Trends of Mansonia (Diptera, Culicidae, Mansoniini) in Porto Velho: Seasonal patterns and meteorological influences.

Entomological research is vital for shaping strategies to control mosquito vectors. Its significance also reaches into environmental management, aiming to prevent inconveniences caused by non-vector mosquitoes like the Mansonia Blanchard, 1901 mosquito. In this study, we carried out a five-year (2019-2023) monitoring of these mosquitoes at ten sites in Porto Velho, Rondônia, using SkeeterVac SV3100 automatic traps positioned between the two hydroelectric complexes on the Madeira River. Throughout this period, we sampled 153,125 mosquitoes, of which the Mansonia genus accounted for 54% of the total, indicating its prevalence in the region. ARIMA analysis revealed seasonal patterns of Mansonia spp., highlighting periods of peak density. Notably, a significant decreasing trend in local abundance was observed from July 2021 (25th epidemiological week) until the end of the study. Wind speed was observed to be the most relevant meteorological factor influencing the abundance of Mansonia spp. especially in the Joana D'Arc settlement, although additional investigation is needed to comprehensively analyze other local events and gain a deeper understanding of the ecological patterns of this genus in the Amazon region.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Study Design of a Brazilian Observational Study of Edoxaban in Patients with Atrial Fibrillation (EdoBRA). / Desenho de Estudo de um Estudo Observacional Brasileiro sobre o uso de Edoxabana em Pacientes com Fibrilação Atrial (EdoBRA).

BACKGROUND: Clinical trials showed the safety of Edoxaban, a non-vitamin K-dependent oral anticoagulant (NOAC), and its efficacy to prevent stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients and also to prevent and treat venous thromboembolism. However, additional research is needed to evaluate the safety and effectiveness of Edoxaban in a real-world scenario in the Brazilian population. OBJECTIVE: In order to understand the risks and benefits of Edoxaban use in routine clinical settings, the EdoBRA study is being conducted to gain insight into the safety and effectiveness of Edoxaban use in non-preselected patients with NVAF in Brazil. METHODS: The EdoBRA study is a multicenter, prospective, observational study conducted in 36 sites in Brazil. NVAF patients ≥ 18 years treated with commercially available Edoxaban who initiated treatment for at least 14 days and no longer than 90 days prior to enrollment, and who are not simultaneously participating in any interventional study are eligible for this study. Seven hundred patients are planned to be enrolled and one-year of follow up, with data collections expected at baseline and 3, 6, and 12 months after the study enrollment. The primary safety objective is ISTH Clinically Relevant Bleeding, and the secondary effectiveness objective focuses on relevant cardiovascular outcomes related to NVAF. CONCLUSION: EdoBRA observational study will generate relevant additional information about NOAC Edoxaban on various aspects of patient management in routine care, such as its safety and effectiveness profile in patients with NVAF in Brazil.

FUNDAMENTO: Os ensaios clínicos demonstraram a segurança da Edoxabana, um anticoagulante oral não dependente de vitamina K (NOAC), e a sua eficácia na prevenção de acidente vascular cerebral e embolia sistémica em pacientes com fibrilação atrial não valvar (FANV) e também na prevenção e tratamento de tromboembolismo venoso. No entanto, pesquisas adicionais são necessárias para avaliar a segurança e a eficácia da Edoxabana em um cenário real na população brasileira. OBJETIVO: A fim de compreender os riscos e benefícios do uso da Edoxabana em cenários clínicos de rotina, o estudo EdoBRA está sendo conduzido para obter informações sobre a segurança e eficácia do uso da Edoxabana em pacientes não pré-selecionados com FANV no Brasil. MÉTODOS: O estudo EdoBRA é um estudo multicêntrico, prospectivo e observacional, realizado em 36 centros no Brasil. São elegíveis para este estudo pacientes com FANV, ≥ 18 anos de idade, tratados com Edoxabana disponível comercialmente, que iniciaram o tratamento por pelo menos 14 dias e não mais do que 90 dias antes da data de inclusão no estudo, e que não estão participando de nenhum outro estudo de intervenção. Ao todo, 700 pacientes devem ser inscritos e acompanhados por um ano, com coletas de dados programadas para o período basal e 3, 6 e 12 meses após a inscrição no estudo. O objetivo primário de segurança é o sangramento clinicamente relevante (de acordo com critérios da Sociedade Internacional de Trombose e Hemostasia - ISTH), e o objetivo secundário de eficácia são desfechos cardiovasculares relevantes relacionados à FANV. CONCLUSÃO: O estudo observacional EdoBRA gerará informações adicionais relevantes sobre a Edoxabana enquanto NOAC em diversos aspectos do manejo de pacientes no atendimento clínico de rotina, como perfil de segurança e efetividade em pacientes com FANV no Brasil.

