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[Background & Aims] Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain., [Methods] This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort., [Results] From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13–8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29–5.98) and 0.70% (95% CI 0.10–4.95) respectively., [Conclusions] These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available., JC is a receptor of a grant of Fondo Investigaciones Sanitarias (FIS): PI18/01304. Immunomediated Nonalcoholic SteaTohepatItis; prevalence and CharacTerization. INSTInCT.

Resumen Antecedentes La esteatosis hepatica metabolica (EHmet) es la causa mas frecuente de hepatopatia cronica en nuestro medio. El «gold standard» para su diagnostico sigue siendo la biopsia hepatica, pero es una tecnica invasiva, no exenta de riesgos, con gran variabilidad interobservador por lo que son necesarios metodos no invasivos de diagnostico. Objetivo Determinar la exactitud diagnostica de indices no invasivos basados en datos clinicos y analiticos comparada con la biopsia hepatica, y analizar la concordancia de estos entre si en la cohorte global y en subpoblaciones de riesgo de EHmet. Metodos Estudio observacional prospectivo de 245 pacientes entre 19 y 80 anos diagnosticados de EHmet mediante biopsia hepatica. Se calcularon indices de esteatosis: Fatty Liver Index (FLI), Liver Accumulation Product (LAP), Hepatitis Score Index HSI) y de fibrosis: Non alcoholic fatty liver disease (NAFLD) fibrosis score, indice fibrosis-4 (FIB-4)y Hepamet Fibrosis Score (HFS). Resultados Los indices no invasivos de esteatosis demostraron alta sensibilidad y los de fibrosis alta especificidad. Para valorar esteatosis el FLI fue el indice mas sensible en todas las subpoblaciones (89-97%) excepto en mujeres. Para valorar fibrosis el HFS ofrece maxima sensibilidad en diabeticos (86,7%) y es el indice con mayor valor predictivo negativo en global. las curvas COR para indices no invasivos en esteatosis y fibrosis comparado con biopsia hepatica mostraron mayores areas bajo la curva para los indices de fibrosis, siendo el NFS y HFS los que ofrecen mayor exactitud diagnostica (area > 0,8, p Conclusiones Los indices no invasivos de esteatosis son mas sensibles y los de fibrosis mas especificos comparados con la biopsia hepatica. El NFS y el HFS, los que ofrecen mayor exactitud diagnostica, siendo el HFS el que presenta mayor valor predictivo negativo

Background. Few studies have examined gene expression in peripheral blood mononuclear cells (PBMCs) after a dietary intervention. Objective. Our study is aimed at evaluating in a pilot study the peripheral blood gene expression in obese patients after weight loss secondary to a hypocaloric Mediterranean diet. Design. A sample of 11 obese subjects without metabolic syndrome was enrolled. Biochemical, anthropometric parameters and microarray analysis were performed at baseline and after 6 months of dietary intervention. Results. The mean age was 43.1 ± 6.3 years, and the mean body mass index (BMI) was 38.6 ± 8.1 kg/m2. All the next improvements were statistically significant: body weight − 7.4 ± 1.9 kg, BMI - 2.5 ± 0.2 kg, fat mass − 5.7 ± 1.2 kg, waist circumference − 5.8 ± 1.2 cm, triglycerides − 17.4 ± 6.5 mg/dl, C-reactive protein − 3.1 ± 1.5 mg/dL, insulin − 2.1 ± 1.0 mUI/L, and HOMA-IR − 0.7 ± 0.2 units. We identified 634 differentially expressed genes: 262 genes with relative higher expression levels and 372 with lower expression levels. Cluster analysis showed 35 genes in nutritional disease and 17 genes in endocrine system. The most relevant gene was thyroid peroxidase (TPO), and this gene was overexpressed, and the next genes carbonic anhydrase VI (CA6), caveolin protein 1 (CAV1) and solute carrier family type 12 (SLLC12A3), soluble carrier family type 12 (SLLC12A3), beta 3 receptor (ADRB3), and glutamate receptor ionotropic N methyl D aspartate 2 A (GRIN2A) were all underexpressed. Conclusion. In PBMC from obese patients after a diet with a Mediterranean pattern, the expression of 634 genes, of the endocrine system and of nutritional disease, is modified.

