler ultrasonography should be conducted to detect atherosclerotic plaque; (v) an abdominal CT and magnetic resonance image should be performed if a properly conducted ultrasound is not informative, especially when malignancy cannot be excluded; (vi) related examinations should be performed to confirm the diagnosis of iron-overload, sleep apnea syndrome, polycystic ovarian syndrome, hypothyroidism, hypofunction of the anterior pituitary and other conditions; and (vii) a liver biopsy. This is not usually required for the clinical diagnosis of NAFLD, although, up to has been the for NASH from simple steatosis and the and stage of NAFLD. It is that a liver biopsy for histological assessment should be mainly used (i) patients to be definitely diagnosed by a routine and diagnostic (ii) those at risk of advanced hepatic fibrosis (in the absence of clinical or imaging evidence of (iii) those in clinical and diagnostic (iv) those to a for other a or and (v) those to the and prognosis of liver 9, 17, 23, 24 The and of a liver biopsy should be its in prognosis and including and should be considered in a liver histology items relevant to research (i) the of IR by the glucose or the of fasting liver glucose and insulin to the liver IR (ii) of hepatic triglycerides by magnetic resonance (iii) of body and by scan or abdominal (iv) heart and coronary artery by and (v) such as serum and to NASH from simple steatosis and to 17, 23, 24 In of the that NAFLD is one of the important components of metabolic syndrome and that the liver histology changes of most patients are at the stage of simple steatosis, the primary of NAFLD is to IR and and metabolic syndrome components and related diseases so as to the of life and their The is to reduce liver and NASH and liver function by the two In for patients with NASH, for liver disease progression and or the development of cirrhosis, liver and their related should be 17, health to correct and the and to the treatment for metabolic syndrome moderate is of a intake of for obese adults; an of the to a low and diet, a reduction of and intake and an increase in moderate at least 4 per with a time of 17, 23, A weight reduction is usually which be for the of components of metabolic syndrome including NAFLD 9 weight gain and decrease waist if patients are obese and to more than weight reduction by their for months, should be to such as and for and 17, 23, might be considered in patients with obesity who not to the patient has liver or moderate or severe gastroesophageal varices 17, 23, abnormal serum zymogram and histopathological in NAFLD patients usually significantly with weight the most and the of drugs and to weight to be further 9, 10 IR and correct metabolic according to clinical related drugs can be to metabolic risk factors and their in some including liver as serum more than the normal and hepatic or decompensated cirrhosis, NAFLD patients may insulin and and to decrease blood glucose and and 17, 23, the effect of drugs on abnormal liver function tests and hepatic pathological changes in patients with NAFLD to be established by further clinical and 17, 23, 24 to of liver NAFLD, especially NASH should a reduction of bodyweight and the of low and a for weight reduction is and contacting hepatotoxic Chinese traditional and western with potential and excess alcohol liver and drugs to and steatohepatitis and advanced there are still on the and of and drugs in and treatment of 17, 23, 24 at there is not evidence to the routine of this of in patients with NAFLD and the of and drugs could be used as mainly for the following 24 (i) patients with NASH confirmed by liver (ii) patients with liver or advanced hepatic or both, as shown by clinical findings and imaging NAFLD patients with elevated serum transaminase, metabolic syndrome or (iii) patients who are suspected of drugs which may liver and who are the of treatment or those who have serum elevation during the of and (iv) patients with a coexisting hepatotropic virus infection or other liver disease. to two of liver and including Chinese traditional and western such as acid and could be according to the disease the stage of the disease, and and The of treatment is usually or more cirrhosis according to clinical related should be to and portal hypertension and of liver transplantation could be considered for patients with NASH complicated by liver and decompensated cirrhosis and those with NAFLD complicated by hepatocellular carcinoma 17, 23, 24 Before a liver an overall assessment of metabolic risk factors and related should be metabolic syndrome components still need treatment to reduce the of NAFLD and increase the rate of 17, 23, 24 health A at diet, bodyweight, waist circumference and other associated with of life should be up for between the and the patient and to the and program 10 a comprehensive on of the components of metabolic syndrome, changes of serum index and liver imaging and of the so as to and treatment in time in order to make a on the effect of the A of liver histology might be for clinical and patients for special 9, 17, 23, 24 It is recommended that patients with NAFLD should their bodyweight, waist circumference, blood liver serum lipids and blood glucose 6 and an abdominal ultrasound the liver, and spleen 9 It is that malignancy, metabolic syndrome related diseases and of cirrhosis as liver carcinoma and gastroesophageal are according to the patient's condition and with reference to relevant diagnosis and treatment guidelines 13,