Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Effect of Early Treatment with Ivermectin among Patients with Covid-19.

BACKGROUND: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear. METHODS: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 µg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. RESULTS: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events. CONCLUSIONS: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. FINDINGS: The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. INTERPRETATION: Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FUNDING: FastGrants and The Rainwater Charitable Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial.

BACKGROUND: Observational studies have postulated a therapeutic role of metformin in treating COVID-19. We conducted an adaptive platform clinical trial to determine whether metformin is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. METHODS: The TOGETHER Trial is a placebo-controled, randomized, platform clinical trial conducted in Brazil. Eligible participants were symptomatic adults with a positive antigen test for SARS-CoV-2. We enroled eligible patients over the age of 50 years or with a known risk factor for disease severity. Patients were randomly assigned to receive either placebo or metformin (750 mg twice daily for 10 days or placebo, twice daily for 10 days). The primary outcome was hospitalization defined as either retention in a COVID-19 emergency setting for > 6 h or transfer to tertiary hospital due to COVID-19 at 28 days post randomization. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to determine probability of success of the intervention compared to placebo. FINDINGS: The TOGETHER Trial was initiated June 2, 2020. We randomized patients to metformin starting January 15, 2021. On April 3, 2021, the Data and Safety Monitoring Committee recommended stopping enrollment into the metformin arm due to futility. We recruited 418 participants, 215 were randomized to the metformin arm and 203 to the placebo arm. More than half of participants (56.0%) were over the age of 50 years and 57.2% were female. Median age was 52 years. The proportion of patients with the primary outcome at 28 days was not different between the metformin and placebo group (relative risk [RR] 1.14[95% Credible Interval 0.73; 1.81]), probability of superiority 0.28. We found no significant differences between the metformin and placebo group on viral clearance through to day 7 (Odds ratio [OR], 0.99, 95% Confidence Intervals 0.88-1.11) or other secondary outcomes. INTERPRETATION: In this randomized trial, metformin did not provide any clinical benefit to ambulatory patients with COVID-19 compared to placebo, with respect to reducing the need for retention in an emergency setting or hospitalization due to worsening COVID-19. There were also no differences between metformin and placebo observed for other secondary clinical outcomes.

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.

Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.

Incorporating evidence-based principles in medical training. Sharing experience with McMaster.

This article was migrated. The article was marked as recommended. Background: This workshop was the second activity of the collaboration between the McMaster University, Botucatu Medical School- São Paulo State University (UNESP) and Pontifical Catholic University of Minas Gerais - PUC Minas that took place in Botucatu, Brazil between March 27th to 28th 2017. Aims: Its prime purpose was to share with the Brazilian professors and students how to include evidence-based concepts in their daily teaching activities. Methods: The participants were involved and guided in discussions on how to explore evidence-based techniques to improve their understanding and their willingness to include new teaching strategies in the future. Results: A final evaluation survey completed by the participants indicated that they were highly satisfied with the workshop experience and that they gained an enhancement of knowledge about evidence-based medicine. Conclusion: Participants had an increase in their self-confidence to implementevidence-based concepts in their future lecture programs.

Excesso de Peso, Variáveis Antropométricas e Pressão Arterial em Escolares de 10 a 18 Anos / Excess Weight, Anthropometric Variables and Blood Pressure in Schoolchildren aged 10 to 18 years

Fundamento: Estima-se que a prevalência de hipertensão em crianças e adolescentes varie entre 1-13%. O excesso de peso e a obesidade central estão relacionados aos níveis pressóricos em adultos e podem ser importantes na patogênese precoce da HAS quando presentes na infância. Objetivos: Identificar a associação entre variáveis antropométricas e níveis pressóricos em escolares de 5.ª a 8.ª séries e avaliar qual medida obteve maior correlação com a medida dos níveis pressóricos. Métodos: Estudo transversal contemporâneo com amostra de base populacional probabilística por conglomerados em escolas públicas do ensino fundamental de Porto Alegre, de alunos matriculados entre a 5.ª e a 8.ª série. Foram coletados dados sobre fatores de risco familiares e antropometria. A análise estatística incluiu correlações e ajuste dos intervalos de confiança para conglomerados. Resultados: A média de idade dos participantes foi de 12,57 (± 1,64) anos, dos quais 55,2% eram do sexo feminino. Encontraram-se 11,3% da amostra com níveis pressóricos alterados e 16,2% com valores limítrofes. Das variáveis antropométricas analisadas, a que demonstrou maior correlação com valores pressóricos aumentados foi o diâmetro do quadril (r = 0,462, p < 0,001) seguido de circunferência abdominal menor (r = 0,404, p < 0,001) e prega cutânea abdominal (r = 0,291, p < 0,001). Conclusão: Foi observada associação entre as circunferências da cintura e dobras cutâneas e níveis pressóricos aumentados nos escolares da amostra. Portanto, é de fundamental importância que a aferição da pressão arterial e as medidas de cintura e quadril sejam rotina nos serviços de saúde ...

Background: The prevalence of hypertension among children and adolescents is estimated to range between 1% and 13%. Excess weight and central obesity are related to blood pressure levels in adults, and may be important in the early pathogenesis of SH when present in childhood. Objectives: To study the association between anthropometric variables and blood pressure levels in schoolchildren from the 5th and 8th grades, and to identify which parameter was more strongly correlated with blood pressure levels. Methods: Contemporary cross-sectional study with probabilistic population-based cluster sampling of schoolchildren enrolled from the 5th to the 8th grades in public elementary schools of Porto Alegre. Data on familial risk factors and anthropometry were collected. Statistical analysis included correlations and cluster-adjusted confidence intervals. Results: The mean age of participants was 12.57 (± 1.64) years, and 55.2% of them were females. Abnormal blood pressure levels were found in 11.3% of the sample and borderline values, in 16.2%. Among the anthropometric variables analyzed, hip circumference was the one with the strongest correlation with increased blood pressure (r = 0.462, p < 0.001), followed by waist circumference (r = 0.404, p < 0.001) and abdominal skinfold (r = 0.291, p < 0.001). Conclusion: We observed an association of waist circumference and skinfolds with increased blood pressure levels in the schoolchildren of the sample. Therefore, it is of the utmost importance that early measurements of blood pressure, and waist and hip circumferences become a routine in health services in order to prevent this condition. .

