Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial.

OBJECTIVE: We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response. DESIGN: A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL. RESULTS: Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) <15 and MELD-Na<15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity. CONCLUSION: For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose. TRIAL REGISTRATION NUMBER: NCT01884415.

A Psychrophilic GelMA: Breaking Technical and Immunological Barriers for Multimaterial High-Resolution 3D Bioprinting.

The increasing demand for tissue replacement has encouraged scientists worldwide to focus on developing new biofabrication technologies. Multimaterials/cells printed with stringent resolutions are necessary to address the high complexity of tissues. Advanced inkjet 3D printing can use multimaterials and attain high resolution and complexity of printed structures. However, a decisive yet limiting aspect of translational 3D bioprinting is selecting the befitting material to be used as bioink; there is a complete lack of cytoactive bioinks with adequate rheological, mechanical, and reactive properties. This work strives to achieve the right balance between resolution and cell support through methacrylamide functionalization of a psychrophilic gelatin and new fluorosurfactants used to engineer a photo-cross-linkable and immunoevasive bioink. The syntonized parameters following optimal formulation conditions allow proficient printability in a PolyJet 3D printer comparable in resolution to a commercial synthetic ink (∼150 µm). The bioink formulation achieved the desired viability (∼80%) and proliferation of co-printed cells while demonstrating in vivo immune tolerance of printed structures. The practical usage of existing high-resolution 3D printing systems using a novel bioink is shown here, allowing 3D bioprinted structures with potentially unprecedented complexity.

Understanding the Molecular Conformation and Viscoelasticity of Low Sol-Gel Transition Temperature Gelatin Methacryloyl Suspensions.

For biomedical applications, gelatin is usually modified with methacryloyl groups to obtain gelatin methacryloyl (GelMA), which can be crosslinked by a radical reaction induced by low wavelength light to form mechanically stable hydrogels. The potential of GelMA hydrogels for tissue engineering has been well established, however, one of the main disadvantages of mammalian-origin gelatins is that their sol-gel transitions are close to room temperature, resulting in significant variations in viscosity that can be a problem for biofabrication applications. For these applications, cold-water fish-derived gelatins, such as salmon gelatin, are a good alternative due to their lower viscosity, viscoelastic and mechanical properties, as well as lower sol-gel transition temperatures, when compared with mammalian gelatins. However, information regarding GelMA (with special focus on salmon GelMA as a model for cold-water species) molecular conformation and the effect of pH prior to crosslinking, which is key for fabrication purposes since it will determine final hydrogel's structure, remains scarce. The aim of this work is to characterize salmon gelatin (SGel) and salmon methacryloyl gelatin (SGelMA) molecular configuration at two different acidic pHs (3.6 and 4.8) and to compare them to commercial porcine gelatin (PGel) and methacryloyl porcine gelatin (PGelMA), usually used for biomedical applications. Specifically, we evaluated gelatin and GelMA samples' molecular weight, isoelectric point (IEP), their molecular configuration by circular dichroism (CD), and determined their rheological and thermophysical properties. Results showed that functionalization affected gelatin molecular weight and IEP. Additionally, functionalization and pH affected gelatin molecular structure and rheological and thermal properties. Interestingly, the SGel and SGelMA molecular structure was more sensitive to pH changes, showing differences in gelation temperatures and triple helix formation than PGelMA. This work suggests that SGelMA presents high tunability as a biomaterial for biofabrication, highlighting the importance of a proper GelMA molecular configuration characterization prior to hydrogel fabrication.

Outcome of liver cancer patients with SARS-CoV-2 infection: An International, Multicentre, Cohort Study.

BACKGROUND & AIMS: Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. METHODS: Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. RESULTS: Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84-11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24-12.74], 11.76% [95% CI 4.73-22.30], 20.69% [95% CI 11.35-31.96] and 34.52% [95% CI 17.03-52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49-4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29-7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection. CONCLUSIONS: This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period.

Laminin as a Biomarker of Blood-Brain Barrier Disruption under Neuroinflammation: A Systematic Review.

Laminin, a non-collagenous glycoprotein present in the brain extracellular matrix, helps to maintain blood-brain barrier (BBB) integrity and regulation. Neuroinflammation can compromise laminin structure and function, increasing BBB permeability. The aim of this paper is to determine if neuroinflammation-induced laminin functional changes may serve as a potential biomarker of alterations in the BBB. The 38 publications included evaluated neuroinflammation, BBB disruption, and laminin, and were assessed for quality and risk of bias (protocol registered in PROSPERO; CRD42020212547). We found that laminin may be a good indicator of BBB overall structural integrity, although changes in expression are dependent on the pathologic or experimental model used. In ischemic stroke, permanent vascular damage correlates with increased laminin expression (ß and γ subunits), while transient damage correlates with reduced laminin expression (α subunits). Laminin was reduced in traumatic brain injury and cerebral hemorrhage studies but increased in multiple sclerosis and status epilepticus studies. Despite these observations, there is limited knowledge about the role played by different subunits or isoforms (such as 411 or 511) of laminin in maintaining structural architecture of the BBB under neuroinflammation. Further studies may clarify this aspect and the possibility of using laminin as a biomarker in different pathologies, which have alterations in BBB function in common.

