Drug-induced Liver Injury in Latin America: 10-year Experience of the Latin American DILI (LATINDILI) Network.

BACKGROUND & AIMS: Latin America is a region of great interest for studying the clinical presentation of idiosyncratic drug-induced liver injury (DILI). A comprehensive analysis of patients enrolled into the LATINDILI Network over a decade is presented. METHODS: Demographics, clinical presentation, histological findings and outcome of prospectively recruited DILI cases in the LATINDILI Network were analyzed. Suspected culprit drugs were classified according to the Anatomical Therapeutic Chemical classification. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) scale. RESULTS: Overall, 468 idiosyncratic DILI cases were analyzed (62% women; mean age, 49 years). Hepatocellular injury predominated (62%); jaundice was present in 60% of patients, and 42% were hospitalized. Of the cases, 4.1% had a fatal outcome, and 24 patients (12%) developed chronic DILI. The most common drug classes were systemic anti-infectives (31%), musculoskeletal agents (12%), antineoplastic and immunomodulating agents (11%), and herbal and dietary supplements (9%). Notably, none of the patients with DILI due to antibacterials or immunosuppressants had a fatal outcome. In fact, Hy's law showed to have drug-specific predictive value, with anti-tuberculosis drugs, nimesulide, and herbal and dietary supplements associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin, and diclofenac, which fulfilled Hy's law, did not have a fatal outcome. CONCLUSION: Features of DILI in Latin America are comparable to other prospective registries. However, the pattern of drugs responsible for DILI differs. An increasing incidence of herbal and dietary supplements, with high mortality rate, and likewise, nimesulide and nitrofurantoin, was noted. Thus, public health policies should raise awareness of the potential adverse effects of these compounds.

Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomized clinical trial.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53 years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. METHODS: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. RESULTS: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p = .001). DILI cases with autoimmune features had significantly longer time to onset (p < .001) and resolution time (p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. CONCLUSIONS: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries.

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96-760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57-141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

BACKGROUND: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. OBJECTIVES: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. METHODS: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. RESULTS: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). CONCLUSIONS: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Profile of herbal and dietary supplements induced liver injury in Latin America: A systematic review of published reports.

Hepatotoxicity related to HDS is a growing global health issue. We have undertaken a systematic review of published case reports and case series from LA from 1976 to 2020 to describe the clinical features of HDS related hepatotoxicity in this region. We search in PubMed, Web of Science, Scopus and specific LA databases according to PRISMA guidelines. Only HILI cases published in LA that met criteria for DILI definition were included. Duplicate records or reports that lacked relevant data that precluded establishing causality were excluded. Finally, 17 records (23 cases) were included in this review. Centella asiatica, Carthamus tinctorius, and Herbalife® were the most reported HDS culprit products, the main reason for HDS consumption was weight loss. The clinical characteristics of HDS hepatotoxicity in our study were compared to those of other studies in the USA, Europe and China showing a similar signature with predominance of young females, hepatocellular damage, a high rate of ALF and mortality, more frequent inadvertent re-challenge and chronic damage. This study underscores the challenge in causality assessment when multi-ingredients HDS are taken and the need for consistent publication practice when reporting hepatotoxicity cases due to HDS, to foster HDS liver safety particularly in LA.

Budd-Chiari syndrome due to hepatic venous web outflow obstruction: percutaneous treatment with balloon angioplasty.

The Budd-Chiari syndrome is a rare hepatic venous disease. It is more prevalent in young adults and may present in acute, subacute, or chronic forms, causing portal hypertension. Traditional treatment consists of thrombolysis techniques and transjugular intrahepatic portosystemic shunt, as a bridge to liver transplantation. Recently, use of balloon or stent angioplasty techniques has been reported for treatment of this condition. In this article, we report and discuss a case of BCS by membranous obstruction in the hepatic vein outflow tract, with middle hepatic vein thrombosis, in a 24-year-old patient. The treatment chosen and employed was transjugular balloon angioplasty, which achieved satisfactory results and good clinical evolution.

Validation of Clinical Indicators of the Nursing Diagnosis of Ineffective Protection in Adolescents With Cancer.

