ABSTRACT
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Previously, it was reported the production of an active human recombinant GALNS (rGALNS) in E. coli BL21(DE3). However, this recombinant enzyme was not taken up by HEK293 cells or MPS IVA skin fibroblasts. Here, we leveraged a glyco-engineered E. coli strain to produce a recombinant human GALNS bearing the eukaryotic trimannosyl core N-glycan, Man3GlcNAc2 (rGALNSoptGly). The N-glycosylated GALNS was produced at 100 mL and 1.65 L scales, purified and characterized with respect to pH stability, enzyme kinetic parameters, cell uptake, and KS clearance. The results showed that the addition of trimannosyl core N-glycans enhanced both protein stability and substrate affinity. rGALNSoptGly was capture through a mannose receptor-mediated process. This enzyme was delivered to the lysosome, where it reduced KS storage in human MPS IVA fibroblasts. This study demonstrates the potential of a glyco-engineered E. coli for producing a fully functional GALNS enzyme. It may offer an economic approach for the biosynthesis of a therapeutic glycoprotein that could prove useful for MPS IVA treatment. This strategy could be extended to other lysosomal enzymes that rely on the presence of mannose N-glycans for cell uptake.
Subject(s)
Cultural Diversity , Public Health , Sexual and Gender Minorities , Humans , Hispanic or Latino , Female , United StatesABSTRACT
BACKGROUND: Evidence on abatacept (ABA) utility for rheumatoid arthritis (RA) - associated interstitial lung disease (ILD) is growing. Clinical trials have shown equivalence in subcutaneous (SC) and intravenous (IV) administration of ABA for articular manifestations. However, this has not been studied in respiratory outcomes. OBJECTIVE: To compare the effectiveness of ABA in RA-ILD patients according to the route of administration. METHODS: National retrospective multicentre study of RA-ILD patients on treatment with ABA. They were divided into 2 groups: a) IV, and b) SC. The following outcomes were analysed from baseline to final follow-up using linear mixed models: a) forced vital capacity (FVC), b) diffusing capacity of the lungs for carbon monoxide (DLCO), c) chest high resolution computed tomography (HRCT), d) dyspnoea, e) RA activity, and f) sparing corticosteroids effect. RESULTS: A total of 397 patients were included (94 IV-ABA and 303 SC-ABA), median follow-up of 24 [10-48] months. After adjustment for possible confounders, FVC and DLCO remained stable during the first 24 months without differences between IV-ABA and SC-ABA (p = 0.6304 and 0.5337). Improvement/ stability of lung lesions in HRCT was observed in 67 % of patients (75 % IV-ABA, 64 % SC-ABA; p = 0.07). Dyspnoea stabilized/ improved in 84 % of patients (90 % IV-ABA, 82 % SC-ABA; p = 0.09). RA - disease activity improved in both groups. No statistically significant differences regarding any of the variables studied between the two groups were found. ABA was withdrawn in 87 patients (21.9 %), 45 % IV-ABA and 37 % SC-ABA (p = 0.29). ILD worsening and articular inefficacy were the most common reasons for ABA discontinuation. CONCLUSION: In patients with RA-ILD, ABA seems to be equally effective regardless of the route of administration.
ABSTRACT
The disadvantages of some conventional drugs, including their low bioavailability, poor targeting efficiency, and important side effects, have led to the rational design of drug delivery systems. In particular, the introduction of drug delivery systems is a potential approach to enhance the uptake of therapeutic agents and deliver them at the right time and in the right amount of concentration at the required site, as well as open new strategies for effective illness treatment. In this review, we provide a basic understanding of drug delivery systems with an emphasis on the use of cyclodextrin-, polymer- and surfactant-based delivery systems. These systems are very attractive because they are biocompatible and biodegradable nanomaterials with multifunctional components. We also provide some details on their design considerations and their use in a variety of medical applications by employing several routes of administration.
