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Mariele Feiffer Charão,1,2 Caroline Souto,2 Natália Brucker,1,2 Anelise Barth,1,2 Denise S Jornada,1,3 Daiandra Fagundez,4 Daiana Silva Ávila,4 Vera L Eifler-Lima,1,5 Silvia S Guterres,1,3 Adriana R Pohlmann,1,6 Solange Cristina Garcia1,21Post-Graduate Programme in Pharmaceutical Sciences, 2Laboratory of Toxicology (LATOX), Department of Analysis, Pharmacy Faculty, 3Department of Production and Control of Drugs, Pharmacy Faculty, Federal University of Rio Grande do Sul, Porto Alegre, 4Research Group in Biochemistry and Toxicology in Caenorhabditis elegans (GBToxCE), Federal University of Pampa – UNIPAMPA, Uruguaiana, 5Laboratory of Medical Synthesis Organic (LaSOM), Pharmacy Faculty, 6Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, RS, BrazilAbstract: Caenorhabditis elegans is an alternative in vivo model that is being successfully used to assess the pharmacological and toxic effects of drugs. The exponential growth of nanotechnology requires the use of alternative in vivo models to assess the toxic effects of theses nanomaterials. The use of polymeric nanocapsules has shown promising results for drug delivery. Moreover, these formulations have not been used in cases of intoxication, such as in treatment of paraquat (PQ) poisoning. Thus, the use of drugs with properties improved by nanotechnology is a promising approach to overcome the toxic effects of PQ. This research aimed to evaluate the absorption of rhodamine B-labeled melatonin (Mel)-loaded lipid-core nanocapsules (LNC) by C. elegans, the application of this model in nanotoxicology, and the protection of Mel-LNC against PQ damage. The formulations were prepared by self-assembly and characterized by particle sizing, zeta potential, drug content, and encapsulation efficiency. The results demonstrated that the formulations had narrow size distributions. Rhodamine B-labeled Mel-LNC were orally absorbed and distributed in the worms. The toxicity assessment of LNC showed a lethal dose 50% near the highest dose tested, indicating low toxicity of the nanocapsules. Moreover, pretreatment with Mel-LNC significantly increased the survival rate, reduced the reactive oxygen species, and maintained the development in C. elegans exposed to PQ compared to those worms that were either untreated or pretreated with free Mel. These results demonstrated for the first time the uptake and distribution of Mel-LNC by a nematode, and indicate that while LNC is not toxic, Mel-LNC prevents the effects of PQ poisoning. Thus, C. elegans may be an interesting alternative model to test the nanocapsules toxicity and efficacy.Keywords: C. elegans, nanotoxicology, rhodamine B-labeled polymer

Background: This study aimed to identify and describe links between pain medication use and self-reported pain among people aged ≥ 50 years with osteoarthritis (OA) in an Irish population, and to examine the relationships between pain, medication usage and socioeconomic and clinical characteristics., Methods: Secondary data analysis of wave 1 cross-sectional data from The Irish Longitudinal Study on Ageing (TILDA) was undertaken of 1042 people with self-reported doctor-diagnosed OA. We examined use of medications typically included in OA clinical guidelines, including non-opioid analgesics (e.g. paracetamol), topical and oral non-steroidal anti-inflammatory drugs (NSAIDs), opioids and nutraceuticals. Latent Class Analysis (LCA) was used to identify underlying clinical subgroups based on medication usage patterns, and self-reported pain severity. Multinomial logistic regression was used to explore sociodemographic and clinical characteristic links to latent class membership., Results: A total of 358 (34.4%) of the 1042 people in this analysis were taking pain medications including oral NSAIDs (17.5%), analgesics (11.4%) and opioids (8.7%). Nutraceutical (glucosamine/chondroitin) use was reported by 8.6% and topical NSAID use reported by 1.4%. Three latent classes were identified: (1) Low medication use/no pain (n = 382, 37%), (2) low medication use/moderate pain (n = 523, 50%) and (3) moderate medication use/high pain (n = 137, 13%). Poorer self-rated health and greater sleep disturbance were associated with classes 2 and 3; depressive symptoms and female gender were associated with class 2, and retirement associated with class 3., Conclusions: Whilst pain medication use varied with pain severity, different medication types reported broadly aligned with OA guidelines. The two subgroups exhibiting higher pain levels demonstrated poorer self-rated health and greater sleep disturbance., (© 2024. The Author(s).)

Background: Identifying mosquito vectors is crucial for controlling diseases. Automated identification studies using the convolutional neural network (CNN) have been conducted for some urban mosquito vectors but not yet for sylvatic mosquito vectors that transmit the yellow fever. We evaluated the ability of the AlexNet CNN to identify four mosquito species: Aedes serratus, Aedes scapularis, Haemagogus leucocelaenus and Sabethes albiprivus and whether there is variation in AlexNet's ability to classify mosquitoes based on pictures of four different body regions., Methods: The specimens were photographed using a cell phone connected to a stereoscope. Photographs were taken of the full-body, pronotum and lateral view of the thorax, which were pre-processed to train the AlexNet algorithm. The evaluation was based on the confusion matrix, the accuracy (ten pseudo-replicates) and the confidence interval for each experiment., Results: Our study found that the AlexNet can accurately identify mosquito pictures of the genus Aedes, Sabethes and Haemagogus with over 90% accuracy. Furthermore, the algorithm performance did not change according to the body regions submitted. It is worth noting that the state of preservation of the mosquitoes, which were often damaged, may have affected the network's ability to differentiate between these species and thus accuracy rates could have been even higher., Conclusions: Our results support the idea of applying CNNs for artificial intelligence (AI)-driven identification of mosquito vectors of tropical diseases. This approach can potentially be used in the surveillance of yellow fever vectors by health services and the population as well., (© 2024. The Author(s).)