Validation of VIRSTA and Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT) Scores to Determine the Priority of Echocardiography in Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: Infective endocarditis (IE) secondary to Staphylococcus aureus bacteremia (SAB) has high morbidity and mortality. The systematic use of echocardiography in SAB is controversial. We aimed to validate VIRSTA and Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT) scores for predicting the risk of IE in Colombian patients with SAB and, consequently, to determine the need for echocardiography. METHODS: Cohort of patients hospitalized with SAB in 2 high complexity institutions in Medellin, Colombia, between 2012 and 2018. The diagnosis of IE was established based on the modified Duke criteria. The VIRSTA and PREDICT scores were calculated from the clinical records, and their operational performance was calculated. RESULTS: The final analysis included 922 patients, 62 (6.7%) of whom were diagnosed with IE. The frequency of IE in patients with a negative VIRSTA scale was 0.44% (2/454). The frequency of IE in patients with a negative PREDICT scale on day 5 was 4.8% (30/622). The sensitivity and negative predictive value (NPV) of the VIRSTA scale was 96.7% and 99.5%, respectively. For the PREDICT scale on day 5, the sensitivity and NPV were 51.6% and 95.1%, respectively. The discrimination, given by the area under the receiver operating characteristic curve, was 0.86 for VIRSTA and 0.64 for PREDICT. CONCLUSIONS: In patients with negative VIRSTA, screening echocardiography may be unnecessary because of the low frequency of IE. In PREDICT-negative patients, despite the low frequency of IE, it is not safe to omit echocardiography.

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

Endocrine hypertension secondary to adrenal tumors: clinical course and predictive factors of clinical remission.

PURPOSE: Endocrinopathies constitute ~ 10% of secondary hypertension (SH) etiologies. Primary aldosteronism, pheochromocytoma (PHEO), and Cushing's syndrome are common causes. Early identification and treatment result in resolution/improvement of SH. The aim of this study was to characterize the clinical course, outcomes, and remission-associated prognostic factors of SH related to adrenal tumors. METHODS: Retrospective cohort study including patients with SH who underwent adrenalectomy from 2000 to 2019. Postoperative outcomes were analyzed. Remission was defined as normalization of blood pressure without drug use. RESULTS: Eighty-three patients with SH were included. Mean ± SD age was 38.8 ± 14.2 years and 75.9% were women. Diagnosis was PHEO in 35 patients (42.2%), aldosteronoma (APA) in 28 (33.7%), cortisol producing adenoma (CPA) in 16 (19.3%), and ACTH-dependent Cushing's in 4 (4.8%). Laparoscopic adrenalectomy was performed in 81 (97.6%) patients. Mean ± SD follow-up was 57.4 ± 49.6 months (range 1-232). Surgical morbidity occurred in 7.2% of patients and there was no mortality. Remission of SH occurred in 61(73.5%): 100% of ACTH-dependent Cushing's, 85.7% of PHEO, 68.8% of CPA, and 57.1% of APA. Biochemical phenotype and the combination of larger tumor size, number of antihypertensive drugs, male gender, older age, obesity, and preoperative SH for more than 5 years were associated with less likely clinical remission in patients with APA (p = 0.004), CPA (p < 0.0001), and PHEO (p < 0.0001). CONCLUSION: SH remission rates are 57-100% after adrenalectomy. Several prognostic factors could be used to predict SH control. Adrenalectomy provides good clinical outcome and must be considered a treatment option in all surgical candidates.

Concomitant onset of systemic lupus erythematosus and disseminated histoplasmosis: a case-based review.