ABSTRACT
Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal inherited disease caused by mutations in gene encoding the lysosomal enzyme N-acetyl-alpha-glucosaminidase (NAGLU). These mutations result in reduced NAGLU activity, preventing it from catalyzing the hydrolysis of the glycosaminoglycan heparan sulfate (HS). There are currently no approved treatments for MPS IIIB. A novel approach in the treatment of lysosomal storage diseases is the use of pharmacological chaperones (PC). In this study, we used a drug repurposing approach to identify and characterize novel potential PCs for NAGLU enzyme. We modeled the interaction of natural and artificial substrates within the active cavity of NAGLU (orthosteric site) and predicted potential allosteric sites. We performed a virtual screening for both the orthosteric and the predicted allosteric site against a curated database of human tested molecules. Considering the binding affinity and predicted blood-brain barrier permeability and gastrointestinal absorption, we selected atovaquone and piperaquine as orthosteric and allosteric PCs. The PCs were evaluated by their capacity to bind NAGLU and the ability to restore the enzymatic activity in human MPS IIIB fibroblasts These results represent novel PCs described for MPS IIIB and demonstrate the potential to develop novel therapeutic alternatives for this and other protein deficiency diseases.
Subject(s)
Acetylglucosaminidase , Mucopolysaccharidosis III , Humans , Mucopolysaccharidosis III/drug therapy , Mucopolysaccharidosis III/metabolism , Mucopolysaccharidosis III/pathology , Acetylglucosaminidase/metabolism , Acetylglucosaminidase/antagonists & inhibitors , Acetylglucosaminidase/chemistry , Acetylglucosaminidase/genetics , Allosteric Site/drug effects , Allosteric Regulation/drug effectsABSTRACT
Human aging is a physiological, progressive, heterogeneous global process that causes a decline of all body systems, functions, and organs. Throughout this process, cognitive function suffers an incremental decline with broad interindividual variability.The first objective of this study was to examine the differences in the performance on the MoCA test (v. 7.3) per gender and the relationship between the performance and the variables age, years of schooling, and depressive symptoms .The second objective was to identify factors that may influence the global performance on the MoCA test (v. 7.3) and of the domains orientation, language, memory, attention/calculation, visuospatial and executive function, abstraction, and identification.A cross-sectional study was carried out in which five hundred seventy-three (573) cognitively healthy adults ≥ 50 years old were included in the study. A sociodemographic questionnaire, the GDS-15 questionnaire to assess depression symptoms and the Spanish version of the MoCA Test (v 7.3) were administered. The evaluations were carried out between the months of January and June 2022. Differences in the MoCA test performance per gender was assessed with Student's t-test for independent samples. The bivariate Pearson correlation was applied to examine the relationship between total scoring of the MoCA test performance and the variables age, years of schooling, and depressive symptoms. Different linear multiple regression analyses were performed to determine variables that could influence the MoCA test performance.We found gender-related MoCA Test performance differences. An association between age, years of schooling, and severity of depressive symptoms was observed. Age, years of schooling, and severity of depressive symptoms influence the MoCA Test performance, while gender does not.
Subject(s)
Depression , Humans , Male , Female , Middle Aged , Cross-Sectional Studies , Aged , Depression/psychology , Depression/diagnosis , Depression/epidemiology , Aged, 80 and over , Cognition/physiology , Sex Factors , Age FactorsABSTRACT
This study aimed to develop and implement a nanotechnology-based alternative to traditional tracers used in the oil and gas industry for assessing interwell connectivity. A simple and rapid hydrothermal protocol for synthesizing carbon quantum dots (CQDs) using agroindustry waste was implemented. Three commercial CQDs were employed (CQDblue, CQDgreen, and CQDred); the fourth was synthesized from orange peel (CQDop). The CQDs from waste and other commercials with spherical morphology, nanometric sizes less than 11 nm in diameter, and surface roughness less than 3.1 nm were used. These tracers demonstrated high colloidal stability with a negative zeta potential, containing carbonyl-type chemical groups and unsaturations in aromatic structures that influenced their optical behavior. All materials presented high colloidal stability with negative values of charge z potential between -17.8 and -49.1. Additionally, individual quantification of these tracers is feasible even in scenarios where multiple CQDs are present in the effluent with a maximum percentage of interference of 15.5% for CQDop in the presence of the other three nanotracers. The CQDs were injected into the field once the technology was insured under laboratory conditions. Monitoring the effluents allowed the determination of connectivity for five first-line producer wells. This study enables the application of CQDs in the industry, particularly in fields where the arrangement of injector and producer wells is intricate, requiring the use of multiple tracers for a comprehensive description of the system.
