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Background Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. Areas of uncertainty The etiopathogenesis of PSC remains an enigma. Data sources We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. Results We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. Therapeutic hypothesis We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.

Introduction Understanding how soldiers die after separation from military service, particularly those who die shortly after separating from service, may help to identify opportunities to ease transitions to civilian life. Materials and Methods Mortality data were analyzed for male U.S. Army soldiers who died within 18 months of their separation from service (from 1999 to 2011). Descriptive statistics were calculated for natural, accidental, suicidal, homicidal, undetermined, and legal/operation of war deaths and were stratified by age, component, time in service, and type of discharge. Crude and age-adjusted mortality rates, standardized for all years using the 2004 Regular Army population, were also calculated. The Public Health Review Board of the U.S. Army Public Health Center approved this study as Public Health Practice. Results Of the 1,884,653 male soldiers who separated from service during the study period, 3,819 died within 18 months of separation. A majority of all separations were Reserve or National Guard (58%), and 62% of decedents were in the Reserve or National Guard. Deaths from natural causes (38%) were the most common, followed by accident deaths (34%), suicides (20%), homicides (6%), undetermined deaths (2%), and legal/operation of war deaths ( Conclusions The time period immediately following separation from the Army presents a unique challenge for many soldiers. Developing more effective pre-separation prevention programs that target specific risks requires knowing the causes of death for natural deaths, suicides, and accidents. Over half of all deaths occurring shortly after separation from service are preventable. Continued surveillance of specific causes of preventable deaths following separation can improve pre-separation prevention programs and transitions to post-service care.

OBJECTIVE To estimate the financial burden to the U.S. Army of suicide by enlisted Soldiers during their first year of service. METHODS This analysis included new Army enlisted Soldiers who started initial entry training from October 2012 through September 2016 and subsequently died by suicide within their first year of service. Outpatient and inpatient direct medical, direct nonmedical, recruiting, and training costs to the Army were calculated. RESULTS During the 48-month observational study period, 29 Soldiers died by suicide within their respective first year of service. The described financial costs accrued by the Army as a result of these deaths were $152,271-with an average of $6,091 per healthcare utilizer. Recruiting and training costs were $1,115,860 for all suicide cases. CONCLUSION Average direct cost per healthcare utilizer increased during a Soldier's first year of service. This may be associated with the transition through different phases of training and to the first operational duty station. PUBLIC HEALTH IMPLICATIONS Results obtained through this cost-of-illness analysis may serve as baseline metrics to inform future cost-effectiveness studies.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient’s response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.

Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV.Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline.30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (totalIn PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

We used administrative data to examine predictors of medically documented suicide ideation among Regular Army soldiers from 2006 through 2009 (n=10,466 ideators, 124,959 control person-months). Enlisted ideators (97.8% of all cases) were more likely than controls to be female, younger, older when entering service, less educated, never or previously deployed, and have a recent mental health diagnosis. Officer ideators were more likely than controls to be female, younger, younger when entering service, never married, and have a recent mental health diagnosis. Risk among enlisted soldiers peaked in the second month of service and declined steadily, whereas risk among officers remained relatively stable over time. Risk of suicide ideation is highest among enlisted soldiers early in Army service, females, and those with a recent mental health diagnosis.

Debate continues about the accuracy of military suicide reporting due to concerns that some suicides may be classified as accidents to minimize stigma and ensure survivor benefits. We systematically reviewed records for 998 active duty Army deaths (510 suicides; 488 accident, homicide and undetermined deaths; 2005-2009) and, using research criteria, reclassified 8.2% of the non-suicide cases to definite suicide (1), suicide probable (4), or suicide possible (35). The reclassification rate to definite suicide was only 0.2% (1/488). This low rate suggests that flagrant misclassification of Army deaths is uncommon and surveillance reports likely reflect the “true” population of Army suicides.

BackgroundCivilian suicide rates vary by occupation in ways related to occupational stress exposure. Comparable military research finds suicide rates elevated in combat arms occupations. However, no research has evaluated variation in this pattern by deployment history, the indicator of occupation stress widely considered responsible for the recent rise in the military suicide rate.MethodThe joint associations of Army occupation and deployment history in predicting suicides were analysed in an administrative dataset for the 729 337 male enlisted Regular Army soldiers in the US Army between 2004 and 2009.ResultsThere were 496 suicides over the study period (22.4/100 000 person-years). Only two occupational categories, both in combat arms, had significantly elevated suicide rates: infantrymen (37.2/100 000 person-years) and combat engineers (38.2/100 000 person-years). However, the suicide rates in these two categories were significantly lower when currently deployed (30.6/100 000 person-years) than never deployed or previously deployed (41.2–39.1/100 000 person-years), whereas the suicide rate of other soldiers was significantly higher when currently deployed and previously deployed (20.2–22.4/100 000 person-years) than never deployed (14.5/100 000 person-years), resulting in the adjusted suicide rate of infantrymen and combat engineers being most elevated when never deployed [odds ratio (OR) 2.9, 95% confidence interval (CI) 2.1–4.1], less so when previously deployed (OR 1.6, 95% CI 1.1–2.1), and not at all when currently deployed (OR 1.2, 95% CI 0.8–1.8). Adjustment for a differential ‘healthy warrior effect’ cannot explain this variation in the relative suicide rates of never-deployed infantrymen and combat engineers by deployment status.ConclusionsEfforts are needed to elucidate the causal mechanisms underlying this interaction to guide preventive interventions for soldiers at high suicide risk.

Purpose of study Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. Methods used Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. Summary of results Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24–48 h were 53 mcmol/l and 62 mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3 months and 5 months. The patients show normal development at ages 7 and 3 years. Conclusion Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Background and aims PSC is an autoimmune biliary inflammatory disorder that is often associated with inflammatory bowel disease (IBD), with 50%-75% of patients with PSC having coexisting IBD, most commonly ulcerative colitis. Currently, no medical therapies have been shown to improve the disease course or slow its progression. However, ongoing research has resulted in a growing interest in the use of antibiotics for treatment of PSC, of which vancomycin is the most studied. In this review, we summarise the current evidence on the use of vancomycin in PSC and comment on future research areas of interest. Methods A comprehensive PUBMED and EMBASE literature search for articles on vancomycin, PSC, therapeutic options and microbiome was performed. Results Two randomised clinical trials, three case series and two case reports were included in the study. These include uncontrolled data from at least 98 patients that include promising improvements in biochemistry and imaging. Optimal dosing regimens are unclear. Conclusion Vancomycin is one of the most studied antibiotics used in the treatment of PSC with promising results. There is not currently sufficient evidence to support treatment recommendations. Further research is needed to establish if vancomycin is a PSC treatment.

