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Background and aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. Approach and results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced >= 1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and = 5.0 and = 10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those 10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to = 5.0 mg/dl, with 79% reaching adulthood with native liver (p < 0.001). Conclusions: in this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB, This study received funding support from the following agencies: The Alagille Syndrome Alliance, Mirum Pharmaceuticals Inc. and Albireo Pharma, Inc. who provided unrestricted educational grants to the Hospital for Sick Children (SickKids Foundation). The study sponsors were not involved in the conduct of the research study or preparation of the manuscript.

BACKGROUND AND OBJECTIVES: After two doses of mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients on dialysis show a defective humoral response, but a third dose could increase anti–SARS-CoV-2 spike IgG titers. Responses could be different in virus-naive and SARS-CoV-2–recovered patients on dialysis. However, characterization of memory B cell response after three doses is lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated the dynamics of antireceptor binding domain IgG titers and antireceptor binding domain memory B cells until 6 months after two and three doses (administered within 6 months after the second dose) of mRNA vaccine in SARS-CoV-2–recovered and virus-naive dialysis populations. Results were analyzed by ordinary one-way ANOVA, the Kruskal–Wallis test, or the Wilcoxon matched-pairs test as appropriate. RESULTS: In total, 108 individuals (59 patients on dialysis and 49 controls) were included. In virus-naive patients on dialysis, antireceptor binding domain IgG response was quantitatively lower after two doses compared with healthy controls, but IgG titers increased by three-fold after three doses (P=0.008). In SARS-CoV-2–recovered patients on dialysis, antireceptor binding domain IgG titers after two doses were significantly higher compared with virus-naive patients on dialysis but did not significantly increase after a third dose. Regarding memory B cell response, we detected receptor binding domain–specific memory B cells at similar proportions in virus-naive patients on dialysis and vaccinated controls after two doses. Moreover, a strong receptor binding domain–specific memory B cell expansion was observed after the third dose in virus-naive patients on dialysis (5.5-fold; P

Background and Aims Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV‐infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. Approach and Results Children with chronic HCV infection, genotype 1‐6, with or without compensated cirrhosis, were divided into three cohorts by age—cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)—and given weight‐based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady‐state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug‐related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. Conclusions A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV‐infected children 3 to < 12 years old.

Aims and background Ophthalmic abnormalities are amongst the five major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudo-papilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report nine pediatric cases of ALGS with bilateral papilledema, five of which were diagnosed with ICHT. Methods The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation for other indications were also analyzed. Results Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all nine patients were normal. These nine patients were categorized into four groups: (1) a non-transplant group (n = 1), (2) a group with pretransplant papilledema persistent after liver transplantation (LT) (n = 2), (3) a group with papilledema occurring after LT with spontaneous resolution (n = 2), and (4) a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in two of the five cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT. Conclusions True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.

utoimmune hepatitis (AIH) can lead to progressive fibrosis in patients refractory to conventional therapy with prednisolone and azathioprine. The use of mammalian target of rapamycin (mTOR) inhibitors has recently emerged in refractory AIH, but no data have been published about everolimus in pediatric AIH to date. Our aim was to share our experience about everolimus as a second-/third-line therapy in pediatric AIH. Methods: Pretransplant AIH patients aged 0-18 years who received everolimus therapy from 2014 to 2021 were retrospectively identified. All patients underwent regular plasma monitoring of everolimus trough levels to avoid toxicity and assess adherence. Special attention was paid to the clinical and biochemical occurrence of everolimus-related adverse events. Results: We report six difficult-to-treat AIH patients who received everolimus therapy for 8-46 months (median 28 months). No side effects were reported when everolimus plasma trough levels were in the therapeutic range. Liver transaminases improved in 5 of 6 patients at everolimus introduction and significantly decreased at the last follow-up (FU) in our cohort (P < 0.05). None of our patients achieved complete biochemical remission at the last FU and 3 of 6 admitted to have suboptimal adherence to therapy. Conclusions: Our data bring preliminary safety for the use of everolimus as a second-/third-line therapy in pediatric AIH. Although liver transaminases improved in our cohort, prospective studies are needed to determine if everolimus can induce long-term remission.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged

Nonalcoholic fatty liver disease (NAFLD) is an emerging entity, becoming the most prevalent pediatric chronic liver disease. Its broad spectrum of histological findings, comorbidities, and complications, including cirrhosis and liver failure, can occur in childhood, emphasizing the severity of pediatric NAFLD. Current lifestyle and diet modifications have been linked to the increasing prevalence of NAFLD, including the rise of fructose consumption, a monosaccharide present in foods that contain added sugar, such as sugar-sweetened beverages. Excessive fructose consumption is believed to cause addiction like alcohol and other drugs. As such, the new term "fructoholism" refers to the consumption of a substance (fructose) that can cause psychological and physical damage and become a major public health concern, highlighting the seriousness of the excessive consumption of fructose in the pediatric age. Hepatic fructose metabolization leads to hepatic steatosis and progression to fibrosis through mechanisms comparable to alcoholic liver disease, hence the term "fructoholic liver disease." Conclusion: The importance of implementing reliable global strategies, such as education campaigns to promote healthy diet, increasing taxes on foods that contain added sugars, subsidies to promote accessibility to fruit and vegetables, and strict food industry regulation to reduce sugar intake in children and adolescents, cannot be overemphasized. info:eu-repo/semantics/publishedVersion

Sodium taurocholate cotransporter polypeptide (NTCP), mainly expressed on the sinusoidal membrane of hepatocytes, is one of the major transporters responsible for liver bile acid (BA) re-uptake. NTCP transports conjugated BA from the blood into hepatocytes and is crucial for correct enterohepatic circulation. Studies have shown that insufficient hepatic clearance of BA correlates with elevated serum BA in infants younger than 1 year of age. In the current study, we investigated human NTCP messenger RNA and protein expression by using reverse-transcription quantitative polymerase chain reaction and immunoblotting in isolated and cryopreserved human hepatocytes from two different age groups, below and above 1 year of age. Here, we show that NTCP messenger RNA expression is not modulated whereas NTCP protein posttranslational glycosylation is modulated in an age-dependent manner. These results were confirmed by quantification analysis of NTCP 55-kDa N-glycosylated bands, which showed significantly less total NTCP protein in donors below 1 year of age compared to donors older than 1 year. NTCP tissue localization was also analyzed by means of immunofluorescence. This revealed that NTCP cellular localization in fetal samples was mainly perinuclear, suggesting that NTCP is not glycosylated, while its postnatal localization on the plasma membrane is age dependent compared to multidrug resistant protein 2, which is apical starting in fetal life. Conclusion: After birth, the NTCP age-dependent maturation process requires approximately 1 year to complete NTCP glycosylation in human hepatocytes. Therefore, NTCP late posttranslational glycosylation appears to be important for correct NTCP membrane localization, which might explain physiologic cholestasis in neonatal life and might play a central role for HBV infection after birth. (Hepatology Communications 2018;2:693-702).

Objectives and Study: Ophthalmic abnormalities are amongst the 5 major criteria for diagnosing autosomal dominant Alagille syndrome (AS), of which embryotoxon, pseudo-papilledema (PPO), and pigmentary retinopathy are the most common. Papilledema (PO), with or without intracranial hypertension (ICHT)/pseudotumor cerebri syndrome (PTCS), are rarely described. We here report 9 cases of bilateral PO in an AS cohort, 5 of whom were diagnosed with PTCS that occurred after liver transplantation. Methods: We reviewed ophthalmologic examination data from 85 pediatric patients with clinically (n = 48) and/or genetically (n = 37) proven AS, who were followed in 2 referral hospitals (UCL St Luc Brussels, n = 75; HUG Geneva, n = 10). Patients who received liver transplantation (LT) (n = 40) were compared with pediatric patients (n = 40) with LT for indications other than AS. Results: Sixty-nine patients fulfilled the inclusion criteria; the PO incidence in this cohort was 13% (9/69, 13%). Forty of these patients (40/69, 58%) underwent LT, of whom 2 developed true PO before LT and 6 developed PO after LT (6/40, 15%). One non-LT child (1/28, 3%) had PO, but had a normal neurological examination and rapid resolution. PO resolved spontaneously or remained stable without complications in 4 patients (2 with pre-transplant onset) (4/69, 6%). The remaining 5 patients had a normal neurological examination and cerebral magnetic resonance imaging findings (5/69, 7%). Probable PTCS was diagnosed in 1 patient and definite PCTS was diagnosed in 4 patients. PTCS was treated with steroids alone in 1 patient, and in combination with acetazolamide in 2 patients. In 2 of these 3 patients, ventriculo-peritoneal derivation was ultimately required for severe progressive visual loss. PPO was present in 10 other (10/69, 10%). One patient in the non-AS cohort had PO, yielding an incidence of 2.5% (1/40). Conclusions: True PTCS may be underdiagnosed in AS, but should be considered as a feature of this syndrome. Our findings supports the necessity of close follow-up of ophthalmologic complications before and/or after LT, because of the risk of severe and irreversible loss of vision.

Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose of analyzing their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplantation (LT) recipients were assessed at 6 months, 3 years, and 7 years after LT. The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining, and the amount of fibrosis, identified by picrosirius red (PSR%) staining, were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Liver allograft fibrosis displayed progression over time by PSR% (P < 0.001) and by LAFSc (P < 0.001). The ASMA expression decreased in the long term, with inverse evolution with respect to fibrosis (P < 0.01). Patients with ASMA-positive HSCs area ≥ 8% at 6 months (n = 20) developed a higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n = 34) at the same period of time and in the long term (P = 0.03 and P < 0.01, respectively), but not at 3 years (P = 0.8). ASMA expression ≥ 8% at 6 months was found to be an independent risk factor for 7-year fibrosis development by PSR% (r(2) = 0.5; P < 0.01) and by LAFSc (r(2) = 0.3; P = 0.03). Furthermore, ASMA expression ≥ 8% at 3 years showed an association with the development of fibrosis at 7 years (P = 0.02). In conclusion, there is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and longterm fibrosis development. In addition, activated HSCs showed inverse evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD.

Background: A serogroup B meningococcal vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a "toddler" booster dose are essential to optimize vaccine utilization. Methods: An open-labeled, multicenter phase-2b follow-on European study conducted from 2009 to 2012. Participants previously receiving 4CMenB with routine vaccines at 2, 4 and 6 or 2, 3 and 4 months (246Con and 234Con) or at 2, 4 and 6 months intercalated with routine vaccines (246Int) received a booster dose at 12, 18 or 24 months. 4CMenB-naive "Control" participants aged 12, 18 or 24 months received 2 doses of 4CMenB 2 months apart. Results: One thousand five hundred eighty-eight participants were recruited. At 12 months, before any booster doses, the proportions with hSBA titers >= 1:5 for strain 44/76-SL (testing vaccine component fHBP) were 73% (120/165) for the "246Con" group, 85% (125/147) for "246Int," 57% (51/90) for "234Con" and 13% (26/199) for Controls. For strain 5/99 (NadA) proportions were >= 96% (all 4CMenB-recipients) and 1% (Controls). For strain NZ98/254 (PorA), these were 18-35% (4CMenB-recipients) and 1% (Controls). By 24 months, 4CMenB-recipient proportions were 13-22% (44/76-SL), 82-94% (5/99) and 7-13% (NZ98/254) and in controls = 95% of previously immunized participants had titers >= 1:5 (all strains). Conclusions: A 4CMenB booster-dose can overcome waning hSBA titers after early-infant immunization. Administration at 12 months could help to maintain immunity during an age of high risk, and the persistence of this response requires further study.

To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance.LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field.Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate.Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (n = 58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; P = 0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; P = 0.041), but only in BA patients.LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.

The diagnostic role of endoscopic ultrasound (EUS) in children has only recently been demonstrated, and that to a lesser extent than in adults. Data on the technique's therapeutic indications remains scarce. We therefore sought to evaluate diagnostic and interventional EUS indications, safety, and impact in children with pancreaticobiliary disorders.

We investigated predictors of clinical evolution in progressive familial intrahepatic cholestasis type 2 patients and how they relate to bile salt export pump (BSEP) expression and its (re)targeting. Our retrospective study included 22 children with progressive familial intrahepatic cholestasis type 2. Clinical, biochemical, and histological characteristics were reviewed on admittance and following treatment with either ursodeoxycholic acid alone (10 mg/kg thrice daily, n = 19) or partial biliary diversion (n = 3). Immunostaining of BSEP was performed in 20 patients. Response to treatment was defined as normalization of pruritus, disappearance of jaundice, and alanine aminotransferase (ALT) levels1.5 times the upper limit of normal. Ten of 22 patients were responders, and paired biopsies were available in six. De novo or retargeted canalicular expression of BSEP occurred in four of these six, two of whom exhibited baseline intracellular expression. Twelve of 22 were nonresponders and exhibited earlier onset of jaundice (9 months), neonatal cholestasis, and higher ALT levels. An ALT165 IU/L produced 72% sensitivity and 55% specificity in predicting nonresponse. Seven patients were still responding at last follow-up (median = 20 months, range 5-67 months). Three responders relapsed after 56, 72, and 82 months, respectively. Of nine surviving responders, median relapse-free survival time was 72 months (95% confidence interval 48-96 months) and 5-year relapse-free survival was 75% (95% confidence interval 33-100%). Intracellular BSEP at baseline was seen in six, of whom five were responders. Genetic analysis was performed in 17 of 22, confirming diagnosis in 13 (76%) and in four (24%) in whom only heterozygous mutation was identified.De novo or retargeted canalicular expression of BSEP occurs in treatment responders; children with late-onset presentation, lower ALT, and intracellular BSEP expression are likely to respond, at least transiently, to nontransplant treatment.

