A computational spatial whole-Cell model for hepatitis B viral infection and drug interactions.

Despite a vaccine, hepatitis B virus (HBV) remains a world-wide source of infections and deaths. We develop a whole-cell computational platform combining spatial and kinetic models describing the infection cycle of HBV in a hepatocyte host. We simulate key parts of the infection cycle with this whole-cell platform for 10 min of biological time, to predict infection progression, map out virus-host and virus-drug interactions. We find that starting from an established infection, decreasing the copy number of the viral envelope proteins shifts the dominant infection pathway from capsid secretion to re-importing the capsids into the nucleus, resulting in more nuclear-localized viral covalently closed circular DNA (cccDNA) and boosting transcription. This scenario can mimic the consequence of drugs designed to manipulate viral gene expression. Mutating capsid proteins facilitates capsid destabilization and disassembly at nuclear pore complexes, resulting in an increase in cccDNA copy number. However, excessive destabilization leads to premature cytoplasmic disassembly and does not increase the cccDNA counts. Finally, our simulations can predict the best drug dosage and its administration timing to reduce the cccDNA counts. Our adaptable computational platform can be parameterized to study other viruses and identify the most central viral pathways that can be targeted by drugs.

Racial Disparities in Pediatric Mortality Following Transfusion Within 72 Hours of Operation.

BACKGROUND: Postoperative bleeding and transfusion are correlated with mortality risk. Furthermore, postoperative bleeding may often initiate the cascade of complications that leads to death. Given that minority children have increased risk of surgical complications, this study aimed to investigate the association of race with pediatric surgical mortality following postoperative transfusion. METHODS: We used the NSQIP-P PUF to assemble a retrospective cohort of children <18 who underwent inpatient surgery during 2012-2021. We included White, Black, Hispanic, and 'Other' children who received a transfusion within 72 h of surgery. The primary outcome was defined as all-cause mortality within 30 days following the primary surgical procedure. Using logistic regression models, we estimated the risk-adjusted odds ratio (aOR) and 95% confidence intervals (CI) of mortality, comparing each racial/ethnic cohort to White children. RESULTS: A total of 466,230 children <18 years of age underwent inpatient surgical procedures from 2012 to 2021. Of these, 46,200 required transfusion and were included in our analysis. The majority of patients were non-Hispanic White (64.6%, n = 29,850), while 18.9% (n = 8752) were non-Hispanic Black, 11.7% (n = 5387) were Hispanic, and 4.8% (n = 2211) were 'Other' race. The overall rate of mortality following transfusion was 2.5%. White children had the lowest incidence of mortality (2.0%), compared to children of 'Other' race (2.5%), Hispanic children (3.1%), and Black children (3.6%). After adjusting for sex, age, comorbidities, case status, preoperative transfusion within 48 h, and year of operation, we found that Black children experienced 1.24 times the odds of mortality following a postoperative transfusion compared to a White child (aOR: 1.24; 95%CI, 1.03-1.51; P = 0.025). Hispanic children were also significantly more likely to die following a postoperative transfusion than White children (aOR: 1.19; 95%CI, 1.02-1.39; P = 0.027). CONCLUSION: We found that minority children who required a postoperative transfusion had a higher odds of death than White children. Future studies should explore adverse events following postoperative transfusion and the differences in their management by race that may contribute to the higher mortality rate for minority children. LEVEL OF EVIDENCE: Level II. CLINICAL TRIAL NUMBER AND REGISTRY: Not applicable.