Malnutrition is common in chronic liver diseases and worsens the patient's prognosis. Many liver disorders are associated with nutritional deficiencies. Some of the main factors that can lead to malnutrition in patients with chronic liver disease include decreased lipid absorption and reduced albumin production. In addition, these patients are sometimes candidates for a liver transplant that requires nutritional intervention after surgery to improve their prognosis. Thus, it is very important to recognise malnutrition in patients with liver failure in order to resolve it, mainly by a complete history of the patient, dietary survey, determination of muscle mass and a subjective assessment. To ensure a good nutritional status, exercise and lifestyle changes are considered, including dietary modifications, especially with a Mediterranean pattern. This article reviews these topics, including dietary modifications before and after liver transplantation. Additionally, nutritional recommendations are offered to patients with metabolic hepatic steatosis.

The prevalence of the non-alcoholic fatty liver disease (NAFLD) in developed countries is up to 30% of the general population, and 50% of patients present type 2 diabetes mellitus (DM2). Fibrosis is the most important prognostic factor in NAFLD. The aim of this study was to search evidence for an early diagnosis of liver fibrosis in subjects with DM2 and to evaluate potential risk and protective factors. This study was conducted among 160 diabetic patients with NAFLD proven biopsy. Anthropometric assessments, laboratory test, liver histological features and follow-up of a Mediterranean diet were evaluated. Diabetic patients with liver fibrosis showed a greater number of positive metabolic criteria than diabetic patients without liver fibrosis. Patients with hepatic fibrosis have a lower score on the PREDIMED test (9.0 (2.4) vs. 6.2 (2.3); p

The risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with obesity. We study the effect of this SNP on cardiovascular risk factors and weight loss secondary to 2hypocaloric diets.361 obese subjects were randomly allocated during 3 months (Diet M - high monounsaturated fat hypocaloric diet vs. Diet P - high polyunsaturated fat hypocaloric diet). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated.All anthropometric parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of anthropometric parameters was higher in non G allele carriers than G allele carriers. After dietary intervention with Diet M, (CC vs. CG + GG); total cholesterol (delta: -10.4 ± 2.1mg/dl vs. -6.4 ± 1.2mg/dl: P.05), LDL-cholesterol (delta:-7.1 ± 0.9mg/dl vs. -2.8 ± 0.8mg/dl: P.05), insulin (delta:-3.0 ± 0.8 UI/L vs. -2.0 ± 1.0 UI/L: P.05) and HOMA-IR (delta:-3.4 ± 1.0 units vs. -2.9 ± 0.9 units: P.05) improved in no G allele carriers. After Diet P, in the group of subjects without G allele CC, insulin levels (delta: -2.9 ± 1.0 UI/L vs. -0.6 ± 0.2 UI/L: P.05) and HOMA-IR (delta (CC vs. CG + GG): -0.8 ± 0.2 units vs. -0.4 ± 0.3 units: P.05) decreased, too.Our study detected a relationship of rs10830963 MTNR1B SNP with body weight loss and insulin resistance modification induced by 2different hypocaloric. Only monounsaturated enriched hypocaloric diet and in no-G allele carriers showed a significant effect on lipoproteins.

Resumen Antecedentes y objetivos El alelo de riesgo (G) de la variante rs10830963 en el gen del receptor de melatonina 1 B (MTNR1B) se relaciona con la obesidad. En este trabajo evaluamos el efecto de este SNP sobre los factores de riesgo cardiovascular y la perdida de peso secundaria a 2 dietas hipocaloricas. Metodos Trescientos sesenta y un sujetos obesos fueron asignados aleatoriamente durante 3 meses (dieta M: dieta hipocalorica alta en grasas monoinsaturadas vs. dieta P: dieta hipocalorica alta en grasas poliinsaturadas). Se midieron los parametros antropometricos, glucemia en ayunas, proteina C reactiva, concentracion de insulina, resistencia a la insulina (HOMA-IR), perfil de lipidos y los niveles de adipocitoquinas. Se evaluo el genotipo del polimorfismo del gen MTNR1B (rs10830963). Resultados Todos los parametros antropometricos, la presion arterial sistolica y los niveles de leptina disminuyeron en todos los sujetos despues de ambas dietas. Esta mejora de los parametros antropometricos fue mayor en los no portadores del alelo G que en los portadores del alelo G. Tras la intervencion con dieta M (CC vs. CG + GG), el colesterol total (delta: –10,4 ± 2,1 mg/dl vs. –6,4 ± 1,2 mg/dl: p Conclusiones Nuestro estudio detecto una relacion de la variante rs10830963 de MTNR1B con la perdida de peso corporal y la modificacion de la resistencia a la insulina inducida por 2 dietas hipocaloricas diferentes. Solo la dieta hipocalorica enriquecida en grasa monoinsaturada y los no portadores del alelo G mostraron un efecto significativo sobre las lipoproteinas.