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Neutrophils, which constitute the most abundant leukocytes in human blood, emerge as crucial players in the induction of endothelial cell death and the modulation of endothelial cell responses under both physiological and pathological conditions. The hallmark of preeclampsia is endothelial dysfunction induced by systemic inflammation, in which neutrophils, particularly through the formation of neutrophil extracellular traps (NETs), play a pivotal role in the development and perpetuation of endothelial dysfunction and the hypertensive state. Considering the potential of numerous pharmaceutical agents to attenuate NET formation (NETosis) in preeclampsia, a comprehensive assessment of the extensively studied candidates becomes imperative. This review aims to identify mechanisms associated with the induction and negative regulation of NETs in the context of preeclampsia. We discuss potential drugs to modulate NETosis, such as NF-κß inhibitors, vitamin D, and aspirin, and their association with mutagenicity and genotoxicity. Strong evidence supports the notion that molecules involved in the activation of NETs could serve as promising targets for the treatment of preeclampsia.
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Latino sexual minority men (SMM) are a highly vulnerable population to HIV, and while pre-exposure prophylaxis (PrEP) has emerged as a promising biomedical tool for HIV prevention among them, its utilization remains disproportionately low in this community despite its potential. Understanding the barriers along the PrEP continuum of care, known as the "PrEP cascade," is crucial for effectively implementing PrEP interventions. Therefore, the objective of our study was twofold: first, to explore the stage of Latino SMM in the PrEP cascade by examining disparities in demographics, social factors, and healthcare aspects; second, to gain insights from healthcare providers who have direct clinical experience with our population regarding the challenges faced by Latino SMM in accessing and adhering to PrEP. Based on the study findings, the majority of participants (n = 74; 49%) were in the contemplation stage, and only one in ten Latino SMM (10.6%) were currently adherent to PrEP. Compared to those who were at least second-generation, first-generation status had a positive association (B = 0.699, SE = 0.208, ß = 0.351, p < .001) with engagement along the PrEP Contemplation Ladder. Conversely, having at least one parent who did not have legal residency, relative to those whose parents were both U.S. citizens or held legal residency documentation, was found to have a negative association (B = - 0.689, SE = 0.245, ß = 0.245, p = .006) with engagement along the PrEP Contemplation Ladder. Additionally, discussing PrEP with a healthcare provider had a positive association (B = 0.374, SE = 0.179, ß = 0.185, p = .038) with engagement along the PrEP Contemplation Ladder. Qualitative results from our study suggest that some Latinos who initially agreed to start using PrEP ended up getting lost in the care pipeline and failed to attend their scheduled appointments. Providers also noted that many patients lacked access to a pharmacy where they felt comfortable obtaining their PrEP prescription, leading them to discontinue use after only a few months. These findings emphasize the importance of considering the unique needs, culture, and background of Latinos, including care delivery and provider attitudes that can facilitate progress through the PrEP cascade.
ABSTRACT
Introduction: Peru is a country that has a high incidence of viral outbreaks and epidemics, which is why it is necessary to validate a scale that measures anxiety and stress in professionals who are on the front lines of these events. Therefore, our objective was to validate the Peruvian-Spanish version of the Stress and Anxiety to Viral Epidemics-9 items (SAVE-9) scale and to concurrently compare its validity and internal consistency with the SAVE-6 scale among healthcare workers (HCWs). Materials and methods: We conducted a cross-sectional study based on data collected from a self-reported survey in paper-and-pencil format between April and July 2023. A total of 203 HCWs participated in the research. We developed a confirmatory factor analysis (CFA) and item response theory (IRT). We calculated Cronbach's α coefficient and McDonald's ω to assess the internal consistency of the scales. Results: The results show that SAVE-9 (a two-factor model) and SAVE-6 (a one-factor model) provided an excellent fit in the confirmatory factor analysis. Both scales demonstrated strong internal consistency (Cronbach's α 0.85 and 0.86, respectively). Significant correlations were found between the SAVE-9 and SAVE-6 scales and Generalized Anxiety Disorder-7 items scale (r = 0.44 and r = 0.38, respectively, p < 0.001) as well as the Patient Health Questionnaire-9 items (r = 0.39 and r = 0.35, respectively, p < 0.001). The optimal cutoff points for SAVE-9 and SAVE-6 were identified for assessing anxiety, aligned with a GAD-7 score ≥5 points. Conclusion: The Peruvian-Spanish SAVE-9 and SAVE-6 scales are reliable and valid rating scales to assess the anxiety response of HCWs in response to viral epidemics. Though COVID-19 is diminished, these scales will be useful for other viral epidemics in the future.
