Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.

Peripheral arterial disease in hemodialysis patients 10 years later.

BACKGROUND AND OBJECTIVE: Patients with chronic kidney disease (CKD) on hemodialysis present high cardiovascular comorbidity. Peripheral arterial disease (PAD) is associated with higher mortality and the interest in its early detection and treatment is increasing. The objective of this study is to determine the frequency and severity of symptomatic PAD, and to establish its relationship with mortality in HD patients that have received treated early and compare them with a cohort of our center already reported. MATERIAL AND METHODS: Retrospective study on a cohort of incident patients since 2014 and followed up until December 2019. Demographic data, cardiovascular risk, the presence of symptomatic PAD at baseline and during follow-up were collected. Trophic lesions were graded using the Rutherford scale. RESULTS: Initially, there were 91 patients and 7 cases that were not included in the study were lost to follow-up. Age 64 ±â€¯16 years, men 51.6% (47/91). The percentage of baseline PAD was 10.7% (9/84). During a median follow-up of 35 months (20-57), the diagnosis of PAD increased to 25% (21/84). Half of the patients with PAD 52.38% (11/21) obtained a score greater than 3 in the Rutherford Clinical Classification, which corresponds to severe disease. 13/21 patients required reoperation due to recurrence of symptoms (61.9% of cases with PAD). The development of PAD was significantly associated with: an elevated index of Charlson (3.9±2.1 vs. 7.7 ±â€¯3.5; P = 0.001),being male (19 vs. 2; P = 0.001), diabetic (no: 7; yes: 15; P = 0.001) and with a history of chronic ischemic heart disease (no: 13; yes: 8; P = 0.001), 38.1% (8/21) had ischemic heart disease in patients who developed PAD, while in the absence of PAD the presence of ischemic heart disease was 9.5% (6/63). Furthermore, more than half (66.7% [14/21]) of those who developed PAD were diabetic. Univariate analysis showed that age, C reactive protein, albumin, and number of surgical interventions, but not PAD, were associated with mortality. In the multivariate analysis adjusted for other factors, only C reactive protein was related to overall survival Exp ß: 2.17; P = 0.011; CI (1.19-3.97). Regarding cardiovascular mortality, in the multivariate Cox analysis, only PAD was related to mortality of cardiovascular origin Exp ß: 1.73; P = 0.006; CI (1.17-2.56). CONCLUSIONS: A significant number of patients on hemodialysis develop PAD requiring peripheral vascular surgery. PAD was not associated with overall mortality in our cohort, but it did show an association with cardiovascular mortality. Prospective studies with a larger sample size are necessary. New surgical treatments and Follow-up by vascular surgeons could improve the severity of PAD and the long-term prognosis.

Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD.

BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.

Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes.

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk.

Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception.

Purpose: Lack of diagnostic and prognostic biomarkers in hepatocellular carcinoma impedes stratifying patients based on their risk of developing cancer. The aim of this study was to evaluate phenotypic and genetic heterogeneity of circulating epithelial cells (CECs) based on asialoglycoprotein receptor 1 (ASGR1) and miR-122-5p expression as potential diagnostic and prognostic tools in patients with hepatocellular carcinoma (HCC) and liver cirrhosis (LC). Methods: Peripheral blood samples were extracted from LC and HCC patients at different disease stages. CECs were isolated using positive immunomagnetic selection. Genetic and phenotypic characterization was validated by double immunocytochemistry for cytokeratin (CK) and ASGR1 or by in situ hybridization with miR-122-5p and CECs were visualized by confocal microscopy. Results: The presence of CECs increased HCC risk by 2.58-fold, however, this was only significant for patients with previous LC (p = 0.028) and not for those without prior LC (p = 0.23). Furthermore, the number of CECs lacking ASGR1 expression correlated significantly with HCC incidence and absence of miR-122-5p expression (p = 0.014; r = 0.23). Finally, overall survival was significantly greater for patients at earlier cancer stages (p = 0.018), but this difference was only maintained in the group with the presence of CECs (p = 0.021) whereas progression-free survival was influenced by the absence of ASGR1 expression. Conclusion: Identification and characterization of CECs by ASGR1 and/or miR-122-5p expression may be used as a risk-stratification tool in LC patients, as it was shown to be an independent prognostic and risk-stratification marker in LC and early disease stage HCC patients.

