Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098.

In silico and In vitro Assessment of Dimeric Flavonoids (Brachydins) on Rhipicephalus microplus Glutathione S-transferase.

INTRODUCTION: Rhipicephalus microplus, an important cattle ectoparasite, is responsible for a substantial negative impact on the economy due to productivity loss. The emergence of resistance to widely used commercial acaricides has sparked efforts to explore alternative products for tick control. METHOD: To address this challenge, innovative solutions targeting essential tick enzymes, like glutathione S-transferase (GST), have gained attention. Dimeric flavonoids, particularly brachydins (BRAs), have demonstrated various biological activities, including antiparasitic effects. The objectives of this study were to isolate four dimeric flavonoids from Fridericia platyphylla roots and to evaluate their potential as inhibitors of R. microplus GST. RESULTS: In vitro assays confirmed the inhibition of R. microplus GST by BRA-G, BRA-I, BRA-J, and BRA-K with IC50 values of 0.075, 0.079, 0.075, and 0.058 mg/mL, respectively, with minimal hemolytic effects. Molecular docking of BRA-G, BRA-I, BRA-J, and BRA-K in a threedimensional model of R. microplus GST revealed predicted interactions with MolDock Scores of - 142.537, -126.831, -108.571, and -123.041, respectively. Both in silico and in vitro analyses show that brachydins are potential inhibitors of R. microplus GST. CONCLUSION: The findings of this study deepen our understanding of GST inhibition in ticks, affirming its viability as a drug target. This knowledge contributes to the advancement of treatment modalities and strategies for improved tick control.

Biology of the non-parasitic phase of the cattle tick Rhipicephalus (Boophilus) microplus in an area of Amazon influence.

BACKGROUND: Rhipicephalus (Boophilus) microplus is the most important tick species affecting cattle in the world. Under field conditions, the non-parasitic phase of R. (B.) microplus is unknown in the Amazon biome, including Brazil. The present study aimed to evaluate the non-parasitic phase of R. (B.) microplus in field (grass plots) and laboratory conditions. METHODS: The study was conducted from September 2020 to April 2022 in an Amazonian region (Maranhão State, Brazil). We evaluated the biological parameters of R. (B.) microplus under laboratory and field conditions. Engorged females were exposed to experimental conditions every 14 days, totaling 20 months of study. The following biological parameters were observed: pre-oviposition period, egg mass incubation period, and maximum larval survival period. RESULTS: Abiotic data (e.g., temperature and humidity) varied little throughout the year. Precipitation was the factor that varied the most throughout the year (dry ~ 30 mm3 and rain 400 mm3), and the parameters of pre-oviposition and pre-hatching are longer during the rainy season. A possible negative effect of the dry season on the percentage of hatched eggs was observed. Larval longevity in the plots of both control and free females was short (mean ~ 50-60 days), below that recorded for larvae under controlled conditions (mean ~ 95 days). CONCLUSIONS: Rhipicephalus (Boophilus) microplus was able to complete its non-parasitic phase by producing host-seeking larvae in the pasture during all months of the study. The results indicate that R. (B.) microplus can complete up to six generations per year in biome Amazon. To our knowledge, this is the highest number of annual generations for R. (B.) microplus in Latin America.

Polymeric films of corn starch enhance the lethal effects of thymol and carvacrol terpenes upon Rhipicephalus microplus ticks.

