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Context: Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. Methods: The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100 ns NPT ensemble employing GAFF2 forcefield in the temperature of 310 K, integration time step of 2 fs, and non-bond cutoff distance of 6.0 Å. [ABSTRACT FROM AUTHOR]

Key Points: Question: What are the best-performing organ dysfunction–based criteria to implement the definition of sepsis and septic shock in children with suspected infection? Findings: In this international, multicenter, retrospective cohort study including more than 3.6 million pediatric encounters, a novel score, the Phoenix Sepsis Score, was derived and validated to predict mortality in children with suspected or confirmed infection. The new criteria for pediatric sepsis and septic shock based on the score performed better than existing organ dysfunction scores and the International Pediatric Sepsis Consensus Conference criteria. Meaning: The new data-driven criteria for pediatric sepsis and septic shock based on measures of organ dysfunction had improved performance compared with prior pediatric sepsis criteria. Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria. This cohort study derives and validates novel criteria for diagnosis of pediatric sepsis and septic shock across high-resource and low-resource international settings. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether use of a language other than English (LOE) would be associated with medical complexity, and whether medical complexity and LOE together would be associated with worse clinical outcomes. METHODS: The primary outcome of this single-site retrospective cohort study of PICU encounters from September 1, 2017, through August 31, 2022 was an association between LOE and medical complexity. Univariable and multivariable analyses were performed between demographic factors and medical complexity, both for unique patients and for all encounters. We investigated outcomes of initial illness severity (using Pediatric Logistic Organ Dysfunction-2), length of stay (LOS), days without mechanical ventilation or organ dysfunction using a mixed effects regression model, controlling for age, sex, race and ethnicity, and insurance status. RESULTS: There were 6802 patients and 10 011 encounters. In multivariable analysis for all encounters, Spanish use (adjusted odds ratio [aOR], 1.29; 95% confidence interval [CI], 1.11-1.49) and language other than English or Spanish (LOES) (aOR, 1.36; 95% CI, 1.02-1.80) were associated with medical complexity. Among unique patients, there remained an association between use of Spanish and medical complexity in multivariable analysis (aOR, 1.26; 95% CI, 1.05-1.52) but not between LOES and medical complexity (aOR, 1.30; 95% CI, 0.92-1.83). Children with medical complexity (CMC) who used an LOES had fewer organ dysfunction-free days (P = .003), PICU LOS was 1.53 times longer (P = .01), and hospital LOS was 1.45 times longer (P = .01) compared with CMC who used English. CONCLUSIONS: Use of an LOE was independently associated with medical complexity. CMC who used an LOES had a longer LOS. [ABSTRACT FROM AUTHOR]