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Background: Bothrops venom consists primarily of metalloproteinase and phospholipase A2 toxins, which are responsible for the acute inflammatory, coagulant and hemorrhagic action following snakebite. The local effects of snakebite envenomation by Bothrops species are particularly prevalent yet poorly studied, but include pain, edema, erythema, blistering, bleeding, and ecchymosis. Methods and findings: In this study, we describe the dermatopathological findings observed in a series of 22 patients diagnosed with Bothrops envenomation treated in a tertiary hospital of Manaus, in the Brazilian Amazon. Clinically, pain and edema were observed in all patients, followed by fang marks (63.6%), secondary infection (36.3%), ecchymosis (31.8%), erythema (22.7%), blister (13.6%), and necrosis (4.5%). Regarding histopathological findings, epidermal alterations such as spongiosis, acanthosis and hyperkeratosis were the most observed characteristics in our cases series, with isolated cases of hyperplasia, hemorrhagic intraepidermal blister and severe necrosis. Changes in dermis and hypodermis consisted mainly of hemorrhage, inflammatory infiltrate, edema, congestion, and vascular damage, whereas cases of collagen damage, necrosis, abscess, and signs of tissue repair, indicated by the presence of granulation tissue, were also observed, with a persistence of inflammatory and hemostatic alterations even days after antivenom administration. Therefore, the tissue damage resulting from Bothrops envenomation could be related to both direct venom activity as well as inflammatory response or presence of infectious process. The histopathological analysis of human skin injury can enlighten the pathological and endogenous effects of local envenomation and could underpin new strategies, including novel treatments, adjuvants or changes in clinical management, that lead to better outcomes in snakebite patients. Author summary: After inoculation of the venom by a snake of the genus Bothrops, a series of changes occur around the site of the bite, as a direct effect of toxins producing tissue damage and changes in blood flow to the site associated to coagulation disorders. Current knowledge about histopathological changes resulting from snakebites is almost exclusively derived from experimental animal models. In this study, we describe the dermatopathological findings observed in a series of 22 patients diagnosed with Bothrops atrox envenomation treated in a tertiary hospital of Manaus, in the Brazilian Amazon. We found relevant changes in all strata of the skin, with emphasis on hemorrhage, inflammatory infiltrate, edema, congestion, and vascular damage. Interestingly, we observed a persistence of inflammatory and vascular alterations days after antivenom administration, suggesting that antivenom may have limited efficacy in reversing or preventing local injury mechanisms, and that inflammation following those pathological processes plays a major role in the progression of tissue damage. [ABSTRACT FROM AUTHOR]

A 9-year-old male with autism and a history of well-controlled epilepsy presented with acute headache, fever, and generalized tonic-clonic seizures. Initial diagnostics, including imaging and cerebrospinal fluid analysis, were inconclusive. However, further serological testing suggested the presence of the chikungunya virus, establishing a diagnosis of chikungunya-associated neurological manifestation. The patient was treated with anticonvulsants, antibiotics for secondary bacterial pneumonia, and supportive care, leading to a gradual recovery. This case highlights the importance of considering systemic viral infections in pediatric patients with neurological symptoms and underscores the potential for arboviruses like chikungunya to cause neurological manifestation. [ABSTRACT FROM AUTHOR]

This scoping review mapped the academic literature focused on the therapeutic itinerary of children who seek care in health services and proposed an explanatory model to expand the concept and classification of these health itineraries. A total of 789 articles were reviewed, of which 28 were eligible for inclusion. In these 28 it was possible to observe that the child's therapeutic itinerary is more than a physical path, but also encompasses all choices within a specific social and cultural environment in which the child is inserted. Our proposal is to expand the concept beyond the therapeutic, classifying the itinerary also according to the objective, the decision‐making agent, respect for the presence of company, the health subsystem used, according to the physical continuity of the itinerary, the perception of efficacy of the patient, the nature of the illness, the administration of healthcare, the means of transport used, the person providing information about the itinerary, the planning of the itinerary and its completeness. Knowing the child's itineraries toward healthcare allows the development of innovative discourses and practices for future public policies, through which the principles of comprehensiveness and resoluteness in children's health would be strengthened. There is still a need to deepen knowledge about the meanings and feelings regarding their interpretations of the events suffered in childhood. [ABSTRACT FROM AUTHOR]

In the Brazilian Amazon, snakebite envenomations (SBEs) disproportionately affect Indigenous populations, and have a significantly higher incidence and lethality than in non‐Indigenous populations. This qualitative study describes the Indigenous and biomedical healthcare domains for SBE care from the perspective of the Indigenous medical and nursing students in Manaus, Western Brazilian Amazon. In‐depth interviews were conducted with five Indigenous students from the Amazonas State University, between January and December 2021. The interviews were analyzed using inductive content analysis. We organized an explanatory model with five themes: (1) participants' identities; (2) causality levels in Indigenous and biomedical systems; (3) therapeutic itineraries in Indigenous and biomedical systems; (4) ideological implications of adding biomedical devices to Indigenous healing systems; and (5) therapeutic failure in and efficacy of Indigenous and biomedical systems. From a noncolonial perspective and seeking to increase the quality and acceptability of health care for the Indigenous populations of the Brazilian Amazon, the training of Indigenous health professionals presents itself as a promising strategy. For this goal, universities should serve as empowering settings for Indigenous health students that support them in their growth and development, raise their awareness of injustice, and catalyze change toward a culturally adapted and effective service for the users. [ABSTRACT FROM AUTHOR]

Leprosy is a chronic infectious disease that has a slow evolution and is characterized by dermatoneurological involvement. The health challenges surrounding this disease are closely related to the stigma that results from the physical disabilities it causes. This is due to its high rate of late diagnosis and the peculiar deformities that occur in its advanced stage. Evaluate the clinical and epidemiological aspects of patients with plantar lesions who were treated for leprosy in a dermatology referral unit. This is a cross-sectional exploratory field study that was conducted at the Reference Center in Tropical Dermatology and Venereology Alfredo da Matta (FUHAM), in Manaus, Amazonas, Brazil. We evaluated 36 patients with disabilities as a result of leprosy and who had plantar lesions. The most common ulcer site was the medial region of the plantar surface, which presented dryness and maceration with yellowish seropurulent exudate, fibrinous tissue and grade 2 depth. The study made it possible to observe the evolution of plantar ulcers resulting from the disease process, then evaluate them and discuss recommendations regarding the treatment and prevention of this type of physical disability. [ABSTRACT FROM AUTHOR]

COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: "early death" (<15 days until death) and "late death" (>15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2+ macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2+ epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (TH17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, TH2 responses, and anti-inflammatory–mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes. Editor's summary: A major challenge early during the COVID-19 pandemic was the inability to determine when a patient was going to recover or succumb to disease. Although vaccines, antivirals, and other therapeutics have limited the fatalities caused by COVID-19, the ability to predict disease progression remains important because it could help determine the best therapeutic approach for each patient. Here, Da Silva Filho et al. integrated antemortem peripheral blood analysis and clinical data with postmortem analysis of lung tissues to define signatures of recovery, early death, and late death from COVID-19. They then used these integrated signatures to identify peripheral blood and clinical parameters that could predict a patient's trajectory. These data could be useful for anticipating a patient's clinical course and for identifying personalized therapeutic approaches. —Courtney Malo [ABSTRACT FROM AUTHOR]

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Snakebite envenomations (SBE) are a significant global public health threat due to their morbidity and mortality. This is a neglected public health issue in many tropical and subtropical countries. Brazil is in the top ten countries affected by SBE, with 32,160 cases reported only in 2020, posing a high burden for this population. In this paper, we describe the data structure of snakebite records from 2007 to 2020 in the Notifiable Disease Information System (SINAN), made available by the Brazilian Ministry of Health (MoH). In addition, we also provide R scripts that allow a quick and automatic updating of data from the SINAN according to its availability. The data presented in this work are related to clinical and demographic information on SBE cases. Also, data on outcomes, laboratory results, and treatment are available. The dataset is available and freely accessible; however, preprocessing, adjustments, and standardization are necessary due to incompleteness and inconsistencies. Regardless of these limitations, it provides a solid basis for assessing different aspects and the national burden of envenoming. Dataset: The dataset is available at https://github.com/LabdataManaus/describe%5fsnakebite/tree/main. Accessed on 26 April 2024. Dataset License: CC BY-NC-SA [ABSTRACT FROM AUTHOR]