Accidents are a leading cause of deaths in U.S. active duty personnel. Understanding accident deaths during wartime could facilitate future operational planning and inform risk prevention efforts. This study expands prior research, identifying health risk factors associated with U.S. Army accident deaths during the Afghanistan and Iraq war. Military records for 2004-2009 enlisted, active duty, Regular Army soldiers were analyzed using logistic regression modeling to identify mental health, injury, and polypharmacy (multiple narcotic and/or psychotropic medications) predictors of accident deaths for current, previously, and never deployed groups. Deployed soldiers with anxiety diagnoses showed higher risk for accident deaths. Over half had anxiety diagnoses prior to being deployed, suggesting anticipatory anxiety or symptom recurrence may contribute to high risk. For previously deployed soldiers, traumatic brain injury (TBI) indicated higher risk. Two-thirds of these soldiers had first TBI medical-encounter while non-deployed, but mild, combat-related TBIs may have been undetected during deployments. Post-Traumatic Stress Disorder (PTSD) predicted higher risk for never deployed soldiers, as did polypharmacy which may relate to reasons for deployment ineligibility. Health risk predictors for Army accident deaths are identified and potential practice and policy implications discussed. Further research could test for replicability and expand models to include unobserved factors or modifiable mechanisms related to high risk. PTSD predicted high risk among those never deployed, suggesting importance of identification, treatment, and prevention of non-combat traumatic events. Finally, risk predictors overlapped with those identified for suicides, suggesting effective intervention might reduce both types of deaths.

Background Accidents are one of the leading causes of death among U.S. active-duty Army soldiers. Evidence-based approaches to injury prevention could be strengthened by adding person-level characteristics (e.g., demographics) to risk models tested on diverse soldier samples studied over time. Purpose To identify person-level risk indicators of accident deaths in Regular Army soldiers during a time frame of intense military operations, and to discriminate risk of not-line-of-duty from line-of-duty accident deaths. Methods Administrative data acquired from multiple Army/Department of Defense sources for active duty Army soldiers during 2004−2009 were analyzed in 2013. Logistic regression modeling was used to identify person-level sociodemographic, service-related, occupational, and mental health predictors of accident deaths. Results Delayed rank progression or demotion and being male, unmarried, in a combat arms specialty, and of low rank/service length increased odds of accident death for enlisted soldiers. Unique to officers was high risk associated with aviation specialties. Accident death risk decreased over time for currently deployed, enlisted soldiers and increased for those never deployed. Mental health diagnosis was associated with risk only for previous and never-deployed, enlisted soldiers. Models did not discriminate not-line-of-duty from line-of-duty accident deaths. Conclusions Adding more refined person-level and situational risk indicators to current models could enhance understanding of accident death risk specific to soldier rank and deployment status. Stable predictors could help identify high risk of accident deaths in future cohorts of Regular Army soldiers.

Background Clinic no shows (NS) create a lost opportunity for provider–patient interaction and impose a financial burden to the healthcare system and on society. We aimed to: (1) to determine the clinical and demographic factors associated with increased NS rates at a children's hospital's subsubspecialty clinics and (2) to estimate the direct institutional financial costs associated with NS events. Methods A comprehensive database was generated from all clinic encounters for 15 subspecialty outpatient clinics (five surgical and 10 medical) between September 12, 2005 and December 30, 2010. Multivariate logistic regressions were performed to identify the variables associated with NS events. Direct costs of NS events were estimated using annual revenue for each clinic. Results A total of 284,275 encounters and 17,024 NS events were available for analysis. Public insurance coverage (Medicaid and Title V), compared to private insurance or self-pay status, was associated with an increased likelihood NS (OR 2.19, 95% CI 2.10–2.28, p < 0.0005 for Medicaid; OR 1.56, 95% CI 1.50–1.62, p < 0.0005 for Title V). Compared to patients 21–30 years of age, patients

Improvised explosive devices (IEDs) were a prominent and initially new threat in the Iraq and Afghanistan war which raised concerns and anticipatory fear in and out of theater. This study examined the association of monthly IED rates with risk of soldier suicide attempt among those deployed and nondeployed.Person-month records for all active duty Regular Army suicide attempters from 2004 through 2009 (n = 9,791) and an equal-probability sample of control person-months (n = 183,826) were identified. Logistic regression analyses examined soldiers' risk of attempting suicide as a function of monthly IED frequency, controlling for sociodemographics, service-related characteristics, rate of deployment/redeployment, and combat deaths and injuries. The association of IED frequency with suicide attempt was examined overall and by time in service and deployment status.Soldiers' risk of suicide attempt increased with increasing numbers of IEDs. Suicide attempt was 26% more likely for each 1,000 IED increase in monthly frequency (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.22-1.30). The association of IED frequency with suicide attempt was greater for soldiers in their first 2 years of service (OR = 1.30, 95% CI = 1.25-1.36) than for those with 3 or more years of service (OR = 1.18, 95% CI = 1.12-1.24). Among soldiers in their first 2 years of service, the association was constant, regardless of deployment status (χTo our knowledge, this is the first study to examine and demonstrate an association between the aggregate frequency of IEDs and risk of suicide attempts among U.S. Army soldiers. This association was observed across deployment status and time in service, and for early-career soldiers in particular. The findings suggest that the threat of new weapons may increase stress burden among soldiers. Targeting risk perception and perceived preparedness, particularly early in a soldier's career, may improve psychological resilience and reduce suicide risk.

