Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia.

BACKGROUND AND AIMS: The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study. APPROACH AND RESULTS: Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0-12.4) in PROBE and 8.0% (5.2-11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST-to-platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant-free survival at 5 years was 45.1% (40.5-49.6) in PROBE and 79.2% (74.1-83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH. CONCLUSIONS: The low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH.

Factors associated with thrombotic and hemorrhagic complications in pediatric liver transplant: A multi-center analysis from the Starzl Network for Excellence in Pediatric Transplantation.

BACKGROUND: Survival after pediatric liver transplantation (PLT) is negatively impacted by thrombotic and hemorrhagic complications. Limited data exists regarding factors associated with these complications and utilization of anticoagulation. METHODS: Retrospective review of donor, recipient variables and outcomes from four centers participating in the Starzl Network for Excellence in Pediatric Transplantation. RESULTS: 76 PLT included 39 (51%) technical variant transplants, with mean follow-up 628 ± 193.6 days. Median age/weight at transplant were 59.3 ± 53.8 months and 19.6 ± 17.2 kg. Seven (9.2%) transplants experienced intraoperative hepatic artery thrombosis (iHAT), all successfully corrected. Four HAT recurred postoperatively on POD 1,7,8 and 616. All three portal vein thromboses (PVT) occurred on POD1. Anticoagulation protocols were initiated intraoperatively in 50 and postoperatively in 66 and were active for all thrombotic and hemorrhagic events. Two patients were re-transplanted for HAT. Two patients died without having thrombotic or hemorrhagic complications. iHAT and post-operative HAT were associated with lower hepatic arterial flows. iHAT was associated with donor variant anatomy, reduced allografts and intraoperative blood loss. Intraoperative ultrasound could not predict post-operative HAT nor PVT. Surgeon pre-operative concern regarding the native portal vein correlated with postoperative PVT. Lower hepatic arterial and portal flows, higher estimated blood losses, higher prothrombin time and use of arterial interposition grafts were associated with postoperative hemorrhagic complications. CONCLUSIONS: Thrombotic and hemorrhagic complications after pediatric liver transplant remain rare but significant events. Their occurrence can be predicted with pre-operative assessment of donor and recipient vascular anatomy and direct flow measurement but may not be predicted with ultrasound evaluation nor prevented with anticoagulation.

Feasibility of using a patient-reported outcome measure into clinical practice following pediatric liver transplantation: The Starzl Network experience.

BACKGROUND: Patient-reported outcome measures (PROMs) are not routinely used in clinical care by pediatric liver transplant (LT) teams. The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) assessed feasibility of using a disease-specific Quality of Life (QoL) questionnaire in the ambulatory setting at 10 SNEPT sites. METHODS: A mixed methods feasibility project assessing administration processes, barriers, and user experiences with the Pediatric Liver Transplant Quality of Life (PeLTQL) tool. Iterative processes sought stakeholder feedback across four phases (Pilot, Extended Pilot, Development of a Mobile App PeLTQL version, and Pilot App use). RESULTS: A total of 149 patient-parent dyads completed the PeLTQL during LT clinic follow-up. Clinicians, parents, and patients evaluated and reported on feasibility of operationalization. Only two of 10 SNEPT sites continued PeLTQL administration after the initial two pilot phases. Reasons include limited clinical time and available personnel aggravated by the COVID-19 pandemic. In response, a mobile application version of the PeLTQL was initiated. Providing PeLTQL responses electronically was "very easy" or "easy" as reported by 96% (22/23) parents. CONCLUSIONS: Administration of a PROM into post-pediatric LT clinical care was feasible, but ongoing utilization stalled. Use of a mobile app towards facilitating completion of the PeLTQL outside of clinic hours may address the time and work-flow barriers identified.

Determination of Fat-Free Mass Density and its Components in Older Hispanic Adults by In Vivo Methods.