Effective radical cure of Plasmodium vivax malaria is essential for malaria elimination in Brazil. P. vivax radical cure requires administration of a schizonticide, such as chloroquine, plus an 8-aminoquinoline. However, 8-aminoquinolines cause hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, requiring prior screening to exclude those at risk. Brazil is pioneering the implementation of tafenoquine, a single-dose 8-aminoquinoline indicated for P. vivax patients with >70% of normal G6PD activity. Tafenoquine implementation in Manaus and Porto Velho, two municipalities located in the western Brazilian Amazon, included comprehensive training of healthcare professionals (HCPs) on point-of-care quantitative G6PD testing and a new treatment algorithm for P. vivax radical cure incorporating tafenoquine. Training was initially provided to higher-level facilities (phase one) and later adapted for primary care units (phase two). This study analyzed HCP experiences during training and implementation and identified barriers and facilitators. In-depth interviews and focus discussion groups were conducted 30 days after each training for a purposive random sample of 115 HCPs. Thematic analysis was employed using MAXQDA software, analyzing data through inductive and deductive coding. Analysis showed that following the initial training for higher-level facilities, some HCPs did not feel confident performing quantitative G6PD testing and prescribing the tafenoquine regimen. Modifications to the training in phase two resulted in an improvement in understanding the implementation process of the G6PD test and tafenoquine, as well as in the knowledge acquired by HCPs. Additionally, knowledge gaps were addressed through in situ training, peer communication via a messaging app, and educational materials. Training supported effective deployment of the new tools in Manaus and Porto Velho and increased awareness of the need for pharmacovigilance. A training approach for nationwide implementation of these tools was devised. Implementing quantitative G6PD testing and tafenoquine represents a significant shift in P. vivax malaria case management. Consistent engagement with HCPs is needed to overcome challenges in fully integrating these tools within the Brazilian health system. Author summary: Brazil has implemented tafenoquine and quantitative G6PD testing as a crucial component of its comprehensive strategy to eliminate Plasmodium vivax malaria. Training of healthcare professionals (HCPs) has played a pivotal role in facilitating the adoption of these new strategies. In any implementation, it is necessary to identify barriers and facilitators and consider data that cannot typically be collected in purely quantitative studies. This qualitative study describes the perceptions of HCPs regarding the training they received and the knowledge gaps that only became apparent in their professional practice after the training. These insights were instrumental in developing various communication and continuing education strategies that enhanced HCP knowledge following training. Finally, the study presents a training approach for applying quantitative G6PD testing and the tafenoquine treatment regimen, including the most effective educational activities and materials to support the HCP learning process. [ABSTRACT FROM AUTHOR]

Malaria is the leading parasitic disease worldwide, with P. vivax being a major challenge for its control. Several studies have indicated metabolomics as a promising tool for combating the disease. The study evaluated plasma metabolomic profiles of patients with recurrent and non-recurrent P. vivax malaria in the Brazilian Amazon. Metabolites extracted from the plasma of P. vivax-infected patients were subjected to LC–MS analysis. Untargeted metabolomics was applied to investigate the metabolic profile of the plasma in the two groups. Overall, 51 recurrent and 59 non-recurrent patients were included in the study. Longitudinal metabolomic analysis revealed 52 and 37 significant metabolite features from the recurrent and non-recurrent participants, respectively. Recurrence was associated with disturbances in eicosanoid metabolism. Comparison between groups suggest alterations in vitamin B6 (pyridoxine) metabolism, tyrosine metabolism, 3-oxo-10-octadecatrienoate β-oxidation, and alkaloid biosynthesis II. Integrative network analysis revealed enrichment of other metabolic pathways for the recurrent phenotype, including the butanoate metabolism, aspartate and asparagine metabolism, and N-glycan biosynthesis. The metabolites and metabolic pathways predicted in our study suggest potential biomarkers of recurrence and provide insights into targets for antimalarial development against P. vivax. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a critical systemic complication caused by Bothrops envenoming, a neglected health problem in the Brazilian Amazon. Understanding the underlying mechanisms leading to AKI is crucial for effectively mitigating the burden of this complication. This study aimed to characterize the urinary protein profile of Bothrops atrox snakebite victims who developed AKI. We analyzed three groups of samples collected on admission: healthy subjects (controls, n = 10), snakebite victims who developed AKI (AKI, n = 10), and those who did not evolve to AKI (No-AKI, n = 10). Using liquid-chromatography tandem mass spectrometry, we identified and quantified (label-free) 1190 proteins. A panel of 65 proteins was identified exclusively in the urine of snakebite victims, with 32 exclusives to the AKI condition. Proteins more abundant or exclusive in AKI's urine were associated with acute phase response, endopeptidase inhibition, complement cascade, and inflammation. Notable proteins include serotransferrin, SERPINA-1, alpha-1B-glycoprotein, and NHL repeat-containing protein 3. Furthermore, evaluating previously reported biomarkers candidates for AKI and renal injury, we found retinol-binding protein, beta-2-microglobulin, cystatin-C, and hepcidin to be significant in cases of AKI induced by Bothrops envenoming. This work sheds light on physiological disturbances caused by Bothrops envenoming, highlighting potential biological processes contributing to AKI. Such insights may aid in better understanding and managing this life-threatening complication. Author summary: Envenomings caused by Bothrops species are a public health problem in the Brazilian Amazon. These envenomings can lead to a renal clinical complication called acute kidney injury. A better understanding of the causes leading to this complication is crucial for patient care. We aimed to describe the protein profile in the urine of patients who suffered envenoming and developed acute kidney injury. For this, we used large-scale analysis methods to compare the urine protein content of three groups of samples: healthy individuals, and snakebite patients with and without acute kidney injury. We identified a total of 1190 proteins, 65 of which were exclusive to patients suffering from snake bite envenoming. For patients with a kidney injury outcome, 32 unique proteins were found, of which the most abundant were associated with the body's inflammatory response. We highlight 4 proteins, including serotransferrin and SERPINA-1. Furthermore, we also evaluated candidate biomarkers of kidney injury already reported in the literature, such as retinol-binding protein, cystatin-C, and hepcidin, concluding that they are significant in cases of kidney injury caused by a jararaca snakebite. This work can help to better understand this serious complication that threatens the lives of the population living in the Amazon. [ABSTRACT FROM AUTHOR]

Snake venoms have evolved in several families of Caenophidae, and their toxins have been assumed to be biochemical weapons with a role as a trophic adaptation. However, it remains unclear how venom contributes to the success of venomous species for adaptation to different environments. Here we compared the venoms from Bothrocophias hyoprora, Bothrops taeniatus, Bothrops bilineatus smaragdinus, Bothrops brazili, and Bothrops atrox collected in the Amazon Rainforest, aiming to understand the ecological and toxinological consequences of venom composition. Transcriptomic and proteomic analyses indicated that the venoms presented the same toxin groups characteristic from bothropoids, but with distinct isoforms with variable qualitative and quantitative abundances, contributing to distinct enzymatic and toxic effects. Despite the particularities of each venom, commercial Bothrops antivenom recognized the venom components and neutralized the lethality of all species. No clear features could be observed between venoms from arboreal and terrestrial habitats, nor in the dispersion of the species throughout the Amazon habitats, supporting the notion that venom composition may not shape the ecological or toxinological characteristics of these snake species and that other factors influence their foraging or dispersal in different ecological niches. [ABSTRACT FROM AUTHOR]

The diagnosis of long COVID is troublesome, even when functional limitations are present. Dynapenia is the loss of muscle strength and power production that is not caused by neurologic or muscular diseases, being mostly associated with changes in neurologic function and/or the intrinsic force-generating properties of skeletal muscle, which altogether, may partially explain the limitations seen in long COVID. This study aimed to identify the distribution and possible associations of dynapenia with functional assessments in patients with long COVID. A total of 113 patients with COVID-19 were evaluated by functional assessment 120 days post-acute severe disease. Body composition, respiratory muscle strength, spirometry, six-minute walk test (6MWT, meters), and hand-grip strength (HGS, Kilogram-force) were assessed. Dynapenia was defined as HGS < 30 Kgf (men), and < 20 Kgf (women). Twenty-five (22%) participants were dynapenic, presenting lower muscle mass (p < 0.001), worse forced expiratory volume in the first second (FEV1) (p = 0.0001), lower forced vital capacity (p < 0.001), and inspiratory (p = 0.007) and expiratory (p = 0.002) peek pressures, as well as worse 6MWT performance (p < 0.001). Dynapenia, independently of age, was associated with worse FEV1, maximal expiratory pressure (MEP), and 6MWT, (p < 0.001) outcomes. Patients with dynapenia had higher intensive care unit (ICU) admission rates (p = 0.01) and need for invasive mechanical ventilation (p = 0.007) during hospitalization. The HGS is a simple, reliable, and low-cost measurement that can be performed in outpatient clinics in low- and middle-income countries. Thus, HGS may be used as a proxy indicator of functional impairment in this population. [ABSTRACT FROM AUTHOR]

