AlcoChange: A digital therapeutic for patients with alcohol-related liver disease.

Background & Aims: Maintenance of abstinence in alcohol-related liver disease (ARLD) is a major unmet therapeutic need. Digital therapeutics can deliver ongoing behavioural therapy, in real-time, for chronic conditions. The aim of this project was to develop and clinically test AlcoChange, a novel digital therapeutic for ARLD. Methods: AlcoChange was developed using validated behaviour change techniques and a digital alcohol breathalyser. This was an open-label, single-centre study. Patients with ARLD, ongoing alcohol use (within 1 month) and possession of a suitable smartphone were eligible. Patients were recruited from inpatient and outpatient settings, and received AlcoChange therapy for 3 months. The primary outcome was reduction in alcohol use from baseline to 3 months, measured by timeline follow-back. Secondary outcomes included: (i) compliance with the AlcoChange app, (ii) alcohol-related and all-cause hospital re-admissions up to 1 year, (iii) qualitative analysis to determine factors associated with compliance. Results: Sixty-five patients were recruited, of whom 41 completed the study per protocol. Patients compliant with the intervention (>60 logins over 3 months) had a significant reduction in alcohol use from baseline compared to non-compliant patients (median [IQR]: -100% [100% to -55.1%] vs. -57.1% [-95.3% to +32.13%], p = 0.029). The proportion attaining abstinence at 3 months was higher in the compliant group (57.1% vs. 22.2%, p = 0.025). The compliant group had a significantly decreased risk of subsequent alcohol-related re-admission up to 12 months (p = 0.008). Qualitative analysis demonstrated that receiving in-app feedback and the presence of a health-related 'sentinel event' were predictors of compliance with the intervention. Conclusions: Use of the novel digital therapeutic, AlcoChange, was associated with a significant reduction in alcohol use and an increase in the proportion of patients with ARLD attaining abstinence. Definitive randomised trials are warranted for this intervention. Impact and implications: Alcohol-related liver disease (ARLD) is an increasing health problem worldwide. The main cause of death and disability in ARLD is ongoing alcohol consumption, but few patients receive medications or talking therapy to maintain abstinence. This study demonstrated that a digital therapeutic, linked to a smartphone, may help reduce alcohol consumption and alcohol-related hospital admissions in these patients. If validated in larger, randomised, trials, digital therapeutics may have a role in the primary and secondary prevention of complicatons from ARLD.

The role of RIPK1 mediated cell death in acute on chronic liver failure.

Acute-on-chronic liver failure (ACLF) is characterized predominantly by non-apoptotic forms of hepatocyte cell death. Necroptosis is a form of programmed lytic cell death in which receptor interacting protein kinase (RIPK) 1, RIPK3 and phosphorylated mixed lineage kinase domain-like (pMLKL) are key components. This study was performed to determine the role of RIPK1 mediated cell death in ACLF. RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL were measured in healthy volunteers, stable patients with cirrhosis, and in hospitalized cirrhotic patients with acutely decompensated cirrhosis, with and without ACLF (AD). The role of necroptosis in ACLF was studied in two animal models of ACLF using inhibitors of RIPK1, necrostatin-1 (NEC-1) and SML2100 (RIPA56). Plasma RIPK3 levels predicted the risk of 28- and 90-day mortality (AUROC, 0.653 (95%CI 0.530-0.776), 0.696 (95%CI 0.593-0.799)] and also the progression of patients from no ACLF to ACLF [0.744 (95%CI 0.593-0.895)] and the results were validated in a 2nd patient cohort. This pattern was replicated in a rodent model of ACLF that was induced by administration of lipopolysaccharide (LPS) to bile-duct ligated rats and carbon tetrachloride-induced fibrosis mice administered galactosamine (CCL4/GalN). Suppression of caspase-8 activity in ACLF rodent model was observed suggesting a switch from caspase-dependent cell death to necroptosis. NEC-1 treatment prior to administration of LPS significantly reduced the severity of ACLF manifested by reduced liver, kidney, and brain injury mirrored by reduced hepatic and renal cell death. Similar hepato-protective effects were observed with RIPA56 in a murine model of ACLF induced by CCL4/GalN. These data demonstrate for the first time the importance of RIPK1 mediated cell death in human and rodent ACLF. Inhibition of RIPK1 is a potential novel therapeutic approach to prevent progression of susceptible patients from no ACLF to ACLF.

Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterised by organ failure(s), high short-term mortality, and, pathophysiologically, deranged inflammatory responses. The extracellular matrix (ECM) is critically involved in regulating the inflammatory response. This study aimed to determine alterations in biomarkers of ECM turnover in ACLF and their association with inflammation, organ failures, and mortality. METHODS: We studied 283 patients with cirrhosis admitted for acute decompensation (AD) with or without ACLF, 64 patients with stable cirrhosis, and 30 healthy controls. A validation cohort (25 ACLF, 9 healthy controls) was included. Plasma PRO-C3, PRO-C4, PRO-C5, PRO-C6, and PRO-C8 (i.e. collagen type III-VI and VIII formation) and C4M and C6M (i.e. collagen type IV and VI degradation) were measured. Immunohistochemistry of PRO-C6 was performed on liver biopsies (AD [n = 7], ACLF [n = 5]). A competing-risk regression analysis was performed to explore the prognostic value of biomarkers of ECM turnover with 28- and 90-day mortality. RESULTS: PRO-C3 and PRO-C6 were increased in ACLF compared to AD (p = 0.089 and p <0.001, respectively), whereas collagen degradation markers C4M and C6M were similar. Both PRO-C3 and PRO-C6 were strongly associated with liver function and inflammatory markers. Only PRO-C6 was associated with extrahepatic organ failures and 28- and 90-day mortality (hazard ratio [HR; on log-scale] 6.168, 95% CI 2.366-16.080, p <0.001, and 3.495, 95% CI 1.509-8.093, p = 0.003, respectively). These findings were consistent in the validation cohort. High PRO-C6 expression was observed in liver biopsies of patients with ACLF. CONCLUSIONS: This study shows, for the first time, evidence of severe net interstitial collagen deposition in ACLF and makes the novel observation of the association between PRO-C6 and (extrahepatic) organ failures and mortality. Further studies are needed to define the pathogenic significance of these observations. LAY SUMMARY: This study describes a disrupted turnover of collagen type III and VI in Acute-on-chronic liver failure (ACLF). Plasma biomarkers of these collagens (PRO-C3 and PRO-C6) are associated with the severity of liver dysfunction and inflammation. PRO-C6, also known as the hormone endotrophin, has also been found to be associated with multi-organ failure and prognosis in acute decompensation and ACLF.

Impact of 2019-2020 mega-fires on Australian fauna habitat.

Australia's 2019-2020 mega-fires were exacerbated by drought, anthropogenic climate change and existing land-use management. Here, using a combination of remotely sensed data and species distribution models, we found these fires burnt ~97,000 km2 of vegetation across southern and eastern Australia, which is considered habitat for 832 species of native vertebrate fauna. Seventy taxa had a substantial proportion (>30%) of habitat impacted; 21 of these were already listed as threatened with extinction. To avoid further species declines, Australia must urgently reassess the extinction vulnerability of fire-impacted species and assist the recovery of populations in both burnt and unburnt areas. Population recovery requires multipronged strategies aimed at ameliorating current and fire-induced threats, including proactively protecting unburnt habitats.

MELD remains the best predictor of mortality in outpatients with cirrhosis and severe ascites.

BACKGROUND: The Model for Endstage Liver Disease (MELD) score may put patients with severe ascites at a disadvantage because they often have a poor quality of life and high mortality despite a favourable MELD score. AIM: To develop a model that is better than the MELD score at predicting 1-year mortality among patients with cirrhosis, severe ascites and MELD ≤18. METHODS: We used data from a randomised trial (SPARe-1) of patients with cirrhosis and severe ascites to develop a model to predict 1-year mortality. We used stepwise backward elimination and Cox regression to identify the strongest predictors. Performance was assessed with the C index and the Brier score. We examined performance in an external cohort of trial participants with cirrhosis and severe ascites (SPARe-2 participants). RESULTS: We included 308 patients with a 1-year mortality of 20.4%. The final prediction model (Severe Ascites Mortality score, "SAM score") included four variables: serum bilirubin, serum sodium, history of SBP (yes or no) and diabetes (yes or no). No indicators of quality of life were included. After correction for optimism bias, the SAM and MELD scores had nearly identical predictive ability. The external validation cohort included 149 patients whose 1-year mortality was 22.4%. The MELD score performed marginally better in this cohort, partly because the effects of SBP and diabetes on mortality were much smaller in this cohort. CONCLUSION: We did not succeed in developing a prediction model that was superior to the MELD score among patients with cirrhosis and severe ascites.

