Search

The balance between ion solvation and ion pairing in aqueous solutions modulates chemical and physical processes from catalysis to protein folding. Yet, despite more than a century of investigation, experimental determination of the distribution of ion-solvation and ion-pairing states remains elusive, even for archetypal systems like aqueous alkali halides. Here, we combine nuclear magnetic resonance (NMR) spectroscopy and multiscale modeling to disentangle ion–solvent interactions from ion pairing in aqueous sodium fluoride solutions. We have developed a high-accuracy method to collect experimental NMR resonance frequencies for both ions as functions of temperature and concentration. Comparison of these data with resonance frequencies for nonassociating salts allows us to differentiate the influence of solvation and ion pairing on NMR spectra. These high-quality experimental NMR data are used to validate our modeling framework comprising polarizable force field molecular dynamics (MD) simulations and quantum chemical calculations of NMR resonance frequencies. Our experimental and theoretical resonance frequency shifts agree over a wide range of temperatures and concentrations. Structural analysis reveals how both trends are dominated by interactions with water molecules. For the more sensitive 19F nucleus, the NMR resonance frequency decreases as hydrogen bonds between fluoride and water molecules are reduced in number with increased temperature and molality. Through a detailed analysis of the theoretical NMR resonance frequencies for both ions, we show that NMR spectroscopy can distinguish both contact ion pairs and single-solvent-separated ion pairs from free ions. This quantitative framework can be applied directly to other systems.

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. 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. 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. The pangenotypic regimen of sofosbuvir–velpatasvir is highly effective and safe in treating children 3–17 years with chronic HCV infection. For treating chronic hepatitis C virus (HCV) infection, the combination antiviral regimen sofosbuvir–velpatasvir is highly effective in treating adults with any HCV genotype.In children, the safety, efficacy, and pharmacokinetics of sofosbuvir–velpatasvir had not been evaluated. For treating chronic hepatitis C virus (HCV) infection, the combination antiviral regimen sofosbuvir–velpatasvir is highly effective in treating adults with any HCV genotype. In children, the safety, efficacy, and pharmacokinetics of sofosbuvir–velpatasvir had not been evaluated. In 216 children aged 3–17 years with chronic HCV infection, sofosbuvir–velpatasvir given once daily for 12 weeks had a cure rate of 92%.Rates of cure were 95% among 12–17‐year‐olds (97/102), 93% in 6–11‐year‐olds (68/73), and 83% in 3–5‐year‐olds (34/41).Overall, sofosbuvir–velpatasvir was well tolerated in both tablet and granule formulations; 1.4% (3/216) of participants discontinued because of an adverse event. Pharmacokinetic simulations supported weight‐based dosing for children. In 216 children aged 3–17 years with chronic HCV infection, sofosbuvir–velpatasvir given once daily for 12 weeks had a cure rate of 92%. Rates of cure were 95% among 12–17‐year‐olds (97/102), 93% in 6–11‐year‐olds (68/73), and 83% in 3–5‐year‐olds (34/41). Overall, sofosbuvir–velpatasvir was well tolerated in both tablet and granule formulations; 1.4% (3/216) of participants discontinued because of an adverse event. Pharmacokinetic simulations supported weight‐based dosing for children.

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–1is used to track the potential dependence of Cl–adsorption. The potential dependence of the dominant 260 cm–1component 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–1that 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–1and 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–1mode emerges congruent with hydride formation and surface reconstruction reported in electrochemical scanning tunneling microscopy studies.

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. 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. 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. HRQoL was generally good and consistent across 5 years in youth with CHB.

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 FeII4L4coordination 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.

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.

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.

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. 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. Differential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19and CD20which are important in B cell regulation and maturation as well as, CD8and 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. 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.