Background: Currently, antivenoms are the only specific treatment available for snakebite envenoming. In Brazil, over 30% of patients cannot access antivenom within its critical care window. Researchers have therefore proposed decentralizing to community health centers to decrease time-to-care and improve morbidity and mortality. Currently, there is no evidence-based method to evaluate the capacity of health units for antivenom treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective antivenom administration and clinical management. Methods: This study utilized a modified-Delphi approach to develop and validate a checklist to evaluate the minimum requirements for health units to adequately treat snakebite envenoming in the Amazon region of Brazil. The modified-Delphi approach consisted of four rounds: 1) iterative development of preliminary checklist by expert steering committee; 2) controlled feedback on preliminary checklist via expert judge survey; 3) two-phase nominal group technique with new expert judges to resolve pending items; and 4) checklist finalization and closing criteria by expert steering committee. The measure of agreement selected for this study was percent agreement defined a priori as ≥75%. Results: A valid, reliable, and feasible checklist was developed. The development process highlighted three key findings: (1) the definition of community health centers and its list of essential items by expert judges is consistent with the Brazilian Ministry of Health, WHO snakebite strategic plan, and a general snakebite capacity guideline in India (internal validity), (2) the list of essential items for antivenom administration and clinical management is feasible and aligns with the literature regarding clinical care (reliability), and (3) engagement of local experts is critical to developing and implementing an antivenom decentralization strategy (feasibility). Conclusion: This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items; identification of training needs across the care continuum; and demonstration of the validity, reliability, and feasibility provided by engaging local experts. Specific to Brazil, further added value comes in the potential use of the checklist for health unit accreditation as well as its applications to logistics and resource distribution. Future research priorities should apply this checklist to health units in the Amazon region of Brazil to determine which community health centers are or could be capable of receiving antivenom and translate this expert-driven checklist and approach to snakebite care in other settings or other diseases in low-resource settings. Author summary: Checklists have been developed and validated to improve patient safety and effectiveness of care in several fields, including emergency medicine, intensive care, and surgery. The Brazilian Ministry of Health (MoH) supplies antivenoms (AVs) to the health system at no cost to patients. AV access is thus limited to hospitals, most of which are in urban areas and difficult for rural, remote, and indigenous populations to reach. Currently, there is no evidence-based method to evaluate the capacity of health units for AV treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective AV administration and clinical management. In this study, we aim to develop and validate a checklist to evaluate the minimum requirements for community health centers to adequately treat snakebite envenoming in the Amazon region of Brazil. This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items, represented by Human Resources, and Equipment, Supplies and Medicines, to provide safe and effective treatment for SBE patients in remote endemic areas. [ABSTRACT FROM AUTHOR]

Background: Malaria transmission modelling has demonstrated the potential impact of semiquantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine for Plasmodium vivax radical cure but has not investigated the associated costs. This study evaluated the cost-effectiveness of P. vivax treatment with tafenoquine after G6PD testing using a transmission model. Methods and findings: We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering 4 scenarios: (1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence; (2) tafenoquine for adults and children aged >2 years assuming 66.7% primaquine adherence; (3) tafenoquine for adults only assuming 90% primaquine adherence; and (4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by dividing the incremental costs by the disability-adjusted life years (DALYs) averted. These were compared to a willingness to pay (WTP) threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed. All 4 scenarios were cost-effective in the base case analysis using this WTP threshold with ICERs ranging from US$154 to US$1,836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semiquantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the WTP threshold. The main limitations of this study are due to parameter uncertainty around our cost estimates for low transmission settings, the costs of G6PD screening, and the severity of vivax malaria Conclusions: In our modelling study that incorporated impact on transmission, tafenoquine prescribed after a semiquantitative G6PD testing was highly likely to be cost-effective in Brazil. These results demonstrate the potential health and economic importance of ensuring safe and effective radical cure. Author summary: Why was this study done?: Radical cure with primaquine or recently approved tafenoquine is required to clear the dormant liver parasites of vivax malaria. While single-dose tafenoquine overcomes the barrier of patient adherence to the current 7-day primaquine treatment, it costs more and requires screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency. While the impact of changing policies to tafenoquine after G6PD screening on transmission has been evaluated, the associated costs and cost-effectiveness will be important considerations for policymakers. What did the researchers find?: Using an economic evaluation model coupled with a transmission model, we found that prescribing tafenoquine to vivax malaria patients without G6PD deficiency would be highly likely to be cost-effective in Brazil. Tafenoquine will be particularly cost-effective in settings where patient adherence to the current 7-day treatment is low and when paediatric tafenoquine is available to treat children as well as adults. What do these findings mean?: To our knowledge, this is the first study that has looked at the cost-effectiveness of tafenoquine when including the impact on disease transmission. The high probability of cost-effectiveness across a wide range of scenarios and municipalities should reassure decision-makers in Brazil, where tafenoquine has recently been adopted into national policy, and aid other countries considering the implementation of tafenoquine after G6PD screening. [ABSTRACT FROM AUTHOR]

Malaria is a severe public health problem in several developing tropical and subtropical countries. Anopheles aquasalis is the primary coastal malaria vector in Central and South America and the Caribbean Islands, and it has the peculiar feature of living in water with large changes in salinity. Recent research has recognised An. aquasalis as an important model for studying the interactions of murine and human Plasmodium parasites. This study presents the complete genome of An. aquasalis and offers insights into its evolution and physiology. The genome is similar in size and gene content to other Neotropical anophelines, with 162 Mb and 12,446 protein-coding genes. There are 1387 single-copy orthologs at the Diptera level (eg. An. gambiae, An. darlingi and Drosophila melanogaster). An. aquasalis diverged from An. darlingi, the primary malaria vector in inland South America, nearly 20 million years ago. Proteins related to ion transport and metabolism belong to the most abundant gene families with 660 genes. We identified gene families relevant to osmosis control (e.g., aquaporins, vacuolar-ATPases, Na+/K+-ATPases, and carbonic anhydrases). Evolutionary analysis suggests that all osmotic regulation genes are under strong purifying selection. We also observed low copy number variation in insecticide resistance and immunity-related genes for all known classical pathways. The data provided by this study offers candidate genes for further studies of parasite-vector interactions and for studies on how anophelines of brackish water deal with the high fluctuation in water salinity. We also established data and insights supporting An. aquasalis as an emerging Neotropical malaria vector model for genetic and molecular studies. [ABSTRACT FROM AUTHOR]

Background: Reducing mosquito abundance or interfering with its ability to support the parasite cycle can help to interrupt malaria in areas of significant risk of malaria transmission. Fluralaner is a safe and effective drug for veterinary use indicated for the treatment against fleas and ticks which acts as an antagonist of chloride ion channels mediated by γ-aminobutyric acid (GABA), preventing the entry of these ions into the postsynaptic neuron, leading to hyperexcitability of the postsynaptic neuron of the central nervous system of arthropods. Fluralaner demonstrated insecticidal activity against different insect species. Methods: The study aimed to evaluate the effects of fluralaner on the biology, survival, and reproductive fitness of Anopheles aquasalis. The following lethal concentrations (LC) were determined for An. aquasalis: LC5 = 0.511 µM; LC25 = 1.625 µM; LC50 = 3.237 µM. Results: A significant decrease (P < 0.001) was evident in the number of eggs, larvae, and pupae in the group exposed to a sublethal dose of fluralaner when compared to a control group (without the drug). Using blood from dogs after administration of fluralaner, it was observed that the drug causes 100% mortality in An. aquasalis in less than 24 h after feeding; this effect remains even after 90 days in all samples. Discussion: Fluralaner showed the same result for up to 60 days, and after that, there was a slight reduction in its effect, evidenced by a decrease in the percentage of dead females; however, still significant when compared to the control group. Conclusion: Fluralaner affects the biology and reduction of survival in An. aquasalis in a lasting and prolonged period, and its fecundity with lower dosages, is a strong candidate for controlling disease vectors. [ABSTRACT FROM AUTHOR]

