Search

Background The diagnosis of hepatitis B virus (HBV) infection requires HBV DNA testing and serologic testing for detection of the surface antigen (HBsAg) and the hepatitis B core antibody (anti-HBc). There is a population of patients with occult HBV infection (OBI), which is not detected by HBsAg or HBV DNA quantification in blood, despite the presence of active replication in the liver. Scope This document provides a definition of OBI and describes the diagnostic techniques currently used. It also addresses the detection of patients with risk factors and the need for screening for OBI in these patients. Summary Correct diagnosis of OBI prevents HBV reactivation and transmission. Diagnosis of OBI is based on the detection of HBV DNA in patients with undetectable HBsAg in blood. Perspectives A high number of patients with OBI may remain undiagnosed; therefore, screening for OBI in patients with factor risks is essential. For a correct diagnosis of OBI, it is necessary that new markers such as ultrasensitive HBsAg are incorporated, and a more comprehensive marker study is performed by including markers such as cccDNA.

Resumen Introducción El diagnóstico actual del virus de la hepatitis B (VHB) está basado en la detección mediante técnicas moleculares de ADN de VHB y ensayos serológicos, como el antígeno de superficie (HBsAg) y anticuerpos frente al core VHB (anti-HBc). Existe un grupo de pacientes con infección oculta de VHB (OBI) en los que estos ensayos no son capaces de detectar el HBsAg ni la cuantificación de ADN de VHB en sangre, aunque exista replicación activa en hígado. Contenido El documento define la OBI, y los métodos actuales para su diagnóstico. También aborda la detección de pacientes con factores de riesgo y la necesidad de realizar el cribado de OBI en ellos. Resumen Un correcto diagnóstico de OBI, previene la reactivación del VHB y su transmisión. El diagnóstico de OBI actualmente está basado en la detección de ADN de VHB en pacientes con HBsAg indetectable en sangre. Perspectivas Un número elevado de pacientes con OBI puede permanecer sin diagnosticar. Es importante realizar el cribado de OBI en determinados pacientes con factores de riesgo. La introducción de nuevos marcadores, como el HBsAg ultrasensible, y estudios más profundos de marcadores, como el ADNccc hepático, serán necesarios para un correcto diagnóstico de OBI.

Introduction Abnormal liver biochemistry is not a rare finding in the context of SARS-CoV-2 infection, regardless of patients having pre-existing chronic disease or not Content This review examines the current body of knowledge on the relationship between COVID-19 and liver injury, which is frequently found in this setting Summary Although the pathogenesis of liver injury is not fully understood, it has been suggested to be the result of a combination of multiple factors. These include direct injury caused by the virus, immune system hyperactivation, ischemic and drug-induced injury. The prognostic valor of these alterations is also the subject of intense research. Due to their potential impact, these alterations require proper management and treatment, especially in patients with chronic liver disease or liver transplant recipients. Outlook Some aspects associated with liver injury during COVID-19, especially in severe presentations, are not well understood. Studies assessing the clinical impact of COVID-19 on the healthy or diseased liver may help adjust treatment and immunization guidelines to the profile of the patient.

Resumen Introducción En el contexto de la infección por SARS-CoV-2 no es infrecuente encontrar alteraciones hepáticas, tanto en pacientes con enfermedad hepática crónica previa como sin ella. Contenido En esta revisión, se examina el conocimiento actual sobre la relación entre la COVID-19 y el daño hepático, frecuentemente observado en el seno de esta enfermedad. Resumen Si bien no está completamente dilucidada la patogénesis del daño hepático, parece ser consecuencia de la combinación de varios factores, entre los que se encuentran el daño directo del virus, el derivado de la hiperactivación del sistema inmune, el isquémico y el farmacológico. El valor pronóstico de estas alteraciones también está bajo intensa investigación. La potencial repercusión de las mismas aboga por la necesidad de adecuar el manejo y el tratamiento de los pacientes, particularmente en el contexto de pacientes con enfermedad hepática crónica o trasplantados hepáticos. Perspectiva Se desconocen actualmente muchos aspectos relativos a la afectación hepática durante la COVID-19, particularmente en las formas graves de la enfermedad. El desarrollo de nuevos estudios referidos a las implicaciones clínicas de la COVID-19 en el hígado, tanto en estado sano como enfermo, podrían ayudar a ajustar las recomendaciones de tratamiento y vacunación según el perfil del paciente.

Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC.A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison.Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis.Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC.Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis.

Whether tubular injury develops in patients with acute kidney injury owing to hepatorenal syndrome (AKI-HRS) is controversial. We performed repeated measurements of biomarkers of tubular injury during a 14-day period in 60 patients with cirrhosis and AKI (34 with AKI-HRS meeting the classical definition of type 1 HRS and 26 with AKI owing to acute tubular necrosis, AKI-ATN). Nineteen of 34 patients had resolution of AKI-HRS, while the remainder had persistent AKI-HRS. The persistence of AKI-HRS was associated with remarkably high short-term mortality. There were no significant differences in urinary NGAL or IL-18 between patients with resolution vs those with persistent AKI-HRS throughout the 14-day period. By contrast, biomarker levels were significantly lower in AKI-HRS, even if persistent, compared to AKI-ATN. These findings are highly suggestive of lack of significant tubular injury in AKI-HRS and could be of value in the clinical decision between combined liver-kidney or liver transplantation alone in patients with cirrhosis and AKI candidates to transplantation.

To develop a predictive model of hypertension resolution after adrenalectomy in patients with primary aldosteronism (PA), based on their presurgical characteristics.A retrospective multicenter study of PA patients in follow-up in 20 Spanish tertiary hospitals between 2018 and 2021 was performed (SPAIN-ALDO Register). Clinical response postadrenalectomy was classified according to the primary aldosteronism surgical outcome (PASO) consensus criteria. The predictive model was developed using a multivariate logistic regression model with the estimation of all possible equations.A total of 146 patients (54.8% females; mean age of 51.5 ± 10.9 years) with PA who underwent unilateral adrenalectomy were included. After a mean follow-up of 29.1 ± 30.43 months after surgery, hypertension cure was obtained in 37.7% ( n = 55) of the patients. The predictive model with the highest diagnostic accuracy to predict hypertension cure combined the variables female sex, use of two or fewer antihypertensive medications, hypertension grade 1, without type 2 diabetes and nonobesity. The area under the receiver operating characteristic curve of this model was 0.841 [0.769-0.914]. Based on this model, the group of patients with a higher probability of cure (80.4%) were those without type 2 diabetes, BMI30 kg/m 2 , female sex, hypertension grade 1 and who use two or fewer antihypertensives. Our predictive model offered a slightly higher diagnostic accuracy than Wachtel's (area under the curve [AUC]: 0.809), Utsumi's (AUC: 0.804) and Zarnegar's (AUC: 0.796) models and was similar than the Burello's (AUC: 0.833) model.Female sex, use of two or fewer antihypertensive medications, hypertension grade 1, no type 2 diabetes and nonobesity may predict hypertension cure after adrenalectomy in patients with PA. Our score provides a potential tool to guide preoperative patient counseling.

Elevated plasma bilirubin levels are a frequent clinical finding. It can be secondary to alterations in any stage of its metabolism: (a) excess bilirubin production (i.e., pathologic hemolysis); (b) impaired liver uptake, with elevation of indirect bilirubin; (c) impaired conjugation, prompted by a defect in the UDP-glucuronosyltransferase; and (d) bile clearance defect, with elevation of direct bilirubin secondary to defects in clearance proteins, or inability of the bile to reach the small bowel through bile ducts. A liver lesion of any cause reduces hepatocyte cell number and may impair the uptake of indirect bilirubin from plasma and diminish direct bilirubin transport and clearance through the bile ducts. Various analytical methods are currently available for measuring bilirubin and its metabolites in serum, urine and feces. Serum bilirubin is determined by (1) diazo transfer reaction, currently, the gold-standard; (2) high-performance liquid chromatography (HPLC); (3) oxidative, enzymatic, and chemical methods; (4) direct spectrophotometry; and (5) transcutaneous methods. Although bilirubin is a well-established marker of liver function, it does not always identify a lesion in this organ. Therefore, for accurate diagnosis, alterations in bilirubin concentrations should be assessed in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations.

