From the Editor’s Desk...

Several second-generation farnesoid X receptor (FXR) agonists are being developed to reproduce the histological benefit demonstrated with obeticholic acid, but an improved safety profile. MET409 is one of these novel, non-biliary FXR altered PK and PD properties that allow once daily dosing. Harrison coworkers present a proof-of-concept trial where 58 patients biopsy-proven non-alcoholic steatohepatitis (NASH), MRI-proven steatosis abnormal ALT values were randomised receive 80 mg, 50 mg or placebo for 12 weeks. The drug clearly reduced liver fat content, relative reductions 55% (high dose) 38% (lower vs. only 6% placebo. It also ALT, though some individuals experienced transient elevations on therapy. Importantly, induced pruritus increases in LDL which both dose related. This new molecule appears be very powerful agonist further studies need identify effective acceptable toxicity. However, hopes next-generation could maintain high efficacy without causing lipid changes seem fading away. Immune checkpoint inhibitors (ICIs) have revolutionized treatment many cancers, activating anti-tumoral immune responses ICIs carries risk immune-related side effects including immune-mediated hepatitis. Gudd meticulously analysed blood samples undergoing ICI therapy malignancies order define characteristic activation patterns associated ICI-related Myeloid lymphoid populations drastically changed livers, inflammatory monocytes cytotoxic, effector-type CD8+ T-cells becoming dominant These data may build foundation better stratification therapy, early diagnosis hepatitis possibly therapeutic preventive interventions. Hepatocyte homeostasis severely disturbed NASH, characterised by lipotoxicity, mitochondrial dysfunction endoplasmic reticulum (ER) stress. Simón now demonstrate this accompanied drastic magnesium (Mg2+) homeostasis, because Mg2+ transporter cyclin M4 (CNNM4) upregulated NASH acts as exporter liver. Using patient samples, primary hepatocyte cultures rodent models, downregulating CNNM4 hepatocytes restored hepatic levels ER stress, translated into steatosis, lower inflammation fibrosis. While indicate inhibiting attractive treat extrahepatic consequences interfering warrant investigation. In “ER stress” activates unfolded protein response (UPR) disturbs homeostasis. Liu identified stress UPR induce Forkhead box A3 (FOXA3) transcription hepatocytes, controls synthesis via PER1/SREBP1c. Genetic FOXA3 deletion siRNA-mediated suppression ameliorated chronic insulin resistance fatty disease (NAFLD) models. next step translating basic findings strategies reduce excessive NASH. He uncovered role IL-20, another cytokine IL-10 family, injury signals novel IL-20-deficient mouse model, IL-20 was found exacerbate acute bacterial infection, upregulating NAD(P)H: quinone oxidoreductase 1 (NQO1) subsequently promoting degradation factor IκBζ. then inhibits IL-6 LCN2 important defence mechanism against bacteria sterile injury. finding opposes IL-22 aggravates potentially leveraged develop therapies control infections. About 15–30% hepatocellular carcinoma (HCC) gain function mutations CTNNB1 gene distinct pathological features. Liang report T-box 3 (TBX3), known target Wnt pathway implicated hepatocarcinogenesis, fact tumour suppressor restricts growth activated mutants. Based analysis expression profiles large public datasets, experiments murine models cancer human HCC cell lines, TBX3 regulating YAP/TAZ likely drives specific phenotypes observed CTNNB1-mutant HCCs. suggest increase HCC, requires clinical exploration. Hypoxia-inducible factors (HIFs) hallmark key regulators immunity metabolism yet their HBV replication poorly defined. replicates within liver, naturally hypoxic organ, however, most viral performed under conditions atmospheric oxygen, HIFs inactive. Wing coauthors investigated impact hypoxia life cycle. Culturing cell-based model systems low oxygen binding DNA basal core promoter, leading increased pre-genomic RNA de novo particle secretion. Identifying conserved sensor suggests virus has evolved exploit HIF-signalling persist environment Most infections during host adulthood do not lead disease, thus, highlighting self-restrictive feature HBV-host interactions. Besides well-defined open reading frames, it interesting ask whether how genome might possess extra coding potential. Yuan EnhI-SL (Enhancer I-stem loop) cis element genome, disrupting elevate polymerase expression. Furthermore, while rediscovering HpZ/P’, previously under-explored isoform polymerase, they HBxZ short HBX confirmed existence functionally characterized them potent suppressors replication. Mechanistically, HpZ/P’ repress partially through interacting sequestering SUPV3L1. abundance mutants deficient disrupted seemed diminished upon system. Finally, SRSF2, HBV-downregulated spliceosome, promote splicing biogenesis. authors conclude SRSF2-HpZ/P’ constitute