Emerging pharmacological treatment options for MAFLD.

Metabolic dysfunction-associated fatty liver disease (MAFLD) prevalence and incidence is rising globally. It is associated with metabolic comorbidities, obesity, overweight, type 2 diabetes mellitus, and at least two metabolic risk factors, such as hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, and cardiovascular risk, increasing the risk of mortality. The excessive accumulation of fat comprises apoptosis, necrosis, inflammation and ballooning degeneration progressing to fibrosis, cirrhosis, and liver decompensations including hepatocellular carcinoma development. The limitation of approved drugs to prevent MAFLD progression is a paradigm. This review focuses on recent pathways and targets with evidence results in phase II/III clinical trials.

Extracellular Vesicles as Biomarkers in Liver Disease.

Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell-cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of 'liquid biopsies', since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.

Obesidad en la mortalidad de pacientes con insuficiencia cardiaca y fracción de eyección reducida / Obesity in the mortality of patients with heart failure and reduced ejection fraction

Introducción: La asociación entre obesidad y menor mortalidad en pacientes con insuficiencia cardiaca y fracción de eyección del ventrículo izquierdo es controversial. Objetivo: Evaluar la asociación entre obesidad y mortalidad en pacientes con insuficiencia cardiaca y fracción de eyección reducida. Métodos: Se realizó un estudio observacional de cohorte prospectivo en pacientes con insuficiencia cardiaca y fracción de eyección reducida en el período comprendido entre enero del 2010 y diciembre de 2020. La muestra quedó conformada por 173 pacientes. Se evaluó la supervivencia mediante el método de Kaplan-Meier, para estimar el efecto del pronóstico de la variable obesidad sobre la mortalidad. Se utilizó el modelo de regresión de Cox. Resultados: Se observó que los pacientes obesos al año de seguimiento tuvieron mejor supervivencia que los que presentaron normopeso (0,6 versus 0,8) a los cinco años presentaron similar supervivencia los tres subgrupos de índice masa corporal (0,6), la mayor mortalidad la presentaron los pacientes bajo peso. La curva de éstos últimos, se distancia del resto de las categorías de IMC, Log Rank p= 0,001. En el modelo de regresión de Cox la obesidad presentó un odd ration OR=´1,159 p=0,648 (intervalo de confianza de 0,615-2,181). Conclusiones: En los pacientes con insuficiencia cardiaca con fracción de eyección reducida no se observó el fenómeno de obesidad paradójica en relación a la mortalidad(AU)

Introduction: The association between obesity and lower mortality in patients with heart failure and left ventricular ejection fraction is controversial. Objective: To evaluate the association between obesity and mortality in patients with heart failure and reduced ejection fraction. Methods: An observational prospective cohort study was carried out, from January 2010 to December 2020, in patients with heart failure and reduced ejection fraction. The sample was made up of 173 patients. Survival was evaluated using Kaplan-Meier method to estimate the prognostic effect of the obesity variable on mortality. Cox regression model was used. Results: It was observed that obese patients at one year of follow-up had better survival than those with normal weight (0.6 versus 0.8). At five years, the three subgroups of body mass index (0.6) showed similar survival and the highest mortality was observed by low weight patients. The curve of the latter differs from the rest of the BMI categories, Log Rank p=0.001. In the Cox regression model, obesity had an odds ratio OR=´1.159 p=0.648 (confidence interval 0.615-2.181). Conclusions: In patients with heart failure with reduced ejection fraction, the phenomenon of paradoxical obesity was not observed in relation to mortality(AU)

Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.

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

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

Serum cytokines to predict systemic lupus erythematosus clinical and serological activity.

