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Background Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America. Methods The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20–65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12–18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ≥ 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ≥ 25% with NFX to claim its trypanocidal effect, 60–80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80–90% power; one-sided alpha level 1%). Discussion The EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents. Trial registration ClinicalTrials.gov, NCT02369978 . Registered on 24 February 2015.

Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.

This study evaluated the effectiveness of low doses of benznidazole (BNZ) on continuous administration (BNZc), combined with allopurinol (ALO), in C57BL/6J and C3H/HeN mice infected with Trypanosoma cruzi Nicaragua strain and T. cruzi Sylvio-X10/4 clone. TcN-C57BL/6J was also treated with intermittent doses of BNZ (BNZit). The drug therapy started 3 months post infection (pi) in the chronic phase of mice with heart disease progression, followed-up at 6 months pi. TcN-C57BL/6J treated with BNZc was also monitored up to 12 months pi by serology and electrocardiogram. These mice showed severe electrical abnormalities, which were not observed after BNZc or BNZit. ALO only showed positive interaction with the lowest dose of BNZ. A clear parasitic effect, with significant reductions in antibody titres and parasitic loads, was achieved in all models with low doses of BNZ, and a 25% reduction of the conventional dose showed more efficacy to inhibit the development of the pathology. However, BNZ 75 showed partial efficacy in the TcSylvio-X10/4-C3H/HeN model. In our experimental designs, C57BL/6J allowed to clearly define a chronic phase, and through reproducible efficacy indicators, it can be considered a good preclinical model.

Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi ( T. cruzi ) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-β, IL-6, MCP1, and CCR2 than cells from uninfected individuals (HI), irrespectively of the clinical stage, asymptomatic (Asy) or with Chagas heart disease (CHD). Fenofibrate reduces the levels of pro-inflammatory mediators and CCR2 in both Asy and CHD patients. We found that CHD patients display a significantly higher percentage of classical monocytes in comparison with Asy patients and HI. Besides, Asy patients have a significantly higher percentage of non-classical monocytes than CHD patients or HI. However, no difference in the intermediate monocyte subpopulation was found between groups. Moreover, monocytes from Asy or CHD patients exhibit different responses upon stimulation in vitro with T. cruzi lysates and fenofibrate treatment. Stimulation with T. cruzi significantly increases the percentage of classical monocytes in the Asy group whereas the percentage of intermediate monocytes decreases. Besides, there are no changes in their frequencies in CHD or HI. Notably, stimulation with T. cruzi did not modify the frequency of the non-classical monocytes subpopulation in any of the groups studied. Moreover, fenofibrate treatment of T. cruzi -stimulated cells, increased the frequency of the non-classical subpopulation in Asy patients. Interestingly, fenofibrate restores CCR2 levels but does not modify HLA-DR expression in any groups. In conclusion, our results emphasize a potential role for fenofibrate as a modulator of monocyte subpopulations towards an anti-inflammatory and healing profile in different stages of chronic Chagas disease.

Chagas disease is a chronic parasitological disease, which could cause cardiac manifestations in approximately one-third of affected individuals. Benznidazole and nifurtimox are used to treat this parasitological infection caused by Trypanosoma cruzi. Conventionally, the criterion for cure is consistently negative serological tests after treatment. We report a case of a patient who was treated when she was 13 years old and achieved T. cruzi negative seroconversion but developed Chagas disease cardiomyopathy as an adult.