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial.

Importance: An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. Objective: To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants: This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. Intervention: Dapagliflozin, 10 mg per day, or placebo. Main Outcomes and Measures: In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. Results: Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). Conclusions and Relevance: Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease.

BACKGROUND: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. OBJECTIVES: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. PRIMARY ENDPOINT: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. RESULTS: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. CONCLUSIONS: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).

First report of stem gray blight on Hylocereus megalanthus and Hylocereus polyrhizus caused by Diaporthe arecae in Brazil.

In November 2021, stem gray blight symptoms were seen on two dragon fruit (pitaya) species (Hylocereus megalanthus and H. polyrhizus) in an orchard with 100% disease incidence in Fortaleza, Ceará, Brazil (3°44'24.5"S 38°34'30.8"W). The symptoms were initially yellowish to dark brown lesions, and as the symptoms progressed, the lesions turned grayish with small black pycnidia in the center. Isolation was carried out by disinfecting small pieces of the symptomatic stems in 70% ethanol for 1 min, followed by 1% NaOCl for 1 min, and then rinsed three times with sterile distilled water. Excess water was removed using sterile filter paper. Then the stem fragments were placed on PDA media. Colonies produced small black pycnidia with conidia and some were sterile after 68 days of incubation. Two monosporic isolates were obtained from the colonies: UFCM 0708 from H. megalanthus and the UFCM 0710 from H. polyrhizus, which were used for pathogenicity test, morphological and molecular identification. The colony on PDA was smoke gray with aerial mycelium and the reverse was smoke grey to dark grey. The α-conidia from UFCM 0708 and UFCM 0710 were hyaline, aseptate and fusiform and measured 6.4 to 9.7 (8.0) x 1.2 to 2.4 (1.7) µm and 6 to 13.1 (8.2) x 1.7 to 2.4 (2.0) µm, respectively. The ß-conidia from UFCM 0708 and UFCM 0710 were hyaline, aseptate and filiform and measured 15 to 22.5 (18.8) x 0.6 to 1.7 (1.0) µm, and 17.2 to 27.5 (22.3) x 0.5 to 1.0 (0.8) µm (n=30), respectively. This morphology placed the isolates as Diaporthe sp. (Udayanga et al. 2012). For further confirmation, genomic DNA was extracted from the isolates (UFCM 0708 and UFCM 0710), and beta-tubulin (TUB2) and translation elongation factor 1-alpha (TEF1) gene fragments were amplified. BLASTn search results with isolates TEF1 and TUB2 sequences varied from 98.58% to 99.52% identity to the ex-type sequence of Diaporthe arecae (CBS 161.64). Phylogenetic analysis of concatenated sequences alignment carried out using the Maxinum-likelihood and Bayesian Inference analysis placed the isolates within D. arecae clade with 86% bootstrap and 0.99 posterior probabilities support. The sequences obtained in this study were deposited in GenBank (TEF1: OP534720 and OP534722; TUB2: OP534717 and OP534719). The isolates were confirmed as D. arecae based on molecular analysis and morphological characteristics (Gomes et al. 2013). Koch's postulates were completed as described by Karim et al. (2019) through the inoculation of six stems of each dragon fruit (pitaya) species. The stems were wounded by removing a 5 mm diameter disc and after that they were inoculated with a 5 mm diameter mycelial plug from 5 days old PDA plates. PDA plugs were used as control. Each stem was covered with a plastic bag and sterilized water was added into the sterilized filter paper to maintain humidity. The bags were kept in a room at day and night temperature of 25 ± 2 °C. The same symptoms seen in the field appeared on the stems 21 days after inoculation. The control stems remained symptomless. Diaporthe arecae have been reported on H. polyrhizus in Malaysia (Huda-Shakirah et al. 2021). To our knowledge, this is the first report of D. arecae on H. megalanthus and H. polyrhizus in Brazil.

STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment-Elevation Myocardial Infarction: A Randomized, Open-Label Trial.

BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.

Primary Prevention of Cardiovascular Disease at Community Clinics in the State of Sao Paulo, Brazil: Results from the Epidemiological Information Study of Communities.

Background: Primary prevention of cardiovascular disease (CVD) remains a major challenge, especially in communities of low- and middle-income countries with poor medical assistance influenced by distinct local, financial, infrastructural, and resource-related factors. Objective: This a community-based study aimed to determine the proportion and prevalence of uncontrolled cardiovascular risk factors (CRF) in Brazilian communities. Methods: The EPICO study was an observational, cross-sectional, and community clinic-based study. Subjects were living in Brazilian communities and were of both sexes and ≥18 years old, without a history of a stroke or myocardial infarction but presenting at least one of the following cardiovascular risk factors: hypertension, diabetes mellitus and hypercholesterolemia. The study was carried out in Brazil, including 322 basic health units (BHU) in 32 cities. Results: A total of 7,724 subjects with at least one CRF were evaluated, and one clinical visit was performed. Mean age was 59.2 years-old (53.7% were >60 years old). A total of 66.7% were women. Of the total, 96.2% had hypertension, 78.8% had diabetes mellitus type II, 71.1% had dyslipidemia, and 76.6% of patients were overweight/obese. Controlled hypertension (defined by <130/80 mmHg or <140/90 mmHg) was observed in 34.9% and 55.5% patients among respective criteria, the rates of controlled blood glucose in patients taking antidiabetic medications was 29.5%, and among those with documented dyslipidemia who received any lipid-lowering medication, only 13.9% had LDL-c on target. For patients presenting three CRF less than 1.9% had LDL-c < 100 mg/dL once their BP and blood glucose were on target. High education level as associated with blood pressure (BP) target of less than 130 / 80mm Hg. The glucose and LDL-c levels on target were associated with the presence of hypertension and diabetes mellitus. Conclusion: In Brazilian community clinics, regarding most patients in primary prevention, the CRF such as BP, blood glucose, and lipid levels are poorly controlled, with a majority of patients not achieving guidelines/recommendations.

Primary prevention of cardiovascular disease at community clinics in the state of Sao Paulo, Brazil: results from the epidemiological information study of communities

BACKGROUND: Primary prevention of cardiovascular disease (CVD) remains a major challenge, especially in communities of low- and middle-income countries with poor medical assistance influenced by distinct local, financial, infrastructural, and resource-related factors. OBJECTIVE: This a community-based study aimed to determine the proportion and prevalence of uncontrolled cardiovascular risk factors (CRF) in Brazilian communities. METHODS: The EPICO study was an observational, cross-sectional, and community clinic-based study. Subjects were living in Brazilian communities and were of both sexes and ≥18 years old, without a history of a stroke or myocardial infarction but presenting at least one of the following cardiovascular risk factors: hypertension, diabetes mellitus and hypercholesterolemia. The study was carried out in Brazil, including 322 basic health units (BHU) in 32 cities. RESULTS: A total of 7,724 subjects with at least one CRF were evaluated, and one clinical visit was performed. Mean age was 59.2 years-old (53.7% were >60 years old). A total of 66.7% were women. Of the total, 96.2% had hypertension, 78.8% had diabetes mellitus type II, 71.1% had dyslipidemia, and 76.6% of patients were overweight/obese. Controlled hypertension (defined by <130/80 mmHg or <140/90 mmHg) was observed in 34.9% and 55.5% patients among respective criteria, the rates of controlled blood glucose in patients taking antidiabetic medications was 29.5%, and among those with documented dyslipidemia who received any lipid-lowering medication, only 13.9% had LDL-c on target. For patients presenting three CRF less than 1.9% had LDL-c < 100 mg/dL once their BP and blood glucose were on target. High education level as associated with blood pressure (BP) target of less than 130 / 80mm Hg. The glucose and LDL-c levels on target were associated with the presence of hypertension and diabetes mellitus. CONCLUSION: In Brazilian community clinics, regarding most patients in primary prevention, the CRF such as BP, blood glucose, and lipid levels are poorly controlled, with a majority of patients not achieving guidelines/recommendations.

