Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series.

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.

Financial costs to the U.S. Army for suicides by newly enlisted Soldiers.

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.

Mortality Among Male U.S. Army Soldiers Within 18 Months of Separation.

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 (<1%). For overall mortality, age-adjusted rates were higher among the male U.S. population when compared to male soldiers who had separated from the Army. 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.

Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.

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.

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis.

BACKGROUND: 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. METHODS: 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 weight <30kg, 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. RESULTS: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. CONCLUSION: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

Prenatal treatment of ornithine transcarbamylase deficiency.

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 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. 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.

Frequency of Improvised Explosive Devices and Suicide Attempts in the U.S. Army.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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 (χ22 = 3.89, p = 0.14). Among soldiers with 3 or more years of service, the association was higher for those never deployed (OR = 1.12, 95% CI = 1.01-1.24) and currently deployed (OR = 1.14, 95% CI = 1.05-1.23) than for those previously deployed. DISCUSSION: To 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.

An Examination of Potential Misclassification of Army Suicides: Results from the Army Study to Assess Risk and Resilience in Servicemembers.

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 nonsuicide 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.

Medically Documented Suicide Ideation Among U.S. Army Soldiers.

We used administrative data to examine predictors of medically documented suicide ideation (SI) 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 SI is highest among enlisted soldiers early in Army service, females, and those with a recent mental health diagnosis.

Risk Factors, Methods, and Timing of Suicide Attempts Among US Army Soldiers.

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.

Nonfatal Suicidal Behaviors in U.S. Army Administrative Records, 2004-2009: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Suicide Attempts in the US Army During the Wars in Afghanistan and Iraq, 2004 to 2009.

IMPORTANCE: The rate of suicide attempts in the US Army increased sharply during the wars in Afghanistan and Iraq. Research on this important health outcome has been hampered by the lack of integration among Army administrative data systems. OBJECTIVE: To identify risk factors for suicide attempts among active-duty members of the regular Army from January 1, 2004, through December 31, 2009. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal, retrospective cohort study, as part of the Army Study to Assess Risk and Resilience in Servicemembers (STARRS), used individual-level person-month records from Army and Department of Defense administrative data systems to examine sociodemographic, service-related, and mental health predictors of medically documented suicide attempts among active-duty regular Army soldiers from January 1, 2004, through December 31, 2009. We analyzed data from 9791 suicide attempters and an equal-probability sample of 183,826 control person-months using a discrete-time survival framework. Data analysis was performed from February 3 through November 12, 2014. MAIN OUTCOMES AND MEASURES: Suicide attempts identified using Department of Defense Suicide Event Report records and diagnostic codes E950 through E958 from the International Classification of Diseases, Ninth Revision, Clinical Modification. Standardized estimates of suicide attempt risk for sociodemographic, service-related, and mental health predictor variables were constructed from Army personnel and medical records. RESULTS: Enlisted soldiers accounted for 98.6% of all suicide attempts (9650 attempters; overall rate, 377.0 [95% CI, 369.7-384.7] per 100,000 person-years). In multivariate models, suicide attempts among enlisted soldiers were predicted (data reported as odds ratio [95% CI]) by female sex (2.4 [2.3-2.5]), entering Army service at 25 years or older (1.6 [1.5-1.8]), current age of 29 years or younger (<21 years, 5.6 [5.1-6.2]; 21-24 years, 2.9 [2.6-3.2]; 25-29 years, 1.6 [1.5-1.8]), white race (black, 0.7 [0.6-0.7]; Hispanic, 0.7 [0.7-0.8]; Asian, 0.7 [0.6-0.8]), an educational level of less than high school (2.0 [2.0-2.1]), being in the first 4 years of service (1-2 years, 2.4 [2.2-2.6]; 3-4 years, 1.5 [1.4-1.6]), having never (2.8 [2.6-3.0]) or previously (2.6 [2.4-2.8]) been deployed, and a mental health diagnosis during the previous month (18.2 [17.4-19.1]). Attempts among officers (overall rate, 27.9 per 100,000 person-years) were predicted by female sex (2.8 [2.0-4.1]), entering Army service at 25 years or older (2.0 [1.3-3.1]), current age of 40 years or older (0.5 [0.3-0.8]), and a mental health diagnosis during the previous month (90.2 [59.5-136.7]). Discrete-time hazard models indicated risk among enlisted soldiers was highest in the second month of service (102.7 per 100,000 person-months) and declined substantially as length of service increased (mean during the second year of service, 56.0 per 100,000 person-years; after 4 years of service, 29.4 per 100,000 person-months), whereas risk among officers remained stable (overall mean, 6.1 per 100,000 person-months). CONCLUSIONS AND RELEVANCE: Our results represent, to our knowledge, the most comprehensive accounting to date of suicide attempts in the Army. The findings reveal unique risk profiles for enlisted soldiers and officers and highlight the importance of research and prevention focused on enlisted soldiers in their first Army tour.

Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations.

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.

Predicting suicides after psychiatric hospitalization in US Army soldiers: the Army Study To Assess Risk and rEsilience in Servicemembers (Army STARRS).

IMPORTANCE: The US Army experienced a sharp increase in soldier suicides beginning in 2004. Administrative data reveal that among those at highest risk are soldiers in the 12 months after inpatient treatment of a psychiatric disorder. OBJECTIVE: To develop an actuarial risk algorithm predicting suicide in the 12 months after US Army soldier inpatient treatment of a psychiatric disorder to target expanded posthospitalization care. DESIGN, SETTING, AND PARTICIPANTS: There were 53,769 hospitalizations of active duty soldiers from January 1, 2004, through December 31, 2009, with International Classification of Diseases, Ninth Revision, Clinical Modification psychiatric admission diagnoses. Administrative data available before hospital discharge abstracted from a wide range of data systems (sociodemographic, US Army career, criminal justice, and medical or pharmacy) were used to predict suicides in the subsequent 12 months using machine learning methods (regression trees and penalized regressions) designed to evaluate cross-validated linear, nonlinear, and interactive predictive associations. MAIN OUTCOMES AND MEASURES: Suicides of soldiers hospitalized with psychiatric disorders in the 12 months after hospital discharge. RESULTS: Sixty-eight soldiers died by suicide within 12 months of hospital discharge (12.0% of all US Army suicides), equivalent to 263.9 suicides per 100,000 person-years compared with 18.5 suicides per 100,000 person-years in the total US Army. The strongest predictors included sociodemographics (male sex [odds ratio (OR), 7.9; 95% CI, 1.9-32.6] and late age of enlistment [OR, 1.9; 95% CI, 1.0-3.5]), criminal offenses (verbal violence [OR, 2.2; 95% CI, 1.2-4.0] and weapons possession [OR, 5.6; 95% CI, 1.7-18.3]), prior suicidality [OR, 2.9; 95% CI, 1.7-4.9], aspects of prior psychiatric inpatient and outpatient treatment (eg, number of antidepressant prescriptions filled in the past 12 months [OR, 1.3; 95% CI, 1.1-1.7]), and disorders diagnosed during the focal hospitalizations (eg, nonaffective psychosis [OR, 2.9; 95% CI, 1.2-7.0]). A total of 52.9% of posthospitalization suicides occurred after the 5% of hospitalizations with highest predicted suicide risk (3824.1 suicides per 100,000 person-years). These highest-risk hospitalizations also accounted for significantly elevated proportions of several other adverse posthospitalization outcomes (unintentional injury deaths, suicide attempts, and subsequent hospitalizations). CONCLUSIONS AND RELEVANCE: The high concentration of risk of suicide and other adverse outcomes might justify targeting expanded posthospitalization interventions to soldiers classified as having highest posthospitalization suicide risk, although final determination requires careful consideration of intervention costs, comparative effectiveness, and possible adverse effects.

Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure.

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

Predictors of suicide and accident death in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS): results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).

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.

Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin.

Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disease of the liver that is marked by inflammation of the bile ducts and damage to the hepatic biliary tree. Approximately 60-70% of patients also have inflammatory bowel disease and progression of PSC can lead to ulcerative colitis and cirrhosis of the liver. Due to limited understanding of the etiology and mechanism of PSC, the only existing treatment option is orthotopic liver transplantation (OLT); however, recurrence of PSC, after OLT is estimated to be between 5% and 35%. We discuss the successful treatment of a pediatric patient, with recurrent PSC, after OLT with oral Vancomycin.

Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis.

Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-ß) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.