Host metabolomic responses in recurrent P. vivax malaria.

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 ß-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.

Urinary proteomics reveals biological processes related to acute kidney injury in Bothrops atrox envenomings.

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.

Venom Composition of Neglected Bothropoid Snakes from the Amazon Rainforest: Ecological and Toxinological Implications.

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.

Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: A cost-effectiveness analysis using a transmission model.

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.

Development and validation of a minimum requirements checklist for snakebite envenoming treatment in the Brazilian Amazonia.

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.

Impact of piperaquine resistance in Plasmodium falciparum on malaria treatment effectiveness in The Guianas: a descriptive epidemiological study.

BACKGROUND: Plasmodium falciparum is an apicomplexan parasite responsible for lethal cases of malaria. According to WHO recommendations, P falciparum cases are treated with artemisinin-based combination therapy including dihydroartemisinin-piperaquine. However, the emergence of resistant parasites against dihydroartemisinin-piperaquine was reported in southeast Asia in 2008 and, a few years later, suspected in South America. METHODS: To characterise resistance emergence, a treatment efficacy study was performed on the reported patients infected with P falciparum and treated with dihydroartemisinin-piperaquine in French Guiana (n=6, 2016-18). Contemporary isolates collected in French Guiana were genotyped for P falciparum chloroquine resistance transporter (pfCRT; n=845) and pfpm2 and pfpm3 copy number (n=231), phenotyped using the in vitro piperaquine survival assay (n=86), and analysed through genomic studies (n=50). Additional samples from five Amazonian countries and one outside the region were genotyped (n=1440). FINDINGS: In field isolates, 40 (47%) of 86 (95% CI 35·9-57·1) were resistant to piperaquine in vitro; these phenotypes were more associated with pfCRTC350R (ie, Cys350Arg) and pfpm2 and pfpm3 amplifications (Dunn test, p<0·001). Those markers were also associated with dihydroartemisinin-piperaquine treatment failure (n=3 [50%] of 6). A high prevalence of piperaquine resistance markers was observed in Suriname in 19 (83%) of 35 isolates and in Guyana in 579 (73%) of 791 isolates. The pfCRTC350R mutation emerged before pfpm2 and pfpm3 amplification in a temporal sequence different from southeast Asia, and in the absence of artemisinin partial resistance, suggesting a geographically distinctive epistatic relationship between these genetic markers. INTERPRETATION: The high prevalence of piperaquine resistance markers in parasite populations of the Guianas, and the risk of associated therapeutic failures calls for caution on dihydroartemisinin-piperaquine use in the region. Furthermore, greater attention should be given to potential differences in genotype to phenotype mapping across genetically distinct parasite populations from different continents. FUNDING: Pan American Health Organization and WHO, French Ministry for Research, European Commission, Santé publique France, Agence Nationale de la Recherche, Fundação de Amparo à Pesquisa do Estado do Amazonas, Ministry of Health of Brazil, Oswaldo Cruz Foundation, and National Institutes of Health. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies.

Amidst the global healthcare landscape, the menace of snakebite envenoming (SBE) has persisted, silently afflicting millions and annually claiming tens of thousands of lives [...].

Methylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients.

IMPORTANCE: The SARS-CoV-2 virus infection in humans induces significant inflammatory and systemic reactions and complications of which corticosteroids like methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous corticosteroids in COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous methylprednisolone in COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the inflammation and biochemistry components may be used, in the future, to leverage the use of methylprednisolone in any future pandemics from the coronavirus family.

Severe Hemolysis during Primaquine Radical Cure of Plasmodium vivax Malaria: Two Systematic Reviews and Individual Patient Data Descriptive Analyses.

Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were diverse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure; 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient (< 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required.

Acute mesenteric ischemia following lancehead snakebite: an unusual case report in the Northernmost Brazilian Amazon.

Snakebites have a great impact in the Brazilian Amazon, being the lancehead Bothrops atrox the species responsible for most accidents, disabilities, and deaths. This study shows a case report of an indigenous patient from the Yanomami ethnicity, male, 33 years-old, envenomed by a B. atrox snake. Envenoming caused by B. atrox are characterized by local manifestations (e.g., pain and edema) and systemic manifestations, mainly coagulation disorders. The indigenous victim was admitted in the main hospital of Roraima and evolved with an unusual complication, an ischemia and necrosis of the proximal ileum, requiring segmental enterectomy with posterior side-to-side anastomosis. The victim was discharge after 27 days of hospitalization with no complaints. Snakebite envenomations may evolve with life-threatening complications, which can be treated by the antivenom following access to a healthcare unit, often late in indigenous population. This clinical case shows the need of strategies that aim improvement in the access to the healthcare by indigenous people, as well as demonstrates an unusual complication that may result from lancehead snakebites. The article also discusses the decentralization of snakebites clinical management to indigenous community healthcare centers to mitigate complications.

Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review.

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.

Prospecting Local Treatments Used in Conjunction with Antivenom Administration Following Envenomation Caused by Animals: A Systematic Review.

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.

Accelerating towards P. vivax elimination with a novel serological test-and-treat strategy: a modelling case study in Brazil.

Background: Plasmodium vivax malaria is challenging to control and eliminate. Treatment with radical cure drugs fails to target the hidden asymptomatic and hypnozoite reservoirs in populations. PvSeroTAT, a novel serological test-and-treat intervention using a serological diagnostic to screen hypnozoite carriers for radical cure eligibility and treatment, could accelerate P. vivax elimination. Methods: Using a previously developed mathematical model of P. vivax transmission adapted to the Brazilian context as a case study for implementation, we evaluate the public health impact of various deployment strategies of PvSeroTAT as a mass campaign. We compare relative reductions in prevalence, cases averted, glucose-6-phosphate dehydrogenase (G6PD) tests, and treatment doses of PvSeroTAT campaigns to strengthened case management alone or mass drug administration (MDA) campaigns across different settings. Findings: Deploying a single round of PvSeroTAT with 80% coverage to treat cases with a high efficacy radical cure regimen with primaquine is predicted to reduce point population prevalence by 22.5% [95% UI: 20.2%-24.8%] in a peri-urban setting with high transmission and by 25.2% [95% UI: 9.6%-42.2%] in an occupational setting with moderate transmission. In the latter example, while a single PvSeroTAT achieves 9.2% less impact on prevalence and averts 300 less cases per 100,000 than a single MDA (25.2% [95% UI: 9.6%-42.2%] point prevalence reduction versus 34.4% [95% UI: 24.9%-44%]), PvSeroTAT requires 4.6 times less radical cure treatments and G6PD tests. Layering strengthened case management and deploying four rounds of PvSeroTAT six months apart is predicted to reduce point prevalence by a mean of 74.1% [95% UI: 61.3%-86.3%] or more in low transmission settings with less than 10 cases per 1000 population. Interpretation: Modelling predicts that mass campaigns with PvSeroTAT are predicted to reduce P. vivax parasite prevalence across a range of transmission settings and require fewer resources than MDA. In combination with strengthened case management, mass campaigns of serological test-and-treat interventions can accelerate towards P. vivax elimination. Funding: This project was funded in part by the Bill and Melinda Gates Foundation and the National Health and Medical Research Council.

Chemistry and Pharmacology of Bergenin or Its Derivatives: A Promising Molecule.

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.

Building an explanatory model for snakebite envenoming care in the Brazilian Amazon from the indigenous caregivers' perspective.

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.

Snakebite envenoming in Brazilian children: clinical aspects, management and outcomes.

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.

Hemodynamic impairment induced by Crotoxin using in vivo and ex vivo approach in a rat model.

Crotalus durissus snakebite represent 10 % of snakebite cases in Brazil, which cardiovascular disorders are associated with severe cases. Considering crotoxin (CTX) as the major venom component, the present study aimed to evaluate the hemodynamic alterations induced by CTX using in vivo and ex vivo approaches in a rat model. In vivo cardiac function parameters were analyzed from anesthetized rats treated with CTX or saline only (Sham), along with serum creatine kinase MB (CK-MB) and lung myeloperoxidase. From the same animals, hearts were isolated and functional parameters evaluated in Langendorff method ex vivo. CTX binding to myoblast cell line in vitro were evaluated using confocal microscopy and flow cytometry. CTX was capable of reducing arterial and diastolic blood pressure, heart rate, along with left ventricle pressure development or decay during systole (LVdP/dtmax and LVdP/dtmin) in vivo, however no differences were found in the ex vivo approach, showing that intrinsic heart function was preserved. In vitro, CTX binding to myoblast cell line was mitigated by hexamethonium, a nicotinic acetylcholine receptor antagonist. The present study has shown that CTX induce hemodynamic failure in rats, which can help improve the clinical management of cardiovascular alterations during Crotalus durissus snakebite.

