Outbreak of indeterminate acute liver failure in children with adenoviraemia - Not a new disease.

BACKGROUND & AIMS: In the year 2022, an outbreak of indeterminate acute hepatitis and indeterminate paediatric acute liver failure (ID-PALF) in association with adenoviraemia in immunocompetent children was reported in the UK. We postulate that this association is not a new disease in immunocompetent children. METHODS: Children with acute hepatitis during the outbreak who were referred to King's College Hospital, London for advice and management were included in the study. Data on the frequency of ID-PALF in 2022, as well as transplantation rates and the association with adenovirus infection, were obtained from electronic health records. The clinical presentation, histology and outcomes of children with ID-PALF and adenoviraemia in 2017-2021 were compared with those in 2022. RESULTS: From January to June 2022, 65 patients with acute hepatitis were referred. Ten children were admitted with ID-PALF. ID-PALF constituted 26% of all PALF cases in 2017-2021, in contrast to 58.8% during the 2022 outbreak. During the outbreak, adenoviraemia was present in 52% of children with acute hepatitis without liver failure (in whom adenoviraemia test results were available) and in 100% of ID-PALF cases. Adenoviraemia was seen in immunocompetent children in 6/13 (46%) of all ID-PALF cases between 2017-2019, with a clear absence of adenoviraemia in the 6 ID-PALF cases during 2020-2021. Compared to ID-PALF with adenoviraemia in 2017-2019 (n = 6), ID-PALF with adenoviraemia during the outbreak (n = 10) was associated with more frequent hepatic encephalopathy, hypotension requiring vasoactive medications and higher plasma ammonia levels (admission and peak), with similar native liver survival. CONCLUSIONS: The recent outbreak of ID-PALF with adenoviraemia in immunocompetent children does not appear to be a new disease, contrary to perception and other reports. The frequency of such cases over the years could be linked to background rates of adenovirus infections. IMPACT AND IMPLICATIONS: Indeterminate paediatric acute liver failure (ID-PALF) associated with adenoviraemia in immunocompetent children is not a new disease specific to 2022. The exclusive role of human adenovirus infection in the causation of this outbreak of acute hepatitis seems unlikely. Indeed, we provide histological data from explants in transplanted patients that do not support direct viral cytotoxicity. The disease is probably mediated by immunological injury directed towards adenovirus infection and/or adeno-associated virus-2.

Acute hepatitis of unknown aetiology in children: a clinical update on the recent outbreak with mechanistic insights.

Since April 2022, over 1000 children across 35 countries have developed episodes of acute hepatitis of unknown origin. At King's College Hospital, a total of 65 children were referred with acute hepatitis of unknown etiology, with 10 of these children presenting with acute liver dysfunction leading to acute liver failure. Multiple hypotheses have been proposed and continue to be investigated worldwide. In this review, we explore the current understanding of potential aetiologies for this outbreak. We further characterize the proposed immunological mechanisms of liver injury in these cases.

Improving the care of term babies at risk of hypoglycaemia: A microsystem approach.

AIM: Neonatal hypoglycaemia is a common problem, often requiring admission to the neonatal intensive care unit (NICU). Our aim was to reduce term admissions to NICU for hypoglycaemia by 50% over 4 years. METHODS: Inborn term babies from 1 January 2015 to 31 December 2018 were included. Using quality-improvement methodology, we designed interventions based on human factors to incorporate best practice recommendations for babies at-risk of hypoglycaemia. This included standardisation of local guidelines, introduction of educational programmes to reiterate changes to practice and a multidisciplinary steering group to review term admissions to better understand the cause of failure of the maternal-neonatal pathway. The outcome measures were the number of term babies admitted to NICU for hypoglycaemia and the proportion of these babies not requiring intravenous (IV) dextrose. Run charts were used to monitor hypoglycaemia admissions and the impact of each intervention. RESULTS: There was an overall reduction in the number of term babies admitted to NICU for hypoglycaemia from 36 babies in 2014 (baseline) to 5 babies in 2018. The percentage of babies admitted to the neonatal unit who did not require IV dextrose decreased from 22/36 (61%) in 2014 to 0/5 (0%) in 2018. Admissions from the delivery suite decreased from 21/36 (58%) to 1/5 (20%). There were no adverse outcomes observed in the period before or after the intervention. CONCLUSIONS: We demonstrate a simple, cost-effective quality improvement project using fundamental human factors principles. This initiative successfully reduced the number of term admissions for hypoglycaemia over 4 years.

