Search

Radical cure of Plasmodium vivax malaria must include elimination of quiescent "hypnozoite" forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials.

Introduction: Emergency departments (ED) are rapidly replacing conventional troponin assays with high-sensitivity troponin tests. We sought to evaluate emergency physician utilization of troponin tests before and after high-sensitivity troponin introduction in our ED. Methods: We retrospectively examined 9,477 ED encounters, identifying the percentage in which physicians ordered a serum troponin both before and after our institution adopted a high-sensitivity troponin test. Results: After introduction of high-sensitivity troponin testing, the percentage of ED encountersin which physicians ordered troponin studies decreased (28.3% before vs 22% after; P

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

Introduction: Patients with malignancy represent a particular challenge for the emergency department (ED) given their higher acuity, longer ED length of stay, and higher admission rate. It is unknown if patients with malignancies and hyperlactatemia are at increased risk of mortality. If serum lactic acid could improve detection of at-risk patients with cancer, it would be useful in risk stratification. There is also little evidence that “alarm” values of serum lactate (such as >/=4 mmol/L) are appropriate for the population of patients with cancer. Methods: This was a continuous retrospective cohort study of approximately two years (2012-2014) at a single, tertiary hospital ED; 5,440 patients had serum lactic acid measurements performed in the ED. Of the 5,440 patients in whom lactate was drawn, 1,837 were cancer patients, and 3,603 were non-cancer patients.Cumulative unadjusted mortality (determined by hospital records and an external death tracking system) was recorded at one day, three days, seven days, and 30 days. We used logistic regression to examine the risk of mortality 30 days after the ED visit after adjusting for confounders.  Results: In an unadjusted analysis, we found no statistically significant difference in the mortality of cancer vs. non-cancer patients at one day and three days. Significant differences in mortality were found at seven days (at lactate levels of