Resumen Un aumento en los niveles plasmáticos de bilirrubina es una alteración frecuente. Puede deberse a cualquier causa que altere alguna de las fases de su metabolismo: a) producción excesiva de bilirrubina (ej. hemólisis patológica); b) defecto en la captación hepática, con aumento de bilirrubina indirecta); c) defecto de conjugación, por alteración del enzima encargada (UDP-glucuronosiltransferasa); y d) defecto de excreción biliar, con aumento de bilirrubina directa, por defectos en las proteínas encargadas de la excreción, o bien por la imposibilidad del paso de la bilis a través de los conductos biliares hasta el intestino. Una lesión hepática de cualquier causa, al disminuir el número de hepatocitos, puede producir una disminución de la captación de bilirrubina indirecta desde el plasma y una disminución del transporte y excreción de la bilirrubina directa hacia los conductillos biliares. Se pueden usar diferentes técnicas analíticas para medir la bilirrubina y sus metabolitos en el suero, la orina y las heces. La bilirrubina sérica se mide mediante (1) la "reacción diazo", actualmente el método de referencia; (2) cromatografía líquida de alta resolución (HPLC); (3) métodos oxidativos, enzimáticos y químicos; (4) espectrofotometría directa; y (5) métodos transcutáneos. Aunque la bilirrubina es un marcador clásico de disfunción hepática, no siempre indica una lesión de este órgano. Por tanto, para obtener un diagnóstico preciso, el significado de las alteraciones de este parámetro biológico ha de valorarse en conjunción con la anamnesis del paciente, la magnitud de la alteración, y el patrón de las alteraciones bioquímicas. acompañantes.

Metabolic-associated fatty liver disease (MAFLD) is defined as fat accumulation in the liver in the presence of metabolic alterations. This disorder is generally asymptomatic and may progress to severe liver disease, which are linked to inflammation and/or fibrosis. MAFLD has a high prevalence (26%) and therefore a considerable number of patients are at high risk of having advanced liver disease. This document provides an overview of the most relevant serological markers in the characterization and diagnosis of MAFLD. An example is provided of a routine diagnostic algorithm that incorporates serological testing. A range of useful serological scores are currently available for the management of MAFLD patients, especially for the stratification of patients at risk of fibrosis. A large proportion of the population is at risk of developing severe liver disease. The integration of non-invasive serological markers in the stratification of patients at risk for liver fibrosis may contribute to improve the control and management of MAFLD patients.

Resumen La enfermedad hepática grasa asociada a la disfunción metabólica (MAFLD) se define por el acúmulo de grasa en el hígado en presencia de alteraciones metabólicas. Suele cursar de forma asintomática y puede progresar a formas graves de enfermedad hepática, ligadas a la aparición de inflamación y/o fibrosis. Su prevalencia es muy elevada (26%), resultando en un alto número de pacientes con riesgo de presentar una enfermedad hepática avanzada. El presente documento describe los marcadores serológicos más relevantes en la caracterización y diagnóstico de la MAFLD, y se propone un ejemplo de su integración en un algoritmo diagnóstico en práctica clínica habitual. En la actualidad se dispone de índices serológicos útiles en el manejo de los pacientes con MAFLD, especialmente en la estratificación del riesgo de la presencia fibrosis. Una gran parte de la población está en riesgo de desarrollar enfermedad hepática grave. La integración de los marcadores serológicos no invasivos en la estratificación del riesgo de fibrosis hepática puede contribuir a un mejor control y manejo de los pacientes con MAFLD.

Objectives This study aimed to characterize the long-term scar remodeling process after an acute myocardial infarction (AMI) and the underlying scar-related arrhythmogenic substrate using serial late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Background Little is known about the time course needed for completion of the scar healing process after an AMI, which can be assessed by noninvasive cardiac imaging techniques such as LGE-CMR. Methods Fifty-six patients with revascularized ST-segment elevation AMI (STEMI) were consecutively included. LGE-CMR (3-T) was obtained at 7 days, 6 months, and 4 years after STEMI. The myocardium was segmented into 10 layers from the endocardium to epicardium, characterizing the core, border zone (BZ), and BZ channels (BZCs) using a dedicated post-processing software. Results Mean age of the patients was 57 ± 11 years; 77% were men. Left ventricular ejection fraction improved at 6 months from 47% to 51% (p Conclusions CMR data post-processing permitted a dynamic assessment of quantitative and qualitative post-AMI scar characteristics. Scar size and number of BZCs steadily decreased 4 years after AMI. BZC distribution was significantly modified during this time. These dynamic parameters could be reliably assessed with CMR; their evaluation might be of prognostic value.