The change in surface stress associated with the adsorption and oxidative stripping of carbon monoxide (CO) on (111)-textured Pt is examined using the wafer curvature method in 0.1 mol/L KHCO3electrolyte. The curvature of the Pt cantilever electrode was monitored as a function of potential in both CO-free and CO-saturated electrolytes. Although CO adsorbs as a neutral molecule, significant compressive stress, up to −1.3 N/m, is induced in the Pt. The magnitude of the stress change correlates directly with the CO coverage and, within the detection limits of the stress measurement, is elastically reversible. Density functional theory calculations of a CO-bound Pt surface indicate that charge redistribution from the first atomic layer of Pt to subsurface layers accounts for the observed compressive stress induced by the charge neutral adsorption of CO. A better understanding of adsorbate-induced surface stress is critical for the development of material platforms for sensing and catalysis.

Supplemental Digital Content is available in the text

The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) “PROBE” protocol with a final diagnosis of IC; they were followed up to 30 months of age. Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks’ gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ?1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis—this warrants further study.

To advance our understanding of monogenic forms of intrahepatic cholestasis. Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype–phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Supplemental Digital Content is available in the text

Genetic susceptibility has been proposed as etiopathogenic in several pediatric liver diseases including autoimmune hepatitis (AIH). High throughput sequencing (HTPS) has been applied to archived needle liver biopsies obtained from adults but rarely to pediatric biopsies. For conclusive diagnosis of AIH, most subjects have an initial formalin-fixed paraffin embedded (FFPE) needle liver biopsy that is eventually archived and may be stored for decades. Our goal was to develop methods to utilize tissue from archived needle liver biopsies for extraction of RNA sufficient to produce HTPS data. We extracted total RNA from 45 FFPE needle liver biopsy samples (24 AIH type 1 patients and 21 controls [ages 15_11 and 19_10]; biopsy storage time 0.5–20 years) and constructed cDNA libraries that were then sequenced on an Illumina HiSeq2000 platform. Forty (89%) of the libraries produced high-quality sequences for further analyses. The average number of sequences obtained per library from HTPS was 55,136,519 (range 14,914,291–184,027,499). There was a significant inverse relationship between the number of human reads obtained and the age of the specimen (P< 2_10_7). It was possible to classify more than 90% of the reads as known genes in samples that had been stored for less than 10 years. Archived needle liver biopsies can be used for sequence based interrogation of the etiologic origins of complex liver diseases of young subjects, such as AIH.

Chronic hepatitis B virus infection is a major cause of morbidity and mortality. The aim of the study is to describe the hepatic histology in children chronically infected with hepatitis B virus living in the United States and Canada. Liver biopsies of 134 treatment-naïve children with chronic hepatitis B virus infection were scored for inflammation, fibrosis, and other histological features, and correlated with clinical and laboratory data. Sixty percentage of subjects acquired the infection vertically, 51% were male, and 69% were hepatitis B e antigen-positive at the time of the biopsy. Hepatitis B DNA levels were generally high (mean 7.70 log IU/mL), as was serum alanine aminotransferase (median 120?U/L). Using the Ishak-modified histology activity index scoring system, interface hepatitis was mild in 31%, moderate in 61%, and severe in 6%. Lobular inflammation was mild in 54%, moderate in 29%, and marked in 7%. Portal inflammation was mild in 38% and moderate in 62% of subjects. Eighteen percentage had no fibrosis, 59% had portal expansion without bridging fibrosis, 19% had bridging fibrosis, and 4% had cirrhosis. Alanine aminotransferase positively correlated with inflammation and fibrosis. Neither age, duration of infection, nor Hepatitis B virus DNA levels correlated with fibrosis. Fibrosis-4 index did not correlate with fibrosis but correlated with inflammation. Aspartate aminotransferase/platelet ratio index correlated with both inflammation and fibrosis. Chronic hepatitis B virus infection results in significant inflammation and fibrosis during childhood. Serum alanine aminotransferase is a strong indicator of the severity and extent of hepatic inflammation and fibrosis.

