Isoliquiritigenin in combination with visceral adipose tissue and related markers as a predictive tool for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world. New non-invasive diagnostic tools are needed to promptly treat this disease and avoid its complications. This study aimed to find key metabolites and related variables that could be used to predict and diagnose NAFLD. Ninety-eight subjects with NAFLD and 45 controls from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. NAFLD was diagnosed and graded by ultrasound and classified into two groups: 0 (controls) and ≥ 1 (NAFLD). Hepatic status was additionally assessed through magnetic resonance imaging (MRI), elastography, and determination of transaminases. Anthropometry, body composition (DXA), biochemical parameters, and lifestyle factors were evaluated as well. Non-targeted metabolomics of serum was performed with high-performance liquid chromatography coupled to time-of-flight mass spectrometry (HPLC-TOF-MS). Isoliquiritigenin (ISO) had the strongest association with NAFLD out of the determinant metabolites. Individuals with higher concentrations of ISO had healthier metabolic and hepatic status and were less likely to have NAFLD (OR 0.13). Receiver operating characteristic (ROC) curves demonstrated the predictive power of ISO in panel combination with other NAFLD and IR-related variables, such as visceral adipose tissue (VAT) (AUROC 0.972), adiponectin (AUROC 0.917), plasmatic glucose (AUROC 0.817), and CK18-M30 (AUROC 0.810). Individuals with lower levels of ISO have from 71 to 82% more risk of presenting NAFLD compared to individuals with higher levels. Metabolites such as ISO, in combination with visceral adipose tissue, IR, and related markers, constitute a potential non-invasive tool to predict and diagnose NAFLD.

Profilaxis primaria estándar versus prolongada de la infección por citomegalovirus en el trasplante de órgano sólido / Standard versus extended primary cytomegalovirus prophylaxis in solid organ transplantation

Antecedentes y objetivo:Se han comparado la eficacia y seguridad de la profilaxis primaria estándar o prolongada de la infección por citomegalovirus (CMV) en el trasplante de órgano sólido.Materiales y métodos:Estudio retrospectivo de los receptores CMV seronegativos de donante seropositivo (D+/R−) que recibieron profilaxis frente a CMV tras un trasplante de órgano sólido (2007-2017). Se comparó la frecuencia de infección por CMV en los 2 primeros años postrasplante en los receptores que recibieron profilaxis durante más o menos de 100 días. Se evaluó asimismo la mielotoxicidad durante la profilaxis.Resultados:Se analizaron 66 pacientes. De ellos el 43,9% (n=29) presentaron infección por CMV. El 68,2% (n=45) recibieron profilaxis prolongada, sin asociarse su uso con una menor tasa de infección (42,2 vs. 47,6%, p=0,44) ni de enfermedad posprofilaxis (15,6 vs. 19%, p=0,72). La profilaxis prolongada se asoció con una mayor frecuencia de mielotoxicidad (68,9 vs. 42,9%, p<0,05).Conclusiones:La prolongación de la profilaxis primaria más de 100 días no aumenta su efectividad pero sí la toxicidad hematológica. (AU)

Background and objective:We compared the efficacy and safety of standard vs. extended primary cytomegalovirus (CMV) prophylaxis in solid organ transplantation.Materials and methods:Retrospective cohort study of CMV seronegative recipients who received CMV prophylaxis after solid organ transplantation from seropositive donor (D+/R−) (2007–2017). CMV infection in the first two years after transplantation in recipients with prophylaxis longer or shorter than 100 days were compared.Results:CMV infection occurred in 29 of 66 patients (43.9%) with prophylaxis. Forty-five patients (68.2%) received extended prophylaxis. CMV infection and disease rates were not different between patients with extended and standard prophylaxis. However, extended prophylaxis was associated with a higher rate of myelotoxicity (68.9% vs. 42.9%, p<0.05).Conclusions:Extending primary CMV prophylaxis over 100 days did not prevent late-onset infection but it was associated with hematological toxicity. (AU)

