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In modern medical diagnostics, magnetic resonance imaging (MRI) is an important technique that provides detailed insights into anatomical structures. In this paper, we present a comprehensive methodology focusing on streamlining the segmentation, reconstruction, and visualization process of 3D MRI data. Segmentation involves the extraction of anatomical regions with the help of state-of-the-art deep learning algorithms. Then, 3D reconstruction converts segmented data from the previous step into multiple 3D representations. Finally, the visualization stage provides efficient and interactive presentations of both 2D and 3D MRI data. Integrating these three steps, the proposed system is able to augment the interpretability of the anatomical information from MRI scans according to our interviews with doctors. Even though this system was originally designed and implemented as part of human brain haptic feedback simulation for surgeon training, it can also provide experienced medical practitioners with an effective tool for clinical data analysis, surgical planning and other purposes

En la actualidad, el personal sanitario se enfrenta a un problema creciente, la falta de cadáveres para poder practicar procedimientos médicos. A través de estos, les es posible entrenarse para poder hacer frente a futuros procedimientos en los que se requiera un mínimo error. Entre los diversos procedimientos en los que es necesaria una elevada precisión, pueden encontrarse aquellos en los que es necesaria la inserción de agujas hipodérmicas para insertar o extraer líquidos. Para ello se debe tener en cuenta la fuerza que se está aplicando y de esta forma saber en qué zona del tejido se encuentran y así minimizar los errores. Gracias a los avances en la robótica médica, es posible crear simuladores que les permitan entrenarse sin necesidad de recurrir a tejidos reales. Estos mecanismos suponen grandes ventajas en la sociedad, mejorando así la calidad de vida de sus pacientes. Para desarrollar estos simuladores en necesario una interfaz háptica movida por motores que les permitan recrear los diferentes movimientos y obtener el feedback necesario. Este proyecto tiene como objetivo el control en par de un motor de corriente continua sin escobillas (BLDC) para poder implementarlo en un simulador médico ya existente. Mediante el control el par o corriente, es posible recrear las diferentes fuerzas obtenidas en el procedimiento médico. Cabe destacar que estos motores son conmutados electrónicamente y pertenecen a la familia de motores síncronos. Mediante el conmutador electrónicos pueden controlarse con precisión, permitiendo ajustar la velocidad y posición del rotor. Para este proyecto es necesario el control en corriente, pero se han llevado a cabo tres modos de funcionamiento, en los que varía la variable de referencia introducida. Esta puede ser tensión, corriente o velocidad de giro. Para esto, primero es necesario el modelado del motor y así conocer los parámetros de este. De esta manera, es más sencillo el cálculo e implementación del controlador. A continuación

During the early stages of the COVID-19 pandemic, EASL and ESCMID published a position paper to provide guidance for physicians involved in the care of patients with chronic liver disease. In the meantime, many countries and healthcare systems have been, or are still overwhelmed by the pandemic, significantly impacting on the care of this group of patients, whilst others have started to return towards their usual routine. In addition, many studies have been published focusing on how COVID-19 may affect the liver and how pre-existing liver diseases might influence the clinical course of COVID-19. While many aspects remain poorly understood, it has become increasingly evident that pre-existing liver diseases and liver injury during the course of the disease have to be kept in mind when caring for patients with COVID-19. Thus, this review should serve as an update on the previous position paper summarizing the evidence for liver disease involvement during COVID-19 and also provid

Objective Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients. Design 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured. Results Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts. Conclusion Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.