Ethnopharmacology Relevance: The plants of Amaryllidaceae family, such as Amaryllis belladonna L., have been used as herbal remedies for thousands of years to address various disorders, including diseases that might today be identified as cancer., Aim of the Study: The objective of this work was to evaluate the potential of three Amaryllidaceae alkaloids against four cancer cell lines., Material and Methods: The alkaloids lycorine, 1-O-acetylcaranine, and montanine were evaluated in vitro against colon adenocarcinoma cell line (HCT-116) and breast carcinoma cell lines (MCF-7, MDAMB231, and Hs578T). Computational experiments (target prediction and molecular docking) were conducted to gain a deeper comprehension of possible interactions between these alkaloids and potential targets associated with these tumor cells., Results: Montanine presented the best results against HCT-116, MDAMB231, and Hs578T cell lines, while lycorine was the most active against MCF-7. In alignment with the target prediction outcomes and existing literature, four potential targets were chosen for the molecular docking analysis: CDK8, EGFR, ER-alpha, and dCK. The docking scores revealed two potential targets for the alkaloids with scores similar to co-crystallized inhibitors and substrates: CDK8 and dCK. A visual analysis of the optimal docked configurations indicates that the alkaloids may interact with some key residues in contrast to the other docked compounds. This observation implies their potential to bind effectively to both targets., Conclusions: In vitro and in silico results corroborate with data literature suggesting the Amaryllidaceae alkaloids as interesting molecules with antitumoral properties, especially montanine, which showed the best in vitro results against colorectal and breast carcinoma. More studies are necessary to confirm the targets and pharmaceutical potential of montanine against these cancer cell lines., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Paracoccidioidomycosis (PCM), a systemic mycosis in Latin America, is regulated by suppressive mechanisms mediated by tolerogenic plasmacytoid-dendritic-cells and regulatory T-cells. Our recent studies revealed that myeloid-derived suppressor cells (MDSCs), are important mediators in PCM. Their suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, IDO-1 and PD-L1. Studies revealed the chemotherapeutic drug 5-Fluorouracil (5-FU) as a selective MDSC apoptosis-inducing agent, but its in vivo effect on infectious processes remains poorly investigated., Methods: MDSCs and other leukocytes were evaluated in the lungs of 5-FU-treated mice after four, six, and eight weeks of P. brasiliensis infection. Disease severity and immunological response were evaluated in MDSCs-depleted., Results: 5-FU treatment caused a significant reduction of pulmonary MDSCs and fungal loads. The specific depletion of MDSCs by 5-FU reduced all pulmonary CD4+ T-cell populations (Th1, Th2, Th17, and Treg) resulting in improved tissue pathology and increased survival rates. Importantly, this reduction was concomitant with increased frequencies of Th1/Th17 cells and the increased levels of Th1/Th2/Th17 cytokines in the lungs and liver of treated mice suggesting an early and efficient protective effect of these cells. Furthermore, the immuneprotection conferred by the specific depletion of MDSCs by 5FU treatment could be reversed by the adoptive transfer of MDSCs., Conclusions: 5-FU treatment depletes lung-MDSCs of P. brasiliensis-infected mice resulting in enhanced immunity. The protective effect of 5-FU treatment in pulmonary PCM suggests that the specific depletion of MDSCs can be viewed as a potential immunotherapeutic tool for PCM., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Paracoccidioidomycosis (PCM) is a systemic endemic fungal disease prevalent in Latin America. Previous studies revealed that host immunity against PCM is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO-1), regulatory T-cells (Tregs), and through the recruitment and activation of myeloid-derived suppressor cells (MDSCs). We have recently shown that Dectin-1, TLR2, and TLR4 signaling influence the IDO-1-mediated suppression caused by MDSCs. However, the contribution of these receptors in the production of important immunosuppressive molecules used by MDSCs has not yet been explored in pulmonary PCM., Methods: We evaluated the expression of PD-L1, IL-10, as well as nitrotyrosine by MDSCs after anti-Dectin-1, anti-TLR2, and anti-TLR4 antibody treatment followed by P. brasiliensis yeasts challenge in vitro . We also investigated the influence of PD-L1, IL-10, and nitrotyrosine in the suppressive activity of lung-infiltrating MDSCs of C57BL/6-WT, Dectin-1KO, TLR2KO, and TLR4KO mice after in vivo fungal infection. The suppressive activity of MDSCs was evaluated in cocultures of isolated MDSCs with activated T-cells., Results: A reduced expression of IL-10 and nitrotyrosine was observed after in vitro anti-Dectin-1 treatment of MDSCs challenged with fungal cells. This finding was further confirmed in vitro and in vivo by using Dectin-1KO mice. Furthermore, MDSCs derived from Dectin-1KO mice showed a significantly reduced immunosuppressive activity on the proliferation of CD4 + and CD8 + T lymphocytes. Blocking of TLR2 and TLR4 by mAbs and using MDSCs from TLR2KO and TLR4KO mice also reduced the production of suppressive molecules induced by fungal challenge. In vitro , MDSCs from TLR4KO mice presented a reduced suppressive capacity over the proliferation of CD4 + T-cells., Conclusion: We showed that the pathogen recognition receptors (PRRs) Dectin-1, TLR2, and TLR4 contribute to the suppressive activity of MDSCs by inducing the expression of several immunosuppressive molecules such as PD-L1, IL-10, and nitrotyrosine. This is the first demonstration of a complex network of PRRs signaling in the induction of several suppressive molecules by MDSCs and its contribution to the immunosuppressive mechanisms that control immunity and severity of pulmonary PCM., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kaminski, Borges, Santos, Preite, Calich and Loures.)

Litterfall is the main source of dry deposition of mercury (Hg) into the soil in forest ecosystems. The accumulation of Hg in soil and litter suggests the possibility of transfer to terrestrial invertebrates through environmental exposure or ingestion of plant tissues. We quantified total mercury (THg) concentrations in two soil layers (organic: 0-0.2 m; mineral: 0.8-1 m), litter, fresh leaves, and terrestrial invertebrates of the Araguaia River floodplain, aiming to evaluate the THg distribution among terrestrial compartments, bioaccumulation in invertebrates, and the factors influencing THg concentrations in soil and invertebrates. The mean THg concentrations were significantly different between the compartments evaluated, being higher in organic soil compared to mineral soil, and higher in litter compared to mineral soil and fresh leaves. Soil organic matter content was positively related to THg concentration in this compartment. The order Araneae showed significantly higher Hg concentrations among the most abundant invertebrate taxa. The higher Hg concentrations in Araneae were positively influenced by the concentrations determined in litter and individuals of the order Hymenoptera, confirming the process of biomagnification in the terrestrial trophic chain. In contrast, the THg concentrations in Coleoptera, Orthoptera and Hymenoptera were not significantly related to the concentrations determined in the soil, litter and fresh leaves. Our results showed the importance of organic matter for the immobilization of THg in the soil and indicated the process of biomagnification in the terrestrial food web, providing insights for future studies on the environmental distribution of Hg in floodplains., 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 © 2024 Elsevier Inc. All rights reserved.)

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer with poor 5-year survival rates. Surgery and radiation are the current first-line treatments for local and nodal disease., Objectives: The Brazilian Society of Surgical Oncology developed this document aiming to guide the surgical oncology role in multimodal MCC management., Methods: The consensus was established in three rounds of online discussion, achieving consensus on specific topics including diagnosis, staging, treatment, and follow-up., Results: Patients suspected of having MCC should undergo immunohistochemical examination and preferably undergo pathology review by a dermatopathologist. Initial staging should be performed with dermatologic and nodal physical examination, combined with complementary imaging. Whole-body imaging, preferably with positron emission tomography (PET) or computed tomography (CT) scans, are recommended. Due to the need for multidisciplinary approaches, we recommend that all cases should be discussed in tumor boards and referred to other specialties as soon as possible, reducing potential treatment delays. We recommend that all patients with clinical stage I or II may undergo local excision associated with sentinel lymph node biopsy. The decision on margin size should consider time to recovery, patient's comorbidities, and risk factors. Patients with positive sentinel lymph nodes or the presence of risk factors should undergo postoperative radiation therapy at the primary site. Exclusive radiation is a viable option for patients with low performance. Patients with positive sentinel lymph node biopsy should undergo nodal radiation therapy or lymphadenectomy. In patients with nodal clinical disease, in addition to primary tumor treatment, nodal radiation therapy and/or lymphadenectomy are recommended. Patients with advanced disease should preferably be enrolled in clinical trials and discussed in multidisciplinary meetings. The role of surgery and radiation therapy in the metastatic/advanced setting should be discussed individually and always in tumor boards., Conclusion: This document aims to standardize a protocol for initial assessment and treatment for Merkel cell carcinoma, optimizing oncologic outcomes in middle-income countries such as Brazil., (© 2024 Wiley Periodicals LLC.)