The tick Rhipicephalus microplus is a parasite of great importance in cattle breeding. It is responsible for huge economic losses. The application of synthetic acaricides is used as a form of control. However, resistant strains have been selected over the years, making it necessary to search for new alternative formulations. The present study aimed to formulate biodegradable films impregnated with the terpenes carvacrol and thymol and evaluate their efficacy on larvae and adults of R. microplus through in vitro tests. The following formulations were prepared: Film 1 (starch based); Film 2 (based on starch and glycerol); Film 1 + Carvarcol or Thymol; Film 2 + Carvarcol or Thymol. Terpenes had a final concentration of 5.0 mg/mL. To evaluate the formulations on larvae, the immersion test was performed by dividing into six groups according to the concentration of terpenes: 5.0, 2.5, 1.25, 0.625, 0.313, 0.156 mg/mL and the control groups: 1% ethanol solution; 10% ethanol solution; Film 1; and Film 2. For the evaluations on adult ticks, ten experimental groups (n = 10) were used: 1) Carvacrol; 2) Film 1 + Carvacrol; 3) Film 2 + Carvacrol; 4) Thymol; 5) Film 1 + Thymol; 6) Film 2 + Thymol; 7) Distilled water; 8) 10% ethanol solution; 9) Film 1; and 10) Film 2. In experimental groups 1-6, carvacrol and thymol (free or incorporated in two different biodegradable film formulations) were evaluated at the same concentration (5.0 mg/mL). Each group of ticks was immersed in their respective solutions for five minutes. The results of the tests on larvae showed that the Film 1 + thymol and Film 2 + carvacrol formulations had the lowest lethal concentrations (0.076 and 0.255 mg/mL, respectively), values up to 9.0-fold lower than the monoterpenes tested outside the formulation. Carvacrol and thymol at the concentrations tested were effective in controlling engorged females with a percentage of 32.2% and 63.8%, respectively. When incorporated into biodegradable film formulations, these monoterpenes showed much greater efficacy. Film 1 + carvacrol and Film 2 + carvacrol with control percentages of 71.6% and 97.2%, respectively, while the formulations Film 1 + thymol and Film 2 + thymol showed values of 96.9% and 100.0%. The tick control activity of the biopolymer formulations with thymol and carvacrol was demonstrated through the high mortality rates of larvae and engorged females of the tick R. microplus. Therefore, the results obtained indicate that these formulations have great potential for tick control mainly because of the percentage of control up to 100% in engorged females in in vitro tests.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study.

BACKGROUND: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. METHODS: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. CONCLUSION: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. CLINICALTRIALS.GOV REGISTRY: NCT05558098.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study / Dapagliflozina em pacientes com doença crítica: justificativa e desenho do estudo DEFENDER

ABSTRACT Background: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. Methods: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. Conclusion: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. ClinicalTrials.gov registry: NCT05558098

RESUMO Antecedentes: A doença crítica é um importante ônus permanente da assistência médica em todo o mundo e está associada a altas taxas de mortalidade. Os inibidores do cotransportador de sódio-glicose do tipo 2 têm demonstrado consistentemente benefícios nos desfechos cardiovasculares e renais. Os efeitos dos inibidores do cotransportador de sódio-glicose do tipo 2 em doenças agudas ainda não foram devidamente investigados. Métodos: O DEFENDER é um estudo de iniciativa do investigador, multicêntrico, randomizado, aberto, desenhado para avaliar a eficácia e a segurança da dapagliflozina em 500 participantes adultos com disfunção orgânica aguda hospitalizados na unidade de terapia intensiva. Os participantes aptos serão randomizados 1:1 para receber 10mg de dapagliflozina e o tratamento padrão por até 14 dias ou apenas o tratamento padrão. O desfecho primário é um composto hierárquico de mortalidade hospitalar, início de terapia renal substitutiva e tempo de internação na unidade de terapia intensiva, até 28 dias. O monitoramento da segurança será rigoroso durante todo o estudo. Conclusão: O DEFENDER é o primeiro estudo desenvolvido para investigar o uso de um inibidor do cotransportador de sódio-glicose do tipo 2 em pacientes de unidade de terapia intensiva geral com disfunção orgânica aguda. O estudo fornecerá informações relevantes sobre o uso de medicamentos dessa classe promissora em pacientes críticos. Registro ClincalTrials.gov: NCT05558098

O corpo no transplante cardíaco: quando é possível incorporar um órgão? / The body in the heart transplant: when is it possible to embody na organ?