We aimed to explore the role of interleukin (IL)-6, interferon-gamma (IFNγ), IL-10, and tumor necrosis factor (TNF) as predictors of systemic lupus erythematosus (SLE) clinical and serological activity, and their correlation with the treatment received. We performed a retrospective analysis of 77 patients with SLE according to the 2012 Systemic Lupus International Collaborative Clinics (SLICC) criteria. The outcomes were serological activity (SA), active disease (AD), complete remission (CR), the low-disease activity state (LDAS), and immunosuppressive treatment. SA was present in 17.1%, AD in 17.3%, CR in 13%, and LDAS in 64.9% of patients. IL-6 values were higher in patients in SA, in AD, in those receiving steroids alone, and in patients without CR or LDAS (p < 0.05). IFNγ was associated with anti-double stranded DNA (dsDNA) antibodies positivity and immunosuppression, whereas IL-10 values were higher in patients with CR (p < 0.05). The IL6-IFN product was able to predict anti-double stranded DNA (anti-dsDNA) antibodies positivity (area under the receiver operating characteristic curve [AUC-ROC] = 0.705, 95% confidence interval [CI] 0.563-0.847), SA (AUC-ROC = 0.720, 95% CI 0.542-0.899), AD (AUC-ROC = 0.701, 95% CI 0.520-0.882), steroid treatment (AUC-ROC = 0.751, 95% CI 0.622-0.879), and the absence of LDAS (AUC-ROC = 0.700, 95% CI 0.558-0.834). The IL6-IFN/IL10 ratio predicted AD (AUC-ROC = 0.742, 955 CI 0.540-0.944), steroid treatment (AUC-ROC = 0.721, 95% CI 0.572-0.870), and the absence of LDAS (AUC-ROC = 0.694, 95% CI 0.536-0.853). In conclusion, IL-6, IL-10, and IFNγ might help to assess SLE serological and clinical activity. Their combination in the IL-6-IFN product and the IL-6xIFN to IL-10 ratio results in novel tools to determine and predict SA, AD, and LDAS. Prompt detection of SLE activity might allow a rapid intervention to avoid established or chronic damage.

Impact of cardiovascular risk factors in antiphospholipid syndrome: an observational study from the Spanish national registry.

OBJECTIVES: To determine the burden and impact of cardiovascular risk factors (CRF) in antiphospholipid syndrome (APS) patients. METHODS: Analysis of the patients diagnosed with APS identified in the Spanish Hospital Discharge Database between 2016 and 2017. We analysed the admissions due to arterial (ATE) and venous thromboembolic events (VTE) and evaluated the incidence and the attributed risk of each CRF. RESULTS: 5424 admissions in patients diagnosed with APS were identified. 64.6% were women and the mean age was 54.6. The mortality rate was 3.1%. Overall, 35.8% of patients had hypertension, 14% were diabetic, 21.7% hypercholesterolaemic, 9.9% obese and 26.7% smokers. Thromboembolic events (67.9% arterial and 32.1% venous) accounted for 11.9% of admissions and 7.1% of deaths. Male sex (OR 1.83, 95% CI 1.41-2.21), cholesterol (OR 1.25, 95% CI 1.01-1.54) and smoking (OR 1.49, 95% CI 1.22-1.81) were independently associated with thromboembolic events. Meanwhile, patients with ATE were older (57 vs. 54.1 years p=0.033), and presented more secondary APS (17.1% vs. 10.6%, p=0.034), hypertension (47.7% vs. 33.5%, p=0.001), diabetes (16.9% vs. 9.6%, p=0.017), cholesterol (34.3% vs. 17.8%, p<0.001) and smoking habit (41.2% vs. 24%, p<0.001) when compared with VTE. Risk factors independently associated with ATE events were male sex (OR=1.61, 95% CI=1.30-2.03), hypertension (OR=1.30, 95% CI=1.03-1.64), cholesterol (OR=1.51, 95% CI=1.18-1.94) and smoking habit (OR=1.84, 95% CI=1.47-2.32), while VTE events were determined by male sex (OR=2.06, 95% CI=1.53-2.77) and obesity (OR=1.61, CI=1.02-2.52). CONCLUSIONS: Thromboembolic events in APS were in part determined by a high prevalence of CRF. The identification of distinct profiles may allow us to undertake a more personalised approach to reduce thromboembolic events and to individualise anticoagulant and antiplatelet therapy.

Long non-coding RNA H19 as a biomarker for hepatocellular carcinoma.

BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer. METHODS: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+ CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort. RESULTS: EpCAM+ CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025). CONCLUSION: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.

Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation.

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.

Systematic review and meta-analysis: analysis of variables influencing the interpretation of clinical trial results in NAFLD.