Oviposition Activity of Mansonia Species in Areas Along the Madeira River, Brazilian Amazon Rainforest.

Mansonia are aggressive mosquito species that are abundant in aquatic ecosystems where the macrophyte plants occur. These mosquitoes are commonly found across the Amazon/Solimões River basin. However, little is known about the oviposition behavior of these species. In the present study, we registered observations on the oviposition activity of 3 species: Mansonia amazonensis, Ma. humeralis, and Ma. cf. titillans, in 5 species of macrophytes in the vicinities of the Madeira River, Porto Velho, State of Rondônia, Brazil. Overall, 197 egg batches were collected. A greater amount of egg batches was found in Salvinia molesta as compared with other macrophytes sampled. In addition, 2 new oviposition habitats were noted in Ludwigia helmintorrhiza and Limnobium spongia. These findings will be important to understand the reproductive dynamics of these mosquitoes in the Brazilian Amazon basin.

Dapagliflozin in Black and White Patients With Heart Failure Across the Ejection Fraction Spectrum.

BACKGROUND: Black people have a higher incidence and prevalence of heart failure (HF) than White people, and once HF has developed, they may have worse outcomes. There is also evidence that the response to several pharmacologic therapies may differ between Black and White patients. OBJECTIVES: The authors sought to examine the outcomes and response to treatment with dapagliflozin according to Black or White race in a pooled analysis of 2 trials comparing dapagliflozin to placebo in patients with heart failure with reduced ejection fraction (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]). METHODS: Because most self-identified Black patients were enrolled in the Americas, the comparator group was White patients randomized in the same regions. The primary outcome was the composite of worsening HF or cardiovascular death. RESULTS: Of the 3,526 patients randomized in the Americas, 2,626 (74.5%) identified as White and 381 (10.8%) as Black. The primary outcome occurred at a rate of 16.8 (95% CI: 13.8-20.4) in Black patients compared with 11.6 (95% CI: 10.6-12.7) per 100 person-years in White patients (adjusted HR: 1.27; 95% CI: 1.01-1.59). Compared with placebo, dapagliflozin decreased the risk of the primary endpoint to the same extent in Black (HR: 0.69; 95% CI: 0.47-1.02) and White patients (HR: 0.73 [95% CI: 0.61-0.88]; Pinteraction = 0.73). The number of patients needed to treat with dapagliflozin to prevent one event over the median follow-up was 17 in White and 12 in Black patients. The beneficial effects and favorable safety profile of dapagliflozin were consistent across the range of left ventricular ejection fractions in both Black and White patients. CONCLUSIONS: The relative benefits of dapagliflozin were consistent in Black and White patients across the range of left ventricular ejection fraction, with greater absolute benefits in Black patients. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 inhibitors are known to reduce heart failure events and slow progression of kidney disease among patients with heart failure and a reduced ejection fraction. Objective: To determine the effect of dapagliflozin on cardiovascular and kidney outcomes and the influence of baseline kidney disease among patients with heart failure and a mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants: This was a prespecified analysis conducted from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This was an international, multicenter trial including patients with ejection fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m2 or higher. Interventions: Dapagliflozin, 10 mg, per day or placebo. Main Outcomes and Measures: Outcomes assessed were whether baseline kidney function modified the treatment effect on the primary outcome (cardiovascular death or worsening heart failure). Also examined was the treatment effect on the prespecified outcomes of eGFR slope and a post hoc composite kidney outcome (first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m2; end-stage kidney disease; death from kidney causes). Results: A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male [56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m2; 3070 patients (49%) had an eGFR less than 60 mL/min/1.73 m2. The effect of dapagliflozin on the primary outcome was not influenced by baseline eGFR category (eGFR ≥60 mL/min/1.73 m2: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00; eGFR 45-<60 mL/min/1.73 m2: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73 m2: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR) follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney composite outcome was low (1.1 events per 100 patient-years) and was not affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However, dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95% CI, 0.1-0.9 mL/min/1.73 m2 per year; P = .01) and from month 1 to 36 (difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m2 per year; P < .001). Conclusions and Relevance: Results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with heart failure and a mildly reduced or preserved ejection fraction. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low. However, dapagliflozin slowed the rate of decline in eGFR compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Effect of Different Cavity Disinfectants on Adhesion to Dentin of Permanent Teeth.

