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Acetaminophen (APAP) overdose stands as the primary cause of acute liver failure in the United States. APAP hepatotoxicity involves hepatic glutathione (GSH) depletion and mitochondrial damage. To counteract the toxicity of APAP, the nuclear factor erythroid 2 like 2 (Nrf2) activates the expression of genes responsible for drug detoxification and GSH synthesis. In this study, we present evidence that the elimination of hepatocyte small heterodimer partner, a critical transcriptional repressor for liver metabolism, results in Nrf2 activation and protects mice from APAP-induced acute liver injury. Initial investigations conducted on wildtype (WT) mice revealed a swift downregulation of Shp mRNA within the first 24 h after APAP administration. Subsequent treatment of hepatocyte-specific Shp knockout (Shp Hep−/−) mice with 300 mg/kg APAP for 2 h exhibited comparable bioactivation of APAP with that observed in the WT controls. However, a significant reduction in liver injury was observed in Shp Hep−/− after APAP treatment for 6 and 24 h. The decreased liver injury correlated with a faster recovery of GSH, attributable to heightened expression of Nrf2 target genes involved in APAP detoxification and GSH synthesis. Moreover, in vitro studies revealed that SHP protein interacted with NRF2 protein, inhibiting the transcription of Nrf2 target genes. These findings hold relevance for humans, as overexpression of SHP hindered APAP-induced NRF2 activation in primary human hepatocytes. In conclusion, our studies have unveiled a novel regulatory axis involving SHP and NRF2 in APAP-induced acute liver injury, emphasizing SHP as a promising therapeutic target in APAP overdose-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Objective: Our objective is to forecast the number of coronavirus disease 2019 (COVID-19) cases in the state of Maryland, United States, using transfer function time series (TS) models based on a Social Distancing Index (SDI) and determine how their parameters relate to the pandemic mechanics., Methods: A moving window of 2 mo was used to train the transfer function TS model that was then tested on the next week data. After accounting for a secular trend and weekly cycle of the SDI, a high correlation was documented between it and the daily caseload 9 days later. Similar patterns were also observed on the daily COVID-19 cases and incorporated in our models., Results: In most cases, the proposed models provide a reasonable performance that was, on average, moderately better than that delivered by TS models based only on previous observations. The model coefficients associated with the SDI were statistically significant for most of the training/test sets., Conclusions: Our proposed models that incorporate SDI can forecast the number of COVID-19 cases in a region. Their parameters have real-life interpretations and, hence, can help understand the inner workings of the epidemic. The methods detailed here can help local health governments and other agencies adjust their response to the epidemic.

The first sustained increase in live kidney donation in the United States in 15 years was observed from 2017 to 2019. To help sustain this surge, we studied 35 900 donors (70.3% white, 14.5% Hispanic, 9.3% black, 4.4% Asian) to understand the increase in 2017-2019 vs 2014-2016 using Poisson regression. Among biologically related donors aged <35, 35-49, and ≥50 years, the number of donors did not change across race/ethnicity but increased by 38% and 29% for Hispanic and black ≥50. Among unrelated donors <35, 35-49, and ≥50, white donors increased by 18%, 14%, and 27%; Hispanic donors <35 did not change but increased by 22% and 35% for 35-49 and ≥50; black donors <35 declined by 23% and did not change for 35-49 and ≥50; Asian donors did not change. Among kidney paired donors <35, 35-49, and ≥50, white donors increased by 42%, 50%, and 68%; Hispanic donors <35 and 35-49 increased by 36% and 55% and did not change for ≥50; black donors did not change; Asian donors <35 did not change but increased by 107% and 82% for 35-49 and ≥50. The increase in donation was driven predominantly by unrelated and paired white donors. Donation among unrelated black individuals should be promoted., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)