To investigate the role of classical (CLM, CD14++CD16−), intermediate (INTM, CD14++CD16+), and non-classical (Non-CLM, CD14+CD16++) monocytes in scar formation after ST-elevation myocardial infarction (STEMI), evaluated with cardiac magnetic resonance (CMR). One hundred two patients with a first STEMI had serial blood analyses after 1, 3, and 7 days. A CMR was performed at 7 days and 6 months, depicting scar core (CO), border zone (BZ), and the presence of BZ channels. CLM and INTM levels progressively decreased, correlated with the scar mass, CO, and BZ at 7 days and 6 months (p

The lymphatic network plays a major role in maintaining tissue fluid homeostasis. Therefore, several pathological conditions associated with edema formation result in deficient lymphatic function. However, traditionally, the lymphatic system has been underestimated until recent years when it has been noticed the importance of this system in chronic liver disease. This review highlights the knowledge of lymphatic biology in the context of portal hypertension and liver cirrhosis. Among different roles of lymphatic system in liver disease, two remarkable ones are the contribution in ascites accumulation and the hepatic lymphangiogenesis in portal hypertension which is regulated by sympathetic nerves. The identification of novel pathological mechanisms has focused efforts into correction of structural changes and function affecting lymphatic vessels in liver disease. Despite the knowledge gained, we still have to face many unresolved questions concerning the role played by the lymphatic system in chronic liver disease and the design of therapeutic targeting.

Obesity is one of the most important public health problems that is associated with an array of metabolic disorders linked to cardiovascular disease, stroke, type 2 diabetes, and cancer. A sustained therapeutic approach to stop the escalating prevalence of obesity and its associated metabolic comorbidities remains elusive. Herein, we developed a novel nanocomposite based on mesoporous silica coated cerium oxide (CeO

Oxidative stress induced by the overproduction of free radicals or reactive oxygen species (ROS) has been considered as a key pathogenic mechanism contributing to the initiation and progression of injury in liver diseases. Consequently, during the last few years antioxidant substances, such as superoxide dismutase (SOD), resveratrol, colchicine, eugenol, and vitamins E and C have received increasing interest as potential therapeutic agents in chronic liver diseases. These substances have demonstrated their efficacy in equilibrating hepatic ROS metabolism and thereby improving liver functionality. However, many of these agents have not successfully passed the scrutiny of clinical trials for the prevention and treatment of various diseases, mainly due to their unspecificity and consequent uncontrolled side effects, since a minimal level of ROS is needed for normal functioning. Recently, cerium oxide nanoparticles (CeO NPs) have emerged as a new powerful antioxidant agent with therapeutic properties in experimental liver disease. CeO NPs have been reported to act as a ROS and reactive nitrogen species (RNS) scavenger and to have multi-enzyme mimetic activity, including SOD activity (deprotionation of superoxide anion into oxygen and hydrogen peroxide), catalase activity (conversion of hydrogen peroxide into oxygen and water), and peroxidase activity (reducing hydrogen peroxide into hydroxyl radicals). Consequently, the beneficial effects of CeO NPs treatment have been reported in many different medical fields other than hepatology, including neurology, ophthalmology, cardiology, and oncology. Unlike other antioxidants, CeO NPs are only active at pathogenic levels of ROS, being inert and innocuous in healthy cells. In the current article, we review the potential of CeO NPs in several experimental models of liver disease and their safety as a therapeutic agent in humans as well., Researches referred by the authors were funded by Fundació La Marató de TV3 (grant Marató 120930), Dirección General de Investigación Científica y Técnica (SAF15-64126-R and RTI2018-094734-B-C21, PID2019-105502RB, and BES-2017-08023), Agència de Gestió d’Ajuts Universitaris i de Recerca (SGR 2017/2019), and Instituto de Salud Carlos III (FIS PI15-00077 and FIS PI19-00774) co-financed by FEDER, European Union, “A way of making Europe” and the National Natural Science Foundation of China (31950410536). The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III.