Adsorbates impact the surface stability and reactivity of metallic electrodes, affecting the corrosion, dissolution, and deposition behavior. Here, we use density functional theory (DFT) and DFT-based Behler–Parrinello neural networks (BPNN) to investigate the geometry, surface formation energy, and atom removal energy of stepped and kinked surfaces vicinal to Cu(100) with a c(2 × 2) Cl adlayer. DFT calculations indicate that the stable structures for the adsorbate-free vicinal surfaces favor steps with ⟨110⟩ orientation, while the addition of a c(2 × 2) Cl adlayer leads to ⟨100⟩ step faceting, in agreement with scanning tunneling microscopy (STM) observations. The BPNN calculations produce energies in good agreement with DFT results (root-mean-square error of 1.3 meV/atom for a randomly chosen set of structures excluded from the training set). We draw three conclusions from the BPNN calculations. First, Cl on the upper ⟨100⟩ step edges occupies the 3-fold hollow sites (as opposed to the 4-fold sites on the terraces), congruent with deviations of the STM height profile for the adsorbate at the upper step edge. Second, disruptions in the continuity of the halide overlayer at the steps result in significant long-range step–step interactions. Third, anisotropic metal dissolution and deposition energetics arise from phase shifts of the c(2 × 2) adlayer at orthogonal ⟨100⟩ steps. This DFT-BPNN approach offers an effective strategy for tackling large-scale surface structure challenges with atomic-level accuracy.

Observed long-term outcomes no longer reflect the survival trajectory facing pediatric liver transplant (LT) recipients today. We aimed to use national registry data and parametric models to project 20- and 30-year post-transplant outcomes for recently transplanted pediatric LT recipients. We conducted a retrospective cohort study of 13,442 first-time pediatric (age <18) LT recipients using 1987 to 2018 Scientific Registry of Transplant Recipients data. We validated the proposed method (ie, to project long-term patient and graft survival using parametric survival models and short-term data) in 2 historic cohorts (1987–1996 and 1997–2006) and estimated long-term projections among patients transplanted between 2007 and 2018. Projections were stratified by raft type, recipient age, and indication for transplant. Parsimonious parametric models with Weibull distribution can be applied to post-transplant data and used to project long-term outcomes for pediatric LT recipients beyond observed data. Projected 20-year patient survival for pediatric LT recipients transplanted in 2007 to 2018 was 84.0% (95% confidence interval 81.5–85.8), compared to observed 20-year survival of 72.8% and 63.6% among those transplanted in 1997 to 2006 and 1987 to 1996, respectively. Projected 30-year survival for pediatric LT recipients in 2007 to 2018 was 80.1% (75.2–82.7), compared to projected 30-year survival of 68.6% (66.1–70.9) in the 1997 to 2006 cohort and observed 30-year survival of 57.5% in the 1987 to 1996 cohort. Twenty- and 30-year patient and graft survival varied slightly by recipient age, graft type, and indication for transplant. Projected long-term outcomes for recently transplanted pediatric LT recipients are excellent, reflective of substantial improvements in medical care, and informative for physician-patient education and decision making in the current era.

The aim of the study was to assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at ages 3 to 12 years and evaluate variables that associate with neurodevelopment. Participants (ages 3–12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III, ages 3–5 years) and Weschler Intelligence Scale for Children, 4th edition (WISC-IV, ages 6–12 years). Continuous scores were analyzed using Kolmogorov-Smironov tests compared with a normal distribution (mean = 100 ± 15). Effect of covariates on Full-Scale Intelligence Quotient (FSIQ) was analyzed using linear regression. Ninety-three participants completed 164 WPPSI-III (mean age 3.9) and 51 WISC-IV (mean age 6.9) tests. WPPSI-III FSIQ (104 ± 14, P< 0.02), Verbal IQ (106 ± 14, P< 0.001), and General Language Composite (107 ± 16, P< 0.001) distributions were shifted higher compared with test norms. WISC-IV FSIQ (105 ± 12, P< 0.01), Perceptual Reasoning Index (107 ± 12, P< 0.01), and Processing Speed Index (105 ± 10, P< 0.02) also shifted upwards. In univariate and multivariable analysis, parent education (P< 0.01) was a significant predictor of FSIQ on WPPSI-III and positively associated with WISC-IV FSIQ. Male sex and higher total bilirubin and gamma glutamyl transferase (GGT) predicted lower WPPSI-III FSIQ. Portal hypertension was predictive of lower WISC-IV FSIQ. This cohort of children with BA and native liver did not demonstrate higher prevalence of neurodevelopmental delays. Markers of advanced liver disease (higher total bilirubin and GGT for age ?5 years; portal hypertension for age =6) correlate with lower FSIQ and may identify a vulnerable subset of patients who would benefit from intervention.