Snakebite envenomation (SBE)-induced immunity refers to individuals who have been previously bitten by a snake and developed a protective immune response against subsequent envenomations. The notion stems from observations of individuals, including in the indigenous population, who present only mild signs and symptoms after surviving multiple SBEs. Indeed, these observations have engendered scientific interest and prompted inquiries into the potential development of a protective immunity from exposure to snake toxins. This review explores the evidence of a protective immune response developing following SBE. Studies suggest that natural exposure to snake toxins can trigger protection from the severity of SBEs, mediated by specific antibodies. However, the evaluation of the immune memory response in SBE patients remains challenging. Further research is needed to elucidate the immune response dynamics and identify potential targets for therapeutic interventions. Furthermore, the estimation of the effect of previous exposures on SBE epidemiology in hyperendemic areas, such as in the indigenous villages of the Amazon region (e.g., the Yanomami population) is a matter of debate. [ABSTRACT FROM AUTHOR]

This document is an editorial introducing a special issue of the journal Toxins focused on snakebite clinics and pathogenesis. The editorial highlights the global impact of snakebite envenoming (SBE) and the efforts of the World Health Organization (WHO) to reduce mortality and disability caused by snakebites. The special issue includes research on various aspects of SBE, such as healthcare professional training, diagnostic advancements, therapeutic strategies, and indigenous perspectives. The articles cover topics such as the experiences of healthcare professionals in the Brazilian Amazon, the development of clinical practice guidelines for SBE management in low-resource areas, alternative methods for antivenom production, and the effects of different snake venoms on acute responses and long-term disabilities. The editorial emphasizes the need for improved access to antivenom treatment and comprehensive healthcare approaches for snakebite survivors. [Extracted from the article]

Introduction: Screening for G6PD deficiency can inform disease management including malaria. Treatment with the antimalarial drugs primaquine and tafenoquine can be guided by point-of-care testing for G6PD deficiency. Methods and findings: Data from similar clinical studies evaluating the performance of the STANDARD G6PD Test (SD Biosensor, South Korea) conducted in Bangladesh, Brazil, Ethiopia, India, Thailand, the United Kingdom, and the United States were pooled. Test performance was assessed in a retrospective analysis on capillary and venous specimens. All study sites used spectrophotometry for reference G6PD testing, and either the HemoCue or complete blood count for reference hemoglobin measurement. The sensitivity of the STANDARD G6PD Test using the manufacturer thresholds for G6PD deficient and intermediate cases in capillary specimens from 4212 study participants was 100% (95% Confidence Interval (CI): 97.5%–100%) for G6PD deficient cases with <30% activity and 77% (95% CI 66.8%–85.4%) for females with intermediate activity between 30%–70%. Specificity was 98.1% (95% CI 97.6%–98.5%) and 92.8% (95% CI 91.6%–93.9%) for G6PD deficient individuals and intermediate females, respectively. Out of 20 G6PD intermediate females with false normal results, 12 had activity levels >60% on the reference assay. The negative predictive value for females with G6PD activity >60% was 99.6% (95% CI 99.1%–99.8%) on capillary specimens. Sensitivity among 396 P. vivax malaria cases was 100% (69.2%–100.0%) for both deficient and intermediate cases. Across the full dataset, 37% of those classified as G6PD deficient or intermediate resulted from true normal cases. Despite this, over 95% of cases would receive correct treatment with primaquine, over 87% of cases would receive correct treatment with tafenoquine, and no true G6PD deficient cases would be treated inappropriately based on the result of the STANDARD G6PD Test. Conclusions: The STANDARD G6PD Test enables safe access to drugs which are contraindicated for individuals with G6PD deficiency. Operational considerations will inform test uptake in specific settings. Author summary: The glucose-6-phosphate dehydrogenase (G6PD) enzyme helps red blood cells work properly. When the body does not have enough of this enzyme and is exposed to oxidative challenges, including certain foods and medicines, red blood cells break down faster than they are made, causing hemolytic anemia. Diagnostics tools for this common condition have been limited but now, new point of care tests are available that can screen more people who are unable to access laboratory services. This is particularly important for the treatment of vivax malaria, where the only treatment options require G6PD screening before administration. This research provides an evaluation of the diagnostic performance of one such tool, the STANDARD G6PD Test (SD Biosensor, South Korea), based on extensive data from multiple studies. These data show that the test can be used to safely identify people with G6PD deficiency, which will help ensure they do not receive contraindicated medicines. The research also provides specific estimates about how this test may impact malaria case management and treatment options. [ABSTRACT FROM AUTHOR]

This study aimed to understand the expressions of fear in the journeys of health professionals who worked in the confrontation of coronavirus disease 2019 (COVID‐19), in the city of Manaus, in the Brazilian Western Amazon. This is an exploratory qualitative study that adopts interpretive description as a method to generate informed knowledge responsive to the needs of the practice. We included 56 participants, comprising 23 health managers and 33 health workers (middle and higher level) of different professional categories. The results revealed three circles of experience: (1) knowledge and professional experience in dealing with the disease (unknown–known–experienced); (2) the growing proximity to death and loss (predicted–witnessed–suffered); and (3) the involvement and proximity to whatever affects the individual, their emotions, and personal transformations in the face of the threat (the collective, the neighbor, and oneself). Our results suggest that health professionals who worked during the COVID‐19 pandemic in Manaus experienced insecurity, dread, and fear, illustrating the complexity of developing their activities in the front line of care and management during the different phases of the pandemic. A contribution of the study is precisely that of capturing this complexity, which suggests the impossibility of analyzing fear only in its simple manifestation, or in each circle of experience. [ABSTRACT FROM AUTHOR]

The Amazon represents the world's greatest biodiversity and covers different countries in South America, including Brazil with the largest area. The interaction between the resident population of this area and its ecosystem is responsible for an intense exposure to venomous animals, which are considered an important health issue in the region. Therefore, the 1st International Symposium on Research in Venomous Animals, held from 2 May to 5 May 2023 in the city of Manaus in the state of Amazonas in Brazil, aimed to address animal envenomation aspects in the Brazilian Amazon and the exchange of ideas and knowledge between research groups from around the world. The event was attended by graduate students as well as renowned researchers from the Americas, Europe, and Asia. The event presented a multidisciplinary and translational approach in the area of toxinology, including themes such as clinical envenomation (clinical management, pathophysiology, and public policy strategies), preclinical studies, biological aspects of venomous animals' venoms (venom composition/variation and geographical distribution), interdisciplinary studies on health anthropology and economics, and bioprospecting aspects (toxins with therapeutic and/or technological potential). [ABSTRACT FROM AUTHOR]

Bothrops snakebite envenomation (SBE) is consider an important health problem in Brazil, where Bothrops atrox is mainly responsible in the Brazilian Amazon. Local effects represent a relevant clinical issue, in which inflammatory signs and symptoms in the bite site represent a potential risk for short and long-term disabilities. Among local complications, secondary infections (SIs) are a common clinical finding during Bothrops atrox SBE and are described by the appearance of signs such as abscess, cellulitis or necrotizing fasciitis in the affected site. However, the influence of SI in the local events is still poorly understood. Therefore, the present study describes for the first time the impact of SBE wound infection on local manifestations and inflammatory response from patients of Bothrops atrox SBE in the Brazilian Amazon. This was an observational study carried out at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus (Brazil), involving victims of Bothrops SBE. Clinical and laboratorial data were collected along with blood samples for the quantification of circulating cytokines and chemokines before antivenom administrations (T0) and 24 h (T1), 48 h (T2), 72 h (T3) and 7 days after (T4). From the 94 patients included in this study, 42 presented SI (44.7%) and 52 were without SI (NSI, 55.3%). Patients classified as moderate envenoming presented an increased risk of developing SI (OR = 2.69; CI 95% = 1.08–6.66, p = 0.033), while patients with bites in hands showed a lower risk (OR = 0.20; CI 95% = 0.04–0.96, p = 0.045). During follow-up, SI patients presented a worsening of local temperature along with a sustained profile of edema and pain, while NSI patients showed a tendency to restore and were highlighted in patients where SI was diagnosed at T2. As for laboratorial parameters, leukocytes, erythrocyte sedimentation ratio, fibrinogen and C-reactive protein were found increased in patients with SI and more frequently in patients diagnosed with SI at T3. Higher levels of circulating IL-2, IL-10, IL-6, TNF, INF-γ and CXCL-10 were observed in SI patients along with marked correlations between these mediators and IL-4 and IL-17, showing a plurality in the profile with a mix of Th1/Th2/Th17 response. The present study reports for the first time the synergistic effects of local infection and envenoming on the inflammatory response represented by local manifestations, which reflected on laboratorial parameters and inflammatory mediators and thus help improve the clinical management of SI associated to Bothrops SBE. [ABSTRACT FROM AUTHOR]