Background: Cirrhosis is known to have a high prevalence and mortality worldwide. However, in Europe, the epidemiology of cirrhosis is possibly undergoing demographic changes, and etiologies may have changed due to improvements in standard of care. The aim of this population-based study was to analyze the trends and the course of liver cirrhosis and its complications in recent years in Germany. Methods: We analyzed the data of all hospital admissions in Germany within diagnosis-related groups from 2005 to 2018. The diagnostic records of cirrhosis and other categories of diseases were based on ICD-10-GM codes. The primary outcome measurement was in-hospital mortality. Trends were analyzed through Poisson regression of annual number of admissions. The impact of cirrhosis on overall in-hospital mortality were assessed through the multivariate multilevel logistic regression model adjusted for age, sex, and comorbidities. Findings: Of the 248,085,936 admissions recorded between 2005 and 2018, a total of 2,302,171(0•94%) were admitted with the diagnosis of cirrhosis, mainly as a comorbidity. Compared with other chronic diseases, patients admitted with cirrhosis were younger, mainly male and had the highest in-hospital mortality rate. Diagnosis of cirrhosis was an independent risk factor of in-hospital mortality with the highest odds ratio (OR:6•2[95%CI:6.1-6•3]) among all diagnoses. The prevalence of non-alcoholic fatty liver disease has increased four times from 2005 to 2018, while alcoholic cirrhosis is 20 times than other etiologies. Bleeding was found to be decreasing over time, but ascites remained the most common complication and was increasing. Interpretation: This nationwide study demonstrates that cirrhosis represents a considerable healthcare burden, as shown by the increasing in-hospital mortality, also in combination with other chronic diseases. Alcohol-related cirrhosis and complications are on the rise. More resources and better management strategies are war

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

Background & Aims: Acute decompensation (AD) of cirrhosis is a heterogeneous clinical entity associated with moderate mortality. In some patients, this condition develops quickly into the more deadly acute-on-chronic liver failure (ACLF), in which other organs such as the kidneys or brain fail. The aim of this study was to characterize the blood lipidome in a large series of patients with cirrhosis and identify specific signatures associated with AD and ACLF development. Methods: Serum untargeted lipidomics was performed in 561 patients with AD (518 without and 43 with ACLF) (discovery cohort) and in 265 patients with AD (128 without and 137 with ACLF) in whom serum samples were available to perform repeated measurements during the 28-day follow-up (validation cohort). Analyses were also performed in 78 patients with AD included in a therapeutic albumin trial (43 patients with compensated cirrhosis and 29 healthy individuals). Results: The circulating lipid landscape associated with cirrhosis was characterized by a generalized suppression, which was more manifest during AD and in non-surviving patients. By computing discriminating accuracy and the variable importance projection score for each of the 223 annotated lipids, we identified a sphingomyelin fingerprint specific for AD of cirrhosis and a distinct cholesteryl ester and lysophosphatidylcholine finger-print for ACLF. Liver dysfunction and infections were the prin-cipal net contributors to these fingerprints, which were dynamic and interchangeable between patients with AD whose condition worsened to ACLF and those who improved. Notably, blood lysophosphatidylcholine levels increased in these patients after albumin therapy. Conclusions: Our findings provide insights into the lipid land-scape associated with decompen

Enfant de Salins-les-Bains, dans le Jura, condisciple et ami de Louis Pasteur, Jules Marcou (1824-1898) fut un autodidacte génial, qui se distingua dès l?âge de 24 ans par ses travaux géologiques très neufs sur le Jura franco-suisse. Lié avec les savants helvétiques, il devint rapidement une grande figure de la science franco-américaine. Pionnier de la connaissance des régions insoumises du Far-West, Jules Marcou publia la première Carte géologique des Etats-Unis et un peu plus tard une Carte géologique de la terre, qui eut un immense succès.

Enfant de Salins-les-Bains, dans le Jura, condisciple et ami de Louis Pasteur, Jules Marcou (1824-1898) fut un autodidacte génial, qui se distingua dès l?âge de 24 ans par ses travaux géologiques très neufs sur le Jura franco-suisse. Lié avec les savants helvétiques, il devint rapidement une grande figure de la science franco-américaine. Pionnier de la connaissance des régions insoumises du Far-West, Jules Marcou publia la première Carte géologique des Etats-Unis et un peu plus tard une Carte géologique de la terre, qui eut un immense succès.