The densitometry method estimates body composition based on cadaver reference values, mainly the fat-free mass density value of 1.100 g/cm3. However, several changes in fat-free mass components by aging, ethnicity, and excess adiposity could influence their density and affect body composition estimations. The present study aimed to compare the mean fat-free mass component values in older Hispanic adults to cadaver reference values. This cross-sectional study included a sample of 420 subjects aged ≥60 yr from northern Mexico. Fat-free mass was determined by the four-compartment model using air displacement plethysmography, the deuterium dilution technique, and dual-energy X-ray absorptiometry for body density, aqueous and mineral fractions of body weight, respectively. A 1-sample t test was used to compare the fat-free mass density and aqueous, mineral, and residue fractions of fat-free mass from subjects in the study to the assumed cadaver reference values. The mean fat-free mass density value for the total sample of older Hispanic adults (1.096 ± 0.011 g/cm3) was significantly (p < 0.001) lower than the assumed value of 1.100 g/cm3, except in obese older men. The mean aqueous fraction of fat-free mass (74.8 ± 3.3%) was higher than the assumed value of 73.8%, and the mean residue fraction of fat-free mass value was lower (18.3 ± 3.4%) than the reference value of 19.4%. Indeed, only the mean mineral fraction of fat-free mass value (6.8 ± 0.8%) was similar to the reference value. In the total sample, all characteristic mean fat-free mass values in these older Hispanic adults differed from cadaver reference values, except the mineral fraction of fat-free mass value.

Pretransplantation and Post-Transplantation Liver Disease Assessment in Adolescents Undergoing Isolated Heart Transplantation for Fontan Failure.

OBJECTIVE: To describe the assessment of Fontan-associated liver disease and determine the clinical and imaging measures that may identify hepatic morbidity risk in isolated heart transplantation candidates and trend those measures post-isolated heart transplantation. STUDY DESIGN: Retrospective analysis of pre-isolated heart transplantation and post-isolated heart transplantation Fontan-associated liver disease (FALD) status using blood tests, magnetic resonance imaging (MRI), and liver biopsy analysis within 6 months before isolated heart transplantation and 12 months after isolated heart transplantation in 9 consecutive patients with Fontan. Pre- and post-isolated heart transplantation standard laboratory values; varices, ascites, splenomegaly, thrombocytopenia (VAST) score; Fontan liver MRI score; liver biopsy scores; Model for End-stage Liver Disease (MELD); MELD excluding the International Normalized Ratio (MELD-XI); AST to platelet ratio index, and cardiac catheterization data were compared. RESULTS: Pretransplantation maximum MELD and MELD-XI was 15 and 16, respectively. Central venous pressures and VAST scores decreased significantly post-transplantation. In 5 paired studies, Fontan liver MRI score maximum was 10 pretransplantation and decreased significantly post-transplantation. Arterially enhancing nodules on MRI persisted in 2 patients post-transplantation. Pretransplantation and post-transplantation liver biopsy scores did not differ in 4 paired biopsy specimens. CONCLUSIONS: Patients with FALD and MELD <15, MELD-XI <16, Fontan liver MRI score <10, and VAST score ≤2 can have successful short-term isolated heart transplantation outcomes. Liver MRI and VAST scores improved post-transplantation. Post-transplantation liver biopsy scores did not change significantly. Pretransplantation liver biopsy demonstrating fibrosis alone should not exclude consideration of isolated heart transplantation. The persistence of hepatic vascular remodeling and fibrosis post-isolated heart transplantation suggests that continued surveillance for hepatic complications post-transplantation for patients with Fontan is reasonable.

Resolution of recurrent pediatric acute liver failure with liver transplantation in a patient with NBAS mutation.

BACKGROUND: Pediatric acute liver failure (PALF) remains an enigmatic process of rapid end-organ dysfunction associated with a variety of pathologic conditions though the predominant cause is indeterminate. A growing body of research has identified mutations in the NBAS gene to be associated with recurrent acute liver failure and multi-systemic disease including short stature, skeletal dysplasia, facial dysmorphism, immunologic abnormalities, and Pelger-Huët anomaly. METHODS AND RESULTS: Here, we describe a 4-year-old girl who presented with dehydration in the setting of acute gastroenteritis and fever but went on to develop PALF on day 2 of hospitalization. She clinically recovered with supportive measures, but after discharge, had at least 2 additional episodes of PALF. Ultimately, she underwent liver transplant and her recurrent episodes of PALF did not recur throughout a 6-year follow-up period. Whole-exome sequencing post-liver transplant initially revealed two variants of uncertain significance in the NBAS gene. Parental studies confirmed the c.1549C > T(p.R517C; now likely pathogenic) variant from her mother and a novel c.4646T > C(p.L1549P) variant from her father. In silico analyses predicted these variants to have a deleterious effect on protein function. Consistent with previously characterized NBAS mutation-associated disease (NMAD), our patient demonstrated the following features: progeroid facial features, hypoplasia of the 12th ribs, Pelger-Huët anomaly on peripheral blood smear, and abnormal B and NK cell function. CONCLUSION: Altogether, we describe a novel pathogenic variant in the NBAS gene of a patient with NMAD and report the resolution of recurrent PALF secondary to NMAD following liver transplantation.