[Objective] The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD., [Design] The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI), [Results] Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069)., [Conclusions] Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. [Lay summary] NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD., This study has been supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 and the Newcastle NIHR Biomedical Research Centre. The authors are contributing members of The European NAFLD Registry. The study was also supported by the Italian Ministry of Health, grant RF-2016-02364358 (Ricerca Finalizzata, Ministero della Salute). ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422).

Background and aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. Conclusions: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification. Funding information: National Institutes of Health (R01DK123763, R01DK119437, HL151328, P30DK52574, P30DK56341, and UL1TR002345); Ministerio de Economía y Competitividad de España (SAF2017-88041-R); Ministerio de Economía y Competitividad de España for the Severo Ochoa Excellence Accreditation (SEV-2016-0644); CIBERehd (Biomedical Research Center in Hepatic and Digestive Diseases) and Netherlands Organization for Applied Scientific Research Program (PMC13 and PMC15); Spanish Carlos III Health Institute (PI15/01132 and PI18/01075); Miguel Servet Program (CON14/00129 and CPII19/00008); ondo Europeo de Desarrollo Regional, CIBERehd, Department of Industry of the Basque Country (Elkartek: KK-2020/00008); La Caixa Scientific Foundation (HR17-00601); Liver Investigation: Testing Marker Utility in Steatohepatitis consortium funded by the Innovative Medicines Initiative Program of the European Union (777377), which receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA; Newcastle NIHR Biomedical Research Center; Czech Ministry of Health (RVO-VFN64165/2020); Fondo Nacional De Ciencia y Tecnología de Chile (1191145); and the Comisión Nacional de Investigación, Ciencia y Tecnología (AFB170005, CARE Chile UC); Agencia Nacional de Investigación y Desarrollo (ANID ACE 210009); European Union's Horizon 2020 Research and Innovation Program (825510).

rs822393 is related to dietary intervention responses. The aim of our study was to analyze the metabolic effects of 2 hypocaloric diets with a different fat profile during 3 months according to the genetic variant rs822393.a population of 361 obese patients were randomly allocated to one of two diets; Diet P (enriched in polyunsaturated fatty acids) vs. Diet M (enriched in monounsaturated fatty acids). Adiposity and biochemical parameters were determined. rs822393 was assessed by real-time PCR, with a dominant model analysis (CC vs CT+TT).genotype distribution was: 221 CC (61.2 %), 115 CT (31.9 %) and 25 TT (6.9 %). Basal and post-intervention HDL cholesterol, adiponectin levels and adiponectin/leptin ratio were lower in T-allele than non-T-allele carriers. After both diets, BMI, weight, fat mass, waist circumference, systolic blood pressure, insulin levels, HOMA-IR, leptin, total cholesterol and LDL-cholesterol improved significantly in both genotype groups. After Diet P, HDL-cholesterol (delta: 5.6 ± 1.1 mg/dl vs. 2.7 ± 0.9 mg/dl; p = 0.01), serum adiponectin (20.1 ± 2.9 ng/dl vs. 6.8 ± 3.0 ng/dl; p = 0.02) and adiponectin/leptin ratio (0.57 ± 0.1 units vs. 0.20 ± 0.08 units; p = 0.03) improved in non-T allele carriers. The same improvements were observed after Diet M: HDL-cholesterol (delta: 5.5 ± 0.8 mg/dl vs. 3.1 ± 0.9 mg/dl; p = 0.03), serum adiponectin (19.5 ± 2.9 ng/dl vs. 4.5 ± 2.8 ng/dl; p = 0.01), and adiponectin/leptin ratio (0.54 ± 0.1 units vs. 0.15 ± 0.08 units; p = 0.03). These parameters remained unchanged in T-allele carriers.after two different hypocaloric diets, obese subjects with the T allele of rs822393 did not improve their adiponectin levels, ratio adiponectin/leptin, and HDL-cholesterol, despite loss of weight.

some studies have evaluated the association of the rs1805134 genetic variant of the LEPR gene with obesity.the objective was to explore the association of the rs1805134 genetic variant of the LEPR gene with obesity measures and metabolic syndrome in obese Caucasian adults.we conducted a cross-sectional study in 212 obese subjects with body mass index (BMI) greater than 30 kg/m2. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C-reactive protein, and prevalence of metabolic syndrome were determined.the distribution of rs1805134 was 128 TT (60.4 %), 77 TC (36.3 %), and 7 CC (3.3 %). C-allele carriers showed higher levels of BMI, body weight, body fat mass, waist circumference, insulin, HOMA-IR, triglycerides, total energy intake, and carbohydrate intake than non-C-allele carriers. A logistic regression analysis reported a high percentage of elevated waist circumference (OR = 2.22, 95 % CI = 1.201-4.97; p = 0.02), hyperglycemia (OR = 1.54, 95 % CI = 1.01-5.44; p = 0.01), and metabolic syndrome percentage (OR = 1.41, 95 % CI = 1.04-5.39; p = 0.03) in C-allele carriers.subjects with the C-allele of the rs1805134 variant of the LEPR gene showed a worse metabolic pattern with a higher percentage of metabolic syndrome, central obesity and hyperglycaemia, probably related to higher energy intake.

Alcohol-related liver disease (ARLD) is the most prevalent cause of advanced liver disease and liver cirrhosis in Europe, including Spain. According to the World Health Organization the fraction of liver cirrhosis attributable to alcohol use in Spain is 73.8% among men and 56.3% among women. ARLD includes various stages such as steatohepatitis, cirrhosis and hepatocellular cancer. In addition, patients with underlying ARLD and heavy alcohol intake may develop alcoholic hepatitis, which is associated with high mortality. To date, the only effective treatment to treat ARLD is prolonged withdrawal. There are no specific treatments, and the only treatment that increases life expectancy in alcoholic hepatitis is prednisolone. For patients with alcoholic hepatitis who do not respond to treatment, some centres offer the possibility of an early transplant. These clinical practice guidelines aim to propose recommendations on ARLD taking into account their relevance as a cause of advanced chronic liver disease and liver cirrhosis in our setting. This paper aims to answer the key questions for the clinical practice of Gastroenterology, Hepatology, as well as Internal Medicine and Primary Health Centres, making the most up-to-date information regarding the management and treatment of ARLD available to health professionals. These guidelines provide evidence-based recommendations for the clinical management of this disease.

Background Oxidative stress may be a key player in COVID-19 pathogenesis due to its significant role in response to infections. A defective redox balance has been related to viral pathogenesis developing a massive induction of cell death provoked by oxidative stress. The aim of this study is to perform a complete oxidative stress profile evaluation regarding antioxidant enzymes, total antioxidant capacity and oxidative cell damage in order to characterize its role in diagnosis and severity of this disease. Methods Blood samples were obtained from 108 COVID-19 patients and 28 controls and metabolites representative of oxidative stress were assessed. The association between lipid peroxidation and 28-day intubation/death risk was evaluated by multivariable regression analysis. Probability of intubation/death to day-28 was analyzed by using Kaplan-Meier curves and tested with the log-rank test. Results Antioxidant enzymes (Superoxide dismutase (SOD) and Catalase) and oxidative cell damage (Carbonyl and Lipid peroxidation (LPO)) levels were significantly higher in COVID-19 patients while total antioxidant capacity (ABTS and FRAP) levels were lower in these patients. The comparison of oxidative stress molecules’ levels across COVID-19 severity revealed that only LPO was statistically different between mild and intubated/death COVID-19 patients. COX multivariate regression analysis identified LPO levels over the OOP (LPO>1948.17 μM) as an independent risk factor for 28-day intubation/death in COVID-19 patients [OR: 2.57; 95% CI: 1.10–5.99; p = 0.029]. Furthermore, Kaplan-Meier curve analysis revealed that COVID-19 patients showing LPO levels above 1948.17 μM were intubated or died 8.4 days earlier on average (mean survival time 15.4 vs 23.8 days) when assessing 28-day intubation/death risk (p, Graphical abstract Image 1

Background Despite growing interest in treatment strategies that limit oxygen exposure in ICU patients, no studies have compared conservative oxygen with standard oxygen in postsurgical patients with sepsis/septic shock, although there are indications that it may improve outcomes. It has been proven that high partial pressure of oxygen in arterial blood (PaO2) reduces the rate of surgical-wound infections and mortality in patients under major surgery. The aim of this study is to examine whether PaO2 is associated with risk of death in adult patients with sepsis/septic shock after major surgery. Methods We performed a secondary analysis of a prospective observational study in 454 patients who underwent major surgery admitted into a single ICU. Patients were stratified in two groups whether they had hyperoxemia, defined as PaO2 > 100 mmHg (n = 216), or PaO2 ≤ 100 mmHg (n = 238) at the day of sepsis/septic shock onset according to SEPSIS-3 criteria maintained during 48 h. Primary end-point was 90-day mortality after diagnosis of sepsis. Secondary endpoints were ICU length of stay and time to extubation. Results In patients with PaO2 ≤ 100 mmHg, we found prolonged mechanical ventilation (2 [8] vs. 1 [4] days, p p p p p = 0.008). Hyperoxemia was associated with higher probability of 90-day survival in a multivariate analysis (OR 0.61, 95%CI: 0.39–0.95, p = 0.029), independent of age, chronic renal failure, procalcitonin levels, and APACHE II score > 19. These findings were confirmed when patients with severe hypoxemia at the time of study inclusion were excluded. Conclusions Oxygenation with a PaO2 above 100 mmHg was independently associated with lower 90-day mortality, shorter ICU stay and intubation time in critically ill postsurgical sepsis/septic shock patients. Our findings open a new venue for designing clinical trials to evaluate the boundaries of PaO2 in postsurgical patients with severe infections.

[Background] Liver fibrosis risk is a heritable trait, the outcome of which is the net deposition of extracellular matrix by hepatic stellate cell-derived myofibroblasts. Whereas nucleotide sequence variations have been extensively studied in liver fibrosis, the role of copy number variations (CNV) in which genes exist in abnormal numbers of copies (mostly due to duplication or deletion) has had limited exploration., [Methods] The impact of the XPO4 CNV on histological liver damage was examined in a cohort comprised 646 Caucasian patients with biopsy-proven MAFLD and 170 healthy controls. XPO4 expression was modulated and function was examined in human and animal models., [Findings] Here we demonstrate in a cohort of 816 subjects, 646 with biopsy-proven metabolic associated liver disease (MAFLD) and 170 controls, that duplication in the exportin 4 (XPO4) CNV is associated with the severity of liver fibrosis. Functionally, this occurs via reduced expression of hepatic XPO4 that maintains sustained activation of SMAD3/SMAD4 and promotes TGF-β1-mediated HSC activation and fibrosis. This effect was mediated through termination of nuclear SMAD3 signalling. XPO4 demonstrated preferential binding to SMAD3 compared to other SMADs and led to reduced SMAD3-mediated responses as shown by attenuation of TGFβ1 induced SMAD transcriptional activity, reductions in the recruitment of SMAD3 to target gene promoters following TGF-β1, as well as attenuation of SMAD3 phosphorylation and disturbed SMAD3/SMAD4 complex formation., [Interpretation] We conclude that a CNV in XPO4 is a critical mediator of fibrosis severity and can be exploited as a therapeutic target for liver fibrosis., ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). AB is supported by an Australian Government Research Training Program (RTP) scholarship. EB is supported by Horizon 2020 under grant 634413 for the project EPoS.

Antigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962, 95%CI (0.933–0.992), p &lt, 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573, 95%CI (8.127–80.469), 0.001) and AUROC (AUC: 0.900, 95%CI (0.846–0.954), 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.

Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis has translated into a significant socioeconomic burden for health systems. Currently, it is the leading cause of noncoronary mortality worldwide and represents one of the most prevalent pathologies both in hospital emergency services and in intensive care units. In this article, we review the role of both endothelial dysfunction and neutrophil dysregulation in the physiopathology of this disease. The lack of a key symptom in sepsis makes it difficult to obtain a quick and accurate diagnosis of this condition. Thus, it is essential to have fast and reliable diagnostic tools. In this sense, the use of biomarkers can be a very important alternative when it comes to achieving these goals. Both new biomarkers and treatments related to endothelial dysfunction and neutrophil dysregulation deserve to be further investigated in order to open new venues for the diagnosis, treatment and prognosis of sepsis.

