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Objectives: We aimed to investigate the effect of insulin sensitivity and insulin resistance status at baseline on longitudinal body mass index, and the possible effect modification by sex., Methods: This is a secondary analysis of a randomized intervention community trial, in which a subgroup of 84 adolescents, aged between 10 and 12 years, were analyzed. Body weight, height, and body mass index (BMI) were determined before and after 8 months of follow-up. Glucose and serum insulin were examined at baseline and IR was defined based on the homeostasis model assessment-insulin resistance (HOMA-IR), with a cutoff >2.5 for both genders. Linear mixed-effects models were performed to evaluate the influence of HOMA-IR at baseline on BMI changes over time. Models were adjusted for age, pubertal stage, and stratified by sex., Results: The sample comprised 65.4% of girls and the prevalence of overweight/obesity was 54.7% among girls and 50.0% among boys. The overall prevalence of IR was 75.3%, of which 60.7% for boys and 83.0% for girls. We found an interaction effect by sex (p = .004) for HOMA-IR as a continuous variable, with a decreased BMI rate of change among boys (β = -0.13; p = .03) but not for girls (β = +0.03; p = .36). Longitudinal BMI changes considering IR status at baseline (IR vs. non-IR) did not demonstrate any statistically significant difference for both boys (-0.1 vs. +0.4; p = .28) and girls (+0.7 vs. +1.0; p = .44)., Conclusion: Increased HOMA-IR values at baseline were associated with greater BMI reduction over time among boys but not girls, with no influence of IR status., (© 2022 Wiley Periodicals LLC.)

Intestinal mucositis is a commonly reported side effect in oncology practice. Probiotics are considered an excellent alternative therapeutic approach to this debilitating condition; however, there are safety questions regarding the viable consumption of probiotics in clinical practice due to the risks of systemic infections, especially in immune-compromised patients. The use of heat-killed or cell-free supernatants derived from probiotic strains has been evaluated to minimize these adverse effects. Thus, this work evaluated the anti-inflammatory properties of paraprobiotics (heat-killed) and postbiotics (cell-free supernatant) of the probiotic Lactobacillus delbrueckii CIDCA 133 strain in a mouse model of 5-Fluorouracil drug-induced mucositis. Administration of paraprobiotics and postbiotics reduced the neutrophil cells infiltrating into the small intestinal mucosa and ameliorated the intestinal epithelium architecture damaged by 5-FU. These ameliorative effects were associated with a downregulation of inflammatory markers ( Tlr2 , Nfkb1 , Il12 , Il17a , Il1b , Tnf ), and upregulation of immunoregulatory Il10 cytokine and the epithelial barrier markers Ocln , Cldn1 , 2 , 5 , Hp and Muc2 . Thus, heat-killed L. delbrueckii CIDCA 133 and supernatants derived from this strain were shown to be effective in reducing 5-FU-induced inflammatory damage, demonstrating them to be an alternative approach to the problems arising from the use of live beneficial microorganisms in clinical practice.

Introduction: Dorsopathies are common among bus drivers and may result in absenteeism due to work disability. Dorsopathies have a multifactorial etiology, including those related to occupational risk factors., Objectives: To analyze the factors associated with sick leave due to dorsopathies among bus drivers from a public transport company., Methods: This was a cross-sectional, analytical study with information from a database of 2,229 professional bus drivers from a company in the city of São Paulo, Brazil. The study period was from 2016 to 2017. Independent variables were sex, age group, length of service, and work shift; the outcome was the history of sick leave due to dorsopathies in the study period. Logistic regression analysis was performed to investigate the factors associated with the outcome., Results: Mean sample age was 47.33 years, and mean length of service was 8.65 years. Most participants were men (98.06%) and worked during the day (85.9%). There was a 17% prevalence of sick leave in the study period, with an average of 1.86 days per medical certificate. Age group was the only variable with a statistically significant distribution, with a reduced probability of sick leave due to dorsopathies in those aged ≥ 40 years., Conclusions: Younger workers were more likely to be on sick leave due to dorsopathies than older workers. Actions aimed at permanent health promotion and disease prevention are important to improve the quality of life and well-being of these workers., Competing Interests: Conflicts of interest: None

Objective: Evaluate the satisfaction of caregivers and older adults who use the home care service provided by the Better at Home Program (Programa Melhor em Casa) and its associated factors., Methods: This is a cross-sectional study with data from the national survey on the Better at Home Program, conducted by the SUS General Ombudsman. We interviewed 5,595 caregivers and 950 older adults. We combined four questions related to satisfaction to formulate the dependent variable by means of latent class analysis and used 13 questions as independent variables., Results: 93.7% of the older adults and 90.2% of the caregivers were satisfied with the service. In the multiple analysis, the variables showing association with satisfaction were: also being accompanied by a family health team (older adults: OR = 4.22; p = 0.014), shorter time between referral and the first visit (older adults: OR = 10.20; p = 0.006), (caregiver: OR = 5.84; p < 0.001), taking examinations with medical requirement (older adults: OR = 5.74; p = 0.037), (caregiver: OR = 7.41; p < 0.001), consultation with specialist (caregiver: OR = 6.02; p < 0.001), visits out of the schedule when necessary (older adults: OR = 8.09; p = 0.014), (caregiver: OR = 1.81; p = 0.015) and understanding the orientations provided by the program team (caregiver: OR = 10.61; p < 0.001)., Conclusions: The majority of the older adults and caregivers showed satisfaction with the program, with a distinction in the aspects associated with this satisfaction, in which only the characteristics directly related to the program influenced the satisfaction, while the same did not occur with the socioeconomic and demographic characteristics.

Background: Some studies have shown a higher prevalence of deaths in patients with cardiovascular risk factors (CRF) during hospitalization for COVID-19., Objectives: To assess the impact of high cardiovascular risk in patients hospitalized in intensive care for COVID-19., Methods: Retrospective study with patients admitted to an intensive care unit, with a diagnosis of COVID-19 confirmed by RT-PCR, and with at least one troponin measurement during hospitalization. The criteria for defining high cardiovascular risk (HCR) patients were: history of established cardiovascular disease (myocardial infarction, stroke, or peripheral arterial disease), diabetes, chronic kidney disease with clearance < 60ml/min, or presence of 3 CRFs (hypertension, smoking, dyslipidemia, or age > 65 years). The primary outcome of this study is all-cause in-hospital mortality. P<0.05 was considered significant., Results: This study included 236 patients, mean age = 61.14±16.2 years, with 63.1% men, 55.5% hypertensive, and 33.1% diabetic; 47.4% of the patients also presented HCR. A significant increase in mortality was observed as the number of risk factors increased (0 FRC: 5.9%; 1 FRC: 17.5%; 2 FRC: 32.2% and ≥3 FRC: 41.2%; p=0.001). In the logistic regression adjusted for severity (SAPS3 score), the HCR and myocardial injury group had a higher occurrence of in-hospital mortality (OR 40.38; 95% CI 11.78-138.39). Patients without HCR but with myocardial injury also exhibited a significant association with the primary outcome (OR 16.7; 95% CI 4.45-62.74)., Conclusion: In patients hospitalized in intensive care for COVID-19, HCR impacts in-hospital mortality only in patients with myocardial injury.