O transplante cardíaco é um procedimento de alta complexidade, o qual resguarda para o sujeito que nele se implica mudanças biológicas, mas também representacionais em relação ao seu corpo. Nesse contexto, a psicologia faz parte da equipe multidisciplinar e visa cuidar desse sujeito por meio da escuta, para além dos parâmetros médicos desse do processo de transplante, que radicaliza a experiência do "outro em si". A escuta clínica ocorre por meio do acompanhamento desses pacientes ao longo do processo de espera por um transplante e, após o procedimento, através da relação transferencial estabelecida com o terapeuta. No caso do presente trabalho, sob a ótica da psicanálise, oferecendo um lugar de potência para que o processo de incorporação desse enxerto em nível subjetivo seja possível. O estudo em questão é uma pesquisa qualitativa, retrospectiva e prospectiva dos fatos clínicos coletados ao longo do acompanhamento do paciente, dos registros clínicos realizados e das supervisões teórico-práticas. Com isso, busca-se sustentar a importância de instituir esse espaço de escuta e essa relação ao longo do processo e no pós-transplante, considerando que o momento da cirurgia é um marco para o corpo do sujeito, mas não é necessariamente o momento da apreensão subjetiva do paciente. O objetivo do trabalho é verificar através da narrativa dos pacientes submetidos ao transplante cardíaco em acompanhamento psicológico, o processo de incorporação do enxerto. Verificou-se que há desdobramentos para além do organismo a partir da cirurgia, sendo o corpo, simbolizado, afetado de maneira subjetiva para cada paciente, demandando um tempo e espaço de elaboração para que seja possível realizar o processo de incorporação.

P2Y12 inhibitor monotherapy versus dual antiplatelet therapy in patients with acute coronary syndromes undergoing coronary stenting: rationale and design of the NEOMINDSET Trial

Dual antiplatelet therapy (DAPT) is currently the standard of care after percutaneous coronary intervention (PCI). Recent studies suggest that reducing DAPT to 1-3 months followed by an aspirin-free single antiplatelet therapy (SAPT) strategy with a potent P2Y12 inhibitor is safe and associated with less bleeding. However, to date, no randomised trial has tested the impact of initiating SAPT immediately after PCI, particularly in patients with acute coronary syndromes (ACS). NEOMINDSET is a multicentre, randomised, open-label trial with a blinded outcome assessment designed to compare SAPT versus DAPT in 3,400 ACS patients undergoing PCI with the latest-generation drug-eluting stents (DES). After successful PCI and up to 4 days following hospital admission, patients are randomised to receive SAPT with a potent P2Y12 inhibitor (ticagrelor or prasugrel) or DAPT (aspirin plus a potent P2Y12 inhibitor) for 12 months. Aspirin is discontinued immediately after randomisation in the SAPT group. The choice between ticagrelor and prasugrel is at the investigator's discretion. The primary hypothesis is that SAPT will be non-inferior to DAPT with respect to the composite endpoint of all-cause mortality, stroke, myocardial infarction or urgent target vessel revascularisation, but superior to DAPT on rates of bleeding defined by Bleeding Academic Research Consortium 2, 3 or 5 criteria. NEOMINDSET is the first study that is specifically designed to test SAPT versus DAPT immediately following PCI with DES in ACS patients. This trial will provide important insights on the efficacy and safety of withdrawing aspirin in the early phase of ACS.

P2Y12 inhibitor monotherapy versus dual antiplatelet therapy in patients with acute coronary syndromes undergoing coronary stenting: rationale and design of the NEOMINDSET Trial.

Dual antiplatelet therapy (DAPT) is currently the standard of care after percutaneous coronary intervention (PCI). Recent studies suggest that reducing DAPT to 1-3 months followed by an aspirin-free single antiplatelet therapy (SAPT) strategy with a potent P2Y12 inhibitor is safe and associated with less bleeding. However, to date, no randomised trial has tested the impact of initiating SAPT immediately after PCI, particularly in patients with acute coronary syndromes (ACS). NEOMINDSET is a multicentre, randomised, open-label trial with a blinded outcome assessment designed to compare SAPT versus DAPT in 3,400 ACS patients undergoing PCI with the latest-generation drug-eluting stents (DES). After successful PCI and up to 4 days following hospital admission, patients are randomised to receive SAPT with a potent P2Y12 inhibitor (ticagrelor or prasugrel) or DAPT (aspirin plus a potent P2Y12 inhibitor) for 12 months. Aspirin is discontinued immediately after randomisation in the SAPT group. The choice between ticagrelor and prasugrel is at the investigator's discretion. The primary hypothesis is that SAPT will be non-inferior to DAPT with respect to the composite endpoint of all-cause mortality, stroke, myocardial infarction or urgent target vessel revascularisation, but superior to DAPT on rates of bleeding defined by Bleeding Academic Research Consortium 2, 3 or 5 criteria. NEOMINDSET is the first study that is specifically designed to test SAPT versus DAPT immediately following PCI with DES in ACS patients. This trial will provide important insights on the efficacy and safety of withdrawing aspirin in the early phase of ACS. (ClinicalTrials.gov: NCT04360720).

