Synthesis and evaluation of (S)-[18F]fesetron in the rat brain as a potential PET imaging agent for serotonin 5-HT3 receptors

Serotonin 5-HT3 receptors are involved in various brain functions including as an emesis target during cancer chemotherapy. We report here the development of (S)-2,3-dimethoxy-5-(3'-[(18)F]fluoropropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide ([(18)F]fesetron) as a potential PET imaging agent for serotonin 5-HT3 receptors. By radiolabeling((S)-2,3-dimethoxy-5-(3'-tosyloxypropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide) with fluorine-18, (S)-[(18)F]fesetron was obtained in 5 to 10% decay-corrected yields and with specific activities >74GBq/μmol at the end of radiosynthesis. PET imaging in rats showed low uptake of [(18)F]fesetron in the brain with retention of binding in the striatal and cerebellar regions. Using colliculi as a reference region, ratios were 3.4 for striata and 2.5 for cerebellum. Ex vivo brain PET analysis displayed binding of [(18)F]fesetron in the hippocampus, striatum and cerebellar regions. Cerebellar regions corresponded to area postrema and nucleus tract solitaris known to contain 5-HT3 receptors. Dorsal hippocampus showed the highest uptake with ratio of >17 with respect to colliculi, while area postrema and striata had ratios of >10. Thus, [(18)F]fesetron exhibited a unique binding profile to rat brain regions known to contain significant amounts of serotonin 5-HT3 receptors. However, the very low brain uptake limits its usefulness as a PET radiotracer in this animal model

Video simulation to learn pediatric resuscitation skills tailored to a low resource setting: A pilot program in Iquitos, Peru

IntroductionThe Hospital Regional de Loreto in Peru partners with the University of California Los Angeles Global Health Program to enhance educational experiences for US and Peruvian trainees. University of California Los Angeles Pediatric faculty led intermittent in-person code simulation sessions for Peruvian residents, and there is a need for regular education on this topic.MethodsUniversity of California Los Angeles residents created a video simulation of a patient in respiratory distress. The video was presented to Hospital Regional de Loreto trainees in pediatrics. Stakeholder interviews and reuse of the video after initial presentation assessed acceptability of this mode of education by the site. Pre- and post-surveys using numerical rating scales evaluated the educational utility of this specific simulation video. Paired t-tests compared the pre- and post-surveys in the effectiveness of increasing the trainees' comfort of specific resuscitation skills.ResultsStakeholder interviews revealed the video simulation was integrated into formal intern orientation trainings as well as used for resident and physician trainings multiple times in the year after the introduction. Twenty trainees completed the pre-intervention survey and 19 completed the post-intervention survey. Trainee comfort with code team leadership (2.6 ± 0.9, 3.5 ± 0.09, p = 0.03) and arrhythmia recognition/automated external defibrillator (AED) management (2.4 ± 0.9, 3.1 ± 0.9, p = 0.03) increased significantly with the video intervention. There was no significant difference in comfort with other skills. Overall, trainees rated the helpfulness of the video as an average of 4.2 (±1.1) out of 5. The most common positive feedback included the utility of reviewing medication dosing and the skill of performing chest compressions. The most common suggestions for improvement were to review more pathophysiology and simulate available resources at Hospital Regional de Loreto more realistically.ConclusionE-learning is an acceptable mode of education in a resource-limited setting when tailored to the local context. This pilot project demonstrated short-term improvement in reported confidence and skills with some aspects of pediatric resuscitation

Amnion responses to intrauterine inflammation and effects of inhibition of TNF signaling in preterm Rhesus macaque.

Intrauterine infection/inflammation (IUI) is a frequent complication of pregnancy leading to preterm labor and fetal inflammation. How inflammation is modulated at the maternal-fetal interface is unresolved. We compared transcriptomics of amnion (a fetal tissue in contact with amniotic fluid) in a preterm Rhesus macaque model of IUI induced by lipopolysaccharide with human cohorts of chorioamnionitis. Bulk RNA sequencing (RNA-seq) amnion transcriptomic profiles were remarkably similar in both Rhesus and human subjects and revealed that induction of key labor-mediating genes such as IL1 and IL6 was dependent on nuclear factor κB (NF-κB) signaling and reversed by the anti-tumor necrosis factor (TNF) antibody Adalimumab. Inhibition of collagen biosynthesis by IUI was partially restored by Adalimumab. Interestingly, single-cell transcriptomics, flow cytometry, and immunohistology demonstrated that a subset of amnion mesenchymal cells (AMCs) increase CD14 and other myeloid cell markers during IUI both in the human and Rhesus macaque. Our data suggest that CD14+ AMCs represent activated AMCs at the maternal-fetal interface