Mother-to-infant transmission (MIT) is the leading cause of hepatitis B virus (HBV) infections globally. The aim of this international study was to assess the impediments to prevention of (MIT) of HBV. A cross-sectional survey was developed by the Federation of the International Societies for Pediatric Gastroenterology, Hepatology and Nutrition. (FISPGHAN) The survey was sent to HBV experts of the 5-member societies of FISPGHAN, and 63 of 91 countries/regions responded. Main outcome measures include percentage of countries having vaccine programs, timing of the first dose of HBV vaccine, availability of HBV vaccine for outborn neonates, payment of HBV vaccine and hepatitis B immune globulin, screening HBV markers during pregnancy, and antivirals to highly infectious pregnant mothers. Among the participating countries/regions, 11% did not implement infant HBV immunization programs. The first dose of vaccine was given >24 hours in 36% of the total countries and 100% of African countries. The recommended birth dose was unavailable for outborn neonates in 45% of the total countries, including 92% of African and 50% of Latin American countries/regions. During pregnancy, 44% countries do not screen maternal viral markers, and 46% do not provide third trimester antiviral therapy for highly viremic pregnant mothers. Our study demonstrated multiple obstacles to achieving the goal of preventing MIT of HBV. Comprehensive public health programs to enhance vaccine coverage rate, supply HBV vaccine for out-born neonates, screening maternal HBV markers, treating highly viremic pregnant mothers are proposed to overcome these obstacles and achieve the goal of preventing MIT of HBV.

The aim of the study was to define chronic HBV phenotypes in a large, cohort of United States and Canadian children utilizing recently published population-based upper limit of normal alanine aminotransferase levels (ULN ALT), compared with local laboratory ULN; identify relationships with host and viral factors. Chronic hepatitis B virus (HBV) infection has been characterized by phases or phenotypes, possibly associated with prognosis and indications for therapy. Baseline enrollment data of children in the Hepatitis B Research Network were examined. Phenotype definitions were inactive carrier: HBeAg-negative with low HBV DNA and normal ALT levels; immune-tolerant: HBeAg-positive with high HBV DNA but normal ALT levels; or chronic hepatitis B: HBeAg-positive or -negative with high HBV DNA and abnormal ALT levels. Three hundred seventy-one participants were analyzed of whom 274 were HBeAg-positive (74%). Younger participants were more likely be HBeAg-positive with higher HBV DNA levels. If local laboratory ULN ALT levels were used, 35% were assigned the immune tolerant phenotype, but if updated ULN were applied, only 12% could be so defined, and the remaining 82% would be considered to have chronic hepatitis B. Among HBeAg-negative participants, only 21 (22%) were defined as inactive carriers and 14 (14%) as HBeAg-negative chronic hepatitis B; the majority (61%) had abnormal ALT and low levels of HBV DNA, thus having an indeterminant phenotype. Increasing age was associated with smaller proportions of HBeAg-positive infection. Among children with chronic HBV infection living in North America, the immune tolerant phenotype is uncommon and HBeAg positivity decreases with age.

Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals. The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues. Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed. Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P? 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P= 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining. There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.