Objectives Pediatric liver transplant (OLT) patients are at risk of posttransplant lymphoproliferative disease (PTLD) from Epstein-Barr virus (EBV). This study examined the impact of induction and immunosuppression on EBV viremia. Methods A retrospective chart review was performed on 197 pediatric patients and induction regimen, immunosuppression levels, and EBV viremia were documented for 1 year post-OLT. Logistic regression models determined associations between induction, immunosuppression, and EBV. Results Fifty six percent of patients developed EBV viremia. Incidence of EBV viremia was 73% with antithymocyte globulin (ATG), 63% with daclizumab, and 39% for neither, though the trend was not significant [ATG: odds ratio (OR) 0.19; 95% confidence interval (CI) 0.024–1.58; P = .125; daclizumab OR; 1.07; 95% CI 0.270–4.23; P = .925]. Tacrolimus immunosuppression levels were supratherapeutic 28.7% of the time; however, only supratherapeutic tacrolimus levels between 0 and 2 weeks increased EBV viremia at 2 to 4 weeks post-OLT (OR 1.80; 95% CI 1.10–2.94; P = .02). Three patients developed PTLD. Conclusions The use of ATG and daclizumab induction likely does not play a role in the development of EBV viremia. Supratherapeutic tacrolimus levels 0 to 2 weeks post-OLT impact the development of EBV viremia at 2 to 4 weeks. The incidence of PTLD was low, suggesting better EBV and immunosuppression monitoring plays an important role in reducing PTLD.

Importance Suicide attempts in the US Army have risen in the past decade. Understanding the association between suicide attempts and deployment, as well as method and timing of suicide attempts, can assist in developing interventions. Objective To examine suicide attempt risk factors, methods, and timing among soldiers currently deployed, previously deployed, and never deployed at the time this study was conducted. Design, Setting, and Participants This longitudinal, retrospective cohort study of Regular Army–enlisted soldiers on active duty from 2004 through 2009 used individual-level person-month records to examine risk factors (sociodemographic, service related, and mental health), method, and time of suicide attempt by deployment status (never, currently, and previously deployed). Administrative data for the month before each of 9650 incident suicide attempts and an equal-probability sample of 153 528 control person-months for other soldiers were analyzed using a discrete-time survival framework. Main Outcomes and Measures Suicide attempts and career, mental health, and demographic predictors were obtained from administrative and medical records. Results Of the 9650 enlisted soldiers who attempted suicide, 86.3% were male, 68.4% were younger than 30 years, 59.8% were non-Hispanic white, 76.5% were high school educated, and 54.7% were currently married. The 40.4% of enlisted soldiers who had never been deployed (n = 12 421 294 person-months) accounted for 61.1% of enlisted soldiers who attempted suicide (n = 5894 cases). Risk among those never deployed was highest in the second month of service (103 per 100 000 person-months). Risk among soldiers on their first deployment was highest in the sixth month of deployment (25 per 100 000 person-months). For those previously deployed, risk was highest at 5 months after return (40 per 100 000 person-months). Currently and previously deployed soldiers were more likely to attempt suicide with a firearm than those never deployed (currently deployed: OR, 4.0; 95% CI, 2.9-5.6; previously deployed: OR, 2.7; 95% CI, 1.8-3.9). Across deployment status, suicide attempts were more likely among soldiers who were women (currently deployed: OR, 3.4; 95% CI, 3.0-4.0; previously deployed: OR, 1.5; 95% CI, 1.4-1.7; and never deployed: OR, 2.4; 95% CI, 2.3-2.6), in their first 2 years of service (currently deployed: OR, 1.9; 95% CI, 1.5-2.3; previously deployed: OR, 2.2; 95% CI, 1.9-2.7; and never deployed: OR, 3.1; 95% CI, 2.7-3.6), and had a recently received a mental health diagnosis in the previous month (currently deployed: OR, 29.8; 95% CI, 25.0-35.5; previously deployed: OR, 22.2; 95% CI, 20.1-24.4; and never deployed: OR, 15.0; 95% CI, 14.2-16.0). Among soldiers with 1 previous deployment, odds of a suicide attempt were higher for those who screened positive for depression or posttraumatic stress disorder after return from deployment and particularly at follow-up screening, about 4 to 6 months after deployment (depression: OR, 1.4; 95% CI, 1.1–1.9; posttraumatic stress disorder: OR, 2.4; 95% CI, 2.1–2.8). Conclusions and Relevance Identifying the timing and risk factors for suicide attempt in soldiers requires consideration of environmental context, individual characteristics, and mental health. These factors can inform prevention efforts.

To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.

Objective. This article aims to examine whether words listed in reasons for appointments could effectively predict laboratory-verified influenza cases in syndromic surveillance systems. Methods. Data were collected from the Armed Forces Health Longitudinal Technological Application medical record system. We used 2 algorithms to combine the impact of words within reasons for appointments: Dependent (DBSt) and Independent (IBSt) Bayesian System. We used receiver operating characteristic curves to compare the accuracy of these 2 methods of processing reasons for appointments against current and previous lists of diagnoses used in the Department of Defense’s syndromic surveillance system. Results. We examined 13,096 cases, where the results of influenza tests were available. Each reason for an appointment had an average of 3.5 words (standard deviation = 2.2 words). There was no difference in performance of the 2 algorithms. The area under the curve for IBSt was 0.58 and for DBSt was 0.56. The difference was not statistically significant (McNemar statistic = 0.0054; P = 0.07). Conclusions. These data suggest that reasons for appointments can improve the accuracy of lists of diagnoses in predicting laboratory-verified influenza cases. This study recommends further exploration of the DBSt algorithm and reasons for appointments in predicting likely influenza cases.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE.Eosinophils and CD3+ lymphocytes were identified directly from 50 μL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset.Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P0.05).Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

Park KT, Nanda P, Bensen R, Strichartz D, Esquivel C, Cox K. Effects of rural status on health outcomes in pediatric liver transplantation: A single center analysis of 388 patients. Pediatr Transplantation 2011: 15: 300–305. © 2011 John Wiley & Sons A/S. Abstract: Rural status of patients may impact health before and after pediatric LT. We used UI codes published by the USDA to stratify patients as urban or rural depending county residence. A total of 388 patients who had LT and who met criteria were included. Rejection, PTLD, and survival were used as primary outcome measures of post-LT health. UNOS Status 1 and PELD/MELD scores >20 were used as secondary outcome measures of poorer pre-LT health. Logistic regression models were run to determine associations. We did not find any statistically significant differences in pre- or post-LT outcomes with respect to rurality. Among rural patients, there was a general trend for decreased incidence of rejection (25.0% vs. 33.4%; OR 0.64, 95% CI 0.29–1.44), increased risk of PTLD (5.6% vs. 3.4%; OR 1.86, 95% CI 0.36–3.31), and decreased survival (OR 0.85, 95% CI 0.34–2.13) after LT. Rural patients also tended to be sicker at the time of LT than patients from urban areas, with increased proportion of Status 1 (OR 1.17, 95% CI 0.51–2.70) and PELD/MELD scores >20 (OR 1.20, 95% CI 0.59–2.45). From a single center experience, we conclude that rurality did not significantly affect health outcomes after LT, although a larger study may validate the general trends that rural patients may have decreased rejection, increased PTLD, and mortality, and be in poorer health at the time of LT.

