Dual-Stage Picolinic Acid-Derived Inhibitors of Toxoplasma gondii

Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both T. gondii parasite forms. Picolinic acid 23, designed from an antiparasitic benzamidobenzoic acid class with challenging ADME properties, showed 60-fold-enhanced solubility, a moderate LogD_7.4, and a 30% improvement in microsomal stability. Furthermore, isotopically labeled glucose tracing revealed that picolinic acid 23 does not function by hexokinase inhibition. Thus, we report a new probe scaffold to interrogate dual-stage inhibition of T. gondii.     

Tracheoesophageal fistula in the developing world: are we ready for thoracoscopic repair?

Tracheoesophageal fistula (TEF) is a bellwether for a country’s ability to care for sick newborns. We aim to review the existing literature from low- and middle-income countries in regard to management of those newborns and the possible approaches to improve their outcomes. A review of the existing English literature was conducted with the aim of assessing challenges faced by providers in LMIC in terms of diagnostic, preoperative, operative and post-operative care for TEF patients. We also review the limited literature for performing thoracoscopic repair in the developing world context and suggest methods for introduction of advanced thoracoscopic procedures including techniques for providing anesthesia to these challenging babies. While outcomes related to technique from LMIC are comparable to the developed world, rates of secondary complications like sepsis and pneumonia are higher. In many areas, repairs are conducted in a staged fashion with minimal utilization of thoracoscopic approach. The paucity of resources creates strain on intraoperative and post-operative management. Clearly, not all developing world contexts are ready to attempt thoracoscopic repair but we outline suggestions for assessing the existing capabilities and a stepwise gradual implementation of advanced thoracoscopy when appropriate.     

Evaluation of admission levels of P,E and L selectins as predictors for thrombosis in hospitalized COVID-19 patients

Thromboembolic complications are the most reported cause of death in coronavirus disease-2019 (COVID-19). Hypercoagulability, platelets activation and endotheliopathy are well-recognized features in COVID-19 patients. The aim of this work was to evaluate circulating soluble selectins P, E and L at the time of hospital admission as predictors for upcoming thrombosis. This retrospective study included 103 hospitalized COVID-19 patients and 50 healthy volunteer controls. COVID-19 patients were categorized into two groups; group 1 who developed thrombosis during hospitalization and group 2 who did not. Soluble selectins were quantitated using ELISA technique. Higher levels of sP-selectin, sE-selectin and sL-selectin were detected in COVID-19 patients compared to controls. Furthermore, significantly higher levels were found in group 1 compared to group 2. Their means were [5.86 ± 1.72 ng/mL vs. 2.51 ± 0.81 ng/mL]; [50 ± 8.57 ng/mL vs. 23.96 ± 6.31 ng/mL] and [4.66 ± 0.83 ng/mL vs. 2.95 ± 0.66 ng/mL] for sP-selectin, sE-selectin and sL-selectin respectively. The elevated selectins correlated with the currently used laboratory biomarkers of disease severity. After adjustment of other factors, sP-selectin, sE-selectin and sL-selectin were independent predictors for thrombosis. At sP-selectin ≥ 3.2 ng/mL, sE-selectin ≥ 32.5 ng/mL and sL-selectin ≥ 3.6 ng/mL thrombosis could be predicted with 97.1%, 97.6% and 96.5% sensitivity. A panel of the three selectins provided 100% clinical sensitivity. Admission levels of circulating soluble selectins P, E and L can predict thrombosis in COVID-19 patients and could be used to identify patients who need prophylactic anticoagulants. E-selectin showed a superior clinical performance, as thrombo-inflammation biomarker, to the most commonly studied P-selectin.