Surgeons progress through a series of four phases following adverse events that are potentially caused by or directly linked to surgeon error. The framework provided by this study has implications for teaching, surgeon wellness and surgeon error.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.

No abstract

With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. Plasmodium falciparum, the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa. The P. falciparum proteasome is an attractive antimalarial target because its inhibition kills the parasite at multiple stages of its life cycle and restores artemisinin sensitivity in parasites that have become resistant through mutation in Kelch K13. Here, we detail our efforts to develop noncovalent, macrocyclic peptide malaria proteasome inhibitors, guided by structural analysis and pharmacokinetic properties, leading to a potent, species-selective, metabolically stable inhibitor.

A patient with relapsed/refractory B-cell acute lymphoblastic leukemia developed babesiosis prior to allogeneic hematopoietic cell transplantation while on atovaquone for Pneumocystis jirovecii pneumonia prophylaxis. Despite receiving a prolonged course of atovaquone and azithromycin until whole blood Babesia microti DNA was no longer detected by polymerase chain reaction, her post-transplant course was complicated by relapsed babesiosis. We investigate the potential host and parasite characteristics causing relapsing/persistent infection.