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

STUDY QUESTION: Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? SUMMARY ANSWER: A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. WHAT IS KNOWN ALREADY: Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. STUDY DESIGN, SIZE, DURATION: Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. MAIN RESULTS AND THE ROLE OF CHANCE: A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). LIMITATIONS, REASONS FOR CAUTION: Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. WIDER IMPLICATIONS OF THE FINDINGS: Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. STUDY FUNDING/COMPETING INTEREST(S): The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov identifier NCT01667406. TRIAL REGISTRATION DATE: 8 August 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 August 2015.

AST-to-platelet ratio index in non-invasive assessment of long-term graft fibrosis following pediatric liver transplantation.

Long-term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post-transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long-term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10-yr follow-up and fibrosis was graded using the Ishak scoring system, with S3-6 denoting "significant fibrosis." APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post-transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non-invasive adjunct in the assessment of significant graft fibrosis in the long-term follow-up of pediatric liver transplant survivors.

Pediatric metabolic (dysfunction)-associated fatty liver disease: current insights and future perspectives.

The historical use of the term non-alcoholic fatty liver disease (NAFLD) in obese/overweight children has been controversial as to the appropriateness of this terminology in children, and lately, in adults too. Newer game-changer terminology, metabolic (dysfunction)-associated fatty liver disease (MAFLD), for this condition signifies a positive step forward that addresses the limitations of the previous definition for both adults and children. The prevalence of MAFLD has surged in tandem with the global rise in obesity rates, establishing itself as a predominant cause of chronic liver disease in both adult and pediatric populations. The adoption of the recently proposed nomenclature reflects a more encompassing comprehension of the disease and its etiology compared to its predecessor, NAFLD. Notably, the revised terminology facilitates the recognition of MAFLD as an autonomous condition while acknowledging the potential coexistence of other systemic fatty liver disorders. Particularly in children, this includes various paediatric-onset genetic and inherited metabolic disorders, necessitating thorough exclusion, especially in cases where weight loss interventions yield no improvement or in the absence of obesity. MAFLD presents as a multifaceted disorder; evidence suggests its origins lie in a complex interplay of nutritional, genetic, hormonal, and environmental factors. Despite advancements, current non-invasive diagnostic biomarkers exhibit limitations in accuracy, often necessitating imaging and histological evaluations for definitive diagnosis. While dietary and lifestyle modifications stand as cornerstone measures for MAFLD prevention and management, ongoing evaluation of therapeutic agents continues. This article provides an overview of the latest developments and emerging therapies in the realm of paediatric MAFLD.

Pediatric Liver Transplantation: Selection Criteria and Post-transplant Medical Management.

Pediatric liver transplantation remains the gold standard for life-threatening acute and chronic liver diseases and multiple liver-based inherited metabolic defects. Advances in surgical techniques, better perioperative care and immunosuppression regimes have resulted in excellent long-term graft and patient survival. The success of pediatric liver transplantation does however bring the additional challenge of long-term patient outcomes including graft hepatitis-related fibrosis and suboptimal biopsychosocial outcomes. In this review, authors will explore the current landscape of pediatric liver transplantation including indications, timing of referral for liver transplantation, surgical techniques and long-term outcomes such as recurrence of pre-transplant liver disease, idiopathic graft hepatitis and biopsychosocial outcomes. Ultimately, early identification and management of potential issues long-term helps ensure our recipients achieve a "meaningful survival".

Transient elastography is a useful noninvasive tool for the evaluation of fibrosis in paediatric chronic liver disease.

BACKGROUND: Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. METHODS: Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. RESULTS: During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥ F2) (P < 0.001), severe fibrosis (≥ F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥ F2, ≥ F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. CONCLUSIONS: The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

Balloon atrial septostomy performed "out-of-hours": effects on the outcome.