After the elimination of dental caries lesions, some microorganisms may remain viable in the tooth structure. Thus, cavity disinfection is an important procedure. The aim of this study was to evaluate the effect of cavity disinfectants on the adhesion to dentin of permanent teeth. Sixty molars were ground flat and randomly assigned to six groups: control; chlorhexidine; Aloe vera; glutaraldehyde; EDTA; ethanol. Cavity disinfectants were applied, rinsed, and air-dried. The restorations were performed with the aid of polyethylene tubes. Shear bond strength, work to detachment, and shear modulus were evaluated. All data were statistically analyzed and the level of significance was set at 5%. The control group showed the lowest shear bond strength (8.34 ± 2.68 MPa). Aloe vera showed the lowest work to debonding (2284 J/m2) while chlorhexidine showed the highest (9347 J/m2). Regarding the shear modulus, ethanol, chlorhexidine, and EDTA presented similar values to the control group (216.11 kPa), and glutaraldehyde and Aloe vera presented values twice as high. The use of chlorhexidine, ethanol, EDTA, glutaraldehyde, and Aloe vera did not impair the adhesion established between the dentin of permanent teeth and composite resin. Even though there is a need for clinical studies to support these findings, all disinfectants seem to be good choices as pretreatment agents.

Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Type 2 diabetes and prediabetes are risk factors for heart failure and adverse heart failure outcomes. The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial showed that dapagliflozin was associated with a reduction in the primary outcome of worsening heart failure or cardiovascular mortality in patients with heart failure with mildly reduced or preserved ejection fraction. We aimed to assess the efficacy and safety of oral dapagliflozin in these patients by their baseline glycaemia categories. METHODS: DELIVER was an international, multicentre, double-blind, randomised, placebo-controlled trial done in 350 health-care centres and hospitals across 20 countries. Patients aged 40 years or older with New York Heart Association class II-IV, left ventricular ejection fraction of more than 40%, elevated natriuretic peptides (N-terminal pro B-type natriuretic peptide ≥300 pg/mL or ≥600 pg/mL for patients in atrial fibrillation or flutter), and evidence of structural heart disease were randomly assigned (1:1) to 10 mg dapagliflozin or placebo, administered orally, and followed up for a median of 2·3 years (IQR 1·7-2·8). The primary outcome, a composite of time from randomisation to first worsening heart failure events (defined as an unplanned hospitalisation or urgent heart failure visit requiring intravenous therapy) or cardiovascular death, in participants with type 2 diabetes (history of or identified by HbA1c ≥6·5% [48 mmol/mol] at baseline) or prediabetes (HbA1c 5·7 to <6·5% [39 mmol/mol to <48 mmol/mol] at baseline) was compared with those with normoglycaemia (HbA1c <5·7% [39 mmol/mol]). Efficacy of dapagliflozin versus placebo was assessed according to glycaemic status and based on HbA1c as a continuous measure. The full-analysis set comprised all patients who were randomly assigned to study treatment, with patients analysed according to their randomised treatment assignment, irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised patients who were randomly assigned to study treatment and who took at least one dose of investigational product, with patients analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT03619213. FINDINGS: Between Sept 1, 2018, and Jan 18, 2021, 6263 patients were randomly assigned to oral dapagliflozin (n=3131) or placebo (n=3132). Of these patients, 1175 had normoglycaemia, 1934 had prediabetes, and 3150 had type 2 diabetes and were included in the glycaemia subgroup analysis (3515 [56·2%] of 6263 patients were men and 4435 [70·9%] were White). The incidence rate of the primary outcome was 6·9 per 100 patient-years in the normoglycaemia subgroup (reference), increasing to 7·6 per 100 patient-years in the prediabetes subgroup (hazard