Directed differentiation of human induced pluripotent stem cells (iPSCs) toward hepatobiliary lineages has been increasingly used as models of human liver development/diseases. As protein kinases are important components of signaling pathways regulating cell fate changes, we sought to define the key molecular mediators regulating human liver development using inhibitors targeting tyrosine kinases during hepatic differentiation of human iPSCs. A library of tyrosine kinase inhibitors was used for initial screening during the multistage differentiation of human iPSCs to hepatic lineage. Among the 80 kinase inhibitors tested, only Src inhibitors suppressed endoderm formation while none had significant effect on later stages of hepatic differentiation. Transient inhibition of c‐Src during endodermal induction of human iPSCs reduced endodermal commitment and expression of endodermal markers, including SOX17 and FOXA2, in a dose‐dependent manner. Interestingly, the transiently treated cells later developed into profibrogenic cholangiocyte‐like cells expressing both cholangiocyte markers, such as CK7 and CK19, and fibrosis markers, including Collagen1 and smooth muscle actin. Further analysis of these cells revealed colocalized expression of collagen and yes‐associated protein (YAP; a marker associated with bile duct proliferation/fibrosis) and an increased production of interleukin‐6 and tumor necrosis factor‐α. Moreover, treatment with verteporfin, a YAP inhibitor, significantly reduced expression of fibrosis markers. In summary, these results suggest that c‐Src has a critical role in cell fate determination during endodermal commitment of human iPSCs, and its alteration in early liver development in human may lead to increased production of abnormal YAP expressing profibrogenic proinflammatory cholangiocytes, similar to those seen in livers of patients with biliary fibrosis. StemCells2019;37:306–317 Cell Fate Diversion Resulting from Transient Src Inhibition During Early Endodermal Commitment of Human Pluripotent Stem Cells Inhibition of Src kinase activity during endodermal commitment of human induced pluripotent stem cells results in significantly reduced endodermal and hepatic specification in a dose‐dependent manner and a cell fate change to cells resembling abnormal fibrogenic cholangiocyte‐like cells.

Biliary atresia (BA) is the most common cause of pediatric end-stage liver disease and the etiology is poorly understood. There is no effective therapy for BA partly due to lack of human BA models. Towards developing in vitro human models of BA, disease-specific induced pluripotent stem cells (iPSCs) from 6 BA patients were generated using non-integrating episomal plasmids. In addition, to determine the functional significance of BA-susceptibility genes identified by genome-wide association studies (GWAS) in biliary development, a genome-editing approach was used to create iPSCs with defined mutations in these GWAS BA loci. Using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system, isogenic iPSCs deficient in BA-associated genes (GPC1 and ADD3) were created from healthy iPSCs. Both the BA patient-iPSCs and the knock out (KO) iPSCs were studied for their in vitro biliary differentiation potential. These BA-specific iPSCs demonstrated significantly decreased formation of ductal structures, decreased expression of biliary markers including CK7, EpCAM, SOX9, CK19, AE2, and CFTR and increased fibrosis markers such as alpha smooth muscle actin, Loxl2, and Collagen1 compared to controls. Both the patient- and the KO-iPSCs also showed increased yes-associated protein (YAP, a marker of bile duct proliferation/fibrosis). Collagen and YAP were reduced by treatment with the anti-fibrogenic drug pentoxifylline. In summary, these BA-specific human iPSCs showed deficiency in biliary differentiation along with increased fibrosis, the 2 key disease features of BA. These iPSCs can provide new human BA models for understanding the molecular basis of abnormal biliary development and opportunities to identify drugs that have therapeutic effects on BA.

