The RIVET RCT: Rifamycin SV MMX improves muscle mass, physical function, and ammonia in cirrhosis and minimal encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) negatively affects the prognosis of cirrhosis, but treatment is not standard. Rifamycin SV MMX (RiVM) is a nonabsorbable rifampin derivative with colonic action. METHODS: In a phase 2 placebo-controlled, double-blind randomized clinical trial patients with MHE were randomized to RiVM or placebo for 30 days with a 7-day follow-up. The primary endpoint was a change in stool cirrhosis dysbiosis ratio. Gut-brain (cognition, stool/salivary microbiome, ammonia, brain magnetic resonance spectroscopy), inflammation (stool calprotectin/serum cytokines), patient-reported outcomes (sickness impact profile: total/physical/psychosocial, high = worse), and sarcopenia (handgrip, bioelectric impedance) were secondary. Between/within groups and delta (post-pre) comparisons were performed. RESULTS: Thirty patients (15/group) were randomized and completed the study without safety concerns. While cirrhosis dysbiosis ratio was statistically similar on repeated measures ANOVA (95% CI: -0.70 to 3.5), ammonia significantly reduced (95% CI: 4.4-29.6) in RiVM with changes in stool microbial α/ß-diversity. MHE status was unchanged but only serial dotting (which tests motor strength) improved in RiVM-assigned patients. Delta physical sickness impact profile (95% CI: 0.33 = 8.5), lean mass (95% CI: -3.3 to -0.9), and handgrip strength (95% CI: -8.1 to -1.0) improved in RiVM versus placebo. Stool short-chain fatty acids (propionate, acetate, and butyrate) increased post-RiVM. Serum, urine, and stool bile acid profile changed to nontoxic bile acids (higher hyocholate/ursodeoxycholate and lower deoxycholate/lithocholate) post-RiVM. Serum IL-1ß and stool calprotectin decreased while brain magnetic resonance spectroscopy showed higher glutathione concentrations in RiVM. CONCLUSIONS: RiVM is well tolerated in patients with MHE with changes in stool microbial composition and function, ammonia, inflammation, brain oxidative stress, and sarcopenia-related parameters without improvement in cognition. RiVM modulates the gut-brain axis and gut-muscle axis in cirrhosis.

Artificial Intelligence Evaluation of Stool Quality Guides Management of Hepatic Encephalopathy Using a Smartphone App.

Lactulose-based hepatic encephalopathy treatment requires bowel movements/day titration, which is improved with Bristol stool scale (BSS) incorporation. Dieta app evaluates artificial intelligence (AI)-based BSS (AI-BSS) with stool images. Initially, controls (N = 13) and cirrhosis patients on lactulose/not on lactulose (n = 33) were trained on the app. They entered self-reported BSS (self-BSS) with AI-BSS communicated. Lactulose dose changes were tracked. A subset (n = 12) was retested with AI communication blocked. Most subjects were comfortable with the app. Self/AI-BSS and lactulose dose/AI-BSS correlation increased with app use. AI-BSS communications improved insight into self-BSS over time. Dieta app to gauge stool AI characteristics was acceptable and increased insight into lactulose dose and BSS in cirrhosis.

Alterations in gut virome are associated with cognitive function and minimal hepatic encephalopathy cross-sectionally and longitudinally in cirrhosis.

