Pre-emptive TIPS in high-risk acute variceal bleeding. An updated and revised individual patient data meta-analysis.

BACKGROUND AND AIMS: A previous individual patient data meta-analysis (IPD-MA) showed that compared with drugs+endoscopy, the placement of transjugular portosystemic shunt within 72 hours of admission (pre-emptive transjugular intrahepatic portosystemic shunt: p-TIPS) increases the survival of high-risk patients (Child-Pugh B+ active bleeding and Child-Pugh C<14 points) with cirrhosis and acute variceal bleeding. However, the previous IPD-MA was not a two-stage meta-analysis, did not consider the potential risk of selection bias of observational studies, and did not include the most recent randomized clinical trial. We performed an updated and revised IPD-MA to reassess the efficacy of p-TIPS, addressing all previous issues. APPROACH AND RESULTS: We included all studies from the previous IPD-MA and searched for other possible eligible publications until September 2022. We performed a two-stage IPD-MA of data from 8 studies (4 randomized clinical trials and 4 observational). In addition, we performed a sensitivity analysis excluding those patients dying up to the first 72 hours after admission in the Drugs+Endoscopy arms of the 4 observational studies. The primary end point was the effects of p-TIPS versus Drugs+Endoscopy on 1-year survival.We identified 1389 patients (342 p-TIPS and 1047 Drugs+Endoscopy). The two-stage IPD-MA showed that p-TIPS significantly reduced the mortality in the overall population (HR=0·43, 95% CI: 0.32-0.60, p <0.001. This effect was observed in both subgroups of patients with Child-Pugh. The sensitivity analysis confirmed the survival benefit of p-TIPS. CONCLUSIONS: The updated two-stage IPD-MA confirms the significant survival advantage of p-TIPS in high-risk patients with cirrhosis and acute variceal bleeding. As a result, we recommend p-TIPS as the preferred first-choice treatment for these patients.

Metabolic phenotyping of patients with advanced chronic liver disease for better characterization of cirrhosis regression.

BACKGROUND & AIMS: Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively suppressed. However, the understanding of the factors contributing to reversibility of fibrosis and cirrhosis is limited. Our aims were to assess clinical factors, perform genotyping of known variants, and comprehensive metabolic phenotyping to characterize the regression of fibrosis in patients with compensated advanced chronic liver disease (cACLD). METHODS: In a case-control pilot study of 81 patients with cACLD, we compared individuals exhibiting histological or clinical evidence of cACLD regression ("regressors"; n = 44) with those showing no improvement ("non-regressors"; n = 37) after a minimum of 24 months of successful treatment of the cause of liver disease. Data were validated using an external validation cohort (n = 30). RESULTS: Regardless of the cause of cACLD, the presence of obesity (odds ratio [OR] 0.267 95% CI 0.072-0.882; p = 0.049), high liver stiffness (OR 0.960, 95% CI 0.925-0.995; p = 0.032), and carriage of GCKR variant rs1260326 (OR 0.148, 95% CI 0.030-0.773; p = 0.019) are associated with a reduced likelihood of fibrosis regression in a subgroup of 60 patients with ACLD genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated with lipid metabolism - especially fatty acids, bile acids, phospholipids, triacylglycerides (biosynthesis), and the carnitine shuttle. In the entire discovery cohort, we further measured metabolites within the defined pathways, which led to the identification of 33 circulating markers differentiating regressors from non-regressors after etiological therapy. The validation cohort confirmed 14 of the differentially expressed markers. CONCLUSIONS: We identified and validated a group of lipid biomarkers associated with regression of fibrosis that could be used as non-invasive biomarkers for detecting regression of fibrosis in cACLD. IMPACT AND IMPLICATIONS: Regression of cirrhosis/advanced chronic liver disease (ACLD) after removal of the underlying cause of liver injury has been observed in human cirrhosis. However, detailed characterization of ACLD regression remains an unmet need. In this study, we provide a comprehensive phenotyping of individuals likely to experience ACLD regression. While obesity, carriage of GCKR variant rs1260326 and high liver stiffness were associated with lower likelihood of regression of ACLD, a signature of circulating lipid metabolites enabled differentiation of regressors from non-regressors after effective etiologic therapy. The lipid signature we discovered and externally validated could be used as non-invasive biomarker to detect regression of fibrosis in patients with compensated ACLD.

