BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality. Liver resection provides a curative option, though recurrence following resection remains a major clinical challenge, as adjuvant therapies evolve, and preservation of liver function becomes increasingly important. AIM To evaluate factors associated with HCC recurrence in a real-world setting. METHODS We retrospectively reviewed records of patients with HCC who underwent primary liver resection at three tertiary referral hospitals between January 2008 and May 2022. Baseline patient and tumour characteristics were assessed. Risk factors for recurrence were analysed using multivariate Cox regression. RESULTS In this cohort, 235 patients underwent surgical resection for HCC. Median survival was 80.9 months. HCC recurred in 94 (40%) patients with median time to recurrence 18.8 months (interquartile range: 8.6-35). An albumin-bilirubin (ALBI) grade of >= 2 [adjusted hazard ratio (aHR): 2.02 (1.27-3.21), P = 0.003], the presence of cirrhosis [aHR: 2.03 (1.27-3.25), P = 0.003], and Barcelona Clinic Liver Cancer (BCLC) stage B/C [aHR: 2.23 (1.23-4.03) P = 0.008] were independently associated with increased risk of recurrence. When combining these risk factors, the adjusted HR for recurrence was 2.73 (1.57-4.75), 4.32 (2.29-8.12) and 7.52 (2.47-22.93) in those with 1, 2, or 3 factors compared to those with 0 (P < 0.001). CONCLUSION HCC recurrence following primary liver resection was independently associated with cirrhosis, ALBI grade >= 2 and BCLC stage B/C. The seed (the liver cancer as reflected by BCLC stage), and the soil (the liver function and presence or absence of cirrhosis) are relevant considerations for recurrence prediction.

Australia has a robust public health system that helps to make medicines affordable. However, evidence shows that a significant proportion of Australians still cannot afford medicines prescribed to them and that some patients import medicines from abroad as a result. The strongest predictor of whether patients import medicines is whether they have discussed it with their doctor. In this article we explore options available to patients and physicians for access to unapproved medicines when approved medicines are unaffordable. Although personal importation is the most obvious option, regulation leaves scope for other possibilities. We propose that guidance should be developed to help physicians address cost-related medicine non-adherence in practice and to help them understand their options and how to navigate them at the individual, speciality and professional levels.

Background:Higher diversity of the oral microbiome has been associated with poorer oral health outcomes in the general population. We aimed to characterize the oral microbiota in patients with inflammatory bowel disease (IBD) and compare this with that of healthy controls (HC). We also sought to examine associations between IBD management and disease control, diet and metabolic disease with oral microbial diversity. Methods:This prospective case-control study compared participants with IBD in clinical remission with HC. Baseline anthropometry and fasting blood metabolic markers were measured, dietary intake recorded, and oral samples were collected for 16S rRNA gene amplicon sequencing. Results:There were 57 patients with IBD (Ulcerative colitis (UC) = 26, Crohns Disease (CD) = 31) and 24 HC enrolled. There were no significant differences in oral microbial diversity between the IBD and HC cohorts. Among participants with IBD, oral microbial diversity did not associate with IBD activity nor risk of subsequent disease flare (adj-P = .28), however the use of biologic medications was associated with a lower oral microbial alpha diversity (species richness P = .01). Higher plasma insulin concentrations were associated with a higher oral alpha diversity (species richness adj-P < .01) and with beta diversity (Pseudo-F: 2.05, P = .02). Conclusions:Oral microbial diversity is not associated with IBD disease activity or course but is positively influenced by biologic treatment. Higher fasting insulin, however, is associated with more diverse "unhealthy" oral microbiota. Within the limitations of this small study, oral microbiota may be a better marker of metabolic health than of IBD activity.