Pediatricians and liver specialists in the United States and Canada continue to encounter hepatitis B virus (HBV) infection in high-risk populations, including unvaccinated children, adopted children, and immigrants. Although hepatocellular carcinoma (HCC) is a known complication of HBV, there exists a paucity of data regarding the clinical presentation of HBV-associated HCC in children in these countries. Investigators at 4 medical centers with large numbers of HBV-positive children queried their pathology and/or oncology databases to identify all cases of HBV-infected children <18 years old presenting with HCC between 1990 and 2015. Clinical data were extracted from chart review. The group identified 8 patients, 8 to 17 years old, including 6 (75%) males. All individuals were assumed to be infected through vertical transmission. Three (38%) presented initially to the emergency room, 2 (25%) to a general pediatrician, 1 (13%) to a hepatologist, and the initial location was not documented in 2 (25%) cases. Three patients were asymptomatic, but the most common symptoms were abdominal pain (50%) and fatigue (38%). Hepatomegaly was present in 5 (63%) patients. Viral load was not documented in any patient. Only 3 patients had their HBeAg status documented and all individuals were HBeAg(-) and anti-HBe(+). Aspartate aminotransferase (AST) ranged from 13 to 575 IU/L, and alanine aminotransferase (ALT) ranged from 14 to 212 IU/L; 4 patients had AST and ALT < 1.5 times the upper limit of normal. Three patients had elevated bilirubin and gamma glutamyl transpeptidase (GGT), and 3 had normal bilirubin and GGT; 1 patient had unknown bilirubin and a separate patient had unknown GGT. Alpha-fetoprotein (AFP) was elevated in 3 patients (range 2.556–7.600 ng/mL), normal in 2 patients, and not documented in 3 patients. Ultrasound was initially used to identify the tumor in 5 patients whereas computerized axial tomography scan was used in 3 patients. Six patients had multiple nodules on initial imaging. Although rare, HBV-associated HCC occurs in young children, often with normal liver enzymes, bilirubin, GGT, and AFP. Only routine imaging with ultrasound or computerized axial tomography scan consistently identified the tumor. These data may help inform screening for HCC including age of initiation and the role for imaging over laboratory testing.

The effect of the alkali-metal cation (Li+, Na+, K+, and Cs+) on the non-Nernstian pH shift of the Pt(554) and Pt(533) step-associated voltammetric peak is elucidated over a wide pH window (1–13), through computation and experiment. In conjunction with our previously reported study on Pt(553), the non-Nernstian pH shift of the step-induced peak is found to be independent of the step density and the step orientation. In our prior work, we explained the sharp peak as due to the exchange between adsorbed hydrogen and hydroxyl along the step and the non-Nernstian shift as a result of the adsorption of an alkali-metal cation and its subsequent weakening of hydroxyl adsorption. Our density functional theory results support this same mechanism on Pt(533) and capture the effect of alkali-metal cation identity and alkali cation coverage well, where increasing electrolyte pH and cation concentration leads to increased cation coverage and a greater weakening effect on hydroxide adsorption. This work paints a consistent picture for the mechanism of these effects, expanding our fundamental understanding of the electrode/electrolyte interface and practical ability to control hydrogen and hydroxyl adsorption thermodynamics via the electrolyte composition, important for improving fuel cell and electrolyzer performance.

African Americans and other minorities are known to face barriers to health care influencing their access to organ transplantation but it is not known whether these barriers exist among pediatric liver transplant waitlist candidates. We sought to determine whether outcomes on the waitlist (ie, mortality, deceased donor liver transplantation [DDLT], and living-donor liver transplantation [LDLT]) varied by race/ethnicity. National registry data were studied to estimate the race/ethnicity-specific risk of waitlist mortality, DDLT and LDLT in children (<18 years) waitlisted between March 2002 and March 2015. There was no evidence of racial/ethnic disparities in waitlist mortality. Compared to Caucasians, LDLT varied by race/ethnicity, with only 6.7% African Americans and 10.3% Hispanic children receiving LDLT compared with 12.4% Caucasian, 13.3% Asian, and 9.4% mix/other children. In an adjusted Cox proportional hazards model, African Americans were half as likely as Caucasians to use LDLT (hazard ratio [HR]: 0.410.550.73) but had similar use of DDLT (HR: 0.981.061.16). In a model that considered mortality, DDLT, and LDLT as competing risks, African Americans had significantly reduced incidence of LDLT (subhazard ratio [sHR]: 0.410.560.75) compared to Caucasians, but increased use of DDLT (sHR: 1.061.161.26). Compared to Caucasian children, African-American children are less likely to use LDLT but have higher rates of DDLT and similar survival on the waitlist. Additional research is necessary to understand the clinical and socioeconomic factors contributing to lower utilization of LDLT among African-American children awaiting transplantation.

