Is There a Safe Alcohol Consumption Limit for the General Population and in Patients with Liver Disease?

Excessive alcohol consumption represents an important burden for health systems worldwide and is a major cause of liver- and cancer-related deaths. Alcohol consumption is mostly assessed by self-report that often underestimates the amount of drinking. While alcohol use disorders identification test - version C is the most widely used test for alcohol use screening, in patients with liver disease the use of alcohol biomarker could help an objective assessment. The amount of alcohol that leads to significant liver disease depends on gender, genetic background, and coexistence of comorbidities (i.e., metabolic syndrome factors). All patients with alcohol-associated liver disease are recommended to follow complete abstinence and they should be treated within multidisciplinary teams. Abstinence slows down and even reverses the progression of liver fibrosis and can help recompensate patients with complicated cirrhosis. Whether there is a safe amount of alcohol in the general population is a matter of intense debate. Large epidemiological studies showed that the safe amount of alcohol to avoid overall health-related risks is lower than expected even in the general population. Even one drink per day can increase cancer-related death. In patients with any kind of chronic liver disease, especially in those with metabolic-associated steatotic liver disease, no alcohol intake is recommended. This review article discusses the current evidence supporting the deleterious effects of small-to-moderate amounts of alcohol in the general population and in patients with underlying chronic liver disease.

A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response.

BACKGROUND: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI. METHODS: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs. RESULTS: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome. CONCLUSIONS: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.

Investigation of the cytotoxicity, genotoxicity and antioxidant prospects of JM-20 on human blood cells: A multi-target compound with potential therapeutic applications.

JM-20 is a 1,5-benzodiazepine compound fused to a dihydropyridine fraction with different pharmacological properties. However, its potential toxic effects on blood cells have not yet been reported. Thus, the present study aimed to investigate, for the first time, the possible cytotoxicity of JM-20 through cell viability, cell cycle, morphology changes, reactive species (RS) to DCFH-DA, and lipid peroxidation in human leukocytes, its hemolytic effect on human erythrocytes, and its potential DNA genotoxicity using plasmid DNA in vitro. Furthermore, the compound's ability to reduce the DPPH radical was also measured. Human blood was obtained from healthy volunteers (30 ± 10 years old), and the leukocytes or erythrocytes were immediately isolated and treated with different concentrations of JM-20. A cytoprotective effect was exhibited by 10 µM JM-20 against 1 mM tert-butyl hydroperoxide (t-but-OOH) in the leukocytes. However, the highest tested concentrations of the compound (20 and 50 µM) changed the morphology and caused a significant decrease in the cell viability of leukocytes (p < 0.05, in comparison with Control). All tested concentrations of JM-20 also resulted in a significant increase in intracellular RS as measured by DCFH-DA in these cells (p < 0.05, in comparison with Control). On the other hand, the results point out a potent antioxidant effect of JM-20, which was similar to the classical antioxidant α-tocopherol. The IC50 value of JM-20 against the lipid peroxidation induced by (FeII) was 1.051 µM ± 0.21, while the IC50 value of α-tocopherol in this parameter was 1.065 µM ± 0.34. Additionally, 50 and 100 µM JM-20 reduced the DPPH radical in a statistically similar way to the 100 µM α-tocopherol (p < 0.05, in comparison with the control). No significant hemolysis in erythrocytes, no cell cycle changes in leukocytes, and no genotoxic effects in plasmid DNA were induced by JM-20 at any tested concentration. The in silico pharmacokinetic and toxicological properties of JM-20, derivatives, and nifedipine were also studied. Here, our findings demonstrate that JM-20 and its putative metabolites exhibit similar characteristics to nifedipine, and the in vitro and in silico data support the low toxicity of JM-20 to mammals.

Therapeutic textiles: A promising approach for human skin dysbiosis?