Background:MS is a chronic inflammatory and degenerative disease of the central nervous system (CNS) resulting in neurological deficits associated with physical and/or cognitive disability. The gut microbiome can interact with the CNS and immune system through various molecular pathways and has been previously implicated in MS. Autologous Haematopoietic Stem Cell Transplant (AHSCT) in MS arrests inflammatory disease and has evidence of long-term therapeutic benefit. To date, no study has explored the effect of AHSCT on the gut microbiome in people with MS. Method:The microbiome of people with MS (pwMS) undergoing AHSCT was compared with pwMS on Natalizumab (NTZ). Longitudinal microbiome analysis was also conducted within the AHSCT cohort at two timepoints. Amplicon sequencing of the 16S ribosomal RNA V3-4 region (Illumina MiSeq) was used to evaluate alpha and beta diversity, oral-stool microbiota distances, and relative taxa abundances on both oral and stool microbiota. Results:The pre-transplant, baseline samples from the AHSCT cohort (n=8) was compared to the Natalizumab group (n=22). The AHSCT cohort had lower oral species richness compared to the NTZ cohort (p=0.026). There was a significant difference in oral beta diversity between the two cohorts (p=0.043). The oral taxa analysis of AHSCT subjects showed increased relative abundances of Porphyromonas and decreased Veillonella. Conclusion:This pilot study identified specific microbiome changes, particularly in the oral alpha diversity and abundance of specific bacteria which may reflect treatment status or disease activity in MS.

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen. Whole-genome sequencing revealed thousands of somatic mutations, numerically comparable to chronic lymphocytic leukemia and normal memory B cells, but with 1-2 corresponding to driver mutations found recurrently in B cell leukemia and lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility in complex with self-IgG. In this virus-induced autoimmune disease, infection promotes a catastrophic confluence of somatic mutagenesis in the descendants of a single B cell.

BACKGROUND:There is currently no pharmacological therapy proven to alter the natural course of primary sclerosing cholangitis (PSC). The PRIMIS trial evaluated the efficacy and harms of the farnesoid X-activated receptor agonist cilofexor in participants with non-cirrhotic PSC. METHODS:In this phase 3, double-blind, placebo-controlled, multicentre trial (205 sites across 16 countries), adults aged 18-75 years with non-cirrhotic (F0-F3 [Ludwig classification]) large-duct PSC were randomly assigned (2:1) via an interactive web response system to receive cilofexor 100 mg or placebo (identical in appearance) orally once daily for 96 weeks. Randomisation was stratified by ursodeoxycholic acid use (yes or no) and the presence of bridging fibrosis (F3 vs F0-F2), with a block size of six within each stratum. Participants, personnel directly involved in the conduct of the study, and outcome assessors were masked to treatment assignment. The primary endpoint was the proportion of participants with histological progression of liver fibrosis (a stage increase of one or more [Ludwig classification]) at week 96. After study termination, the primary endpoint analysis set was amended to include all participants in the harms analysis set (all who received at least one dose of the study drug) who had biopsy data at baseline and week 96. This trial is complete (ClincalTrials.gov, NCT03890120). FINDINGS:Between June 13, 2019, and July 22, 2021, 419 participants were randomly assigned, and 416 were included in the full and harms analysis sets (cilofexor: n=277; placebo: n=139); 257 (62%) men and 159 (38%) women. The study was terminated early on Sept 26, 2022, after a planned interim futility analysis after 160 patients had reached 96 weeks of follow-up indicated a 6·8% probability of detecting a significant difference between cilofexor over placebo (futility boundary ≤10%). In the final analysis of the primary endpoint, for which 133 patients in the cilofexor group and 64 in the placebo group had liver biopsy results available, fibrosis progression occurred in 41 (31%) participants in the cilofexor group and 21 (33%) in the placebo group at week 96 (treatment difference -1·4% [95% CI -15·2 to 12·3]; p=0·42). The most common adverse events were pruritus (cilofexor: 136 [49%] of 277 patients; placebo: 50 [36%] of 139 patients; grade 3 or higher in 11 [4%] patients in the cilofexor group and one [1%] patient in the placebo group), COVID-19 (cilofexor: 65 [23%]; placebo: 26 [19%]), and upper abdominal pain (cilofexor: 40 [14%]; placebo 20 [14%]). The proportion of serious adverse events was similar between groups (cilofexor: 53 [19%]; placebo: 26 [19%]). There were no treatment-related deaths. INTERPRETATION:Cilofexor did not significantly reduce the rate of fibrosis progression (vs placebo) in participants with non-cirrhotic PSC. A greater percentage of cilofexor-treated participants had pruritus than placebo-treated participants; this study provides valuable harms data for cilofexor and other drugs in its class. FUNDING:Gilead Sciences.

