The long-term histological outcome after pediatric liver transplantation (OLT) is not yet fully understood. De novo autoimmune hepatitis, consisting of histological chronic hepatitis associated with autoantibody formation and allograft dysfunction, is increasingly recognized as an important complication of liver transplantation, particularly in the pediatric population. In this study, 158 asymptomatic children with 5-year graft survival underwent protocol liver biopsies (113, 135, and 64 at 1, 5, and 10 years after OLT, respectively). Histological changes were correlated with clinical, biochemical, and serological findings. All patients received cyclosporine A as primary immunosuppression with withdrawal of corticosteroids at 3 months post OLT. Normal or near-normal histology was reported in 77 of 113 (68%), 61 of 135 (45%), and 20 of 64 (31%) at 1, 5, and 10 years, respectively. The commonest histological abnormality was chronic hepatitis (CH), the incidence of which increased with time [25/113 (22%), 58/135 (43%), and 41/64 (64%) at 1, 5, and 10 years, respectively) (P < .0001)]. The incidence of fibrosis associated with CH increased with time [13/25 (52%), 47/58 (81%), and 37/41 (91%) at 1, 5, and 10 years, respectively) (P < .0001)]. The severity of fibrosis associated with CH also increased with time, such that by 10 years 15% had progressed to cirrhosis. Aspartate aminotransferase (AST) levels were slightly elevated in children with CH (median levels 52 IU/L, 63 IU/L, and 48 IU/L at 1, 5, and 10 years, respectively), but this did not reach statistical significance compared with those with normal histology. On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity (present in 13% and 10% of children with normal biopsies at 5 and 10 years, respectively, and 72% and 80% of those with CH at 5 and 10 years, respectively) (P < .0001). Four children with CH and autoantibodies, who also had raised immunoglobulin G (IgG) levels and AST greater than 1.5؋ normal fulfilled the diagnostic criteria for de novo autoimmune hepatitis (AIH). Another two were found to be hepatitis C positive. No definite cause for CH could be identified in the other cases. In conclusion, chronic hepatitis is a common finding in children after liver transplantation and is associated with a high risk of developing progressive fibrosis, leading to cirrhosis. Standard liver biochemical tests cannot be relied on either in the diagnosis or in the monitoring of progress of chronic allograft hepatitis. In contrast, the presence of autoantibodies is strongly associated with the presence of CH. The cause of chronic hepatitis in transplanted allografts is uncertain but may be immune mediated, representing a hepatitic form of chronic rejection.

Cough is a common symptom of many respiratory diseases. The evaluation of its intensity and frequency of occurrence could provide valuable clinical information in the assessment of patients with chronic cough. In this paper we propose the use of hidden Markov models (HMMs) to automatically detect cough sounds from continuous ambulatory recordings. The recording system consists of a digital sound recorder and a microphone attached to the patient's chest. The recognition algorithm follows a keyword-spotting approach, with cough sounds representing the keywords. It was trained on 821 min selected from 10 ambulatory recordings, including 2473 manually labeled cough events, and tested on a database of nine recordings from separate patients with a total recording time of 3060 min and comprising 2155 cough events. The average detection rate was 82% at a false alarm rate of seven events/h, when considering only events above an energy threshold relative to each recording's average energy. These results suggest that HMMs can be applied to the detection of cough sounds from ambulatory patients. A postprocessing stage to perform a more detailed analysis on the detected events is under development, and could allow the rejection of some of the incorrectly detected events.

Currently, there are no interferon-free treatments available for hepatitis C virus (HCV)-infected patients younger than 12 years. We evaluated the safety and effectiveness of the all-oral regimen ledipasvir-sofosbuvir ± ribavirin in HCV-infected children aged 6 to<12 years. In an open-label study, patients aged 6 to <12 years received ledipasvir 45 mg-sofosbuvir 200 mg as two fixed-dose combination tablets 22.5/100 mg once daily, with or without ribavirin, for 12 or 24 weeks, depending on HCV genotype and cirrhosis status. The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Twelve patients underwent intensive pharmacokinetic sampling to confirm the appropriateness of the ledipasvir and sofosbuvir dosages. Ninety-two patients were enrolled (88 genotype 1, 2 genotype 3, and 2 genotype 4), with a median age of 9 years (range, 6-11). Most were perinatally infected (97%) and treatment-naive (78%). Two were confirmed to have cirrhosis, while the degree of fibrosis was unknown in 55 patients. The overall SVR12 rate was 99% (91/92; 95% confidence interval, 94%-100%). The single patient not reaching SVR relapsed 4 weeks after completing 12 weeks of treatment. The most common adverse events were headache and pyrexia. One patient had three serious adverse events, which were considered to be not related to study treatment: tooth abscess, abdominal pain, and gastroenteritis. The area under the concentration-time curve and maximum concentration values for sofosbuvir, its primary metabolite GS-331007, and ledipasvir were within predefined pharmacokinetic equivalence boundaries (50%-200%) compared to values in adults in phase 2/3 of the ledipasvir and sofosbuvir studies. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 6 to <12 years old with chronic HCV.

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In 92% children with renal dysfunction after OLT, MMF treatment provided safe and effective immunosuppression and allowed CsA or Tac to be discontinued or reduced, leading to improvement of renal function. The improvement was greatest in younger children and those who began MMF early postOLT. Side effects were uncommon. Additional steroid cover during the transfer to MMF should be considered to prevent liver-allograft rejection.

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