PHES scores have limited impact on the risk of overt HE in patients with minimal HE.

BACKGROUND: Minimal hepatic encephalopathy, defined by the portosystemic hepatic encephalopathy score (PHES), is associated with a higher risk of subsequent OHE. It remains unclear if there is a stepwise increase in OHE risk with worse PHES results. METHODS: In this multicenter study, patients with minimal hepatic encephalopathy, as defined by abnormal PHES, were followed for OHE development. RESULTS: In all, 207 patients were included. There was no stepwise increase in OHE risk with worse PHES results. CONCLUSIONS: Abnormal PHES is associated with a higher OHE risk, but we found no stepwise increase in OHE risk with worse PHES results below the established cutoff.

Development and Evaluation of a Patient Cirrhosis Knowledge Assessment.

BACKGROUND AND AIMS: Self-management skills improve outcomes for patients with cirrhosis. While education programs exist to teach these skills, there are limited patient assessments to evaluate their efficacy. We aimed to develop and evaluate cirrhosis knowledge assessments for patients with compensated and decompensated cirrhosis. METHODS: Across two institutions, a 4-stage process was undertaken: first, we developed a comprehensive set of questions regarding cirrhosis self-management. Second, the questions underwent critical review by patients and hepatology providers. Third, patients with cirrhosis answered these questions before and after a written educational tool. Questions were updated based on results. Fourth, patients answered the updated questions before and after a video educational tool. Binomial test or paired sample t-test was used to compare pre- and post-tests depending on question type. RESULTS: In phase 3, 134 patients completed pre- and post-tests. 44% were decompensated, 81% were diagnosed with cirrhosis at least 3 years, and 52% were 60-75 years. 95% of single-answer questions were answered correctly by at least 70% of patients in the pre-test. None of the answers improved significantly with education. After phase 3, 6 questions were removed and 6 questions were edited to increase challenge. In phase 4, 96 patients (42 compensated, 54 decompensated) completed pre- and post-tests. In the compensated assessment, 3 questions improved after education and the summative score increased (7.9 to 9.0, P < 0.001). In the decompensated assessment, 4 questions improved after education and the summative score increased (7.0 to 7.7, P = 0.004). CONCLUSION: Through a rigorous process, we created and evaluated cirrhosis knowledge assessments for patients with compensated and decompensated cirrhosis. Further validation is required and then these assessments can be used to improve patient education.

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies. METHODS: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx). RESULTS: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival. CONCLUSIONS: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival.

Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations.

HE is a complication of cirrhosis characterized by neuropsychiatric and motor dysfunction, and results in decreased quality of life and increased mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966, though many questions about its use remain unanswered. Lactulose reverses minimal HE, prevents overt HE, improves quality of life, increases the rate of recovery from overt HE, and improves survival rates. Lactulose's clinical effect appears to be derived from its impact on intestinal microbes, likely a result of its enteric acidifying effect, positive pressure on beneficial taxa, and improvement of gut barrier function. There are several practical considerations with lactulose including (1) a need to avoid excessive bowel movements and subsequent dehydration, (2) treatment titration protocols need further investigation, (3) baseline or treatment-induced gastrointestinal side effects limit adherence in some cases, and (4) the utility of monitoring stool consistency or pH remains unknown. Further research is needed to optimize our use of this effective treatment for HE.

Regional changes in intestinal permeability in cirrhosis are associated with mucosal bacteria.

BACKGROUND: Several complications of cirrhosis are theorized to result from the translocation of bacteria or their products across the intestinal epithelium. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with cirrhosis. APPROACH AND RESULTS: We collected 247 duodenum, ileum, and colon biopsies from 58 consecutive patients with cirrhosis and 33 controls during clinically indicated endoscopies. Patients with cirrhosis were similarly aged to controls (60 vs. 58 y) and had a median Model for End-stage Liver Disease of 8 (interquartile range 7, 10). Biopsies underwent 16S rRNA-encoding gene amplicon sequencing to determine mucosal bacteria composition and transepithelial electrical resistance (TEER) to determine epithelial permeability. In the entire cohort, there were regional differences in TEER with the lowest TEER (ie, more permeable) in the ileum; duodenum TEER was 43% higher and colon TEER 20% higher than ileum TEER (ANOVA p = 0.0004). When comparing patients with cirrhosis and controls, both TEER (26% lower in cirrhosis, p = 0.006) and alpha diversity differed in the duodenum (27% lower in cirrhosis, p = 0.01) but not ileum or colon. A beta-binomial model found that 26 bacteria were significantly associated with TEER. Bifidobacteriaceae Bifidobacterium in duodenal mucosa was protective of epithelial permeability and future hospitalization for hepatic decompensation. CONCLUSIONS: Duodenal epithelial permeability was higher, and mucosal bacteria alpha diversity was lower in cirrhosis compared to controls, while no such differences were seen in the ileum or colon. Specific bacteria were associated with epithelial permeability and future hepatic decompensation.

