Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Larval density mediates knockdown resistance to pyrethroid insecticides in adult Aedes aegypti

Abstract Background Understanding mechanisms driving insecticide resistance in vector populations remains a public health priority. To date, most research has focused on the genetic mechanisms underpinning resistance, yet it is unclear what role environmental drivers may play in shaping phenotypic expression. One of the key environmental drivers of Aedes aegypti mosquito population dynamics is resource-driven intraspecific competition at the larval stage. We experimentally investigated the role of density-dependent larval competition in mediating resistance evolution in Ae. aegypti, using knockdown resistance (kdr) as a marker of genotypic resistance and CDC bottle bioassays to determine phenotype. We reared first-instar larvae from susceptible and pyrethroid-resistant field-derived populations of Ae. aegypti at high and low density and measured the resulting phenotypic resistance and population kdr allele frequencies. Results At low density, only 48.2% of the resistant population was knocked down, yet at high density, the population was no longer phenotypically resistant - 93% were knocked down when exposed to permethrin, which is considered susceptible according to WHO guidelines. Furthermore, the frequency of the C1534 kdr allele in the resistant population at high density decreased from 0.98 ± 0.04 to 0.69 ± 0.04 in only one generation of selection. Conclusions Our results indicate that larval conditions, specifically density, can impact both phenotype and genotype of pyrethroid-resistant populations. Furthermore, phenotypic susceptibility to pyrethroids may be re-established in a resistant population through a gene x environment interaction, a finding that can lead to the development of novel resistance management strategies that capitalize on density-induced costs

Factors associated to mortality in children with critical COVID-19 and multisystem inflammatory syndrome in a resource-poor setting

Abstract SARS-CoV-2 infection in children is usually asymptomatic/mild. However, some patients may develop critical forms. We aimed to describe characteristics and evaluate the factors associated to in-hospital mortality of patients with critical COVID-19/MIS-C in the Amazonian region. This multicenter prospective cohort included critically ill children (1 mo–18 years old), with confirmed COVID-19/MIS-C admitted to 3 tertiary Pediatric Intensive Care Units (PICU) in the Brazilian Amazon, between April/2020 and May/2023. The main outcome was in-hospital mortality and were evaluated using a multivariable Cox proportional regression. We adjusted the model for pediatric risk of mortality score version IV (PRISMIV) score and age/comorbidity. 266 patients were assessed with 187 in the severe COVID-19 group, 79 included in the MIS-C group. In the severe COVID-19 group 108 (57.8%) were male, median age was 23 months, 95 (50.8%) were up to 2 years of age. Forty-two (22.5%) patients in this group died during follow-up in a median time of 11 days (IQR, 2–28). In the MIS-C group, 56 (70.9%) were male, median age was 23 months and median follow-up was 162 days (range, 3–202). Death occurred in 17 (21.5%) patients with a median death time of 7 (IQR, 4–13) days. The mortality was associated with higher levels of Vasoactive Inotropic-Score (VIS), presence of acute respiratory distress syndrome (ARDS), higher levels of Erythrocyte Sedimentation Rate, (ESR) and thrombocytopenia. Critically ill patients with severe COVID-19 and MIS-C from the Brazilian Amazon showed a high mortality rate, within 12 days of hospitalization