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In this work, we aim to find physical evidence demonstrating the crucial role that the effective concentration of antioxidants (AOs) present at the interfacial region of emulsions has in controlling the inhibition of the lipid oxidation reaction. We prepared a series of antioxidants of different hydrophobicities derived from chlorogenic and protocatechuic acids. We first monitored, in intact emulsions, the (sigmoidal) production of conjugated dienes and determined the corresponding induction times, tind. Independently, we determined the effective concentrations of the antioxidants in the same intact emulsions. Results show that both the length of the induction periods and the antioxidant interfacial concentrations parallel each other, with a maximum at the octyl-dodecyl derivatives. The ratio between the interfacial antioxidant concentrations and the induction periods remains constant for all AOs in the same series, so that the rates of initiation of lipid oxidation are the same regardless of the hydrophobicity of the antioxidant employed. The constancy in the rate of initiation provides strong experimental evidence for a direct relationship between interfacial concentrations and antioxidant efficiencies. Results suggest new possibilities to investigate lipid peroxidation under non-forced conditions and are of interest to formulators interested in preparing emulsions with antimicrobial properties.
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OBJECTIVE: We aimed to conduct an umbrella review to summarize the existing evidence regarding the prevalence of peri-ictal psychiatric manifestations (PM) in people with epilepsy (PWE) including pre-ictal, ictal, and postictal stages. METHODS: Databases were searched up to June 2023 for systematic reviews (SR) of observational studies that included patients with epilepsy peri-ictal PM. Data selection, data extraction, and risk of bias assessment (with the AMSTAR-2 instrument) were performed by two independent reviewers. We performed a narrative synthesis using previous guidelines. We used a self-developed decision table according to the GRADE system adapted for narrative outcomes if the certainty of outcomes was not determined by systematic review authors. RESULTS: Four SRs were included comprising 66 primary studies (n = 10 217). Three SRs evaluated one period (pre-ictal, ictal, and postictal), and one did not determine it. During the pre-ictal period, the more prevalent symptom was confusion, although with a low certainty (due to the heterogeneity and serious risk of bias). One systematic review that only included case reports evaluated the ictal period, finding mood/anxiety disorders, psychosis, and personality changes. The postictal period included the most PM (anxiety: 45.0% and depressive symptoms: 43.0%), with very low certainty, due to risk of bias, potential publication bias, heterogeneity, and failure to report the confidence intervals. SIGNIFICANCE: With very low certainty, epileptic periods are characterized by a wide spectrum of PM, being postictal symptoms the most prevalent, predominantly anxiety, and depressive symptoms. Further understanding of these PM of epilepsy could improve the attention of the people with epilepsy. PLAIN LANGUAGE SUMMARY: In this review of reviews, we summarize the frequency in which psychiatric manifestations occur in relation to an epileptic seizure. A total of 10 217 patients were reported in the reviews. The most common manifestations included symptoms of anxiety and depression, as well as changes in the normal behavior of the patient. These manifestations occurred most frequently right after the seizure finished.
Subject(s)
Epilepsy , Mental Disorders , Humans , Epilepsy/psychology , Epilepsy/complications , SeizuresABSTRACT
OBJECTIVE: To explore the experiences of individuals who develop projects and interventions where community participation-action constitutes a strategic tool for reducing health inequalities. METHOD: Qualitative study based on semi-structured, in-depth online interviews with individuals considered experts in the development of health promotion strategies involving community participation. A total of 12 individuals from the healthcare, social healthcare, academic, and associative backgrounds were selected. The texts were analyzed following the thematic content analysis approach. RESULTS: The prominent strength of the processes involving the interviewed individuals is their participatory approach. However, there is no genuine commitment to promoting community participation from primary healthcare, and precarity has been identified as a significant weakness in the development of participatory health promotion projects. The sustainability of participatory processes relies on the transfer of knowledge to the community and their empowerment. CONCLUSIONS: Participatory processes have demonstrated their ability to reposition the community as an essential part of the healthcare system. It would be interesting to use a measurement tool for participation in all community health actions, both to guide their design and planning and to assess the depth of participation and its impact on the process. Enhancing community action expectations for health in the near future involves promoting a community-oriented approach in primary care and intersectoral collaboration, which requires a significant institutional and policy commitment.
ABSTRACT
The burden of epilepsy in the Latin America and the Caribbean (LAC) region causes a profound regional impact on the health care system and significantly contributes to the global epilepsy burden. As in many other resource-limited settings worldwide, health care professionals and patients with epilepsy in LAC countries face profound challenges due to a combination of factors, including high disease prevalence, stigmatization of epilepsy, disparities in access to care, limited resources, substantial treatment gaps, insufficient training opportunities for health care providers, and a diverse patient population with varying needs. This article presents an overview of the epidemiology of epilepsy and discusses the principal obstacles to epilepsy care and key contributors to the epilepsy diagnosis and treatment gap in the LAC region. We conclude by highlighting various initiatives across different LAC countries to improve epilepsy care in marginalized communities, listing strategies to mitigate treatment gaps and facilitate better health care access for patients with epilepsy by enhancing the epilepsy workforce.
Subject(s)
Epilepsy , Health Services Accessibility , Humans , Caribbean Region/epidemiology , Latin America/epidemiology , PrevalenceABSTRACT
BACKGROUND: More than one-third of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) participants identify as Latino, but participation has been declining and individuals who speak predominantly Spanish face additional barriers to participation. During the COVID-19 pandemic, there were changes in WIC eligibility and benefits that may have been differentially accessible to Spanish-speaking Latina participants due to factors such as language barriers and lack of awareness of changes. Understanding Spanish-speaking Latinas' experiences with the WIC program generally and during the pandemic can inform efforts to equitably implement future emergency food response policies and improve the WIC program and Latina participant enrollment more broadly. OBJECTIVE: This study aimed to understand the perceptions and experiences of Spanish-speaking Latina WIC participants with the WIC program generally and with COVID-19 pandemic-related policy changes made to the WIC program. DESIGN: Qualitative in-depth interviews were conducted virtually in Spanish in August 2022 using a semi-structured guide. PARTICIPANTS/SETTING: Study participants were 18 Spanish-speaking Latina adult WIC participants living in North Carolina recruited using convenience sampling. ANALYSIS: All interviews were recorded, transcribed, and coded in Spanish. Thematic analysis with inductive coding was used to derive key themes. RESULTS: Perceptions about the WIC program in this sample were mixed. Participants felt positively about the healthfulness of foods included in the WIC food packages but expressed concern about the monthly benefit amounts being too low and the cultural appropriateness of food options. Pandemic policy changes, such as remote appointments and the Cash Value Benefit increase were perceived positively; however, barriers to using benefits during this time included limited communication from WIC agencies, food shortages, and concerns about not being granted US citizenship or permanent resident status due to use of WIC (ie, public charge rule). Social networks played an important role in learning about and enrolling in WIC and navigating food shortages during the pandemic. CONCLUSIONS: Concerns about the cultural appropriateness of foods provided, communication challenges, and the public charge rule emphasized the need for resources dedicated in the WIC program to improving Spanish-speaking Latina women's experiences with WIC.
Subject(s)
COVID-19 , Food Assistance , Hispanic or Latino , Adult , Female , Humans , Young Adult , Communication Barriers , COVID-19/prevention & control , COVID-19/ethnology , Hispanic or Latino/psychology , Language , North Carolina , Pandemics , Qualitative ResearchABSTRACT
Flavin mononucleotide (FMN) is a highly efficient photosensitizer (PS) yielding singlet oxygen (1 O2 ). However, its 1 O2 production efficiency significantly decreases upon isoalloxazine ring encapsulation into the protein matrix in genetically encoded photosensitizers (GEPS). Reducing isoalloxazine ring interactions with surrounding amino acids by protein engineering may increase 1 O2 production efficiency GEPS, but at the same time weakened native FMN-protein interactions may cause undesirable FMN dissociation. Here, in contrast, we intentionally induce the FMN release by light-triggered sulfur oxidation of strategically placed cysteines (oxidation-prone amino acids) in the isoalloxazine-binding site due to significantly increased volume of the cysteinyl side residue(s). As a proof of concept, in three variants of the LOV2 domain of Avena sativa (AsLOV2), namely V416C, T418C, and V416C/T418C, the effective 1 O2 production strongly correlated with the efficiency of irradiation-induced FMN dissociation (wild type (WT) < V416C < T418C < V416C/T418C). This alternative approach enables us: (i) to overcome the low 1 O2 production efficiency of flavin-based GEPSs without affecting native isoalloxazine ring-protein interactions and (ii) to utilize AsLOV2, due to its inherent binding propensity to FMN, as a PS vehicle, which is released at a target by light irradiation.
Subject(s)
Flavoproteins , Photosensitizing Agents , Flavoproteins/chemistry , Flavoproteins/metabolism , Protein Domains , Binding Sites , Amino Acids , Flavin Mononucleotide/chemistryABSTRACT
OBJECTIVES: The situation caused by the COVID-19 pandemic has had an impact on the mental, physical, and social health of nursing home staff. The operations and protocols of long-term care facilities had to be adapted to a new, unforeseen, and unknown situation in which a devastating and highly contagious disease was causing large numbers of deaths. The aim of this study was to determine the cumulative impact of the COVID-19 pandemic on care, technical, coordinating-supervisory, and managerial staff working in nursing homes. METHODS: Correlation analysis and between-group comparisons were carried out to study the relationship between burnout scores, emotional balance, and organic and behavioral symptoms. RESULTS: The results indicate high levels of burnout and psychological exhaustion. Management professionals displayed higher levels of organic and behavioral symptoms than other professional categories in the same care settings. Despite this negative symptomatology, most professionals showed a positive emotional balance. CONCLUSION: The need to develop intervention programs to improve the mental, physical, and occupational health of the staff in nursing homes, considering the needs of different professional categories, is emphasized.
ABSTRACT
The maned wolf, Chrysocyon brachyurus, is the largest South American canid, with a natural distribution that stretches across Peru, Bolivia, Brazil, Argentina, Paraguay and Uruguay. The present study reports the case of a rescued specimen of maned wolf that underwent a rehabilitation process in Paraguay, starting in October 2020 with its rescue, and finalising in May 2021 with the reintroduction. Herein, we document findings regarding the general management, biometrics, feeding and environmental enrichment; chemical immobilisation and monitoring; haematology, blood biochemistry and specific serology-relevant pathogens; skin examination and bone marrow cytology; orthopaedic, ophthalmological and dental evaluation; abdominal and cardiac ultrasonography; radiology and copro-parasitology. Main findings include the feeding habits of the individual and enrichment opportunities. The animal weighed 7 kg on arrival, with an estimated age of 5 months, and 18 kg on reintroduction, with an estimated age of 1 year. The animal tested negative to serologic tests for Brucella canis, Dirofilaria, canine distemper, Toxoplasmosis and canine parvovirus. Leptospira testing showed antibodies against L. grippotyphosa on both samplings, L. wolffi and L. ictero on the first sampling, and L. pomona on the second sampling. Abdominal organs were examined and measured through ultrasound evaluation and kidneys showed no alterations. Echocardiography showed preserved mitral, tricuspid and aortic valve flows, but turbulent pulmonary valve flow. Copro-parasitology reported the presence of Lagochilascaris sp. and Balantidium sp. All the information gathered aided in diagnosing the health status of the individual, and the response to environmental enrichment helped assess the behaviour, which led to the suggestion of reintroducing the animal. These data constitute the first published health check of a maned wolf in Paraguay, which can contribute to the species' conservation in the country. The protocol presented in this study can serve as a basis for developing an action plan for the maned wolf in Paraguay.