BACKGROUND AND AIMS:Covert hepatic encephalopathy (CHE) is clinically underrecognized. Using MRI, we explored the relationship between functional connectivity as a marker of executive dysfunction and the blood-brain barrier permeability marker K TRANS in a cross-sectional cohort of CHE, no hepatic encephalopathy (NHE), and healthy controls (HCs). APPROACH AND RESULTS:This study was a single-center prospective cohort study conducted between 2018 and 2021. CHE was diagnosed using the Psychometric Hepatic Encephalopathy Score (PHES) with an abnormality threshold of <-4. Blood-brain barrier permeability was determined using MRI K TRANS , based on cerebral efflux of gadolinium from blood plasma to the extravascular space. Resting-state functional MRI determined the intrinsic dynamics of regions of the brain.Three cohorts were recruited: cirrhosis and CHE (n=17); cirrhosis with NHE (n=13); and HCs (n=10). There was a significant negative correlation ( r =-0.59, p =0.003) between K TRANS and components of the Default Mode Network (DMN). Group-level ANOVA ( F test) revealed a significant difference between groups in functional connectivity within the Salience Network (SN) (cluster-level significance, F (4, 62)=8.45, pcorrected =0.000005) and the DMN (cluster-level significance, F (4, 62)=6.20, pcorrected =0.0004). The analysis revealed significant differences in regional homogeneity between the CHE and HCs. CONCLUSIONS:There was a strong association between disrupted blood-brain barrier integrity and attenuated functional connectivity, with reductions in functional connectivity within the DMN and Frontoparietal Network (FPN), circuits closely linked to executive control. This attenuation was evident both in local regional and in distant connectivity within these networks.

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-CV). We traced the evolution of the pathogenic rheumatoid factor (RhF) autoantibodies in four HCV-CV patients by deep single cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive accumulation of a large disease causing clone. A sensitive method for quantifying low affinity binding revealed three recurring heavy/light chain combinations created by V(D)J recombination bound self IgG but not viral E2 antigen. Whole genome sequencing revealed accumulation of thousands of somatic mutations, at levels comparable to CLL and normal memory B cells, but with 1-2 corresponding to driver mutations found recurrently in B cell leukemia/lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility. In this virus-induced autoimmune disease, infection promotes a perfect storm of somatic mutagenesis in the descendants of a single B cell.### Competing Interest StatementThe authors have declared no competing interest.

[This corrects the article DOI: 10.1016/j.jhepr.2022.100552.].

AimsAdvanced chronic liver disease and advanced chronic liver disease-related ascites have a high mortality. The pharmacological treatment of ascites and fluid overload has changed little over time. Empagliflozin, a sodium-glucose cotransporter type 2 inhibitor is an untested potential novel treatment in cirrhosis, as it has survival benefits in heart failure, which has similar pathophysiological fluid overload mechanisms. Before investigating empagliflozin's potential benefit in cirrhosis, its safety must be addressed.MethodsTen participants (five each with compensated or decompensated advanced chronic liver disease, based on Child-Pugh class) received empagliflozin 10 mg orally daily for 4 weeks with 2 weeks follow-up. Empagliflozin safety, pharmacokinetics and pharmacodynamics were investigated.ResultsIn total, eight patients (80%) reported an adverse event, and three patients (30%) experienced a serious adverse event, one of which was attributed to empagliflozin. Overall, the frequency of adverse events was similar to previous phase 3 trials of gliflozins. Higher plasma empagliflozin concentrations did not significantly increase the risk of adverse events.ConclusionsFour-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data support assessment of long-term treatment on disease-related and mortality outcomes in patients with cirrhosis through randomized control trials.