negative feedback controlling life-cycle. Targeting machinery represent strategy intervene HEV outside been proven vitro experimentally infected neuronal placental well cerebrospinal fluid, kidney, placenta, intestine, lymph nodes tonsils. Various viruses detected ejaculate can outlast duration viremia, indicating beyond blood-testis barrier. Horvatits aimed determine occurrence, features morphology ejaculate. none 6 from infection pig testis tested positive, 2 chronically HEV-infected patients, HEV-RNA (genotype-3c) seminal plasma semen loads >2 logs higher than serum. Genomic sequencing showed significant differences between strains compared stool. Under ribavirin-treatment, shedding outlasted viremia >9 months. male reproductive system niche persistence chronic, infection. We already knew high-fructose intake lipogenesis content decreases sensitivity independently weight gain. study attempted comprehensive evaluation metabolic fructose adipose tissue lipolysis acid oxidation. Moreover, respective alone (usual beverage sweetener US), sucrose (fructose glucose, usual Europe) glucose compared. Geidl-Flueck randomized 94 healthy lean men receive, 7 weeks, diets supplemented types carbohydrates group no equivalent caloric intake. tracer-based methodology, elegantly shows fructose-based sweeteners contrary enhance VLDL production. There change distribution towards smaller, more atherogenic particles. microbial fermentation feeds acetate. Fructose sucrose, did peripheral nor “metabolic switch” adaptive process recurrent pave way diseases such type diabetes. Stephens et al. presented 843 drug-induced (DILI) enrolled Spanish DILI Registry over 20-year time period (up 2018). Cases identified, diagnosed followed prospectively features, information outcomes. Patients had mean age 54 years (48% females). Anti-infective agents represented common class central nervous system, musculoskeletal drugs cardiovascular agents. Hepatocellular predominant phenotype (57%) all groups except ≥80 whom cholestatic predominated. Liver-related mortality frequent damage aged ≥65 years-old underlying disease. Independent predictors liver-related death/transplantation outcome included Ratio (nR = AST, whichever highest × ULN/ALP ULN) – based definition injury, female sex, onset AST bilirubin values. Thus, concluded elevation at strong predictor poor should routinely older mortality. Golexanolone, small GABA-A modulating steroid antagonist, proved restore spatial learning motor coordination animal encephalopathy (HE) mitigate intravenous allopregnanolone adults dose-dependent fashion. paper Montagnese reported golexanolone, its affect electroencephalogram (EEG) subjective sleepiness cognitive performance adult cirrhosis. Golexanolone exhibited satisfactory Baseline characteristics similar respectively. By prespecified analyses, golexanolone directionally favourable measures performance. Considering variability improvement screening baseline, post hoc analyses suggested efficacy. tolerated They stated results implicate neurosteroids pathogenesis HE holds promise option. Taiwan introduced number population-wide interventions burden last decades, providing natural opportunity evaluate what extent incidence case-fatality population level. Liao studied topic using registry before after universal B vaccination, health care, According age, trends dropped elderly group. Both remarkable decline rate attributed care contributed declining Hepatitis vaccination led 36% reduction those 30 below antiviral resulted around 15% 69 years. confirm benefits access Screening cirrhosis ultrasound every months recommended guidelines. overall procedure suboptimal abbreviated MRI (AMRI) alternative. Gupta systematic review diagnostic accuracy AMRI compare ultrasound. Fifteen total 2,807 917 cases meta-analysis. pooled per-patient specificity 86% 94%, irrespective setting. detection (<2 cm) 69%. non-contrast comparable contrast-enhanced protocols comparable. therefore valuable tool screening. coronary artery (CAD) peri-liver transplantation cardiac events. Rachwan 1,771 who underwent pre-liver transplant single US Center, echocardiography (SE) catheterization (CATH). Risk-adjusted CAD CATH gender, diabetes, hypertension, tobacco use, family history CAD, personal CAD. created score stratified (≤2%), intermediate (3% 9%), (≥10%). Among CATH, risk-based testing algorithm compatible risk, would 97% avoided unnecessary testing. CAD-liver effectively stratify Patrizia Burra Department Surgery, Oncology Gastroenterology, Padua University Hospital, Padua, Italy. Frank Tacke Hepatology Charité Universitätsmedizin Berlin, Germany Vlad Ratziu Insitute Cardiometabolism Nutrition, Sorbonne Université Hospital Pitié Salpêtrière, Paris, France. Stefan Zeuzem Medicine I, Goethe Frankfurt, Germany. Bruno Sangro Liver Unit, Clinica Universidad Navarra CIBEREHD, Pamplona, Spain. Paolo Angeli Unit Internal Hepatology,