A new species of rock-dwelling gecko (Gekkonidae: Gehyra) from the Mt Surprise region of northern Queensland, Australia.

We describe a new species of rock-dwelling Gehyra Gray, 1834 (Gekkonidae) from the Einasleigh Uplands of inland north Queensland, Australia. Morphological, ecological, and molecular data clearly support the new species as distinct and place it within the 'australis group'. Gehyra electrum sp. nov. is distinguished from congeners by a combination of medium adult size (SVL 46-50 mm), an orange-brown to pinkish-orange background colouration with a pattern of distinct whitish spots and irregular black to purple-brown blotches or bars, possessing 7-8 undivided subdigital lamellae on the expanded portion of the fourth toe, and a wedge-shaped mental scale that separates the inner-postmental scales along 40% or more of their length. Gehyra electrum sp. nov. is a rock specialist currently known only from granite outcrops of the Mt Surprise region, Queensland. This is the second recently described Gehyra from the Einasleigh Uplands and adds to the growing number of endemic reptiles recognised in the region.

Quality of life measures predict mortality in patients with cirrhosis and severe ascites.

BACKGROUND: Severe ascites is associated with both a poor health-related quality of life (HRQL) and a mortality in excess of that captured by current prognostic clinical scores. AIM: To determine the association between HRQL and mortality in patients with severe ascites. METHODS: The HRQL data from previously published randomised controlled trials examining the efficacy of satavaptan in ascites were retrospectively evaluated. RESULTS: Of the 496 patients randomised who completed the SF-36, 405 patients had complete datasets and were included in the analysis (difficult-to-treat ascites, n = 164 or refractory ascites, n = 241). Overall, patients reported poor HRQL, in particular the physical component score (PCS) of SF-36. The physical component score (PCS) correlated with the mental component score (MCS) of SF-36 (Spearman rank correlation = 0.68) but not with markers of severity of liver disease. The PCS, but not the MCS, was significantly lower in patients who died (P = 0.01 and P = 0.84, respectively). After confounder-adjustment, the hazard ratio for a 10-point increase in the physical component score was 0.83 (95% CI; 0.72-0.97) for all-cause mortality and 0.84 (95% CI; 0.71-0.99) for cirrhosis-related deaths only, indicating that patients with better physical HRQL live longer on average. CONCLUSIONS: Poor physical component score (PCS) of SF-36 is an independent predictor of 12-month mortality in patients with severe ascites independent of current prognostic clinical scores. It holds promise not only in prognostic modelling but also as an endpoint in the evaluation of therapies targeting ascites.

Short-term abstinence from alcohol and changes in cardiovascular risk factors, liver function tests and cancer-related growth factors: a prospective observational study.

