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.

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.

Profile of natural killer cells after a previous natural Vaccinia virus infection in an in vitro viral re-exposure.

The present study compares the profile of NK cells in an in vitro re-exposure by Vaccinia virus (VACV), in groups that have had a previous vaccination or natural infection. Our data suggests that stimulation with VACV triggers a cytotoxic response by NK cells marked by an increase of NCRs: NKp30, NKp44, and NKp46 in infected (vaccinated and unvaccinated) subjects and in non-infected vaccinated patients, when compared with non-infected unvaccinated individuals. However, the degranulation and secretion processes are inhibited in infected (vaccinated and unvaccinated) subjects and in the non-infected vaccinated patients, when compared with non-infected unvaccinated individuals. We demonstrated that stimulation with VACV downregulates the percentage of expression of Perforin, Granzyme A, and CD107a, but upregulate CD94 in infected (vaccinated and unvaccinated) subjects and in non-infected vaccinated patients, when compared with non-infected unvaccinated individuals. Furthermore, the percentage of IFN-γ(+) NK cells was significantly lower in non-infected unvaccinated subjects, when compared with infected (vaccinated and unvaccinated) and non-infected vaccinated individuals. Our results also show that the percentage of TNF-α(+) NK cells was significantly higher in infected (vaccinated and unvaccinated) subjects and in non-infected vaccinated patients, when compared with non-infected unvaccinated individuals, after in vitro stimulation with UV-inactivated VACV. Our data suggest that the expression of NCRs NKp30, NKp44, NKp46 and cytokines by NK cells are important in the innate response against VACV.

CD4 and CD8 T cells participate in the immune memory response against Vaccinia virus after a previous natural infection.

The present study evaluates the immune response of memory CD4(+) and CD8(+) T cells from patients following a natural Vaccinia virus (VACV) infection. A total of 42 individuals were involved in the study being: 22 previously infected individuals (vaccinated or not against smallpox) and 20 non-infected individuals (vaccinated or not). A short-term in vitro stimulation with UV-inactivated VACV of whole blood cells was performed. Our study showed that previously infected individuals have a lower percentage of CD4(+) T cells expressing lymph-node homing receptors (CD4(+)CD62L(+)CCR7(+)) and higher percentage of memory CD4(+) T cells subsets (CD4(+)CD45RO(High)) when compared with non-infected subjects, after in vitro viral stimulation. We also showed that infected individuals presented higher percentages of CD4(+) and CD8(+) memory T lymphocytes expressing IFN-γ when compared to non-infected individuals. We verified that the percentage of CD4(+) and CD8(+) T memory cells expressing TNF-α was higher in infected and non-infected vaccinated subjects when compared with non-infected unvaccinated individual. We also observed that previously infected individuals have higher percentages of CD8(+) T cells expressing lymph-node homing receptors (CCR7(+) and CD62L(+)) and that the memory T cells expressing IFN-γ and TNF-α were at higher percentages in the whole blood cells from infected and non-infected vaccinated individuals, when compared to unvaccinated non-infected subjects. Thus, our findings suggest that CD4(+) and CD8(+) T cells are involved in the immune memory response against Vaccinia virus natural infection.

Conhecimento das enfermeiras da Pós-Graduação em Saúde da Família sobre avulsão dentária / Nurses’ knowledge of the Postgraduate Program in Family’s Health on dental avulsion

Objetivos: investigar o conhecimento, as atitudes e práticas das enfermeiras alunas da especialização em Saúde daFamília do Instituto de Educação Continuada da PUC de Sete Lagoas sobre a avulsão dentária. Método: foi realizado umestudo transversal e descritivo. A população estudada constituiu-se de 17 enfermeiras, alunas do curso de Especializaçãoem Saúde da Família, que se voluntariaram a participar do estudo. Como instrumento para coleta de dados foi utilizadoum questionário adaptado, com perguntas acerca da temática avulsão dentária. Os dados obtidos foram submetidos aanálises quantitativas, através de métodos estatísticos descritivos. Resultados: a maioria das enfermeiras (71%) nuncaouviu falar de avulsão dentária. Cinco enfermeiras (29%) não saberiam quais as providências necessárias em caso deavulsão dentária, seis (35%) armazenariam o dente e encaminhariam a pessoa ao dentista, três (18%) apenasencaminhariam a pessoa ao dentista, uma enfermeira (6%) encaminharia a pessoa para fazer a restauração, uma aluna(6%) armazenaria o dente em leite e entregaria o dente ao socorrista, e apenas uma (6%) delas faria imediatamente oreimplante. Conclusões: pode-se afirmar que as enfermeiras analisadas não apresentaram conhecimentos sólidos quandoquestionadas acerca de diferentes aspectos de procedimentos em casos de tratamento de urgência por avulsão dentáriaocasional.

Processo de trabalho: sua importância na organização da prática assistencial de enfermagem na saúde coletiva / Work process: the importance in the organization of nursing assistant practices in collective health

Objetivo: analisar o processo de trabalho da enfermagem e discutir a importância do enfermeiro, em sua práticaassistencial, em desvelar o seu objeto e instrumentos de trabalho para então compreender o seu processo de trabalho e, asua real identidade profissional, com ênfase na saúde coletiva. Metodologia: pesquisa realizada na Biblioteca Regional deMedicina (BIREME), na qual foram obtidos 1741 artigos. Após, análise e síntese desses materiais foram selecionados 13artigos e, também foi realizada uma busca retroativa das referências dos artigos consultados a fim de ampliar as fontes depesquisa. Resultados: a partir dessa pesquisa, verificou-se que é crucial que a enfermagem se liberte desse velhoparadigma (biomédico, hegemônico) e, busque novas concepções que permitam alcançar autonomia e autogoverno doprofissional enfermeiro. Conclusão: o enfermeiro necessita clarificar as suas ferramentas de trabalho em sua práticaprofissional para que possa compreender o seu processo de trabalho.