Tolerance has been defined as stable graft function off IMS. We reviewed the data of 369 pediatric liver transplant patients to examine demographic differences that may have a PV of pediatric LT tolerance. Of the 369 patients, 280 patients were stable with detectable blood levels of IMS agents and with good graft function without biopsy proven REJ > 1 yr posttransplantation, 18 patients were noted to be TOL off IMS, 27 patients were taking MIS with drug levels below detectable range by standard laboratory parameters, and 44 patients developed one or more episodes of biopsy proven acute or chronic REJ > 1 yr post-transplantation. Variables, including percentage of biliary atresia, type of transplanted organ, history of EBV infection, patient and donor gender, and ABO blood type mismatch between recipient and donor did not have PV of tolerance. Average age in years was 1.37 ± 1.53 (0.3-4.9) for TOL, 1.14 ± 0.89 (0.4-3.1) for MIS and 3.35 ± 4.45 (0.3-16) for REJ. Age difference of TOL/MIS vs. REJ was significant (p =0.002) and TOL vs. REJ was significant (0.01). Age at the time of transplantation is an important predictor in the development of pediatric LT tolerance.

Background Human leukocyte antigen (HLA)-G displays immunotolerogenic properties toward the main effector cells involved in graft rejection through inhibition of natural killer cell- and cytotoxic T-lymphocyte-mediated cytolysis, and CD4 T-cell alloproliferation. An increase in serum and graft levels of HLA-G has been noted in transplant patients with improved allograft survival. However, the clinical relevance of soluble serum HLA-G molecules in tolerant pediatric and young adult liver transplant patients remains to be studied. Methods We examined the serum HLA-G levels in 42 pediatric and young adult liver transplant patients with a mean age of 15 years; 13 patients had operational tolerance (TOL), with complete immunosuppression withdrawal for 2.3 to 13.2 years. Results Median HLA-G level in patients with acute rejection (AR) was similar to the level in pediatric healthy volunteers (9.9 vs. 4.2 U/mL, P=0.13). HLA-G was higher in patients with stable liver function on immunosuppression (54.6 U/mL) than in patients with AR (P=0.01) and healthy volunteers (P=0.003), but almost 6-fold lower than in TOL patients (325.4 U/mL). HLA-G did not correlate with clinical confounders or a history of posttransplant lymphoproliferative disease or Epstein-Barr virus; although levels in the TOL group were negatively correlated with time after immunosuppression withdrawal (r=-0.75, P=0.003). In rejectors, HLA-G levels trended to negatively correlate with a higher number (r=-0.58) and greater severity of AR episodes (r=-0.56) after 1 year posttransplantation. Conclusions Increased serum HLA-G levels track with operational tolerance of liver grafts and support favorable outcomes in pediatric and young adult recipients.

OBJECTIVE The aim of the study was to investigate whether eosinophils have increased human leukocyte antigen (HLA)-DR expression in subjects with eosinophilic esophagitis (EoE) compared with controls. PATIENTS AND METHODS Patients who were undergoing an upper endoscopy with biopsies for suspected gastroesophageal reflux disease (GERD) or EoE at Lucile Packard Children's Hospital were enrolled. In total, the blood and tissue samples of 10 healthy controls (HC), 11 subjects with GERD, and 10 with EoE were studied. Multiple tissue staining to identify eosinophils (via eosinophil cationic protein-clone EG2) and major histocompatibility complex class II cell surface receptors (via HLA-DR) was performed via immunohistochemistry. The peripheral blood was analyzed using flow cytometry to detect eosinophil HLA-DR expression among these subjects. RESULTS In the tissue, a greater proportion of eosinophils expressed HLA-DR among the subjects with EoE (mean 0.83 +/- 0.14, n = 9) relative to those with GERD (mean 0.18 +/- 0.19, n = 8, P < 0.01) and HC (mean 0.18 +/- 0.13, n = 6, P < 0.01). In total, 6 participants (4 HC subjects and 2 subjects with GERD) did not have any eosinophils identified on tissue staining and were unable to be included in the present statistical analysis. In the blood, there was no statistically significant difference in eosinophil HLA-DR expression among HC subjects (mean 415 +/- 217, n = 6), subjects with GERD (mean 507 +/- 429, n = 2), and those with EoE (mean 334 +/- 181, n = 6). CONCLUSIONS These data demonstrate that the eosinophils from the esophagus of subjects with EoE have increased HLA-DR expression within this tissue.

This study examined the prevalence, demographic variables and adverse outcomes associated with non-adherence to post-transplant care in adolescent liver transplant recipients. We conducted a retrospective chart review of 111 adolescent patients (age 12-21 yr) greater than six months post-transplantation and defined non-adherence as not taking the immunosuppressive(s) or not attending any clinic visit in 2005. Fifty subjects (45.0%) were non-adherent and 61 (55.0%) were adherent. Twenty percent of the subjects did not attend clinic and 10.9% did not complete laboratory tests. Non-adherence was significantly associated with fewer completed laboratory tests (p < 0.0001), single parent status (p < 0.0186), and older age and greater years post-transplantation by both univariate and multivariate analyses (p < 0.008, p < 0.0141 and p < 0.0012, p < 0.0174, respectively). Non-adherence to medication was significantly associated with a rejection episode in 31 patients (p < 0.0069) but not in the subgroup of seven patients who stopped their immunosuppression completely. Non-adherence to post-transplant care is a prevalent problem in adolescents particularly of an older age and greater years post-transplantation. Rejection was a significant consequence of medication non-adherence except in a subgroup with presumed graft tolerance who discontinued their immunosuppression. These results emphasize the need for strict monitoring of adherence to post-transplant care to improve long-term survival and quality of life in adolescent transplant patients.