Background: The novel coronavirus disease 2019 (COVID-19) presents with complex pathophysiological effects in various organ systems. Following the COVID-19, there are shifts in biomarker and cytokine equilibrium associated with altered physiological processes arising from viral damage or aggressive immunological response. We hypothesized that high daily dose methylprednisolone improved the injury biomarkers and serum cytokine profiles in COVID-19 patients. Methods: Injury biomarker and cytokine analysis was performed on 50 SARS-Cov-2 negative controls and 101 hospitalized severe COVID-19 patients: 49 methylprednisolone-treated (MP group) and 52 placebo-treated serum samples. Samples from the treated groups collected on days D1 (pre-treatment) all the groups, D7 (2 days after ending therapy) and D14 were analyzed. Luminex assay quantified the biomarkers HMGB1, FABP3, myoglobin, troponin I and NTproBNP. Immune mediators (CXCL8, CCL2, CXCL9, CXCL10, TNF, IFN-γ, IL-17A, IL-12p70, IL-10, IL-6, IL-4, IL-2, and IL-1β) were quantified using cytometric bead array. Results: At pretreatment, the two treatment groups were comparable demographically. At pre-treatment (D1), injury biomarkers (HMGB1, TnI, myoglobin and FABP3) were distinctly elevated. At D7, HMGB1 was significantly higher in the MP group (p=0.0448) compared to the placebo group, while HMGB1 in the placebo group diminished significantly by D14 (p=0.0115). Compared to healthy control samples, several immune mediators (IL-17A, IL-6, IL-10, MIG, MCP-1, and IP-10) were considerably elevated at baseline (all p≤0.05). At D7, MIG and IP-10 of the MP-group were significantly lower than in the placebo-group (p=0.0431, p=0.0069, respectively). Longitudinally, IL-2 (MPgroup) and IL-17A (placebo-group) had increased significantly by D14. In placebo group, IL-2 and IL-17A continuously increased, as IL-12p70, IL-10 and IP-10 steadily decreased during follow-up. The MP treated group had IL-2, IFN-γ, IL-17A and IL-12p70 progressively increase while IL-1b and IL-10 gradually decreased towards D14. Moderate to strong positive correlations between chemokines and cytokines were observed on D7 and D14. Conclusion: These findings suggest MP treatment could ameliorate levels of myoglobin and FABP3, but appeared to have no impact on HMGB1, TnI and NTproBNP. In addition, methylprednisolone relieves the COVID-19 induced inflammatory response by diminishing MIG and IP-10 levels. Overall, corticosteroid (methylprednisolone) use in COVID-19 management influences the immunological molecule and injury biomarker profile in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: The indigenous populations of Brazil present poor health indicators and a disproportionate prevalence and case-fatality rate of neglected tropical diseases, including snakebite envenomations (SBEs). This study aims to estimate access to medical care for SBEs and analyze the barriers that prevent victims from accessing healthcare in indigenous communities in two health districts located in the Western Brazilian Amazon. Methodology/Principal findings: This cross-sectional study used semi-structured interviews to collect data from individuals who experienced SBEs in the Upper Rio Solimões and Upper Rio Negro indigenous health districts. Of the 187 participants, 164 (87.7%) reported that they had access to healthcare and received assistance in a hospital in the urban area of the municipalities. Frequency was 95.4% in the Upper Rio Solimões SIHD, and 69.6% in the Upper Rio Negro SIHD (P<0.0001). The study found that the availability of indigenous medicine as the only choice in the village was the main reason for not accessing healthcare (75%), followed by a lack of financial resources and means of transportation (28.1%). Four deaths were reported from SBEs, resulting in a case-fatality rate of 2.1%. Conclusions/Significance: In the study areas, there are records of SBE patients who did not receive medical attention. Availability of pre-hospital emergency transport using motorboats, a greater number of hospitals and better navigability of the Solimões River and its tributaries would make access easier for indigenous people living in the region of the Upper Solimões River. The implementation of cross-cultural hospital care needs to be considered in order to reduce the resistance of indigenous populations in relation to seeking treatment for SBEs. Author summary: Interdisciplinary research on snakebites and the engagement of indigenous and riverine populations of the Amazon are essential for the formulation of innovative and tailored strategies towards achieving the global target of halving the number of deaths and disabilities due to snakebite envenomations by 2030 in Brazil. These populations are key to reducing these poor outcomes since they are disproportionately affected by snakebites. In this work, we evaluated access to medical care in SBE patients and analyzed barriers that prevent victims from accessing healthcare in indigenous villages in two health districts in the Brazilian Amazon. Snakebites were reported in all age groups, including a high rate among children, which demonstrates their great contact with venomous snakes in indigenous villages. A proportion of 12.3% of individuals with a lifetime history of snakebites did not receive hospital treatment, ranging from 4.6% in the Upper Rio Solimões health district to 30.4% in the Upper Rio Negro health district. Availability of pre-hospital emergency transport using motorboats, a greater number of hospitals and better navigability of the Solimões River and its tributaries would make access easier for indigenous people living in this district. We discuss the role that the implementation of cross-cultural hospital care, which considers specific indigenous needs for accommodation and food, may have in reducing the resistance of indigenous populations to seek western treatment for snakebites. [ABSTRACT FROM AUTHOR]

Snakebite envenoming represents a major health problem in tropical and subtropical countries. Considering the elevated number of accidents and high morbidity and mortality rates, the World Health Organization reclassified this disease to category A of neglected diseases. In Latin America, Bothrops genus snakes are mainly responsible for snakebites in humans, whose pathophysiology is characterized by local and systemic inflammatory and degradative processes, triggering prothrombotic and hemorrhagic events, which lead to various complications, organ damage, tissue loss, amputations, and death. The activation of the multicellular blood system, hemostatic alterations, and activation of the inflammatory response are all well-documented in Bothrops envenomings. However, the interface between inflammation and coagulation is still a neglected issue in the toxinology field. Thromboinflammatory pathways can play a significant role in some of the major complications of snakebite envenoming, such as stroke, venous thromboembolism, and acute kidney injury. In addition to exacerbating inflammation and cell interactions that trigger vaso-occlusion, ischemia–reperfusion processes, and, eventually, organic damage and necrosis. In this review, we discuss the role of inflammatory pathways in modulating coagulation and inducing platelet and leukocyte activation, as well as the inflammatory production mediators and induction of innate immune responses, among other mechanisms that are altered by Bothrops venoms. [ABSTRACT FROM AUTHOR]

Background: Snakebite envenoming (SBE) is a neglected tropical disease capable of causing both significant disability and death. The burden of SBE is especially high in low- and middle-income countries. The aim of this study was to perform a geospatial analysis evaluating the association of sociodemographics and access to care indicators on moderate and severe cases of SBE in Brazil. Methods: We conducted an ecological, cross-sectional study of SBE in Brazil from 2014 to 2019 using the open access National System Identification of Notifiable Diseases (SINAN) database. We then collected a set of indicators from the Brazil Census of 2010 and performed a Principal Component Analysis to create variables related to health, economics, occupation, education, infrastructure, and access to care. Next, a descriptive and exploratory spatial analysis was conducted to evaluate the geospatial association of moderate and severe events. These variables related to events were evaluated using Geographically Weighted Poisson Regression. T-values were plotted in choropleth maps and considered statistically significant when values were <-1.96 or >+1.96. Results: We found that the North region had the highest number of SBE cases by population (47.83/100,000), death rates (0.18/100,000), moderate and severe rates (22.96/100,000), and proportion of cases that took more than three hours to reach healthcare assistance (44.11%). The Northeast and Midwest had the next poorest indicators. Life expectancy, young population structure, inequality, electricity, occupation, and more than three hours to reach healthcare were positively associated with greater cases of moderate and severe events, while income, illiteracy, sanitation, and access to care were negatively associated. The remaining indicators showed a positive association in some areas of the country and a negative association in other areas. Conclusion: Regional disparities in SBE incidence and rates of poor outcomes exist in Brazil, with the North region disproportionately affected. Multiple indicators were associated with rates of moderate and severe events, such as sociodemographic and health care indicators. Any approach to improving snakebite care must work to ensure the timeliness of antivenom administration. [ABSTRACT FROM AUTHOR]