PURPOSE: To validate the clinical indicators of the nursing diagnosis of Ineffective protection in adolescents with cancer based on diagnostic accuracy measurements. DESIGN AND METHODS: Measurements of sensitivity and specificity for the indicators were calculated using latent class analysis with random effects in a sample of 127 adolescents between 10 and 19 years of age. RESULTS: The prevalence of diagnosis was estimated at 93.7%. The indicators deficient immunity and weakness showed higher sensitivity values, whereas opportunistic infections, recurrent infections, insomnia, mucosal lesions, and coughing showed high specificity. CONCLUSIONS: Seven indicators were clinically validated. PRACTICE IMPLICATIONS: The validation of clinical indicators provides nurses with the knowledge of useful signs and symptoms to identify early spectra of a nursing diagnosis or confirm their presence in a specific population. In clinical practice, this knowledge contributes to an accurate diagnostic inference and the planning of nursing interventions directed to the idiosyncrasies of individuals.

Nuclear subcompartments: an overview.

The advance in biochemical and microscopy techniques has revealed the complexity and intricate nucleoplasm structure. Several subcompartments were identified in nucleus and the importance of these subcompartments in processes crucial for normal nuclear activity has been demonstrated. In this mini-review, we will give an overview about the composition, function, and importance of the major nuclear subcompartments. Also, we will show the impact that perturbing these structures can cause in normal nuclear activity, and how these can contribute to the development of some human diseases.

Catalase expression impairs oxidative stress-mediated signalling in Trypanosoma cruzi.

Trypanosoma cruzi is exposed to oxidative stresses during its life cycle, and amongst the strategies employed by this parasite to deal with these situations sits a peculiar trypanothione-dependent antioxidant system. Remarkably, T. cruzi's antioxidant repertoire does not include catalase. In an attempt to shed light on what are the reasons by which this parasite lacks this enzyme, a T. cruzi cell line stably expressing catalase showed an increased resistance to hydrogen peroxide (H2O2) when compared with wild-type cells. Interestingly, preconditioning carried out with low concentrations of H2O2 led untransfected parasites to be as much resistant to this oxidant as cells expressing catalase, but did not induce the same level of increased resistance in the latter ones. Also, presence of catalase decreased trypanothione reductase and increased superoxide dismutase levels in T. cruzi, resulting in higher levels of residual H2O2 after challenge with this oxidant. Although expression of catalase contributed to elevated proliferation rates of T. cruzi in Rhodnius prolixus, it failed to induce a significant increase of parasite virulence in mice. Altogether, these results indicate that the absence of a gene encoding catalase in T. cruzi has played an important role in allowing this parasite to develop a shrill capacity to sense and overcome oxidative stress.

Chromatin Proteomics Reveals Variable Histone Modifications during the Life Cycle of Trypanosoma cruzi.

Histones are well-conserved proteins that form the basic structure of chromatin in eukaryotes and undergo several post-translational modifications, which are important for the control of transcription, replication, DNA damage repair, and chromosome condensation. In early branched organisms, histones are less conserved and appear to contain alternative sites for modifications, which could reveal evolutionary unique functions of histone modifications in gene expression and other chromatin-based processes. Here, by using high-resolution mass spectrometry, we identified and quantified histone post-translational modifications in two life cycle stages of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. We detected 44 new modifications, namely: 18 acetylations, seven monomethylations, seven dimethylations, seven trimethylations, and four phosphorylations. We found that replicative (epimastigote stage) contains more histone modifications than nonreplicative and infective parasites (trypomastigote stage). Acetylations of lysines at the C-terminus of histone H2A and methylations of lysine 23 of histone H3 were found to be enriched in trypomastigotes. In contrast, phosphorylation in serine 23 of H2B and methylations of lysine 76 of histone H3 predominates in proliferative states. The presence of one or two methylations in the lysine 76 was found in cells undergoing mitosis and cytokinesis, typical of proliferating parasites. Our findings provide new insights into the role of histone modifications related to the control of gene expression and cell-cycle regulation in an early divergent organism.

LmHus1 is required for the DNA damage response in Leishmania major and forms a complex with an unusual Rad9 homologue.

Genotoxic stress activates checkpoint-signalling pathways leading to cell cycle arrest and DNA repair. In many eukaryotes, the Rad9-Hus1-Rad1 (9-1-1) checkpoint complex participates in the early steps of the DNA damage response to replicative stress and is a pivotal contributor to genome homeostasis. The remarkable genome plasticity of the protozoan Leishmania hints at a peculiar DNA metabolism in these ancient eukaryotes. Therefore, we set out to investigate the existence of homologues of the 9-1-1 components in Leishmania major and found that LmHus1 and LmRad9 are phylogenetically related to the 9-1-1 complex subunits from other eukaryotes. Altered levels of LmHus1 and LmRad9 affected the parasite ability to manage genotoxic stress and LmHus1-defficent cells were defective in controlling cell cycle progression in response to genotoxic stress. Upon DNA damage, LmHus1 was recruited to the chromatin and colocalized with the single-stranded DNA-binding protein LmRpa1. Also, LmHus1 interacted with LmRad9 to form a DNA damage responsive complex in vivo. Altogether, our data strongly indicate the participation of LmHus1, LmRad9 and LmRpa1 in the L. major DNA damage response and suggest their involvement in genome maintenance mechanisms.

