Neutralizing antibodies to interferon alfa arising during peginterferon therapy of chronic hepatitis B in children and adults: Results from the HBRN Trials.

BACKGROUND AIMS: Pegylated interferon-α (PegIFNα) is of limited utility during immunotolerant or immune active phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some patients receiving treatment are associated with limited/no virological responses. The study aimed to determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies. APPROACH RESULTS: Pre-treatment, on-treatment, and post-treatment sera from 61 immunotolerant trial participants on PegIFNα/entecavir therapy and 88 immune active trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by preincubation of sera±recombinant human IFNα added to Huh7 cells with the measurement of interferon-stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated. Preincubation of on-treatment serum from 26 immunotolerant (43%) and 13 immune active (15%) participants with recombinant-human IFNα markedly blunted ISG-induction in Huh7 cells. The degree of ISG inhibition correlated with IFNα antibody titer ( p < 0.0001; r = 0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced quantitative HBsAg and qHBeAg declines ( p < 0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults ( p = 0.004) but nAbs in children had less impact on virological responses. CONCLUSIONS: The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for the optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.

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

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

SHINERS Study of Chloride Order-Disorder Phase Transition and Solvation of Cu(100).

Shell-isolated nanoparticle enhanced Raman spectroscopy (SHINERS) and density functional theory (DFT) are used to probe Cl- adsorption and the order-disorder phase transition associated with the c(2 × 2) Cl- adlayer on Cu(100) in acid media. A two-component ν(Cu-Cl) vibrational band centered near 260 ± 1 cm-1 is used to track the potential dependence of Cl- adsorption. The potential dependence of the dominant 260 cm-1 component tracks the coverage of the fluctional c(2 × 2) Cl- phase on terraces in good agreement with the normalized intensity of the c(2 × 2) superstructure rods in prior surface X-ray diffraction (SXRD) studies. As the c(2 × 2) Cl- coverage approaches saturation, a second ν(Cu-Cl) component mode emerges between 290 and 300 cm-1 that coincides with the onset and stiffening of step faceting where Cl- occupies the threefold hollow sites to stabilize the metal kink saturated Cu <100> step edge. The formation of the c(2 × 2) Cl- adlayer is accompanied by the strengthening of ν(O-H) stretching modes in the adjacent non-hydrogen-bonded water at 3600 cm-1 and an increase in hydronium concentration evident in the flanking H2O modes at 3100 cm-1. The polarization of the water molecules and enrichment of hydronium arise from the combination of Cl- anionic character and lateral templating provided by the c(2 × 2) adlayer, consistent with SXRD studies. At negative potentials, Cl- desorption occurs followed by development of a sulfate νs(S═O) band. Below -1.1 V vs Hg/HgSO4, a new 200 cm-1 mode emerges congruent with hydride formation and surface reconstruction reported in electrochemical scanning tunneling microscopy studies.

Improving the Accuracy of Atomistic Simulations of the Electrochemical Interface.

Atomistic simulation of the electrochemical double layer is an ambitious undertaking, requiring quantum mechanical description of electrons, phase space sampling of liquid electrolytes, and equilibration of electrolytes over nanosecond time scales. All models of electrochemistry make different trade-offs in the approximation of electrons and atomic configurations, from the extremes of classical molecular dynamics of a complete interface with point-charge atoms to correlated electronic structure methods of a single electrode configuration with no dynamics or electrolyte. Here, we review the spectrum of simulation techniques suitable for electrochemistry, focusing on the key approximations and accuracy considerations for each technique. We discuss promising approaches, such as enhanced sampling techniques for atomic configurations and computationally efficient beyond density functional theory (DFT) electronic methods, that will push electrochemical simulations beyond the present frontier.

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

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

Quantifying the Effect of Guest Binding on Host Environment.

The environment around a host-guest complex is defined by intermolecular interactions between the complex, solvent molecules, and counterions. These interactions govern both the solubility of these complexes and the rates of reactions occurring within the host molecules and can be critical to catalytic and separation applications of host-guest systems. However, these interactions are challenging to detect using standard analytical chemistry techniques. Here, we quantify the hydration and ion pairing of a FeII4L4 coordination cage with a set of guest molecules having widely varying physicochemical properties. The impact of guest properties on host ion pairing and hydration was determined through microwave microfluidic measurements paired with principal component analysis (PCA). This analysis showed that introducing guest molecules into solution displaced counterions that were bound to the cage, and that the solvent solubility of the guest has the greatest impact on the solvent and ion-pairing dynamics surrounding the host. Specifically, we found that when we performed PCA of the measured equivalent circuit parameters and the solubility and dipole moment, we observed a high (>90%) explained variance for the first two principal components for each circuit parameter. We also observed that cage-counterion pairing is well-described by a single ion-pairing type, with a one-step reaction model independent of the type of cargo, and that the ion-pairing association constant is reduced for cargo with higher water solubility. Quantifying hydration and cage-counterion interactions is a critical step to building the next generation of design criteria for host-guest chemistries.