Background: The role of ADIPOQ gene variants in weight loss after different dietary fat amounts remains unclear. Objective: Our aim was to analyze the effects of ADIPOQ gene polymorphism rs266729 on metabolic changes after two different amounts of dietary fat in two hypocaloric diets. Design: A population of 283 obese patients was recruited in a randomized clinical trial with two diets: Diet HF (high-fat diet: 38% carbohydrates, 24% proteins, and 38% fats) versus Diet LF (low-fat diet: 53% carbohydrates, 20% proteins, and 27% fats). Before and after 3 months, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were carried out. The variant of the ADIPOQgene was assessed by real-time PCR. Results: Weight loss was similar with both diets in both genotypes (CC vs. CG+GG). After dietary intervention with Diet HF, only subjects with CC genotype showed a significant improvement in insulin levels (–3.3 ± 0.6 vs. –1.8 ± 0.9 mU/L; p = 0.03) and the homeostasis model assessment for insulin resistance (HOMA-IR) (–1.3 ± 0.1 vs. –0.8 ± 0.2 units; p = 0.02). After Diet LF, subjects with CC genotype showed a significant improvement in total cholesterol levels (CC vs. CG+GG) (–15.3 ± 1.4 vs. –6.4 ± 1.3 mg/dL; p = 0.01), LDL cholesterol (–14.6 ± 1.8 vs. –6.4 ± 1.3 mg/dL; p = 0.01), insulin levels (–4.6 ± 1.0 vs. –1.6 ± 0.5 mU/L; p = 0.01), and HOMA-IR (–1.6 ± 0.1 vs. –1.0 ± 0.2 units; p = 0.02). Only subjects with CC genotype showed a significant increase of adiponectin levels after both diets (CC vs. CG+GG): Diet HF (10.6 ± 2.0 vs. 1.8 ± 1.0 ng/dL; p = 0.01) and Diet LF (16.1 ± 2.8 vs. 1.3 ± 1.0 ng/dL: p = 0.03). Conclusion: CC genotype of ADIPOQgene variantrs266729 was associated with a better metabolic response after both diets. Additionally, Diet LF produced a significant improvement in lipid profile in noncarriers of allele G.

Objective Some adiponectin gene (ADIPOQ) single-nucleotide polymorphisms (SNPs) have been related to basal and adiponectin levels and metabolic parameters. The aim of this study was to evaluate the effect of the genetic variant rs1501299 ADIPOQ gene on biochemical changes after weight loss secondary to a high-protein and low-carbohydrate diet versus a standard severe hypocaloric diet over 9 mo as the primary endpoint. Methods A white population of 270 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (high-protein and low carbohydrate diet [HP] versus standard diet [S]) over 9 mo of intervention. The statistical analysis was performed for the combined GT and TT as a group (T-allele carriers) and GG as second group (non–T-allele carriers). Before and after 12 wk on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were realized. Results With both dietary interventions, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, and leptin levels decreased. In non–T-allele carriers after both diets, the decrease in total cholesterol levels –12.3 ± 2.2 mg/dL (T-allele carriers –6.9 ± 2.1 mg/dL; P = 0.01 diet HP) and 12.2 ± 3.1 mg/dL (T-allele carriers –4.7 ± 1.2 mg/dL; P = 0.02 after diet S), low-density lipoprotein cholesterol –13.2 ± 2.7 mg/dL (T-allele carriers –6.1 ± 2.1 mg/dL; P = 0.02 after diet HP) and –9.3 ± 1.8 mg/dL (T-allele carriers –4.8 ± 2.9 mg/dL; P = 0.01 after diet S), triacylglycerol levels –12.7 ± 6.1 mg/dL (T-allele carriers –6 ± 2.9 mg/dL; P = 0.01 after diet HP) and –16.3 ± 7.2 mg/dL (T-allele carriers –5.3 ± 1.4 mg/dL; P = 0.03 after diet S), insulin levels –5 ± 1.1 mUI/L (in T-allele –1.7 ± 0.9 mUI/L; P = 0.02 after diet HP) and –3.2 1.1 mUI/L (T-allele carriers –0.7 ± 0.7 mUI/L; P = 0.02 after diet S), and homeostatic model assessment of insulin resistance levels –0.4 ± 0.2 units (T-allele group –0.1 ± 0.1; P = 0.04 after diet HP) and –0.7 ± 0.1 units (T-allele carriers –0.1 ± 0.5 mg/dL; P = 0.01 after diet S) was higher than T-allele carriers. Only no T-allele carriers showed an increase in adiponectin levels after both diets. Conclusion After two different hypocaloric diets during 9 mo of intervention, the GG genotype of an ADIPOQ gene variant (rs1501299) is related to better improvement in adiponectin levels, insulin resistance, and lipid profile than T-allele carriers.