The metabolic ratios lactate/pyruvate and β-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and mitochondria, respectively. The aim of the current study was to validate a gas-chromatography mass spectrometry method for simultaneous determination of the four metabolites in plasma and liver tissue. The procedure included an o-phenylenediamine microwave-assisted derivatization, followed by liquid-liquid extraction with ethyl acetate and silylation with bis(trimethylsilyl)trifluoroacetamide:trimethylchlorosilane 99:1. The calibration curves presented acceptable linearity, with a limit of quantification of 0.001 mM for pyruvate, β-hydroxybutyrate and acetoacetate and of 0.01 mM for lactate. The intra-day and inter-day accuracy and precision were within the European Medicines Agency’s Guideline specifications. No significant differences were observed in the slope coefficient of three-point standard metabolite-spiked curves in plasma or liver and water, and acceptable recoveries were obtained in the metabolite-spiked samples. Applicability of the method was tested in precision-cut liver rat slices and also in HepG2 cells incubated under different experimental conditions challenging the redox state. In conclusion, the validated method presented good sensitivity, specificity and reproducibility in the quantification of lactate/pyruvate and β-hydroxybutyrate/acetate metabolites and may be useful in the evaluation of in vivo redox states.

Liver fibrosis is a major health problem with multiple associated complications, which, to date, has no effective treatment. Hepatic stellate cells are the main responsible cells for fibrosis formation; upon their activation, excess accumulation of extracellular matrix and collagen deposits occurs. The mitogen platelet-derived growth factor (PDGF) and its receptor β (PDGFRβ) play a major role in hepatic stellate cells activation and are, therefore, promising targets for antifibrotic therapies. Gold nanorods hold great potential for diseased liver treatments, since their passive hepatic accumulation enhances active targeting strategies, hence increasing therapeutic efficiency. In addition, gold nanorods have photothermal properties that, combined with specific cell delivery, can be exploited to induce localized near-infrared light-mediated thermal ablation. Here, we demonstrate that gold nanorods coated with anti-PDGFRβ specifically target activated hepatic stellate cells in vivo. Additionally, gold nanorods-PDGFRβ-mediated photothermal therapy decreases fibrosis, hepatic inflammation, and hepatocyte injury in the experimental model of CCl4-induced liver fibrosis in mice.

DHX15 is a downstream substrate for Akt1, which is involved in key cellular processes affecting vascular biology. Here, we explored the vascular regulatory function of DHX15. Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15 zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development. DHX15 mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and proteome analysis of DHX15 silenced endothelial cells revealed differential expression of genes involved in the metabolism of ATP biosynthesis. The validation of these results demonstrated a lower activity of the Complex I in the mitochondrial membrane of endothelial cells, resulting in lower intracellular ATP production and lower oxygen consumption. After injection of syngeneic LLC1 tumor cells, DHX15 mice showed partially inhibited primary tumor growth and reduced lung metastasis. Our results revealed an important role of DHX15 in vascular physiology and pave a new way to explore its potential use as a therapeutical target for metastasis treatment., This study was supported by grants from MCIN/AEI/10.13039/501100011033 (SAF2016-75358-R and PDI2019-105502RB-100 to MM-R, SAF2017-85877R, PID2019-111669RB-100, PID2020-115055RB-I00). CIBERehd, CIBERonc and CIBERbbn are financed by the Instituto de Salud Carlos III. I.P. was recipient of a predoctoral fellowship supported by MCIN/AEI/10.13039/501100011033 y FSE “El FSE invierte en tu futuro” (BES-2017-080823). A.E-.C. is funded by ISCIII of the MINECO (reference PT17/0009/0019) and co-financed by FEDER. J.R-.V. was a recipient of a BIOTRACK Postdoctoral Fellowship supported by the European Community’s Seventh Framework Programme and the MINECO (Contract 229673). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. The center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595). The authors would like to thank Drs. Simone Calzolari, Rafael Miñana and Javier Terriente from ZeClinics for their helpful collaboration with the zebrafish model generation and experimentation.

