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OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.
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Transplante de Fígado , Criança , Humanos , Masculino , Feminino , Estudos de Casos e Controles , Estudos Retrospectivos , Terapia de Imunossupressão , Rejeição de Enxerto/epidemiologia , Sistema de RegistrosRESUMO
BACKGROUND: Shortages of liver allografts for children awaiting transplantation have led to high LT waitlist mortality. Prior studies have shown that usage of TVG can reduce waiting time and waitlist mortality, but their use is not universal. We sought to compare patient and graft survival between WLG and TVG and to identify potential associated risk factors in a contemporary pediatric LT cohort. METHODS: We performed a retrospective analysis of patient survival, graft survival, and biliary and vascular complications for LT recipients <18 years old entered into the Society of Pediatric Liver Transplantation prospective multicenter database. RESULTS: Of 1839 LT recipients, 1029 received a WLG and 810 received a TVG from either a LD or a DD. There was no difference in patient survival or graft survival by graft type. Three-year patient survival and graft survival were 96%, 93%, and 96%, and 95%, 89%, and 92% for TVG-LD, TVG-DD, and WLG, respectively. Biliary complications were more frequent in TVG. Hepatic artery thrombosis was more frequent in WLG. Multivariate analysis revealed primary diagnosis was the only significant predictor of patient survival. Predictors for graft survival included time-dependent development of biliary and vascular complications. CONCLUSIONS: There were no significant differences in patient and graft survival based on graft types in this North American multi-center pediatric cohort. Widespread routine use of TVG should be strongly encouraged to decrease mortality on the waitlist for pediatric LT candidates.
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Doenças Cardiovasculares , Transplante de Fígado , Criança , Humanos , Adolescente , Estudos Retrospectivos , Estudos Prospectivos , Sobrevivência de Enxerto , Sistema de Registros , Doenças Cardiovasculares/etiologia , Fígado , Resultado do TratamentoRESUMO
Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.
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Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Transplante de Fígado , Idoso , Carcinoma Hepatocelular/patologia , Criança , Hepatoblastoma/patologia , Hepatoblastoma/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
Although transplant outcomes for biliary atresia (BA) have improved, there are few data to predict the risk of specific posttransplant complications. We therefore defined the impact of comorbidities in BA on posttransplant outcomes. Patients enrolled in the Society of Pediatric Liver Transplantation registry from 2011 to 2019 (n = 1034) were grouped by comorbidities of >1.0% incidence: any supplemental feeding, dialysis, other abdominal surgery (not Kasai portoenterostomy [KPE]), hepatopulmonary syndrome, and cardiac disease requiring intervention. Demographic and outcome data were compared using the Kruskal-Wallis, chi-square, and log-rank tests. Cox proportional hazards models and binary logistic regression were performed for modeling. Patients with BA with comorbidities comprised 77% (n = 799) of our cohort and had evidence of greater medical acuity, including higher calculated Pediatric End-Stage Liver Disease scores and hospitalizations in the intensive care unit before transplant (P < 0.001 for both) versus those without comorbidities. After transplant, patients with BA with comorbidities had more graft loss (P = 0.02), longer initial hospitalization and intubation (P < 0.001 for both), and increased rates of reoperation (P = 0.001) and culture-proven infection (P < 0.001) within 30 days after transplant. Only patients with BA with comorbidities on supplemental feed had increased rates of patient death (P = 0.02). Multivariate analysis identified lower z weight and higher creatinine as risk factors for graft and patient loss in patients with BA with comorbidities. Prior KPE was protective against culture-proven infection and vascular complications within 30 and 90 days, respectively. Patients with BA with comorbidities have evidence of higher medical acuity at transplant and reduced graft survival; however, they overall did not experience greater incidence of patient death. Our data provide organ-system-specific data to risk-stratify patients with BA and posttransplant outcomes.
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Atresia Biliar , Doença Hepática Terminal , Transplante de Fígado , Atresia Biliar/complicações , Atresia Biliar/epidemiologia , Atresia Biliar/cirurgia , Criança , Doença Hepática Terminal/complicações , Humanos , Lactente , Transplante de Fígado/efeitos adversos , Portoenterostomia Hepática/efeitos adversos , Diálise Renal , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
With advances in surgical techniques, medical management, and more equitable allocation systems, children who receive a liver transplantation (LT) today can expect remarkable outcomes early after LT. However, beyond 1 year after transplant, attrition rates have not improved. We reviewed two separate eras (Era 1: January 1995-June 2004 vs. Era 2: July 2004-March 2018) of the Society of Pediatric Liver Transplantation registry to explore the evolution and associated factors contributing to late graft loss (LGL) and late mortality (LM). The fraction of long-term pediatric LT recipients surviving after 1 year with their first graft significantly improved (81.5% in Era 1 vs. 85.7% in Era 2; p < 0.0001). This improvement occurred despite significant changes in patient selection toward higher risk populations (p < 0.001) and without notable improvement in perioperative complications such as hepatic artery thrombosis (p = 0.24) and early posttransplant reoperation (p = 0.94) that have historically contributed to poor late-allograft outcomes. Improved outcomes were associated with changes in patient characteristics and perioperative practices, which subsequently impacted both early post-LT complications as well as other sequalae known to contribute to adverse events in long-term pediatric LT recipients. In conclusion, despite significant changes in patient selection toward higher risk populations, and without notable improvement in several perioperative complications known to contribute to poor late-allograft outcomes, significant improvements in LGL and a trend toward improvement in LM was seen in a more contemporary cohort of children receiving an LT.
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Sobrevivência de Enxerto , Transplante de Fígado , Criança , Humanos , Transplante de Fígado/métodos , Reoperação , Fatores de Risco , Transplantados , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Dexamethasone is a synthetic glucocorticoid approved for treating disorders of various organ systems in both adult and pediatric populations. Currently, approved pediatric dosing recommendations are weight-based, but it is unknown whether differences in dexamethasone drug disposition and exposure exist for children with obesity. This study aimed to develop a population pharmacokinetic (PopPK) model for dexamethasone with data collected from children with obesity. Dexamethasone was given as either IV or oral/enteral administration, and a salt factor correction was used for dexamethasone sodium phosphate injection. A PopPK analysis using dexamethasone plasma concentration versus time was performed using the software NONMEM. A virtual population of 1000 children with obesity across three age groups was generated for dosing simulations. Data from 59 study participants with 82 PK plasma samples were used in the PopPK analysis. A one-compartment model with first-order absorption and the inclusion of total body weight as a covariate characterized the data. No other covariates were included in the PopPK model. Single and multiple IV dose(s) of 0.5 and 1 mg/kg every 8 h resulted in 68% or more of virtual children with obesity attaining simulated exposures that were within exposure ranges previously reported in adult studies. In conclusion, this was the first study to characterize dexamethasone's PopPK in children with obesity. Simulation results suggest that virtual children with obesity receiving oral doses of 0.5 and 1 mg/kg had generally comparable dexamethasone exposures as adult estimates. Additional studies are needed to characterize the dexamethasone's target exposure in children.
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Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.
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Dexmedetomidina , Hipnóticos e Sedativos , Modelos Biológicos , Humanos , Dexmedetomidina/farmacocinética , Dexmedetomidina/administração & dosagem , Dexmedetomidina/sangue , Lactente , Criança , Pré-Escolar , Adolescente , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/administração & dosagem , Masculino , Feminino , Adulto Jovem , Recém-Nascido , Estudos ProspectivosRESUMO
Currently, most licensed vaccines against SARS-CoV-2 infection are approved for adults and not for children. We conducted a test negative case-control study to assess the effectiveness of Measles Containing Vaccines (MCVs) against SARS-CoV-2 infection in Pune, India, in children who were ≥1 year and <18 years of age and were tested for SARS-CoV-2 infection by Reverse transcription polymerase chain reaction (RT-PCR). The enrolled participants included 274 SARS-CoV-2 positive cases (216 vaccinated and 58 unvaccinated) along with 274 SARS-CoV-2 negative controls (265 vaccinated and 9 unvaccinated). Of the 274 cases, 180 (65.7%) were asymptomatic while 94 (34.3%) were symptomatic, all with mild severity. The number of participants with symptomatic SARS-CoV-2 infection was significantly lower in the vaccinated group compared to the unvaccinated group (p < .0001). The unadjusted overall Vaccine Effectiveness (VE) in the vaccinated group compared to unvaccinated group was 87.4% (OR = 0.126, 95% CI of VE: 73.9-93.9) while the adjusted overall VE after adjusting for age and sex was 87.5% (OR = 0.125, 95% CI of VE: 74.2-94.0). MCVs reduced incidence of laboratory confirmed SARS-CoV-2 infection in children. Number of symptomatic cases were also lower in the vaccinated group compared to the unvaccinated group. Results of our study have provided strong preliminary evidence that MCVs have a good effectiveness against SARS-CoV-2 infection in the pediatric population, which needs to be confirmed further through prospective randomized clinical trials.
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COVID-19 , Sarampo , Adulto , Vacinas contra COVID-19 , Estudos de Casos e Controles , Criança , Humanos , Índia/epidemiologia , Estudos Prospectivos , SARS-CoV-2 , Resultado do TratamentoRESUMO
Smaller organisms may have too little tissue to allow assaying as individuals. To get a sufficient sample for assaying, a collection of smaller individual organisms is pooled together to produce a simple observation for modeling and analysis. When a dataset contains a mix of pooled and individual organisms, the variances of the observations are not equal. An unweighted regression method is no longer appropriate because it assumes equal precision among the observations. A weighted regression method is more appropriate and yields more precise estimates because it incorporates a weight to the pooled observations. To demonstrate the benefits of using a weighted analysis when some observations are pooled, the bias and confidence interval (CI) properties were compared using an ordinary least squares and a weighted least squares t-based confidence interval. The slope and intercept estimates were unbiased for both weighted and unweighted analyses. While CIs for the slope and intercept achieved nominal coverage, the CI lengths were smaller using a weighted analysis instead of an unweighted analysis, implying that a weighted analysis will yield greater precision.