The close interaction between skin and clothing has become an attractive cornerstone for the development of therapeutic textiles able to alleviate skin disorders, namely those correlated to microbiota dysregulation. Skin microbiota imbalance is known in several skin diseases, including atopic dermatitis (AD), psoriasis, seborrheic dermatitis, rosacea, acne and hidradenitis suppurative (HS). Such microbiota dysregulation is usually correlated with inflammation, discomfort and pruritus. Although conventional treatments, that is, the administration of steroids and antibiotics, have shown some efficacy in treating and alleviating these symptoms, there are still disadvantages that need to be overcome. These include their long-term usage with side effects negatively impacting resident microbiota members, antibiotic resistance and the elevated rate of recurrence. Remarkably, therapeutic textiles as a non-pharmacological measure have emerged as a promising strategy to treat, alleviate the symptoms and control the severity of many skin diseases. This systematic review showcases for the first time the effects of therapeutic textiles on patients with skin dysbiosis, focusing on efficacy, safety, adverse effects and antimicrobial, antioxidant and anti-inflammatory properties. The main inclusion criteria were clinical trials performed in patients with skin dysbiosis who received treatment involving the use of therapeutic textiles. Although there are promising outcomes regarding clinical parameters, safety and adverse effects, there is still a lack of information about the impact of therapeutic textiles on the skin microbiota of such patients. Intensive investigation and corroboration with clinical trials are needed to strengthen, define and drive the real benefit and the ideal biomedical application of therapeutic textiles.

Fishing profile and commercial landings of shark and batoids in a global elasmobranchs conservation hotspot.

This paper describes the fishing profile and the temporal variation in the commercial landings of elasmobranchs in a global hotspot for their conservation and investigates the variables that influenced the landings. Census data on commercial catches were obtained between April 2008 and October 2010 from nine landing sites in Bragança (Pará, northern Brazil). Five vessel types, four fishing gears, and eight fishing techniques engaged with elasmobranch capture were identified. A total of 2,357 landings were recorded, with a total production of 354 t. The highest yields were recorded in 2009, with sharks being harvested mostly by small and medium-sized vessels, and batoids, by small vessels and canoes. Drifting nets and longlines played a prominent role in elasmobranch fisheries. The results show that the landings were influenced by days at sea, which is common in tropical fisheries. The elasmobranch data series is discontinuous as statistics are absent for most fishing sites albeit imperative for proper management, as well as relevant for decision-makers focusing on their conservation.

Hippocampal acetylcholinesterase activation induced by streptozotocin in mice is protected by an organotellurium compound without evidence of toxicity.

The cognitive deficit, which is like Alzheimer's disease and is associated with oxidative damage, may be induced by exposure to streptozotocin. This study aimed to evaluate if the tellurium-containing organocompound, 3j, 5'-arylchalcogeno-3-aminothymidine derivative, interferes with the effects of streptozotocin, as well as to investigate its toxicity in adult mice. Cognitive deficit was induced by two doses of streptozotocin (2.25 mg/kg/day, 48 h interval) intracerebroventricularly. After, the mice were subcutaneously treated with 3j (8.62 mg/kg/day) for 25 days. The effects were assessed by evaluating hippocampal and cortical acetylcholinesterase and behavioral tasks. 3j toxicity was investigated for 10 (0, 21.55, or 43.10 mg/kg/day) and 37 (0, 4.31, or 8.62 mg/kg/day) days by assessing biometric parameters and glucose and urea levels, and alanine aminotransferase activity in blood plasma. 3j exposure did not alter the behavioral alterations induced by streptozotocin exposure. On the other hand, 3j exposure normalized hippocampus acetylcholinesterase activity, which is enhanced by streptozotocin exposure. Toxicity evaluation showed that the administration of 3j for either 10 or 37 days did not cause harmful effects on the biometric and biochemical parameters analyzed. Therefore, 3j does not present any apparent toxicity and reverts acetylcholinesterase activity increase induced by streptozotocin in young adult mice.

Dysphagia Days as an Assessment of Clinical Treatment Outcome in Eosinophilic Esophagitis.

INTRODUCTION: The aim of this study was to evaluate Dysphagia Days as a measure of symptom improvement in patients with eosinophilic esophagitis from the HEROES study. METHODS: Dysphagia Days, defined as a yes answer to the following question: During any meal today, did food go down slowly or get stuck in your throat or chest? was assessed for cendakimab vs placebo. RESULTS: A statistically significant reduction in the mean number of Dysphagia Days experienced was observed with cendakimab 360 mg vs placebo at week 16 (-4.67 vs -1.83; P = 0.0115); an even greater improvement was observed in steroid-refractory patients vs placebo (-4.48 vs -0.04; P = 0.0079). DISCUSSION: Dysphagia Days represents a relevant clinical end point to capture dysphagia-related symptoms.

Genomics reveals the role of admixture in the evolution of structure among sperm whale populations within the Mediterranean Sea.