OBJECTIVE: To assess changes in metabolic risk factors and cancer-related growth factors associated with short-term abstinence from alcohol. DESIGN: Prospective, observational study. SETTING: Single tertiary centre. PARTICIPANTS: Healthy subjects were recruited based on intention to: (1) abstain from alcohol for 1 month (abstinence group), or (2) continue to drink alcohol (control group). Inclusion criteria were baseline alcohol consumption >64 g/week (men) or >48 g/week (women). Exclusion criteria were known liver disease or alcohol dependence. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was change in insulin resistance (homeostatic model assessment (HOMA) score). Secondary outcomes were changes in weight, blood pressure (BP), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and liver function tests. Primary and secondary outcomes were adjusted for changes in diet, exercise and cigarette smoking. RESULTS: The abstinence group comprised 94 participants (mean age 45.5 years, SD ±1.2) and the control group 47 participants (mean age 48.7 years, SD ±1.8). Baseline alcohol consumption in the abstinence group was 258.2 g/week, SD ±9.4, and in the control group 233.8 g, SD ±19.0. Significant reductions from baseline in the abstinence group (all p<0.001) were found in: HOMA score (-25.9%, IQR -48.6% to +0.3%), systolic BP (-6.6%, IQR -11.8% to 0.0%), diastolic BP (-6.3%, IQR -14.1% to +1.3%), weight (-1.5%, IQR -2.9% to -0.4%), VEGF (-41.8%, IQR -64.9% to -17.9%) and EGF (-73.9%, IQR -86.1% to -36.4%). None of these changes were associated with changes in diet, exercise or cigarette smoking. No significant changes from baseline in primary or secondary outcomes were noted in the control group. CONCLUSION: These findings demonstrate that abstinence from alcohol in moderate-heavy drinkers improves insulin resistance, weight, BP and cancer-related growth factors. These data support an independent association of alcohol consumption with cancer risk, and suggest an increased risk of metabolic diseases such as type 2 diabetes and fatty liver disease.

Patients with refractory ascites treated with alfapump® system have better health-related quality of life as compared to those treated with large volume paracentesis: the results of a multicenter randomized controlled study.

BACKGROUND: Refractory ascites (RA) is a complication of cirrhosis which is treated with large volume paracentesis (LVP) as the standard of care. Alfapump® system is a fully implantable pump system which reduces the need for LVP. The aim was to assess health-related quality of life (HRQL) in patients treated with alfapump® versus LVP. METHODS: The data were collected in a multicenter open-label randomized controlled trial (clinicaltrials.gov #NCT01528410). Subjects with cirrhosis Child-Pugh class B or C accompanied by RA were randomized to receive alfapump® or LVP. The SF-36v2 and CLDQ scores were compared between the two treatment arms at screening and monthly during treatment. RESULTS: Of 60 subjects randomized, HRQL data were available for 58 (N = 27 received alfapump® and N = 31 received LVP only). At baseline, no differences were seen between the treatment arms (all p > 0.05): age 61.9 ± 8.4, 79.3% male, MELD scores 11.7 ± 3.3, 85.2% Child-Pugh class B, 70.7% had alcoholic cirrhosis. The mean number of LVP events/subject was lower in alfapump® than LVP (1.1 vs. 8.6, p < 0.001). The HRQL scores showed a moderate improvement from the baseline levels in subjects treated with alfapump® (p < 0.05 for abdominal and activity scores of CLDQ) but not with LVP (all one-sided p > 0.05) in the first 3 months. Multivariate analysis showed that treatment with alfapump® was independently associated with better HRQL at 3 months (total CLDQ score: beta = 0.67 ± 0.33, p = 0.05). CONCLUSION: As compared to LVP, the use of alfapump® system is associated with both a reduction in the number of LVP events and improvement of health-related quality of life.

Adjusting to climate: Acclimation, adaptation and developmental plasticity in physiological traits of a tropical rainforest lizard.

The impact of climate change may be felt most keenly by tropical ectotherms. In these taxa, it is argued, thermal specialization means a given shift in temperature will have a larger effect on fitness. For species with limited dispersal ability, the impact of climate change depends on the capacity for their climate-relevant traits to shift. Such shifts can occur through genetic adaptation, various forms of plasticity, or a combination of these processes. Here we assess the extent and causes of shifts in 7 physiological traits in a tropical lizard, the rainforest sunskink (Lampropholis coggeri). Two populations were sampled that differ from each other in both climate and physiological traits. We compared trait values in each animal soon after field collection versus following acclimation to laboratory conditions. We also compared trait values between populations in: (i) recently field-collected animals; (ii) the same animals following laboratory acclimation; and (iii) the laboratory-reared offspring of these animals. Our results reveal high trait lability, driven primarily by acclimation and local adaptation. By contrast, developmental plasticity, resulting from incubation temperature, had little to no effect on most traits. These results suggest that, while specialized, tropical ectotherms may be capable of rapid shifts in climate-relevant traits.