The Joint Medical Work Station (JMeWS) is a theater medical surveillance system that integrates information from three separate health data collection systems for the Army, Navy, Air Force, and Marines. Our objective was to characterize JMeWS data during its first year of implementation in 2003. We conducted a descriptive analysis of health events documented in JMeWS among military personnel deployed to Operations Enduring Freedom and Iraqi Freedom. Among the 38,498 individuals (7.8%) with a JMeWS record, women, college-educated, older individuals, and Reserve/Guard personnel were over-represented. There was wide variability by service (Air Force, 25%; Army, 5.5%; Marine Corps, 1.2%; and Navy, 0.6%). The most common diagnoses were in the categories of injury and poisoning, respiratory conditions, and musculoskeletal disorders. Differences in distribution of the various patient encounter modules in theater likely resulted in variable data capture across services. System enhancements should improve future applications.

HBL and HCC are the most common hepatic malignancies in children. The role of OLT in children with HCC is still a matter of debate. The aim of this study was to review our experience of OLT for HCC. Medical records of patients (< 18 yr) who underwent OLT for HCC were reviewed and compared to children who underwent OLT for HBL and for indications other than malignancy. There were 25 patients: HCC (10 cases) and HBL (15 cases). The actuarial patient survival for HCC at one and five yr was 100% and 83.3%, for the HBL group the survival was 86.7% at both one and five yr, and for indications (n = 377) other than malignancy the patient survival for pediatric OLT at our center was 87.7% and 84.7% at one and five yr, respectively. The actuarial recurrence free survival at five yr was 83.3% for HCC and 66.8% for HBL. In conclusion, OLT is a good therapeutic modality for children with HCC and HBL.

Objectives The purpose of this study was to determine the prevalence of small bowel bacterial overgrowth in patients with pancreatic-insufficient cystic fibrosis (CF) compared with age-matched controls and to identify potential risk factors for small bowel bacterial overgrowth. Patients and methods Fifty patients, 25 pancreatic-insufficient CF study patients (mean age, 17 y) and 25 gastrointestinal clinic control patients (mean age, 15 y), completed a glucose-hydrogen breath test after an overnight fast. Study patients completed a quality-of-life questionnaire modified from the Cystic Fibrosis Questionnaire. The medical history of each patient was compared with breath test results. A positive breath test was defined as a fasting hydrogen > or =15 ppm or a rise of > or =10 ppm hydrogen over baseline during the test. Results The prevalence of positive breath tests was higher in the CF study group (56%) than in the control group (20%) (P = 0.02). The mean fasting hydrogen levels of patients in the study and control groups were 22 and 5 ppm (P = 0.0001). The mean questionnaire scores were not significantly different between breath test-positive and -negative study patients. The use of azithromycin was associated with an increased risk of a positive breath test. Use of laxatives and inhaled ipratropium was associated with a decreased risk of a positive breath test. Conclusions Patients with CF were more likely to have elevated fasting hydrogen levels compared with controls. This suggests a high prevalence of small bowel bacterial overgrowth in CF patients. Medications commonly used by CF patients may influence intestinal health.

Although the U.S. Army suicide rate is known to have risen sharply over the past decade, information about medically documented, nonfatal suicidal behaviors is far more limited. Here we examine trends and sociodemographic correlates of suicide attempts, suspicious injuries, and suicide ideation among regular Army soldiers.Data come from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) Historical Administrative Data Study (HADS), which integrates administrative records for all soldiers on active duty during the years 2004 through 2009 (n = 1.66 million).We identified 21,740 unique regular Army soldiers with a nonfatal suicidal event documented at some point during the HADS study period. There were substantial increases in the annual incidence rates of suicide attempts (179-400/100,000 person-years) and suicide ideation (557-830/100,000 person-years), but not suspicious injuries. Using hierarchical classification rules to identify the first instance of each soldier's most severe behavior, we found increased risk of all outcomes among those who were female, non-Hispanic White, never married, lower-ranking enlisted, less educated, and of younger age when entering Army service. These sociodemographic associations significantly differed across outcomes, despite some patterns that appear similar.Results provide a broad overview of nonfatal suicidal trends in the U.S. Army during 2004 through 2009 and demonstrate that integration of multiple administrative data systems enriches analysis of the predictors of such events.

Few studies have examined the prevalence, demographic variables and adverse consequences associated with non-adherence to immunosuppressive therapy in the adolescent liver transplant population. Our hypothesis is that a significant proportion of adolescent liver transplant recipients exhibit non-adherence to medical regimens and that certain demographic and medical condition-related characteristics can be identified as potential predictors of non-adherent behavior. Furthermore, non-adherence leads to a greater incidence of morbidity and mortality in this population as compared with the adherent subset of adolescent patients. We reviewed the charts of 97 patients from 1987 to 2002 who by December of 2002 had survived at least 1 yr post-transplant and were followed by the Pediatric Liver Transplant Service at any point during their adolescent period (ages of 12-21). Non-adherence was defined as documentation of a report of non-adherence by a patient, parent or healthcare provider that was recorded in the patient's legal medical record. Descriptive statistics were used to determine the prevalence, demographic variables and adverse outcomes associated with non-adherence to immunosuppressive therapy. Categorical variables were analyzed using the chi-square test or the Fisher exact probability test. The unpaired Student's t-test was used to analyze the continuous variable of age at transplant. Using the inclusion criteria, a total of 97 patients represented the study sample of whom 37 subjects (38.1%) were defined as non-adherent and 60 (61.8%) were adherent. Non-adherent subjects were more likely to be female, older (>18 yr) and from a single-parent household. There was no significant difference in immunosuppressive regimen between non-adherent and adherent patients. Non-adherence was significantly (p