Enfant de Salins-les-Bains, dans le Jura, condisciple et ami de Louis Pasteur, Jules Marcou (1824-1898) fut un autodidacte génial, qui se distingua dès l?âge de 24 ans par ses travaux géologiques très neufs sur le Jura franco-suisse. Lié avec les savants helvétiques, il devint rapidement une grande figure de la science franco-américaine. Pionnier de la connaissance des régions insoumises du Far-West, Jules Marcou publia la première Carte géologique des Etats-Unis et un peu plus tard une Carte géologique de la terre, qui eut un immense succès.

Extracellular release of HMGB1 contributes to acetaminophen-induced liver injury. HMGB1 acts as a danger-associated molecular patterns during this toxic process but the mechanisms of action and targeted cells are incompletely defined. Here we studied, in vitro, the role of HMGB1 in amplifying the acetaminophen-induced hepatocyte necrosis process. Using cultured HepaRG cells, primary human hepatocytes and selective chemical inhibitors we evaluated acetaminophen-induced toxicity. We confirmed that addition of acetaminophen induced HepaRG cell death and HMGB1 release. We showed that inhibition of HMGB1 decreased acetaminophen-induced HepaRG cell death, suggesting a feedforward effect. We provide the first evidence that exposure of HepaRG cells to recombinant human HMGB1 (rhHMGB1) also resulted in cell death. Moreover, we found that both acetaminophen and rhHMGB1 induced programmed HepaRG cell necrosis through a RIPK3-dependent mechanism. By using TLR4 blocking antibody, we demonstrated the reduction of the HepaRG cell death induced by acetaminophen and rhHMGB1. Furthermore, inhibition of TRIF, known to induce a RIPK3-dependent cell death, reduced rhHMGB1-induced HepaRG cell death. Our data support that released HMGB1 from acetaminophen-stressed hepatocytes induced necrosis of neighboring hepatocytes by TLR4-TRIF-RIPK3- pathway. This in vitro study gives new insights in the role of HMGB1 in the amplification of acetaminophen-induced toxicity.

Acute clinical deterioration of a patient with chronic liver disease remains a decisive time point both in terms of medical management and prognosis. This condition, also known as acute decompensation (AD), is an important event determining a crossroad in the trajectory of patients. A significant number of patients with AD may develop hepatic or extrahepatic organ failure, or both, which defines the syndrome acute-on-chronic liver failure (ACLF), and ACLF is associated with a high morbidity and short-term mortality. ACLF may occur at any phase during chronic liver disease and is pathogenetically defined by systemic inflammation and immune metabolic dysfunction. When organ failures develop in the presence of cirrhosis, especially extrahepatic organ failures, liver transplantation (LT) may be the only curative treatment. This review outlines the evidence supporting LT in ACLF patients, highlighting the role of timing, bridging to LT, and possible indicators of futility. Importantly, prospective studies on ACLF and transplantation are urgently needed.

Background & Aims: Acute‐on‐chronic liver failure (ACLF) is characterized by high short‐term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL‐33 receptor (sIL‐33R). Patients were divided according to CI (<3.2; 3.2‐4.2; >4.2 L/min/m2) in hypo‐ (n = 84), normo‐ (n = 69) and hyperdynamic group (n = 55). After a median follow‐up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL‐6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P =.011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., SCOPUS: ar.j, info:eu-repo/semantics/published

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., SCOPUS: ar.j, info:eu-repo/semantics/published

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P =.011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

Background & Aims: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). Methods: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. Results: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). Conclusions: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279., SCOPUS: ar.j, info:eu-repo/semantics/published