Brincidofovir for the treatment of human adenovirus infection in pediatric solid organ transplant recipients: A case series.

HAdV viremia can cause significant morbidity among pediatric recipients of SOT with variability in incidence and severity of disease based on the type of allograft. Currently, there are no US FDA-approved treatments for HAdV infections, and historically, the mainstay of treatment has been decreasing immunosuppression, with antiviral therapies reserved for those with severe disease. We describe the treatment of four pediatric SOT recipients (two kidney, one combined kidney-liver, and one liver) presenting with HAdV disease at our institution using brincidofovir. Our case series highlights the variability in presentation and the potential for severe disease in pediatric SOT recipients as we review disease presentation, disease course, complications, and treatment with brincidofovir.

Racial disparities in presentation and outcomes of paediatric autoimmune hepatitis.

BACKGROUND & AIMS: Most studies on autoimmune hepatitis (AIH) in children are in predominantly Caucasian cohorts. Paediatric AIH in African Americans (AA) is understudied, with a dearth of clinical predictors of outcome, often leading to serious complications and even mortality. The aim of the study was to define disease presentation, progression, response to therapy and outcomes in paediatric AIH in a well-defined, large, single centre, demographically diverse population. METHODS: We conducted a review of patients with AIH who were followed at this tertiary liver transplant centre. Clinical and laboratory covariates were assessed with regard to disease presentation, progression and outcomes in AA vs Non-AA children. RESULTS: African Americans patients constituted 42% of this cohort. At 1-year follow-up, AA children were receiving significantly higher doses of steroids compared to non-AA. More AA presented with end-stage liver disease (ESLD) with high immunoglobulin G and GGT:platelet ratio. After adjusting for other risk factor variables like gender, age at presentation and ESLD, AA children were at 4.5 times higher risk for significant outcome liver transplant/death within the first 12 months of presentation. Post-transplant, recurrent AIH was seen in 50% of AA vs 8% in non-AA. CONCLUSIONS: African American patients with AIH are more likely to present with ESLD and have an increased early risk for transplantation with high likelihood of disease recurrence post-transplantation. Studies are needed to delineate factors such as inherent biology, genetics and access to care. Early referral and tailored immunosuppressive regimens are required for AA patients with AIH.

A learning health network for pediatric liver transplantation: Inaugural meeting report from the Starzl Network for Excellence in Pediatric Transplantation.

Learning Health Networks (LHN) improve the well-being of populations by aligning clinical care specialists, technology experts, patients and patient advocates, and other thought leaders for continuous improvement and seamless care delivery. A novel LHN focused on pediatric transplantation, the Starzl Network for Excellence in Pediatric Transplantation (SNEPT), convened its inaugural meeting in September 2018. Clinical care team representatives, patients, and patient families/advocates partnered to take part in educational sessions, pain point exercises, and project identification workshops. Participants discussed the global impact of transplant from both a population and individual perspective, identifying challenges and opportunities where the Starzl Network could work to improve outcomes at scale across a variety of transplant-related conditions.

A preliminary investigation of sleep quality and patient-reported outcomes in pediatric solid organ transplant candidates.

The current cross-sectional, single-center study aimed to examine sleep quality in a sample of adolescents awaiting solid organ transplantation and to explore associations between sleep quality and both health-related quality of life and barriers to adherence. Thirty adolescents between the ages of 12 and 18 years (M age = 15.26, SD = 1.89) who were awaiting transplantation participated in this study. Participants completed measures of sleep quality, health-related quality of life, and barriers to adherence. T test and correlational analyses were performed to examine study aims. Adolescents awaiting transplantation had significantly lower levels of overall sleep quality compared to published norms of healthy peers. Domains of sleep quality were positively related to emotional and psychosocial health-related quality of life. Sleep quality domains were also negatively related to adherence barriers. This study provides preliminary evidence demonstrating that sleep quality among transplant candidates is compromised, and that poor sleep quality is related to adolescents' functioning across a number of domains during the pretransplant period. Results highlight the clinical importance of assessing and targeting sleep functioning in adolescents awaiting transplantation in order to reduce the negative influence of suboptimal sleep on functioning during this vulnerable period.

Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA.

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; ß = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10-11 ), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10-9 ); genetic distances at HLA were greater than at random markers (P = 1.6 × 10-46 ). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10-10 ). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.

A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients.

BACKGROUND & AIMS: Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)-they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. METHODS: We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. RESULTS: The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1-2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). CONCLUSIONS: In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial.

OBJECTIVE: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00294684.

Multimethod Assessment of Medication Nonadherence and Barriers in Adolescents and Young Adults With Solid Organ Transplants.

Objective: To (a) examine levels of medication nonadherence in adolescent and young adult (AYA) solid organ transplant recipients based on AYA- and caregiver proxy-reported nonadherence to different medication types and the medication-level variability index (MLVI) for tacrolimus, and (b) examine associations of adherence barriers and AYA and caregiver emotional distress symptoms with reported nonadherence and the MLVI. Method: The sample included 47 AYAs (M age = 16.67 years, SD = 1.74; transplant types: 25% kidney, 47% liver, 28% heart) and their caregivers (94 total participants). AYAs and caregivers reported on AYAs' adherence barriers and their own emotional functioning. Nonadherence was measured with AYA self- and caregiver proxy-report and the MLVI for tacrolimus. Results: The majority of AYAs and caregivers denied nonadherence, with lower rates of nonadherence reported for antirejection medications. In contrast, 40% of AYAs' MLVI values indicated nonadherence to tacrolimus. AYAs and caregivers who verbally acknowledged nonadherence had more AYA barriers and greater caregiver emotional distress symptoms compared with those who denied nonadherence. AYAs with MLVIs indicating nonadherence had more barriers than AYAs with MLVIs indicating adherence. Conclusions: Multimethod nonadherence evaluations for AYA transplant recipients should assess objective nonadherence using the MLVI, particularly in light of low reported nonadherence rates for antirejection medications. Assessments should include adherence barriers measures, given associations with the MLVI, and potentially prioritize assessing barriers over gauging nonadherence via self- or proxy-reports. Caregiver emotional distress symptoms may also be considered to provide insight into family or environmental barriers to adherence.

Prevalence of prediabetes and modifiable factors in an ethnic group of Mexico: the Comcáac Project.

OBJECTIVE: To determine the prevalence of and modifiable factors associated with prediabetes in the Comcáac Indians. DESIGN: Cross-sectional study where prediabetes was defined using fasting plasma glucose, 2 h plasma glucose and glycated Hb (HbA1c). Physical, anthropometric and biochemical measurements, medical record, socio-economic, dietary and physical activity information were collected. The modifiable factors associated with prediabetes were assessed using multiple logistic regression. Settings Comcáac Indian communities of Punta Chueca and El Desemboque, Sonora, Mexico. SUBJECTS: Adults (n 227) aged 20 years or older. RESULTS: The sex- and age-adjusted prevalence (95 % CI) of prediabetes was 47·1 (40·8, 53·5) % in the overall population; age-adjusted prevalence was 47·3 (35·6, 59·0) % in men and 46·7 (39·1, 54·3) % in women. The modifiable factors associated with a risk of prediabetes (OR; 95 % CI) were light-intensity physical activity (per 1 h/week increase: 1·04; 1·01, 1·07) and insulin resistance (homeostasis model assessment of insulin resistance score >6·1 v. <4·1: 4·62; 1·37, 15·51). Increased consumption of a traditional dietary pattern based on fish and seafood, low-fat cereals, fruits and vegetables was a protective factor (0·49; 0·31, 0·79). All variables were modelled together and adjusted for age and sex. CONCLUSIONS: The high prediabetes prevalence found in the Comcáac community is alarming because it represents a large number of people who are at risk for type 2 diabetes. The identification of modifiable factors associated with prediabetes that are specific to this population may be useful for designing effective strategies to prevent prediabetes.

Successful liver transplantation for non-resectable desmoplastic nested spindle cell tumor complicated by Cushing's syndrome.

Desmoplastic spindle cell tumors of liver are rare tumors of low malignant potential characterized by well-demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma. While surgery remains the definitive treatment, there have been reports of tumor recurrence locally and metastasis which respond poorly to chemotherapy. Hepatic transplant has been attempted in cases of recurrence or large size of primary tumor. Long-term follow-up and imaging surveillance are required as these tumors have shown a tendency for recurrence many years after initial therapy.