Malaria is an infectious disease caused by Plasmodium spp. and it is mainly transmitted to humans by female mosquitoes of the genus Anopheles. Malaria is an important global public health problem due to its high rates of morbidity and mortality. At present, drug therapies and vector control with insecticides are respectively the most commonly used methods for the treatment and control of malaria. However, several studies have shown the resistance of Plasmodium to drugs that are recommended for the treatment of malaria. In view of this, it is necessary to carry out studies to discover new antimalarial molecules as lead compounds for the development of new medicines. In this sense, in the last few decades, animal venoms have attracted attention as a potential source for new antimalarial molecules. Therefore, the aim of this review was to summarize animal venom toxins with antimalarial activity found in the literature. From this research, 50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs. [ABSTRACT FROM AUTHOR]

Snakebites are a major public health problem in the Brazilian Amazon and may lead to local complications and physical deficiencies. Access to antivenom treatment is poorer in indigenous populations compared to other populations. In this study, we report three cases of long-term severe disabilities as a result of Bothrops atrox snakebites in indigenous children, according to the narratives of the parents. The three cases evolved to compartment syndrome, secondary bacterial infection and extensive necrosis. The cases are associated with delayed antivenom treatment due to very fragmented therapeutic itineraries, which are marked by several changes in means of transport along the route. The loss of autonomy at such an early stage of life due to a disability caused by a snakebite, as observed in this study, may deprive children of sensory and social experiences and of learning their future roles in the community. In common to all cases, there was precarious access to rehabilitation services, which are generally centralized in the state capital, and which leads to a prolonged hospitalization of patients with severe snakebite, and distances them from their territory and family and community ties. Prospective studies should be conducted in the Amazon that estimate the burden of disabilities from snakebites in order to formulate public policies for the treatment and rehabilitation of patients through culturally tailored interventions. [ABSTRACT FROM AUTHOR]

Methylene blue (MB) is an alternative for combating drug-resistant malaria parasites. Its transmission-blocking potential has been demonstrated in vivo in murine models, in vitro, and in clinical trials. MB shows high efficacy against Plasmodium vivax asexual stages; however, its efficacy in sexual stages is unknown. In this study, we evaluated the potential of MB against asexual and sexual forms of P. vivax isolated from the blood of patients residing in the Brazilian Amazon. An ex vivo schizont maturation assay, zygote to ookinete transformation assay, direct membrane feed assay (DMFA), and standard membrane feed assay (SMFA) using P. vivax gametocytes with MB exposure were performed. A cytotoxicity assay was also performed on freshly collected peripheral blood mononuclear cells (PBMCs) and the hepatocyte carcinoma cell line HepG2. MB inhibited the P. vivax schizont maturation and demonstrated an IC50 lower than that of chloroquine (control drug). In the sexual forms, the MB demonstrated a high level of inhibition in the transformation of the zygotes into ookinetes. In the DMFA, MB did not considerably affect the infection rate and showed low inhibition, but it demonstrated a slight decrease in the infection intensity in all tested concentrations. In contrast, in the SMFA, MB was able to completely block the transmission at the highest concentration (20 μM). MB demonstrated low cytotoxicity to fresh PBMCs but demonstrated higher cytotoxicity to the hepatocyte carcinoma cell line HepG2. These results show that MB may be a potential drug for vivax malaria treatment. [ABSTRACT FROM AUTHOR]

Envenomation caused by venomous animals may trigger significant local complications such as pain, edema, localized hemorrhage, and tissue necrosis, in addition to complications such as dermonecrosis, myonecrosis, and even amputations. This systematic review aims to evaluate scientific evidence on therapies used to target local effects caused by envenomation. The PubMed, MEDLINE, and LILACS databases were used to perform a literature search on the topic. The review was based on studies that cited procedures performed on local injuries following envenomation with the aim of being an adjuvant therapeutic strategy. The literature regarding local treatments used following envenomation reports the use of several alternative methods and/or therapies. The venomous animals found in the search were snakes (82.05%), insects (2.56%), spiders (2.56%), scorpions (2.56%), and others (jellyfish, centipede, sea urchin—10.26%). In regard to the treatments, the use of tourniquets, corticosteroids, antihistamines, and cryotherapy is questionable, as well as the use of plants and oils. Low-intensity lasers stand out as a possible therapeutic tool for these injuries. Local complications can progress to serious conditions and may result in physical disabilities and sequelae. This study compiled information on adjuvant therapeutic measures and underscores the importance of more robust scientific evidence for recommendations that act on local effects together with the antivenom. [ABSTRACT FROM AUTHOR]

Remote areas, such as the Amazon Forest, face unique geographical challenges of transportation-based access to health services. As transportation to healthcare in most of the Amazon Forest is only possible by rivers routes, any travel time and travel distance estimation is limited by the lack of data sources containing rivers as potential transportation routes. Therefore, we developed an approach to convert the geographical representation of roads and rivers in the Amazon into a combined, interoperable, and reusable dataset. To build the dataset, we processed and combined data from three data sources: OpenStreetMap, HydroSHEDS, and GloRiC. The resulting dataset can consider distance metrics using the combination of streets and rivers as a transportation route network for the Amazon Forest. The created dataset followed the guidelines and attributes defined by OpenStreetMap to leverage its reusability and interoperability possibilities. This new data source can be used by policymakers, health authorities, and researchers to perform time-to-care analysis in the International Amazon region. [ABSTRACT FROM AUTHOR]

Snakebite envenoming is currently considered a neglected tropical disease, which affects over 5 million people worldwide, and causes almost 150 000 deaths every year, as well as severe injuries, amputations and other sequelae. Snakebite envenoming in children, although proportionally less frequent, is generally more severe, and represents an important challenge for pediatric medicine, since they often result in worse outcomes. In Brazil, given its ecological, geographic and socioeconomic characteristics, snakebites are considered an important health problem, presenting approximately 30 000 victims per year, approximately 15% of them in children. Even with low snakebite incidence, children tend to have higher snakebite severity and complications due to the small body mass and same venom volume inoculated in comparison to adults, even though, due to the lack of epidemiological information about pediatric snakebites and induced injuries, it is difficult to measure the treatment effectiveness, outcomes and quality of emergency medical services for snakebites in children. In this review, we report how Brazilian children are affected by snakebites, describing the characteristics of this affected population, clinical aspects, management, outcomes and main challenges. [ABSTRACT FROM AUTHOR]

Numerous studies have focused on inflammation-related markers to understand COVID-19. In this study, we performed a comparative analysis of spike (S) and nucleocapsid (N) protein-specific IgA, total IgG and IgG subclass response in COVID-19 patients and compared this to their disease outcome. We observed that the SARS-CoV-2 infection elicits a robust IgA and IgG response against the N-terminal (N1) and C-terminal (N3) region of the N protein, whereas we failed to detect IgA antibodies and observed a weak IgG response against the disordered linker region (N2) in COVID-19 patients. N and S protein-specific IgG1, IgG2 and IgG3 response was significantly elevated in hospitalized patients with severe disease compared to outpatients with non-severe disease. IgA and total IgG antibody reactivity gradually increased after the first week of symptoms. Magnitude of RBD-ACE2 blocking antibodies identified in a competitive assay and neutralizing antibodies detected by PRNT assay correlated with disease severity. Generally, the IgA and total IgG response between the discharged and deceased COVID-19 patients was similar. However, significant differences in the ratio of IgG subclass antibodies were observed between discharged and deceased patients, especially towards the disordered linker region of the N protein. Overall, SARS-CoV-2 infection is linked to an elevated blood antibody response in severe patients compared to non-severe patients. Monitoring of antigen-specific serological response could be an important tool to accompany disease progression and improve outcomes. [ABSTRACT FROM AUTHOR]