Objectives The role of ADIPOQ gene variants on weight loss after a dietary intervention remain unclear. The aim of this study was to analyze the effects of rs266729 of the ADIPOQ gene on cardiovascular risk factors and adiposity parameters after adherence to a Mediterranean-type hypocaloric diet. Method Eighty-three obese patients were studied before and after 12 wk on a Mediterranean-type hypocaloric diet. Anthropometric parameters and biochemical profiles were measured. The variant of ADIPOQ gene rs266729 was assessed at basal time by polymerase chain reaction at real time. Results Two genotype groups were realized (CC versus CG + GG). The final genotype distribution was 48 patients CC (57.8%), 30 patients CG (36.2%) and 5 patients GG (6%). After dietary intervention with a moderate calorie restriction and in both genotypes, body mass index (BMI), weight, fat mass, systolic blood pressure, and waist circumference decreased. After dietary intervention and in non-G allele carriers (CC versus CG+ GG), glucose (δ: –6.2 ± 1.1 versus –2.9 ± 1.2 mg/dL; P = 0.02), total cholesterol (δ:-15.2 ± 3.1 versus –3.4 ± 2 mg/dL; P = 0.02), low-density lipoprotein cholesterol (δ, –14.9 ± 3.1 versus –4.9 ± 1.2 mg/dL; P = 0.01), insulin levels (δ, –4± 0.6 versus 0.7 ± 0.3 UI/L;P = 0.01), homeostasis model assessment for insulin resistance (δ, –1.6 ± 0.4 versus –0.2 ± 0.4 units; P = 0.01), and adiponectin (δ, –10.4 ± 3.1 versus –1.3 ± 1.0 ng/dL; P = 0.01) improved. Conclusion After weight loss, the CC genotype of ADIPOQ gene variant (rs266729) is associated with increases in adiponectin levels and decreases of low-density lipoprotein cholesterol, insulin and homeostasis model assessment for insulin resistance after weight loss.

Background and rationale This study was intended to assess the influence of the rs16147 variant of the NPY gene on liver histology in patients with non-alcoholic fatty liver disease (NAFLD). Material and methods Eighty-nine patients with NAFLD were recruited into the study. Serum chemistry tests were done including lipid profile, transaminases, adipokines, and insulin resistance. Genotype of polymorphism (rs161477) of the NPY gene was studied. Results Twenty-three patients (25.0%) had the GG genotype (wild type) and sixty-six patients (75%) the GA (n = 39) or AA (n = 27) (mutant) types. Patients with A allele had a lower percentage of lobular inflammation and steatohepatitis (lobular inflammation plus ballooning) than those with wild genotype. Patients with A allele showed lower SAF (Steatosis, Activity, Fibrosis) scores than non-A allele carriers (5.4 ± 2.7 points vs. 4.1 ± 1.1 points; p = 0.01). In the analysis without fibrosis (NAS score), the same differences were detected (4.5 ± 1.8 points vs. 3.4 ± 1.8 points; p = 0.01). In the logistic regression analysis A allele carriers showed lower odds for inflammation (OR 0.11, 95% CI 0.02–0.84, p = 0.03) and steatohepatitis (OR 0.39, 95% CI 0.14–0.86, p = 0.04) after adjusting for age, sex, and body mass index. Conclusions A variant of polymorphism rs16147 of the NPY gene is independently associated to a lower percentage of steatohepatitis and lobular inflammation in obese subjects with biopsy-proven NAFLD.

Background & aims A common G-to-A transition located 75 base pairs upstream (rs670) from transcription start site of the APOA1 gene has been related with some metabolic parameters. Our aim was to analyze the effects of rs670 APOA1 gene polymorphism on lipid profile and metabolic changes after two different hypocaloric diets. Methods 282 obese subjects were randomly allocated during 12 weeks (Diet HF – high fat diet vs. Diet LF – low fat diet). Anthropometric and biochemical status were evaluated. Results Body mass index, weight, fat mass, waist circumference, systolic blood pressure, leptin levels and waist circumference decreased in all patients in average after both diets. In A allele carriers after 12 weeks with both diets, insulin levels (Delta diet HF: −5.3 + 1.2 UI/L; P = 0.02 and Delta diet LF: −5.8 + 1.3 UI/L; P = 0.02) and HOMA-IR (Delta diet HF: −2.9 + 0.8 units; P = 0.01 and Delta diet LF: −2.2 + 0.9 units; P = 0.03) improved in a significant way. With the low fat diet, A allele carriers showed a statistical improvement in HDL-cholesterol levels (Delta: 4 + 1 mg/dl; P = 0.03). Conclusions Our study showed the association of rs670 ApoA1 polymorphism with a decrease of insulin resistance induced by both diets and provided additional evidence on HDL-cholesterol increase after a LF hypocaloric diet in A allele carriers.