In oceanic ecosystems, the nature of barriers to gene flow and the processes by which populations may become isolated are different from the terrestrial environment, and less well understood. In this study we investigate a highly mobile species (the sperm whale, Physeter macrocephalus) that is genetically differentiated between an open North Atlantic population and the populations in the Mediterranean Sea. We apply high-resolution single nucleotide polymorphism (SNP) analysis to study the nature of barriers to gene flow in this system, assessing the putative boundary into the Mediterranean (Strait of Gibraltar and Alboran Sea region), and including novel analyses on structuring among sperm whale populations within the Mediterranean basin. Our data support a recent founding of the Mediterranean population, around the time of the last glacial maximum, and show concerted historical demographic profiles in both the Atlantic and the Mediterranean. In each region there is evidence for a population decline around the time of the founder event. The largest decline was seen within the Mediterranean Sea where effective population size is substantially lower (especially in the eastern basin). While differentiation is strongest at the Atlantic/Mediterranean boundary, there is also weaker but significant differentiation between the eastern and western basins of the Mediterranean Sea. We propose, however, that the mechanisms are different. While post-founding gene flow was reduced between the Mediterranean and Atlantic populations, within the Mediterranean an important factor differentiating the basins is probably a greater degree of admixture between the western basin and the North Atlantic and some level of isolation between the western and eastern Mediterranean basins. Subdivision within the Mediterranean Sea exacerbates conservation concerns and will require consideration of what distinct impacts may affect populations in the two basins.

Improved detection of hepatitis C virus-positive blood donors and determination of infection status.

BACKGROUND: In low-risk populations, variability in the sensitivity of current serological tests for Hepatitis C virus (HCV) blood donor screening may lead to the presence of false-positive results. This contributes to the unnecessary loss of blood donor samples as well as to difficulty in accurate donor counselling. The present study determined the optimal cut-off value of a chemiluminescent immunoassay for identification of HCV-reactive blood donors. STUDY DESIGN AND METHODS: In a retrospective cross-sectional analysis of 193 973 blood donations, 578 samples that were positive for HCV antibody in a chemiluminescent immunoassay and/or RNA screening tests were identified. Blood from 379 of these positive samples was available for retesting by a second confirmatory HCV immunoassay followed by a receiver operating characteristic (ROC) curve analysis. Donors were also recalled for a new analysis. RESULTS: Only 71 (18.7%) blood samples remained HCV-positive upon retesting, while 233 (61.5%) now tested negative and 75 (19.8%) yielding indeterminate results. A signal to cutoff ratio ≥4.32 was determined as the best differential threshold between a positive and negative result, increasing the positive predictive value from 27.3% to 66.7%. CONCLUSION: Using a higher threshold for an HCV-positive blood sample enhances the chemiluminescent immunoassay screening test´s accuracy and helps to improve donor counselling and notification processes.

Impaired anti-HBV vaccine response in non-cirrhotic chronic HCV is not overcome by double dose regimen: randomized control trial.

INTRODUCTION AND OBJECTIVES: Some studies suggest chronic HCV infection diminishes responses to the anti-HBV vaccine. We evaluated the efficacy of double versus standard dose HBV vaccination among HCV patients without cirrhosis. PATIENTS AND METHODS: 141 adults with untreated chronic HCV were randomized to HBV vaccination with double dose (40µg) or standard dose (20µg) at 0, 1 and 6 months; 70 healthy HCV-negative patients given standard dose served as controls. Vaccine response was defined by anti-HBs ≥10 mIU/mL. RESULTS: 128 patients (60 double, 68 standard doses) completed the study. Patients were of median age 52 years, 61% female, 60% fibrosis <2 of 4, and 76% genotype 1 with median 6-log 10 IU/mL HCV RNA. Overall seroprotection rate was 76.7% (95% CI: 65-87) in the 40µg versus 73.5% (95% CI: 63-84) in the 20µg dose HCV-positive groups (p =0.68) and 91.2% (95%CI:84-99) in HCV-negative controls (p =0.011 and 0.003, respectively). In multivariate logistic regression, vaccine dose (double vs. standard dose) was not associated with vaccine response (OR=0.63, p =0.33). Of 32 HCV-infected patients who were non-responders to 3- doses, 25 received the fourth dose of vaccine. The fourth dose seroconversion rate for the 40µg and 20µg groups were 45.5% and 21.4%, respectively. CONCLUSIONS: In HCV-infected patients without cirrhosis, impaired responses to HBV vaccination cannot be overcome by the use of double dose HBV vaccination, but adding a fourth dose of vaccine for non-responders may be an effective strategy. Other adjuvant measures are needed to enhance seroconversion rates in these patients. TRIAL REGISTER: U 1111-1264-2343 (www.ensaiosclinicos.gov.br).