Transient elastography and serum markers of liver fibrosis associate with epicardial adipose tissue and coronary artery calcium in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease morbimortality. However, it is not clear if NAFLD staging may help identify early or subclinical markers of cardiovascular disease. We aimed to evaluate the association of liver stiffness and serum markers of liver fibrosis with epicardial adipose tissue (EAT) and coronary artery calcium (CAC) in an observational cross-sectional study of 49 NAFLD patients that were seen at Clínica Universidad de Navarra (Spain) between 2009 and 2019. Liver elastography and non-invasive fibrosis markers were used to non-invasively measure fibrosis. EAT and CAC, measured through visual assessment, were determined by computed tomography. Liver stiffness showed a direct association with EAT (r = 0.283, p-value = 0.049) and CAC (r = 0.337, p-value = 0.018). NAFLD fibrosis score was associated with EAT (r = 0.329, p-value = 0.021) and CAC (r = 0.387, p-value = 0.006). The association of liver stiffness with CAC remained significant after adjusting for metabolic syndrome features (including carbohydrate intolerance/diabetes, hypertension, dyslipidaemia, visceral adipose tissue, and obesity). The evaluation of NAFLD severity through liver elastography or non-invasive liver fibrosis biomarkers may contribute to guide risk factor modification to reduce cardiovascular risk in asymptomatic patients. Inversely, subclinical cardiovascular disease assessment, through Visual Scale for CAC scoring, may be a simple and effective measure for patients with potential liver fibrosis, independently of the existence of other cardiovascular risk factors.

A nutrigenetic tool for precision dietary management of non-alcoholic fatty liver disease deeming insulin resistance markers.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) development is linked to insulin resistance and influenced by environmental factors, but it also underlined a genetic predisposition. The aim of this research was to build a predictive model based on genetic and hepatic health information, deeming insulin resistance markers in order to personalize dietary treatment in overweight/obese subjects with NAFLD. METHODS: A 6-month nutritional intervention was conducted in 86 overweight/obese volunteers with NAFLD randomly assigned to 2 energy-restricted diets: the American Heart Association (AHA) diet and the Fatty Liver in Obesity (FLiO) diet. Individuals were genotyped using a predesigned panel of 95 genetic variants. A Genetic Risk Score (GRS) for each diet was computed using statistically relevant SNPs for the change on Fatty Liver Index (FLI) after 6-months of nutritional intervention. Body composition, liver injury and insulin resistance markers, as well as physical activity and dietary intake were also assessed. RESULTS: Under energy restriction, both the AHA and FLiO diets induced similar significant improvements on body composition, insulin resistance markers, hepatic health and dietary and lifestyle outcomes. The calculated score included in the linear mixed regression model was able to predict the change of FLI adjusted by diet, age and sex. This model allowed to personalize the most suitable diet for 72% of the volunteers. Similar models were also able to predict the changes on Triglycerides and Glucose (TyG) Index and retinol-binding protein 4 (RBP4) levels depending on diet. CONCLUSIONS: Models integrating genetic screening and insulin resistance markers can be useful for the personalization of NAFLD weight loss treatments.

[Standard versus extended primary cytomegalovirus prophylaxis in solid organ transplantation]. / Profilaxis primaria estándar versus prolongada de la infección por citomegalovirus en el trasplante de órgano sólido.

BACKGROUND AND OBJECTIVE: We compared the efficacy and safety of standard vs. extended primary cytomegalovirus (CMV) prophylaxis in solid organ transplantation. MATERIALS AND METHODS: Retrospective cohort study of CMV seronegative recipients who received CMV prophylaxis after solid organ transplantation from seropositive donor (D+/R-) (2007-2017). CMV infection in the first two years after transplantation in recipients with prophylaxis longer or shorter than 100 days were compared. RESULTS: CMV infection occurred in 29 of 66 patients (43.9%) with prophylaxis. Forty-five patients (68.2%) received extended prophylaxis. CMV infection and disease rates were not different between patients with extended and standard prophylaxis. However, extended prophylaxis was associated with a higher rate of myelotoxicity (68.9% vs. 42.9%, p<0.05). CONCLUSIONS: Extending primary CMV prophylaxis over 100 days did not prevent late-onset infection but it was associated with hematological toxicity.

Effects of two personalized dietary strategies during a 2-year intervention in subjects with nonalcoholic fatty liver disease: A randomized trial.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) management is focused on lifestyle modifications, but long-term maintenance is a challenge for many individuals. This study aimed to evaluate the long-term effects of two personalized energy-restricted dietary strategies on weight loss, metabolic and hepatic outcomes in overweight/obese subjects with NAFLD. METHODS: Ninety-eight subjects from the Fatty Liver in Obesity (FLiO) study (NCT03183193) were randomly assigned to the American Heart Association (AHA) or the FLiO dietary group in a 2-year controlled trial. Anthropometry, body composition (DXA), biochemical parameters and hepatic status (ultrasonography, Magnetic Resonance Imaging, and elastography) were assessed at baseline, 6, 12 and 24 months. RESULTS: Both the AHA and FLiO diets significantly reduced body weight at 6 (-9.7% vs -10.1%), 12 (-6.7% vs -9.6%), and 24 months (-4.8% vs -7.6%) with significant improvements in body composition, biochemical and liver determinations throughout the intervention. At the end of the follow-up, the FLiO group showed a greater decrease in ALT, liver stiffness and Fatty Liver Index, among others, compared to AHA group, although these differences were attenuated when the analyses were adjusted by weight loss percentage. The FLiO group also showed a greater increase in adiponectin compared to AHA group. CONCLUSIONS: The AHA and FLiO diets were able to improve body weight and body composition, as well as metabolic and hepatic status of participants with overweight/obesity and NAFLD within a 2-year follow-up. These findings show that both strategies are suitable alternatives for NAFLD management. However, the FLiO strategy may provide more persistent benefits in metabolic and hepatic parameters.