Cognitive dysfunction due to minimal hepatic encephalopathy (MHE) adversely impacts patients with cirrhosis and more precise therapies are needed. Gut-brain axis changes are therapeutic targets, but prior studies have largely focused on bacterial changes. Our aim was to determine linkages between individual cognitive testing results and bacteria with the virome using a cross-sectional and longitudinal approach. We included cross-sectional (n = 138) and longitudinal analyses (n = 36) of patients with cirrhosis tested using three cognitive modalities, which were psychometric hepatic encephalopathy score (PHES), inhibitory control test (ICT), Stroop, and all three. Stool metagenomics with virome and bacteriome were analyzed studied cross-sectionally and in a subset followed for development/reversal of MHE repeated at 6 months (longitudinally only using PHES). Cross-sectional: We found no significant changes in α/ß diversity in viruses or bacteria regardless of cognitive testing. Cognitively impaired patients were more likely to have higher relative abundance of bacteriophages linked with Streptococcus, Faecalibacterium, and Lactobacillus, which were distinct based on modality. These were also linked with cognition on correlation networks. Longitudinally, 27 patients remained stable while 9 changed their MHE status. Similar changes in phages that are linked with Streptococcus, Faecalibacterium, and Lactobacillus were seen. These phages can influence ammonia, lactate, and short-chain fatty acid generation, which are neuro-active. In conclusion, we found linkages between bacteriophages and cognitive function likely due to impact on bacteria that produce neuroactive metabolites cross-sectionally and longitudinally. These findings could help explore bacteriophages as options to influence treatment for MHE in cirrhosis.

Palliative Care in Survivors of Critical Illness: A Qualitative Study of Post-Intensive Care Unit Program Clinicians.

Background: Survivors of critical illness experience high rates of serious health-related suffering. The delivery of palliative care may assist in decreasing this burden for survivors and their families. Objectives: To understand beliefs, attitudes, and experiences of post-intensive care unit (ICU) program clinicians regarding palliative care and explore barriers and facilitators to incorporating palliative care into critical illness survivorship care. Design: Qualitative inquiry using semistructured interviews and framework analysis. Results were mapped using the Consolidated Framework for Implementation Research. Setting/Subjects: We interviewed 29 international members (United States, United Kingdom, Canada) of the Critical and Acute Illness Recovery Organization post-ICU clinic collaborative. Results: All interprofessional clinicians described components of palliative care as essential to post-ICU clinic practice, including symptom management, patient/family support, facilitation of goal-concordant care, expectation management and anticipatory guidance, spiritual support, and discussion of future health care wishes and advance care planning. Facilitators promoting palliative care strategies were clinician level, including first-hand experience, perceived value, and a positive attitude regarding palliative care. Clinician-level barriers were reciprocals and included insufficient palliative care knowledge, lack of self-efficacy, and a perceived need to protect ICU survivors from interventions the clinician felt may adversely affect recovery or change the care trajectory. System-level barriers included time constraints, cost, and lack of specialty palliative care services. Conclusion: Palliative care may be an essential element of post-ICU clinic care. Implementation efforts focused on tailoring strategies to improve post-ICU program clinicians' palliative care knowledge and self-efficacy could be a key to enhanced care delivery for survivors of critical illness.

Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis.

OBJECTIVE: First decompensation development is a critical milestone that needs to be predicted. Transkingdom gut microbial interactions, including archaeal methanogens, may be important targets and predictors but a longitudinal approach is needed. DESIGN: Cirrhosis outpatients who provided stool twice were included. Group 1: compensated, group 2: 1 decompensation (decomp), group 3: >1 decompensationwere followed and divided into those who remained stable or decompensated. Bacteria, viral and archaeal presence, α/ß diversity and taxa changes over time adjusted for clinical variables were analysed. Correlation networks between kingdoms were analysed. RESULTS: 157 outpatients (72 group 1, 33 group 2 and 52 group 3) were followed and 28%-47% developed outcomes. Baseline between those who remained stable/developed outcome: While no α/ß diversity differences were seen, commensals were lower and pathobionts were higher in those who decompensated. After decompensation: those experiencing their first decompensation showed greater decrease in α/ß-diversity, bacterial change (↑Lactobacillus spp, Streptococcus parasanguinis and ↓ beneficial Lachnospiraceae and Eubacterium hallii) and viral change (↑Siphoviridae, ↓ Myoviridae) versus those with further decompensation. Archaea: 19% had Methanobacter brevii, which was similar between/within groups. Correlation networks: Baseline archaeal-viral-bacterial networks were denser and more homogeneous in those who decompensated versus the rest. Archaea-bacterial correlations collapsed post first decompensation. Lactobacillus phage Lc Nu and C2-like viruses were negatively linked with beneficial bacteria. CONCLUSION: In this longitudinal study of cirrhosis outpatients, the greatest transkingdom gut microbial changes were seen in those reaching the first decompensation, compared with subsequent decompensating events. A transkingdom approach may refine prediction and provide therapeutic targets to prevent cirrhosis progression.