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients is associated with a high mortality (up to 60%) and the younger age groups, who are predominantly EBV-naive, are at highest risk for development of this disease. The aim of this study is to assess, in this high-risk group, patient outcome and graft loss to rejection when complete withdrawal of immunosuppressive agents (IMS) is instituted as the mainstay of treatment in addition to the use of standard therapy. A retrospective analysis of 335 pediatric patients whose liver transplants were performed by our team between September 1988 and September 2002, was carried out through review of computer records, database and patient charts. Fifty patients developed either EBV or PTLD; 80% were < or =2 yr of age. Of these 50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed with EBV infection, 14 of whom had positive tissue for EBV. Fifty-eight percent of patients who developed PTLD and 51.6% of patients with EBV received antibody for induction or treatment of rejection prior to onset of disease. Forty-six patients (92%) received post-transplant antiviral prophylaxis with ganciclovir or acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and Cytogam (in addition to one of the former agents) in 44%. In those with PTLD, treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection and was held as long as there was no allograft rejection. Eight patients have remained off IMS for a mean of 1535.5 +/- 623 days. Of the 21 patients who were restarted on IMS for acute rejection, 18 responded to steroids and/or reinstitution of low-dose calcineurin inhibitors. The mean time to rejection while off IMS in this group was 107.43 +/- 140 days (range: 7-476). Two patients were re-transplanted for chronic rejection; one had chronic rejection that existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in those with PTLD and 6% in those with EBV disease. The cause of death was related to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or chronic rejection. PTLD is associated with high mortality in the pediatric population. Based on this report, we advocate aggressive management of PTLD that is composed of early cessation of IMS, the use of antiviral therapy, and chemotherapy when indicated. Episodes of rejection that occur after stopping IMS can be successfully treated with standard therapy without graft loss to acute rejection.

Background Combined liver-kidney transplantation is the definitive treatment for end-stage renal disease caused by primary hyperoxaluria type I (PH1). The infantile form is characterized by renal failure early in life, advanced systemic oxalosis, and a formidable mortality rate. Although others have reported on overall results of transplantation for PH1 covering a wide age spectrum, none has specifically addressed the high-risk infantile form of the disease. Methods Six infants with PH1 underwent simultaneous liver-kidney transplantation at our center between May 1994 and August 1998. Diagnosis was made at 5.2+/-3.3 months of age, they were on dialysis for 11.8+/-2.3 months, and they underwent transplantation at 14.8+/-3.0 months of age when they weighed 10.6+/-1.7 kg. Results At a mean follow-up of 6.4+/-1.7 years (range, 3.9-8.1 years), we report 100% patient and kidney allograft survival. There were no cases of acute tubular necrosis. Long-term kidney allograft function remained stable in all patients, with serum creatinine values of less than 1.1 mg/dL and a mean creatinine clearance of 99 mL/min/1.73 m2 at follow-up. Those who received combined hemodialysis and peritoneal dialysis pretransplant had lower posttransplant urinary oxalate values than those receiving peritoneal dialysis alone. There was improvement in growth and psychomotor and mental developmental scores after transplantation. Conclusions Combined liver-kidney transplantation for the infantile presentation of PH1 is associated with excellent outcome when the approach includes early diagnosis and early combined transplantation, aggressive pretransplant dialysis, and avoidance of posttransplant renal dysfunction.

Patients with pancreatic agenesis are born without a pancreas, causing permanent neonatal diabetes and pancreatic enzyme insufficiency. These patients require insulin and enzyme replacement therapy to survive, grow, and maintain normal blood glucose levels. Pancreatic agenesis is an uncommon condition but high-throughput sequencing methods provide a rare opportunity to identify critical genes that are necessary for human pancreas development. Here we present the clinical history, evaluation, and the genetic and molecular analysis from two patients with pancreatic agenesis. Both patients were born with intrauterine growth restriction, minor heart defects and neonatal diabetes. In both cases, pancreatic agenesis was confirmed by imaging studies. The patients are clinically stable with pancreatic enzymes and insulin therapy. In order identify the etiology for their disease, we performed whole exome sequencing on both patients. For each proband we identified a de novo heterozygous mutation in the GATA6 gene. GATA6 is a homeobox containing transcription factor involved in both early development of the pancreas and heart. In vitro functional analysis of one of the variants revealed that the mutation creates a premature stop codon in the coding sequence resulting in the production of a truncated protein with loss of activity. These results show how genetic mutations in GATA6 may lead to functional inactivity and pancreatic agenesis in humans.

Background. Pediatric transplant recipients are at increased risk for Epstein Barr virus (EBV)-related B cell lymphomas. In healthy individuals, the expansion of EBV-infected B cells is controlled by CD8 + cytotoxic T cells. However, immunosuppressive therapy may compromise antiviral immunity. We identified and determined the frequency of EBV-specific T cells in the peripheral blood of pediatric transplant recipients. Methods. HLA-B*0801 and HLA-A*0201 tetramers folded with immunodominant EBV peptides were used to detect EBV-specific CD8 + T cells by flow cytometry in peripheral blood mononuclear cells from 24 pediatric liver and kidney transplant recipients. The expression of CD38 and CD45RO on EBV-specific, tetramer-binding cells was also examined in a subset of patients by immunofluorescent staining and flow cytometry. Results. Tetramer-binding CD8 + T cells were identified in 21 of 24 transplant recipients. EBV-specific CD8 + T cells were detected as early as 4 weeks after transplant in EBV seronegative patients receiving an organ from an EBV seropositive donor. The frequencies (expressed as a percentage of the CD8 + T cells) of the tetramer-binding cells were HLA-B8-RAKFKQLL (BZLF1 lytic antigen peptide) tetramer, range=0.96 to 3.94%; HLA-B8-FLRGRAYGL (EBNA3A latent antigen peptide) tetramer, range=0.03 to 0.59%; and HLA-A2-GLCTLVAML (BMLF1 lytic antigen peptide) tetramer, range=0.06 to 0.76%. The majority of tetramer reactive cells displayed an activated/memory phenotype. Conclusions. Pediatric transplant recipients receiving immunosuppression can generate EBV-specific CD8 + T cells. Phenotypic and functional analysis of tetramer + cells may prove useful in defining and monitoring EBV infection in the posttransplant patient.