Background/Aim Several adiponectin gene (ADIPOQ) single nucleotide polymorphisms (SNPS) have been related with adiponectin levels and risk for obesity. Our aim was to analyze the effects of rs1501299 ADIPOQ gene polymorphism on total adiponectin levels, insulin resistance and weight loss after a Mediterranean hypocaloric diet in obese subjects. Methods A Caucasian population of 82 obese patients was analyzed, before and after 3 months on a Mediterranean hypocaloric diet. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. Results After dietary treatment and in wild type group, weight, BMI, fat mass, leptin levels, systolic blood pressure and waist circumference decreases were similar to the mutant type group. In wild type group, the decrease in total cholesterol was −28.1 ± 15.3 mg/dl (mutant group: −12.6 ± 16.7 mg/dl:p = 0.009), LDL- cholesterol was −31.8 ± 20.5 mg/dl (−12.2 ± 11.5 mg/dl:p = 0.006), fasting glucose plasma −4.8 ± 2.5 mg/dL (−0.5 ± 0.1 mg/dL:p = 0.02), insulin −3.6 ± 1.5 mUI/L (+0.6 ± 1.1 mUI/L:p = 0.02) and HOMA-IR −1.2 ± 0.9 (−0.1 ± 1.1:p = 0.03). Conclusion The present study suggests that T allele of ADIPO (rs1501299) could be a predictor of a lack of response of HOMA-IR, insulin, fasting glucose and LDL cholesterol secondary to a Mediterranean hypocaloric diet in obese subjects.

Summary Background & aims Omentin-1 might play a role on insulin resistance, dyslipidemia and obesity. The aim of this investigation was to evaluate the influence of weight loss on omentin-1 concentrations after a hypocaloric diet with Mediterranean pattern. Methods A Caucasian sample of 67 obese patients was analyzed before and after 3 months on a hypocaloric diet. Anthropometric parameters, blood pressure, fasting blood glucose, C-reactive protein (CRP), fasting insulin, insulin resistance (HOMA-IR), lipid concentrations and omentin-1 were measured. Results Sixty-seven obese subjects were enrolled in the study. The mean age was 48.3 ± 8.0 years (range: 25–66) and the mean BMI 34.5 ± 4.8 kg/m2 (range: 30.2–40.8). Gender distribution was 50 females (74.6%) and 17 males (25.4%). After dietary intervention and in males and females; body mass index, weight, fat mass, waist circumference, blood pressure, glucose, LDL cholesterol, insulin and HOMA-IR decreased. Omentin-1 levels increase after dietary intervention (males vs females) (delta basal vs 3 months: 10.0 ± 3.8 ng/dl: p = 0.01 vs 9.9 ± 4.1 ng/dl; p = 0.03). In the multiple regression analysis adjusted for age and sex; BMI and insulin remained independently associated with baseline and post-treatment levels of omentin-1. Conclusions Our investigation showed a significant increase in omentin-1 levels after weight loss secondary to a hypocaloric diet with a Mediterranean pattern.

Metabolic hepatic steatosis (metHS) is the most frequent cause of chronic liver disease in our environment. The "gold standard" for its diagnosis continues to be liver biopsy, but this is an invasive technique, is not risk-free, and has great interobserver variability, so noninvasive diagnostic methods are necessary.To determine the diagnostic accuracy of non-invasive methods based on clinical and analytical data compared to liver biopsy, and to analyse their concordance with each other in the overall cohort and in subpopulations at risk of metHS.Prospective observational study of 245 patients aged 19-80 years diagnosed with metHS by liver biopsy. Steatosis indices were calculated: FLI (Fatty Liver Index), LAP (Liver Accumulation Product), HSI-(Hepatitis Score Index) and fibrosis indices: Non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 index (FIB-4) and Hepamet Fibrosis Score (HFS).The non-invasive steatosis indices showed high sensitivity, and those of fibrosis, high specificity. To assess steatosis, FLI was the most sensitive index in all subpopulations (89-97%), except in women. To assess fibrosis, HFS offers maximum sensitivity in diabetics (86.7%) and is the index with the highest negative predictive value overall. The COR curves for non-invasive indices in steatosis and fibrosis compared to liver biopsy showed greater areas under the curve for the fibrosis indices, with NFS and HFS offering greater diagnostic accuracy (area 0.8, p 0.05). HFS also offers high diagnostic sensitivity in the diabetic population.Non-invasive indices of steatosis are more sensitive and those of fibrosis more specific than liver biopsy. NFS and HFS offer the highest diagnostic accuracy, with HFS having the highest negative predictive value.