Changes in serum hepatitis B surface and e antigen, interferon-inducible protein 10, and aminotransferase levels during combination therapy of immune-tolerant chronic hepatitis B.

BACKGROUND AND AIMS: Treatment of immune-tolerant (IT) children and adults with combined peginterferon alfa-2a and entecavir results in a decline in serum HBeAg and HBsAg concentrations but rarely results in loss of HBeAg or sustained off-treatment response. Factors associated with declines in these viral antigens during treatment remain unexplored. APPROACH AND RESULTS: We investigated the pattern of virologic and biochemical response in 86 participants (59 children, 27 adults) by serial quantitative measurement of HBsAg (qHBsAg), quantitative HBeAg (qHBeAg), HBV RNA, interferon-inducible protein (IP-10), IL-18, and alanine aminotransferase (ALT). Each individual had previously been treated with 8 weeks of entecavir followed by 40 weeks of combined peginteferon and entecavir. We defined the interrelationships between these parameters and virologic response measured as nadir declines from baseline for HBeAg and HBsAg. The patterns of HBsAg and HBeAg decline were similar in pediatric and adult participants. Higher levels of IP-10 were observed during treatment in participants with greater ALT elevations and greater reductions of qHBsAg and qHBeAg. Individuals with peak ALT values exceeding three times the upper limit of normal were significantly more likely to have >1 log10 decline in both viral antigens. HBV DNA became undetectable in 21 of 86 (24%) and HBV RNA in 4 of 77 (5%) during therapy, but both markers remained negative only in those who became HBsAg negative, all of whom also had ALT elevations. CONCLUSIONS: Induction of IP-10 during peginterferon treatment in adults and children in the IT phase of chronic HBV infection is associated with ALT elevations and decline in viral antigens, suggesting a degree of interferon-inducible viral control.

Improving Hepatitis B Screening at Family Health Centers Using Quality Improvement and Electronic Medical Record Tools.

Chronic hepatitis B viral (HBV) infection is associated with significant morbidity and mortality with endemic areas carrying most of the global burden of HBV disease. Current HBV screening rates in the United States are suboptimal. We aimed to improve HBV screening rates at regional family health centers serving high-risk refugee populations by 20% over 2 years. We used quality improvement (QI) methodology and implemented interventions providing electronic medical record (EMR)-enabled HBV screening tools within known clinical workflows. EMR tools captured country-of-origin data to identify persons from HBV-endemic regions with provision of a laboratory order set to ensure performance of appropriate HBV screening tests. The project was initiated prior to the COVID pandemic but continued during the pandemic with imposed social isolation measures. We nevertheless demonstrated 4 statistical process control chart shifts and achieved our QI smart aim. Further, we demonstrated a high HBV detection rate (8.2%-12.8%) among persons identified for screening.

Change in Health-Related Quality of Life in Youth with Chronic Hepatitis B Living in North America: A 5-Year Cohort Study.

BACKGROUND: Greater hepatitis-related symptomology is associated with lower health-related quality-of-life (HRQoL) among untreated youth with chronic hepatitis B (CHB). How HRQoL changes over time in this population is unknown. METHODS: Children from 7 hepatology centers in North America positive for hepatitis B surface antigen, not taking anti-viral therapy, were enrolled in the Hepatitis B Research Network. A validated self-report HRQoL measure, the Child Health Questionnaire Child Report (CHQ-CF87), was completed annually by participants 10-17 years, with demographic variables, liver disease symptoms, and laboratory tests. Linear mixed-effects models were used to evaluate the 10 CHQ-CF87 subscale scores over 5 years among participants who completed the CHQ-CF87 at least twice. RESULTS: Participants (N = 174) completed the CHQ-CF87 a median of 4 times. Median age was 12 years (interquartile range: 10-14) at baseline; 60% were female, 79% Asian, and 47% adopted. The CHQ-CF87 subscale scores were high at baseline (median range: 75.4-100) and did not differ by time point, except for the Family Activities subscale (mean [95% CI]: 82.3 [79.8-84.8] at baseline; 90.8 [86.1-94.6] week 240). Most subscale scores lacked sufficient individual-level variability in change over time to evaluate predictors. Being White versus Asian predicted a more favorable change in Behavior (6.5 [95% CI: 2.0-11.0]). Older age predicted less favorable change in Mental Health (-0.8 [95% CI: -1.36 to -0.23] per year). Changes in liver enzymes and hepatitis B antigens, DNA, or symptom count were not related to changes in these subscale scores. CONCLUSION: HRQoL was generally good and consistent across 5 years in youth with CHB.