The incidence and natural history of ascites after liver transplantation.

BACKGROUND: Ascites is common in cirrhosis but uncommon after liver transplant. We aimed to characterize the incidence, natural history, and current management strategies of post-transplant ascites. METHODS: We performed a retrospective cohort study of patients who underwent liver transplantation at 2 centers. We included patients who underwent deceased donor whole graft liver transplants between 2002 and 2019. Chart review identified patients with post-transplant ascites, requiring a paracentesis between 1 and 6-month post-transplants. Detailed chart review identified clinical and transplant characteristics, evaluation of ascites etiology, and treatments. RESULTS: Of 1591 patients who successfully underwent a first-time orthotopic liver transplant for chronic liver disease, 101 (6.3%) developed post-transplant ascites. Only 62% of these patients required large volume paracentesis for ascites before transplant. 36% of patients with post-transplant ascites had early allograft dysfunction. Most patients with post-transplant ascites (73%) required a paracentesis within 2 months of transplant, but 27% had delayed ascites onset. From 2002 to 2019, ascites studies were obtained less often, and hepatic vein pressure measurement was performed more often. Diuretics were the mainstay of treatment (58%). The use of albumin infusion and splenic artery embolization to treat post-transplant ascites increased over time. Larger pre-transplant spleen size was associated with a greater number of post-transplant paracenteses (r=0.32 and p=0.003). For patients who underwent splenic intervention, paracentesis frequency was significantly reduced (1.6-0.4 paracenteses/month, p=0.0001). The majority (72%) of patients had clinical resolution of their ascites at 6-month post-transplant. CONCLUSIONS: Persistent or recurrent ascites continues to be a clinical issue in the modern era of liver transplantation. Most had clinical resolution within 6 months, some requiring intervention.

Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study.

INTRODUCTION: The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. METHODS: In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. RESULTS: In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). DISCUSSION: The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Long-term clinical outcomes of patients with COVID-19 and chronic liver disease: US multicenter COLD study.

BACKGROUND: COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited. METHODS: We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19. RESULTS: We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19-2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62-2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01-2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26-2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06-2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine. CONCLUSIONS: Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

Microbiome therapeutics for the treatment of recurrent Clostridioides difficile infection.

INTRODUCTION: The gut microbiome is implicated in Clostridioides difficile infection (CDI) and recurrent CDI (rCDI). AREAS COVERED: This review covers the mechanisms by which microbiome therapeutics treat rCDI, their efficacy and safety, and clinical trial design considerations for future research. EXPERT OPINION: Altering the chemical environment of the gut and reconstituting colonization resistance is a promising strategy for preventing and treating rCDI. Fecal microbiota transplant (FMT) is safe and effective for the treatment of rCDI. However, limitations of FMT have prompted investigation into alternative microbiome therapeutics. These alternative microbiome therapies require further evaluation, and adaptive trial designs should be strongly considered to more rapidly discern variables including the need for bowel preparation, timing and selection of pre-treatment antibiotics, and dose and duration of microbiome therapeutics. A broad range of adverse events must be prospectively evaluated in these controlled trials, as microbiome therapeutics have the potential for numerous effects. Future studies will lead to a greater understanding of the mechanisms by which microbiome therapies can break the cycle of rCDI, which should ultimately yield a personalized approach to rCDI treatment that restores an individual's specific deficit(s) in colonization resistance to C. difficile.

Incidental Hepatocellular Carcinoma Bony Metastasis in a Patient Listed for Liver Transplant.

A 67-year-old man with a history of alcohol and hepatitis C-associated cirrhosis is diagnosed with incidental metastatic liver cancer during hospitalization for hepatic encephalopathy. He had 2 LI-RADS-3 (indeterminant) lesions on liver magnetic resonance imaging 3 months prior but had no history of hepatocellular carcinoma and was listed for liver transplant. During inpatient paracentesis, the ascites fluid was bloody, so the abdominal and pelvic computed tomography was performed showing a lytic lesion in the left posterior inferior pubic rami. Alpha fetoprotein was within normal limits. His liver was imaged on several occasions without definite evidence of malignancy. Bone biopsy revealed metastatic hepatocellular carcinoma. On return to baseline mental status, patient endorsed no bony pain.

Physician Practice Pattern Variations in Common Clinical Scenarios Within 5 US Metropolitan Areas.

Importance: While variations in quality of care have been described between US regions, physician-level practice pattern variations within regions remain poorly understood, notably among specialists. Objective: To examine within-area physician-level variations in decision-making in common clinical scenarios where guidelines specifying appropriateness or quality of care exist. Design Setting and Participants: This cross-sectional study used 2016 through 2019 data from a large nationwide network of commercial insurers, provided by Health Intelligence Company, LLC, within 5 metropolitan statistical areas (MSAs). Physician-level variations in appropriateness and quality of care were measured using 14 common clinical scenarios involving 7 specialties. The measures were constructed using public quality measure definitions, clinical guidelines, and appropriateness criteria from the clinical literature. Physician performance was calculated using a multilevel model adjusted for patient age, sex, risk score, and socioeconomic status with physician random effects. Measure reliability for each physician was calculated using the signal-to-noise approach. Within-MSA variation was calculated between physician quintiles adjusted for patient attributes, with the first quintile denoting highest quality or appropriateness and the fifth quintile reflecting the opposite. Data were analyzed March through October 2021. Main Outcomes and Measures: Fourteen measures of quality or appropriateness of care, with 2 measures each in the domains of cardiology, endocrinology, gastroenterology, pulmonology, obstetrics, orthopedics, and neurosurgery. Results: A total of 8788 physicians were included across the 5 MSAs, and about 2.5 million unique patient-physician pairs were included in the measures. Within the 5 MSAs, on average, patients in the measures were 34.7 to 40.7 years old, 49.1% to 52.3% female, had a mean risk score of 0.8 to 1.0, and more likely to have an employer-sponsored insurance plan that was either self-insured or fully insured (59.8% to 97.6%). Within MSAs, physician-level variations were qualitatively similar across measures. For example, statin therapy in patients with coronary artery disease ranged from 54.3% to 70.9% in the first quintile of cardiologists to 30.5% to 42.6% in the fifth quintile. Upper endoscopy in patients with gastroesophageal reflux disease without alarm symptoms spanned 14.6% to 16.9% in the first quintile of gastroenterologists to 28.2% to 33.8% in the fifth quintile. Among patients with new knee or hip osteoarthritis, 2.1% to 3.4% received arthroscopy in the first quintile of orthopedic surgeons, whereas 25.5% to 30.7% did in the fifth quintile. Appropriate prenatal screening among pregnant patients ranged from 82.6% to 93.6% in the first quintile of obstetricians to 30.9% to 65.7% in the fifth quintile. Within MSAs, adjusted differences between quintiles approximated unadjusted differences. Measure reliability, which can reflect consistency and reproducibility, exceeded 70.0% across nearly all measures in all MSAs. Conclusions and Relevance: In this cross-sectional study of 5 US metropolitan areas, sizeable physician-level practice variations were found across common clinical scenarios and specialties. Understanding the sources of these variations may inform efforts to improve the value of care.

Fecal microbiota transplant improves cognition in hepatic encephalopathy and its effect varies by donor and recipient.

Early data suggest fecal microbiota transplant (FMT) may treat hepatic encephalopathy (HE). Optimal FMT donor and recipient characteristics are unknown. We assessed the safety and efficacy of FMT in patients with prior overt HE, comparing five FMT donors. We performed an open-label study of FMT capsules, administered 5 times over 3 weeks. Primary outcomes were change in psychometric HE score (PHES) and serious adverse events (SAEs). Serial stool samples underwent shallow shotgun metagenomic sequencing. Ten patients completed FMT administration and 6-month follow-up. Model for End-Stage Liver Disease (MELD) score did not change after FMT (14 versus 14, p = 0.51). Thirteen minor adverse events and three serious adverse events (two unrelated to FMT) were reported. One SAE was extended-spectrum beta-lactamase Escherichia coli bacteremia. The PHES improved after three doses of FMT (+2.1, p < 0.05), after five doses of FMT (+2.9, p = 0.007), and 4 weeks after the fifth dose of FMT (+3.1, p = 0.02). Mean change in the PHES ranged from -1 to +6 by donor. Two taxa were identified by random forest analysis and confirmed by linear regression to predict the PHES- Bifidobacterium adolescentis (adjusted R2 = 0.27) and B. angulatum (adjusted R2 = 0.25)-both short-chain fatty acid (SCFA) producers. Patients who responded to FMT had higher levels of Bifidobacterium as well as other known beneficial taxa at baseline and throughout the study. The FMT donor with poorest cognitive outcomes in recipients had the lowest fecal SCFA levels. Conclusion: FMT capsules improved cognition in HE, with an effect varying by donor and recipient factors (NCT03420482).

Provider Attitudes Toward Risk-Based Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis in the United States.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers' opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient's HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient's HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients' estimated HCC risk, instead of our current "one-size-fits all" strategy.