Association of scopophobia with online learning fatigue among medical students in Brazil.

BACKGROUND: Scopophobia can be described in the medical field as the fear of being watched or stared at. Despite the relevance of scopophobia in remote learning scenarios, which have always existed and have been largely expanded during the pandemic in medical education, studies on this topic are exceedingly rare worldwide. Hence, to fill up this gap, a cross-sectional study of medical students was developed to assess the association of scopophobia with the prevalence of online learning fatigue. METHODS: A cross-sectional, quantitative, analytical study was carried out in Medical Schools of Brazil. To assess the risk of scopophobia, questions were developed, based on the literature on the topic. The Zoom Exhaustion & Fatigue Scale (ZEF) was used, and the questions have currently been validated for Brazilian Portuguese. Logistic regression models were also used to assess the relationship of scopophobia risk and ZEF scores. RESULTS: A total of 283 students from Brazil participated in the study. The median age was 23 years, and 64% of the participants were female. In total, 14.5% were considered to be at high risk for scopophobia. It was found that after adjusting for sex, income and number of residents in the household, scopophobia and the total zoom fatigue score remained associated. For the total score, each additional point on the scale increased the chance of scopophobia by 3%, and for the overall domain, 19% (p-values < 0.05). CONCLUSIONS: In conclusion, this study shows a relevant prevalence of students with scopophobia, which requires a differentiated approach on the part of teachers. The causes of scopophobia are often specific and have a psychological origin that goes beyond the usual pedagogical management. Therefore, motivation strategies are necessary in a general, as well as an individualized manner, aiming to favor the improvement of the online teaching and learning process.

Validation of a Satisfaction Scale with a Telemedicine COVID-19 Service: Satis-COVID.

Objectives: Despite being a widespread tool, telehealth was significantly incorporated during the COVID-19 pandemic period, but it still lacks analysis methodologies, greater digital security, and satisfaction assessment instruments that are still little explored and validated. The objective is to assess user satisfaction through the validation of a satisfaction scale with a telemedicine COVID-19 service (TeleCOVID). Methods: Cross-sectional study of a cohort of confirmed COVID-19 cases evaluated and monitored by the TeleCOVID team. To study the scale's measurement qualities, a factorial analysis was performed to test the validity of the construct. Correlation between items and the global scale was assessed using Spearman's correlation coefficient, and the instrument's internal consistency was assessed using Cronbach's alpha coefficient. Results: There were 1,181 respondents evaluating the care received from the TeleCOVID project. A total of 61.6% were female, and 62.4% aged between 30 and 59 years. The correlation coefficients indicated a good correlation between the items present in the instrument. The internal consistency of the global scale was high (Cronbach's alpha = 0.903) and the item-total correlations for the scale ranged from 0.563 to 0.820. The average overall user satisfaction was 4.58, based upon a 5-point Likert scale where 5 is the highest level of satisfaction. Conclusions: The results presented here show how much telehealth can contribute to improving access, resolutibility, and quality of care to the population in general in Public Health Care. In view of the results found, it can be said that the TeleCOVID team offered excellent care and fulfilled its proposed objectives. The scale fulfills its objective of evaluating the quality of teleservice, bringing good results in terms of validity and reliability, in addition to showing high levels of user satisfaction.

Assessment of Neurotoxic Effects of Oxycodone and Naloxone in SH-SY5Y Cell Line.

Opioid drugs have analgesic properties used to treat chronic and post-surgical pain due to descending pain modulation. The use of opioids is often associated with adverse effects or clinical issues. This study aimed to evaluate the toxicity of opioids by exposing the neuroblastoma cell line (SH-SY5Y) to 0, 1, 10, and 100 µM oxycodone and naloxone for 24 h. Analyses were carried out to evaluate cell cytotoxicity, identification of cell death, DNA damage, superoxide dismutase (SOD), glutathione S-transferase (GST), and acetylcholinesterase (AChE) activities, in addition to molecular docking. Oxycodone and naloxone exposure did not alter the SH-SY5Y cell viability. The exposure to 100 µM oxycodone and naloxone significantly increased the cells' DNA damage score compared to the control group. Naloxone exposure significantly inhibited AChE, GST, and SOD activities, while oxycodone did not alter these enzymes' activities. Molecular docking showed that naloxone and oxycodone interact with different amino acids in the studied enzymes, which may explain the differences in enzymatic inhibition. Naloxone altered the antioxidant defenses of SH-SY5Y cells, which may have caused DNA damage 24 h after the exposure. On the other hand, more studies are necessary to explain how oxycodone causes DNA damage.