Metabolomics as a tool to predict the risk of decompensation or liver-related death in patients with compensated cirrhosis.

BACKGROUND AND AIMS: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG > 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients. APPROACH AND RESULTS: This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664-0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model's performance [C-index of 0.808 (CI95% 0.735-0.882); p =0.032]. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710-0.860), not significantly different from the HVPG-based models including or not metabolites. CONCLUSIONS: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.

Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis.

OBJECTIVE: In retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH. DESIGN: We used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3-F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis. RESULTS: Progression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p<0.0001) and a ≥5 kPa (and ≥20%) increase (adjusted HR 1.98; 95% CI 1.20 to 3.26, p=0.008) were independent predictors of progression to cirrhosis in participants with bridging fibrosis, while baseline LS ≥30.7 kPa (adjusted HR 10.13, 95% CI 4.38 to 23.41, p<0.0001) predicted liver-related events in participants with cirrhosis. CONCLUSION: The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis.

Incidence and factors predictive of recurrent thrombosis in people with non-cirrhotic portal vein thrombosis.

BACKGROUND & AIMS: Clinical guidelines do not recommend long-term anticoagulation in non-cirrhotic splanchnic vein thrombosis (NC-SVT) without underlying thrombophilia because it is assumed that there is a very low risk of recurrent thrombosis (RT). Our first aim was to describe the incidence of RT in people with NC-SVT without an indication for long-term anticoagulation. The second aim was to identify RT risk factors and afterwards verify them in a validation cohort. METHODS: This is a multicentre, retrospective observational study evaluating risk factors for RT in 64 people with NC-SVT of idiopathic/local factor aetiology. In a subgroup of 48 individuals, the potential value of additional thrombophilic parameters to predict RT was analysed. Findings were validated in 70 individuals with idiopathic/local factor NC-SVT. RESULTS: Of the 64 participants in the training cohort, 17 (26%) presented splanchnic and/or extrasplanchnic RT (overall-RT) during follow-up (cumulative incidence: 2, 10, 19, and 34% at 1, 2, 5, and 10 years, respectively). In addition, 53% of people with splanchnic RT were asymptomatic. No clinical or biochemical parameters predicted overall-RT. However, in the 48 people with an additional comprehensive thrombophilic study, factor VIII ≥150% was the only independent factor predicting overall-RT (hazard ratio 7.10, 95% CI 2.17-23.17, p <0.01). In the validation cohort, 19 individuals (27%) presented overall-RT, and it was also independently predicted by factor VIII >150% (hazard ratio 3.71, 95% CI 1.31-10.5, p <0.01). The predictive value of factor VIII was confirmed in both people with idiopathic/local factor aetiology associated NC-SVT. CONCLUSIONS: People with idiopathic/local factor NC-SVT are at risk of overall-RT. Splanchnic RT can be asymptomatic and requires screening for its detection. Values of factor VIII ≥150% may help identify individuals at high risk of overall-RT who could benefit from long-term anticoagulation. IMPACT AND IMPLICATIONS: People with idiopathic/isolated local factor non-cirrhotic portal vein thrombosis were previously thought to be at minimal risk of re-thrombosis and therefore did not receive scheduled follow-up. The results of this study are of special interest for hepatologists treating people with non-cirrhotic splanchnic thrombosis, as they show a 25% incidence of re-thrombosis and support the close follow-up of people with factor VIII >150% to ensure the early identification of new thrombotic events.

Accelerometer-based detection of African swine fever infection in wild boar.