Intestinal mucositis promoted by the use of anticancer drugs is characterized by ulcerative inflammation of the intestinal mucosa, a debilitating side effect in cancer patients undergoing treatment. Probiotics are a potential therapeutic option to alleviate intestinal mucositis due to their effects on epithelial barrier integrity and anti-inflammatory modulation. This study investigated the health-promoting impact of Lactobacillus delbrueckii CIDCA 133 in modulating inflammatory and epithelial barrier markers to protect the intestinal mucosa from 5-fluorouracil-induced epithelial damage. L. delbrueckii CIDCA 133 consumption ameliorated small intestine shortening, inflammatory cell infiltration, intestinal permeability, villus atrophy, and goblet cell count, improving the intestinal mucosa architecture and its function in treated mice. Upregulation of Muc2 , Cldn1 , Hp , F11r , and Il10 , and downregulation of markers involved in NF-κB signaling pathway activation ( Tlr2, Tlr4, Nfkb1, Il6 , and Il1b ) were observed at the mRNA level. This work suggests a beneficial role of L. delbrueckii strain CIDCA 133 on intestinal damage induced by 5-FU chemotherapy through modulation of inflammatory pathways and improvement of epithelial barrier function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barroso, de Jesus, da Silva, Batista, Laguna, Coelho-Rocha, Vital, Fernandes, Cardoso, Ferreira, Martins, Drumond, Mancha-Agresti, Birbrair, Barh and Azevedo.)

This study evaluated the effect of replacing soybean meal by a blend of ground corn and urea-ammonium sulphate (GCU-S) in the diet of lactating buffaloes on milk production and composition, digestibility, N balance and blood metabolites. Twelve multiparous dairy Murrah buffaloes (Bubalus bubalis), at 100 ± 4 d in milk and yielding 10 ± 2.5 kg/d, were randomly distributed in a triple 4 × 4 Latin square, with four different inclusions of GCU-S at U-S levels: 0 (control), 8.0, 16.4 and 24.1 g/kg dry matter (DM) total. Replacing soybean meal with GC-US had a significant depressing effect on absolute DM intake, which was still numerically evident but no longer significant when expressed on a body weight-related basis. Intakes of crude protein (CP) and N as well as N-urinary excretion were also significantly depressed. Digestibility of dry matter was improved and, as a proportion of DMI, intake of total digestible nutrients increased significantly. Perhaps as a result, feed efficiency (kg DMI required per kg 6% fat-corrected milk) was significantly improved. Efficiency of protein use for milk production was significantly improved, but not when expressed as milk protein output. N transfer into milk, as a proportion of total N intake, also increased significantly. However, GC-US inclusion had no significant effect on milk production or milk composition, nor did it affect serum metabolites, digestibilities (apart from dry matter) or N measures of balance apart from those mentioned above. Inclusion of this blend of ground corn with urea and ammonium suplate can be recommended for dairy buffalo because, although it decreases DMI and N-excretion, it improves DM digestibility and feeding efficiency whilst maintaining milk production and composition.

Purposes: Mental disorders are responsible for 16% of the global burden of disease in adolescents. This review focuses on one contextual factor called community violence that can contribute to the development of mental disorders OBJECTIVE: To evaluate the impact of community violence on internalizing mental health symptoms in adolescents, to investigate whether different proximity to community violence (witness or victim) is associated with different risks and to identify whether gender, age, and race moderate this association., Methods: systematic review of observational studies. The population includes adolescents (10-24 years), exposition involves individuals exposed to community violence and outcomes consist of internalizing mental health symptoms. Selection, extraction and quality assessment were performed independently by two researchers., Results: A total of 2987 works were identified; after selection and extraction, 42 works remained. Higher exposure to community violence was positively associated with internalizing mental health symptoms. Being a witnessing is less harmful for mental health than being a victim. Age and race did not appear in the results as modifiers, but male gender and family support appear to be protective factors in some studies., Conclusion: This review confirms the positive relationship between community violence and internalizing mental health symptoms in adolescents and provides relevant information that can direct public efforts to build policies in the prevention of both problems., (© 2022. The Author(s).)

Background: There are several groups of viruses including Insect Specific Viruses (ISV) such as the taxon Negevirus, a group of viruses phylogenetically related to plant viruses. Negeviruses replicate in mosquito cells, but not in vertebrate cells., Methods: Pools of hematophagous arthropods were inoculated in Vero and C6/36 cells. The cells were observed to detect possible cytopathic effect. Then, indirect immunofluorescence, RT-PCR, and nucleotide sequencing were performed., Results: Seven samples which presented negative results for flaviviruses, alphaviruses and bunyaviruses, but showed cytopathic effect in C6/36 cells were sequenced. We identified the occurrence of a variety of ISVs, most of them belonging to the taxon Negevirus: The Brejeira, Negev, Cordoba and Wallerfield viruses, including a new virus for science, tentatively named Feitosa virus., Conclusions: We detected negeviruses in the Amazon region, including two viruses that were isolated for the first time in Brazil: Cordoba virus and the Negev virus and, a new virus for science: the Feitosa virus., (© 2022. The Author(s).)

Leishmaniasis still stands as one of the most prevalent neglected tropical diseases in the least developed and emerging countries. The recommended therapeutic arsenal to treat leishmaniasis is characterized by several shortcomings, and resistance has already been reported. Hence, this dramatic background highlights the pressing need to develop novel, affordable, and safe antileishmanial drugs. Multiple classes of natural compounds have been reported to possess antileishmanial activity. Among these classes, iridoids stand out as a special type of monoterpenoids with diverse biological properties-including their antileishmanial potential. This review aims to discuss the available literature between 1991 and 2020 related to the antileishmanial activity of the iridoid class. Throughout the past decades, various investigations attributed antileishmanial action to assorted iridoid types, including inhibitory potential towards validated drug targets and immunomodulatory activity. The latter deserves special attention due to the ability of some iridoids to improve the host's immune response against parasites. It opens the possibility of iridoids become adjuncts in leishmaniasis treatments by improving the efficacy of currently employed drugs. Furthermore, the present study intends to provide a convenient visual representation of which iridoids and Leishmania spp. species have been most investigated as a guide for further researches., Competing Interests: Conflicts of interestThe authors have no conflicts of interest to declare., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