Obesity is one of the most important public health problems that is associated with an array of metabolic disorders linked to cardiovascular disease, stroke, type 2 diabetes, and cancer. A sustained therapeutic approach to stop the escalating prevalence of obesity and its associated metabolic comorbidities remains elusive. Herein, we developed a novel nanocomposite based on mesoporous silica coated cerium oxide (CeO2) nanozymes that reduce the circulating levels of fatty acids and remarkably improve the metabolic phenotype in a model of obese Zucker rats five weeks after its administration. Lipidomic and gene expression analyses showed an amelioration of the hyperlipidemia and of the hepatic and adipose metabolic dysregulations, which was associated with a down-regulation of the hepatic PI3K/mTOR/AKT pathway and a reduction of the M1 proinflammatory cytokine TNF-a. In addition, the coating of the CeO2 maximized its cell antioxidant protective effects and minimized non-hepatic biodistribution. The one-pot synthesis method for the nanocomposite fabrication is implemented entirely in aqueous solution, room temperature and open atmosphere conditions, favoring scalability and offering a safe and translatable lipid-lowering and antioxidant nanomedicine to treat metabolic comorbidities associated with obesity. This approach may be further applied to address other metabolic disorders related to hyperlipidemia, low-grade inflammation and oxidative stress., This research was supported by the Instituto de Salud Carlos III (PI19/00774 to G. C. and G. F.-V.), Dirección General de Investigación Científica y Técnica (RTI2018-094734-B-C2 to W. J.), co-financed by FEDER, European Union, “A way of making Europe”, and the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de la Generalitat de Catalunya (2018_PROD_00187 to W. J.), the National Natural Science Foundation of China (31950410536 to E. C. and 22005221 to M. Z.), the Wuyi University Funding (2018TP010 to E. C., and 2018TP011 and 2020FKZX05 to M. Z.), Guangdong Science and Technology Department (2019A050512006 to E. C.), and the Academy of Finland (309374 to J. M. R.).

IntroductionChronic liver disease is associated with high mortality. Liver transplantation is the definitive treatment for patients with end-stage liver disease, improving their survival and quality of life. However, chronic rejection of the graft and the imbalance between the demand and the availability of organs limit its applicability. Therefore, finding therapeutic and/or diagnostic alternatives for these patients is a priority. In this context, preclinical studies in rodents have demonstrated that Akt plays a key role in liver dysfunction. Even with all this evidence, the activation status of Akt and its downstream targets in the liver of patients with chronic hepatopathy is still unknown. Hence, the present study aims to determine the activation status of the molecules involved in the Akt signaling pathway in livers of cirrhotic patients.Materials and MethodsIn this study, 36 liver tissue samples from a cohort of 27 cirrhotic patients and 9 patients without cirrhosis were included. A total of 10 proteins involved in Akt/mTOR pathway (GSK3β, IGF1R, IRS1, mTOR, p70S6K, IR, PTEN, GSK3α, TSC2, and RPS6) were analyzed using a multiplex immunoassay based on Luminex® technology.ResultsSignificant differences were found in several Akt/mTOR target proteins between the groups of cirrhotic patients vs. non-cirrhotic: FoxO1 (9.5 vs. 4.4; ppppppConclusionFoxO1 is overexpressed in the liver of cirrhotic patients after partial hepatectomy. FoxO1 levels are also associated with the degree of liver injury, showing a positive correlation with current biomarkers used in clinical practice to detect liver injury.

DHX15 is an ATP-dependent RNA helicase involved in pre-mRNA splicing and a downstream substrate for Akt1, which plays a significant role in vascular biology. The aim of this study was to explore the regulatory function of DHX15 over the vasculature and endothelial cell biology. Results: DHX15-/- was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed an undeveloped parachordal line, which leads to the formation of lymphatic structures. DHX15+/- mice triggered lower vascular network density and impaired lymphatic function postnatally. Transcriptome and proteome analysis of DHX15 silenced LEC revealed alterations in the glycolysis and gluconeogenesis pathways. The validation of these results demonstrated an uncoupling of the glycolysis with the oxidation of pyruvate in the mitochondria and a lower activity of the Complex I, resulting in lower cellular ATP production. Noteworthy, DHX15+/- mice partially inhibited primary tumor growth and reduced lung metastasis after injection of LLC1 tumor cells.