Infectious wildlife diseases that circulate at the interface with domestic animals pose significant threats worldwide and require early detection and warning. Although animal tracking technologies are used to discern behavioural changes, they are rarely used to monitor wildlife diseases. Common disease-induced behavioural changes include reduced activity and lethargy ('sickness behaviour'). Here, we investigated whether accelerometer sensors could detect the onset of African swine fever (ASF), a viral infection that induces high mortality in suids for which no vaccine is currently available. Taking advantage of an experiment designed to test an oral ASF vaccine, we equipped 12 wild boars with an accelerometer tag and quantified how ASF affects their activity pattern and behavioural fingerprint, using overall dynamic body acceleration. Wild boars showed a daily reduction in activity of 10-20% from the healthy to the viremia phase. Using change point statistics and comparing healthy individuals living in semi-free and free-ranging conditions, we show how the onset of disease-induced sickness can be detected and how such early detection could work in natural settings. Timely detection of infection in animals is crucial for disease surveillance and control, and accelerometer technology on sentinel animals provides a viable complementary tool to existing disease management approaches.

Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis. APPROACH AND RESULTS: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. CONCLUSIONS: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.

Effect of natural abiotic soil vibrations, rainfall and wind on anuran calling behavior: a test with captive-bred midwife toads (Alytes obstetricans).

Anurans are known to detect vibrations, but few studies explore relationships between vibrations and resultant behaviors. We studied the reaction of calling captive-bred male midwife toads (Alytes obstetricans) to the randomized playback of a vibrational crescendo stimulus train. We considered two sources of natural abiotic vibrational stimuli: rainfall and wind. Rainfall was expected to induce calling and wind was expected to inhibit it. Playback experiments with two synthetic tones (200 Hz and 300 Hz) tested the sensitivity to pure tones and could possibly reveal a hearing sensitivity trend between these frequencies. The toads did not increase call rate in response to rainfall vibrations and only one of the five wind stimulus levels caused a significant decrease in call rate. This limited response could be explained, because the tested toads came from a captive population, where emergence may not be mediated by rainfall vibrations. We found that A. obstetricans is highly sensitive to very low frequencies, which could explain the sensitivity observed to vibrational stimuli. Playback of a random crescendo stimulus train proves to be a valid approach for addressing behavioral questions. However, the use of a captive population may have been a limitation in the clarity of the results.

Alcohol-related liver disease phenotype impacts survival after an acute variceal bleeding episode.

BACKGROUND & AIMS: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis. METHODS: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD. RESULTS: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH. CONCLUSIONS: Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results.

Relationship between two pathogens in an amphibian community that experienced mass mortalities.

Because host species tend to harbor multiple parasitic species, coinfection in a host is common. The chytrid fungus Batrachochytrium dendrobatidis (Bd) and the viruses in the genus Ranavirus (Rv) are responsible for the decline of amphibians worldwide. Despite wide geographical co-occurrence and the serious conservation problem that coinfection with these pathogens could represent, little is known about their possible synergistic interactions and effects in a host community. We investigated the occurrence and associations between these two pathogens in an amphibian community after Rv-driven disease outbreaks were detected in four populations of the Iberian ribbed newt (Pleurodeles waltl) in northwestern Spain. We collected tissue samples from amphibians and fish and estimated Bd and Rv infection loads by qPCR. A few months after the most recent mass mortality event, Rv infection parameters at the affected sites decreased significantly or were lower than such registered at the sites where no outbreaks were recorded. Both pathogens were simultaneously present in almost all sites, but coinfection in a single host was rare. Our findings suggest that the co-occurrence of Bd and Rv does not predict adverse outcomes (e.g., enhanced susceptibility of hosts to one pathogen due to the presence or infection intensity of the other) following an outbreak. Other variables (such as species identity or site) were more important than infection with a pathogen in predicting the infection status and severity of infection with the other pathogen. Our results highlight the importance of host-specific and environmental characteristics in the dynamics of infections, coinfection patterns, and their impacts.