The discovery of a new drug requires over a billion dollars and around 12 years of research efforts, and toxicity is the leading reason for the failure to approve candidate drugs. Many alternative methods have been validated to detect toxicity as early as possible to diminish the waste of resources and efforts in medicinal chemistry research, and in vivo alternative methods are especially valuable for the amount of information they can provide at little cost and in a short time. In this work, we present a review of the literature published between the years 2000 and 2021 on in vivo alternative methods of toxicity screening employed in medicinal chemistry, which we believe will be useful because, in addition to shortening the research time, these studies provide much additional information aside from the toxicity of drug candidate compounds. These in vivo models include zebrafish, Artemia salina, Galleria mellonella, Drosophila melanogaster, planarians, and Caenorhabditis elegans. The most published ones in the last decade were zebrafish, D. melanogaster, and C. elegans due to their reliability, ease, and cost-effectiveness in implementation and flexibility. Special attention is given to C. elegans because of its rising popularity, a wide range of uses, including toxicity screening, and active effects measurement, from antioxidant effects to anthelmintic and antimicrobial activities, and its fast and reliable results. Over time, C. elegans also became a viable high-throughput (HTS) automated drug screening option. Additionally, this manuscript lists briefly the other screening methods used for the initial toxicological analyses and the role of alternative in vivo methods in these scenarios, classifying them as in silico, in vitro and alternative in vivo models that have been receiving a growing increase in interest in recent years., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Interleukin-6 (IL-6) influences both inflammatory response and anti-inflammatory processes. This cytokine can be released by exercising skeletal muscle, which characterizes it as a myokine. Unlike what is observed in inflammation, IL-6 produced by skeletal muscle is not preceded by the release of other pro-inflammatory cytokines, but it seems to be dependent on the lactate produced during exercise, thus causing different effects from those seen in inflammatory state. After binding to its receptor, myokine IL-6 activates the PI3K-Akt pathway. One consequence of this upregulation is the potentiation of insulin signaling, which enhances insulin sensitivity. IL-6 increases GLUT-4 vesicle mobilization to the muscle cell periphery, increasing the glucose transport into the cell, and also glycogen synthesis. Muscle glycogen provides energy for ATP resynthesis, and regulates Ca2+ release by the sarcoplasmic reticulum, influencing muscle contraction, and, hence, muscle function by multiple pathways. Another implication for the upregulation of the PI3K-Akt pathway is the activation of mTORC1, which regulates mRNA translational efficiency by regulating translation machinery, and translational capacity by inducing ribosomal biogenesis. Thus, IL-6 may contribute to skeletal muscle hypertrophy and function by increasing contractile protein synthesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Training and supporting homecare staff in reablement aims to change staff behavior from "doing for" to "doing with" older adults, i.e., supporting client activation. We evaluated the effectiveness of the reablement training program "Stay Active at Home" (SAaH) on staff self-efficacy and outcome expectations regarding client activation in a cluster randomized controlled trial. Ten Dutch homecare nursing teams, comprising 135 nursing team members and 178 domestic workers, were randomized into the intervention group (SAaH) or control group (usual care). Data on self-efficacy and outcome expectations were collected at baseline, 6 and 12 months using scales developed for this study. Mixed-effects regression showed no differences between the study groups on either outcome. Therefore, widespread implementation of SAaH in its current form cannot be recommended. More research is needed on the development and psychometric properties of scales to assess staff behavior and behavioral determinants (e.g., self-efficacy and outcomes expectations) regarding client activation., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dihydropyrimidinones (DHPMs) are heterocycles obtained by the multicomponent Biginelli reaction. Recently, new synthetic protocols have allowed us to explore functionalisation at less explored positions of DHPMs, such as the N1 position. In this context, a full literature survey of N1- substituted DHPMs was performed. We analysed 27 papers and identified 379 compounds with substituents at the N1 position, most of them with alkyl groups, and a total of 28% compounds with aromatic substituents attached at the N1 position. N1-substituted DHPMs were explored mainly due to their effects on cancer cell proliferation via numerous targets, such as kinesin Eg5, heat shock protein 70, heat shock protein 90, and the epidermal growth factor receptor. Similarity analyses were performed using the data of 379 DHPMs from different cheminformatic approaches, i.e., chemical property correlations, principal component analysis, similarity networks, and compound clustering., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The expression of the inositol 1,4,5-trisphosphate receptor type 3 (ITRP3) in hepatocytes is a common event in the pathogenesis of hepatocellular carcinoma (HCC), regardless of the type of underlying liver disease. However, it is not known whether ITPR3 expression in hepatocytes is involved in tumor maintenance. The aim of the present study was to determine whether there is an association between ITPR3 expression and clinical and morphological parameters using HCC samples obtained from liver explants from patients (n=53) with different etiologies of underlying chronic liver disease (CLD). ITPR3 expression, mitosis and apoptosis were analyzed in human liver samples by immunohistochemistry. Clinical and event-free survival data were combined to assess the relationship between ITPR3 and liver cancer growth in patients. RNA sequencing analysis was performed to identify apoptotic genes altered by ITPR3 expression in a liver tumor cell line. ITPR3 was highly expressed in HCC tumor cells relative to adjacent CLD tissue and healthy livers. There was an inverse correlation between ITPR3 expression and mitotic and apoptotic indices in HCC, suggesting that ITPR3 contributed to the maintenance of HCC by promoting resistance to apoptosis. This was confirmed by the upregulation of CTSB, CHOP and GADD45, genes involved in the apoptotic pathway in HCC. The expression of ITPR3 in the liver may be a promising prognostic marker of HCC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Dos Santos et al.)

Aim: To identify retinal findings using dilated eye examination, which are possibly related to SARS-CoV-2 infection in hospitalised patients with confirmed severe COVID-19., Methods: In this cross-sectional study, hospitalised patients with confirmed severe COVID-19 in a single referral centre for the treatment of COVID-19, in Santo André, São Paulo Metropolitan Area, Brazil, underwent dilated eye examination of both eyes performed by a retina specialist. Findings were recorded using a portable digital fundus camera. Retinographies were analysed by two retina specialists. Medical records were reviewed for assessment of patient demographics, baseline comorbidities and clinical data., Results: There were a total of 18 patients, nine (50%) male, median IQR age of 62.5 (12) years. Ten of the 18 patients (55.6%; 95% CI 33.7 to 75.4) had abnormalities on dilated eye examination. The main findings were flame-shaped haemorrhages (N=4; 22.2%; 95% CI 9.0 to 45.2) and ischaemic pattern lesions (cotton wool spots and retinal sectorial pallor) (N=4; 22.2%; 95% CI 9.0 to 45.2), with one patient having both cotton wool spots and flame-shaped haemorrhages., Conclusion: These findings suggest that patients with severe COVID-19 have acute vascular lesions of the inner retina including flame-shaped haemorrhages and cotton wool spots. Further studies controlling for confounding factors are necessary to properly assess these findings so as to increase the understanding of COVID-19 pathophysiology and to identify new therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Coenzyme Q (CoQ) is an essential molecule that consists of a highly substituted benzene ring attached to a polyprenyl tail anchored in the inner mitochondrial membrane. CoQ transfers electrons from NADH dehydrogenase and succinate dehydrogenase complexes toward ubiquinol-cytochrome c reductase, and that allows aerobic growth of cells. In Saccharomyces cerevisiae, the synthesis of CoQ depends on fourteen proteins Coq1p-Co11p, Yah1p, Arh1p, and Hfd1p. Some of these proteins are components of CoQ synthome. Using ab initio molecular modeling and site-directed mutagenesis, we identified the functional residues of the O-methyltransferase Coq3p, which depends on S-adenosylmethionine for catalysis and is necessary for two O-methylation steps required for CoQ maturation. Conserved residues as well as those that coevolved in the protein structure were found to have important roles in respiratory growth, CoQ biosynthesis, and also in the stability of CoQ synthome proteins. Finally, a multiple sequence alignment showed that S. cerevisiae Coq3p has a 45 amino acid residues insertion that is poorly conserved or absent in oleaginous yeast, cells that can store up to 20% of their dry weight as lipids. These results point to the Coq3p structural determinants of its biological and catalytic function and could contribute to the development of lipid-producing yeast for biotechnology., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the severity of COVID-19 in cancer patients to describe clinical and epidemiological factors associated with poor outcomes (mortality and need of intensive care unit admission or mechanical ventilation)., Methods: Retrospective data from patients with cancer and laboratory diagnosis of COVID-19, obtained between March 16 and May 29, 2020, were retrieved out of a cancer center database. Data analyzed included patient history, age, sex, comorbidities, types of cancer and anticancer therapy., Results: This sample comprised 105 patients aged 18-92 years, 80.9% of whom were females. Dyspnea was the most prevalent initial symptom (30.4%) among patients who died (p<0.0001). Overall, 57.1% of patients had metastatic disease and 60% had poor performance status (Eastern Cooperative Oncologic Group ≥2) at the time of COVID-19 diagnosis. The overall mortality rate was 40.95%. Mortality rates were higher in male patients and those with poor performance status (p<0.0001)., Conclusion: This cohort is one of the largest Brazilian studies describing clinical and epidemiological features of patients with cancer and concurrent COVID-19. Findings of this study emphasize the vulnerability of cancer patients in the current pandemic, and indicate high mortality from COVID-19 among male cancer patients and cancer patients with poor performance status. This analysis may assist the selection of patients who may benefit from strict isolation and eventual discontinuation of anticancer therapy to reduce exposure to infection.