Background: In the Brazilian Amazon, snakebite envenomings (SBE) disproportionately affect indigenous peoples. Communication between indigenous and biomedical health sectors in regards to SBEs has never been explored in this region. This study aims to build an explanatory model (EM) of the indigenous healthcare domain for SBE patients from the perspective of the indigenous caregivers. Methodology/Principal findings: This is a qualitative study involving in-depth interviews of eight indigenous caregivers who are representatives of the Tikuna, Kokama and Kambeba ethnic groups, in the Alto Solimões River, western Brazilian Amazon. Data analysis was carried out via deductive thematic analysis. A framework was built containing the explanations based on three explanatory model (EM) components: etiology, course of sickness, and treatment. To indigenous caregivers, snakes are enemies and present conscience and intention. Snakebites have a natural or a supernatural cause, the last being more difficult to prevent and treat. Use of ayahuasca tea is a strategy used by some caregivers to identify the underlying cause of the SBE. Severe or lethal SBEs are understood as having been triggered by sorcery. Treatment is characterized by four components: i) immediate self-care; ii) first care in the village, mostly including tobacco smoking, chants and prayers, combined with the intake of animal bile and emetic plants; iii) a stay in a hospital, to receive antivenom and other treatments; iv) care in the village after hospital discharge, which is a phase of re-establishment of well-being and reintroduction into social life, using tobacco smoking, massages and compresses to the affected limb, and teas of bitter plants. Dietary taboos and behavioral interdictions (avoiding contact with menstruating and pregnant women) prevent complications, relapses, and death, and must be performed up to three months after the snakebite. Caregivers are in favor of antivenom treatment in indigenous areas. Conclusions/Significance: There is a potential for articulation between different healthcare sectors to improve the management of SBEs in the Amazon region, and the aim is to decentralize antivenom treatment so that it occurs in indigenous health centers with the active participation of the indigenous caregivers. Author summary: The Brazilian Amazon is the region of the Americas that has the highest incidence of SBEs, and indigenous populations are disproportionately affected. In order for Brazil to achieve a reduction in mortality and disability from snakebite envenomations, it is vital to understand how indigenous and professional healthcare sectors interact in indigenous villages. The indigenous caregivers interviewed explained that the occurrence of a snakebite can be a natural event, usually due to the lack of attention of an indigenous person during their daily activities in the forest, or a supernatural event that was caused as a punishment or by witchcraft. The latter type of snakebites is more serious and it is difficult to intervene to promote healing. Indigenous caregivers recommend a series of rituals in order to protect an individual from snakebite or heal the already diseased body. In addition, a series of therapeutic resources derived from plants and animals is used for treatment and rehabilitation of the indigenous person. In this itinerary, there is no impediment on the part of the caregivers to include a stay in hospital in order to carry out the treatment with antivenom and other care deemed necessary by the doctors. This finding is crucial to improve the effectiveness of snakebite treatment in an integrated biomedical-indigenous model, thus reducing the contradictions and tensions present in the daily practices of both health teams and indigenous caregivers. The engagement with local caregivers to combine the indigenous health care model with a timely referral of SBE patients to a facility equipped with antivenom is a major determinant of success in the control of SBEs. [ABSTRACT FROM AUTHOR]

Background: Over the last decades, enormous successes have been achieved in reducing malaria burden globally. In Latin America, South East Asia, and the Western Pacific, many countries now pursue the goal of malaria elimination by 2030. It is widely acknowledged that Plasmodium spp. infections cluster spatially so that interventions need to be spatially informed, e.g. spatially targeted reactive case detection strategies. Here, the spatial signature method is introduced as a tool to quantify the distance around an index infection within which other infections significantly cluster. Methods: Data were considered from cross-sectional surveys from Brazil, Thailand, Cambodia, and Solomon Islands, conducted between 2012 and 2018. Household locations were recorded by GPS and finger-prick blood samples from participants were tested for Plasmodium infection by PCR. Cohort studies from Brazil and Thailand with monthly sampling over a year from 2013 until 2014 were also included. The prevalence of PCR-confirmed infections was calculated at increasing distance around index infections (and growing time intervals in the cohort studies). Statistical significance was defined as prevalence outside of a 95%-quantile interval of a bootstrap null distribution after random re-allocation of locations of infections. Results: Prevalence of Plasmodium vivax and Plasmodium falciparum infections was elevated in close proximity around index infections and decreased with distance in most study sites, e.g. from 21.3% at 0 km to the global study prevalence of 6.4% for P. vivax in the Cambodian survey. In the cohort studies, the clustering decreased with longer time windows. The distance from index infections to a 50% reduction of prevalence ranged from 25 m to 3175 m, tending to shorter distances at lower global study prevalence. Conclusions: The spatial signatures of P. vivax and P. falciparum infections demonstrate spatial clustering across a diverse set of study sites, quantifying the distance within which the clustering occurs. The method offers a novel tool in malaria epidemiology, potentially informing reactive intervention strategies regarding radius choices of operations around detected infections and thus strengthening malaria elimination endeavours. [ABSTRACT FROM AUTHOR]

Bothrops atrox envenomations are common in the Brazilian Amazon. The venom of B. atrox is highly inflammatory, which results in severe local complications, including the formation of blisters. Moreover, there is little information on the immune mechanisms associated with this condition. Thus, a longitudinal study was carried out to characterize the profile of the cell populations and soluble immunological mediators in the peripheral blood and blisters in B. atrox patients s according to their clinical manifestations (mild and severe). A similar response in both B. atrox patient groups (MILD and SEV) was observed, with an increase in inflammatory monocytes, NKT, and T and B cells, as well as CCL2, CCL5, CXCL9, CXCL10, IL-1β and IL-10, when compared with the group of healthy blood donors. After the administration of antivenom, the participation of patrolling monocytes and IL-10 in the MILD group was observed. In the SEV group, the participation of B cells was observed, with high levels of CCL2 and IL-6. In the blister exudate, a hyperinflammatory profile was observed. In conclusion, we revealed the involvement of cell populations and soluble mediators in the immune response to B. atrox envenomation at the local and peripheral level, which is related to the onset and extent of the inflammation/clinical manifestation. [ABSTRACT FROM AUTHOR]

Specific and sensitive tools for the diagnosis and monitoring of accidents by venomous animals are urgently needed. Several diagnostic and monitoring assays have been developed; however, they have not yet reached the clinic. This has resulted in late diagnoses, which represents one of the main causes of progression from mild to severe disease. Human blood is a protein-rich biological fluid that is routinely collected in hospital settings for diagnostic purposes, which can translate research progress from the laboratory to the clinic. Although it is a limited view, blood plasma proteins provide information about the clinical picture of envenomation. Proteome disturbances in response to envenomation by venomous animals have been identified, allowing mass spectrometry (MS)-based plasma proteomics to emerge as a tool in a range of clinical diagnostics and disease management that can be applied to cases of venomous animal envenomation. Here, we provide a review of the state of the art on routine laboratory diagnoses of envenomation by snakes, scorpions, bees, and spiders, as well as a review of the diagnostic methods and the challenges encountered. We present the state of the art on clinical proteomics as the standardization of procedures to be performed within and between research laboratories, favoring a more excellent peptide coverage of candidate proteins for biomarkers. Therefore, the selection of a sample type and method of preparation should be very specific and based on the discovery of biomarkers in specific approaches. However, the sample collection protocol (e.g., collection tube type) and the processing procedure of the sample (e.g., clotting temperature, time allowed for clotting, and anticoagulant used) are equally important to eliminate any bias. [ABSTRACT FROM AUTHOR]

Bergenin is a glycosidic derivative of trihydroxybenzoic acid that was discovered in 1880 by Garreau and Machelart from the rhizomes of the medicinal plant Bergenia crassifolia (currently: Saxifraga crassifolia—Saxifragaceae), though was later isolated from several other plant sources. Since its first report, it has aroused interest because it has several pharmacological activities, mainly antioxidant and anti-inflammatory. In addition to this, bergenin has shown potential antimalarial, antileishmanial, trypanocidal, antiviral, antibacterial, antifungal, antinociceptive, antiarthritic, antiulcerogenic, antidiabetic/antiobesity, antiarrhythmic, anticancer, hepatoprotective, neuroprotective and cardioprotective activities. Thus, this review aimed to describe the sources of isolation of bergenin and its in vitro and in vivo biological and pharmacological activities. Bergenin is distributed in many plant species (at least 112 species belonging to 34 families). Both its derivatives (natural and semisynthetic) and extracts with phytochemical proof of its highest concentration are well studied, and none of the studies showed cytotoxicity for healthy cells. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is transmitted to humans by the infectious bite of mosquitoes such as Aedes aegypti. In a city, the population control of mosquitoes is carried out according to alerts generated by different districts via the analysis of the mosquito index. However, we do not know whether, besides mosquito abundance, the susceptibility of mosquitoes could also diverge among districts and thus impact the dissemination and transmission of arboviruses. After a viremic blood meal, the virus must infect the midgut, disseminate to tissues, and reach the salivary gland to be transmitted to a vertebrate host. This study evaluated the patterns of ZIKV infection in the Ae. aegypti field populations of a city. The disseminated infection rate, viral transmission rate, and transmission efficiency were measured using quantitative PCR at 14 days post-infection. The results showed that all Ae. aegypti populations had individuals susceptible to ZIKV infection and able to transmit the virus. The infection parameters showed that the geographical area of origin of the Ae. aegypti influences its vector competence for ZIKV transmission. [ABSTRACT FROM AUTHOR]