Objective: To analyze whether the COVID-19 pandemic had an impact on the screening, diagnosis and treatment of breast cancer in women up to 50 years of age in the state of Pará., Methods: Retrospective, cross-sectional study with a quantitative approach, using data from the Information Technology Department of the Brazilian Unified Health System. (DATASUS). The number of exams carried out in the pre-pandemic (2018-2019) and pandemic (2020-2021) period was analyzed based on the percentage variation, application of the chi-square test and G test for the time of exams and start time of treatment., Results: During the pandemic period, there was a greater number of screening mammograms (+3.68%), cytological (+23.68%), histological (+10.7%) and a lower number of diagnostic mammograms (-38.7%). The time interval for carrying out the exams was up to 30 days for screening and diagnostic exams and more than 60 days to start treatment during the pandemic period., Conclusion: Although the results indicate an increase in the number of screening and diagnostic procedures for breast cancer during the pandemic period, with the exception of diagnostic mammography, when considering probability values, the study points out that statistically the COVID-19 pandemic did not interfere with actions of breast cancer, in women over 50 years of age, in the state of Pará. Considering the autonomy of nursing and its role in public health, it is up to the professionals who are in charge of primary care programs to implement contingency plans in periods of crisis so that the population is not left unassisted., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright� by the Universidad de Antioquia.)

Background: The community of lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other identities (LGBTQIA+), comprising sexual and gender minorities, frequently encounters violence, discrimination, and numerous obstacles in accessing health care services. Pharmacists have the potential to significantly contribute to the health care provision for this community., Objective: To assess pharmacists' perceptions regarding academic preparedness and health care provision for the LGBTQIA+ community in Brazil., Methods: An online cross-sectional survey was conducted from August 2022 to February 2023, focusing on the academic training of pharmacists and the provision of health care to the LGBTQIA+ community in Brazil. Data collection was achieved through a 28-question online questionnaire, comprising both closed-ended questions, and Likert-type items. The study variables were subjected to an exploratory descriptive analysis., Results: We received 261 complete and valid responses. A majority of pharmacists indicated that they provided health care to the LGBTQIA+ community (n = 161, 61.7%); however, they lacked formal education on LGBTQIA+ health care during their pharmacy program (n = 256, 98.1%). Most participants strongly agreed that pharmacists play a crucial role in promoting health care for this community (n = 213, 81.6%). However, only a small percentage felt confident in addressing issues related to the effectiveness and safety of hormone use for transgender patients (n = 38, 14.6%). Furthermore, less than a third believed that the health care provided by pharmacists should be differentiated for patients within and outside of the LGBTQIA+ community (n = 76, 29.1%)., Conclusion: The results of this study underscore the necessity and significance of incorporating this topic both in pharmacy training and continuing education. This approach is crucial to enhance and bolster the clinical practice of pharmacists., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Orthoflavivirus ilheusense (ILHV) is a member of the Flaviviridae family. It was first isolated in 1944 from pools of Aedes serratus and Psorophora ferox mosquitoes; however, it has also been detected in species of the genus Culex , such as Cx . portesi and Cx . coronator . The objective of this study was to examine the vector competence of Cx . quinquefasciatus mosquitoes to ILHV infection and the subsequent transmission of the virus through their saliva during feeding on blood., Methods: F1 generation females of Cx . quinquefasciatus (Ananindeua/PA) were orally infected with goose blood infected with strain BeH7445, and body, head and saliva samples were analyzed at 7, 14, and 21 dpi using the techniques of virus isolation in cells and indirect immunofluorescence., Results: The presence of ILHV was not detected in the body and head samples of Cx . quinquefasciatus females at any of the three dpi's analyzed, indicating that the lineage of mosquitoes analyzed was resistant to ILHV., Conclusions: According to the results obtained in this study, the species Cx . quinquefasciatus proved resistant to ILHV, regardless of the virus titers to which it was exposed, which suggests the possibility that this species does not act as a vector in the ILHV transmission cycle.

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Preite, Borges, Kaminski, Ayupe, Gonçalves, dos Santos, Fonseca, Filgueiras, Salgado, Muxel, Cabral-Marques, da Fonseca, Loures and Calich.)

Mercury (Hg) is a chemical element that, depending on its concentration, may become toxic to living organisms due to the ability of Hg to bioaccumulate in food chains. In this study, we collected samples of soil, litter, and organisms in the Middle Araguaia floodplain, Brazil. Total mercury (THg) concentrations in litter were significantly higher (p < 0.0001) than that in soil, ranging from 10.68 ± 0.55 to 48.94 ± 0.13 and 20.80 ± 1.07 to 55 .19 ± 1.59 ng g -1 , respectively. Total mercury concentration levels in soil showed a linear, inversely proportional relationship with soil organic matter (SOM) contents and soil pH, consistent with the geochemical behavior of chemical elements in flooded environments. Ten orders of organisms were identified, and the average THg concentrations determined in their bodies were up to 20 times higher than those in soil and litter. We found a significant linear relationship between the levels of THg in litter and those found in soil organisms, thereby allowing the prediction of THg concentration levels in soil organisms through the analysis of litter at the sample units. The different dynamics and feeding habits of soil organisms and the concentration of THg in these organisms may be influenced by the river's course. This study provides evidence of the bioaccumulation of THg in soil organisms in the floodplain of the Middle Araguaia River, an important river basin in the Brazilian savanna., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Regulatory T lymphocytes play a critical role in immune regulation and are involved in the aberrant cell elimination by facilitating tumor necrosis factor connection to the TNFR2 receptor, encoded by the TNFRSF1B polymorphic gene. We aimed to examine the effects of single nucleotide variants TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T on the clinicopathological characteristics and survival of cutaneous melanoma (CM) patients. Patients were genotyped using RT-PCR. TNFRSF1B levels were measured using qPCR. Luciferase reporter assay evaluated the interaction of miR-96 and miR-1271 with the 3'-UTR of TNFRSF1B . The c.587TT genotype was more common in patients younger than 54 years old than in older patients. Patients with c.*922CT or TT, c.587TG or GG + c.*922CT or TT genotypes, as well as those with the haplotype TATT, presented a higher risk of tumor progression and death due to the disease effects. Individuals with the c.*922TT genotype had a higher TNFRSF1B expression than those with the CC genotype. miR-1271 had less efficient binding with the 3'-UTR of the T allele when compared with the C allele of the SNV c.*922C>T. Our findings, for the first time, demonstrate that TNFRSF1B c.587T>G and c.*922C>T variants can serve as independent prognostic factors in CM patients.