Flipped classroom improves results in pathophysiology learning: results of a nonrandomized controlled study.

The flipped classroom has become increasingly popular in health professions education. The aim of this study was to analyze its effect on learning in a pathophysiology course. Flipped classroom was introduced to teach respiratory pathophysiology in 2018. We compared the exam results in respiratory pathophysiology in 2017 and 2018 and the exam results in blood pathophysiology from both years (taught by the same teacher, in a traditional way). Groups were compared with Student's t test. Students answered a survey after finishing the term. Two hundred and one students were examined in 2018 (and 229 in 2017). Gender distribution and the qualifications obtained in general pathology (in the previous year) were comparable in both years. Results in respiratory pathophysiology were significantly better in 2018 than in 2017 (mean: 48 vs. 42 out of 100; P = 0.004), but the results in blood pathophysiology remained similar. The improvement was significant only in students who scored below the median (mean: 40 vs. 33; P = 0.009) and was more evident in male than in female students (mean: 52 vs. 44; P = 0.01) and in those who did not have an academic delay (mean 51 vs. 44; P = 0.002). Most students considered that flipped classroom was more attractive and helped them to learn more and with less effort. Flipped classroom increased medical students' knowledge acquisitions in pathophysiology. It was more beneficial to male students and those with lower qualifications with no academic delay.

Tolerance Biomarkers in Liver Transplantation: Independent External Validation of the Predictive Strength of SENP6 and FEM1C Gene Expression.

BACKGROUND: Numerous studies have emphasized the genetic and phenotypic profiles of tolerant transplant patients. Moreover, different groups have defined several biomarkers, trying to distinguish patients who are going to be tolerant from those who are going to reject. However, most of these biomarkers have not been validated by other groups or even established for clinical practice. METHODS: We reanalyzed and stratified the predictive capacity of 20 previously described biomarkers for liver transplantation tolerance in a cohort of 17 liver transplant patients subjected to an independent, nonrandomized, prospective study of immunosuppression drug withdrawal. RESULTS: Only 4 of the 20 studied biomarkers (expression of SENP6, FEM1C, miR31, and miR95) showed a strong predictive capacity in the present study. miR31 and FEM1C presented an area under the ROC curve of 96.7%, followed by SENP1 with 93.3%. Finally, miR95 had an area under the ROC curve value <86.7%. CONCLUSIONS: Even though this independent analysis seems to confirm the predictive strength of SENP6 and FEM1C in liver transplantation tolerance, there are also risks in establishing biomarkers for clinical phenotypes without an understanding of how they are biologically relevant. Future collaborations between groups should be promoted so that the most promising biomarkers can be validated and implemented in daily clinical practice.

Extracellular adenosine reversibly inhibits the activation of human regulatory T cells and negatively influences the achievement of the operational tolerance in liver transplantation.

The artificial induction of tolerance in transplantation is gaining strength. In mice, a differential role of extracellular adenosine (eADO) for regulatory and effector T cells (Tregs and Teffs, respectively) has been proposed: inhibiting Teffs and inducing Tregs. The aim of this study was to analyze the action of extracellular nucleotides in human T cells and, moreover, to examine the influence of CD39 and CD73 ectonucleotidases and subsequent adenosine signaling through adenosine 2 receptor (A2 R) in the induction of clinical tolerance after liver transplant. The action of extracellular nucleotides in human T cells was analyzed by in vitro experiments with isolated T cells. Additionally, 17 liver transplant patients were enrolled in an immunosuppression withdrawal trial, and the differences in the CD39-CD73-A2 R axis were compared between tolerant and nontolerant patients. In contrast to the mice, the activation of human Tregs was inhibited similarly to Teffs in the presence of eADO. Moreover, the expression of the enzyme responsible for the degradation of ADO, adenosine deaminase, was higher in tolerant patients with respect to the nontolerant group along the immunosuppression withdrawal. Our data support the idea that eADO signaling and its degradation may play a role in the complex system of regulation of liver transplant tolerance.