Animal-derived venoms are complex mixtures of toxins triggering important biological effects during envenomings. Although venom-derived toxins are known for their potential of causing harm to victims, toxins can also act as pharmacological agents. During the COVID-19 pandemic, there was observed an increase in in-depth studies on antiviral agents, and since, to date, there has been no completely effective drug against the global disease. This review explores the crosstalk of animal toxins and COVID-19, aiming to map potential therapeutic agents derived from venoms (e.g., bees, snakes, scorpions, etc.) targeting COVID-19. [ABSTRACT FROM AUTHOR]

Scorpion sting envenomations (SSE) are feared by the intense pain that they produce in victims. Pain from SSE is triggered mainly by the presence of neurotoxins in the scorpion venom that modulates voltage-gated ion channels. In Brazil, SSE is mostly caused by Tityus serrulatus, popularly known as yellow scorpion. Here, we evaluated experimental spontaneous nociception induced by T. serrulatus venom as well as its isolated neurotoxins Ts1, Ts5, Ts6, Ts8, and Ts19 frag II, evidencing different degrees of pain behavior in mice. In addition, we developed a mice-derived polyclonal antibody targeting Ts5 able to neutralize the effect of this neurotoxin, showing that Ts5 presents epitopes capable of activating the immune response, which decreased considerably the nociception produced by the whole venom. This is the pioneer study to explore nociception using different classes of T. serrulatus neurotoxins on nociception (α-NaTx, β-NaTx, α-KTx, and β-KTx), targeting potassium and sodium voltage-gated channels, besides demonstrating that Ts5 plays an important role in the scorpion sting induced-pain. Author summary: The Brazilian Tityus serrulatus scorpion envenoming is well recognized to be responsible for its painful sting. The pain reported by victims of T. serrulatus has shown variations, varying from mild to severe. However, little is known regarding the mechanisms involving the venom-derived toxins and their relationship a role in causing nociception. This research pioneer shows how each T. serrulatus classes of neurotoxins (Ts1: β-NaTx; Ts5: α-NaTx; Ts6: α-KTx; Ts8 and Ts19: β-KTx) are involved in the spontaneous nociception. The new knowledge may contribute to a better overall understanding of the mechanisms underlying T. serrulatus painful envenomings. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) are an important mechanism for defense against pathogens. Their overproduction can be harmful since excessive NET formation promotes inflammation and tissue damage in several diseases. Nucleases are capable to degrade NET on basis of their DNA hydrolysis activity, including the CdcPDE, a nuclease isolated from Crotalus durissus collilineatus snake venom. Here, we report a new finding about CdcPDE activity, demonstrating its efficiency in degrading cell-free DNA from NETs, being a potential candidate to assist in therapies targeting inflammatory diseases. [ABSTRACT FROM AUTHOR]

Snakebite envenomations (SBEs) in pregnant women can result in adverse maternal or neonatal effects, such as abortion, placental abruption, preterm labor, fetal malformations, and maternal, fetal or neonatal deaths. Despite the high incidence of SBEs in the Brazilian Amazon, there is no literature on the impact of SBEs on pregnancy outcomes. The objective of this study was to describe clinical epidemiology and outcomes associated with SBEs in women of childbearing age and pregnant women in the state of Amazonas, Western Brazilian Amazon, from 2007 to 2021. Information on the population was obtained from the Reporting Information System (SINAN), Mortality Information System (SIM) and Live Birth Information System (SINASC) for the period from 2007 to 2021. A total of 36,786 SBEs were reported, of which 3,297 (9%) involved women of childbearing age, and 274 (8.3%) involved pregnant women. Severity (7.9% in pregnant versus 8.7% in non-pregnant women) (P = 0.87) and case-fatality (0.4% in pregnant versus 0.3% in non-pregnant women) rates were similar between groups (P = 0.76). Pregnant women who suffered snakebites were at higher risk for fetal death (OR: 2.17, 95%CI: 1.74–2.67) and neonatal death (OR = 2.79, 95%CI: 2.26–3.40). This study had major limitations related to the completeness of the information on the pregnancy outcomes. Although SBE incidence in pregnant women is low in the Brazilian Amazon, SBEs increased the risk of fetal and neonatal deaths. Author summary: Snakebite envenomations (SBEs) are a health problem in tropical and subtropical countries. In endemic areas, this health problem more frequently involves men engaged in agricultural activities. However, in many areas of the world, women of childbearing age are also very affected by snakebites, as they also actively participate in activities that put them at risk of encountering snakes. In this context, SBEs can occur during pregnancy, with deleterious consequences for both the mother and the fetus or neonate. However, the little that is known about the consequences of SBEs in pregnancy comes from case reports. In this study, we linked the surveillance databases Snakebites Reporting Information System (SINAN), Mortality Information System (SIM) and Live Birth Information System (SINASC) of the state of Amazonas, Western Brazilian Amazon, to gain a more integrative view of the problem in the region. Although severity and case-fatality rates of SBEs were similar between pregnant and non-pregnant women, pregnant women who suffered SBEs were at higher risk for fetal and neonatal deaths. [ABSTRACT FROM AUTHOR]

Background: The groundwork for malaria elimination does not currently consider the potential of Plasmodium zoonotic cycles that involve non-human primates (NHPs) in sylvatic environments. Since vivax malaria is less responsive to control measures, fnding Plasmodium vivax infected NHPs adds even more concern. Methods: Both Free-living monkeys in forest fragments inside the urban area and captive monkeys from a local zoo had blood samples tested for Plasmodium species. Results: In this study, among the Neotropical monkeys tested, three (4.4%), one captive and two free-living, were found to be naturally infected by P. vivax. Conclusion: This important fnding indicates that it is necessary to estimate the extent to which P. vivax NHP infection contributes to the maintenance of malaria transmission to humans. Therefore, the discussion on wildlife conservation and management must be incorporated into the malaria elimination agenda. [ABSTRACT FROM AUTHOR]

Globally, malaria and human immunodeficiency virus (HIV) are both independently associated with a massive burden of disease and death. While their co-infection has been well studied for Plasmodium falciparum, scarce data exist regarding the association of P. vivax and HIV. In this cohort study, we assessed the effect of HIV on the risk of vivax malaria infection and recurrence during a 4-year follow-up period in an endemic area of the Brazilian Amazon. For the purpose of this study, we obtained clinical information from January 2012 to December 2016 from two databases. HIV screening data were acquired from the clinical information system at the tropical hospital Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD). The National Malaria Surveillance database (SIVEP malaria) was utilized to identify malaria infections during a 4-year follow-up period after diagnosis of HIV. Both datasets were combined via data linkage. Between 2012 and 2016, a total of 42,121 people were screened for HIV, with 1569 testing positive (3.7%). Out of all the patients diagnosed with HIV, 198 had at least one episode of P. vivax malaria in the follow-up. In the HIV-negative group, 711 participants had at least one P. vivax malaria episode. When comparing both groups, HIV patients had a 6.48 [(5.37–7.83); P < 0.0001] (adjusted relative risk) greater chance of acquiring P. vivax malaria. Moreover, being of the male gender [ARR = 1.41 (1.17–1.71); P < 0.0001], Amerindian ethnicity [ARR = 2.77 (1.46–5.28); P < 0.0001], and a resident in a municipality of the Metropolitan region of Manaus [ARR = 1.48 (1.02–2.15); P = 0.038] were independent risk factors associated with an increased risk of clinical malaria. Education ≥ 8 years [ARR = 0.41 (0.26–0.64); P < 0.0001] and living in the urban area [ARR = 0.44 (0.24–0.80); P = 0.007] were associated to a lower risk of P. vivax malaria. A total of 28 (14.1%) and 180 (25.3%) recurrences (at least a second clinical malaria episode) were reported in the HIV-positive and HIV-negative groups, respectively. After adjusting for sex and education, HIV-positive status was associated with a tendency towards protection from P. vivax malaria recurrences [ARR = 0.55 (0.27–1.10); P = 0.090]. HIV status was not associated with hospitalizations due to P. vivax malaria. CD4 + counts and viral load were not associated with recurrences of P. vivax malaria. No significant differences were found in the distribution of parasitemia between HIV-negative and HIV-positive P. vivax malaria patients. Our results suggest that HIV-positive status is a risk factor for vivax malaria infection, which represents an additional challenge that should be addressed during elimination efforts. [ABSTRACT FROM AUTHOR]