Background: COVID-19 causes high mortality and long hospitalization periods. The aim of this study was to search for new early prognostic strategies accessible to most health care centers. Methods: Laboratory results, demographic and clinical data from 500 patients with positive SARS-CoV-2 infection were included in our study. The data set was split into training and test set prior to generating different multivariate models considering the occurrence of death as the response variable. A final computational method called the BGM score was obtained by combining the previous models and is available as an interactive web application. Results: The logistic regression model comprising age, creatinine (CREA), D-dimer (DD), C-reactive protein (CRP), platelet count (PLT), and troponin I (TNI) showed a sensitivity of 47.3%, a specificity of 98.7%, a kappa of 0.56, and a balanced accuracy of 0.73. The CART classification tree yielded TNI, age, DD, and CRP as the most potent early predictors of mortality (sensitivity = 68.4%, specificity = 92.5%, kappa = 0.61, and balanced accuracy = 0.80). The artificial neural network including age, CREA, DD, CRP, PLT, and TNI yielded a sensitivity of 66.7%, a specificity of 92.3%, a kappa of 0.54, and a balanced accuracy of 0.79. Finally, the BGM score surpassed the prediction accuracy performance of the independent multivariate models, yielding a sensitivity of 73.7%, a specificity of 96.5%, a kappa of 0.74, and a balanced accuracy of 0.85. Conclusions: The BGM score may support clinicians in managing COVID-19 patients and providing focused interventions to those with an increased risk of mortality.

Resumen Introducción El estradiol en suero (E2) se emplea para el diagnóstico y/o seguimiento de una amplia variedad de patologías. El objeto del presente estudio es evaluar el ensayo enhanced estradiol (eE2) de Siemens en el sistema Atellica IM 1600 (Siemens Healthineers) y llevar a cabo una comparación de muestras con el analizador Advia Centaur XP (Siemens Healthineers). Métodos Los coeficientes de variación (CV) intradía e interdía se evaluaron utilizando pools de muestras séricas y materiales de control de calidad. El límite de cuantificación se determinó mediante el empleo de seis muestras de suero con concentraciones decrecientes de E2. La linealidad fue evaluada a través del análisis de dos muestras diferentes de suero. La exactitud se determinó midiendo tres materiales de referencia certificados. Comparamos los sistemas Atellica y Centaur XP con el método de regresión de Passing–Bablok y el gráfico de Bland–Altman utilizando 119 muestras de suero con concentraciones de entre 45 y 10.059 pmol/L. Resultados La imprecisión intradía e interdía fue Conclusiones Este estudio indica que el ensayo eE2 tiene una imprecisión y una exactitud aceptables, mostrando una buena correlación con el sistema Centaur XP.

The alfapump system has been proposed as a new treatment for the management of refractory ascites. The system removes ascites from the peritoneal cavity to urinary bladder, producing a continuous low-volume paracentesis. The aim of the study is to investigate the effects of treatment with the alfapump™ system on kidney and circulatory function in patients with cirrhosis and refractory ascites. This was a prospective study including 10 patients with cirrhosis and refractory ascites. Primary outcomes were changes in glomerular filtration rate (GFR), as assessed by isotopic techniques, and changes in circulatory function assessed by arterial pressure, cardiac output, and activity of vasoconstrictor systems. Secondary outcomes were the need for large-volume paracentesis and adverse events. Follow-up was 1 year. GFR decreased significantly from 67 mL/minute/1.73 m2 (41-90 mL/minute/1.73 m2) at baseline to 45 mL/minute/1.73 m2 (36-74 mL/minute/1.73 m2) at month 6 (P = 0.04). Mean arterial pressure and cardiac output did not change significantly; however, there was a marked increase in plasma renin activity and norepinephrine concentration (median percent increase with respect to baseline +191% and 59%, respectively). There were 68 episodes of complications of cirrhosis in 8 patients during follow-up, the most frequent being acute kidney injury. In conclusion, treatment with alfapump™ system was associated with marked activation of endogenous vasoconstrictor systems and impairment of kidney function. The chronological relationship observed between kidney impairment and vasoconstrictor systems activation after device insertion suggests a cause-effect relationship, raising the possibility that treatment with alfapump impairs effective arterial blood volume mimicking a postparacentesis circulatory dysfunction syndrome. In this context, the potential role of albumin in counteracting these effects should be investigated in future studies. Liver Transplantation 23 583–593 2017 AASLD.