BACKGROUND: NAFLD clinical trials have shown suboptimal results, particularly for liver fibrosis, despite the robust preclinical drug development. We aimed to assess the histological response after the experimental treatment versus placebo by carrying out a meta-analysis of NAFLD clinical trials. METHODS: After a systematic review of NAFLD clinical trials to May 2021, applying strict selection criteria, the following primary outcomes were observed: (a) NASH resolution, with no worsening of fibrosis when available; (b) fibrosis improvement ≥ 1 stage, with no worsening of NAS when available; (c) worsening of NAS; (d) worsening of liver fibrosis ≥ 1 stage, including the progression to cirrhosis on histopathology. Other histological, clinical, and biochemical outcomes were considered secondary endpoints. Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. RESULTS: Twenty-seven randomized clinical trials were included. The pooled efficacy for NASH resolution receiving experimental therapy was 19% (95%CI 15-23; I2 96.2%) compared with placebo 10% (95%CI 7-12; I2 85.8%) (OR 1.66 (95%CI 1.24-2.21); I2 57.8%), while it was 26% (95%CI 22-29); I2 90%)) versus 18% (95%CI 15-21; I2 59%)) for fibrosis improvement (OR 1.34 (95%CI 1.13-1.58); I2 25.4%). For these outcomes, the therapy showed higher efficacy in trials longer than 48 weeks, with < 60% of diabetic population, and when it targeted FXR, PPAR, and antidiabetic mechanisms, and with a NAS < 5 for NASH resolution. Also, NASH (OR 0.57 (95%CI 0.39-0.84); I2 67%) and fibrosis worsening (OR 0.65 (95%CI 0.46-0.92); I2 61.9%) were prevented with the therapy. CONCLUSION: This meta-analysis provides information about the efficacy of the therapy versus placebo by comparing different and combined trial outcomes such as NASH resolution, fibrosis improvement, and NAS and fibrosis worsening. Changes in the experimental design and selection criteria of the clinical trials might be suitable to increase the efficacy.

Trends in Hospital Admissions and Death Causes in Patients with Systemic Lupus Erythematosus: Spanish National Registry.

BACKGROUND: the admission and death causes of SLE patients might have changed over the last years. METHODS: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997-2000, 2001-2005, 2006-2010, and 2011-2015). RESULTS: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997-2000 to 31,977 in 2011-2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). CONCLUSIONS: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality.

Comorbilidades en pacientes con artropatía psoriásica / omorbidities in patients with psoriatic arthropathy

Introducción: En los últimos años, diversas investigaciones han demostrado que la presencia de comorbilidad agrava el pronóstico de los pacientes con artritis psoriásica. Objetivo: Determinar las comorbilidades en pacientes con diagnóstico de artritis psoriásica. Métodos: Se realizó un estudio descriptivo de corte transversal, en el servicio de Reumatología del Hospital Clínico Quirúrgico Hermanos Ameijeiras, que incluyó 111 pacientes con artritis psoriásica durante el periodo comprendido entre enero de 2016 a febrero de 2018. Resultados: El grupo de edad más representado fue el de 50 a 60 años, predominó el sexo femenino (63,1 por ciento) y el color de piel blanca (77,5 por ciento). El 50,5 por ciento presentó un tiempo de evolución de la artritis psoriásica mayor de 10 años. El 94,5 por ciento expresó el patrón articular periférico y la forma clínica articular más frecuente fue la oligoarticular (56,7 por ciento). Las comorbilidades identificadas con mayor frecuencia fueron la obesidad (80,18 por ciento), dislipidemia (68,46 por ciento), hipertensión arterial (HTA) (54,95 por ciento) y el hígado graso no alcohólico (53,15 por ciento). El 73,0 por ciento presentó tres o más comorbilidades. El sexo y el tiempo de evolución de la enfermedad y la actividad inflamatoria no mostraron una relación significativa. La actividad inflamatoria de la enfermedad se demostró en el 83,8 por ciento. Conclusiones: Se evidenció la presencia de comorbilidades asociadas en pacientes con APs, presentándose con mayor frecuencia, la obesidad, dislipidemia, HTA e hígado graso no alcohólico. Un porcentaje elevado de pacientes presentaron más de tres comorbilidades y no se demostró asociación significativa entre el número de comorbilidades y variables de la enfermedad(AU)