The management of esophageal varices (EV) in children experiencing biliary atresia (BA) remains controversial. Recent studies in children proposed initiating a prophylactic treatment in patients with severe (grade III) EV and/or EV associated with red color signs. Our study was aimed at assessing the risk of bleeding from EV in a series of patients with BA, identifying risk factors for bleeding to develop a predictive model of bleeding.This was a retrospective study including 83 eligible patients with BA. Clinical, ultrasonographic, endoscopic, and laboratory parameters were studied from the beginning of medical management up to the occurrence of upper gastrointestinal bleeding. In patients not presenting any bleeding, data were analyzed until liver transplantation, endoscopic treatment of EV was performed, or last follow-up. Risk factors were investigated using univariate and multivariate statistical analyses.Seventeen of 83 patients (20%) presented gastrointestinal bleeding, with a median age of 9.5 months (6-50 months). In univariate and multivariate analyses, high-grade EV, red color signs on endoscopic examination, and low fibrinogen levels, at first endoscopy, were identified as risk factors for bleeding. When tested in10,000 different models, these 3 variables appeared to play the most significant role in predicting bleeding.Our study confirmed that grade III EV and red color signs are risk factors for bleeding in patients followed up for BA. We identified low fibrinogen levels as an additional risk factor. The relevance of these 3 factors to predict bleeding from EV requires validation in a prospective study.

Objectives and study: Hepatocellular adenoma (HCA) is a benign tumor occurring in a non cirrhotic liver. HCA may be symptomatic due to hemorrhage, compression or malignant transformation; however, the tumor is mostly found incidentally. In children, HCA develops in patients with underlying diseases such as MODY3, portosystemic shunt, glycogenosis or sexual hormone imbalance. In adults, HCA can be subclassified according to their immunophenotype and genotype. However exceptionally described, HCA might complicate with malignant transformation. Risk factors for transformation are poorly understood in pediatrics. We aimed to investigate the immunophenotype and natural evolution of HCA in pediatric patients. We further searched predictors of malignant transformation according to tumor immunophenotype. Finally, we assessed the usefulness of alpha-fetoprotein and imaging techniques in early diagnosis of HCC. Methods: Our retrospective, single center study included 13 children with HCA. Clinical, biochemical, imaging and histologic characteristics were reviewed on admittance and during follow-up. Results: Thirteen patients were followed for HCA of whom 2 girls and 11 boys. Seven had multiple lesions. Eight HCA were discovered during routine ultrasound follow-up of the underlying liver disease, 4 by chance and 1 had an enlarged liver on physical examination. All patients presenting HCA had an underlying risk factor for developing adenomas: 1 was diagnosed with MODY3, 4 with glycogenosis, 7 with portosystemic shunts or intrahepatic vascular anomalies and 1 had Mc Cune Albright. HCA could be categorized into 4 distinct groups after immunophenotyping: inflammatory (n=1), beta-catenin mutated (B-HCA, n=2), HNF1alpha mutated (n=4) and unclassified adenoma (n=1); three of the tumors had a combined inflammatory and B-HCA phenotype. HCA transformed in hepatocellular carcinoma (HCC) in three patients, at a mean age of 19 years (range 11-24 years). All these patients had a B-HCA immunophenotype and only one of them had a high alpha-fetoprotein. Ultrasound was poorly sensitive to early diagnose HCC. Contrast enhanced MRI was the most accurate imaging modality to distinguish HCA from HCC. Conclusion: HCA in children could be classified according to immunophenotype and may transform. Children with beta-catenin mutated HCA are the most at risk to evolve to hepatocellular carcinoma. Contrast MRI imaging is recommended to follow-up HCA as it is the most sensitive technique, and neither alpha-fetoprotein and ultrasound are sufficiently accurate to formally rule out HCC.