Association of Statins and 28-Day Mortality Rates in Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: Statins may be protective in severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection. The aim of the current study was to evaluate the effect of in-hospital statin use on 28-day mortality rates and intensive care unit (ICU) admission among patients with SARS-CoV-2, stratified into 4 groups: those who used statins before hospitalization (treatment continued or discontinued in the hospital) and those who did not (treatment newly initiated in the hospital or never initiated). METHODS: In a cohort study of 1179 patients with SARS-CoV-2, record review was used to assess demographics, laboratory measurements, comorbid conditions, and time from admission to death, ICU admission, or discharge. Using marginal structural Cox models, we estimated hazard ratios (HRs) for death and ICU admission. RESULTS: Among 1179 patients, 676 (57%) were male, 443 (37%) were >65 years old, and 493 (46%) had a body mass index ≥30 (calculated as weight in kilograms divided by height in meters squared). Inpatient statin use reduced the hazard of death (HR, 0.566; P=.008). This association held among patients who did and those who did not use statins before hospitalization (HR, 0.270 [P=.003] and 0.493 [P=.04], respectively). Statin use was associated with improved time to death for patients aged >65 years but not for those ≤65 years old. CONCLUSION: Statin use during hospitalization for SARS-CoV-2 infection was associated with reduced 28-day mortality rates. Well-designed randomized control trials are needed to better define this relationship.

A Telemonitoring Intervention for Cirrhotic Ascites Management Is Cost-Saving.

BACKGROUND: Patients with cirrhosis and ascites experience frequent hospital admissions, leading to poor quality of life and high healthcare costs. Monitoring weight is a component of ascites care and telemonitoring may improve outcomes and costs. Goals We aimed to evaluate the cost and outcomes of current care compared to a telemonitoring system for ascites. Study We developed a decision-analytic model that examined 100 simulated patients over a 6-month horizon. We compared usual care to a new telemonitoring program, which we estimate costs $50,000/6 months. RESULTS: The cost of standard of care for 100 patients with cirrhotic ascites over a 6-month period is $167,500 more expensive than telemonitoring. By varying parameter probabilities by ± 10% and outcome costs by ± 20%, we found that standard of care remains more expensive than care with a telemonitoring intervention by $9400 to $340,200 per 6-month period. Standard of care leads to 9 more admissions (range 4 to 12) than a telemonitoring intervention, while telemonitoring leads to 9 more outpatient visits (range 6 to 9) and 28 additional outpatient large volume paracenteses (LVPs) (range 17 to 28). With more and less expensive telemonitoring interventions, standard of care remained more expensive. With 50% adherence to the intervention, standard of care was $89,848 more expensive. CONCLUSIONS: In almost all probability and cost scenarios, a telemonitoring intervention is cost-saving for the management of cirrhotic ascites. Using hospital admissions as a surrogate for quality of care, patient outcomes are improved primarily though more proactive medical intervention and more LVPs.

Hepatic Encephalopathy is Associated With Slow Speech on Objective Assessment.

INTRODUCTION: There are no available low-burden, point-of-care tests to diagnose, grade, and predict hepatic encephalopathy (HE). METHODS: We evaluated speech as a biomarker of HE in 76 English-speaking adults with cirrhosis. RESULTS: Three speech features significantly correlated with the following neuropsychiatric scores: speech rate, word duration, and use of particles. Patients with low neuropsychiatric scores had slower speech (22 words/min, P = 0.01), longer word duration (0.09 seconds/word, P = 0.01), and used fewer particles (0.85% fewer, P = 0.01). Patients with a history of overt HE had slower speech (23 words/min, P = 0.005) and longer word duration (0.09 seconds/word, P = 0.005). DISCUSSION: HE is associated with slower speech.

Microbiome therapeutics for hepatic encephalopathy.

Hepatic encephalopathy (HE) is a complication of cirrhosis characterised by neuropsychiatric and motor dysfunction. Microbiota-host interactions play an important role in HE pathogenesis. Therapies targeting microbial community composition and function have been explored for the treatment of HE. Prebiotics, probiotics and faecal microbiota transplant (FMT) have been used with the aim of increasing the abundance of potentially beneficial taxa, while antibiotics have been used to decrease the abundance of potentially harmful taxa. Other microbiome therapeutics, including postbiotics and absorbents, have been used to target microbial products. Microbiome-targeted therapies for HE have had some success, notably lactulose and rifaximin, with probiotics and FMT also showing promise. However, there remain several challenges to the effective application of microbiome therapeutics in HE, including the resilience of the microbiome to sustainable change and unpredictable clinical outcomes from microbiota alterations. Future work in this space should focus on rigorous trial design, microbiome therapy selection, and a personalised approach to HE.