Influence of social and environmental factors for Culex quinquefasciatus distribution in Northeastern Brazil: a risk index.

Culex quinquefasciatus is a vector of lymphatic filariasis. One important component in planning filariasis control activities is the mapping of vector distribution. A tool that involves socio-environmental factors and Cx. quinquefasciatus density can contribute to the identification of areas that should be prioritized in surveillance actions. This is an ecological study based on the construction and validation of a risk score of urban areas according to social and environmental variables extracted from a national database. Based on this stratification, female Cx. quinquefasciatus were captured. In total, 30,635 Cx. quinquefasciatus were captured, of which 17,161 (56%) were females. The highest vector density index of mosquitoes were captured in households located in the high-risk stratum and the indicator proved to be a tool that identified an association between social and environmental conditions and areas with the highest vector density index of females Cx. quinquefasciatus.

Incidence and Predictors of Progression to Chagas Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.

BACKGROUND: There are few contemporary cohorts of Trypanosoma cruzi-seropositive individuals, and the basic clinical epidemiology of Chagas disease is poorly understood. Herein, we report the incidence of cardiomyopathy and death associated with T. cruzi seropositivity. METHODS: Participants were selected in blood banks at 2 Brazilian centers. Cases were defined as T. cruzi-seropositive blood donors. T. cruzi-seronegative controls were matched for age, sex, and period of donation. Patients with established Chagas cardiomyopathy were recruited from a tertiary outpatient service. Participants underwent medical examination, blood collection, ECG, and echocardiogram at enrollment (2008-2010) and at follow-up (2018-2019). The primary outcomes were all-cause mortality and development of cardiomyopathy, defined as the presence of a left ventricular ejection fraction <50% or QRS complex duration ≥120 ms, or both. To handle loss to follow-up, a sensitivity analysis was performed using inverse probability weights for selection. RESULTS: We enrolled 499 T. cruzi-seropositive donors (age 48±10 years, 52% male), 488 T. cruzi-seronegative donors (age 49±10 years, 49% male), and 101 patients with established Chagas cardiomyopathy (age 48±8 years, 59% male). The mortality in patients with established cardiomyopathy was 80.9 deaths/1000 person-years (py) (54/101, 53%) and 15.1 deaths/1000 py (17/114, 15%) in T. cruzi-seropositive donors with cardiomyopathy at baseline. Among T. cruzi-seropositive donors without cardiomyopathy at baseline, mortality was 3.7 events/1000 py (15/385, 4%), which was no different from T. cruzi-seronegative donors with 3.6 deaths/1000 py (17/488, 3%). The incidence of cardiomyopathy in T. cruzi-seropositive donors was 13.8 (95% CI, 9.5-19.6) events/1000 py (32/262, 12%) compared with 4.6 (95% CI, 2.3-8.3) events/1000 py (11/277, 4%) in seronegative controls, with an absolute incidence difference associated with T. cruzi seropositivity of 9.2 (95% CI, 3.6-15.0) events/1000 py. T. cruzi antibody level at baseline was associated with development of cardiomyopathy (adjusted odds ratio, 1.4 [95% CI, 1.1-1.8]). CONCLUSIONS: We present a comprehensive description of the natural history of T. cruzi seropositivity in a contemporary patient population. The results highlight the central importance of anti-T. cruzi antibody titer as a marker of Chagas disease activity and risk of progression.

The Adjuvanted Recombinant Zoster Vaccine Confers Long-Term Protection Against Herpes Zoster: Interim Results of an Extension Study of the Pivotal Phase 3 Clinical Trials ZOE-50 and ZOE-70.

BACKGROUND: This ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination. METHODS: Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination. RESULTS: Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9-89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2-93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels. CONCLUSIONS: Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.

Interaction of Microbiome, Diet, and Hospitalizations Between Brazilian and American Patients With Cirrhosis.

