Browsing by Author "Lavoie, Pascal M."

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    Cellular metabolism constrains innate immune responses in early human ontogeny
    (Nature Research, 2018-11-16) Kan, Bernard; Michalski, Christina; Fu, Helen; Au, Hilda H.T.; Lee, Kelsey; Marchant, Elizabeth A.; Cheng, Maye F.; Anderson-Baucum, Emily; Aharoni-Simon, Michal; Tilley, Peter; Mirmira, Raghavendra G.; Ross, Colin J.; Luciani, Dan S.; Jan, Eric; Lavoie, Pascal M.; Medicine, School of Medicine
    Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.
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    Verbal Autopsy to Assess Postdischarge Mortality in Children With Suspected Sepsis in Uganda
    (American Academy of Pediatrics, 2023) Knappett, Martina; Hooft, Anneka; Maqsood, Muhammad Bilal; Lavoie, Pascal M.; Kortz, Teresa; Mehta, Sonia; Duby, Jessica; Akech, Samuel; Maina, Michuki; Carter, Rebecca; Popescu, Constantin R.; Daftary, Rajesh; Mugisha, Nathan Kenya; Mwesigwa, Douglas; Kabakyenga, Jerome; Kumbakumba, Elias; Ansermino, J. Mark; Kissoon, Niranjan; Mutekanga, Andrew; Hau, Duncan; Moschovis, Peter; Kangwa, Mukuka; Chen, Carol; Firnberg, Maytal; Glomb, Nicolaus; Argent, Andrew; Reid, Stephen J.; Bhutta, Adnan; Wiens, Matthew O.; Pediatrics, School of Medicine
    Background: Reducing child mortality in low-income countries is constrained by a lack of vital statistics. In the absence of such data, verbal autopsies provide an acceptable method to determining attributable causes of death. The objective was to assess potential causes of pediatric postdischarge mortality in children younger than age 5 years (under-5) originally admitted for suspected sepsis using verbal autopsies. Methods: Secondary analysis of verbal autopsy data from children admitted to 6 hospitals across Uganda from July 2017 to March 2020. Structured verbal autopsy interviews were conducted for all deaths within 6 months after discharge. Two physicians independently classified a primary cause of death, up to 4 alternative causes, and up to 5 contributing conditions using the Start-Up Mortality List, with discordance resolved by consensus. Results: Verbal autopsies were completed for 361 (98.6%) of the 366 (5.9%) children who died among 6191 discharges (median admission age: 5.4 months [interquartile range, 1.8-16.7]; median time to mortality: 28 days [interquartile range, 9-74]). Most deaths (62.3%) occurred in the community. Leading primary causes of death, assigned in 356 (98.6%) of cases, were pneumonia (26.2%), sepsis (22.1%), malaria (8.5%), and diarrhea (7.9%). Common contributors to death were malnutrition (50.5%) and anemia (25.7%). Reviewers were less confident in their causes of death for neonates than older children (P < .05). Conclusions: Postdischarge mortality frequently occurred in the community in children admitted for suspected sepsis in Uganda. Analyses of the probable causes for these deaths using verbal autopsies suggest potential areas for interventions, focused on early detection of infections, as well as prevention and treatment of underlying contributors such as malnutrition and anemia.