Examining the needs of survivors of critical illness through the lens of palliative care: A qualitative study of survivor experiences.

OBJECTIVE: To examine the needs of adult survivors of critical illness through a lens of palliative care. RESEARCH METHODOLOGY: A qualitative study of adult survivors of critical illness using semi-structured interviews and framework analysis. SETTING: Participants were recruited from the post-intensive care unit clinic of a mid-Atlantic academic medical center in the United States. FINDINGS: Seventeen survivors of critical illness aged 34-80 (median, 66) participated in the study. The majority of patients were female (64.7 %, n = 11) with a median length of index ICU stay of 12 days (interquartile range [IQR] 8-19). Interviews were conducted February to March 2021 and occurred a median of 20 months following the index intensive care stay (range, 13-33 months). We identified six key themes which align with palliative care principles: 1) persistent symptom burden; 2) critical illness as a life-altering experience; 3) spiritual changes and significance; 4) interpreting/managing the survivor experience; 5) feelings of loss and burden; and 6) social support needs. CONCLUSION: Our findings suggest that palliative care components such as symptom management, goals of care discussions, care coordination, and spiritual and social support may assist in the assessment and treatment of survivors of critical illness.

Impact of bacterial infections and spontaneous bacterial peritonitis prophylaxis on phage-bacterial dynamics in cirrhosis.

BACKGROUND AND AIMS: Gut microbiota, including bacteria and phages, are altered in cirrhosis, but their role during infections and spontaneous bacterial peritonitis (SBP) prophylaxis is unclear. Our aim was determine metagenomic changes in gut bacteria; phages and their linkages centered around Gram-negative and Gram-positive pathobionts in patients with cirrhosis with/without infections or SBP prophylaxis. APPROACH AND RESULTS: We included uninfected (n = 231) and infected (n = 30, SBP n = 19 and urinary tract infection n = 11 before antibiotics) patients who gave stool for bacterial and phage metagenomics. We matched uninfected to infected patients 1:1 on a model for end-stage liver disease (MELD). We also analyzed subgroups of patients with ascites matched on an MELD (n = 73) to patients on SBP prophylaxis (n = 7) and then to SBP infection. Phage and bacterial taxa differences (DESeq2) and correlation networks centered around Escherichia coli and Enterococcus faecium were analyzed. Infections were mostly due to Enterobacteriaceae and Enterococcus spp. On metagenomics, higher fold changes of Enterobacteriaceae members, Enterococcus and Streptococcus spp., and Escherichia phages were seen in infected patients. Correlation networks showed more complex bacteria-phage linkages in infected patients compared with uninfected ones overall and centered around E. coli and E. faecium. SBP prophylaxis induced higher Gram-positive bacteria. In SBP, Enterococcus and Escherichia were higher versus ascites. Correlation networks around E. coli were complex in ascites but sparse with SBP prophylaxis, whereas the reverse was seen with E. faecium. Lytic phages and those associated with antibiotic resistance were correlated with E. faecium. CONCLUSION: In cirrhosis, there are significant changes in phage-bacterial linkages in infected patients and those on SBP prophylaxis compared to the remaining patients. SBP prophylaxis enriches complexity of E. faecium-centered but induces a collapse in E. coli-centered phage-bacterial correlations.

Bristol Stool Scale as a Determinant of Hepatic Encephalopathy Management in Patients With Cirrhosis.