Snakebite clinics and pathogenesis: from preclinical to resource mapping studies

Amidst the global healthcare landscape, the menace of snakebite envenoming (SBE) has persisted, silently afflicting millions and annually claiming tens of thousands of lives. Indeed, in 2017, the World Health Organization (WHO) reclassified snakebite envenoming as a Category A Neglected Tropical Disease (NTD), finally prompting worldwide recognition of the profound health and economic devastation caused by these venomous encounters. Then, in 2019, WHO unveiled an ambitious strategy: to slash snakebite envenoming-related mortality and disability by 50% before 2030 [1,2]. This editorial marks the inception of our Special Issue, “Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies”, which stands as a guiding light in our collective effort to confront SBEs. Gathering insights from research on snakebite envenoming outcomes, diagnostic advancements, uncommon case reports, therapeutic strategies, and healthcare professional training, this Special Issue is dedicated to disseminating knowledge and charting a course towards a future where snakebite envenomings cease to be a neglected tragedy and evolve into a preventable and manageable challenge. In their pioneering study, Murta et al. [3] explored the experiences of healthcare professionals (HCPs) providing medical care to indigenous people with SBEs in the Brazilian Amazon. They conducted group discussions during a three-day training session for HCPs from the Indigenous Health Care Subsystem, involving 56 participants split between Boa Vista (Roraima) and Manaus (Amazonas), which are state capitals located in the Brazilian Amazon Forest. The study revealed three key findings: indigenous people are open to receiving antivenom but prefer not to leave their villages for hospitals; HCPs require antivenom and additional resources to improve patient care; and HCPs advocate for a collaborative, culturally sensitive approach to SBE treatment. To address these challenges, the study suggests decentralizing antivenom distribution to local health units. However, the diverse ethnicities in the Brazilian Amazon pose a challenge, necessitating further research on preparing HCPs for intercultural contexts. Even when antivenom is available in low-resource areas, health workers do not receive adequate training to manage SBEs. The study of Rocha et al. (2022) [4] aimed to develop and validate a clinical practice guideline (CPG) for SBE management across Brazil. Content validation was performed by a panel of expert judges with academic and/or technical expertise in SBE management, and semantic validation was performed by analyzing focus group discussions with doctors and nurses from three municipalities of the Brazilian Amazon. This study presents the successful development and validation process of a CPG for SBE management, which is targeted to a specific low-resource, high-burden setting. This development and validation process can be adapted to other settings and/or other neglected tropical diseases. In the health system domain, this strategy involves ensuring the production and distribution of safe and effective antivenom treatment and strengthening local health systems. Bhatia et al. (2022) [5] highlight that there is an urgent need to replace the excessive use of animals in snake antivenom production. We tested the efficacy of a single batch of polyvalent antivenom from bioproducts limited to Echis carinatus venom collected from Tamil Nadu, Goa, and Rajasthan, using different in vitro assays. The use of both binding and functional assays allowed us to measure the efficacy of the antivenom. By normalizing the scale of measurements of the neutralization capacity of the Indian polyvalent antivenom using different in vitro assays, we were able to arrive at an efficacy score for Echis carinatus venoms that could be used to predict the ED50. This approach captures the variation in venom toxins shown by snake species and paves the way to replace the use of mice for evaluating antivenom potency. Protobothrops mucrosquamatus snakebites are frequent in Taiwan, and the species’ widespread distribution and diverse habitats drove Chiang et al. (2022) [6] to investigate envenoming effects and relevant venom variations. The results showed minor differences in the protein family, with variations in acidic phospholipases A2s, serine proteinases, metalloproteinases, C-type lectin-like proteins, and other less abundant components. Moreover, clinical manifestations of envenomed patients hospitalized in northern Taiwan revealed differences in local symptoms, such as ecchymosis and blistering. The mechanism of these local effects is probably related to the venom components’ geographical variability. These findings will help to improve the management of P. mucrosquamatus bites in Taiwan. Vera-Palacios et al. (2022) [7] investigated in vivo the ability of Urospatha sagittifolia (Araceae) to modulate the catalytic activity of Bothrops atrox venom, and their toxic consequences, such as edema, skin hemorrhage, and lethality. Ethanolic extract, which is rich in phenolics, alkaloids, coumarins, and flavonoids, reduced these three parameters. The authors concluded that these findings will support future studies with purified metabolites as new agents for the treatment of B. atrox snakebites, an important public health problem