Relaciones entre dos patógenos en una comunidad anfibia que experimentó mortalidad masiva Resumen La coinfección es común en especies hospederas ya que estas especies tienden a albergar muchas especies parasíticas. El hongo quitridio Batrachochytrium dendrobatidis (Bd) y los virus del género Ranavirus (Rv) son responsables de la declinación mundial de anfibios. A pesar de la amplia co-ocurrencia geográfica y el problema serio de conservación que podría representar la coinfección con estos patógenos, se conoce muy poco sobre sus posibles interacciones sinérgicas y sus efectos en una comunidad hospedera. Investigamos la incidencia y las asociaciones entre estos dos patógenos en una comunidad anfibia después de que se detectaron brotes de enfermedades causados por Rv en cuatro poblaciones del tritón estriado ibérico (Pleurodeles waltl) en el noroeste de España. Recolectamos muestras de tejido de anfibios y peces y estimamos la carga infecciosa de Bd y Rv con una qPCR. Unos meses después del evento de mortalidad masiva más reciente, los parámetros de infección de Rv en los sitios afectados disminuyeron significativamente o fueron más bajos que los registrados en sitios sin brotes. Ambos patógenos estuvieron presentes de forma simultánea en casi todos los sitios, pero fue raro encontrar la coinfección en un solo hospedero. Nuestros descubrimientos sugieren que la coocurrencia de Bd y Rv no pronostica resultados adversos (aumento en la susceptibilidad de los hospederos a un patógeno debido a la presencia o intensidad de infección del otro patógeno) después de un brote. Otras variables, como la identidad de la especie o el sitio, fueron más importantes que la infección con un patógeno en la predicción del estado de infección y la severidad de la infección con otro patógeno. Nuestros resultados resaltan la importancia de las características ambientales y aquellas específicas del hospedero en las dinámicas de infección, los patrones de coinfección y sus impactos.

Drivers of Batrachochytrium dendrobatidis infection load, with evidence of infection tolerance in adult male toads (Bufo spinosus).

Chytridiomycosis is affecting hundreds of amphibian species worldwide, but while in tropical areas, adult individuals have been the focus of most investigations, the exact role played by infection intensity of breeding adults is not well understood in temperate areas. We conducted mark-recapture-capture surveys during spiny common toad breeding seasons from 2006 to 2018 at the site of the first recorded outbreak of chytridiomycosis in Europe, the Peñalara Massif (Sierra de Guadarrama National Park, central Spain), and collected infection samples and several variables related to the reproductive effort of male individuals. We used general linear mixed models to evaluate the contribution of study variables on the infection loads of adult male toads exhibited at their capturing date. We also analysed the differences on several male characteristics between the pond with the largest breeding population against the rest of the ponds. We found that the duration of time spent in the waterbody and the condition of the host predicted infection loads. Animals of good physical condition, that spent longer in water, have higher infection levels than individuals with the opposite set of traits. The pond supporting the largest breeding population housed smaller male toads and in poorer condition. Our results are consistent with a shift in reproductive strategy in response to infection and potentially a strategy of tolerance, rather than resistance to infection. These findings have applications for disease mitigation and theoretical implications related to the trade-offs made and the evolution of traits in response to the disease.

Baveno VII - Renewing consensus in portal hypertension.

To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD - defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled "Personalized Care for Portal Hypertension". The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of cACLD and CSPH, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. A summary of the most important conclusions/recommendations derived from the workshop is reported here. The statements are classified as unchanged, changed, and new in relation to Baveno VI.

Host Identity Matters-Up to a Point: The Community Context of Batrachochytrium dendrobatidis Transmission.

AbstractThe level of detail on host communities needed to understand multihost parasite invasions is an unresolved issue in disease ecology. Coarse community metrics that ignore functional differences between hosts, such as host species richness, can be good predictors of invasion outcomes. Yet if host species vary in the extent to which they maintain and transmit infections, then explicitly accounting for those differences may be important. Through controlled mesocosm experiments and modeling, we show that interspecific differences between host species are important for community-wide infection dynamics of the multihost fungal parasite of amphibians (Batrachochytrium dendrobatidis [Bd]), but only up to a point. The most abundant host species in our system, fire salamander larvae (Salamandra salamandra), did not maintain or transmit infections. Rather, two less abundant "auxiliary" host species, Iberian tree frog (Hyla molleri) and spiny toad (Bufo spinosus) larvae, maintained and transmitted Bd. Frogs had the highest mean rates of Bd shedding, giving them the highest contributions to the basic reproduction number, R0. Toad contributions to R0 were substantial, however, and when examining community-level patterns of infection and transmission, the effects of frogs and toads were similar. Specifying more than just host species richness to distinguish salamanders from auxiliary host species was critical for predicting community-level Bd prevalence and transmission. Distinguishing frogs from toads, however, did not improve predictions. These findings demonstrate limitations to the importance of host species identities in multihost infection dynamics. Host species that exhibit different functional traits, such as susceptibility and infectiousness, may play similar epidemiological roles in the broader community.