The natural absence of RPA1N domain did not impair Leishmania amazonensis RPA-1 participation in DNA damage response and telomere protection.

We have previously shown that the subunit 1 of Leishmania amazonensis RPA (LaRPA-1) alone binds the G-rich telomeric strand and is structurally different from other RPA-1. It is analogous to telomere end-binding proteins described in model eukaryotes whose homologues were not identified in the protozoan´s genome. Here we show that LaRPA-1 is involved with damage response and telomere protection although it lacks the RPA1N domain involved with the binding with multiple checkpoint proteins. We induced DNA double-strand breaks (DSBs) in Leishmania using phleomycin. Damage was confirmed by TUNEL-positive nuclei and triggered a G1/S cell cycle arrest that was accompanied by nuclear accumulation of LaRPA-1 and RAD51 in the S phase of hydroxyurea-synchronized parasites. DSBs also increased the levels of RAD51 in non-synchronized parasites and of LaRPA-1 and RAD51 in the S phase of synchronized cells. More LaRPA-1 appeared immunoprecipitating telomeres in vivo and associated in a complex containing RAD51, although this interaction needs more investigation. RAD51 apparently co-localized with few telomeric clusters but it did not immunoprecipitate telomeric DNA. These findings suggest that LaRPA-1 and RAD51 work together in response to DNA DSBs and at telomeres, upon damage, LaRPA-1 works probably to prevent loss of single-stranded DNA and to assume a capping function.

ALX/FPR2 Activation by Stereoisomers of D1 Resolvins Elucidating with Molecular Dynamics Simulation.

Chronic inflammation contributes to several diseases, but its resolution is driven by specialized pro-resolving mediators (SPM) such as resolvin D1 (RvD1) and its epimer aspirin-triggered resolvin D1 (AT-RvD1), both biosynthesized from ω-3 fatty docosahexaenoic acid (DHA). RvD1 and AT-RvD1 have anti-inflammatory and pro-resolution potentials, and their effects could be mediated by formyl peptide receptor type 2 receptor ALX/FPR2, a G-protein-coupled receptor (GPCR). In this work, we performed 44 µs of molecular dynamics simulations with two complexes: FPR2@AT-RvD1 and FPR2@RvD1. Our results show the following: (i) in the AT-RvD1 simulations, the ALX/FPR2 receptor remained in the active state in 62% of the frames, while in the RVD1 simulations, the receptor remained in the active state in 74% of the frames; (ii) two residues, R201 and R205, of ALX/FPR2 appear, establishing interactions with both resolvins in all simulations (22 in total); (iii) RvD1 hydrogen bonds with R201 and R205 presented higher frequency than AT-RvD1; and (iv) residues R201 and R205 are the two receptor hotspots, demonstrated by the binding free calculations. Such results show that the ALX/FPR2 receptor remained in the active state for longer in the FPR2@RvD1 simulations than in the FPR2@AT-RvD1 simulations.

Aqueous extract of pummelo pulp (Citrus maxima) improves the biochemical profile and reduces the inflammation process in Wistar rats with non-alcoholic fatty liver disease.

This study investigated the effect of pummelo extract (Citrus maxima) on biochemical, inflammatory, antioxidant and histological changes in NAFLD rats. Forty male Wistar rats divided into four groups were used: (1) control group; (2) fructose associated with high-fat diet - DHF; (3) normal diet + pummelo extract (50 mg/kg); and (4) FHD + pummelo extract. This was administered at dose of 50 mg/kg of the animal's weight, by gavage, for 45 days. Significant improvement in lipid profile, liver and kidney function, inflammation, oxidative stress markers was identified in group 4 compared to group 2. Regarding TNF-α and IL-1ß, group 2 showed higher values (respectively 142, 5 ± 0.7 and 560.5 ± 2.7 pg/mg protein) compared to group 4 (respectively 91.4 ± 0.9 and 402.1.4 ± 0.9 pg/mg protein), p < 0.05. Significant increases were found in SOD and CAT activities, respectively 0.10 ± 0.06 and 8.62 ± 1.67 U/mg protein for group 2 and respectively 0.28 ± 0.08 and 21.52 ± 2.28 U/mg of protein for group 4. Decreases in triglycerides, hepatic cholesterol and fat droplets in hepatic tissue were observed in group 4 compared to group 2. Results highlight that pummelo extract may be useful for prevent the development of NAFLD.