Automatic method based on deep learning to identify and account Rhipicephalus microplus larval hatching.

Reports of Rhipicephalus microplus resistant populations worldwide have increased extensively, making it difficult to control this ectoparasite. The adult immersion test, commonly used to screen for acaricide resistance, produces the results only after 40 days of the tick collection because it needs the eggs to be laid and larvae to hatch. The present study aims to develop an automatic method, based on deep learning, to predict the hatching of R. microplus larva based on egg morphology. Initially, the time course of embryonic development of tick eggs was performed to discriminate between viable and non-viable eggs. Secondly, using artificial intelligence deep learning techniques, a method was developed to classify and count the eggs. The larval hatching rate of three populations of R. microplus was evaluated for the software validation process. Groups of three and six images of eggs with 12 days of embryonic development were submitted to the software to predict the larval hatching percent automatically. The results obtained by the software were compared with the prediction results of the hatching percentage performed manually by the specialist and with the results of the hatching percentage of larvae obtained in the biological assay. The group with three images of each population submitted to the software for automatic prediction of the larval hatching percent presented mean values of 96.35% ± 3.33 (Piracanjuba population), 95.98% ± 3.5 (Desterro population) and 0.0% ± 0.0 (Barbalha population). For groups with six images, the values were 94.41% ± 3.84 (Piracanjuba population), 95.93% ± 2.36 (Desterro population) and 0.0% ± 0.0 (Barbalha population). Biological assays showed the following hatching percentage values: 98% ± 1.73 (Piracanjuba population); 96% ± 2.1 (Desterro population); and 0.14% ± 0.25 (Barbalha population). There was no statistical difference between the evaluated methods. The automatic method for predicting the hatching percentage of R. microplus larvae was validated and proved to be effective, with considerable reduction in time to obtain results.

The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms.

The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.

Diagnostic Accuracy of ECG to Detect Left Ventricular Hypertrophy in Patients with Left Bundle Branch Block: A Systematic Review and Meta-analysis.

Background: Electrocardiographic (ECG) criteria to detect left ventricular hypertrophy (LVH) in patients with left bundle branch block (LBBB) remain under debate. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of different ECG criteria for diagnosing LVH in patients with LBBB. Methods: We searched PubMed, Embase, Cochrane, and LILACS for articles evaluating the diagnostic accuracy of ECG criteria for LVH in patients with LBBB published between 1984 and 2023. Echocardiogram, magnetic resonance imaging, or autopsy were used as the reference standard for diagnosis of LVH. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The co-primary outcomes were sensitivity, specificity, the diagnostic odds ratio, and likelihood ratios, estimated using a bivariate generalized linear mixed model for each ECG criterion. The prespecified protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). Results: We included 12 studies with a total of 1023 patients. We analyzed 10 criteria for LVH on ECG, including the Sokolow-Lyon criterion, the Cornell criterion, the RaVL (R wave in aVL) criterion, the Gubner-Ungerleider criterion, and the Dálfo criterion, among others. The Dalfó criterion was used for 487 patients and had the highest pooled sensitivity of 86% (95% confidence interval [CI] 57%-97%). All the other criteria had poor sensitivities. The Gubner-Ungerleider criterion and the RV5 or RV6 > 25 mm criterion had the highest specificities, with the former being used for 805 patients, obtaining a specificity of 99% (95% CI 80%-100%) and the latter being used for 355 patients, obtaining a specificity of 99% (95% CI 94%-100%). Conclusions: In patients with LBBB, the use of ECG criteria had poor performance for ruling out LVH, mostly due to low sensitivities. None of the criteria analyzed demonstrated a balanced tradeoff between sensitivity and specificity, suggesting that ECG should not be used routinely to screen for LVH.