BACKGROUND: Balloon atrial septostomy is a common palliative procedure in neonates with cyanotic congenital heart disease with restricted interatrial blood flow. Despite its advantages, balloon atrial septostomy is not a risk-free procedure and can be associated with numerous complications. The objective of this study is to determine whether the performance of this procedure out-of-hours has a significant impact on the incidence of adverse outcome measures. METHODS AND RESULTS: A total of 106 neonates who underwent balloon atrial septostomy between 2004 and 2010 were studied retrospectively. In all, 64 infants had the procedure performed within routine hours (9 am to 6 pm), whereas 42 neonates underwent the procedure out-of-hours (6:01 pm to 8:59 am). Procedure-related complications occurred in 32 infants (30.2%), which included 12 out of 64 (18.8%) infants in the routine-hours group and 20 out of 42 (47.6%) in the out-of-hours group. During further follow-up after surgery and including both major and minor adverse events, seven more infants (10.9%) suffered complications after balloon atrial septostomy in the routine-hours group and four more infants (9.5%) suffered complications in the out-of-hours group. This totalled the complication rate in the routine-hours group to 19 infants (29.7%) and 24 infants (57.1%) in the out-of-hours group (p = 0.001). A higher overall mortality rate was also noted in the out-of-hours group. CONCLUSIONS: Balloon atrial septostomy performed out-of-hours produced higher complication rates as opposed to balloon atrial septostomy performed during routine hours. Only essential cases should be undertaken at night, and all other cases should be deferred to the daytime to limit unnecessary adverse complication.

Liver disease in adolescents.

In this article, we discuss common liver diseases in the adolescent population. We describe the initial evaluation of an adolescent presenting with new-onset liver enzyme abnormalities, based on the clinical history and physical examination. The management approach to the adolescent with liver disease is exemplified, including monitoring for adherence, risk-taking behaviours and focusing on psychosocial aspects of their care. Finally, we highlight the challenges of caring for the adolescent patient and the importance of addressing not only the liver disease but, more importantly, the holistic approach towards their management.

Epidemiology, Risk Factors and Outcome Due to Multidrug Resistant Organisms in Paediatric Liver Transplant Patients in the Era of Antimicrobial Stewardship and Screening.

(1) Background: Multidrug-resistant organisms (MDRO) are a growing problem in liver transplant recipients (LTR), associated with high morbidity and mortality. We reviewed the impact of antimicrobial stewardship (AMS) and active screening of MDRO on the epidemiology and outcomes in paediatric LTR. (2) Methods: Single-centre retrospective review of paediatric LTR from January 2017 to December 2018. (3) Results: Ninety-six children were included; 32 (33%) patients were colonised with ≥1 MDRO and 22 (23%) patients had MDRO infections. Median (IQR) duration for start of infection was 9.5 (1.8−16.0) days. Colonisation rate with Gram-positive MDRO was 15.6%, with infection rate of 6.2%; majority due to Vancomycin-Resistant Enterococcus faecium (VRE). Colonisation with Gram-negative MDRO was 27.0%, with infection rate of 16.6%; majority due to extended-spectrum ß-lactamase producing Enterobacteriaceae. Colonisation and infection rate due to Carbapenem-resistant Enterobacteriaceae was 6% and 3%, respectively, during screening and AMS, compared to historical control of 25% and 30%, respectively, without screening and AMS. There was significant reduction in VRE and CRE infection during AMS period in comparison to historical control. Pre-transplant risk factors including bacterial infections pre-transplant (p < 0.01), diagnosis of biliary atresia (p = 0.03), exposure to antibiotics (p < 0.01), EBV viraemia (p = 0.01), and auxiliary transplantation (p < 0.01) were associated with post-transplant MDRO infections. Patients with MDRO infections had longer length of hospital and paediatric intensive care unit stay days (p < 0.01) but associated with no mortality. (4) Conclusions: Our results demonstrate low incidence of colonisation and infections with MDRO, which were associated with high morbidity but no mortality in paediatric LTR. There was significant reduction in MRSA, VRE, and CRE during AMS period compared to pre-AMS era. Some risk factors are unavoidable but antibiotic overuse, early initiation of appropriate antibiotic therapy and effective infection prevention strategies can be monitored with multifaceted approach of AMS and screening of MDRO. With limited therapeutic options for MDRO and efficacy data of newer antibiotics in paediatric LTR, robust infection control practices are of paramount importance.

Cellular Therapies in Pediatric Liver Diseases.

Liver transplantation is the gold standard for the treatment of pediatric end-stage liver disease and liver based metabolic disorders. Although liver transplant is successful, its wider application is limited by shortage of donor organs, surgical complications, need for life long immunosuppressive medication and its associated complications. Cellular therapies such as hepatocytes and mesenchymal stromal cells (MSCs) are currently emerging as an attractive alternative to liver transplantation. The aim of this review is to present the existing world experience in hepatocyte and MSC transplantation and the potential for future effective applications of these modalities of treatment.

Virtual Reality in Medical Students' Education: Scoping Review.