FIB-4 Improves LSM-Based Prediction of Complications in Overweight or Obese Patients With Compensated Advanced Chronic Liver Disease.

Liver stiffness measurement (LSM) by transient elastography (TE) is able to stratify the risk of decompensation in patients with compensated advanced chronic liver disease (cACLD).1 Recently, we demonstrated that this holds true also in overweight or obese patients with cACLD due to nonalcoholic steatohepatitis (NASH) studied by the XL probe. An LSM cutoff of ≥21 kPa remained associated with a high risk of complications in this population.2.

Effects of Early Placement of Transjugular Portosystemic Shunts in Patients With High-Risk Acute Variceal Bleeding: a Meta-analysis of Individual Patient Data.

BACKGROUND & AIMS: Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS. METHODS: We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients. RESULTS: Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323-0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307-0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253-0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy. CONCLUSIONS: In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy.

A Machine Learning Approach to Liver Histological Evaluation Predicts Clinically Significant Portal Hypertension in NASH Cirrhosis.

BACKGROUND AND AIMS: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm. APPROACH AND RESULTS: Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome-stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held-out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver-related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML-HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P < 0.001). The ML HVPG score differentiated patients with normal (0-5 mm Hg) and elevated (5.5-9.5 mm Hg) HVPG and CSPH (median: 1.51 vs. 1.93 vs. 2.60; all P < 0.05). The areas under receiver operating characteristic curve (AUROCs) (95% CI) of the ML-HVPG score for CSPH were 0.85 (0.80, 0.90) and 0.76 (0.68, 0.85) in the training and test sets, respectively. Discrimination of the ML-HVPG score for CSPH improved with the addition of a ML parameter for nodularity, Enhanced Liver Fibrosis, platelets, aspartate aminotransferase (AST), and bilirubin (AUROC in test set: 0.85; 95% CI: 0.78, 0.92). Although baseline ML-HVPG score was not prognostic, changes were predictive of clinical events (HR: 2.13; 95% CI: 1.26, 3.59) and associated with hemodynamic response and fibrosis improvement. CONCLUSIONS: An ML model based on trichrome-stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis.

Amphibian loss alters periphyton structure and invertebrate growth in montane streams.

Amphibians are declining worldwide due to a combination of stressors such as climate change, invasive species, habitat loss, pollution and emergent diseases. Although their losses are likely to have important ecological consequences on the structure and functioning of freshwater ecosystems, this issue has been scarcely explored. We conducted an experiment in three montane streams-where primary production is the main source of energy and carbon-to assess the effects of amphibian disappearance (i.e. presence or absence of the common midwife toad Alytes obstetricans, a common species found in pools of these streams) on several aspects of ecosystem functioning and structure: periphyton biomass and chlorophyll a concentration, algal assemblage structure, and growth of macroinvertebrate grazers. We compared four types of experimental enclosures: (i) without macroinvertebrates or amphibians; (ii) with larvae of the caddisfly Allogamus laureatus; (iii) with A. obstetricans tadpoles; and (iv) with both A. laureatus larvae and A. obstetricans tadpoles. The absence of tadpoles increased periphyton biomass, but did not cause differences on inorganic sediment accrual. The algal assemblage had a higher diversity in the absence of tadpoles, and their characteristic taxa differed from the assemblages in presence of tadpoles. A. laureatus presented higher mass in presence of tadpoles; however, tadpole length was not affected by presence of macroinvertebrates. Our results suggest that presence of tadpoles is a driver of periphyton accrual and assemblage structure, acting as top-down control and with key potential consequences on the functioning of montane stream ecosystems.