Solvent effects determine the sign of the charges of maximum entropy and capacitance at silver electrodes.

Fully harnessing electrochemical interfaces for reactions requires a detailed understanding of solvent effects in the electrochemical double layer. Predicting the significant impact of solvents on entropic and electronic properties of electrochemical interfaces has remained an open challenge of computational electrochemistry. Using molecular dynamics simulations of silver-water and silver-acetonitrile interfaces, we show that switching the solvent changes the signs for both the charge of maximum capacitance (CMC) and charge of maximum entropy (CME). Contrasting the capacitance and CME behavior of these two interfaces, we demonstrate that the preferred orientation of the solvent molecule and the corresponding charge density determine the sign of the CMC and CME and, hence, the qualitatively different charge asymmetry of the electrochemical interface.

Simulating dielectric spectra: A demonstration of the direct electric field method and a new model for the nonlinear dielectric response.

We demonstrate a method to compute the dielectric spectra of fluids in molecular dynamics (MD) by directly applying electric fields to the simulation. We obtain spectra from MD simulations with low magnitude electric fields (≈0.01 V/Å) in agreement with spectra from the fluctuation-dissipation method for water and acetonitrile. We examine this method's trade-off between noise at low field magnitudes and the nonlinearity of the response at higher field magnitudes. We then apply the Booth equation to describe the nonlinear response of both fluids at low frequency (0.1 GHz) and high field magnitude (up to 0.5 V/Å). We develop a model of the frequency-dependent nonlinear response by combining the Booth description of the static nonlinear dielectric response of fluids with the frequency-dependent linear dielectric response of the Debye model. We find good agreement between our model and the MD simulations of the nonlinear dielectric response for both acetonitrile and water.

The Inflammatory Cytokine Profile Associated With Liver Damage Is Broader and Stronger in Patients With Chronic Hepatitis B Compared to Patients With Acute Hepatitis B.

Liver damage in hepatitis B is immune driven and correlates with inflammatory markers in patient serum. There is no comparison of these markers to determine if inflammatory profiles are distinct to different types of liver damage across patients at different stages of disease. We measured 25 inflammatory markers in patients with acute hepatitis B and chronic hepatitis B with hepatitis B e antigen seroconversion and chronic patients stopping nucleoside analogue therapy. Myeloid markers dominated the inflammatory profile in all stages of hepatitis B. More inflammatory markers were detectable in chronic patients, including elevated concentrations of cytotoxic effectors Fas ligand, TRAIL, and TNF-α.

Survival Benefit of Split-Liver Transplantation for Pediatric and Adult Candidates.

Patient and graft survival are similar following whole-liver transplantations (WLTs) versus split-liver transplantations (SLTs) among pediatric and adult recipients, yet SLTs are rarely used. We sought to determine the survival benefit associated with accepting a splittable graft offer for SLT versus declining and waiting for a subsequent offer using 2010 to 2018 Scientific Registry of Transplant Recipients (SRTR) data on 928 pediatric and 1814 adult liver transplantation candidates who were ever offered a splittable graft. We compared eventual mortality, regardless of subsequent transplants, between those patients who accepted versus declined a split liver offer with adjustments for Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease (MELD) scores, diagnosis, and weight among pediatric candidates and matching for MELD score, height, and offer among adult candidates. Among pediatric candidates ≤7 kg, split liver offer acceptance versus decline was associated with a 63% reduction in mortality (adjusted hazard ratio [aHR], 0.17 0.370.80 [P = 0.01]; 93.1% versus 84.0% 1-year survival after decision). Within 1 year of decline for those ≤7 kg, 6.4% died and 31.1% received a WLT. Among pediatric candidates >7 kg, there was no significant difference associated with acceptance of a split liver offer (aHR, 0.63 1.071.82 [P = 0.81]; 91.7% versus 94.4% 1-year survival after decision). Within 1 year of decline for those >7 kg, 1.8% died and 45.8% received a WLT. Among adult candidates, split liver offer acceptance was associated with a 43% reduction in mortality (aHR, 0.39 0.570.83 [P = 0.005]; 92.2% versus 84.4% 1-year survival after decision). Within 1 year of decline for adult candidates, 7.9% died and 39.3% received a WLT. Accepting split liver offers for SLT could significantly improve survival for small children and adults on the waiting list.

Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis.

BACKGROUND AND AIMS: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.

Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study.

BACKGROUND AND AIMS: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. APPROACH AND RESULTS: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). CONCLUSIONS: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Expression of HLA and Autoimmune Pathway Genes in Liver Biopsies of Young Subjects With Autoimmune Hepatitis Type 1.

OBJECTIVES: To test the hypothesis that autoimmune hepatitis (AIH type I) in young subjects is due to genetic differences in proinflammatory genes responding to viral triggers in patients and controls. METHODS: Intrahepatic gene expression was compared between AIH type I (n = 24, age 9-30 years) patients (hereafter referred to as the AIH group) and controls (n = 21, age 4-25 years). RNA sequencing was performed on complementary DNA (cDNA) libraries made from total RNA extracted from formalin-fixed paraffin-embedded (FFPE) liver biopsy samples. Gene expression levels were quantified, and differentially expressed genes were functionally analyzed. Pathway analysis was performed using the databases Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER. The remaining sequences were mapped to the RefSeq complete set of viral genomes. RESULTS: Differential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19 and CD20 which are important in B cell regulation and maturation as well as, CD8 and LY9 , which are T-cell related, were upregulated in our AIH group. Genes implicated in AIH pathogenesis including CXCL10 , which is thought to be associated with AIH severity and progression, complement genes ( C1QA, C1QB , and C1QC ), and human leucocyte antigen ( HLA ) genes ( HLA-DRB1, HLA-DRA, HLA-B , and HLA-C ) were upregulated in samples from the AIH group. Specific viral etiologies were not found. CONCLUSIONS: Unbiased next-generation sequencing and differential gene expression analysis of the AIH group has not only added support for the role of B cells in the pathogenesis and treatment of AIH but also has introduced potential new therapeutic targets: CXCL10 (anti- CXCL10 ) and several complement system-related genes.

Interfacial water asymmetry at ideal electrochemical interfaces.

Controlling electrochemical reactivity requires a detailed understanding of the charging behavior and thermodynamics of the electrochemical interface. Experiments can independently probe the overall charge response of the electrochemical double layer by capacitance measurements and the thermodynamics of the inner layer with potential of maximum entropy measurements. Relating these properties by computational modeling of the electrochemical interface has so far been challenging due to the low accuracy of classical molecular dynamics (MD) for capacitance and the limited time and length scales of ab initio MD. Here, we combine large ensembles of long-time-scale classical MD simulations with charge response from electronic density functional theory to predict the potential-dependent capacitance of a family of ideal aqueous electrochemical interfaces with different peak capacitances. We show that while the potential of maximum capacitance varies, this entire family exhibits an electrode charge of maximum capacitance (CMC) between -2.9 and -2.2 µC/cm2, regardless of the details in the electronic response. Simulated heating of the same interfaces reveals that the entropy peaks at a charge of maximum entropy (CME) of -5.1 ± 0.6 µC/cm2, in agreement with experimental findings for metallic electrodes. The CME and CMC both indicate asymmetric response of interfacial water that is stronger for negatively charged electrodes, while the difference between CME and CMC illustrates the richness in behavior of even the ideal electrochemical interface.

Colorectal Dysplasia and Cancer in Pediatric-Onset Ulcerative Colitis Associated With Primary Sclerosing Cholangitis.

Inflammatory bowel disease (IBD), especially when associated with primary sclerosing cholangitis (PSC), is a risk factor for developing colorectal cancer (CRC).1-3 We aimed to determine the incidence of CRC in a large cohort of pediatric-onset PSC-ulcerative colitis (UC) patients.

Chronic Hepatitis Is Common and Often Untreated Among Children with Hepatitis B Infection in the United States and Canada.

OBJECTIVE: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada. STUDY DESIGN: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data. RESULTS: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations. CONCLUSIONS: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated.