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

Concurrent predictors of mathematics achievement for 9-year-old children with Williams syndrome

Abstract Research on mathematics achievement by children with Williams syndrome (WS) has been very limited. We describe the math achievement of 72 9-year-olds with WS, compare their math and reading achievement, and explore concurrent predictors of math achievement using the Wechsler Individual Achievement Test-III (WIAT-III) to measure achievement and the Differential Ability Scales-II (DAS-II) to measure cognitive abilities. For both Numerical Operations and Math Problem Solving, mean standard scores (SSs) were in the mild disability range with a full range from severe disability to average ability. Bayesian robust estimation indicated decisive evidence that average reading performance was higher than average math performance. Bayesian multiple linear regression models with informative priors accounted for 60% of the variance in Numerical Operations SS with decisive evidence supporting an effect of Working Memory SS and strong evidence for Nonverbal Reasoning SS and Spatial SS and 71% of the variance in Math Problem Solving SS with decisive evidence supporting effects of Working Memory and Nonverbal Reasoning SS, strong evidence for Verbal SS, and substantial evidence for Spatial SS. These predictors are consistent with those for typically developing individuals, supporting consideration of interventions that have been highly effective for children with math difficulties in the general population

Effect of a Multifaceted Intervention on Use of Evidence-Based Therapies in Patients With Acute Coronary Syndromes in Brazil the BRIDGE-ACS Randomized Trial

Context Studies have found that patients with acute coronary syndromes (ACS) often do not receive evidence-based therapies in community practice. This is particularly true in low- and middle-income countries.Objective To evaluate whether a multifaceted quality improvement (QI) intervention can improve the use of evidence-based therapies and reduce the incidence of major cardiovascular events among patients with ACS in a middle-income country.Design, Setting, and Participants the BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes) trial, a cluster-randomized (concealed allocation) trial conducted among 34 clusters (public hospitals) in Brazil and enrolling a total of 1150 patients with ACS from March 15, 2011, through November 2, 2011, with follow-up through January 27, 2012.Intervention Multifaceted QI intervention including educational materials for clinicians, reminders, algorithms, and case manager training, vs routine practice (control).Main Outcome Measures Primary end point was the percentage of eligible patients who received all evidence-based therapies (aspirin, clopidogrel, anticoagulants, and statins) during the first 24 hours in patients without contraindications.Results Mean age of the patients enrolled was 62 (SD, 13) years; 68.6% were men, and 40% presented with ST-segment elevation myocardial infarction, 35.6% with non-ST-segment elevation myocardial infarction, and 23.6% with unstable angina. the randomized clusters included 79.5% teaching hospitals, all from major urban areas and 41.2% with 24-hour percutaneous coronary intervention capabilities. Among eligible patients (923/1150 [80.3%]), 67.9% in the intervention vs 49.5% in the control group received all eligible acute therapies (population average odds ratio [ORPA], 2.64 [95% CI, 1.28-5.45]). Similarly, among eligible patients (801/1150 [69.7%]), those in the intervention group were more likely to receive all eligible acute and discharge medications (50.9% vs 31.9%; ORPA,, 2.49 [95% CI, 1.08-5.74]). Overall composite adherence scores were higher in the intervention clusters (89% vs 81.4%; mean difference, 8.6% [95% CI, 2.2%-15.0%]). In-hospital cardiovascular event rates were 5.5% in the intervention group vs 7.0% in the control group (ORPA, 0.72 [95% CI, 0.36-1.43]); 30-day all-cause mortality was 7.0% vs 8.4% (ORPA, 0.79 [95% CI, 0.46-1.34]).Conclusion Among patients with ACS treated in Brazil, a multifaceted educational intervention resulted in significant improvement in the use of evidence-based therapies.Brazilian Ministry of HealthHospital do CoracaoHCor Hosp Coracao, Res Inst, BR-04004030 São Paulo, BrazilUniversidade Federal de São Paulo, Paulista Sch Med, Brazilian Clin Res Inst, São Paulo, BrazilDuke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USAUniversidade Federal de São Paulo, Paulista Sch Med, Brazilian Clin Res Inst, São Paulo, BrazilWeb of Scienc

Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity

Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, PfHsp90 and PfHsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation-a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design

Supplemental Material - Risk factors for mortality in 1528 Brazilian childhood-onset systemic lupus erythematosus patients

Supplemental Material for Risk factors for mortality in 1528 Brazilian childhood-onset systemic lupus erythematosus patients by Ana P Sakamoto, Clovis A Silva, Ana C Pita, Vitor C Trindade, Aline G Islabao, Fernanda J Fiorot, Sandra RM Lopes, Rosa MR Pereira, Claudia Saad-Magalhaes, Gleice CS Russo, Claudio A Len, Rogerio do Prado, Lucia MA Campos, Nadia E Aikawa, Simone Appenzeller, Virginia PL Ferriani, Marco F Silva, Marta Felix, Adriana R Fonseca, Ana PL Assad, Flavio R Sztajnbok, Maria C Santos, Blanca E Bica, Evaldo G Sena, Ana J Moraes, Melissa M Fraga, Teresa C Robazzi, Paulo F Spelling, Iloite M Scheibel, Andre S Cavalcanti, Erica N Matos, Luciano J Guimaraes, Flavia P Santos, Licia MH Mota, Eloisa Bonfa and Maria T Terreri in Lupus</p