in the Amazon region. The study by Manson et al. [8] marks a groundbreaking leap forward in the realm of SBE treatment, with a particular focus on combating the toxicity of Three-Finger Toxins (3FTxs) of Naja ashei snake venom. These potent venom-derived toxins are prevalent in N. ashei venom and have posed a formidable challenge to effective antivenom therapy. What sets this research apart is the development of monoclonal antibodies (i.e., P4G6a, P6D9a, and P6D9b) meticulously designed to target these troublesome 3FTxs. Remarkably, the monoclonal antibodies demonstrated exceptional binding capabilities to the target 3FTxs, outperforming even the leading commercial antivenoms available in the Kenyan market. The true breakthrough lies in the combined use of these monoclonal antibodies, where their cocktail exhibited superior toxin inhibition compared to traditional antivenoms. Alsolaiss et al. [9] sheds essential light on the complex and diverse acute responses triggered by African snake venoms, a critical aspect of understanding the pathophysiology of SBEs. Using a well-designed murine model, the research systematically evaluated the acute-phase and inflammatory reactions induced by ten different African snake venoms, with a particular focus on sub-Saharan African species, including the spitting cobra (Naja nigricollis) and forest cobra (N. melanoleuca), as potent inducers of acute-phase and inflammatory responses, with N. nigricollis venom stimulating a remarkable 100-fold increase in systemic interleukin 6 (IL-6). Moreover, the study revealed species-specific changes in red blood cell morphology, lymphopenia, neutrophil leukocytosis, and marked hemolysis and platelet aggregation levels in response to these venoms. These findings underscore the intricate and diverse nature of acute responses to envenoming, paving the way for potential diagnostic and therapeutic advancements that could greatly benefit snakebite victims. A very interesting review was also presented in the Special Issue. Huang et al. [10] analyzes 35 cases of snakebites, primarily from front-fanged snakes, like vipers and cobras, as well as a few rare instances from rear-fanged snakes. Viper bites often result in severe complications, such as ischemic strokes and intracranial hemorrhages, leading to fatalities in some cases. In contrast, elapid bites are primarily manifested as neural, cardiac, and ophthalmic disorders. Remarkably, rear-fanged snakebites, characterized by shallow bites and minimal venom injection, rarely cause severe complications. An essential takeaway from the review is the pivotal role of antivenom (AV) treatment, although it also discusses various therapeutic agents that could potentially complement AV treatment for snakebite-induced complications. Furthermore, the Special Issue delved into two unconventional snakebite case reports, one conducted in Romania and the other in Brazil, subjecting them to comprehensive examination and discussion. Nitescu et al. [11] offers a unique perspective on snake envenomation, focusing on a specific exception within the European viper (Vipera berus) species. While most V. berus bites typically lack neurotoxic effects, their study highlights rare cases involving subspecies found in the Carpathian Basin of southeastern Europe that do induce such symptoms. The study presents a compelling case of a 5-year-old girl from southern Romania who experienced neurotoxicity, alongside systemic and local symptoms, following a bite from one of these Carpathian Basin V. berus subspecies. This case provides pivotal insights, affirming that venom from V. berus subspecies in the Carpathian Basin region can indeed induce neurotoxic effects. Additionally, it underscores the effectiveness of monospecific antivenom treatment in rapidly and completely mitigating the envenomation’s effects, offering valuable clinical guidance for the management of such rare cases. In contrast, Oliveira et al.’s [12] case report delves into the often-overlooked long-term musculoskeletal disabilities resulting from snakebites in indigenous communities in Brazil. The report focuses on a 32-year-old male indigenous patient envenomed by a Bothrops species (lancehead snake), highlighting the significant and enduring health challenges posed by snakebites. Over approximately 2 years and 6 months, the patient underwent various medical interventions, including debridement, tissue reconstruction, and physical therapy, resulting in improved mobility but a lasting impact on his gait. This case report emphasizes the need for a comprehensive healthcareapproach, including physiotherapy, plastic surgery, orthopedics, and social support, to aid in the reintegration of snakebite survivors into their communities. Antivenom treatments for SBE patients have existed for more than 130 years, remaining the only therapeutics available for this neglected problem. Remarkably, despite advances in the health system, access to antivenom treatment is poor in most areas of low-income countries. Better logistics for the transportation of antivenoms and other commodities is an issue to be addressed, as well as realistic and comprehensive health programs. In parallel, many investments are still needed for the research and development of more effective antivenoms for some species of snakes, as well as for the advance of small-molecule inhibitor-based drug therapies.