Extracellular release of HMGB1 contributes to acetaminophen-induced liver injury. HMGB1 acts as a danger-associated molecular patterns during this toxic process but the mechanisms of action and targeted cells are incompletely defined. Here we studied, in vitro, the role of HMGB1 in amplifying the acetaminophen-induced hepatocyte necrosis process. Using cultured HepaRG cells, primary human hepatocytes and selective chemical inhibitors we evaluated acetaminophen-induced toxicity. We confirmed that addition of acetaminophen induced HepaRG cell death and HMGB1 release. We showed that inhibition of HMGB1 decreased acetaminophen-induced HepaRG cell death, suggesting a feedforward effect. We provide the first evidence that exposure of HepaRG cells to recombinant human HMGB1 (rhHMGB1) also resulted in cell death. Moreover, we found that both acetaminophen and rhHMGB1 induced programmed HepaRG cell necrosis through a RIPK3-dependent mechanism. By using TLR4 blocking antibody, we demonstrated the reduction of the HepaRG cell death induced by acetaminophen and rhHMGB1. Furthermore, inhibition of TRIF, known to induce a RIPK3-dependent cell death, reduced rhHMGB1-induced HepaRG cell death. Our data support that released HMGB1 from acetaminophen-stressed hepatocytes induced necrosis of neighboring hepatocytes by TLR4-TRIF-RIPK3- pathway. This in vitro study gives new insights in the role of HMGB1 in the amplification of acetaminophen-induced toxicity., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Acute-on-chronic liver failure (ACLF) is a common complication of cirrhosis characterized by single or multiple organ failures and high short-term mortality. Treatment of ACLF consists of standard medical care (SMC) and organ(s) support. Whether the efficacy of artificial liver support (ALS) depends on the severity of ACLF or on the intensity of this treatment, or both, is unclear. This study aimed to further assess these issues.Methods: We performed an individual patient data meta-analysis assessing the efficacy of Molecular Adsorbent Recirculating System (MARS) in ACLF patients enrolled in prior randomized control trials (RCTs). The meta-analysis was designed to assess the effect of patient severity (ACLF grade) and treatment intensity [low-intensity therapy (LIT), SMC alone or SMC plus ⩽ 4 MARS sessions, high-intensity therapy (HIT), SMC plus > 4 MARS sessions] on mortality.Results: Three RCTs suitable for the meta-analysis (n = 285, ACLF patients = 165) were identified in a systematic review. SMC plus MARS (irrespective of the number of sessions) did not improve survival compared with SMC alone, neither in the complete population nor in the ACLF patients. Survival, however, was significantly improved in the subgroup of patients receiving HIT both in the entire cohort (10-day survival: 98.6% versus 82.8%, p = 0.001; 30-day survival: 73.9% versus 64.3%, p = 0.032) and within the ACLF patients (10-day survival: 97.8% versus 78.6%, p = 0.001; 30-day survival: 73.3% versus 58.5%, p = 0.041). Remarkably, HIT increased survival independently of ACLF grade. Independent predictors of survival were age, Model for End-Stage Liver Disease (MELD), ACLF grade, number of MARS sessions received, and intensity of MARS therapy.Conclusion: HIT with albumin dialysis may improve survival in patients with ACLF. Appropriate treatment schedules should be determined in future clinical trials.

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these p

Background & Aims: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. Methods: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). Results: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. Conclusions: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocircula

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality., info:eu-repo/semantics/published

We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these p, SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: re.j, info:eu-repo/semantics/published

Acute on chronic liver failure (ACLF) is the culmination of chronic liver disease and extrahepatic organ failures, which is associated with a high short-term mortality and immense health care expenditure. There are varying definitions for organ failures and ACLF in Europe, North America, and Asia. These differing definitions need to be reconciled to enhance progress in the field. The pathogenesis of ACLF is multifactorial and related to interactions between the immunoinflammatory system, microbiota, and the various precipitating factors. Individual organ failures related to the kidney, brain, lungs, and circulation have cumulative adverse effects on mortality and are often complicated or precipitated by infections. Strategies to prevent and rapidly treat these organ failures are paramount in improving survival. With the aging population and paucity of organs for liver transplant, the prognosis of ACLF patients is poor, highlighting the need for novel therapeutic strategies. The role of liver transplant in ACLF is evolving and needs further investigation across large consortia. A role for early palliative care and management of frailty as approaches to alleviate disease burden and improve patient-reported outcomes is being increasingly recognized. Conclusion: ACLF is a clinically relevant syndrome that is epidemic worldwide and requires a dedicated multinational approach focused on prognostication and management; investigations are underway worldwide to prepare ACLF for prime time. (Hepatology 2018; 00:000-000)., SCOPUS: re.j, info:eu-repo/semantics/published

The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4).CONCLUSION: Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241).