ratio 1·09 [95% CI 0·90-1·31]) and 10·1 per 100 patient-years in the type 2 diabetes subgroup (1·46 [1·24-1·73]; p<0·0001 for trend). Dapagliflozin reduced the risk of the primary outcome versus placebo in each subgroup (hazard ratio 0·77 [95% CI 0·57-1·04], log-rank p=0·088, for patients with normoglycaemia, 0·87 [0·69-1·08], log-rank p=0·21, for patients with prediabetes, and 0·81 [0·69-0·95], log-rank p=0·0077, for patients with type 2 diabetes; pinteraction=0·82) and across the continuous HbA1c range (pinteraction=0·85). Volume-related or renal serious adverse events or adverse events leading to discontinuation of the study drug, hypoglycaemia, and amputations were not differentially affected by treatment in any of the glycaemia categories. INTERPRETATION: In patients with heart failure with mildly reduced or preserved ejection fraction, oral dapagliflozin improved heart failure outcomes to a similar extent in three glycaemia subgroups: normoglycaemia, prediabetes, and type 2 diabetes. Moreover, the heart failure benefits of dapagliflozin seem to be consistent across a continuous glycaemic range. FUNDING: AstraZeneca.

Guideline of the Brazilian Society of Cardiology on Diagnosis and Treatment of Patients with Chagas Disease Cardiomyopathy / Diretriz da Sociedade Brasileira de Cardiologia sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas

This guideline aimed to update the concepts and formulate the standards of conduct and scientific evidence that support them, regarding the diagnosis and treatment of the Cardiomyopathy of Chagas disease, with special emphasis on the rationality base that supported it.  Chagas disease in the 21st century maintains an epidemiological pattern of endemicity in 21 Latin American countries. Researchers and managers from endemic and non-endemic countries point to the need to adopt comprehensive public health policies to effectively control the interhuman transmission of T. cruzi infection, and to obtain an optimized level of care for already infected individuals, focusing on diagnostic and therapeutic opportunistic opportunities.   Pathogenic and pathophysiological mechanisms of the Cardiomyopathy of Chagas disease were revisited after in-depth updating and the notion that necrosis and fibrosis are stimulated by tissue parasitic persistence and adverse immune reaction, as fundamental mechanisms, assisted by autonomic and microvascular disorders, was well established. Some of them have recently formed potential targets of therapies.  The natural history of the acute and chronic phases was reviewed, with enhancement for oral transmission, indeterminate form and chronic syndromes. Recent meta-analyses of observational studies have estimated the risk of evolution from acute and indeterminate forms and mortality after chronic cardiomyopathy. Therapeutic approaches applicable to individuals with Indeterminate form of Chagas disease were specifically addressed. All methods to detect structural and/or functional alterations with various cardiac imaging techniques were also reviewed, with recommendations for use in various clinical scenarios. Mortality risk stratification based on the Rassi score, with recent studies of its application, was complemented by methods that detect myocardial fibrosis.  The current methodology for etiological diagnosis and the consequent implications of trypanonomic treatment deserved a comprehensive and in-depth approach. Also the treatment of patients at risk or with heart failure, arrhythmias and thromboembolic events, based on pharmacological and complementary resources, received special attention. Additional chapters supported the conducts applicable to several special contexts, including t. cruzi/HIV co-infection, risk during surgeries, in pregnant women, in the reactivation of infection after heart transplantation, and others.     Finally, two chapters of great social significance, addressing the structuring of specialized services to care for individuals with the Cardiomyopathy of Chagas disease, and reviewing the concepts of severe heart disease and its medical-labor implications completed this guideline.