Contexte: Les critères électrocardiographiques (ECG) visant à détecter une hypertrophie ventriculaire gauche (HVG) chez les patients présentant un bloc de branche gauche (BBG) font encore l'objet de discussions. Nous avons réalisé une synthèse des publications et une méta-analyse afin d'évaluer l'exactitude diagnostique de différents critères ECG pour le diagnostic de l'HVG chez les patients présentant un BBG. Méthodologie: Nous avons effectué une recherche dans les bases de données PubMed, Embase, Cochrane et LILACS afin de recenser les articles publiés entre 1984 et 2023 portant sur l'évaluation de l'exactitude de critères ECG pour le diagnostic d'une HVG chez les patients présentant un BBG. L'échocardiographie, l'imagerie par résonance magnétique et l'autopsie ont servi de normes de référence pour le diagnostic de l'HVG. Le risque de biais a été évalué au moyen de l'outil QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). Les principaux critères d'évaluation étaient la sensibilité, la spécificité, le risque relatif approché diagnostique et les rapports de vraisemblance, estimés au moyen d'un modèle linéaire mixte généralisé à deux variables pour chaque critère ECG. Le protocole défini au préalable a été enregistré dans le registre international de revues systématiques prospectives PROSPERO. Résultats: Nous avons recensé 12 études, comptant au total 1 023 patients. Nous avons analysé 10 critères pour le diagnostic d'HVG à l'ECG, notamment l'indice de Sokolow-Lyon, l'indice de Cornell, l'onde R en aVL, l'indice de Gubner-Ungerleider et l'indice de Dálfo. Ce dernier a été utilisé pour 487 patients et avait la sensibilité regroupée la plus élevée, soit 86 % (intervalle de confiance [IC] à 95 % : 57-97 %). La sensibilité de tous les autres critères était faible. L'indice de Gubner-Ungerleider et le critère de l'onde R en V5 ou V6 > 25 mm étaient associés aux spécificités les plus élevées. Le premier a été utilisé pour 805 patients et présentait une spécificité de 99 % (IC à 95 % : 80-100 %). Le second a été utilisé pour 355 patients et présentait une spécificité de 99 % (IC à 95 % : 94-100 %). Conclusions: Chez les patients présentant un BBG, l'utilisation de critères ECG a été associée à un rendement médiocre pour exclure un diagnostic d'HVG, principalement en raison de la faible sensibilité de ces critères. Aucun des critères analysés n'offrait un compromis équilibré entre la sensibilité et la spécificité, ce qui porte à croire que l'ECG ne devrait pas être utilisée systématiquement pour dépister une HVG.

Anonaine from Annona crassiflora inhibits glutathione S-transferase and improves cypermethrin activity on Rhipicephalus (Boophilus) microplus (Canestrini, 1887).

Rhipicephalus (Boophilus) microplus (Canestrini, 1887) is one of the most important ectoparasites of cattle, causing severe economic losses in tropical and subtropical regions of the world. The selection of resistance to the most commonly used commercial acaricides has stimulated the search for new products for tick control. The identification and development of drugs that inhibit key tick enzymes, such as glutathione S-transferase (GST), is a rational approach that has already been applied to other parasites than ticks. In this context, alkaloids such as anonaine display several biological activities, including an acaricidal effect. This study aimed to assess the specific inhibition of the R. microplus GST by anonaine, and analyze the effect on ticks when anonaine is combined with cypermethrin. For this purpose, a molecular docking analysis was performed using an R. microplus GST three-dimensional structure model with anonaine and compared with a human GST-anonaine complex. The absorption, distribution, metabolism, excretion, and toxicity properties of anonaine were also predicted. Then, for in vitro analyses, anonaine was isolated from Annona crassiflora (Martius, 1841) leaves. The inhibition of purified recombinant R. microplus GST (rRmGST) by anonaine and the effect of this alkaloid on cypermethrin efficacy towards R. microplus were assessed. Anonaine has a higher affinity to the tick enzyme than to the human enzyme in silico and has moderate toxicity, being able to inhibit, in vitro, rRmGST up to 37.5% in a dose-dependent manner. Although anonaine alone has no activity against R. microplus, it increased the cypermethrin effect on larvae, reducing the LC50 from 44 to 22 µg/mL. In conclusion, anonaine is a natural compound that can increase the effect of cypermethrin against R. microplus.

Effects of dabigatran versus warfarin on 2-year cognitive outcomes in old patients with atrial fibrillation: results from the GIRAF randomized clinical trial.