BackgroundThe Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) has found that the proportional elevation in the US Army enlisted soldier suicide rate during deployment (compared with the never-deployed or previously deployed) is significantly higher among women than men, raising the possibility of gender differences in the adverse psychological effects of deployment.MethodPerson-month survival models based on a consolidated administrative database for active duty enlisted Regular Army soldiers in 2004–2009 (n = 975 057) were used to characterize the gender × deployment interaction predicting suicide. Four explanatory hypotheses were explored involving the proportion of females in each soldier's occupation, the proportion of same-gender soldiers in each soldier's unit, whether the soldier reported sexual assault victimization in the previous 12 months, and the soldier's pre-deployment history of treated mental/behavioral disorders.ResultsThe suicide rate of currently deployed women (14.0/100 000 person-years) was 3.1–3.5 times the rates of other (i.e. never-deployed/previously deployed) women. The suicide rate of currently deployed men (22.6/100 000 person-years) was 0.9–1.2 times the rates of other men. The adjusted (for time trends, sociodemographics, and Army career variables) female:male odds ratio comparing the suicide rates of currently deployed v. other women v. men was 2.8 (95% confidence interval 1.1–6.8), became 2.4 after excluding soldiers with Direct Combat Arms occupations, and remained elevated (in the range 1.9–2.8) after adjusting for the hypothesized explanatory variables.ConclusionsThese results are valuable in excluding otherwise plausible hypotheses for the elevated suicide rate of deployed women and point to the importance of expanding future research on the psychological challenges of deployment for women.

Importance The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multicomponent study designed to generate actionable recommendations to reduce Army suicides and increase knowledge of risk and resilience factors for suicidality. Objectives To present data on prevalence, trends, and basic sociodemographic and Army experience correlates of suicides and accident deaths among active duty Regular Army soldiers between January 1, 2004, and December 31, 2009, and thereby establish a foundation for future Army STARRS investigations. Design, Setting, and Participants Analysis of trends and predictors of suicide and accident deaths using Army and Department of Defense administrative data systems. Participants were all members of the US Regular Army serving at any time between 2004 and 2009. Main Outcomes and Measures Death by suicide or accident during active Army service. Results The suicide rate rose between 2004 and 2009 among never deployed and currently and previously deployed Regular Army soldiers. The accident death rate fell sharply among currently deployed soldiers, remained constant among the previously deployed, and trended upward among the never deployed. Increased suicide risk was associated with being a man (or a woman during deployment), white race/ethnicity, junior enlisted rank, recent demotion, and current or previous deployment. Sociodemographic and Army experience predictors were generally similar for suicides and accident deaths. Time trends in these predictors and in the Army’s increased use of accession waivers (which relaxed some qualifications for new soldiers) do not explain the rise in Army suicides. Conclusions and Relevance Predictors of Army suicides were largely similar to those reported elsewhere for civilians, although some predictors distinct to Army service emerged that deserve more in-depth analysis. The existence of a time trend in suicide risk among never-deployed soldiers argues indirectly against the view that exposure to combat-related trauma is the exclusive cause of the increase in Army suicides.

After completing this article, readers should be able to: 1. Identify the two diseases emerging in the neonatal period that account for more than 50% of all pediatric liver transplantations completed each year. 2. List the factors that affect growth in infants who have chronic liver disease. 3. Delineate the factors affecting growth after liver transplantation. 4. Identify factors that are associated with poor developmental outcome among children who undergo liver transplantation. Liver transplantation currently is the definitive therapy for various forms of end-stage liver disease in children. Each year, 400 to 600 children are diagnosed with a liver disease that requires transplantation. Such disease may be the result of metabolic (eg, alpha-1-antitrypsin deficiency), structural (eg, biliary atresia), obstructive (eg, hepatocellular disease), infectious (eg, hepatitis), or toxic (eg, drug overdose) causes. All of these conditions can progress to cirrhosis and end-stage liver disease. The incidence of neonatal liver disease is estimated as 1 in 2,500 live births. Two diseases emerging in the neonatal period account for 80% of the pediatric diagnoses: biliary atresia (50%) and neonatal hepatitis (30%). Consequently, children 1 year of age and younger account for approximately 50% of all pediatric transplantations completed in the United States each year (United Network for Organ Sharing, 2001). Managing chronic liver disease in infants and children is a challenge because of the multiple complications that can result from the damaged liver. Among the complications of end-stage cirrhotic liver disease are growth failure and developmental deficits. Failure to grow is a serious consequence of chronic liver disease that increases morbidity and mortality. A number of factors affect linear growth in infancy, including nutritional status, underlying liver diagnosis and alterations in the growth hormone (GH)/insulin-like growth factor (IGF)/insulin-like growth factor binding proteins (IGFBP) axis. The prevalence of malnutrition associated with chronic liver disease varies according to the …

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR) = 2.63, P

Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated illnesses. The early identification and diagnosis of EBV-associated disorders is critical because disease progression can often be curtailed by modification of immunosuppression. We have previously shown that detection of EBV-specific sequences in the circulation by polymerase chain reaction (PCR) correlated well with the clinical symptoms of EBV infection. The purpose of the current study is to determine the significance of detecting EBV-specific sequences by PCR in asymptomatic pediatric liver transplant recipients. Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from asymptomatic pediatric liver transplant recipients were analyzed from the immediate postoperative period and at 2- to 4-month intervals thereafter. We followed up 13 of these asymptomatic recipients who tested positive for EBV compared with 7 asymptomatic recipients who tested negative for EBV during the early posttransplantation period. Follow-up ranged from 1.5 to 4 years posttransplantation. Nine patients (69%) initially positive for EBV and asymptomatic ultimately developed symptoms of EBV infection, including fever, lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or hepatitis. Five of these patients (56%) went on to develop posttransplant lymphoproliferative disorder based on histological examination of biopsied tissue and immunohistochemical identification of the EBV antigen/DNA in tissue. This is the first report suggesting that detection of EBV-specific sequences in the absence of symptoms may herald impending EBV-associated disorders. Thus, routine monitoring for circulating EBV sequences in asymptomatic recipients may be useful in the early identification of those at risk for developing EBV-associated disease and its ultimate prevention.