Excess weight, anthropometric variables and blood pressure in schoolchildren aged 10 to 18 years.

BACKGROUND: The prevalence of hypertension among children and adolescents is estimated to range between 1% and 13%. Excess weight and central obesity are related to blood pressure levels in adults, and may be important in the early pathogenesis of SH when present in childhood. OBJECTIVES: To study the association between anthropometric variables and blood pressure levels in schoolchildren from the 5th and 8th grades, and to identify which parameter was more strongly correlated with blood pressure levels. METHODS: Contemporary cross-sectional study with probabilistic population-based cluster sampling of schoolchildren enrolled from the 5th to the 8th grades in public elementary schools of Porto Alegre. Data on familial risk factors and anthropometry were collected. Statistical analysis included correlations and cluster-adjusted confidence intervals. RESULTS: The mean age of participants was 12.57 (± 1.64) years, and 55.2% of them were females. Abnormal blood pressure levels were found in 11.3% of the sample and borderline values, in 16.2%. Among the anthropometric variables analyzed, hip circumference was the one with the strongest correlation with increased blood pressure (r = 0.462, p < 0.001), followed by waist circumference (r = 0.404, p < 0.001) and abdominal skinfold (r = 0.291, p < 0.001). CONCLUSION: We observed an association of waist circumference and skinfolds with increased blood pressure levels in the schoolchildren of the sample. Therefore, it is of the utmost importance that early measurements of blood pressure, and waist and hip circumferences become a routine in health services in order to prevent this condition.

Análise in vitro da infiltração marginal apical na obturação de canais radiculares / In Vitro Analysis Apical Marginal Infiltration in the Filling of Master Cones

Objetivo: O selamento apical constitui um dos fatores decisivos no sucesso da terapia endodôntica. Material e Métodos: No presente estudo foi analisado in vitro o comportamento de diferentes métodos de se obter o travamento do cone principal de guta-percha na obturação do canal radicular frente à infiltração marginal apical. Foram utilizados quarenta e dois incisivos centrais superiores, sendo dois utilizados como grupos controle positivo e negativo e os restantes divididos em quatro grupos, quais sejam: adaptação do cone principal padronizado, adaptação do cone principal por meio do corte da extremidade, adaptação do cone principal por meio da moldagem com clorofórmio e cone principal sem travamento. A obturação foi feita pela técnica de condensação lateral, utilizando-se um cimento à base de resina epóxica. Os dentes foram imersos em tinta Nanquim e submetidos ao processo de diafanização para a visualização do nível de infiltração marginal. Resultados: Os dados foram submetidos à análise estatística não paramétrica, que evidenciou não haver diferença estatística (p>0,05) entre os grupos. Conclusão: os diferentes tipos de adaptação do cone principal não interferem na infiltração marginal apical quando um cimento obturador à base de resina epóxica é utilizado

Reservatórios e vetores silvestres do Trypanosoma cruzi e suas relaçöes com o domicílio humano na Ilha de Santa Catarina / Wild reservois and vectors of Trypanosoma cruzi and their relations with human habitation in the island of Santa Catarina

Estudos sobre reservatórios e vetores silvestres da doença de Chagas realizados em várias localidades da Ilha de Santa Catarina revelaram que 23,5% (8/34) dos gambás e 5,2% (1/19) dos roedores estavam infectados pelo Trypanosoma cruzi. Por sua vez, 25,0% (3/12) dos morcegos exibiam, no sangue periférico, formas flageladas indistinguíveis do T.cruzi. Em relaçäo aos vetores silvestres verificou-se a existência de duas espécies de triatomíneos nos ecótopos naturais: Panstrongylus megistus e Rhodnius domesticus, com índices de infecçäo pelo T. cruzi excepcionalmente elevados, de 84,5% (115/136) e 66,6% (6/9) respectivamente. Nestes ecótopos, os triatomíneos encontravam-se exclusivamente em ninhos de gambás e roedores situados em ocos de árvores e touceiras de gravatás e todos os exemplares de P. megistus capturados eram formas jovens (ninfas). Por outro lado, pela primeira vez em Santa Catarina demonstrou-se a colonizaçäo de ecótopos artificiais (galinheiros e casa abandonada), por esta espécie de triatomíneo, no distrito de Lagoa da Conceiçäo. Sobre a doença de Chagas humana, säo mencionados dois novos casos seguramente adquiridos no Estado de Santa Catarina, um dos quais, provavelmente na Ilha de Santa Catarina. A transmissäo deve ter ocorrido por meio de adultos de P. megistus que nas épocas quentes do ano costumam invadir as habitaçöes humanas, apesar de, até o momento, näo ter sido registrada sua adaptaçäo ao domicílio. Os autores sugerem a inclusäo da doença de Chagas no diagnóstico diferencial das cardiopatias em indivíduos que sempre residiram na Ilha de Santa Catarina e recomendam a realizaçäo de inquéritos sorológicos humanos e de animais domésticos e a pesquisa de triatomíneos em domicílios na Lagoa da Conceiçäo