Nearly half a billion dollars in resources are lost each time a drug candidate is withdrawn from the market by the Food and Drug Administration (FDA) for reasons of liver toxicity. The number of late-phase drug developmental failures due to liver toxicity could potentially be reduced through the use of hepatocyte-based systems capable of modeling the response of in vivo liver tissue to toxic insults. With this article, we report progress toward the goal of realizing an array of primary hepatocytes for use in high-throughput liver toxicity studies. Described herein is the development of a 64 (8 x 8) element array of microfluidic wells capable of supporting micropatterned primary rat hepatocytes in coculture with 3T3-J2 fibroblasts. Each of the wells within the array was continuously perfused with medium and oxygen in a nonaddressable format. The key features of the system design and fabrication are described, including the use of two microfluidic perfusion networks to provide the coculture with an independent and continuous supply of cell culture medium and oxygen. Also described are the fabrication techniques used to selectively pattern hepatocytes and 3T3-J2 fibroblasts within the wells of the array. The functional studies used to demonstrate the synthetic and metabolic capacity of the array are outlined in this article. These studies demonstrate that the hepatocytes contained within the array are capable of continuous, steady-state albumin synthesis (78.4 microg/day, sigma = 3.98 microg/day, N = 8) and urea production (109.8 microg/day, sigma = 11.9 microg/day, N = 8). In the final section of the article, these results are discussed as they relate to the final goal of this research effort, the development of an array of primary hepatocytes for use in physiologically relevant toxicology studies.
Purpose The purpose of this study was to examine risk-adjusted associations between race and gender on postoperative morbidity, mortality, and resource utilization in pediatric surgical patients within the United States. Methods 91,891 pediatric surgical patients were evaluated using the U.S. national KID Inpatient Database (2003 and 2006): appendectomy (81.2%), pyloromyotomy (9.8%), intussusception (6.2%), decortication (1.9%), congenital diaphragmatic hernia repair (0.7%), and colonic resection for Hirschsprung’s disease (0.2%). Patients were stratified according to gender (male: 62.6%, n=57,557) and race: white (n=52,334), Hispanic (n=25,697), black (n=6,951), Asian (n=1,855), Native American (n=470), and other (n=4,584). Multivariable logistic regression modeling was utilized to evaluate risk-adjusted associations between race, gender, and outcomes. Results After risk-adjustment, race was independently associated with in-hospital death (p=0.02), with an increased risk for black children. Gender was not associated with mortality (p=0.77). Post-operative morbidity was significantly associated with gender (p<0.001) and race (p=0.008). Gender (p=0.003) and race (p<0.001) were further associated with increased hospital length of stay. Importantly, these results were dependent on operation type. Conclusion Race and gender significantly affect post-operative outcomes following pediatric surgery. Black patients are at disproportionate risk for post-operative mortality, while black and Hispanic patients have increased morbidity and hospital resource utilization. While gender does not affect mortality, gender is a determinant of both post-operative morbidity and increased resource utilization.
Purpose Current healthcare reform efforts have highlighted the potential impact of insurance status on patient outcomes. The influence of primary payer status (PPS) within the pediatric surgical patient population remains unknown. The purpose of this study was to examine risk-adjusted associations between PPS and postoperative morbidity, mortality, and resource utilization in pediatric surgical patients within the United States. Methods A weighted total of 153,333 pediatric surgical patients were evaluated using the national Kids’ Inpatient Database (2003 and 2006): appendectomy, intussusception, decortication, pyloroplasty, congenital diaphragmatic hernia repair, and colonic resection for Hirschsprung’s disease. Patients were stratified according to PPS: Medicare (n=180), Medicaid (n=51, 862), uninsured (n=12,539), and private insurance (n=88,753). Multivariable hierarchical regression modeling was utilized to evaluate risk-adjusted associations between PPS and outcomes. Results Overall median patient age was 12 years, operations were primarily non-elective (92.4%), and appendectomies accounted for the highest proportion of cases (81.3%). After adjustment for patient, hospital, and operation-related factors, PPS was independently associated with in-hospital death (p<0.0001) and postoperative complications (p<0.02), with increased risk for Medicaid and uninsured populations. Moreover, Medicaid PPS was also associated with greater adjusted lengths of stay and total hospital charges (p<0.001). Importantly, these results were dependent on operation type. Conclusions Primary payer status is associated with risk-adjusted postoperative mortality, morbidity, and resource utilization among pediatric surgical patients. Uninsured patients are at increased risk for postoperative mortality while Medicaid patients accrue greater morbidity, hospital lengths of stay, and total charges. These results highlight a complex interaction between socioeconomic and patient-related factors, and primary payer status should be considered in the preoperative risk stratification of pediatric patients.
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