Background: The relationship of vitamin D status and other biochemical parameters with the risk of SARS-CoV-2 infection remains inconclusive, especially in regions with high solar incidence. Therefore, we aimed to associate the 25-hydroxyvitamin D (25(OH)D) concentrations and lipid profile prior to the SARS-CoV-2 tests in a population from a sunny region in Brazil (5 degrees S, 35 degrees W)., Methods: This retrospective cohort study enrolled 1634 patients tested for SARS-CoV-2 of a private medical laboratory with 25(OH)D concentration and lipid profile measured ≥ 7 days before the date of the first SARS-CoV-2 RT-PCR test and were categorized according to 25(OH)D sufficiency (≥30 ng/mL) or insufficiency (<30 ng/mL). Multiple logistic regression analyses were performed to assess risk factors associated with positive tests for SARS-CoV-2., Results: Average serum 25(OH)D was 33.6 ng/mL. Vitamin D deficiency (<20 ng/mL) was only found in 2.6% of the participants. Multivariate analysis demonstrated that patients > 49 y with insufficient 25(OH)D (<30 ng/mL) presented increased odds to test positive for SARS-CoV-2 (OR: 2.02, 95 %CI: 1.15 to 3.55, P = 0.015). The same is observed among those with total cholesterol > 190 mg/dL (OR: 1.90, 95 %CI: 1.10 to 3.28, P = 0.020)., Conclusions: Previous insufficient 25(OH)D (<30 ng/mL) concentration and high total cholesterol were associated with SARS-CoV-2 infection among adults > 48 y in the study population. Further studies should be conducted to confirm whether measurement of 25(OH)D and lipid profile could be useful to identify patients who are more susceptible to COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.92 for predicting outcomes at 24 and 72 h from the time of initial presentation to the emergency room, and it provided 16% improvement in average AUC measured across all participating sites and an average increase in generalizability of 38% when compared with models trained at a single site using that site's data. For prediction of mechanical ventilation treatment or death at 24 h at the largest independent test site, EXAM achieved a sensitivity of 0.950 and specificity of 0.882. In this study, FL facilitated rapid data science collaboration without data exchange and generated a model that generalized across heterogeneous, unharmonized datasets for prediction of clinical outcomes in patients with COVID-19, setting the stage for the broader use of FL in healthcare., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Here, we report the draft genomic sequences of Bacillus amyloliquefaciens strain CBMAI 1301, isolated from soybean seeds, and Bacillus subtilis strain CBMAI 1302, isolated from soil. These strains have potential applications for the biological control of phytopathogens, and the sequencing of these two genomes could greatly benefit soybean cultivation.

Triatomine assassin bugs comprise hematophagous insect vectors of Trypanosoma cruzi, the causative agent of Chagas disease. Although the microbiome of these species has been investigated to some extent, only one virus infecting Triatoma infestans has been identified to date. Here, we describe for the first time seven (+) single-strand RNA viruses (RpV1-7) infecting Rhodnius prolixus, a primary vector of Chagas disease in Central and South America. We show that the RpVs belong to the Iflaviridae, Permutotetraviridae and Solemoviridae and are vertically transmitted from the mothers to the progeny via transovarial transmission. Consistent with this, all the RpVs, except RpV2 that is related to the entomopathogenic Slow bee paralysis virus, established persistent infections in our R. prolixus colony. Furthermore, we show that R. prolixus ovaries express 22-nucleotide viral siRNAs (vsiRNAs), but not viral piRNAs, that originate from the processing of dsRNA intermediates during viral replication of the RpVs. Interestingly, the permutotetraviruses and sobemoviruses display shared pools of vsiRNAs that might provide the basis for a cross-immunity system. The vsiRNAs are maternally deposited in the eggs, where they likely contribute to reduce the viral load and protect the developing embryos. Our results unveil for the first time a complex core virome in R. prolixus and begin to shed light on the RNAi-based antiviral defenses in triatomines., Competing Interests: The authors have declared that no competing interests exist.

Candida albicans is the main fungal species associated with the development of oral candidiasis. Currently, therapeutic options for these infections are limited by the adverse effects of antifungal drugs and by the emergence of drug resistant strains. Thus, the development of new antifungal agents is needed for the prevention and treatment of oral Candida infections. Caffeic acid phenethyl ester (CAPE) is a natural compound from propolis polyphenolic groups that exhibits many pharmacological properties. In this study, we investigated whether CAPE can have antifungal and immunomodulatory effects on oral candidiasis. Preliminary tests to assess the antifungal activity of CAPE were performed using the Minimum Inhibitory Concentration (MIC) assay that demonstrated inhibition in a range from 16 to 32 μg/mL, confirming its antifungal activity on several C. albicans strains isolated from the oral cavity. Subsequently, we analyzed Candida spp biofilms formed in vitro , in which CAPE treatment at 5 x MIC caused a reduction of 68.5% in the total biomass and ~2.60 Log in the viable cell count (CFU/mL) in relation to the untreated biofilm ( p <0.0001). Next, RNA was extracted from untreated and CAPE-treated biofilms and analyzed by real-time qPCR. A series of genes analyzed ( ALS1, ECE1, EPA1, HWP1 , YWP1, BCR1, BGR1, CPH1, EFG1 , NDT80, ROB1, TEC1 , UME6 , SAP2 , SAP5 , PBL2 , and LIP9 ) were downregulated by CAPE compared to the untreated control group ( p <0.0001). In in vivo studies using Galleria mellonella , the treatment with CAPE prolonged survival of larvae infected by C. albicans by 44.5% ( p < 0.05) and accompanied by a 2.07-fold increase in the number of hemocytes. Flow cytometry revealed the most prominent increases were in types P2 and P3 hemocytes, granular cells, which phagocytize pathogens. In addition, CAPE treatment decreased the fungal load in the hemolymph and stimulated the expression of antifungal peptide genes such as galiomicin and gallerimycin . The antifungal and immunomodulatory activities observed in G. mellonella were extended to a murine model of oral candidiasis, in which CAPE decreased the levels of C. albicans colonization (~2 log CFU/mL) in relation to the untreated control group. In addition, CAPE treatment significantly reduced pseudomembranous lesions, invasion of hyphae on epithelium surfaces, tissue damage and inflammatory infiltrate ( p < 0.05). CAPE was also able to increase the expression of β-defensin 3 compared to the infected and untreated group by 3.91-fold ( p < 0.0001). Taken together, these results show that CAPE has both antifungal and immunomodulatory effects, making it a promising natural antifungal agent for the treatment and prevention of candidiasis and shows impact to oral candidiasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Barros, Rossoni, Garcia, Kaminski, Loures, Fuchs, Mylonakis and Junqueira.)