BACKGROUND: Observational studies support a role for oral anticoagulation to reduce the risk of dementia in atrial fibrillation patients, but conclusive data are lacking. Since dabigatran offers a more stable anticoagulation, we hypothesized it would reduce cognitive decline when compared to warfarin in old patients with atrial fibrillation. METHODS: The GIRAF trial was a 24-month, randomized, parallel-group, controlled, open-label, hypothesis generating trial. The trial was done in six centers including a geriatric care unit, secondary and tertiary care cardiology hospitals in São Paulo, Brazil. We included patients aged ≥ 70 years and CHA2DS2-VASc score > 1. The primary endpoint was the absolute difference in cognitive performance at 2 years. Patients were assigned 1:1 to take dabigatran (110 or 150 mg twice daily) or warfarin, controlled by INR and followed for 24 months. Patients were evaluated at baseline and at 2 years with a comprehensive and thorough cognitive evaluation protocol of tests for different cognitive domains including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), a composite neuropsychological test battery (NTB), and computer-generated tests (CGNT). RESULTS: Between 2014 and 2019, 5523 participants were screened and 200 were assigned to dabigatran (N = 99) or warfarin (N = 101) treatment. After adjustment for age, log of years of education, and raw baseline score, the difference between the mean change from baseline in the dabigatran group minus warfarin group was - 0.12 for MMSE (95% confidence interval [CI] - 0.88 to 0.63; P = 0.75), 0.05 (95% CI - 0.07 to 0.18; P = 0.40) for NTB, - 0.15 (95% CI - 0.30 to 0.01; P = 0.06) for CGNT, and - 0.96 (95% CI - 1.80 to 0.13; P = 0.02) for MoCA, with higher values suggesting less cognitive decline in the warfarin group. CONCLUSIONS: For elderly patients with atrial fibrillation, and without cognitive compromise at baseline that did not have stroke and were adequately treated with warfarin (TTR of 70%) or dabigatran for 2 years, there was no statistical difference at 5% significance level in any of the cognitive outcomes after adjusting for multiple comparisons. TRIAL REGISTRATION: Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF), NCT01994265 .

In vitro assessment of the acaricidal activity of a carvacrol shampoo on tick larvae.

Ticks are a widely distributed arthropod of veterinary importance. Resistance of ticks to synthetic acaricides has become widespread, warranting the development of new drugs for tick management. Carvacrol is a volatile monoterpene, with promising results against various species of ticks; however, to be used for therapeutic purposes, carvacrol must be included in a formulation that makes its application feasible. This study aims to develop a formulation of a carvacrol-containing shampoo that is effective against two species of ticks: Rhipicephalus sanguineus and R. microplus. Shampoo sensory characteristics and pH were evaluated at 37, 25 and 5 °C, for a maximum of 15 days. The shampoo remained stable at 25 and 5 °C. The efficacy of the carvacrol-containing formulation against two species of ticks was assessed by the larval immersion test. Mortality of both tick species was significantly higher for the carvacrol shampoo than for a carvacrol hydroalcoholic solution. In conclusion, the carvacrol-containing shampoo showed larvicidal efficacy on ticks.

Unraveling the interplay between dipeptidyl peptidase 4 and the renin-angiotensin system in heart failure.

AIMS: Emerging evidence suggests the existence of a crosstalk between dipeptidyl peptidase 4 (DPP4) and the renin-angiotensin system (RAS). Therefore, combined inhibition of DPP4 and RAS may produce similar pharmacological effects rather than being additive. This study tested the hypothesis that combining an inhibitor of DPP4 with an angiotensin II (Ang II) receptor blocker does not provide additional cardioprotection compared to monotherapy in heart failure (HF) rats. MAIN METHODS: Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were assigned into four groups and received vehicle (water), vildagliptin, valsartan, or both drugs, for four weeks by oral gavage. KEY FINDINGS: Vildagliptin and valsartan in monotherapy reduced LV hypertrophy, alleviated cardiac interstitial fibrosis, and improved systolic and diastolic function in HF rats, with no additional effect of combination treatment. HF rats displayed higher cardiac and serum DPP4 activity and abundance than sham. Surprisingly, not only vildagliptin but also valsartan in monotherapy downregulated the catalytic function and expression levels of systemic and cardiac DPP4. Moreover, vildagliptin and valsartan alone or in combination comparably upregulate the components of the cardiac ACE2/Ang-(1-7)/MasR while downregulating the ACE/Ang II/AT1R axis. SIGNIFICANCE: Vildagliptin or valsartan alone is as effective as combined to treat cardiac dysfunction and remodeling in experimental HF. DPP4 inhibition downregulates classic RAS components, and pharmacological RAS blockade downregulates DPP4 in the heart and serum of HF rats. This interplay between DPP4 and RAS may affect HF progression and pharmacotherapy.