La población de anfibios está reduciéndose globalmente debido a una combinación de factores como el cambio climático, las especies invasoras, la pérdida de hábitat, la contaminación y las enfermedades emergentes. Aunque su desaparición probablemente causará consecuencias ecológicas importantes en la estructura y el funcionamiento de los ecosistemas de agua dulce, es un aspecto que ha sido poco explorado. Se realizó un experimento en tres arroyos de montaña, donde la producción primaria es la principal fuente de energía y carbono, para determiner los efectos de la desaparición de los anfibios (presencia o ausencia del sapo partero común Alytes obstetricans, una especie común en pozas de estos arroyos) en varios aspectos del funcionamiento y la estructure del ecosistema: la biomasa de perifiton y la concentración de clorofila, la estructura de la comunidad algal y el crecimiento de los macroinvertebrados raspadores. Comparamos cuatro tipos de recintos: (i) sin macroinvertebrados ni anfibios; (ii) con larvas del tricóptero Allogamus laureatus; (iii) con renacuajos de A. obstetricans; y (iv) con tanto larvas de A. laureatus como renacuajos de A. obstetricans. La ausencia de renacuajos aumentaba la biomasa de perifiton, aunque no causaba diferencias en la acumulación de sedimento inorgánico. La comunidad de algas presentaba una mayor diversidad en ausencia de renacuajos, y sus taxones característicos eran distintos de los de las comunidades con presencia de renacuajos. A. laureatus tenía una mayor masa en presencia de renacuajos, pero la longitud de los renacuajos no se veía afectada por la presencia de macroinvertebrados. Nuestros resultados sugieren que la presencia de renacuajos controla la acumulación de perifiton y la estructura de las comunidades, ejerciendo un control de arriba hacia abajo, con consecuencias clave en el funcionamiento de los ecosistemas de arroyos de montaña.

Cryptic diversity of a widespread global pathogen reveals expanded threats to amphibian conservation.

Biodiversity loss is one major outcome of human-mediated ecosystem disturbance. One way that humans have triggered wildlife declines is by transporting disease-causing agents to remote areas of the world. Amphibians have been hit particularly hard by disease due in part to a globally distributed pathogenic chytrid fungus (Batrachochytrium dendrobatidis [Bd]). Prior research has revealed important insights into the biology and distribution of Bd; however, there are still many outstanding questions in this system. Although we know that there are multiple divergent lineages of Bd that differ in pathogenicity, we know little about how these lineages are distributed around the world and where lineages may be coming into contact. Here, we implement a custom genotyping method for a global set of Bd samples. This method is optimized to amplify and sequence degraded DNA from noninvasive skin swab samples. We describe a divergent lineage of Bd, which we call BdASIA3, that appears to be widespread in Southeast Asia. This lineage co-occurs with the global panzootic lineage (BdGPL) in multiple localities. Additionally, we shed light on the global distribution of BdGPL and highlight the expanded range of another lineage, BdCAPE. Finally, we argue that more monitoring needs to take place where Bd lineages are coming into contact and where we know little about Bd lineage diversity. Monitoring need not use expensive or difficult field techniques but can use archived swab samples to further explore the history-and predict the future impacts-of this devastating pathogen.

Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease.

BACKGROUND & AIMS: In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD. METHODS: Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. RESULTS: TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. CONCLUSIONS: Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. LAY SUMMARY: Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.

Noninvasive Diagnosis of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease.

INTRODUCTION: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. METHODS: This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH. RESULTS: A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences of portal hypertension in patients with NASH were maintained across different strata of LSM values. LSM ≥25 kPa was the best cutoff to rule in CSPH in alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, and nonobese patients with NASH, whereas in obese NASH patients, the positive predictive value was only 62.8%. A new model for patients with NASH (ANTICIPATE-NASH model) to predict CSPH considering body mass index, LSM, and platelet count was developed, and a nomogram was constructed. LSM ≤15 kPa plus platelets ≥150 × 10/L ruled out CSPH in most etiologies. DISCUSSION: Patients with cACLD of NASH etiology, especially obese patients with NASH, present lower prevalences of portal hypertension compared with other cACLD etiologies. LSM ≥25 kPa is sufficient to rule in CSPH in most etiologies, including nonobese patients with NASH, but not in obese patients with NASH.