Introduction: In recent years, various investigations have shown that the presence of comorbidity worsens the prognosis of patients with psoriatic arthritis. Objective: To determine the comorbidities in patients diagnosed with psoriatic arthritis. Methods: A descriptive cross-sectional study was conducted in the Rheumatology service of the Hermanos Ameijeiras Clinical-Surgical Hospital, which included 111 patients with psoriatic arthritis from January 2016 to February 2018. Results: The age group most represented was that of 50 to 60 years, female sex (63.1`percent) and white skin color (77.5percent) patients predominated. 50.5percent had a psoriatic arthritis evolution time greater than 10 years. 94.5percent expressed the peripheral joint pattern and the most frequent joint clinical form was oligoarticular (56.7percent). The most frequently identified comorbidities were obesity (80.18percent), dyslipidemia (68.46percent), arterial hypertension (HBP) (54.95percent) and non-alcoholic fatty liver (53.15percent). 73.0percent had three or more comorbidities. The sex and the time of evolution of the disease and the inflammatory activity did not show significant relationship. The inflammatory activity of the disease was demonstrated in 83.8percent. Conclusions: The presence of associated comorbidities was evidenced in patients with PsA, with obesity, dyslipidemia, hypertension, and non-alcoholic fatty liver occurring more frequently. A high percentage of patients had more than three comorbidities and no significant association was demonstrated between the number of comorbidities and disease variables(AU)

Complicaciones de la nefrolitotomía percutánea como tratamiento de la litiasis renal coraliforme

RESUMEN Introducción: La nefrolitotomía percutánea es la primera opción terapéutica para la litiasis renal coraliforme. Objetivo: Caracterizar a los pacientes con complicaciones de la nefrolitotomía percutánea para el tratamiento de la litiasis renal coraliforme. Método: Se estudió una serie de 191 pacientes, operados mediante nefrolitotomía percutánea. Variables estudiadas: tipo de litiasis coraliforme, posición para la técnica, condición de libre de litiasis después de la operación, presencia de complicaciones, momento, tipo y grado según clasificación de Clavien-Dindo. Se hallaron frecuencias absolutas, relativas y se utilizó el test de ji cuadrado para determinar asociación entre variables. Resultados: El 86,9 % tenía menos de 60 años, 67,0 % eran masculinos, 61,7 % presentaba comorbilidades. La litiasis coraliforme era parcial o total (30,3 % y 46,5 %, respectivamente). En 60,2 % afectaba el riñón izquierdo; 58,1 % se operaron en supino y 70,2 % quedaron libre de litiasis con la nefrolitotomía percutánea monoterapéutica. Ocurrieron complicaciones en 19,9 %; 16,2 % fueron postoperatorias, 14,1 % infecciosas, 7,8 % Clavien-Dindo I y 5,2 % IIIb. El tipo de litiasis y la posición de la nefrolitotomía percutánea no se asociaron con las complicaciones (p> 0,05). El grado de la complicación no se relacionó con el tipo de litiasis (p> 0,05). Conclusiones: Las complicaciones postoperatorias más frecuentes son las relacionadas con la infección y el sangrado; predominan ligeramente en los pacientes con litiasis coraliformes parcial, total y en los operados en supino; el grado Clavien-Dindo de las complicaciones, es mayor en las litiasis coraliformes más complejas.

ABSTRACT Introduction: Percutaneous nephrolithotomy is the first therapeutic option for staghorn kidney stones. Objective: To characterize patients with complications of percutaneous nephrolithotomy for the treatment of staghorn renal lithiasis. Method: A series of 191 patients, operated by percutaneous nephrolithotomy, was studied. Variables studied: type of staghorn lithiasis, position for the technique, stone-free condition after the operation, presence of complications, time, type and grade according to the Clavien-Dindo classification. Absolute and relative frequencies were found and the chi-square test was used to determine the association between variables. Results: 86.9 % were less than 60 years old, 67,0 % were male, 61,7 % had comorbidities. The staghorn lithiasis was partial or total (30,3 % and 46,5 %, respectively). In 60,2 % it affected the left kidney; 58.1 % underwent supine surgery and 70,2 % were stone free with monotherapeutic percutaneous nephrolithotomy. Complications occurred in 19,9 %; 16,2 % were postoperative, 14,1 % infectious, 7,8 % Clavien-Dindo I, and 5,2 % IIIb. The type of lithiasis and the position of the percutaneous nephrolithotomy were not associated with complications (p> 0,05). The degree of complication was not related to the type of lithiasis (p> 0,05). Conclusions: The most frequent postoperative complications are those related to infection and bleeding; they slightly predominate in patients with partial and total staghorn stones and in those operated on in the supine position; the Clavien-Dindo grade of complications is higher in the more complex staghorn stones.