Alcohol-related liver disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well-designed trials before clinical implementation., SCOPUS: re.j, info:eu-repo/semantics/published

BACKGROUND & AIMS: Non-selective beta blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation and high mortality. As NSBBs may have beneficial effects on gut motility and permeability and, systemic inflammation, the aims of this prospective, observational study were to determine whether ongoing use of NSBBs reduced 28-day mortality in ACLF patients.METHODS: The study was performed in 349 patients with ACLF included in the CANONIC study, which is a prospective observational investigation in hospitalized cirrhotic patients with acute deterioration. The data about the use of NSBBs, its type and dosage was specifically recorded. Patient characteristics at enrollment significantly associated with treatment and mortality were taken into account as potential confounders to adjust for treatment effect. A logistic regression model was fitted.RESULTS: 164 (47%) ACLF patients received NSBBs whereas 185 patients did not. Although the CLIF-C ACLF scores were similar at presentation, more patients in the NSBB treated group had lower grades of ACLF (p=0.047) at presentation and significantly more patients improved. Forty patients (24.4%) died in NSBB treated group compared with 63 patients (34.1%) (p=0.048) [estimated risk-reduction 0.596 (95%CI: 0.361-0.985; p=0.0436)]. This improvement in survival was associated with a significantly lower white cell count (NSBB: 8.5 (5.8); no NSBB: 10.8 (6.6); p=0.002). No long-term improvement in survival was observed.CONCLUSIONS: This study shows for the first time that ongoing treatment with NSBBs in cirrhosis is safe and reduces the mortality if they develop ACLF. Careful thought should be given before stopping NSBBs in cirrhotic patients.

In immune cells, constitutively and acutely produced type I interferons (IFNs) engage autocrine/paracrine signaling pathways to induce IFN-stimulated genes (ISGs). Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. We aimed to investigate the poorly known ISG expression in systemic immune cells from patients with decompensated alcoholic cirrhosis and its association with outcome., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: cp.j, info:eu-repo/semantics/published

An error was introduced in the ‘Clinical and laboratory tests to assess the risk of bleeding and thrombosis – Recommendations’ section of this article. Recommendation, SCOPUS: er.j, info:eu-repo/semantics/published

SCOPUS: er.j, info:eu-repo/semantics/published

Background & Aims Cirrhotic patients with acute decompensation frequently develop acute-on-chronic liver failure (ACLF), which is associated with high mortality rates. Recently, a specific score for these patients has been developed using the CANONIC study database. The aims of this study were to develop and validate the CLIF-C AD score, a specific prognostic score for hospitalised cirrhotic patients with acute decompensation (AD), but without ACLF, and to compare this with the Child-Pugh, MELD, and MELD-Na scores. Methods The derivation set included 1016 CANONIC study patients without ACLF. Proportional hazards models considering liver transplantation as a competing risk were used to identify score parameters. Estimated coefficients were used as relative weights to compute the CLIF-C ADs. External validation was performed in 225 cirrhotic AD patients. CLIF-C ADs was also tested for sequential use. Results Age, serum sodium, white-cell count, creatinine and INR were selected as the best predictors of mortality. The C-index for prediction of mortality was better for CLIF-C ADs compared with Child-Pugh, MELD, and MELD-Nas at predicting 3- and 12-month mortality in the derivation, internal validation and the external dataset. CLIF-C ADs improved in its ability to predict 3-month mortality using data from days 2, 3-7, and 8-15 (C-index: 0.72, 0.75, and 0.77 respectively). Conclusions The new CLIF-C ADs is more accurate than other liver scores in predicting prognosis in hospitalised cirrhotic patients without ACLF. CLIF-C ADs therefore may be used to identify a high-risk cohort for intensive management and a low-risk group that may be discharged early., SCOPUS: ar.j, info:eu-repo/semantics/published