Objectives: To investigate, through a network meta-analysis, the effectiveness of blood concentrates in reducing pain perception, trismus, and edema after mandibular third molar extraction., Materials and Methods: An electronic search was performed in nine databases to locate randomized clinical trials comparing blood concentrate use after mandibular third molar extraction. Two authors selected and extracted the data independently. The individual risk of bias in the studies was assessed with the RoB v2.0 tool. A network meta-analysis compared postoperative pain and trismus scores after applying different blood concentrates, using the mean difference (MD) as an effect estimate. The GRADE approach assessed the certainty of evidence., Results: Thirty-one randomized clinical trials were included in the review and 18 in the meta-analysis. Leukocyte- and platelet-rich fibrin (L-PRF) was the most used blood concentrate, followed by platelet-rich plasma (PRP). The network meta-analysis, depending on the analyzed period, evaluated up to 1240 surgeries. Among the analyzed blood concentrates, advanced platelet-rich fibrin (A-PRF) performed better among the analyzed blood concentrates, decreasing postoperative pain in 1, 2, 3, and 7 days and reducing trismus up to the inflammatory peak compared to blood clots. Only two studies had a low risk of bias., Conclusions: Based on very low certainty of evidence, using concentrates seemed efficient compared to blood clots in reducing pain and trismus after mandibular third molar surgeries. A-PRF decreased postoperative pain throughout the evaluated time and trismus during the acute inflammatory peak., Clinical Relevance: A-PRF after mandibular third molar extractions performed better among the analyzed blood concentrates and seemed efficient in improving postoperative quality by decreasing inflammatory signs and symptoms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Radiosurgery for multiple brain metastases has been more reported recently without using whole-brain radiotherapy. Nevertheless, the sparsity of the data still claims more information about toxicity and survival and their association with both dosimetric and geometric aspects of this treatment., Aim: To assess the toxicity and survival outcome of radiosurgery in patients with multiple (four or more lesions) brain metastases., Methods: In a single institution, data were collected retrospectively from patients who underwent radiosurgery to treat brain metastases from diverse primary sites. Patients with 4-21 brain metastases were treated with a single fraction with a dose of 18 Gy or 20 Gy. The clinical variables collected were relevant to toxicity, survival, treatment response, planning, and dosimetric variables. The Spearman's rank correlation coefficients, Mann-Whitney test, Kruskal-Wallis test, and Log-rank test were used according to the type of variable and outcomes., Results: From August 2017 to February 2020, 55 patients were evaluated. Headache was the most common complaint (38.2%). The median overall survival (OS) for patients with karnofsky performance status (KPS) > 70 was 8.9 mo, and this was 3.6 mo for those with KPS ≤ 70 ( P = 0.047). Patients with treated lesions had a median progression-free survival of 7.6 mo. There were no differences in OS (19.7 vs 9.5 mo) or progression-free survival (10.6 vs 6.3 mo) based on prior irradiation. There was no correlation found between reported toxicities and planning, dosimetric, and geometric variables, implying that no additional significant toxicity risks appear to be added to the treatment of multiple (four or more) lesions., Conclusion: No associations were found between the evaluated toxicities and the planning dosimetric parameters, and no differences in survival rates were detected based on previous treatment status., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Altered immune response during pregnancy has been associated with ASD susceptibility. HLA-G is expressed by the trophoblast at the maternal/fetal interface and induces allogenic tolerance toward the fetus. A 14-bp insertion in the HLA-G 3'UTR (rs371194629) was associated with reduced levels of HLA-G. We aimed to assess the influence of the HLA-G*14 bp indel variant in ASD susceptibility and symptomatology in a Brazilian admixed sample. The insertion genotype (14 bp+/14 bp+) was firstly associated with hetero aggression, but statistical significance was lost after correction (p = 0.035, p corrected  = 0.35). No association between the HLA-G variant and susceptibility to ASD or differential clinical manifestations were observed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest regarding this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Lipolytic substance injections to reduce localized fat have been extensively used because it is a low-invasive method. This review aimed to evaluate the efficacy and safety of deoxycholic acid in submental fat reduction compared to a placebo and investigate the potential industry sponsorship bias in the results of randomized clinical trials on this topic. Ten electronic databases were extensively searched for randomized clinical trials without restriction on language and year of publication. Two reviewers extracted the data and assessed the individual risk of bias in the studies with the RoB 2.0 tool. The industry sponsorship bias was evaluated according to citations in the articles regarding industry funding/sponsorship throughout the texts. Fixed and random effects meta-analyses were performed, and the results were reported in Risk Ratio (RR) at a 95% Confidence Interval (95% CI). The initial search provided 5756 results, of which only five were included. Only two studies had a low risk of bias. All studies showed a potential industry bias. The meta-analysis showed that patients treated with deoxycholic acid had significant positive results for all efficacy outcomes and a higher risk of fibrosis, pain, erythema, numbness, swelling, edema, pruritus, nodules, headache, and paresthesia. The low to moderate certainty of evidence found allows concluding that deoxycholic acid is effective in submental fat reduction, causing well-tolerated adverse effects. However, all eligible studies showed a potential industry bias., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Granulomas are important immunological structures in the host defense against the fungus Paracoccidioides brasiliensis , the main etiologic agent of Paracoccidioidomycosis (PCM), a granulomatous systemic mycosis endemic in Latin America. We have performed transcriptional and proteomic studies of yeasts present in the pulmonary granulomas of PCM aiming to identify relevant genes and proteins that act under stressing conditions. C57BL/6 mice were infected with 1x10 6 yeasts and after 8- and 12-weeks of infection, granulomatous lesions were obtained for extraction of fungal and murine RNAs and fungal proteins. Dual transcriptional profiling was done comparing lung cells and P. brasiliensis yeasts from granulomas with uninfected lung cells and the original yeast suspension used in the infection, respectively. Mouse transcripts indicated a lung malfunction, with low expression of genes related to muscle contraction and organization. In addition, an increased expression of transcripts related to the activity of neutrophils, eosinophils, macrophages, lymphocytes as well as an elevated expression of IL-1β, TNF-α, IFN-γ, IL-17 transcripts were observed. The increased expression of transcripts for CTLA-4, PD-1 and arginase-1, provided evidence of immune regulatory mechanisms within the granulomatous lesions. Also, our results indicate iron as a key element for the granuloma to function, where a high number of transcripts related to fungal siderophores for iron uptake was observed, a mechanism of fungal virulence not previously described in granulomas. Furthermore, transcriptomics and proteomics analyzes indicated a low fungal activity within the granuloma, as demonstrated by the decreased expression of genes and proteins related to energy metabolism and cell cycle., Competing Interests: The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Borges, Ramos, Preite, Kaminski, Alves de Castro, Camacho, Maximo, Fill, Calich, Traynor, Sarikaya-Bayram, Doyle, Bayram, de Campos, Zelanis, Goldman and Loures.)