Chronic infection by Trypanosoma cruzi could cause heart conduction disturbances. We sought to analyze electrocardiographic abnormalities among children with chronic T. cruzi infection with and without trypanocidal treatment with benznidazole. We studied 111 children 6-16 years of age with asymptomatic chronic T. cruzi infection who were recruited in 1991-1992 in Salta, Argentina. Most children were randomly assigned to benznidazole 5 mg/Kg/day (n = 47) or matching placebo (n = 48) for 60 days. Remaining children (n = 16) received treatment with benznidazole 5 mg/Kg/day open-label. Electrocardiograms were obtained at baseline and in 1995-1996, 1998, 2000 and 2005, and were analyzed using the Buenos Aires method. Among the 94 children with an electrocardiogram at baseline, 8 (8.5%) had electrocardiographic abnormalities, including 4 (4.7%) children with right bundle branch block. Proportion of abnormal electrocardiograms in the full population (n = 111) remained constant over time (media follow-up 8.6 years). Multivariable adjusted prevalence ratios (95% confidence interval [95%CI]) for electrocardiographic abnormalities in 1995-1996, 1998, 2000 and 2005 comparing children treated with benznidazole versus those not treated were 2.76 (0.66, 11.60), 2.33 (0.44, 12.31), 3.06 (0.48, 19.56), and 1.94 (0.33, 11.25), respectively. Among the 86 children with a normal electrocardiogram at baseline, 16 (18.6%) developed electrocardiographic abnormalities during follow-up. The multivariable adjusted hazard ratio for incident electrocardiographic abnormalities comparing children treated with benznidazole versus those not treated was 0.68 (95%CI: 0.25, 1.88). Electrocardiographic abnormalities are frequent among children with chronic T. cruzi infection. Treatment with benznidazole for 60 days may not be associated with less electrocardiographic abnormalities.

Following publication of the original article [1], the authors notified us of a few requested editions that were not implemented adequately during proofing. The publisher apologizes for the inconvenience caused to our authors and readers.

Since the COVID-19 pandemic arrived, various options have been created to export products, with the creation and development of startups becoming a viable and significant option. Previous research has described the influence of competitive business advantage on international performance. However, the novelty of the current research was to evaluate the influence of the company’s capabilities, through the competitive advantage of the company as a mediator in international performance. The study was based on the responses of 200 active startups in Peru. The PLS-SEM technique was utilized with the company’s capabilities linked to internationalization processes as independent variables, as well as market intelligence, product innovation, and pricing. The mediating variable was competitive advantage, and the dependent variable was international performance. It was found that all three capabilities influenced competitive advantage and, ultimately, international performance. It was concluded that competitive advantage does not act as a mediator between pricing capabilities and the international performance of startups. Moreover, it was determined that competitive advantage acts as a mediator between two of the three assessed capabilities: market intelligence capabilities and product innovation capabilities. The results were supported by the reflective and formative evaluation of the results obtained through the applied technique. These results could help create better programs to promote startups interested in internationalizing and exporting products.

ObjectiveTo describe the sexual practices and behaviour towards HIV infection among Ecuadorian university students.MethodsThis was a cross-sectional, descriptive study carried out between February 2019 and August 2020 among university students from all over the country. Students aged 18 years and older of each participating institution were contacted by an official email account and invited to fill out a survey through Google Forms.ResultsData from a total of 5677 sexually active participants were analysed. The majority were female (57.1%), 48.7% corresponded to the age range 18–20 years and nearly half studied in the field of health. Only 28.5% (n=1612) mentioned having ever been tested for HIV at least once. Regarding sexual behaviour, the vast majority reported having only one partner in the last 2 months. Condom use during the ‘last’ sexual contact was significantly lower in the never tested group (33.5% vs 43.3%, p<0.0001, respectively). Having a higher number of ever or current sexual partners (OR 0.94, 95% CI 0.78 to 1.13) and not using a condom (OR 0.73, 95% CI 0.64 to 0.82) were significantly related to having an HIV test performed. More than half of the participants indicated that they took the HIV test as part of their routine control, and nearly half mentioned not taking it because they felt sure they were free of HIV.ConclusionsBehaviour towards testing for HIV in university students was related to their risky sexual practices and behaviour. Prevention campaigns focused on the general population as well as at-risk populations, including university students, are needed to curb the escalating incidence of HIV in Ecuador.

The authors would like to make the following corrections to the published paper [...]