BACKGROUND: Virtual reality (VR) produces a virtual manifestation of the real world and has been shown to be useful as a digital education modality. As VR encompasses different modalities, tools, and applications, there is a need to explore how VR has been used in medical education. OBJECTIVE: The objective of this scoping review is to map existing research on the use of VR in undergraduate medical education and to identify areas of future research. METHODS: We performed a search of 4 bibliographic databases in December 2020. Data were extracted using a standardized data extraction form. The study was conducted according to the Joanna Briggs Institute methodology for scoping reviews and reported in line with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. RESULTS: Of the 114 included studies, 69 (60.5%) reported the use of commercially available surgical VR simulators. Other VR modalities included 3D models (15/114, 13.2%) and virtual worlds (20/114, 17.5%), which were mainly used for anatomy education. Most of the VR modalities included were semi-immersive (68/114, 59.6%) and were of high interactivity (79/114, 69.3%). There is limited evidence on the use of more novel VR modalities, such as mobile VR and virtual dissection tables (8/114, 7%), as well as the use of VR for nonsurgical and nonpsychomotor skills training (20/114, 17.5%) or in a group setting (16/114, 14%). Only 2.6% (3/114) of the studies reported the use of conceptual frameworks or theories in the design of VR. CONCLUSIONS: Despite the extensive research available on VR in medical education, there continue to be important gaps in the evidence. Future studies should explore the use of VR for the development of nonpsychomotor skills and in areas other than surgery and anatomy. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2020-046986.

Outcomes, Measurement Instruments, and Their Validity Evidence in Randomized Controlled Trials on Virtual, Augmented, and Mixed Reality in Undergraduate Medical Education: Systematic Mapping Review.

BACKGROUND: Extended reality, which encompasses virtual reality (VR), augmented reality (AR), and mixed reality (MR), is increasingly used in medical education. Studies assessing the effectiveness of these new educational modalities should measure relevant outcomes using outcome measurement tools with validity evidence. OBJECTIVE: Our aim is to determine the choice of outcomes, measurement instruments, and the use of measurement instruments with validity evidence in randomized controlled trials (RCTs) on the effectiveness of VR, AR, and MR in medical student education. METHODS: We conducted a systematic mapping review. We searched 7 major bibliographic databases from January 1990 to April 2020, and 2 reviewers screened the citations and extracted data independently from the included studies. We report our findings in line with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Of the 126 retrieved RCTs, 115 (91.3%) were on VR and 11 (8.7%) were on AR. No RCT on MR in medical student education was found. Of the 115 studies on VR, 64 (55.6%) were on VR simulators, 30 (26.1%) on screen-based VR, 9 (7.8%) on VR patient simulations, and 12 (10.4%) on VR serious games. Most studies reported only a single outcome and immediate postintervention assessment data. Skills outcome was the most common outcome reported in studies on VR simulators (97%), VR patient simulations (100%), and AR (73%). Knowledge was the most common outcome reported in studies on screen-based VR (80%) and VR serious games (58%). Less common outcomes included participants' attitudes, satisfaction, cognitive or mental load, learning efficacy, engagement or self-efficacy beliefs, emotional state, competency developed, and patient outcomes. At least one form of validity evidence was found in approximately half of the studies on VR simulators (55%), VR patient simulations (56%), VR serious games (58%), and AR (55%) and in a quarter of the studies on screen-based VR (27%). Most studies used assessment methods that were implemented in a nondigital format, such as paper-based written exercises or in-person assessments where examiners observed performance (72%). CONCLUSIONS: RCTs on VR and AR in medical education report a restricted range of outcomes, mostly skills and knowledge. The studies largely report immediate postintervention outcome data and use assessment methods that are in a nondigital format. Future RCTs should include a broader set of outcomes, report on the validity evidence of the measurement instruments used, and explore the use of assessments that are implemented digitally.

Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver.

Wilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary and adverse effects, including paradoxical neurological worsening, can occur. In this Review, we provide a practical guide to the diagnosis of Wilson's disease. We include recommendations on indications for testing, how to interpret results, and when additional investigations are required. We also cover treatment initiation, ideally under the guidance of a specialist centre for Wilson's disease, and the principles behind long-term management. This guidance was developed by a multidisciplinary group of Wilson's disease experts formed through the British Association for the Study of the Liver. The guidance has been endorsed by the British Society of Gastroenterology and approved by the Association of British Neurologists.