BACKGROUND & AIMS: Gut microbiota are affected by diet, country, and affect outcomes in cirrhosis. Western diets are associated with dysbiosis. Comparisons with other diets is needed. We aimed to compare cirrhosis patients from the United States with cirrhosis patients from Brazil with respect to diet, microbiota, and impact on hospitalizations. METHODS: Healthy controls and compensated/decompensated outpatients with cirrhosis from the United States and Brazil underwent dietary recall and stool for 16S ribosomal RNA sequencing. Demographics and medications/cirrhosis details were compared within and between countries. Patients with cirrhosis were followed up for 90-day hospitalizations. Regression for Shannon diversity was performed within cirrhosis. Regression for hospitalizations adjusting for clinical and microbial variables was performed. RESULTS: Model for end-stage liver disease (MELD), diabetes, ascites, and albumin were similar, but more Americans were men, had higher hepatic encephalopathy and alcohol/hepatitis C etiology, with lower nonalcoholic fatty liver disease than Brazilians. Brazilians had higher cereal, rice, and yogurt intake vs the United States. As disease progressed, cereals, rice/beans, coffee, and chocolate consumption was reduced. Microbial diversity was higher in Brazilians. Within cirrhosis, high diversity was related to Brazilian origin (P < .0001), age, and cereal intake (P = .05), while high MELD scores (P = .009) and ascites (P = .05) did the reverse. Regardless of stage, beneficial taxa and taxa associated with grant and yogurt intake were higher (Ruminococcaceae, Christensenellacae, and Prevotellaceae), while pathobionts (Porphyromonadaceae, Sutterellaceae, and Enterobacteriaceae) were lower in Brazilians. More Americans were hospitalized vs Brazilians (P = .002). On regression, MELD (P = .001) and ascites (P = .001) were associated with higher hospitalizations, while chocolate (P = .03) and Brazilian origin (P = .001) were associated with lower hospitalizations with/without microbiota inclusion. CONCLUSIONS: Brazilian cirrhotic patients follow a diet richer in cereals and yogurt, which is associated with higher microbial diversity and beneficial microbiota and could contribute toward lower hospitalizations compared with a Western-diet-consuming American cohort.

Emerging modulators for osteogenic differentiation: a combination of chemical and topographical cues for bone microenvironment engineering.

Bone presents an intrinsic ability for self-regeneration and repair, however critical defects and large fractures require invasive and time-consuming clinical interventions. As an alternative to current therapy, bone tissue engineering (BTE) has primarily aimed to recreate the bone microenvironment by delivering key biomolecules and/or by modification of scaffolds to guide cell fate towards the osteogenic lineage or other phenotypes that may benefit the bone regeneration mechanism. Considering that bone cells communicate, in their native microenvironment, through biochemical and physical signals, most strategies fail when considering only chemical, geometrical or mechanical cues. This is not representative of the physiological conditions, where the cells are simultaneously in contact and stimulated by several cues. Therefore, this review explores the synergistic effect of biochemical/physical cues in regulating cellular events, namely cell adhesion, proliferation, osteogenic differentiation, and mineralization, highlighting the importance of the combined modifications for the development of innovative bone regenerative therapies.

Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: Immunohistochemical Assessment of Markers of Cancer Cell Metabolism.

INTRODUCTION: Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. METHODS: We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. RESULTS: Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m2; 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. CONCLUSION: Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.

Temporal Reduction in COVID-19-Associated Fatality Among Kidney Transplant Recipients: The Brazilian COVID-19 Registry Cohort Study.

Data from the general population suggest that fatality rates declined during the course of the pandemic. This analysis, using data extracted from the Brazilian Kidney Transplant COVID-19 Registry, seeks to determine fatality rates over time since the index case on March 3rd, 2020. Data from hospitalized patients with RT-PCR positive SARS-CoV-2 infection from March to August 2020 (35 sites, 878 patients) were compared using trend tests according to quartiles (Q1: <72 days; Q2: 72-104 days; Q3: 105-140 days; Q4: >140 days after the index case). The 28-day fatality decreased from 29.5% (Q1) to 18.8% (Q4) (pfor-trend = 0.004). In multivariable analysis, patients diagnosed in Q4 showed a 35% reduced risk of death. The trend of reducing fatality was associated with a lower number of comorbidities (20.7-10.6%, p for-trend = 0.002), younger age (55-53 years, pfor-trend = 0.062), and better baseline renal function (43.6-47.7 ml/min/1.73 m2, pfor-trend = 0.060), and were confirmed by multivariable analysis. The proportion of patients presenting dyspnea (pfor-trend = 0.001) and hypoxemia (pfor-trend < 0.001) at diagnosis, and requiring intensive care was also found reduced (pfor-trend = 0.038). Despite possible confounding variables and time-dependent sampling differences, we conclude that COVID-19-associated fatality decreased over time. Differences in demographics, clinical presentation, and treatment options might be involved.