Clinical and experimental aspects of hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatnc syndrome associated with severe liver disease. Clinical symptoms range from minimal changes in mental state and neuromuscular defects to unresponsive coma. 1-' The syndrome of HE can be divided into three major groups: HE associated with liver cirrhosis, HE associated with acute liver necrosis and HE associated with errors of metabolism (table I). HE is most often observed in patients with cirrhosis of the liver, either as a result of decreased hepatic parenchymal function or as a result of increasing portal-systemic shunting without liver insufficiency (also defined as portal-systemic encephalopathy 1 - ')_ In patients with cirrhosis, HE can be induced or aggravated by a number of precipitating factors (table 2). ' HE associated with acute liver necrosis has a dramatic clinicaJ course, leading to acute liver failure in most patients. Apart from jaundice, HE can be the first alarming symptom of acute liver failure. The degree of HE is a strong predictor of outcome in acute liver failure~ patients who only reach grade II HE have a possibility of spontaneous recovery of 65 - 70 %; with grade III HE it is 40 - 50 % and in grade IV HE it is only 20 %. In the majority of patients with grade III HE cerebral edema is present, which can evolve to an increase in intracranial pressure, cerebral herniation and death.

Pharmacogenomic testing in paediatrics: Clinical implementation strategies

Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well-recognised barriers to obtaining high-quality PGx evidence, particularly when patient numbers may be small, and off-label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost-effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy

The identification of celiac disease in asymptomatic children: the Generation R Study

Background: The objective of our study was to assess whether TG2A levels in the healthy childhood population can be predictive of subclinical CD. Methods: A total of 4442 children (median age, 6.0 years) participating in a population-based prospective cohort study were screened on serum TG2A. Those with positive TG2A (≥7 U/ml; n = 60, 1.4%) were invited for clinical evaluation (median age, 9.0 years). Medical history, physical examination, serum TG2A, and IgA-endomysium (EMA) were assessed, as well as HLA DQ 2.2/2.5/8 typing. Patients with positive serologies and genetic risk types underwent duodenal biopsies. TG2A levels at the time of biopsy were compared with the degree of enteropathy. Results: Fifty-one TG2A-positive children were included in the follow-up: 31 (60.8%) children had CD, ten (19.6%) did not have CD, and ten (19.6%) were considered potential CD cases because of inconclusive serologies. Duodenal biopsies were performed in 26/31 children. CD with Marsh 3a/b enteropathy was observed in 75% (15/20) of children having TG2A levels ≥10ULN at 6 years of age, as well as in 75% (6/8) of children having a positive TG2A <10 ULN (OR 1.00; 95% CI 0.15–6.64). CD cases had a lower BMI SDS (mean −0.49, SD 0.92) than children without CD (mean 0.47, SD 1.37; p = 0.02). No differences were observed in gastrointestinal symptoms. Conclusions: Serum TG2A screening at 6 years of age in the healthy childhood population has a positive predictive value of 61% to detect subclinical CD. We did not find a positive correlation between serum TG2A levels and the degree of enteropathy

Psychological Outcomes of a Cognitive Behavioral Therapy for Youth with Inflammatory Bowel Disease: Results of the HAPPY-IBD Randomized Controlled Trial at 6-and 12-Month Follow-Up

Youth with infammatory bowel disease (IBD) often experience psychological difculties, such as anxiety and depression. This randomized controlled study tested whether a 3-month disease-specifc cognitive behavioral therapy (CBT) in addition to standard medical care versus standard medical care only was efective in improving these youth’s psychological outcomes. As this study was aimed at prevention, we included 70 youth (10–25 years) with IBD and symptoms of subclinical anxiety and/ or depression, and measured psychological outcomes at 6- and 12-month follow-up. In general, participants in both groups showed improvements in anxiety, depression, health-related quality of life, social functioning, coping, and illness perceptions, sustained until 12 months follow-up. Overall, we found no diferences between those receiving additional CBT and those receiving standard medical care only. We assume that this can be explained by the perceived low burden (both somatically and psychologically) or heightened awareness of psychological difculties and IBD

Gut-directed hypnotherapy in children with irritable bowel syndrome or functional abdominal pain (syndrome): A randomized controlled trial on self exercises at home using CD versus individual therapy by qualified therapists

Background: Irritable bowel syndrome (IBS) and functional abdominal pain (syndrome) (FAP(S)) are common pediatric disorders, characterized by chronic or recurrent abdominal pain. Treatment is challenging, especially in children with persisting symptoms. Gut-directed hypnotherapy (HT) performed by a therapist has been shown to be effective in these children, but is still unavailable to many children due to costs, a lack of qualified child-hypnotherapists and because it requires a significant investment of time by child and parent(s). Home-based hypnotherapy by means of exercises on CD has been shown effective as well, and has potential benefits, such as lower costs and less time investment. The aim of this randomized controlled trial (RCT) is to compare cost-effectiveness of individual HT performed by a qualified therapist with HT by means of CD recorded self-exercises at home in children with IBS or FAP(S).Methods/Design: 260 children, aged 8-18 years with IBS or FAP(S) according to Rome III criteria are included in this currently conducted RCT with a follow-up period of one year. Children are randomized to either 6 sessions of individual HT given by a qualified therapist over a 3-month period or HT through self-exercises at home with CD for 3 months.The primary outcome is the proportion of patients in which treatment is successful at the end of treatment and after one year follow-up. Treatment success is defined as at least 50% reduction in both abdominal pain frequency and intensity scores. Secondary outcomes include adequate relief, cost-effectiveness an

Evaluation of exclusive enteral nutrition and corticosteroid induction treatment in new-onset moderate-to-severe luminal paediatric Crohn's disease

To induce remission in luminal paediatric Crohn's disease (CD), the ESPGHAN/ECCO guideline recommends treatment with exclusive enteral nutrition (EEN) or oral corticosteroids. In newly diagnosed moderate-to-severe paediatric CD patients, we determined the proportion of patients in which EEN or corticosteroids induced remission and maintained remission on azathioprine monotherapy. We included patients from the "TISKids" study assigned to the conventional treatment arm. Patients were aged 3-17 years and had new-onset, untreated luminal CD with weighted paediatric CD activity index (wPCDAI)> 40. Induction treatment consisted of EEN or oral corticosteroids; all received azathioprine maintenance treatment from start of treatment. The primary outcome of this study was endoscopic remission defined as a SES-CD score Conclusion: In children with moderate-to-severe newly diagnosed CD, induction treatment with EEN or CS regularly is insufficient to achieve endoscopic remission without treatment escalation at week 10.Peer reviewe

Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease

Background: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. Aim: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. Methods: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. Results: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03–2.35, p = 0.036). Conclusions: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. Trial registration number: NCT02517684

First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: An open-label multicentre randomised controlled trial

Objective: In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. Design: In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. Results: 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was no

Quality indicators for patients with traumatic brain injury in European intensive care units

Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measur