Cell death markers in patients with cirrhosis and acute decompensation.

The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05). CONCLUSION: Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002).

Using connectivity to identify climatic drivers of local adaptation.

Understanding the climatic drivers of local adaptation is vital. Such knowledge is not only of theoretical interest but is critical to inform management actions under climate change, such as assisted translocation and targeted gene flow. Unfortunately, there are a vast number of potential trait-environment combinations, and simple relationships between trait and environment are ambiguous: representing either plastic or evolved variation. Here, we show that by incorporating connectivity as an index of gene flow, we can differentiate trait-environment relationships reflecting genetic variation vs. phenotypic plasticity. In this way, we rapidly shorten the list of trait-environment combinations that are of significance. Our analysis of an existing data set on geographic variation in a tropical lizard shows that we can effectively rank climatic variables by the strength of their role in local adaptation. The promise of our method is a rapid and general approach to identifying the environmental drivers of local adaptation.

Alfapump® system vs. large volume paracentesis for refractory ascites: A multicenter randomized controlled study.

BACKGROUND AND AIMS: Patients with refractory ascites (RA) require repeated large volume paracenteses (LVP), which involves frequent hospital visits and is associated with a poor quality-of-life. This study assessed safety and efficacy of an automated, low-flow pump (alfapump® [AP]) compared with LVP standard of care [SoC]. METHODS: A randomized controlled trial, in seven centers, with six month patient observation was conducted. Primary outcome was time to first LVP. Secondary outcomes included paracentesis requirement, safety, health-related quality-of-life (HRQoL), and survival. Nutrition, hemodynamics, and renal injury biomarkers were assessed in a sub-study at three months. RESULTS: Sixty patients were randomized and 58 were analyzed (27 AP, 31 SoC, mean age 61.9years, mean MELD 11.7). Eighteen patients were included in the sub-study. Compared with SoC, median time to first LVP was not reached after six months in the AP group, meaning a significant reduction in LVP requirement for the AP patients (AP, median not reached; SoC, 15.0days (HR 0.13; 95%CI 13.0-22.0; p<0.001), and AP patients also showed significantly improved Chronic Liver Disease Questionnaire (CLDQ) scores compared with SoC patients (p<0.05 between treatment arms). Improvements in nutritional parameters were observed for hand-grip strength (p=0.044) and body mass index (p<0.001) in the sub-study. Compared with SoC, more AP patients reported adverse events (AEs; 96.3% vs. 77.4%, p=0.057) and serious AEs (85.2 vs. 45.2%, p=0.002). AEs consisted predominantly of acute kidney injury in the immediate post-operative period, and re-intervention for pump related issues, and were treatable in most cases. Survival was similar in AP and SoC. CONCLUSIONS: The AP system is effective for reducing the need for paracentesis and improving quality of life in cirrhotic patients with RA. Although the frequency of SAEs (and by inference hospitalizations) was significantly higher in the AP group, they were generally limited and did not impact survival. Lay summary: The alfapump® moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, the alfapump reduces the need for large volume paracentesis (manual fluid removal by needle) in patients with medically untreatable ascites. This can improve life quality for these patients. www.clinicaltrials.gov#NCT01528410.

A rare case of acute hepatitis induced by use of Babchi seeds as an Ayurvedic remedy for vitiligo.

This case highlights that hepatitis is a potential side effect of Babchi seeds, an Ayurvedic remedy used to treat vitiligo. The patient, a 52-year-old Indian woman, presented with a 1 week history of jaundice, vomiting, pruritus and abdominal pain. Progressive deterioration in liver function prompted a liver biopsy which was consistent with the diagnosis of a drug-induced hepatitis. The hepatitis resolved after withdrawal of its use. A PubMed search found no previous UK cases and only two cases have been reported globally. This potentially serious side effect of a widely available substance is not acknowledged by manufacturers, and those purchasing the product are unaware of the risk of harm. To compound this risk, there is an absence of dosing advice or maximum recommended daily intake. It is important to ask about topical and oral herbal remedies in cases of acute jaundice as patients rarely perceive these preparations as 'medications'.