INTRODUCTION: Bowel movement (BM) frequency is used to titrate lactulose for hepatic encephalopathy (HE). However, stool consistency using the Bristol stool scale (BSS, 0-7) is often ignored. METHODS: The study included pre-BSS and post-BSS cohorts. BSS was incorporated into decision-making after training in outpatients with cirrhosis. Two to 3 BMs/d and BSS 3-4 were considered normal, whereas the rest were considered high or low; concordance between the metrics was evaluated. Medication changes and 6-month admissions were compared between this group (post-BSS) and a comparable previous group (pre-BSS). Concordance and regression analyses for all-cause admissions and HE-related admissions were performed, and comparisons were made for HE-related medication stability. In the longitudinal analysis, an outpatient group seen twice was analyzed for BSS and BMs. RESULTS: In the post-BSS cohort, 112 patients were included with only 46% BSS and BMs concordance and modest BSS/BMs correlation (r = 0.27, P = 0.005). Compared with a pre-BSS cohort (N = 114), there was a lower 6-month total (4% vs 0.36%, P < 0.001) or HE-related admission (1% vs 0.12%, P = 0.002). Regression showed model for end-stage liver disease (odds ratio [OR]: 1.10, P = 0.003) and pre-BSS/post-BSS (OR: 0.04, P < 0.001) for all-cause admissions and HE (OR: 3.59, P = 0.04) and preera/postera (OR: 0.16, P = 0.02) for HE-related admissions as significant. HE medication regimens were more stable post-BSS vs pre-BSS (32% vs 20%, P = 0.04), which was due to patients with BSS > BMs (P = 0.02). In the longitudinal analysis, 33 patients without medication changes or underlying clinical status changes were tested 36 ± 24 days apart. No changes in BSS (P = 0.73) or BMs (P = 0.19) were found. DISCUSSION: BSS is complementary and additive to BM frequency, can modulate the risk of readmissions and stabilize HE-related therapy changes in outpatients with cirrhosis, and could help personalize HE management.

Gut Microbial Signature of Hepatocellular Cancer in Men With Cirrhosis.

The gut microbiome is altered in cirrhosis. Recent evidence has suggested a key role for the gut microbiota in the progression of cirrhosis and the development of hepatocellular carcinoma (HCC). We studied the differences in the microbial composition in patients with cirrhosis with prior and future HCC in the context of other complications (eg, infections, hepatic encephalopathy). The following 2 cohorts were recruited prospectively: the prior HCC cohort, in which outpatients with HCC within 2 years were age-matched, sex-matched, and Model for End-Stage Liver Disease (MELD) score-matched with those without HCC; and the future HCC cohort, in which patients were followed for 2 years and divided into future HCC versus no HCC after age, sex, and MELD-score matching and other complications were also recorded. Microbiota composition and predicted function were analyzed with ribosomal RNA sequencing and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PiCRUST)and compared between (1) prior HCC versus none and (2) future HCC versus none, and in the future cohort, comparisons were also made between those patients who developed (1) HCC only versus without complications, (2) HCC only versus non-HCC complications only, and (3) HCC + other complications versus non-HCC complications only. A total of 142 men (76 total in the prior cohort [38 with/38 without HCC] and 66 total in the future cohort [33 with/33 without future HCC]) were included. The groups had similar etiology, lactulose/rifaximin/proton pump inhibitor use, diabetes mellitus, and non-HCC complications. Microbial diversity was similar between prior HCC/not or future HCC/not. On DESeq2 higher Clostridium sensu stricto and Anaerotruncus were significantly associated with protection from HCC, whereas the reverse was seen with Raoultella and Haemophilus regardless of prior/future HCC comparisons. Functions focused on urea cycle, bioenergetics, tryptophan, and toluene metabolism were different between the groups. Rothia was specific for other complications. Despite age, sex, and MELD-score matching and accounting for other complications, gut microbiota composition and the predicted function are different in men with cirrhosis with and without prior HCC and can be extended toward future HCC development.

Admission Factor V Predicts Transplant-Free Survival in Acute Liver Failure.

