Dr Alex Knisely today in JPGN Journal Club is in a dogfight against Dr Jake Mann – it’s Jake’s first solo flight as Journal Club pilot, will he be shot down? Jake first offers us, out of Berlin, with co-authors from European and Israeli centres, and published in J Pediatr Gastroenterol Nutr : Kalveram et al., Noninvasive scores are poorly predictive of histological fibrosis in pediatric fatty liver disease. Then he steers away from the sunlit uplands of JPGN and into the dark and stormy clouds of basic science, with, out of Aurora / Denver, Colorado, and claiming a double handful of co-authors on that side of the Atlantic and this, published in J Exp Med : Lui et al., A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation. A tip of the school cap to Molesworth, N., here – and as any paediatric hepatopathologist would predict, the Berlin- based consortium found that clinical parameters and values for various biomarkers, assessed in differing combinations, did not identify or correctly stratify liver fibrosis, and that the proper set of tests to use in non-invasive diagnosis of liver fibrosis still awaits definition in paediatric fatty liver disease. To be regretted – in this histopathologist’s opinion – is that the extent of fibrosis was not verified by a review team ; that is, the co-authors contributed not glass slides bearing tissue sections but copies of reports. Not the firmest of foundations, then . . . Well, however they got there, the conclusion of the study was prima facie correct : Keep those biopsy specimens coming ! The Coloradans and their co-workers report from Immunology World, in which evaluation of two brothers, born to first-cousin parents, for features of immunodeficiency found that they harboured a novel variant in LCK, encoding lymphocyte-specific protein tyrosine kinase (LCK). The effects of the variant included chronic diarrhoea ; histopathologic assessment of bowel mucosa is not reported. In knock-in mice with the same variant in Lck, however, chronic intestinal mucosal inflammation was present – not a feature in Lck knock-out mice. Immunophenotyping in the siblings and in the mice found selective deficiency in numbers of regulatory T-cells. The lads were successfully treated with bone-marrow transplantation. The mice could be successfully treated by topping up regulatory T-cells or by depleting CD4-expressing T-cells. Aside from the effects that the variant had on orderly development of T-cell subsets, the report interested Jake (and our listeners, we hope!) because of parallels that can be drawn with genetic contributions to chronic inflammatory intestinal disease. Patients like these have a lot to teach us, Jake maintains, as – like every British boy’s hero, “Biggles” – he returns safely to his home airfield, mission accomplished and Alex foiled. As always, happy listening – and happy reading !

Today we are speaking with Prof Thomas Attard, of the University of Missouri and Children’s Mercy Hospital of Kansas City, Missouri, where he directs gastrointestinal endoscopy services and leads the hereditary gastrointestinal polyposis multidisciplinary clinic. He is from Malta, where he studied medicine, although by far most of his career has been in the United States. At the 2023 ESPGHAN annual meeting in Vienna this May he presented his and his institution’s experience with video-capsule endoscopy in children with Peutz- Jeghers syndrome, in which hamartomatous polyps develop from stomach through large bowel, complicated by intussusception with obstruction of the lumen. A good double handful of interesting observations – particularly that one should not wait till trouble occurs to evaluate these patients endoscopically.

Dr Alex Knisely today in JPGN Journal Club is speaking not only with Kassel’s best, Dr Andreas Jenke, but also with Dr Jake Mann, pride of Birmingham and the Channel Islands – that’s right, double trouble. We say thank you and goodbye to Andreas, thank you and hello to Jake, who is stepping into Andreas’ shoes as primary Journal Club discussant. Andreas leads off with Predicting Insulin Resistance in a Pediatric Population With Obesity, a JPGN article from Portugal, by Daniela Arauj́ o and colleagues, using non-invasive parameters to identify children at increased metabolic-syndrome risk and thereby perhaps opening restricted-prescription gateways for early pharmacologic intervention. Jake is next up at bat, with a non-JPGN entry (Hepatology Communications) from Sagar Mehta et al. at Toronto’s Hospital for Sick Children – Severe Acute Hepatitis of Unknown Etiology in a Large Cohort of Children, a look at the recent purported worldwide spike in numbers of such patients. Was it really all about adeno-associated virus infection ? The tiller then returns to Andreas, who steers us safely into port aboard Peter Osgood and co-workers’ Intrapyloric Botulinum Toxin Injection for Refractory Nausea and Vomiting in Pediatric Patients, again in JPGN, from Chicago and Cleveland – will you follow these authors’ lead when confronted with what well may be functional disorders ? Both the discussants appraise the articles – why are they important ? How could they be better ? What might come next in these corners of our field ? – two perspectives for one in this podcast, and an interesting change from the approach employed thus far. What do you think ? Should Jake invite guest co-discussants now that he is in charge ? Let us know : Comments on a postcard, please (sorry, wrong century ! By e-mail), via the ESPGHAN main office.