Acoplamiento molecular sobre la proteína dUTPasa de Trypanosoma cruzi para el descubrimiento de inhibidores en el tratamiento de la enfermedad de Chagas

Introducción: la enfermedad de Chagas es endémica de las zonas tropicales de América Latina y presenta una importante prevalencia, sin embargo, existen pocos tratamientos disponibles en el mercado por lo que la búsqueda de moléculas con potencial farmacológico que actúen en el parásito Trypanosoma cruzi, causante de la enfermedad, es necesaria considerando las graves complicaciones. Objetivo: evaluar las potenciales proteínas blanco, disponibles en la base de datos de PDB considerando como parámetro inicial, la similitud con proteínas humanas e identificar potenciales inhibidores del blanco elegido por medio de acoplamiento molecular. Metodología: se realizó una evaluación de las proteínas del parásito por medio de alineamiento de secuencias y posteriormente un cribado virtual por acoplamiento molecular con bases de datos y recursos informáticos disponibles en el Centro de Cómputo Avanzado de la Universidad de Texas (TACC), y se evaluaron los mejores resultados en función de afinidad, farmacocinética y toxicidad. Resultados: el blanco molecular elegido fue la dUTPasa. Posterior al cribado virtual se seleccionaron 12 moléculas que presentan potencial inhibidor de estas, la 4-{3-[3-(trifluorometil)fenil]isoxazol-5-il}pirimidin-2-amina es una de las moléculas con mejor perfil para convertirse en candidato en el tratamiento de la enfermedad de Chagas.

SUMMARY Introduction: Chagas disease is endemic to the tropical areas of Latin America and has an important prevalence, however, there are few treatments available in the market, so the search for molecules with pharmacological potential that can act in the same way as the disease, it is necessary considering the serious complications. Aim: to evaluate the possible target proteins available in the PDB database, considering the similarity with human proteins as an initial parameter and identify potential inhibitors of the chosen target using molecular docking. Methodology: an evaluation of the parasite proteins was carried out by means of sequence alignment and subsequently a virtual molecular coupling screening was performed with databases and computer resources available at Centro de Cómputo Avanzado de Universidad de Texas (TACC), and the best results were evaluated based on affinity, pharmacokinetics, and toxicity. Results: the molecular target chosen was the dUTPase. After virtual screening, 12 moles showing inhibitory potential were selected of these, 4- {3-[3- (trifluoromethyl) phenyl] isoxazole-5-yl} pyrimidine-2-amine is one of the molecules with the best profile to become a candidate in the treatment of Chagas disease.

Introdução: a doença de Chagas é endêmica das áreas tropicais da América Latina e possui importante prevalência, porém, poucos são os tratamentos disponíveis no mercado, por isso a busca por moléculas com potencial farmacológico que possam atuar da mesma forma que a doença, é necessário considerando as complicações graves. Objetivo: avaliar as possíveis proteínas-alvo disponíveis na base de dados do PDB, considerando a similaridade com proteínas humanas como parâmetro inicial e identificação de potenciais inibidores do alvo escolhido por meio de acoplamento molecular. Metodologia: uma avaliação das proteínas do parasita foi realizada por meio de alinhamento de sequências e posteriormente foi realizada uma triagem de acoplamento molecular virtual com bancos de dados e recursos computacionais disponíveis no Centro de Cómputo Avanzado de Universidad de Texas (TACC), e os melhores resultados foram avaliados com base na afinidade, farmacocinética e toxicidade. Resultados: o alvo molecular escolhido foi a dUTPase. Após a triagem virtual, 12 moles mostrando potencial inibitório foram selecionados destes, 4- {3- [3- (trifluorometil) fenil] isoxazol-5-il} pirimidina-2-amina é uma das moléculas com o melhor perfil para se tornar um candidato no tratamento da doença de Chagas.