BACKGROUND AND AIMS: Traditional laboratory markers are insensitive in distinguishing between patients with acute liver failure (ALF) who will require urgent liver transplantation (LT) from those who will recover spontaneously, particularly within 24 h of presentation. Coagulation factor-V (FV) may improve the accuracy of outcome prediction in ALF due to its predominant synthesis in the liver and short half-life in plasma. METHODS: Patients enrolled in the ALF Study Group Registry from a single site had FV determined within 24 h of presentation (Derivation-Cohort). Area under the receiver operating characteristic curves (AUROC) dichotomized by ALF etiology [acetaminophen (APAP) or non-APAP] were constructed to evaluate the diagnostic performance of FV for transplant-free-survival (TFS). Multivariate logistic regression modeling was performed using FV and other clinical variables to predict TFS. Accuracy of FV and multivariable model were performed in a Validation-Cohort from a different site. RESULTS: 90-patients (56% with APAP) were included in the Derivation-Cohort. Median FV was significantly higher in TFS versus those who died/LT (31% vs. 15%, respectively; p = 0.001). When dichotomized by etiology, AUROC for FV was 0.77 for APAP (cutoff, sensitivity, specificity 10.5%, 79%, 69%, respectively) and 0.77 for non-APAP (22%, 85%, 67%, respectively). When the optimal cutoffs for FV in the Derivation-Cohort were applied to the Validation-Cohort (N = 51; 59% with APAP), AUROC for FV was 0.75 for APAP (sensitivity/specificity 81/44) and 0.95 for non-APAP (sensitivity/specificity 90/73). In multivariate analyses, AUROC for FV model was 0.86 in the Derivation-Cohort and 0.90 in the Validation-Cohort. CONCLUSION: Admission FV may improve selection of patients who are likely to improve without LT.

Training of hepatology providers improves the screening and resultant interventions for alcohol use disorder.

Alcohol use disorder (AUD) screening is important but focused training with using AUDIT-10 with counselling/mental health (MH) referral may be needed. We aimed to compare the effect of training on AUD screening/intervention in hepatology clinics in pre vs post-training phases of a quality-improvement initiative. Pre-training encounters were evaluated for inquiry into AUD, AUDIT-10 and MH referrals. Dedicated AUD-related training was provided to hepatology providers and analyses repeated post-training. Pre-training (n = 378) and post-training patients(n = 318) had similar demographics and disease characteristics. Post-training there was higher inquiry about alcohol(92% vs 80%, P < .0001), counselling (82% vs 68%, P < .0001). This led to higher diagnosis of drinkers (49% vs 31%, P < .0001) of whom higher proportion had AUDIT-10 administered(91% vs 34%, P < .0001) and referred to MH(29% vs 8%, P < .0001). On regression presumed alcohol-related aetiology, younger age and post-training period were associated with AUDIT-10 administration. AUD-focused training significantly improves rates of screening and MH referral for problem drinking in a hepatology clinic population.

Education on cancer risk assessment and genetic counseling to address cancer health disparities among racial/ethnic groups and rural populations: Implementing culturally tailored outreach through community health educators.

While significant progress is being made in cancer prevention and treatment, opportunity exists to make a difference for populations bearing an uneven burden of the disease. Research indicates that increased inherited risk and more-aggressive forms of cancer among underserved racial/ethnic (R/E) groups (e.g., African American/Black, American Indian/Alaska Native, Asian, Hispanic/Latino, and Native Hawaiian/Other Pacific Islander) and rural populations may explain the cancer incidence and mortality disparities these populations experience. These racial and ethnic (R/E) categories reflect the standard naming convention for the classification of federal data on race and ethnicity. One method by which progress can be made for these underserved populations is to expand knowledge of, access to, and uptake of two existing and impactful preventive oncology tools-cancer screening and genetic counseling and risk assessment (GCRA). Individuals from these populations who have cancer may benefit by learning about treatment options, risk projections for secondary cancers, and clinical trial participation. Effecting change in community beliefs and behaviors regarding these preventive tools and yielding the aforementioned benefits will see greater success if shepherded by individuals accepted and trusted in the respective communities. This was the charge taken on and embraced by Community Health Educators in the National Cancer Institute (NCI) Center to Reduce Cancer Health Disparities' (CRCHD) National Outreach Network (NON) and U54 Comprehensive Partnerships to Advance Cancer Health Equity (CPACHE) programs. The NCI CRCHD integrated into the work of these CHEs an emphasis on cancer genetic education. As part of their undertaking, NON and CPACHE CHEs detail education and outreach strategies that may be helpful to increase GCRA awareness and uptake in R/E groups and rural populations and, in turn, bring positive change for those with or at risk for heritable cancers.