Newer surgical techniques and immunosuppressive therapies have resulted in paediatric liver transplantation being available for most children with end-stage liver disease and has resulted in a greater than 80% 5-year survival rate. The most common indications for paediatric liver transplantation are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approximately 75% of children with acute hepatic failure, the cause is unknown. Timing of liver transplantation not only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numerous types of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, have reduced the mortality of children who are waiting for liver transplantation. However, the mortality and morbidity before and after liver transplantation remain high for children who have fulminant hepatic failure or are less than 5 months of age at the time of transplantation. The principle medical complications after liver transplantation are rejection and infection. Although use of newer immunosuppressive regimens has reduced the rate of rejection, Epstein-Barr virus infection with associated lymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

Cao S, Cox KL, Berquist W, Hayashi M, Concepcion W, Hammes GB, Ojogho OK, So SKS, Frerker M, Castillo RO, Monge H, Esquivel CO. Long-term outcomes in pediatric liver recipients: Comparison between cyclosporin A and tacrolimus. Pediatr Transplantation 1999: 3: 22–26. © Munksgaard, 1999 In recent years, Tacrolimus® (FK506, TAC) has been increasingly utilized in liver transplantation. However, long-term risks and benefits as compared with conventional cyclosporin A (CsA) have not been fully elucidated. This retrospective study examined the potential outcome differences between TAC- and CsA-based immunosuppressive therapy in pediatric liver transplant recipients. From March 1988 to December 1996, 218 children (aged 0.1 – 17 yr) underwent 238 orthotopic liver transplantations; 58.7% (128/218) were under 2 yr old at time of transplant. Initially, the maintenance immunosuppressive regimen consisted of CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as induction therapy. Subsequently, TAC was used first as rescue therapy for steroid refractory rejection in CsA patients and then as maintenance immunosuppression. Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons while 71 patients were placed on TAC as primary maintenance immunosuppression. 62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy-proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p = 0.09); likewise, 34% (50/147) of CsA patients had more than one episode of rejection vs. 18.3% (13/71) for patients on TAC (p

BACKGROUND:Bile acids are synthesized and secreted by the liver. During liver failure and hepatic dysfunction, a marked reduction of bile acid synthesis has been shown. The purpose of this study was to determine whether the biliary bile acid pattern was affected by preservation injury and rejection and whether it was a reliable marker for graft function in pediatric liver recipients after liver transplantation. METHODS:We prospectively measured the biliary bile acid pattern in 126 serial bile samples obtained from 15 consecutive pediatric liver recipients by reversed phase high pressure liquid chromatography and correlated our results with clinical findings: preservation injury, no rejection, rejection, or infection. RESULTS:There was a significant change of the bile acid pattern during the first 3 days after transplant. Total biliary bile acids, cholic acid (CA), and CA/chenodeoxycholic acid (CDCA) ratio increased in 12 of 15 patients with mild preservation injury. These changes of the bile acid pattern were markedly delayed in patients with severe preservation injury. During 16 rejection episodes, total biliary bile acid, CA, and CA/CDCA ratio decreased significantly, but returned to normal after successful treatment of rejection. Bacterial infection, observed in nine children, and cyclosporine toxicity, observed in three children, seemed to have no affect on the biliary bile acids. CONCLUSIONS:Liver cell damage as a result of preservation injury or rejection leads to a reduction of biliary CA, resulting in a decrease of total biliary bile acids and the CA/CDCA ratio in pediatric liver recipients. This might be caused by a diminished secretion of bile acids and by a decreased synthesis of bile acids.

Study design: Forty children

Recent advancements in liver transplantationhave resulted in extended survival both for grafts andrecipients. Such improvement, together with the shortageof donor organs has prompted expansion of the donor pool to include less than ideal donors,especially in life-threatening situations. The use ofolder liver donors has been associated with lowerlong-term survival. However, potential morbidity such as gallstone formation has not been explored.We analyzed bile composition in a child who developedcholesterol gallstones in the proximal bile duct twoyears after undergoing emergency liver transplantation with a liver from a 78-year-old donor. Oraladministration of ursodeoxycholic acid (ursodiol)shifted the cholesterol composition of the bile from asupersaturated, potentially crystallized state to aliquid (micellar) state. Unlike cyclosporin A, FK506showed an increase in the proportion of chenodeoxycholicacid and a decrease in the proportion of cholic acid,and thus may exhibit minimal or no hepatotoxic effect. Thus, in donor livers with factorsknown to be associated with cholesterol gallstoneformation (such as age, sex, or obesity), one mayconsider analyzing the bile composition at the time ofprocurement. Depending on cholesterol and bile acidcomposition, the use of FK506 with or without additionof ursodeoxycholic acid may be warranted.

We have adopted the use of an oral tacrolimus induction protocol in pediatric liver transplantation since the commercial release of tacrolimus in 1994. In this study we analyzed the efficacy of oral tacrolimus induction therapy in 17 consecutive transplants (15 patients) performed between 6/94 and 2/95 and 4 additional patients who were retransplanted between 11/93-5/94 and received compassionate oral tacrolimus induction. Sixteen transplants were treated with oral tacrolimus induction only ; 5 transplants, oral tacrolimus + ATGAM/OKT3 induction. The protocol consisted of 0.2 mg/kg of tacrolimus orally on the first postoperative day with a corticosteroid taper. Oral tacrolimus was started at day 1-8 in the 5 patients receiving ATGAM/OKT3 induction. Dosages were adjusted over time to maintain a whole-blood trough level of 12-15 ng/ml at 0-1 month, 10-12 ng/ml at 1-3 months, and 5-10 ng/ml after 3 months. The incidence of acute rejection was 50% (8/16) in children on oral tacrolimus induction alone and 80% (4/5) in the tacrolimus + ATGAM/OKT3 group. Epstein-Barr virus infection occurred in 6 of 19 children (32%), with no child developing lymphoproliferative disorder. No adverse effect on renal function was noted. Serum fasting glucose was stable over time while a trend was noted in decreasing serum cholesterol levels at 6 months. Antihypertensive medication was required in 4 of 19 children (21%) posttransplantation. Corticosteroids were withdrawn in 11% (2/19) of patients. Actuarial 1-year patient and graft survivals were 95% and 86%, respectively. The use of oral tacrolimus induction therapy was associated with excellent survival and a low incidence of complications.