BACKGROUND:HE is a neuropsychiatric complication of liver disease characterized by systemic elevation in ammonia and proinflammatory cytokines. These neurotoxins cross the blood-brain barrier and cause neuroinflammation, which can activate the kynurenine pathway (KP). This results in dysregulated production of neuroactive KP metabolites, such as quinolinic acid, which is known to cause astrocyte and neuronal death. Our aim was to compare KP activity between patients with covert HE (CHE), patients without encephalopathic cirrhosis (NHE), and healthy controls (HCs). METHODS:This was a single-center prospective cohort study conducted between 2018 and 2021 at St Vincent's Hospital, Sydney. Overall, 13 patients with CHE, 10 patients with NHE, and 12 with HC were recruited. Patients with cirrhosis were diagnosed with CHE if they scored ≤-4 on the Psychometric Hepatic Encephalopathy Score. KP metabolite levels were quantified on plasma samples via HPLC and gas chromatography/mass spectrometry. One-way Kruskal-Wallis test was used to compare the expression levels of KP enzymes. RESULTS:KP was highly activated in patients with cirrhosis, demonstrated by higher levels of activity in the rate-limiting enzymes, indoleamine 2,3-dioxygenase, and tryptophan-2,3-dioxygenase in both CHE (65.04±20.72, p=0.003) and patients with NHE (64.85±22.10, p=0.015) compared to HC (40.95±7.301). Higher quinolinic acid concentrations were demonstrated in CHE (3726 nM±3385, p<0.001) and patients with NHE (1788 nM±632.3, p=0.032) compared to HC (624 nM±457). KP activation was positively correlated with inflammatory marker C-reactive protein in patients with CHE (Rs=0.721, p≤0.01). CONCLUSIONS:KP is highly activated in patients with CHE, resulting in heightened production of neurotoxic metabolites. Dysregulation of the pathway is demonstrable in patients who do not yet show clinical signs of neurocognitive impairment. Therapeutic agents that modulate KP activity may be able to alleviate symptoms of patients with CHE.

Background: Diet has been linked to gut dysbiosis and the onset, course, and response to treatment of patients with IBD and metabolic disease. Methods: This single-centre prospective case-control study investigated the relationship between dietary intake, metabolic profile, and stool microbial composition in 57 individuals with IBD in clinical remission and 24 healthy individuals (HC). Participants’ baseline anthropometric measurements, serum metabolic parameters, lipid profiles, and oral and stool samples for microbiota testing were collected. Their dietary intake and physical activity were documented. A partially corrected correlation was performed to examine the associations between variables and p-values adjusted for multiple comparisons using the Benjamini–Hochberg equation (adj-p). Results: In participants with IBD, the intake of saturated fat correlated positively, and the intake of dietary fibre correlated negatively with anthropometric indices (saturated fat and BMI: r = 0.37, adj-p = 0.04, fibre and BMI: r = −0.45, adj-p = 0.01). Higher anthropometric indices were associated with poorer glucose control and a less favourable serum lipid profile (BMI and insulin: r = 0.48, p < 0.01, WHR and triglycerides: r = 0.57, p < 0.01). The stool microbiota of participants in the IBD group was less diverse and more similar to their oral microbiota than was observed in the HC group (Mann–Whitney U test p = 0.03). Within the IBD group, a higher intake of added sugar and processed meat and a higher serum insulin level was associated with lower stool microbial alpha diversity (processed meat intake and Shannon’s diversity: r = −0.43, adj-p = 0.02; added sugar and Shannon’s diversity: r = −0.39, adj-p = 0.03; insulin and Shannon’s diversity: r = −0.45, adj-p = 0.02). Neither the dietary intake nor stool microbial composition correlated with the risk of disease flaring. Conclusions: Our findings suggest that dietary intake is associated with the metabolic health and gut microbial composition of IBD patients.

incidence of major bleeding. The lack of an aspirin effect on HCC incidence in cirrhosis is intriguing. Intuitively, the low hanging fruit of a chemopreventative strategy would be to target patients with cirrhosis who are at the highest risk of HCC and liver-related mortality, however, that is not born out in this study. Rather, this study suggests that the “window of opportunity” to intervene with chemoprevention is prior to the development of cirrhosis. The reason for this has not been defined in the study, but a number of factors could be considered. Biologically, cirrhosis may impact the postulated mechanism of aspirin’s action. The platelet-dependent effects of aspirin may be limited by thrombocytopenia, and the platelet-independent effects on fibrogenesis mediated via hepatic stellate cells may be mitigated by advanced fibrosis. Genetic factors may also be important as this was a Korean population, in contrast to the large Swedish population registry study which demonstrated a