Effects of Alcohol on the Brain in Cirrhosis: Beyond Hepatic Encephalopathy.

Recent advances have led to a greater understanding of how alcohol alters the brain, both in acute stages (intoxication and alcohol withdrawal) and in chronic misuse. This review focuses on the current understanding of how alcohol affects the brain in cirrhosis patients with and without hepatic encephalopathy (HE). Chronic alcohol use is associated with nutritional deficiencies, dementia, cirrhosis, and decompensating events such as HE. Direct toxicity on brain tissue, induction of neuro-inflammation, and alcohol's alterations of the gut microbiome are possible mechanisms for the clinical features of HE associated with alcohol use. Acute management of the alcoholic cirrhosis patient with altered mental status should focus on ruling out other causes, best intensive care, and use of gut-based therapies such as lactulose and rifaximin. Long-term management centers on optimizing treatment of concurrent mood disorders, nutritional support, and medical management of complications associated with cirrhosis. Future studies are needed to clarify mechanisms of brain injury in concomitant alcohol misuse and HE in addition to designing treatment interventions in order to improve outcomes in these patients.

Liver Transplantation: the Role of Metabolic Syndrome.

OPINION STATEMENT: The long-term survival in liver transplant recipients (LTRs) is currently at an historical high level stemming from improvement in perioperative care, infection control, and immunosuppression medications. However, compared to the general population, LTRs have decreased survival. Metabolic diseases like hypertension, dyslipidemia, type 2 diabetes, and obesity are key determinants of long-term mortality in LTRs. The incidence and prevalence of these metabolic comorbidities is considerably higher in LTRs and likely results from a combination of factors including exposure to chronic immunosuppression, weight gain, and recurrence of chronic liver disease after liver transplantation (LT). Although there is currently little guidance in managing these metabolic conditions post-LT, recommendations are often extrapolated from non-transplant cohorts. In the current review, we explore the relationship between metabolic syndrome and its comorbidities in LTRs.

Heat stroke leading to acute liver injury & failure: A case series from the Acute Liver Failure Study Group.

BACKGROUND & AIMS: In the United States, nearly 1000 annual cases of heat stroke are reported but the frequency and outcome of severe liver injury in such patients is not well described. The aim of this study was to describe cases of acute liver injury (ALI) or failure (ALF) caused by heat stroke in a large ALF registry. METHODS: Amongst 2675 consecutive subjects enrolled in a prospective observational cohort of patients with ALI or ALF between January 1998 and April 2015, there were eight subjects with heat stroke. RESULTS: Five patients had ALF and three had ALI. Seven patients developed acute kidney injury, all eight had lactic acidosis and rhabdomyolysis. Six patients underwent cooling treatments, three received N-acetyl cysteine (NAC), three required mechanical ventilation, three required renal replacement therapy, two received vasopressors, one underwent liver transplantation, and two patients died-both within 48 hours of presentation. All cases occurred between May and August, mainly in healthy young men because of excessive exertion. CONCLUSIONS: Management of ALI and ALF secondary to heat stroke should focus on cooling protocols and supportive care, with consideration of liver transplantation in refractory patients.

Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits. METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test. CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.