Antivirals virtual screening to SARS-CoV-2 non-structural proteins.

In March 2020, the World Health Organization (WHO) declared coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Since then, the search for a vaccine or drug for COVID-19 treatment has started worldwide. In this regard, a fast approach is the repurposing of drugs, primarily antiviral drugs. Herein, we performed a virtual screening using 22 antiviral drugs retrieved from the DrugBank repository, azithromycin (antibiotic), ivermectin (antinematode), and seven non-structural proteins (Nsps) of SARS-CoV-2, which are considered important targets for drugs, via molecular docking and molecular dynamics simulations. Drug-receptor binding energy was employed as the main descriptor. Based on the results, paritaprevir was predicted as a promising multi-target drug that favorably bound to all tested Nsps, mainly adipose differentiation-related protein (ADRP) (-36.2 kcal mol-1) and coronavirus main proteinase (Mpro) (-32.2 kcal mol-1). Moreover, the results suggest that simeprevir is a strong inhibitor of Mpro (-37.2 kcal mol-1), which is an interesting finding because Mpro plays an important role in viral replication. In addition to drug-receptor affinity, hot spot residues were characterized to facilitate the design of new drug derivatives with improved biological responses.

Obliterative portal venopathy: A neglected and probably misdiagnosed disease with peculiar etiology in South America.

Background and Aim: Obliterative portal venopathy (OPV) is one of the causes of non-cirrhotic portal hypertension. However, many aspects of OPV remain unclear, including the etiology, pathogenesis, and natural history. The aim of this study was to describe the clinical features of OPV in a series of patients in Brazil in whom OPV was diagnosed through liver biopsy. Methods: Forty-three consecutive adult patients with OPV were retrospectively selected as a case series based on histologic criteria, defined by the presence of at least portal fibrosis, phlebosclerosis, disappearance and/or reduction of the caliber of portal vein branches, and exclusion of cirrhosis. Clinical and laboratory data were analyzed. Clinically significant portal hypertension was considered in the presence of esophageal varices and/or ascites. Results: The mean age of patients at diagnosis was 44.5 ± 11 years, who were predominantly female (81%). Clinically significant portal hypertension was found in 28% of cases. The most frequent indication for liver biopsy was the elevation of liver enzymes, mostly γ-glutamyl transferase (GGT) in 76% of patients, averaging 222 IU/L (upper limit of normality up to 40 IU/L) and alanine aminotransferase (ALT) in 64%, mean 84 IU/L (38 IU/L). One-third of our patients had exposure to medications, especially herbal medicines, at the time of enzymatic changes. Other risk factors highlighted were features of autoimmunity in 25% of patients or thrombophilia in 20%. Conclusion: OPV can be diagnosed even before the onset of portal hypertension, ALT elevation, and especially GGT elevation in most cases. Its etiology is not defined, but autoimmune diseases, thrombophilia, and the use of medications or herbal medicines may play a role.

Epidemiological analysis of stroke patients with emphasis on access to acute-phase therapies.

BACKGROUND: Stroke is a public health problem. For patients with ischemic stroke, venous thrombolysis and mechanical thrombectomy are effective therapeutic options. However, even after the National Stroke Treatment Guidelines were published in 2012, the number of cases treated is still lower than expected. OBJECTIVE: To identify the determining factors for obtaining access to acute-phase therapies in the state of Espírito Santo (ES) and investigate the profile of stroke patients treated at the Central State Hospital (HEC). METHODS: Retrospective data from the medical records of 1078 patients from May 2018 to December 2019 were analyzed. RESULTS: Among the 1,078 patients, 54.9% were men and the most prevalent age group was 60 to 79 years. Systemic arterial hypertension was the main single risk factor. Regarding treatment modality among the patients who arrived at the HEC within the therapeutic window, 47% received some type of acute-phase therapy. Waking up with the deficit was the main contraindication for venous thrombolysis in these cases. CONCLUSIONS: Application of the flowchart established by SESA-ES seemed to be effective for enabling responsiveness of care for stroke victims. Public emergency transport services had a fundamental role in this process. In addition, the care provided by the tertiary stroke center provided excellent access to acute-phase therapies. However, despite the efficiency of the service provided at the HEC, it only reached a maximum of 50% of the ES population. This service model therefore needs to be expanded throughout the state.