Contribution of the vectorcardiogram in the differential diagnosis of Brugada electrocardiographic pattern.

BACKGROUND: The electrocardiogram (ECG) is a powerful tool for differential diagnosis among a group of pathologies with different therapeutic approaches/prognoses, the so-called J-wave syndrome. The vectorcardiogram (VCG) can be used as a complementary method to the ECG in several dubious electrocardiographic alterations. OBJECTIVE: We carried out a VCG analysis after conceiving and measuring a novel parameter (JT-distance) that allows diagnosis of the Brugada ECG pattern. METHODS: A retrospective cohort study selected ninety-six ECGs with J-point elevation in V1/V2, ECG superior leads and VCGs, all performed on the same day. A new VCG measurement by Frank method (JT-distance) was conceived and designed in transverse and right sagittal planes by 3 lines drawn 1) at the final third of the QRS loop, comprehending the J-point; 2) at the initial portion of the T loop; 3) a parallel of the J-point line at the beginning of the T loop. JT measure was determined by the distance between parallels. A validation cohort was established in a new sample of thirty-five patients. RESULTS: JT-distance ≥1.5 mm (tranverse plane) and JT-distance >1.25 mm, in the sagittal plane, differentiated Brugada type-1 from Brugada type-2, early repolarization and others, with 95% sensitivity and 68% specificity. JT-distance <1.5 mm (transverse plane) and JT >1.25 mm (sagittal plane) had 100% sensitivity and 85% specificity for Brugada type-1 diagnosis. A validation cohort showed very similar Cohen's kappa levels (0.65 and 0.77, test and validation cohorts, respectively), with overlapping 95% confidence intervals. CONCLUSIONS: The novel vectorcardiogram measurement (JT-distance) presented a new diagnostic criterion to identify Brugada pattern. Nevertheless, prospective studies should be performed by other centers to confirm these findings.

Clinical, Laboratory, and Imaging Profile in Patients with Systemic Amyloidosis in a Brazilian Cardiology Referral Center. / Perfil Clínico, Laboratorial e de Métodos de Imagem na Amiloidose Sistêmica em um Centro de Referência Cardiológico Brasileiro.

BACKGROUND: Systemic amyloidosis is a disease with heterogeneous clinical manifestations. Diagnosis depends on clinical suspicion combined with specific complementary methods. OBJECTIVE: To describe the clinical, laboratory, electrocardiographic, and imaging profile in patients with systemic amyloidosis with cardiac involvement. METHODS: This study was conducted with a convenience sample, analyzing clinical, laboratory, electrocardiographic, echocardiographic, nuclear medicine, and magnetic resonance data. Statistical significance was set at p < 0.05. RESULTS: A total of 105 patients were evaluated (median age of 66 years), 62 of whom were male. Of all patients, 83 had transthyretin (ATTR) amyloidosis, and 22 had light chain (AL) amyloidosis. With respect to ATTR cases, 68.7% were the hereditary form (ATTRh), and 31.3% were wild type (ATTRw). The most prevalent mutations were Val142Ile (45.6%) and Val50Met (40.3%). Time from onset of symptoms to diagnosis was 0.54 and 2.15 years, in the AL and ATTR forms, respectively (p < 0.001). Cardiac involvement was observed in 77.9% of patients with ATTR and in 90.9% of those with AL. Alterations were observed in atrioventricular and intraventricular conduction in 20% and 27.6% of patients, respectively, with 33.7% in ATTR and 4.5% in AL (p = 0.006). In the ATTRw form, there were more atrial arrhythmias than in ATTRh (61.5% versus 22.8%; p = 0.001). On echocardiogram, median septum thickness in ATTRw, ATTRh, and AL was 15 mm, 12 mm, and 11 mm, respectively (p = 0.193). Elevated BNP was observed in 89.5% of patients (median 249, ICR 597.7), and elevated troponin was observed in 43.2%. CONCLUSION: In this setting, it was possible to characterize cardiac involvement in systemic amyloidosis in its different subtypes by means of clinical history and the diagnostic methods described.

