A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

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 for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

Infection rate and colonization with antibiotic-resistant organisms in skilled nursing facility residents with indwelling devices.

The objective of this prospective surveillance study was to quantify colonization with antimicrobial-resistant organisms (AROs) and infections attributable to indwelling devices in skilled nursing facility (SNF) residents. The study was conducted in 15 SNFs in Southeast Michigan. Residents with (n=90) and without (n=88) an indwelling device were enrolled and followed for 907 resident-months. Residents were cultured monthly from multiple anatomic sites and data on infections were obtained. The device-attributable rate was calculated by subtracting the infection rate in the device group from the infection rate in the non-device group. A total of 197 new infections occurred during the study period; 87 in the device group (incidence rate [IR] =331/1,000 resident-months) and 110 infections in the non-device group (IR=171/1,000 resident-months), with a relative risk of 1.9 (95% confidence interval [CI]: 1.4-2.6). The attributable rate of excess infections among residents in the device group was 160/1,000 resident-months, with an attributable fraction of 48% (95% CI: 31-61%). Prevalence rates for all AROs were higher in the device group compared with the no-device group. The prevalence of the number of AROs per 1,000 residents cultured increased from no-device to those with only feeding tubes, followed by those with only urinary catheters and both these devices. In conclusion, the presence of indwelling devices is associated with higher incidence rates for infections and prevalence rates for AROs. Our study quantifies this risk and shows that approximately half of all infections in SNF residents with indwelling devices can be eliminated with device removal. Effective strategies to reduce infections and AROs in these residents are warranted.

Occupational therapy for chronic obstructive lung disease.

The role of occupational therapy in a multi-disciplinary approach to treatment of chronic obstructive pulmonary disease is described in this paper in terms of the evaluation and implementation of the role in the general hospital settings of two neighboring Cleveland institutions. Cleveland is a heavily industrialized urban region with a high concentration of patients suffering from chronic obstructive pulmonary disease. Motivated by this fact and by the knowledge of the increasing incidence of chronic obstructive pulmonary disease in the United States, therapists at the two facilities wanted occupational therapy to become an intrinsic part of both the Lutheran Medical Center's outpatient demonstration program and St. John's Hospital's pulmonary rehabilitation team. Although of differing natures, these programs were similar in purpose, complementing one another and therefore enhancing the quality of rehabilitative care of the patient with a chronic lung disease within this geographic area.