Aims: To gain insights into the barriers towards the prevention and/or reduction of involuntary treatment in long-term geriatric care., Design: Mixed methods., Background: Measures to which a person resists and/or does not provide consent for are defined as involuntary treatment. The use of involuntary treatment violates the autonomy of (older) persons and causes more harm than benefit. Moreover, it contradicts the values of person-centred care. Nevertheless, its use among people living with dementia (PLWD) is still common practice., Methods: We conducted a cross-sectional, mixed methods study, including an online survey for professional caregivers and a semistructured focus group interview with professional caregivers., Results: A total of 218 participants completed the questionnaire. The percentage of participants who perceived barriers in one of the 22 survey items ranged from 15% to 42%. Lack of time, the experienced need to use involuntary treatment, uncertainty about responsibilities of stakeholders and a lack of knowledge on methods to prevent and/or reduce the use of involuntary treatment were most seen as barriers. Nursing staff perceived a lack of time hindering them in the prevention or reduction of involuntary treatment more often than other professional caregivers. Working in home care and having no former experience with involuntary treatment usage increased perceived barriers. Participants of the focus group interview confirmed these findings and added that professional caregivers in general lack awareness on the concept of involuntary treatment., Conclusions: One out of four professional caregivers experiences barriers hindering prevention and/or reduction of involuntary treatment. More research is needed to gain a better understanding of how professional caregivers can be supported to remove barriers and, consequently, prevent and/or reduce the use of involuntary treatment., Relevance to Clinical Practice: Professional caregivers experience many barriers towards the prevention and reduction of involuntary treatment. Future initiatives should aim to remove the perceived barriers., (© 2023 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to compare the use of fibrin glue on the corneal epitheliectomy site at the end of pterygium surgery versus conventional eye patch regarding pain levels, need for oral analgesic medications, number of days feeling pain, and awakening due to pain after surgery., Methods: Forty-eight eyes of 24 patients with bilateral primary pterygium were included in this prospective, randomized, double-masked controlled trial. Each eye of the same patient was randomized to the intervention or control group. The intervention group received 2 drops of fibrin glue in the epitheliectomy site at the end of surgery and an eye patch, whereas the control group was only received an eye patch. Patients returned on the first and seventh days after surgery. Pain intensity (measured using the visual pain analog scale), need for oral analgesics, the number of days the pain lasted, and quality of sleep were assessed during follow-up visits and compared between groups. Comparison analysis accounted for sex, age, pterygium grading, and comorbidities., Results: Visual analog pain scale after surgery was significantly lower in eyes receiving fibrin glue (-1.58; 95% confidence interval: -2.84 to -0.32; P = 0.014). In addition, the intervention group presented a 73% lower chance of using oral analgesics (OR: 0.27; 95% confidence interval: 0.07-0.95; P = 0.041). No difference in the awakenings at night was noted ( P = 0.240) nor the mean days of ocular pain in the first week after surgery ( P = 0.474)., Conclusions: Fibrin glue at the end of pterygium surgery effectively reduces pain and the need for oral analgesics compared with conventional eye patching. This study is the first to describe the results of this strategy., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: to analyze the knowledge of community health agents about hearing and language development milestones in early childhood, in the context of home visits, before and after a team cooperation workshop., Methods: action research was developed, with a quantitative and qualitative approach., Results: Significant contribution to the agents' learning, enriching their home visit practices., Conclusion: Team cooperation is an important tool to qualify the performance of community health agents regarding guidelines on hearing and language milestones in early childhood.

Bladder cancer is the fourth most common malignancy in men. It can present along the entire continuum of severity, from mild to well-differentiated disease to extremely malignant tumors with low survival rates. Human RAS genes are the most frequently mutated oncogenes in human cancers, and the critical role of aberrant Ras protein function in carcinogenesis is well established. Therefore, considerable efforts have been devoted to the development of anti-Ras inhibitors for cancer treatment. This study presents the biphenyl dihydropyrimidinone LaSOM 335 with high activity against T24 bladder cancer cells (IC 50  = 10.73 ± 0.53 μM) and selectivity of cytotoxicity for this cancer cell line compared to two non-cancer cell lines investigated. Furthermore, we also show that this compound reduced vulvar development in the mutant let-60 gene of Caenorhabditis elegans. Let-60 is a homolog of the mammalian Ras gene. In addition, we observed that LaSOM 335 inhibits the enzymatic activity of CD73 and decreases CD73 expression. Possibly, this expression decrease is due to downstream EGFR signaling via the Ras-Raf-ERK pathway, that directly regulates CD73 expression via ERK1/2. Evidence suggests that non-immunomodulating functions of CD73 play an equally important role for cancer cell survival, progression, and migration. Regarding we also notice that LaSOM 335 was safe in the in vivo model of C. elegans. The set of these findings makes this biphenyl dihydropyrimidinone a promising candidate for further investigations in the bladder cancer field., (© 2023 John Wiley & Sons Ltd.)

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders mainly characterized by repetitive, restrictive and stereotypical behaviors, and impaired communication skills. Several lines of evidence indicate that alterations of the immune system account for ASD development, including the presence of brain-reactive antibodies, abnormal T cell activation, altered cytokine levels in brain, cerebrospinal fluid and peripheral blood circulation, increased levels of circulating monocytes, and dysregulation in Natural Killer (NK) cells activity. Regarding NK cells, a lower cytotoxic activity, a higher level of activation and an increased number of these cells in individuals with ASD have been described. In 2019, a study showed that NK cells derived from patients with ASD show a characteristic pattern of NKG2C overexpression, highlighting the importance of the NK cell pathway in ASD. In fact, the study of genes related to NK cell activity has proven to be an excellent research target, both in terms of susceptibility as well as a marker for the different clinical manifestations observed in ASD individuals. Here, we evaluated the influence of KLRC2 gene deletion as well as KLRK1 rs1049174 and rs2255336 variants in a cohort of 185 children diagnosed with ASD and their respective biological parents in southern Brazil. Of note, this is the first study concerning genetic variants of the KLRC2 and KLRK1 genes in an ASD sample. The KLRC2 gene deletion (p = 0.001; pc = 0.009), KLRK1 rs1049174 (p = 0.005; pc = 0.045) and KLRK1 rs2255336 (p = 0.001; pc = 0.009) were associated with epilepsy in ASD patients. The results indicate that KLRC2 deletion, KLRK1 rs2255336, and KLRK1 rs1049174 could be involved in epilepsy manifestation in ASD patients, possibly impacting the NK dysregulation already described in ASD and epileptic patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Paracoccidioidomycosis (PCM) is a systemic mycosis with a high incidence in Latin America. Prior studies have demonstrated the significance of the enzyme Indoleamine 2,3-dioxygenase (IDO-1) in the immune regulation of PCM as well as the vital role of myeloid-derived suppressor cells (MDSCs) in moderating PCM severity. Additionally, Dectin-1 and Toll-Like Receptors (TLRs) signaling in cancer, infection, and autoimmune diseases have been shown to impact MDSC-IDO-1 + activity. To expand our understanding of MDSCs and the role of IDO-1 and pattern recognition receptors (PRRs) signaling in PCM, we generated MDSCs in vitro and administered an IDO-1 inhibitor before challenging the cells with Paracoccidioides brasiliensis yeasts. By co-culturing MDSCs with lymphocytes, we assessed T-cell proliferation to examine the influence of IDO-1 on MDSC activity. Moreover, we utilized specific antibodies and MDSCs from Dectin-1, TLR4, and TLR2 knockout mice to evaluate the effect of these PRRs on IDO-1 production by MDSCs. We confirmed the importance of these in vitro findings by assessing MDSC-IDO-1 + in the lungs of mice following the fungal infection. Taken together, our data show that IDO-1 expression by MDSCs is crucial for the control of T-cell proliferation, and the production of this enzyme is partially dependent on Dectin-1, TLR2, and TLR4 signaling during murine PCM., (© 2023. The Author(s).)