Predicting sudden cardiac death risk in the first months after ST-segment elevation myocardial infarction (STEMI) remains challenging.The purpose of this study was to investigate the ability of late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) to identify the potentially arrhythmogenic substrate and its temporal evolution after STEMI.One hundred consecutive patients with a first STEMI were included. Three-dimensional high-resolution LGE-CMR was obtained at 3 T on days 7 and 180. Left ventricular wall was segmented and characterized by pixel signal intensity algorithm in 5 layers from endocardium to epicardium. A 3-dimensional color-coded shell map was obtained for each layer, depicting scar core and border zone (BZ) distribution. Presence and characteristics of BZ channels were registered for each layer.At 180 days, left ventricular ejection fraction had improved significantly (from 46.7% ± 10% to 51.5% ± 10%; P.001) and scar mass was reduced (from 22.6 ± 20 g to 13.8 ± 12 g; P.001). Most BZ channels (89%) were identified in the same myocardial layer and American Heart Association (AHA) segment, with the same orientation and morphology in both studies. Early LGE-CMR had 96% sensitivity and 90% specificity for predicting presence of BZ channels at 180 days. Greater presence was observed in patients with no-reflow phenomenon at baseline (P = .01).Most BZ channels can be identified by LGE-CMR at day 7 post-STEMI and, despite scar mass reduction, remain unaltered at 6 months, suggesting that the potentially arrhythmogenic substrate is established within the first week post-STEMI.

Background The use of plasma biomarkers is relevant for the prognosis of ST-segment elevation myocardial infarction (STEMI) patients. Apelin, an adipocytokine, plays a pivotal role in the pathophysiology of both ischemia/reperfusion injury and its potential subsequent heart failure. We evaluated apelin concentrations at admission as a biomarker to assess risk of 6-month mortality. Methods Consecutive patients with STEMI were recruited from January 2012 to January 2013 (n = 250). Plasma apelin, brain natriuretic peptide (BNP) and sensitive troponin I (sTnI) were assessed in EDTA-plasma samples obtained at admission. Clinical, hemodynamic and other laboratory variables were also registered. All-cause mortality was assessed at 6-month follow-up. Results Increased plasma apelin concentrations at admission were predictive of 6- month mortality, after adjustment for age, diabetes, systolic blood pressure, heart rate, glomerular filtration rate, Killip class, left ventricular ejection fraction, BNP and sTnI. The combination of apelin with BNP and sTnI further improved the apelin predictive value. Finally, apelin concentrations were associated with markers of ischemic heart failure severity, but not with markers of ischemic insult severity. Conclusions Increased plasma concentrations of apelin at admission in patients with STEMI were associated with a higher risk of mortality at 6 months, adding prognostic value to the provided by BNP. Moreover, apelin levels were also related to markers of ischemic heart failure severity, but not markers of ischemia severity.

Background Serum estradiol (E2) levels may be used in the diagnostic and/or monitoring of a broad variety of clinical conditions. The aims of this study were to evaluate the Siemens enhanced estradiol assay (eE2) on Atellica IM 1600 (Siemens Healthineers) and to perform a sample comparison with the Siemens ADVIA Centaur XP (Siemens Healthineers). Methods Within-day and between-day coefficient of variation (CV) were determined using serum sample pools and quality control materials. Six serum samples with decreasing concentrations of E2 were used to assess the limit of quantification. Linearity was evaluated using two different serum samples. Accuracy was evaluated by measuring three certified reference materials. Passing–Bablok regression and Bland–Altman plot were used for comparing Atellica and Centaur XP in 119 serum samples ranging from 45 to 10,059 pmol/L. Results Within-day and between-day imprecision was R = 0.99), with recoveries ranging from 77 to 93%. Comparison study showed good agreement and no significant bias. Conclusions The study shows that Atellica eE2 assay presents acceptable imprecision and accuracy and correlates well with Centaur XP.