Dr Alex Knisely today is speaking with Dr Jake Mann, of the Children’s Hospital of Birmingham and the University of Birmingham – Dr Mann’s second contribution to these podcasts. At the annual meeting of ESPGHAN in Vienna this May Dr Mann presented information on the potential relevance of genetic variants “of unknown significance”, the sort of thing that often is uncovered in exomic or genomic studies of children with hepatobiliary disease; one can’t pin the hepatobiliary disease on those variants, not exactly, but what is one to do with them ? – to abnormalities in biomarker values assessed in adults. Indeed such variants and such abnormalities co-map, suggesting rôles for the variants as loci minoris resistentiae that may confer adverse prognoses. Worth our attention, although neither easy reading nor easy listening : As Mark Twain famously had Huckleberry Finn say of The Pilgrim’s Progress, “The statements was interesting, but tough.” But who can better explicate Dr Mann’s statements, which indeed are both interesting and tough, than Jake himself, despite all the impedimenta that Alex tries to cast in his way ?

Dr Alex Knisely today is speaking with Prof Marc Benninga and Dr Klaartje de Bruijn, both of Amsterdam’s Academisch Medisch Centrum. Prof Benninga is visiting these podcasts for a second time ; Dr de Bruijn is facing her baptism of fire. Their topic? Shudder and thrill – faecal transplantation. In 2020 their group published a protocol for faecal transplantation in adolescents with refractory irritable-bowel syndrome (PMID : 32864480), midway through the study described. In nuce : Healthy- donor stool or recipient’s own stool, delivered by nasoduodenal sonde immediately after irrigating the bowel clean from above, two doses six weeks apart ; both clinical well-being and stool microbiome assessed ; one-year follow-up. At the annual meeting of ESPGHAN in Vienna this May Dr de Bruijn presented study results : Thirty recipients of healthy-donor stool felt better and experienced shifts in stool microbiome, changes that persisted throughout the year of follow-up. In effect, if this were a field-hockey match, the Dutch national team against irritable-bowel syndrome, we would all now be screaming Gooooooaaaaaalllllll! (Those who heard Prof Benninga’s initial contribution know that his love for field hockey is rabid – well, so is Dr de Bruijn’s) Listen, and follow Prof Benninga and Dr de Bruijn as they swap the informational ball back and forth, bringing it downfield despite Alex’s rhetorical backsticks, foot-advancing, and, yes, even high- sticks, to notch up a fantastic win – score – goooaaallll!

Dr Alex Knisely today is speaking with Dr Andreas Jenke – it’s Journal Club again. Dr Jenke has chosen from the August, 2023, number of JPGN three articles for discussion – from Brisbane (Queensland), Australia, and, in India, Lucknow, Jodhpur, and Rishikesh (a thousand-kilometre span across the centre and north of the subcontinent ! ), Oral Tacrolimus in Steroid-Refractory and - Dependent Pediatric Ulcerative Colitis - a Systematic Review and Meta-Analysis ; from a group in San Diego, California, with contributions from a group at Columbia University in New York City, An Open Label, Randomized, Multicenter Study of Elafibranor in Children with Nonalcoholic Steatohepatitis ; and from Edmonton (Alberta), Canada, Clinical Features of Children with Serology-Negative, Biopsy-Positive Celiac Disease. The Indian / Australian study is a meta-analysis and review rather than primary work ; it concludes that tacrolimus may allow caregivers to temporise, with an initially good response that rather rapidly tails off, and that it may be less effective in the steroid-refractory child. The elafibranor study holds out promise – but that promise is based on findings in only a few children and adolescents. (The study was ended early, with enrolment curtailed when drug- company sponsorship was withdrawn after elafibranor failed to meet expectations in adult patients.) Does seronegative coeliac disease differ clinically from seropositive coeliac disease ? Well, maybe. Hypogammaglobulinaemia A is more frequent in the former, albeit not universally found. But overall no particular feature, no single clinical-laboratory biomarker, emerged as both sensitive and specific for either form of coeliac disease : The search continues.