Real-World Multicenter Experience of Immunosuppression Minimization Among 661 Liver Transplant Recipients.

BACKGROUND Long-term morbidity and mortality in liver transplant recipients is frequently secondary to immunosuppression toxicity. However, data are scarce regarding immunosuppression minimization in clinical practice. MATERIAL AND METHODS In this cross-sectional, multicenter study, we reviewed the indications of immunosuppression minimization (defined as tacrolimus levels below 5 ng/mL or cyclosporine levels below 50 ng/mL) among 661 liver transplant recipients, as well as associated factors and the effect on renal function. RESULTS Fifty-three percent of the patients received minimized immunosuppression. The median time from transplantation to minimization was 32 months. The most frequent indications were renal insufficiency (49%), cardiovascular risk (19%), de novo malignancy (8%), and cardiovascular disease (7%). The factors associated with minimization were older age at transplantation, longer post-transplant follow-up, pre-transplant diabetes mellitus and renal dysfunction, and the hospital where the patients were being followed. The patients who were minimized because of renal insufficiency had a significant improvement in renal function (decrease of the median serum creatinine level, from 1.50 to 1.34 mg/dL; P=0.004). Renal function significantly improved in patients minimized for other indications, too. In the long term, glomerular filtration rate significantly decreased in non-minimized patients and remained stable in minimized patients. CONCLUSIONS Immunosuppression minimization is frequently undertaken in long-term liver transplant recipients, mainly for renal insufficiency. Substantial variability exists regarding the use of IS minimization among centers.

Prognostic factors and prevention of radioembolization-induced liver disease.

UNLABELLED: Radioembolization (RE)-induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low-dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P<0.0001). Treatment efficacy was not jeopardized since 3-month disease control rates were virtually identical in both groups (66.7% and 67.2%, P=0.93). Exposure to chemotherapy in the 2-month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume<1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. CONCLUSION: REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD.

Impact of non-neurological complications in severe traumatic brain injury outcome.

INTRODUCTION: Non-neurological complications in patients with severe traumatic brain injury (TBI) are frequent, worsening the prognosis, but the pathophysiology of systemic complications after TBI is unclear. The purpose of this study was to analyze non-neurological complications in patients with severe TBI admitted to the ICU, the impact of these complications on mortality, and their possible correlation with TBI severity. METHODS: An observational retrospective cohort study was conducted in one multidisciplinary ICU of a university hospital (35 beds); 224 consecutive adult patients with severe TBI (initial Glasgow Coma Scale (GCS) < 9) admitted to the ICU were included. Neurological and non-neurological variables were recorded. RESULTS: Sepsis occurred in 75% of patients, respiratory infections in 68%, hypotension in 44%, severe respiratory failure (arterial oxygen pressure/oxygen inspired fraction ratio (PaO2/FiO2) < 200) in 41% and acute kidney injury (AKI) in 8%. The multivariate analysis showed that Glasgow Outcome Score (GOS) at one year was independently associated with age, initial GCS 3 to 5, worst Traumatic Coma Data Bank (TCDB) first computed tomography (CT) scan and the presence of intracranial hypertension but not AKI. Hospital mortality was independently associated with initial GSC 3 to 5, worst TCDB first CT scan, the presence of intracranial hypertension and AKI. The presence of AKI regardless of GCS multiplied risk of death 6.17 times (95% confidence interval (CI): 1.37 to 27.78) (P < 0.02), while ICU hypotension increased the risk of death in patients with initial scores of 3 to 5 on the GCS 4.28 times (95% CI: 1.22 to 15.07) (P < 0.05). CONCLUSIONS: Low initial GCS, worst first CT scan, intracranial hypertension and AKI determined hospital mortality in severe TBI patients. Besides the direct effect of low GCS on mortality, this neurological condition also is associated with ICU hypotension which increases hospital mortality among patients with severe TBI. These findings add to previous studies that showed that non-neurological complications increase the length of stay and morbidity in the ICU but do not increase mortality, with the exception of AKI and hypotension in low GCS (3 to 5).

Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system recommends first-line therapy for each tumor stage. We evaluated the effect of compliance with BCLC treatment allocation on the prognosis of patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 359 consecutive, newly diagnosed HCC patients treated in our Liver Unit during a 14-year period. For each stage, survival was compared according to whether treatment matched the BCLC recommendation. We also compared the survival of patients in the same BCLC stage who received different treatments, and patients in different BCLC stages receiving the same treatment. RESULTS: BCLC-A patients treated with radical therapies (66%) survived longer (117 vs. 20 months; p < 0.001) than patients (33%) who received locoregional or systemic therapies. Survival of BCLC-B patients treated with locoregional treatments (57%) was shorter (24 vs. 71 months; p < 0.001) than that of patients receiving radical therapies (32%). BCLC-C patients treated with systemic therapy or supportive care survived shorter (6 vs. 11 months; p = 0.003) than those receiving locoregional therapies (39%). Survival of BCLC-D patients receiving systemic therapies or supportive care was significantly lower than that of patients treated by liver transplantation (5 vs. 137 months; p < 0.001). CONCLUSIONS: In addition to BCLC stage, actual treatment determines survival in patients with HCC.

A prospective randomized open study in liver transplant recipients: daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids.

This open-label, randomized study compared the efficacy of a regimen of corticosteroids and tacrolimus (standard therapy group, n = 79) with a regimen of daclizumab induction therapy in combination with mycophenolate mofetil and tacrolimus (modified therapy group, n = 78) in primary liver transplant recipients. The primary endpoint was biopsy-proven acute rejection (BPAR) at 24 weeks. Secondary endpoints included time to rejection and patient and graft survival. The incidence of BPAR was significantly reduced in the modified therapy group compared to the standard therapy group (11.5% versus 26.6%, respectively, P = 0.017). The time to rejection was significantly shorter in the standard therapy group compared with the modified therapy group (P = 0.044). There was no significant difference between groups in patient or graft survival. Hepatitis C virus-positive patients exhibited no differences from hepatitis C virus-negative patients with respect to the incidence of BPAR. A steroid-sparing regimen of daclizumab, mycophenolate mofetil, and tacrolimus was effective and well tolerated in the prevention of BPAR in adult liver transplant recipients in comparison with a standard regimen of tacrolimus and steroids.

A retrospective comparative analysis of the effect of Y90-radioembolization on the survival of patients with unresectable hepatocellular carcinoma.

BACKGROUND/AIMS: to determine the impact of Y90-Radioembolization on survival when used as a first-line treatment for unresectable HCC. METHODOLOGY: We retrospectively analyzed 35 consecutive patients with unresectable HCC who received 90Y-labeled resin microspheres as first-line treatment and compared their overall survival from the time of diagnosis with that of a cohort of 43 patients with unresectable HCC that were potential candidates for Y90-Radioembolization but had received conventional care due to unavailability or technical contraindications. Patients in both groups had a similar liver function and tumor burden. RESULTS: Median survival from diagnosis was significantly higher in the radioembolization group compared with controls (16 vs. 8 months; p < 0.05), even after adjusting for cirrhosis, multinodular disease, bilobar involvement or vascular invasion. In a multivariate analysis, treatment by radioembolization was the only prognostic factor independently associated with improved survival. In an intention-to-treat analysis, patients evaluated for radioembolization (finally treated or not) survived longer than controls (13 vs. 10 months; p < 0.05). CONCLUSION: Y90-Radioembolization is likely to improve survival among patients with unresectable HCC compared with conventional treatment. Further prospective studies are needed to evaluate the potential of this new treatment modality in unresectable HCC.

Efficacy and toxicity of intra-arterial cisplatin and etoposide for advanced hepatocellular carcinoma.

OBJECTIVE: To analyze the results of an intra-arterially delivered combination chemotherapy in a group of patients with regionally advanced hepatocellular carcinoma (HCC). METHODS: 26 patients with proven locally advanced HCC treated with hepatic artery infusion of cisplatin (20 mg/m(2), days 1-5) and etoposide (75 mg/m(2), days 1-5) every 4 weeks were retrospectively studied. RESULTS: In an intention-to-treat analysis, overall and complete response rates were 38 and 7%, respectively. Median duration of response was 5 months. Median survival time was 10 months and survival rates at 6, 12 and 24 months were 53, 33 and 24%, respectively. Survival was significantly longer for responders than for non-responders (median: 13 and 3 months, respectively). There were 4 treatment-related deaths among cirrhotics. CONCLUSIONS: Intra-arterial chemotherapy using cisplatin and etoposide seems to have some anti-tumor effect against advanced HCC, although a high rate of life- threatening complications precludes the indication of this regimen at least for patients with non-compensated cirrhosis.