INTRODUCTION: Concomitant infections during the debut or relapse of systemic lupus erythematosus are a common scenario, due to multiple mechanisms including the use of immunosuppressive drugs and autoimmunity per se. Invasive fungal infections are rare in systemic lupus erythematosus and are associated with profound immunosuppressed states. Disseminated histoplasmosis in patients with lupus has rarely been reported and the concomitant presentation of both entities is exceptional. METHODS: We describe a case and performed a literature review in order to identify all case reports. A literature search was carried out using in PubMed/MEDLINE, EMBASE and Google Scholar (the first 200 relevant references) bibliographic databases. All available inclusion studies from January 1968 through July 2020. All data were tabulated, and outcomes were cumulatively analyzed. RESULTS: Thirty-one additional cases were identified. Disseminated histoplasmosis was the most common clinical presentation and most cases have been reported in patients with a prior diagnosis of lupus in the setting of moderate to high steroid dose use, usually in combination with some other immunosuppressant. Description at systemic lupus disease onset was only reported in 3 cases with a high associated mortality. In our patient, severe disease activity, significant immunosuppression, malnutrition and multi-organ compromise conditioned the patient's fatal outcome. CONCLUSION: Histoplasmosis can closely mimic activity of lupus. Thus, early clinical recognition is important since a delay in diagnosis and treatment can lead to fatal outcomes.

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

BACKGROUND & AIMS: 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. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

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 cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen.

OBJECTIVES: To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. METHODS: Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. RESULTS: We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. CONCLUSIONS: One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

Predictive Value of Matrix Metalloproteinases and Their Inhibitors for Mortality in Septic Patients: A Cohort Study.

PURPOSE: Over 170 biomarkers are being investigated regarding their prognostic and diagnostic accuracy in sepsis in order to find new tools to reduce morbidity and mortality. Matrix metalloproteinases (MMPs) and their inhibitors have been recently studied as promising new prognostic biomarkers in patients with sepsis. This study is aimed at determining the utility of several cutoff points of these biomarkers to predict mortality in patients with sepsis. MATERIALS AND METHODS: A multicenter, prospective, analytic cohort study was performed in the metropolitan area of Bucaramanga, Colombia. A total of 289 patients with sepsis and septic shock were included. MMP-9, MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2, TIMP-1/MMP-9 ratio, and TIMP-2/MMP-2 ratio were determined in blood samples. Value ranges were correlated with mortality to estimate sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiving operating characteristic curve. RESULTS: Sensitivity ranged from 33.3% (MMP-9/TIMP-1 ratio) to 60.6% (TIMP-1) and specificity varied from 38.8% (MMP-2/TIMP-2 ratio) to 58.5% (TIMP-1). As for predictive values, positive predictive value range was from 17.5% (MMP-9/TIMP-1 ratio) to 70.4% (MMP-2/TIMP-2 ratio), whereas negative predictive values were between 23.2% (MMP-2/TIMP-2 ratio) and 80.9% (TIMP-1). Finally, area under the curve scores ranged from 0.31 (MMP-9/TIMP-1 ratio) to 0.623 (TIMP-1). CONCLUSION: Although TIMP-1 showed higher sensitivity, specificity, and negative predictive value, with a representative population sample, we conclude that none of the evaluated biomarkers had significant predictive value for mortality.

Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.

BACKGROUND & AIMS: Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis. METHODS: This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018. RESULTS: A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; p < 0.001), intensive care unit admission (OR 2.09; p = 0.02), and recent hospitalization (OR 1.93; p = 0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series. CONCLUSIONS: MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. LAY SUMMARY: Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.

Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and Cirrhosis.

BACKGROUND & AIMS: In phase 3 trials and real-world settings, smaller proportions of patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have a sustained virologic response 12 weeks after treatment (SVR12) with the combination of sofosbuvir and velpatasvir than in patients without cirrhosis. It is unclear whether adding ribavirin to this treatment regimen increases SVRs in patients with genotype 3 HCV infection and cirrhosis. METHODS: We performed a phase 2 trial of 204 patients with genotype 3 HCV infection and compensated cirrhosis (mean age 51 ± 7.4 years) at 29 sites in Spain from August 19, 2016 through April 18, 2017. Patients were assigned to groups given sofosbuvir and velpatasvir for 12 weeks (n = 101) or sofosbuvir and velpatasvir plus ribavirin for 12 weeks (n = 103). The primary efficacy end point was SVR12. RESULTS: The overall rates of SVR12 were 91% (92 of 101; 95% CI 84-96) for the sofosbuvir-velpatasvir group and 96% (99 of 103; 95% CI 90-99) for the sofosbuvir-velpatasvir plus ribavirin group. In the sofosbuvir-velpatasvir group, a smaller proportion of patients with baseline resistance-associated substitutions (RASs) in nonstructural protein 5A (NS5A) achieved an SVR12 (84%) than did patients without (96%). In the sofosbuvir-velpatasvir plus ribavirin group, baseline RASs had less effect on the proportion of patients with an SVR12 (96% for patients with baseline RASs; 99% for patients without). The most common adverse events (which occurred in ≥10% of patients) were asthenia (12%) in the sofosbuvir-velpatasvir group and asthenia (27%), headache (24%), and insomnia (12%) in the sofosbuvir-velpatasvir plus ribavirin group. CONCLUSIONS: Consistent with findings from previous studies, a high rate of patients (91% and 96%) with genotype 3 HCV infection and compensated cirrhosis achieved an SVR12 with sofosbuvir and velpatasvir, with or without ribavirin. Of patients treated with sofosbuvir and velpatasvir without ribavirin, fewer patients with baseline NS5A RASs achieved an SVR12 compared with patients without baseline NS5A. ClinicalTrials.govNCT02781558.

Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

Real-life chromoendoscopy for neoplasia detection and characterisation in long-standing IBD.

OBJECTIVE: Outside clinical trials, the effectiveness of chromoendoscopy (CE) for long-standing IBD surveillance is controversial. We aimed to assess the effectiveness of CE for neoplasia detection and characterisation, in real-life. DESIGN: From June 2012 to 2014, patients with IBD were prospectively included in a multicentre cohort study. Each colonic segment was evaluated with white light followed by 0.4% indigo carmine CE. Specific lesions' features were recorded. Optical diagnosis was assessed. Dysplasia detection rate between expert and non-expert endoscopists and learning curve were ascertained. RESULTS: Ninety-four (15.7%) dysplastic (1 cancer, 5 high-grade dysplasia, 88 low-grade dysplasia) and 503 (84.3%) non-dysplastic lesions were detected in 350 patients (47% female; mean disease duration: 17 years). Colonoscopies were performed with standard definition (41.5%) or high definition (58.5%). Dysplasia miss rate with white light was 40/94 (57.4% incremental yield for CE). CE-incremental detection yield for dysplasia was comparable between standard definition and high definition (51.5% vs 52.3%, p=0.30). Dysplasia detection rate was comparable between expert and non-expert (18.5% vs 13.1%, p=0.20). No significant learning curve was observed (8.2% vs 14.2%, p=0.46). Sensitivity, specificity, and positive and negative predictive values for dysplasia optical diagnosis were 70%, 90%, 58% and 94%, respectively. Endoscopic characteristics predictive of dysplasia were: proximal location, loss of innominate lines, polypoid morphology and Kudo pit pattern III-V. CONCLUSIONS: CE presents a high diagnostic yield for neoplasia detection, irrespectively of the technology and experience available in any centre. In vivo, CE optical diagnosis is highly accurate for ruling out dysplasia, especially in expert hands. Lesion characteristics can aid the endoscopist for in situ therapeutic decisions. TRIAL REGISTRATION NUMBER: NCT02543762.

Clinical course and short-term mortality of cirrhotic patients with infections other than spontaneous bacterial peritonitis.

BACKGROUND & AIMS: Clinical course and risk factors of death in non-spontaneous bacterial peritonitis (SBP) infections are poorly known. We assessed the prevalence of acute kidney injury (AKI) and type-1 hepatorenal syndrome (HRS), hospital, 30-day and 90-day mortality and risk factors of death in 441 decompensated patients. METHODS: Analysis of 615 non-SBP infections (161 urinary infections (UTI), 95 cellulitis, 92 suspected infections, 92 bacteraemias, 84 pneumonias, 21 bronchitis, 18 cholangitis, 15 spontaneous empyema, 13 secondary peritonitis, 24 other). RESULTS: Ninety-six percent of infections solved. AKI and type-1 HRS were developed in 37% and 9% of infections respectively. Overall hospital, 30-day and 90-day mortality rates were 11%, 12% and 18% respectively. Clinical course and mortality differed markedly across infections. Endocarditis, osteoarticular infections, pneumonia, spontaneous bacteraemia, cholangitis, secondary peritonitis and UTI showed higher rates of AKI. Prevalence of type-1 HRS was not significantly different among infections. Endocarditis, secondary peritonitis, pneumonia and bacteraemia showed lower rates of renal impairment resolution and higher hospital mortality associated with AKI (42% vs 12%, P<.0001) or type-1 HRS (71% vs 27%, P=.003) than the rest of infections. Age (HR: 1.04), serum sodium (HR: 0.91), serum bilirubin (HR: 1.06), INR (HR: 1.91), hepatic encephalopathy (HR: 2.44), ascites (HR: 3.06) and multidrug-resistant isolation (HR: 2.27) at infection diagnosis were independent predictors of death during hospitalization. CONCLUSIONS: Non-SBP infections constitute a heterogeneous group regarding clinical course and prognosis. Endocarditis, secondary peritonitis, pneumonia and bacteraemia show worse prognosis. The combination of data of liver and renal dysfunction and of the type of infection allows the identification of patients with poor prognosis.

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4.

BACKGROUND AND AIMS: Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. METHODS: This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. RESULTS: Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. CONCLUSIONS: In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.