The aim of the study was to assess the effect of treatment with ledipasvir/sofosbuvir (LDV/SOF) on the health-related quality of life (HRQL) of pediatric patients with chronic hepatitis C virus (HCV) infection. Adolescents (12–17 years) with HCV were treated with LDV/SOF (90/400 mg daily) for 12 weeks. HRQL was assessed using the PedsQLv4.0-SF15 completed by the children and caregivers before, during, and after treatment. We included 100 adolescents with HCV genotype 1 infection (14.7 ± 2.0 years, 1% known cirrhosis, 80% treatment-naïve, 97% sustained virologic response-12). At baseline, HRQL the caregiver- perceived HRQL scores were lower than adolescents’ self-reported scores (by 6.7–7.9 points, all P< 0.01). At the end of 12 weeks of treatment, however, the caregiver-reported HRQL scores showed a significant improvement (+all P< 0.04), whereas the adolescents’ self-reported scores did not change from the baseline. HRQL scores reported by caregivers remained higher than baseline (by +4.7–+7.5, P< 0.01) through 12 weeks after treatment, as did the adolescents’ self-reported Emotional Functioning scores (+4.3 from baseline, P= 0.0009); observed improvements were sustained after 24 weeks of follow-up (all P< 0.04). Multivariate analysis showed that, after adjustment for location, age, and sex, having a history of anxiety and panic disorders were consistent predictors of impaired HRQL in adolescents with HCV infection (P< 0.05). Treatment of HCV in adolescents with LDV/SOF is associated with some improvement in HRQL. Caregivers’ reports of HRQL in adolescents with HCV significantly increased with treatment and were similar to the adolescent self-reported HRQL after sustained virologic response-12.

Chronic viral hepatitis is a global health threat and financial burden. Hepatitis B and C viruses (HBV and HCV) are the most common causes of chronic viral hepatitis in the United States. Most cases are asymptomatic before adulthood. Research has resulted in effective therapy for HCV and the promise of effective therapies for HBV. For HCV, therapy is pegylated interferon and ribavirin. Clinical trials with effective direct-acting antiviral agents are underway in pediatrics. For HBV, approved agents are alpha-interferon, lamivudine, adefovir, tenofovir, and entecavir. However, treatment seldom results in functional cure and more effective therapies are urgently needed.

Supplemental Digital Content is available in the text

The aim of the study was to determine whether selected sociodemographic and hepatitis B virus (HBV)-specific clinical factors are associated with health-related quality of life (HRQoL) among pediatric patients chronically infected with HBV. Children with chronic HBV enrolled in the Hepatitis B Research Network completed the Child Health Questionnaire at study entry. Caregivers of children 5 to <10 years completed the parent-reported form (CHQ-Parent Report Form); youth 10 to <18 years completed the child-reported CHQ-Child Report Form. We examined univariable associations of the Child Health Questionnaire scores with selected independent variables: sex, adoption status, maternal education, alanine aminotransferase (U/L), aspartate aminotransferase-to-platelet ratio index, and HBV-specific symptom count. A total of 244 participants (83 young children 5–<10 years, 161 youth 10–<18 years) were included, all HBV treatment-naïve. Among young children, increased alanine aminotransferase level was negatively associated with CHQ-Parent Report Form psychosocial summary tscore (r = -0.28, P= 0.01). No other subscale comparisons for young children were statistically significant. Among youth, adoption was associated with better physical functioning and general health (P< 0.01). Higher maternal education was associated with better role/functioning-physical and -emotional scores (P< 0.05). Maternal education and adoption status were linked with adoption associated with higher maternal education. Increased symptom count in youth was associated with worse HRQoL in subscales measuring bodily pain, behavior, mental health, and self-esteem (P< 0.01). Although overall HRQoL is preserved in children with chronic HBV, some sociodemographic and HBV-related clinical factors were associated with impaired HRQoL in our pediatric patients at baseline. Measurement of HRQoL can focus resources on education and psychosocial support in children and families most in need.