Objective: The oral and oropharyngeal squamous cell carcinoma (OOSCC) accounts for 90-95% of tumours in the oral cavity. Single nucleotide polymorphism (SNP) in the coding region of PON1, tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) have been associated with to development of different cancers. Our aim was to investigate the prognostic value of PON1 (rs854560 and rs662), TNF-α (rs1800629 and rs361525) and TGF-β (rs1800469) SNPs in OOSCC., Materials and Methods: We genotyped 163 OOSCC patients and 146 patients from group of control for PON1 (rs854560 and rs662), TNF-α (rs1800629 and rs361525) and TGF-β (rs1800469) SNPs by real-time polymerase chain reaction (PCR)., Results: TNF-α (rs1800629) GG genotype was significantly more frequent in intraoral lesions and clinical stages III and IV, while the polymorphic AA genotype in lip lesion and clinical stages I and II. Moreover, TGF-β (rs1800469) AG and AA genotypes were significantly more frequent in larger tumours (T3 e T4). TNF-α (rs1800629) AG genotype had poor survival and patients carrying the PON1 (rs662) TT genotype tended to poor survival., Conclusions: Results suggest that the rs1800629 and rs1800469 could exert influence in the more aggressive behaviour of OOSCC and the genotypes AG of rs1800629, and TT of rs662 could be markers with prognostic value in OOSCC.

Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults and the current treatments only have a modest effect on patient survival. Recent studies show that bozepinib (BZP), a purine derivative, has potential applications in cancer treatment. The aim of this study was to evaluate the effect of BZP against GBM cells, specially concerning the purinergic system. Thus, GBM cells (C6 and U138 cell lines) were treated with BZP and cell viability, cell cycle, and annexin/PI assays, and active caspase-3 measurements were carried out. Besides, the effect of BZP over the purinergic system was also evaluated in silico and in vitro. Finally, we evaluate the action of BZP against important markers related to cancer progression, such as Akt, NF-κB, and CD133. We demonstrate here that BZP reduces GBM cell viability (IC 50  = 5.7 ± 0.3 µM and 12.7 ± 1.5 µM, in C6 and U138 cells, respectively), inducing cell death through caspase-dependent apoptosis, autophagosome formation, activation of NF-κB, without any change in cell cycle progression or on the Akt pathway. Also, BZP modulates the purinergic system, inducing an increase in CD39 enzyme expression and activity, while inhibiting CD73 activity and adenosine formation, without altering CD73 enzyme expression. Curiously, one cycle of treatment resulted in enrichment of GBM cells expressing NF-κB and CD133 + , suggesting resistant cells selection. However, after another treatment round, the resistant cells were eliminated. Altogether, BZP presented in vitro anti-glioma activity, encouraging further in vivo studies in order to better understand its mechanism of action., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Use Lead-DBS software to analyze stereotactical surgical outcome of an operated population and demonstrate that small target deviations do not compromise the stimulation of desired structures, even with small amperages., Methods: Image exams of patients submitted to deep brain stimulation for movement disorders treatment were processed in Lead-DBS software. Electrode stereotactic coordinates were subtracted from the planned target and those deviations, compared among different anatomical targets and sides operated firstly and secondly. We also quantified the frequency of relation between the activated tissue volume and the planned target through computer simulations., Results: None of the 16 electrodes were exactly implanted at the planned coordinates. A stimulation of 3 mA reached 62.5% of the times the planned coordinates, rising to 68.75% with a 3,5 mA. No statistical significance was demonstrated in any comparison of laterality and anatomical sites., Conclusions: The simulation of small amperage fields could reach the intended target even when electrode placement is suboptimal. Furthermore, such a goal can be achieved without overlapping the volume of activated tissue with undesired structures. Software Lead-DBS proved to be a valuable complementary asset for surgical stereotactical result assessment.

The scope of this article is to identify factors associated with personal autonomy among the elderly. It is a systematic review of analytical epidemiological studies selected from the PubMed, Web of Science, Scopus and Lilacs databases, without time and language constraints. The search located 3,435 articles and selection was conducted in two phases: reading of abstracts and entire articles, with inclusion and exclusion criteria, by two independent reviewers, resulting in seven selected studies. The risk of bias was assessed using the Newcastle-Ottawa Scale protocol. All studies included were of sectional design and analyzed autonomy from the perspective of the perception of increased autonomy. The instruments used were the Hertz Perceived Entity of Autonomy Scale and the Chinese version of Perceived Enactment of Autonomy Scale. The factors associated with the autonomy of the elderly identified were grouped by functionality, family relations, interpersonal relations, life perception, satisfaction with health services, demographic factors, schooling, general health status and quality of life. The study of personal autonomy among the elderly presented a multifactorial and biopsychosocial character, although it is a recent theme in which further research with more detailed scientific evidence is necessary.

The human body experiences physiological changes under microgravity environment that phenocopy aging on Earth. These changes include early onset osteoporosis, skeletal muscle atrophy, cardiac dysfunction, and immunosenescence, and such adaptations to the space environment may pose some risk to crewed missions to Mars. To investigate the effect of microgravity on aging, many model organisms have been used such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and mice. Herein we report that the budding yeast Saccharomyces cerevisiae show decreased replicative lifespan (RLS) under simulated microgravity in a clinostat. The reduction of yeast lifespan is not a result of decreased tolerance to heat shock or oxidative stress and could be overcome either by deletion of FOB1 or calorie restriction, two known interventions that extend yeast RLS. Deletion of the sirtuin gene SIR2 worsens the simulated microgravity effect on RLS, and together with the fob1Δ mutant phenotype, it suggests that simulated microgravity augments the formation of extrachromosomal rDNA circles, which accumulate in yeast during aging. We also show that the chronological lifespan in minimal medium was not changed when cells were grown in the clinostat. Our data suggest that the reduction in longevity due to simulated microgravity is conserved in yeast, worms, and flies, and these findings may have potential implications for future crewed missions in space, as well as the use of microgravity as a model for human aging., (Copyright © 2020 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Background: The compensatory effect of exercise on total volume of physical activity and food intake has been described as a possible explanation for the limited body weight loss observed during exercise interventions., Objective: To investigate the effect of different exercise intensities on total volume of physical activity and energy intake amongst active men with overweight., Design: Young men with overweight from a naval academy (n = 72; mean ± SD, age 21 ± 2 years, BMI 27.9 ± 2.13 kg/m 2 ) were randomised to a control group (CG), moderate-intensity (MEG), or vigorous-intensity exercise group (VEG). MEG and VEG performed exercise sessions three times per week, for 60 min, during a 2-week period. Physical activity was assessed using triaxial accelerometers for 13 days. Energy intake was assessed at four time-points by 24-hour food recall. Intention-to-treat analyses were performed using linear mixed effect models., Results: MEG and VEG presented a greater compensatory effect in the total volume of physical activity over time compared to CG, with a significant difference in the rate of change between VEG and CG (∆ = -250,503 counts vs. ∆ = -61,306 counts, respectively; p = 0.01), and MEG and CG (∆ = -253,336 counts vs. ∆ = -61,306 counts, respectively; p = 0.01). There was no difference between MEG and VEG (p = 0.97). Changes in energy intake were not different between groups (p = 0.18); however, MEG presented greater energy intake compared to CG (β=491 kcal/day; p = 0.01) and VEG (β=319 kcal/day; p = 0.07). VEG presented a greater reduction in body weight compared to MEG (-1.3 kg vs. -0.4 kg; p = 0.03) and CG (-1.3 kg vs. -0.6 kg; p = 0.07)., Conclusions: Two weeks of exercise promoted a compensatory effect in total volume of physical activity in active men with overweight, regardless of exercise intensity. The compensatory effect was not observed for energy intake, although there was a trend for higher absolute energy intake in the MEG. Consequently, individuals in the VEG showed greater reduction in body weight over the intervention period., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Verbesina macrophylla (Cass.) S.F.Blake is a medicinal plant from South America, popularly known as "asa de peixe", "asa de peixe branco", "cambará branco" or "cambará guaçu", being used by traditional communities for its healing powers in the form of teas, infusions, liqueurs and extracts, for the treatment of bacterial and fungal infections of the urinary and respiratory tracts, such as kidney problems, bronchitis, inflammation and fever. However, none of the ethnopharmacological properties has been scientifically evaluated., Aim of the Study: Based on the ethnopharmacological use of the species, this study investigated the chemical composition, and for the first time acute toxicity, hemolytic, antimicrobial, anti-inflammatory and antipyretic activities of the essential oil from leaves of V. macrophylla., Material and Methods: The essential oil was obtained from the leaves by hydrodistillation (HD), being characterized by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography coupled to flame ionization detection (GC-FID). The antimicrobial activity was evaluated by the broth microdilution technique in bacteria and fungi that cause infections of the respiratory and urinary tract, and toxicological safety regarding hemolytic activity on human red blood cells (hRBCs), and acute toxicity in mice. The anti-inflammatory activity was evaluated by the model carrageenan-induced peritonitis with quantification of the levels of TNF-α and IL-1β in the intraperitoneal fluid, and ear edema induced by croton oil. The antipyretic activity evaluated in mice with pyrexia induced by yeast., Results: The extraction of essential oil by hydrodistillation (HD) showed a yield of 0.33 ± 0.04%, with its composition constituted mainly by sesquiterpenes of hydrocarbons (94.00%). The essential oil demonstrated antibacterial and antifungal activity, with a low rate of hemolysis in human red blood cells (hRBCs) and no clinical signs of toxicity were observed in animals after acute treatment, which suggested that the LD 50 is greater than 5000 mg/kg; p.o. The essential oil demonstrated anti-inflammatory activity reducing levels of pro-inflammatory cytokines TNF-α (38.83%, 72.42% and 73.52%) and IL-1β (37.70%, 75.92% and 87.71%), and ear edema by 49.53%, 85.04% and 94.39% at concentrations of 4, 40 and 400 mg/kg, respectively. The antipyretic activity presented by the essential oil is statistically similar to dipyrone., Conclusion: The set of results obtained, validates the main activities attributed to the traditional use of Verbesina macrophylla (Cass.) S.F.Blake. These data add industrial value to the species, considering that the antimicrobial, anti-inflammatory and antipyretic activities present results similar to the drugs already used also presenting safety. The results suggest that essential oil from V. macrophylla may be used by industry for the development of drugs with natural antimicrobial, anti-inflammatory and antipyretic effect., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The ongoing COVID-19 pandemic has caught the attention of the global community and rekindled the debate about our ability to prevent and manage outbreaks, epidemics, and pandemics. Many alternatives are suggested to address these urgent issues. Some of them are quite interesting, but with little practical application in the short or medium term. To realistically control infectious diseases, human, animal, and environmental factors need to be considered together, based on the One Health perspective. In this article, we highlight the most effective initiatives for the control and prevention of infectious diseases: vaccination; environmental sanitation; vector control; social programs that encourage a reduction in the population growth; control of urbanization; safe sex stimulation; testing; treatment of sexually and vertically transmitted infections; promotion of personal hygiene practices; food safety and proper nutrition; reduction of the human contact with wildlife and livestock; reduction of social inequalities; infectious disease surveillance; and biodiversity preservation. Subsequently, this article highlights the impacts of human genetics on susceptibility to infections and disease progression, using the SARS-CoV-2 infection as a study model. Finally, actions focused on mitigation of outbreaks and epidemics and the importance of conservation of ecosystems and translational ecology as public health strategies are also discussed.

Rhodnius prolixus is a Triatominae insect species and a primary vector of Chagas disease. The genome of R. prolixus has been recently sequenced and partially assembled, but few transcriptome analyses have been performed to date. In this study, we describe the stage-specific transcriptomes obtained from previtellogenic stages of oogenesis and from mature eggs. By analyzing ~ 228 million paired-end RNA-Seq reads, we significantly improved the current genome annotations for 9206 genes. We provide extended 5' and 3' UTRs, complete Open Reading Frames, and alternative transcript variants. Strikingly, using a combination of genome-guided and de novo transcriptome assembly we found more than two thousand novel genes, thus increasing the number of genes in R. prolixus from 15,738 to 17,864. We used the improved transcriptome to investigate stage-specific gene expression profiles during R. prolixus oogenesis. Our data reveal that 11,127 genes are expressed in the early previtellogenic stage of oogenesis and their transcripts are deposited in the developing egg including key factors regulating germline development, genome integrity, and the maternal-zygotic transition. In addition, GO term analyses show that transcripts encoding components of the steroid hormone receptor pathway, cytoskeleton, and intracellular signaling are abundant in the mature eggs, where they likely control early embryonic development upon fertilization. Our results significantly improve the R. prolixus genome and transcriptome and provide novel insight into oogenesis and early embryogenesis in this medically relevant insect.

Isoxazoline is a 5-membered heterocycle present in the active compounds of many commercial veterinary anti-ectoparasitic products. The molecular target of isoxazolines is the inhibition of GABA-gated chloride channels in insects. These facts have inspired the use of the isoxazoline scaffold in the design of novel insecticide compounds. The main strategies used for isoxazoline synthesis are either the 1,3-dipolar cycloaddition between a nitrile oxide and an alkene or the reaction between hydroxylamine and an α,β-unsaturated carbonyl compound. This review highlights the utilization of isoxazoline as insecticide: its mode of action, its commercial preparations and its consideration in the design of novel insecticides. Similarity analyses were performed with 235 isoxazoline derivatives in three different cheminformatic approaches - chemical property correlations, similarity network and compound clustering. The cheminformatic methodologies are interesting tools to use in evaluating the similarity between commercial isoxazolines and to clarify the main features explored within their derivatives., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

5-Fluorouracil (5-FU) is an antineoplastic drug that causes, as a side effect, intestinal mucositis, acute inflammation in the small bowel. The Heat Shock Protein (Hsp) are highly expressed in inflammatory conditions, developing an important role in immune modulation. Thus, they are potential candidates for the treatment of inflammatory diseases. In the mucositis mouse model, the present study aimed to evaluate the beneficial effect of oral administration of milk fermented by Lactobacillus delbrueckii CIDCA 133 (pExu: hsp65 ), a recombinant strain. This approach showed increased levels of sIgA in the intestinal fluid, reducing inflammatory infiltrate and intestinal permeability. Additionally, the histological score was improved. Protection was associated with a reduction in the gene expression of pro-inflammatory cytokines such as Tnf, Il6, Il12, and Il1b, and an increase in Il10, Muc2, and claudin 1 (Cldn1) and 2 (Cldn2) gene expression in ileum tissue. These findings are corroborated with the increased number of goblet cells, the electronic microscopy images, and the reduction of intestinal permeability. The administration of milk fermented by this recombinant probiotic strain was also able to reverse the high levels of gene expression of Tlrs caused by the 5-FU. Thus, the rCIDCA 133:Hsp65 strain was revealed to be a promising preventive strategy for small bowel inflammation.

Objective: To assess the effectiveness of different anesthetic solutions for pain control immediately after the extraction of lower third molars., Methods: Nine databases were used to identify randomized clinical trials, without restriction of language or year of publication. The "JBI Critical Appraisal Tools for Systematic Reviews" was used to assess the risk of bias in the studies. The network meta-analysis was performed to compare the effectiveness of different anesthetics to control the pain immediately after the surgery of lower third molars, using the standardized mean difference (SMD) as the effect estimate. The GRADE approach was used to assess the certainty of evidence., Results: The search presented 13,739 initial results, from which 45 met the eligibility criteria and presented low to moderate risk of bias. Thirteen studies were included in the meta-analysis. The 2% lidocaine + clonidine presented the lowest pain scores (SMD = - 1.44; - 2.72 to - 0.16) compared to 4% articaine + adrenaline, followed by 0.5% bupivacaine + adrenaline (SMD = - 1.36; - 2.13 to - 0.59). The certainty of evidence varied between very low to moderate., Conclusion: 2% lidocaine + clonidine and 0.5% bupivacaine + adrenaline were the anesthetics with the highest probability for pain control immediately after the surgical procedure of removing impacted lower third molars., Clinical Significance: The use of an adequate anesthetic with effective pain control can contribute to a more comfortable postoperative period.

Lactic acid bacteria comprise a large group of Gram-positive organisms capable of converting sugar into lactic acid. They have been studied due to their therapeutic potential on the mucosal surface. Among the species, Lactococcus lactis is considered the model bacterium and it has been explored as an important vehicle for providing therapeutic molecules and antigens in the mucosa. They can be genetically engineered to produce a variety of molecules as well as deliver heterologous DNA and protein. DNA vaccines consist of the administration of a bacterial plasmid under the control of a eukaryotic promoter encoding the antigen of interest. The resulting proteins are capable of stimulating the immune system, becoming a promising technique for immunization against a variety of tumors and infection diseases and having several advantages compared to conventional nucleic acid delivery methods (such as bioballistic delivery, electroporation, and intramuscular administration).

The complexity of Chagas disease is still a challenge in endemic regions and an emergent public health problem in non-endemic countries. The causative agent of this neglected tropical disease, Trypanosoma cruzi, is mainly transmitted by triatomine vectors and possesses multiple epidemiologically important strains. Current chemotherapeutics are outdated and their limited efficacy is one of the major reasons for treatment discontinuation. In this context, the development of novel, safe and economically accessible antichagasic drugs is required. Various classes of heterocycles and natural compounds have been described as potential antichagasic scaffolds, and coumarins are no exception. These versatile compounds have a wide spectrum of biological activities, and numerous natural and synthetic coumarins have been reported with antichagasic potential. This review aims to discuss the available literature between 2001 and 2020 regarding natural and synthetic coumarins with anti- Trypanosoma cruzi activity. Moreover, some of the studies herein comprised are dedicated to the potential of coumarins to inhibit promising targets in Trypanosoma cruzi., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

BRAF, NRAS and TERT mutations occur in more than 2/3 of melanomas. Its detection in patient's blood, as circulating tumor DNA (ctDNA), represents a possibility for identification and monitoring of metastatic disease. We proposed to standardize a liquid biopsy platform to identify hotspot mutations in BRAF, NRAS and TERT in plasma samples from advanced melanoma patients and investigate whether it was associated to clinical outcome. Firstly, we performed digital polymerase chain reaction using tumor cell lines for validation and determination of limit of detection (LOD) of each assay and screened plasma samples from healthy individuals to determine the limit of blank (LOB). Then, we selected 19 stage III and IV patients and determined the somatic mutations status in tumor tissue and track them in patients' plasma. We established a specific and sensitive methodology with a LOD ranging from 0.13 to 0.37%, and LOB ranging from of 0 to 5.201 copies/reaction. Somatic mutations occurred in 17/19 (89%) patients, of whom seven (41%) had ctDNA detectable their paired plasma. ctDNA detection was associated with shorter progression free survival (p = 0.01). In conclusion, our data support the use of ctDNA as prognosis biomarker, suggesting that patients with detectable levels have an unfavorable outcome.

Objectives: To evaluate athletes' frequency of attendance at the eye clinic during the Olympic and Paralympic Games Rio 2016 and to correlate it to WHO core indicators on progress in ophthalmology care in a country., Methods: Frequencies of athletes' attendance at the eye clinic were calculated for each country. Countries were classified according to the World Bank income levels in high, upper-middle, low-middle or low-income country. Data on ophthalmology care for each country were derived from the International Agency for the Prevention of Blindness atlas. Data were analysed in view of WHO indicators for each country: visual impairment prevalence considering presenting visual acuity <6/18 to ≥3/60 in the better vision eye; number of ophthalmologists per million people and the cataract surgical rate per year, per million population., Results: The athletes' overall frequency of attendance in the eye clinic was 6.47%. Frequencies of attendance for high, upper-middle, low-middle or low-income country were 1.97%, 9.66%, 16.54% and 22.43%, respectively. A positive correlation was observed between the athletes' attendance frequency of a country and its visual impairment prevalence (r=0.2290, p=0.0017). A negative correlation was observed between the athletes' attendance frequency of a country and its eye health workforce (r=-0.2152, p=0.0026)., Conclusion: Countries with highest athletes' frequencies of attendance were those that face barriers to eye care provision. These results reinforce the importance of the eye clinic service during the Olympic and Paralympic Games proving access to specialised care to athletes and members of delegation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Acca sellowiana (feijoa) and Eugenia involucrata (cherry) are fruits species of Brazilian biodiversity (Myrtaceae family). In this study, a sampling process was used with three different harvesting sites. The composition of phenolic compounds of these fruits was determined by HPLC-DAD-MS/MS. Moreover, the antioxidant capacity of hydroethanolic extracts against hydrogen peroxide (H 2 O 2 ), hydroxyl (OH), peroxyl (ROO - ) and ABTS radicals was evaluated. Thirty and twenty-seven phenolic compounds were identified in feijoa and cherry, respectively. The major phenolic compounds found were pedunculagin isomer (5040.87, 3443.66 and 1324.95 μg·g -1 ) in feijoa and procyanidin (1406.54, 1888.00 and 1380.64 μg·g -1 ) in cherry. Hydroethanolic extract of these fruits was a potent scavenger of free radicals and excellent source of phenolic compounds. In hydroethanolic extracts of feijoa, the phenolic content increased by around 50%, while in the cherry the content was similar to that found in the fruit. For ORAC method, sample 2 of feijoa and cherry showed values of 383 and 126 µM·TE·g -1 , respectively, featuring the highest antioxidant capacity. This study is the first to report the identification of castalagin, catechin and epicatechin in feijoa, and rutin in cherry. Besides, the health benefits, these fruits can contribute to biodiversity conservation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Despite the advances in the cure rate for acute myeloid leukemia (AML), a considerable number of patients die from the disease due to the occurrence of multidrug resistance (MDR). Overexpression of the transporter proteins, such as P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP), confers resistance to the treatment of these leukemias., Methods: To analyze the expression of the Pgp and MRP1 in patients with AML and determine their correlation between expression and demographic, clinical, and laboratorial variables, bone marrow and peripheral blood samples from 346 patients with a diagnosis of AML were assessed for the expression of Pgp and MRP1 by flow cytometry., Results: The expression of Pgp and MRP1 was found in 111 (32.1%) and 133 (38.4%) patients, respectively, with greater prevalence in older patients and lower in children, while also observing a high incidence in patients with refractory, recurrence, and secondary disease in comparison with the cases of de novo AML. Regarding the laboratory findings, we observed an association between the expression of Pgp and MRP1 and CD34, CD7, and also M7, M5a, and M2-AML of French-American-British classification., Conclusions: The results showed that the detection of MDR phenotype by flow cytometry can be a molecular marker for prognosis of patients with AML., (© 2020 John Wiley & Sons Ltd.)

Human HSP27 is a small heat shock protein that modulates the ability of cells to respond to heat shock and oxidative stress, and also functions as a chaperone independent of ATP, participating in the proteasomal degradation of proteins. The expression of HSP27 is associated with survival in mammalian cells. In cancer cells, it confers resistance to chemotherapy; in neurons, HSP27 has a positive effect on neuronal viability in models of Alzheimer's and Parkinson's diseases. To better understand the mechanism by which HSP27 expression contributes to cell survival, we expressed human HSP27 in the budding yeast Saccharomyces cerevisiae under control of different mutant TEF promoters, that conferred nine levels of graded basal expression, and showed that replicative lifespan and proteasomal activity increase as well as the resistance to oxidative and thermal stresses. The profile of these phenotypes display a dose-response effect characteristic of hormesis, an adaptive phenomenon that is observed when cells are exposed to increasing amounts of stress or toxic substances. The hormetic response correlates with changes in expression levels of HSP27 and also with its oligomeric states when correlated to survival assays. Our results indicate that fine tuning of HSP27 concentration could be used as a strategy for cancer therapy, and also for improving neuronal survival in neurodegenerative diseases.

The identification of inflammatory markers in HIV+ individuals on ART is fundamental since chronic ART-controlled HIV infection is linked to an increased inflammatory state. In this context, we assessed plasma levels of pro-inflammatory cytokines (IL-1β, IL-8, and IL-12p70) of HIV+ individuals who initiated ART after immunosuppression (CD4 + T cell counts <350 cells/mm 3 ). HIV+ individuals were stratified according to two extreme phenotypes: Slow Progressors (SPs; individuals with at least 8 years of infection before ART initiation) and Rapid Progressors (RPs; individuals who needed to initiate ART within 1-4 years after infection). A control group was composed of HIV-uninfected individuals. We found increased IL-8 levels (median: 5.13 pg/mL; SPs and RPs together) in HIV-infected individuals on ART as compared to controls (median: 3.2 pg/mL; p = 0.04), although no association with the progression profile (slow or rapid progressors) or CD4 + T cell counts at sampling was observed. This result indicates that IL-8 is a general marker of chronic inflammation in HIV+ individuals on ART, independently of CD4 + T cell counts at the beginning of the treatment or of the potential progression profile of the patient. In this sense, IL-8 may be considered a possible target for novel therapies focused on reducing inflammation in chronic HIV infection., Competing Interests: Declaration of Competing Interest We have no conflicts of interest regarding this study., (Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Intestinal mucositis, a cytotoxic side effect of the antineoplastic drug 5-fluorouracil (5-FU), is characterized by ulceration, inflammation, diarrhea, and intense abdominal pain, making it an important issue for clinical medicine. Given the seriousness of the problem, therapeutic alternatives have been sought as a means to ameliorate, prevent, and treat this condition. Among the alternatives available to address this side effect of treatment with 5-FU, the most promising has been the use of probiotics, prebiotics, synbiotics, and paraprobiotics. This review addresses the administration of these "biotics" as a therapeutic alternative for intestinal mucositis caused by 5-FU. It describes the effects and benefits related to their use as well as their potential for patient care., (Copyright © 2020 Batista, da Silva, de Jesus, Coelho-Rocha, Barroso, Tavares, Azevedo, Mancha-Agresti and Drumond.)

Indoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFNγ) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human C-C chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: This study describes swallow-related quality of life (SWAL-QOL) in patients with myotonic dystrophy type 1 (DM1) and investigates its association with swallowing function and disease severity., Methods: A SWAL-QOL questionnaire was completed by 75 DM1 patients and 25 healthy control subjects. The severity of the disease was evaluated using the muscular impairment rating scale (MIRS). Twenty-eight DM1 patients underwent a videofluroscopic swallowing examination (VFS). Spearman's correlation coefficient was used to measure the direction and strength of associations., Results: The SWAL-QOL median scores were significantly lower for the DM1 group than for the healthy control group. The scores for the majority of the SWAL-QOL domains were lower in patients with proximal muscular weakness (MIRS 4 and 5). Postswallow vallecular pooling and piecemeal deglutition were the most impaired VFS outcome variables., Conclusion: Our results suggest that a multidimensional swallowing assessment is recommended for DM1 patients as SWAL-QOL and VFS measure different aspects of the swallowing function, thus providing complementary information.

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features.