Associations between childhood ethnoracial minority density, cortical thickness, and social engagement among minority youth at clinical high-risk for psychosis.

An ethnoracial minority density (EMD) effect in studies of psychotic spectrum disorders has been observed, whereby the risk of psychosis in ethnoracial minority group individuals is inversely related to the proportion of minorities in their area of residence. The authors investigated the relationships among area-level EMD during childhood, cortical thickness (CT), and social engagement (SE) in clinical high risk for psychosis (CHR-P) youth. Data were collected as part of the North American Prodrome Longitudinal Study. Participants included 244 ethnoracial minoritized (predominantly Hispanic, Asian and Black) CHR-P youth and ethnoracial minoritized healthy controls. Among youth at CHR-P (n = 164), lower levels of EMD during childhood were associated with reduced CT in the right fusiform gyrus (adjusted ß = 0.54; 95% CI 0.17 to 0.91) and right insula (adjusted ß = 0.40; 95% CI 0.05 to 0.74). The associations between EMD and CT were significantly moderated by SE: among youth with lower SE (SE at or below the median, n = 122), lower levels of EMD were significantly associated with reduced right fusiform gyrus CT (adjusted ß = 0.72; 95% CI 0.29 to 1.14) and reduced right insula CT (adjusted ß = 0.57; 95% CI 0.18 to 0.97). However, among those with greater SE (n = 42), the associations between EMD and right insula and fusiform gyrus CT were not significant. We found evidence that lower levels of ethnic density during childhood were associated with reduced cortical thickness in regional brain regions, but this association may be buffered by greater levels of social engagement.

Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet.

BACKGROUND & AIMS: How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression. METHODS: Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. RESULTS: Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. CONCLUSIONS: The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.