Density-functional theory (DFT) has revolutionized computational prediction of atomic-scale properties from first principles in physics, chemistry and materials science. Continuing development of new methods is necessary for accurate predictions of new classes of materials and properties, and for connecting to nano- and mesoscale properties using coarse-grained theories. JDFTx is a fully-featured open-source electronic DFT software designed specifically to facilitate rapid development of new theories, models and algorithms. Using an algebraic formulation as an abstraction layer, compact C++11 code automatically performs well on diverse hardware including GPUs (Graphics Processing Units). This code hosts the development of joint density-functional theory (JDFT) that combines electronic DFT with classical DFT and continuum models of liquids for first-principles calculations of solvated and electrochemical systems. In addition, the modular nature of the code makes it easy to extend and interface with, facilitating the development of multi-scale toolkits that connect to ab initiocalculations, e.g. photo-excited carrier dynamics combining electron and phonon calculations with electromagnetic simulations.

Supplemental Digital Content is available in the text

The aim of our study was to describe the changing prevalence, demographic features, etiologies, and treatment of ascites in children hospitalized during a 27-year period at the Johns Hopkins Hospital (Baltimore, MD). We retrospectively reviewed discharges from 1983 to 2010 to select patients whose records included a diagnosis of ascites. We assessed the etiologies and degrees of ascites (ascites grade 1 detectable only by radiologic tests; ascites grades 2 and 3 recognized by moderate and marked abdominal distension by physical examinations). We classified 518 children into 9 etiology groups: intrahepatic disease (IH) (105), hepatic vein outflow obstruction (HVOO) (45), congestive heart disease (CH) (33), nephrotic syndrome (NS) (36), pancreatitis (26), inflammatory and infectious diseases (77), malignancy (49), idiopathic (71), and miscellaneous (76). IH and CH were predominant in the younger age group (0–5 years) versus HVOO, pancreatitis, and malignancy in the older age group (13–21 years) (P< 0.001). The prevalence of ascites increased over time from 1983 to 2006 and declined thereafter. Ascites grade 1 was more common than ascites grades 2 and 3 in all the groups (P= 0.048). IH and NS were more likely to have ascites grade 2 and 3 (P= 0.02). Although spironolactone was more frequently used in the IH group versus other etiologies, furosemide was used more frequently in NS and CH versus other etiologies (P< 0.001). The increased prevalence of ascites during the initial study period could reflect improved detection radiologic detection. The proportion of severe ascites and the various medical treatments differed among the etiologic groups.

No long-term data have been published on the durability of response following pegylated interferon (PegIFN) treatment in children with chronic hepatitis C. This prospective, multicenter, long-term follow-up (LTFU) study aimed to assess long-term durability of sustained virological response (SVR), long-term safety and tolerability, and the association between IL28Bgenotype and treatment response, in children previously treated with PegIFN alfa-2a?±?ribavirin (RBV) in the PEDS-C trial. A total of 93 patients were assessed for enrollment, and 38 enrolled in the study. Patients attended 2 study visits: 5 (mean 5.6, range 4.1–6.6) and 6 (6.6, 5.1–7.7) years after treatment cessation. Standardized medical history, physical examination, and laboratory testing were performed at these visits. Reminder telephone calls were conducted at 4 and 8 months after the initial visit. The LTFU cohort was the representative of the original PEDS-C cohort because both baseline and treatment characteristics were comparable. Of the 38 participants, 21 achieved SVR (responders) during the PEDS-C trial and 17 had not (nonresponders). All 21 responders maintained undetectable hepatitis C virus RNA during the LTFU (4.4–7.0 years after achieving SVR) in contrast to the nonresponders who demonstrated persistent viremia. IL28BCC genotype was associated with SVR (67% vs 30% in non-CC, P?=?0.028). Long-term durability of SVR is excellent following PegIFN alfa-2a treatment in children with chronic hepatitis C; SVR is higher in those with IL28BCC versus non-CC.