FUNDAMENTO: Amiloidose sistêmica é uma doença com manifestações clínicas diversas. O diagnóstico envolve suspeita clínica, aliada a métodos complementares. OBJETIVO: Descrever o perfil clínico, laboratorial, eletrocardiográfico e de imagem no acometimento cardíaco da amiloidose sistêmica. MÉTODOS: Estudo de uma amostra de conveniência, analisando dados clínicos, laboratoriais, eletrocardiográficos, ecocardiográficos, medicina nuclear e ressonância magnética. Considerou-se significância estatística quando p < 0,05. RESULTADOS: Avaliaram-se 105 pacientes (com mediana de idade de 66 anos), sendo 62 homens, dos quais 83 indivíduos apresentavam amiloidose por transtirretina (ATTR) e 22 amiloidose por cadeia leve (AL). Na ATTR, 68,7% eram de caráter hereditário (ATTRh) e 31,3% do tipo selvagem (ATTRw). As mutações mais prevalentes foram Val142Ile (45,6%) e Val50Met (40,3%). O tempo de início dos sintomas ao diagnóstico foi 0,54 e 2,15 anos nas formas AL e ATTR (p < 0,001), respectivamente. O acometimento cardíaco foi observado em 77,9% dos ATTR e 90,9% dos AL. Observaram-se alterações de condução atrioventricular em 20% e intraventricular em 27,6% dos pacientes, sendo 33,7 % na ATTR e 4,5% das AL (p = 0,006). A forma ATTRw apresentou mais arritmias atriais que os ATTRh (61,5% x 22,8%; p = 0,001). Ao ecocardiograma a mediana da espessura do septo na ATTRw x ATTRh x AL foi de 15 mm x 12 mm x 11 mm (p = 0,193). Observou-se BNP elevado em 89,5% dos indivíduos (mediana 249 ng/mL, IQR 597,7) e elevação da troponina em 43,2%. CONCLUSÃO: Foi possível caracterizar, em nosso meio, o acometimento cardíaco na amiloidose sistêmica, em seus diferentes subtipos, através da história clínica e dos métodos diagnósticos descritos.

Effects of carvacrol and thymol on the antioxidant and detoxifying enzymes of Rhipicephalus microplus (Acari: Ixodidae).

The present study was conducted to evaluate the effects of carvacrol and thymol on the antioxidant and detoxifying enzymes of larvae from two populations of R. microplus: Jaguar (tick population resistant to six classes of acaricides) and Porto Alegre (susceptible tick population). Carvacrol and thymol were tested at concentrations ranging from 0.14 to 5.0 mg mL-1 in both populations to determine the LC50. In addition, the LC1, LC25, and LC75 were estimated using the LC50 and HillSlope of each compound. Larvae of both populations of R. microplus were then treated with the LC1, LC25, LC50, and LC75 of each monoterpene, and those that survived were processed to evaluate the effects of the compounds on the antioxidant and detoxifying systems of larvae; these effects were assessed by determining the activity of the enzymes, glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Larvae from the Jaguar population treated with different lethal concentrations of carvacrol and thymol displayed a dose-dependent increase in CAT, GPX, SOD, and GST after treatment with LC25. Further, larvae treated with the LC75 had the highest levels of enzyme activity for carvacrol (1.76 mg mL-1) and thymol (1.32 mg mL-1). CAT, GPX, SOD, and GST activity in Porto Alegre population larvae treated with carvacrol and thymol also increased significantly up to the LC50 of each monoterpene. However, at the LC75 of carvacrol and thymol, a decrease in the activity of all enzymes was observed for this tick population. These findings indicate that carvacrol and thymol induced increased activity of all evaluated enzymes at different lethal concentrations in R. microplus larvae from two populations. Such findings unveil the possible mechanisms of action of these natural acaricides.