Most children with chronic hepatitis C are infected vertically, have a low natural seroconversion rate, and carry a lifetime risk of cirrhosis and cancer. Affected children are usually asymptomatic, and histological findings are mild with a low risk of progression, although 5% develop significant liver disease in childhood. The use of combination treatment with pegylated interferon-α and ribavirin has changed the outcome and prognosis for this disease, with approximately 60% of children achieving sustained viral clearance. Combination therapy is not ideal for children because pegylated interferon is administered subcutaneously, impairs growth velocity, and both interferon and ribavirin have significant adverse effects that affect compliance. In addition, approximately 50% of children infected with genotype 1 do not respond to therapy. Thus, additional treatment options are required including improvement in dosing, reduction in the length of treatment, and evaluation of new drugs, such as protease inhibitors, which could be more effective for patients infected with genotype 1. The primary goal of treatment is to eradicate the infection. The future clinical trial design should ensure that any new drugs demonstrate noninferiority to the present standard regimen in both children and adults. The measure for documenting substantial improvement above present therapy should be increased viral clearance rate or the same clearance rate, with a shorter duration of treatment and/or fewer adverse effects. We do not believe there is any need for a placebo arm because approved therapy is available and new treatments can be compared with present therapy. Safety measures should include the standard recommended laboratory investigations, growth parameters, quality-of-life or psychological measures, and a requirement for long-term follow-up for up to 5 years.

Purpose: Semen analysis is a common laboratory procedure but few data are available to support recommendations as to whether centrifugation is necessary in the post-vasectomy context. We evaluated the accuracy of a pre-centrifugation determination of azoospermia compared with post-centrifugation results.Materials and Methods: We conducted a secondary analysis of data from 3,205 semen analyses performed during a randomized clinical trial of 2 vasectomy techniques—ligation and excision with fascial interposition vs ligation and excision without fascial interposition. We performed brief, initial microscopic examinations to categorize sperm numbers per high power field to decide whether centrifugation or dilution was needed before estimation of sperm concentration. For specimens initially categorized as azoospermic, we reviewed the post-centrifugation semen analysis results to estimate the accuracy of the initial finding.Results: Of 2,104 samples categorized as azoospermic before centrifugation, post-centrifu...

This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to 7 to 12 to

Purpose of review Hepatocyte transplantation is gaining increasing interest among clinicians, because it has now been shown to be feasible and well tolerated, with demonstrated clinical benefit. It is less invasive than orthotopic liver transplantation, preserving the native liver, avoiding early technical complications and the consequences of long-term I progressive graft damage. The technique ideally suits patients with inborn errors of metabolism, either as a full treatment option, or in more severe situations as a bridge to transplantation. Hepatocyte transplantation in these patients can bring metabolic control for variable periods of time, up to 18 months after infusions. The current review will focus on the recent developments of new strategies and discuss their potential benefits for the improvement of liver regenerative medicine using cell therapy. Recent findings No new cases of hepatocyte transplantation have been reported since 2006, whereas appreciable advances have been published in the fields of liver stem cells, hepatocyte cryopreservation and the control of rejection. Summary These developed strategies may help to improve the efficacy of the technique by understanding the outcome of transplanted cells, and on this basis may limit their loss after transplantation and evaluate the benefit of the use of stem cell sources.

Background: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Aβ 42 as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. Methods: We determined the ratio of CSF tau/Aβ 42 (T/Aβ) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). Results: We identified 16% of the control group with abnormally elevated CSF T/Aβ; all were 53 years or older. Using age-matched controls with normal CSF T/Aβ we showed that the high CSF T/Aβ subgroup of controls had significantly increased frequency of the e4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. Conclusions: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.

Liver cell transplantation (LCT) aims to correct inborn liver function defects by infusing metabolically active cells into the diseased liver. Further improvement in LCT might depend on the prevention of early loss of transplanted cells. As tissue factor (TF)-dependent activation of coagulation was found to contribute to a low rate of beta cell engraftment in islet transplantation, we investigated the potential procoagulant activity (PCA) of hepatocyte preparations. TF expression on hepatocyte preparations was assessed by flow cytometry, reverse-transcription polymerase chain reaction and immunofluorescence. PCA depending on TF was evaluated in human plasma and in whole blood systems. Coagulation parameters were followed by routine techniques in a LCT recipient Crigler-Najjar patient. We determined that hepatocytes express soluble and membrane-bound forms of TF. We showed that hepatocytes exert a TF-dependent PCA. In parallel, delayed increase in D-dimer levels was observed following the hepatocyte infusions in the Crigler-Najjar patient. Furthermore, in vitro experiments demonstrated that TF-dependent PCA of hepatocytes is inhibited by N-acetyl-L-cysteine. In conclusion, hepatocytes exert TF-dependent PCA, which may contribute to early loss of infused cells. Addition of N-acetyl-L-cysteine to the suspensions of hepatocytes might be beneficial in LCT by inhibiting activation of coagulation.