Esta diretriz teve como objetivo principal atualizar os conceitos e formular as normas de conduta e evidências científicas que as suportam, quanto ao diagnóstico e tratamento da CDC, com especial ênfase na base de racionalidade que a embasou. A DC no século XXI mantém padrão epidemiológico de endemicidade em 21 países da América Latina. Investigadores e gestores de países endêmicos e não endêmicos indigitam a necessidade de se adotarem políticas abrangentes, de saúde pública, para controle eficaz da transmissão inter-humanos da infecção pelo T. cruzi, e obter-se nível otimizado de atendimento aos indivíduos já infectados, com foco em oportunização diagnóstica e terapêutica. Mecanismos patogênicos e fisiopatológicos da CDC foram revisitados após atualização aprofundada e ficou bem consolidada a noção de que necrose e fibrose sejam estimuladas pela persistência parasitária tissular e reação imune adversa, como mecanismos fundamentais, coadjuvados por distúrbios autonômicos e microvasculares. Alguns deles recentemente constituíram alvos potenciais de terapêuticas. A história natural das fases aguda e crônica foi revista, com realce para a transmissão oral, a forma indeterminada e as síndromes crônicas. Metanálises recentes de estudos observacionais estimaram o risco de evolução a partir das formas aguda e indeterminada e de mortalidade após instalação da cardiomiopatia crônica. Condutas terapêuticas aplicáveis aos indivíduos com a FIDC foram abordadas especificamente. Todos os métodos para detectar alterações estruturais e/ou funcionais com variadas técnicas de imageamento cardíaco também foram revisados, com recomendações de uso nos vários cenários clínicos. Estratificação de risco de mortalidade fundamentada no escore de Rassi, com estudos recentes de sua aplicação, foi complementada por métodos que detectam fibrose miocárdica. A metodologia atual para diagnóstico etiológico e as consequentes implicações do tratamento tripanossomicida mereceram enfoque abrangente e aprofundado. Também o tratamento de pacientes em risco ou com insuficiência cardíaca, arritmias e eventos tromboembólicos, baseado em recursos farmacológicos e complementares, recebeu especial atenção. Capítulos suplementares subsidiaram as condutas aplicáveis a diversos contextos especiais, entre eles o da co-infecção por T. cruzi/HIV, risco durante cirurgias, em grávidas, na reativação da infecção após transplante cardíacos, e outros.    Por fim, dois capítulos de grande significado social, abordando a estruturação de serviços especializados para atendimento aos indivíduos com a CDC, e revisando os conceitos de cardiopatia grave e suas implicações médico-trabalhistas completaram esta diretriz. 

Reconstruction of Oronasal Fistula with Tongue Flap: A Cleft Palate Report.

Oronasal fistula can persist after conventional secondary alveolar bone graft surgery, which may lead to functional issues, such as regurgitation of fluids from the oral to the nasal cavity. This manuscript describes a clinical case of a patient with a bilateral cleft lip and palate that underwent tongue graft surgery for closure of an oronasal fistula after three failed local mucosa flap surgeries. The multidisciplinary treatment was comprised of orthodontic treatment, mucosa and alveolar grafts for palate closure and aesthetic rehabilitation of the anterior maxillary teeth. Smile aesthetics were noticeably improved, enhancing the patient's self-perception and confidence.

Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO2/FiO2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).