Bacterial infection has become the leading cause of death in patients with cirrhosis. This susceptibility is explained by the paradoxical association of an immune defect in the clearance of bacteria and an overexpression of pro-inflammatory mediators responsible of sepsis-related organ failure. Bacterial infections must be suspected and screened for in all patients with decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP) and urinary tract infection (UTI) are the most frequent types of infection followed by pneumonia, skin and soft tissue infection (SSTI), spontaneous bacteremia, and catheter-related infections. The prompt initiation of an adequate antibiotic therapy is the key to effective management. Broad use of long-term quinolones for prophylaxis and an increasing use of invasive procedures contributes to the development of multidrug-resistant bacteria. The choice of an adequate empiric antibiotic becomes a challenge, particularly in nosocomial infections. The administration of intravenous albumin can prevent the development of organ failure, at least in SBP. Sepsis-related organ failures are associated with a very poor outcome in cirrhotic patients. Multiple prophylactic strategies are effective in preventing bacterial infection in high-risk cirrhotic patients., SCOPUS: ch.b, info:eu-repo/semantics/published

Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

Background & Aims Cirrhotic patients with acute decompensation frequently develop acute-on-chronic liver failure (ACLF), which is associated with high mortality rates. Recently, a specific score for these patients has been developed using the CANONIC study database. The aims of this study were to develop and validate the CLIF-C AD score, a specific prognostic score for hospitalised cirrhotic patients with acute decompensation (AD), but without ACLF, and to compare this with the Child-Pugh, MELD, and MELD-Na scores. Methods The derivation set included 1016 CANONIC study patients without ACLF. Proportional hazards models considering liver transplantation as a competing risk were used to identify score parameters. Estimated coefficients were used as relative weights to compute the CLIF-C ADs. External validation was performed in 225 cirrhotic AD patients. CLIF-C ADs was also tested for sequential use. Results Age, serum sodium, white-cell count, creatinine and INR were selected as the best predictors of mortality. The C-index for prediction of mortality was better for CLIF-C ADs compared with Child-Pugh, MELD, and MELD-Nas at predicting 3- and 12-month mortality in the derivation, internal validation and the external dataset. CLIF-C ADs improved in its ability to predict 3-month mortality using data from days 2, 3-7, and 8-15 (C-index: 0.72, 0.75, and 0.77 respectively). Conclusions The new CLIF-C ADs is more accurate than other liver scores in predicting prognosis in hospitalised cirrhotic patients without ACLF. CLIF-C ADs therefore may be used to identify a high-risk cohort for intensive management and a low-risk group that may be discharged early., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: er.j, info:eu-repo/semantics/published

Bacterial infection has become the leading cause of death in patients with cirrhosis. This susceptibility is explained by the paradoxical association of an immune defect in the clearance of bacteria and an overexpression of pro-inflammatory mediators responsible of sepsis-related organ failure. Bacterial infections must be suspected and screened for in all patients with decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP) and urinary tract infection (UTI) are the most frequent types of infection followed by pneumonia, skin and soft tissue infection (SSTI), spontaneous bacteremia, and catheter-related infections. The prompt initiation of an adequate antibiotic therapy is the key to effective management. Broad use of long-term quinolones for prophylaxis and an increasing use of invasive procedures contributes to the development of multidrug-resistant bacteria. The choice of an adequate empiric antibiotic becomes a challenge, particularly in nosocomial infections. The administration of intravenous albumin can prevent the development of organ failure, at least in SBP. Sepsis-related organ failures are associated with a very poor outcome in cirrhotic patients. Multiple prophylactic strategies are effective in preventing bacterial infection in high-risk cirrhotic patients., SCOPUS: ch.b, info:eu-repo/semantics/published

Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

info:eu-repo/semantics/published

info:eu-repo/semantics/published

info:eu-repo/semantics/published

Bacterial infections are the cause of death in cirrhosis. In Western countries, bacterial infection is the principal identifiable precipitating event of acute-on-chronic liver failure (ACLF) which is associated with high short-term mortality. Bacterial translocation due to increased gut permeability and intestinal bacterial overgrowth/dysbiosis contributes mainly to the susceptibility of cirrhotic patients to develop bacterial infections. The diagnosis of bacterial infection in cirrhosis is challenging due to the lack of sensitive and specific classical clinical and biological parameters. The early diagnosis of bacterial infections and the prompt initiation of adequate antibiotic treatment are the cornerstone of management. Due to the frequent use of broad-spectrum antibiotics and increased invasiveness of procedures, nonclassical pathogen and multiresistant bacteria are increasingly reported. Third generation cephalosporins continue to be the gold-standard antibiotic treatment of many of the infections acquired in the community. By contrast, the empirical treatment of nosocomial infections should be tailored according to the local epidemiological pattern of multiresistant bacteria., SCOPUS: ch.b, info:eu-repo/semantics/published

Portal hypertension has traditionally been viewed as a progressive process, involving ultrastructural changes including fibrosis, nodule formation, and vascular thrombosis, leading to increased intrahepatic resistance to flow. However, it is increasingly recognized that a significant component of this vascular resistance results from a dynamic process, regulated by complex interactions between the injured hepatocyte, the sinusoidal endothelial cell, the Kupffer cell and the hepatic stellate cell, which impact on sinusoidal calibre. Recent findings suggest these haemodynamic findings are most marked in patients with superimposed inflammation. The precise mechanisms for vascular dysfunction in cirrhosis with superimposed inflammation remain to be fully elucidated but several studies over the past decade have started to generate the hypothesis that inflammation may be a key mediator of the pathogenesis and severity of portal hypertension in this context. This review provides a comprehensive overview of the biological mechanisms for inflammation playing a key role in the severity of portal hypertension, and illustrates potential novel therapies that act by modifying these processes., REVIEW, SCOPUS: re.j, info:eu-repo/semantics/published

Acute-on Chronic Liver Failure (ACLF) is a frequent syndrome (30% prevalence) characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

This publication gives an overview of peer language learning, from its creation and concepts, to its future in today’s world, implying new technologies such as social media. Part I describes the concepts, principles and history of peer language learning (PLL), followed by a discussion around the expansion of PLL through social media, exposing the new dimensions which emerged with the evolution of the Internet and web 2.0. Part II focuses on analysing 14 instances of naturally-occurring PLL adult interactions (corpus PEER). Both the concepts and phenomena discussed in Part I, and the analysis of PLL interactions of Part II feed into the recommendations, which constitute Part III. The current publication is of interest for: PLL pluri-linguals who could use the publication to integrate peer learning into their language learning, drawing from previous PLL experiences; for teachers and coordinators of language learning programs; and also for researchers.

This publication gives an overview of peer language learning, from its creation and concepts, to its future in today’s world, implying new technologies such as social media. Part I describes the concepts, principles and history of peer language learning (PLL), followed by a discussion around the expansion of PLL through social media, exposing the new dimensions which emerged with the evolution of the Internet and web 2.0. Part II focuses on analysing 14 instances of naturally-occurring PLL adult interactions (corpus PEER). Both the concepts and phenomena discussed in Part I, and the analysis of PLL interactions of Part II feed into the recommendations, which constitute Part III. The current publication is of interest for: PLL pluri-linguals who could use the publication to integrate peer learning into their language learning, drawing from previous PLL experiences; for teachers and coordinators of language learning programs; and also for researchers.