Ticks are vectors for several pathogens, including bacteria belonging to the Rickettsia genus, such as Rickettsia rickettsii and Rickettsia parkeri, the causative agents of spotted fever. The aim of the present study was to investigate the tick species richness and rickettsial agents associated with wild birds captured in the Humaita Forest Reserve, Acre, in the Western Amazon region. Wild birds were captured with ornithological nets for visual inspection with the purpose of collecting ticks, which were identified through morphological analyses and molecular tests for several genes (12S rDNA, 16S rDNA, gltA, ompA, and sca4). A total of 607 wild birds were captured, 12% of which were parasitized by 268 ticks of the Amblyomma genus, with new host-parasite associations reported for Amblyomma calcaratum, Amblyomma geayi, Amblyomma longirostre, Amblyomma naponense, Amblyomma nodosum, and Amblyomma varium. Of the total ticks collected, 113 were tested for the presence of rickettsial DNA fragments, with 19 testing positive for R. parkeri in A. geayi, Rickettsia tamurae-like in Amblyomma sp., and Rickettsia amblyommatis in A. geayi, A. longirostre, and Amblyomma sp. We detected R. tamurae-like in Amblyomma larvae for the first time in the Western Brazilian Amazon biome, and registered spotted fever group rickettsiae, although the relevance of the detected species in a public health context should be further explored in South America, as well as new host-parasite interactions in this underexplored region., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Intestinal mucositis is a commonly reported side effect in oncology patients undergoing chemotherapy and radiotherapy. Probiotics, prebiotics, and synbiotics have been investigated as alternative therapeutic approaches against intestinal mucositis due to their well-known anti-inflammatory properties and health benefits to the host. Previous studies showed that the potential probiotic Lactobacillus delbrueckii CIDCA 133 and the prebiotic Fructooligosaccharides (FOS) alleviated the 5-Fluorouracil (5-FU) chemotherapy-induced intestinal mucosa damage. Based on these previous beneficial effects, this work evaluated the anti-inflammatory property of the synbiotic formulation containing L. delbrueckii CIDCA 133 and FOS in mice intestinal mucosa inflammation induced by 5-FU. This work showed that the synbiotic formulation was able to modulate inflammatory parameters, including reduction of cellular inflammatory infiltration, gene expression downregulation of Tlr2, Nfkb1, and Tnf, and upregulation of the immunoregulatory Il10 cytokine, thus protecting the intestinal mucosa from epithelial damage caused by the 5-FU. The synbiotic also improved the epithelial barrier function by upregulating mRNA transcript levels of the short chain fatty acid (SCFA)-associated GPR43 receptor and the occludin tight junction protein, with the subsequent reduction of paracellular intestinal permeability. The data obtained showed that this synbiotic formulation could be a promising adjuvant treatment to be explored against inflammatory damage caused by 5-FU chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders usually observed in early life, with impacts on behavioral and social skills. Incidence of ASD has been dramatically increasing worldwide, possibly due to increase in awareness/diagnosis as well as to genetic and environmental triggers. Currently, it is estimated that ∼1% of the world population presents ASD symptoms. In addition to its genetic background, environmental and immune-related factors also influence the ASD etiology. In this context, maternal immune activation (MIA) has recently been suggested as a component potentially involved in ASD development. In addition, extracellular vesicles (EVs) are abundant at the maternal-fetal interface and are actively involved in the immunoregulation required for a healthy pregnancy. Considering that alterations in concentration and content of EVs have also been associated with ASD, this article raises a debate about the potential roles of EVs in the processes surrounding MIA. This represents the major differential of the present review compared to other ASD studies. To support the suggested correlations and hypotheses, findings regarding the roles of EVs during pregnancy and potential influences on ASD are discussed, along with a review and update concerning the participation of infections, cytokine unbalances, overweight and obesity, maternal anti-fetal brain antibodies, maternal fever, gestational diabetes, preeclampsia, labor type and microbiota unbalances in MIA and ASD., Competing Interests: The authors declare no competing interests.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, (© 2023 The Authors.)

Viruses with encephalitogenic potential can cause neurological conditions of clinical and epidemiological importance, such as Saint Louis encephalitis virus , Venezuelan equine encephalitis virus , Eastern equine encephalitis virus , Western equine encephalitis virus , Dengue virus , Zika virus , Chikungunya virus , Mayaro virus and West Nile virus . The objective of the present study was to determine the number of arboviruses with neuroinvasive potential isolated in Brazil that corresponds to the collection of viral samples belonging to the Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute (SAARB/IEC) of the Laboratory Network of National Reference for Arbovirus Diagnosis from 1954 to 2022. In the analyzed period, a total of 1,347 arbovirus samples with encephalitogenic potential were isolated from mice; 5,065 human samples were isolated exclusively by cell culture; and 676 viruses were isolated from mosquitoes. The emergence of new arboviruses may be responsible for diseases still unknown to humans, making the Amazon region a hotspot for infectious diseases due to its fauna and flora species characteristics. The detection of circulating arboviruses with the potential to cause neuroinvasive diseases is constant, which justifies the continuation of active epidemiological surveillance work that offers adequate support to the public health system regarding the virological diagnosis of circulating arboviruses in Brazil.

Immune checkpoint blockade (ICB) agents are prominent immunotherapies for the treatment of advanced melanoma. However, they fail to promote any durable clinical benefit in a large cohort of patients. This study assessed clinical and molecular predictors of ICB response and survival in advanced melanoma. A retrospective analysis was performed on 210 patients treated with PD-1 or CTLA-4 inhibitors at Barretos Cancer Hospital, Brazil. PD-L1 expression was assessed by immunohistochemistry using formalin-fixed paraffin-embedded tumor tissues collected prior to ICB therapy. Patients were divided into responders (complete and partial response and stable disease for more than 6 months) and non-responders (stable disease for less than 6 months and progressive disease). Among them, about 82% underwent anti-PD-1 immunotherapy, and 60.5% progressed after the ICB treatment. Patients that received ICB as first-line therapy showed higher response rates than previously treated patients. Higher response rates were further associated with superficial spreading melanomas and positive PD-L1 expression (>1%). Likewise, PD-L1 positive expression and BRAF V600 mutations were associated with a higher overall survival after ICB therapy. Since ICBs are expensive therapies, evaluation of PD-L1 tumor expression in melanoma patients should be routinely assessed to select patients that are most likely to respond.

Four coumarin-triazole hybrids were selected from our in house library and screened for cytotoxic activity on A549 (lung cancer), HepG2 (liver cancer), J774A1 (mouse sarcoma macrophage), MCF7 (breast cancer), OVACAR (ovarian cancer), RAW (murine leukaemia macrophage), and SiHa (uterus carcinoma) and their in vitro toxicity was assessed on 3T3 (healthy fibroblasts) cell lines. SwissADME pharmacokinetic prediction was performed. Effects on ROS production, mitochondrial membrane potential, apoptosis/necrosis and DNA damage were evaluated. All of the hybrids have good pharmacokinetic predictions. Each of them showed cytotoxic activity against the MCF7 breast cancer cell line, with IC 50 between 2.66 and 10.08 μM, lower than cisplatin (45.33 μM) for the same test. One can observe an order of reactivity from the most potent: LaSOM 186 > LaSOM 190 > LaSOM 185 > LaSOM 180, with a better selectivity index than the reference drug cisplatin and the precursor hymecromone, and caused cell death by apoptosis induction. Two compounds showed antioxidant activity in vitro and three disrupted the mitochondrial membrane potential. None of the hybrids caused genotoxic damage to healthy 3T3 cells. All hybrids showed potential for further optimization, mechanism elucidation, in vivo activity and toxicity tests., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The purinergic signaling has drawn attention from academia and more recently from pharmaceutical industries as a potential therapeutic route for cancer treatment, since ATP may act as chemotactic agent and possess in vitro antineoplastic activity. On the other way, adenosine, produced in extracellular medium by ecto-5'-NT, acts as immunosuppressor and is related to neoangiogenesis, vasculogenesis and evasion to the immune system. Consequently, inhibitors of ecto-5'-NT may prevent tumor progression, reducing adenosine concentrations, preventing escape from the host's immune system and slowing cancer's growth. This review aims to highlight important biochemical and structural features of ecto-5'NT, highlight its expression profile in normal and cancer cell lines detailing compounds which may act as expression regulators and to review the several classes of ecto-5'NT inhibitors developed in the past 12 years, in order to build a general structure-activity relationship model to guide further compound design., 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 © 2022 Elsevier Masson SAS. All rights reserved.)

The complex epidemiological profile of Brazil, the aging population and the proportion of individuals with disabilities have led to a substantial increase in the demand for rehabilitation. The spatiotemporal distribution of the offer of physiotherapy, speech therapy and occupational therapy in the Brazilian public healthcare system from 2007 to 2019 was analyzed for the five macro-regions of the country. Data from the National Register of Health Establishments and census estimates from the Brazilian Institute of Geography and Statistics were used. Indicators of the offer of professionals in these fields services and relative changes in the offer were calculated. The spatial distribution of the relative change in the offer was also determined. A regression model with inflection points was adopted for the analysis of the temporal trend. A growing temporal trend was found in the offer of the three professionals in Brazil as a whole and in all regions of the country, but with a slowdown in growth. Differences were observed in the offer among the regions of the country, revealing healthcare inequality that needs to be overcome. The present findings can assist in planning to expand access to rehabilitation services in the country.

Previous studies on paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that host immunity is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO-1), and regulatory T-cells (Tregs). IDO-1 orchestrates local and systemic immunosuppressive effects through the recruitment and activation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells possessing a potent ability to suppress T-cell responses. However, the involvement of MDSCs in PCM remains uninvestigated. The presence, phenotype, and immunosuppressive activity of MDSCs were evaluated at 96 h, 2 weeks, and 8 weeks of pulmonary infection in C57BL/6 mice. Disease severity and immune responses were assessed in MDSC-depleted and nondepleted mice using an anti-Gr1 antibody. Both monocytic-like MDSCs (M-MDSCs) and polymorphonuclear-like MDSCs (PMN-MDSCs) massively infiltrated the lungs during Paracoccidioides brasiliensis infection. Partial reduction of MDSC frequency led to a robust Th1/Th17 lymphocyte response, resulting in regressive disease with a reduced fungal burden on target organs, diminishing lung pathology, and reducing mortality ratio compared with control IgG2b-treated mice. The suppressive activity of MDSCs on CD4 and CD8 T-lymphocytes and Th1/Th17 cells was also demonstrated in vitro using coculture experiments. Conversely, adoptive transfer of MDSCs to recipient P. brasiliensis -infected mice resulted in a more severe disease. Taken together, our data showed that the increased influx of MDSCs into the lungs was linked to more severe disease and impaired Th1 and Th17 protective responses. However, protective immunity was rescued by anti-Gr1 treatment, resulting in a less severe disease and controlled tissue pathology. In conclusion, MDSCs have emerged as potential target cells for the adjuvant therapy of PCM., 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 © 2023 Preite, Kaminski, Borges, Calich and Loures.)

Background: Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section). Some dimeric acylphloroglucinols, such as uliginosin B, display similar pharmacological activities, namely antidepressant and antinociceptive. However, there is no knowledge about the pharmacokinetic profile and no toxicity studies of these compounds in intact mammals., Objective: To perform an in silico evaluation of the similarity, pharmacokinetics and toxicity (ADMET) properties of dimeric acylphloroglucinols from species native to Central and South America., Methods: ADMET prediction of eleven elected phloroglucinols followed by the chemical space evaluation of thirty-five dimeric acylphloroglucinols derivatives labeled according to their prenylation/ geranylation pattern through principal component analysis (PCA). The similarity analysis was performed using the Tanimoto similarity index. ADMET properties were predicted with the opensource software SwissADME and pkCSM-pharmacokinetics., Results: Several compounds showed good human intestinal absorption. However, they may present difficulties in crossing the blood-brain barrier, probably due to the high tPSA values. The predicted toxicity parameters indicated that most compounds have low toxicity. Most non-prenylated phloroglucinols were disposed into Lipinski's rule limits. Uliginosin B, isouliginosin B and japonicin A seem to be druglike compounds. The PCA model explained 77.49% of the total variance, and molecular similarity analyses revealed some expected similarities between isomers and different compounds., Conclusion: Dimeric acylphloroglucinols may be promising drug candidates and deserve further pharmacological and medicinal chemistry studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This systematic review explored the literature pertaining to patient exposure to bisphenol A (BPA) through medical-hospital devices. The acronym PICO: Patient (Medical-hospital devices), Intervention/Exposure (Bisphenol A), Comparison (Different grades of exposure) and Outcome (Assessment of exposure levels) was used. The databases used were LILACS, IBECS, MEDLINE, Capes Journal Portal, Food Science Source, FSTA and CINAHL with Full Text from EBSCO, Embase and Scopus by Elsevier, Web of Science and SCIELO. A total of 9747 references were found. After removing duplicate records, 7129 studies remained. After applying exclusion criteria and qualitative analysis, 12 articles remained. Studies have shown associations between the use of medical-hospital devices and patients' exposure to BPA. For chronic renal patients, there was an association between plasma BPA and disease severity. This review identifies that exposure to BPA is increased after the use of medical-hospital devices. More studies that address the clinical outcome of patients exposed to medical-hospital materials containing BPA are needed., 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 © 2022 Elsevier B.V. All rights reserved.)

The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Prcis: We investigate the efficacy of triple-fixed-combination of bimatoprost/brimonidine/timolol once and twice a day, demonstrating higher intraocular pressure reduction with once-a-day use, and discuss possible implications based on previous literature., Purpose: The purpose of this study was to compare the efficacy of a fixed combination bimatoprost-timolol-brimonidine (Triplenex) instilled once-daily with twice-daily in primary open angle glaucoma., Patients and Methods: A randomized clinical trial at a public eye care institution. Thirty patients with primary open angle glaucoma were followed up for 3 months. The right and left eyes of these patients were randomly assigned to once-daily (10:00  pm ) or twice-daily (10:00  am ; 10:00  pm ) regimens of fixed combination bimatoprost-timolol-brimonidine. Intraocular pressure peaks were obtained with the water drinking test before the introduction of this medication (basal WDT0), 1 month (WDT1), 2 months (WDT2), and 3 months (WDT3) after starting the use of the fixed combination of bimatoprost/timolol/brimonidine (Triplenex). Variation from peak intraocular pressure at WDT3 to peak at WDT0 was compared within groups of 2 versus once-daily regimen., Results: Sixty eyes of 30 patients (age: 70.67±9.70 y) were included in this study. Baseline clinical characteristics were comparable between groups. The mean reduction in peak intraocular pressure from WDT0 to WDT3 was 6.1±6.1 mm Hg (30.5%) in the eyes receiving 1 drop per day and 4.3±5.7 mm Hg (21.5%) in the eyes receiving 2 drops per day ( P =0.023). Mean reduction in peak intraocular pressure considering all WDT was also higher in the group with once-a-day treatment (5.90±6.03 vs. 4.46±4.28 mm Hg, P =0.006)., Conclusion: Fixed combination of bimatoprost 0.01%, brimonidine tartrate 0.15%, and timolol maleate 0.5% once-a-day is more effective in reducing peak intraocular pressure as measured by the WDT than twice-a-day dosing., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Alterations in lipid and lipoprotein metabolism are factors that trigger several negative metabolic complications. Hyperlipidemia is the starting point for the development of comorbidities of the cardiovascular system, such as atherosclerosis. The search for compounds that reduce high levels of total cholesterol and triglycerides has been widely reported in several publications in the literature. Phthalimide derivatives have been extensively researched with various biological actions. In this study we evaluated the antihyperlipidemic ability of three phthalimide derivatives (FGT-2, FGT-3 and FGT-4) on a model of obesity and insulin resistance in mice. The animals were submitted to a hyperlipid diet for 60 days. On the thirtieth day they were treated with phthalimides (20 mg/kg). The positive control group was treated with Simvastatin (20 mg/kg) and the negative control received only the carboxymethylcellulose vehicle. Biochemical and histological analyzes of all groups were analyzed. The animals treated with phthalimidic derivatives had a reduction in total cholesterol, low density and very low density lipoproteins (LDL-c and VLDL-c), triglycerides and fasting glycemia when compared to the negative control group. The treated animals also showed good results when analyzing the atherogenic indexes Castelli i and II and the ratio Triglycerides/HDL-c. In the oral glucose tolerance test and in the insulin tolerance test, animals treated with phthalimides were more sensitive to the action of the hormone regulating carbohydrate uptake. In the evaluation of the transaminases (AST/ALT), the animals of the group treated with phthalimides presented a lower elevation than the other groups of the experiment, the same observed with the uric acid evaluation. Histological analyzes were performed on liver, kidney, heart and pancreas samples. The groups treated with the compounds FGT-2 and FGT3 presented discrete alterations in the liver and kidney. FGT-4 did not present histological alterations for both tissues and the three phthalimide derivatives did not cause alterations in the other organs. These results suggest that the phthalimides tested can act as antihyperlipidemic agents and have a pleiotropic action, by acting also reducing glycemia in insulin resistance model mimicking diabetes mellitus type 2. These compounds may appear as a new approach in the treatment of obesity and complications, which are multifaceted., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Circular single stranded DNA viruses (CRESS DNA) encoding a homologous replication-associated protein (REP) have been identified in most of eukaryotic groups. It is not clear yet the role in human diseases or details of the life cycle of these viruses. Recently, much interest has been raised in the evolutionary history of CRESS DNA owing to the increasing number of new sequences obtained by Next-Generation Sequencing (NGS) in distinct host species. In this study we describe two full-length CRESS DNA genomes obtained of two newly diagnosed HIV patients from São Paulo State, Brazil. The initial BLASTx search indicated that both sequences (named SP-FFB/2020 and SP-MJMS/2020) are highly similar (98%) to a previous CRESS DNA sequence detected in human fecal sample from Peru in 2016 and designated as pecovirus (Peruvian stool-associated circo-like virus). This study reported for the first time the Human feces pecovirus in the feces of two newly diagnosed HIV patients in Brazil. Our comparative analysis showed that although pecoviruses in South America share an identical genome structure they diverge and form distinct clades. Thus, we suggest the circulation of different species of pecoviruses in Latin America. Nevertheless, further studies must be done to examine the pathogenicity of this virus., Competing Interests: The authors have declared that no competing interests exist.

A new virus, named Mutum virus, related to members of the family Tymoviridae, was isolated from mosquitoes (Mansonia spp.) in clone C6/36 cells, and its complete genome was sequenced. Its genome is 6494 nt in size with an organization resembling that of tymovirids. The isolated virus is phylogenetically related to two viruses isolated from Culex spp. mosquitoes: Ek Balam virus, reported in Mexico, and Culex-originated Tymoviridae-like virus, isolated in China. The results of this study suggest that this virus is a new member of the family Tymoviridae., (© 2022. The Author(s).)

One in two persons living with dementia (PLWD) at home receive care which they resist to and/or have not given consent to, defined as involuntary treatment. District nurses play a key role in the use of involuntary treatment. However, little is known how their attitudes and opinions influence the use of involuntary treatment. This cross-sectional study aims to investigate the attitudes of district nurses towards the use of involuntary treatment in dementia care at home, determinants and their opinion about its restrictiveness and discomfort. Results show that district nurses perceive involuntary treatment as regular part of nursing care, having neither positive nor negative attitude towards its appropriateness. They consider involuntary treatment usage as moderately restrictive to PLWD and feel moderately uncomfortable when using it. These findings underscore the need to increase the awareness of district nurses regarding the negative consequences of involuntary treatment use to PLWD at home., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.