JPGN Journal Club reports from the Milan venue of ESPGHAN’s 2024 annual meeting, seizing the opportunity to learn from those rarely in Europe – as today with Prof Binita Kamath, in transit between Toronto and Philadelphia professionally, who along with Dr Jake Mann will tag-team her way down the field shooting for goal with two articles of interest (Winter et al.’s Biomarkers predicting the effect of anti‐TNF treatment in paediatric and adult inflammatory bowel disease, from J Pediatr Gastroenterol Nutr 2024 May 2 doi: 10.1002/jpn3.12221, and Islam et al.’s A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway, from Hepatol Commun 2024 Feb 268[3]:e0389).   In the study from Rotterdam (Prof J Escher, team leader), proteomics screening identified several species more abundant in material from persons who had developed resistance to anti-tumour necrosis factor inhibition than in persons without such resistance.  The numbers of subjects in these two cohorts ?  Small.  The p value of the increases in abundance seen ?  Slight.  Larger numbers called for, perhaps with different statistical handling – but a promising start and an interesting attack on the question of “What leads to treatment failure ? “ Prof Kamath stepped forward to explicate the work by Islam et al. – quite properly, since it is her team’s work.  Extrahepatic bile-duct cholangiocytes, grown as organoids, were challenged with taurocholic acid and other agents, and the cholangiocytes’ responses, categorised by pathways of involved molecules, were charted and analysed.  Of interest was that a hitherto little-studied molecule, sphingosine-1-phosphate receptor 2, was implicated as participating strongly :  New routes for investigation !     The information, viewpoints, and recommendations shared in this podcast are solely those of the hosts and guests, and may evolve over time as the field advances.  

O-makase is the word of the day, the phrase that in Japan tells your chef that your meal is both literally and metaphorically in her hands – “Choose for me,” it means. Most fine dining has an equivalent; the French say menu de dégustation, here in Milan / Mailand / Milano it’s called menù degustazione. That is: Non prevede scelte da parte del cliente! You, the diner, have no say. Either eat what’s set on the plate in front of you or stand up and leave the restaurant. O-makase, baby !   We hope you don’t leave, that is, switch off this podcast, although equally to please all 5300-plus delegate-guests at the ESPGHAN Annual Meeting Restaurant this year would be a miracle.  That’s 104 different countries-cuisines !  With courses in interventional ultrasound and in inflammatory bowel disease, also on offer are working-group and special-interest group meetings, an endoscopy learning zone, and an allied health professional course, together with 1433 accepted abstracts, uhm, menu items.  Now what about working a miracle? You ask. Well, there’s riches there, something for everybody – has our chef assembled from among this a tasting menu for everybody ?  We think so.  She’s reviewed the entire bill of fare and has selected a double armful of dishes to set before you ; meaty, piquant, provocative, and in every instance driving forward the intellectual, clinically relevant, and tasty art of paediatric gastroenterology, hepatology, and nutrition.  Here’s your table! Loosen your clothing unobtrusively, say to Dr Elena Cernat of Leeds, chef extraordinaire – now what was that phrase ? Right! O-makase! – and get ready to feast.   Below, a listing.  Standard cutlery is available if you can’t easily manage o-hashi (chopsticks) – or use fingers, made before forks, and just have fun.  Off we go, and guten Appetit ! 1) DUPILUMAB IN CHILDREN WITH EOSINOPHILIC ESOPHAGITIS AND PRIOR USE OF SWALLOWED TOPICAL CORTICOSTEROIDS: RESULTS FROM THE EOE-KIDS STUDY Cehade M et al. Mount Sinai, New YorkUniversity of RomeWestern University, London, Ontarioand  2) DUPILUMAB IMPROVES CAREGIVER-REPORTED EOSINOPHILIC ESOPHAGITIS (EOE) SYMPTOMS IN CHILDREN AGED 1 TO < 12 YEARS WITH EOE: 16-WEEK RESULTS FROM PHASE 3 EOE KIDS STUDY Rothenberg M E et al.Children's Hospital Medical Center, Cincinnati, Ohio, Western University, London, OntarioUnversity of Rome, ItalyFlavour highlight – what should one know about the new agent dupilumab and how it works in EOE and other atopic conditions ? * * * 3) THERAPY DE-ESCALATION IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN REMISSION – CHARACTERIZATION OF PHENOTYPE, TREATMENT, AND COURSE: DATA ANALYSIS FROM THE CEDATA REGISTRY Sila E. CekinFaculty of Medicine and University Hospital Köln, GermanyFlavour highlight – what other factors (immunomodulators, biologics) must be taken into account with de-escalation ? * * * 4) DOES INFANT FEEDING INFLUENCE LATER APPETITE TRAITS? Mahmood A et al. ICH, University College London, UKFlavour highlight – Less enjoyment, slower rates of eating in the breast-fed :  What might underlie these observed behaviours ? * * * 5) LONG-TERM TEDUGLUTIDE TREATMENT IN CHILDREN WITH SHORT BOWEL SYNDROME: A REAL-LIFE, MULTICENTER, RETROSPECTIVE STUDY OF PATIENTS TREATED FOR MORE THAN 1 YEAR Molinaro A et al.Ospedale Papa Giovanni XXIII, Bergamo, ItalyHospital La Paz, Madrid, SpainHôpital Necker, Paris, FranceUniversity Hospital Köln, GermanyFlavour highlight – Is teduglutide a (remarkably expensive) “lifetime drug” ?  What follows withdrawal of this agent ? * * * 6) MARALIXIBAT IMPACT ON CONCOMITANT MEDICATION USE FOR THE TREATMENT OF CHOLESTATIC PRURITUS IN ALAGILLE SYNDROME: REAL-WORLD EXPERIENCE Howard R et alMirium Pharmaceuticals, USAFlavour highlight – How does maralixibat alter liver injury in Alagille syndrome ?  Are its beneficial effects limited to thinning out the medicine chest ? * * * 7) LONG-TERM MAINTENANCE OF RESPONSE AND IMPROVED LIVER HEALTH WITH MARALIXIBAT IN PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (PFIC): 2-YEAR DATA FROM THE MARCH-ON STUDY Miethke A et al.Children's Hospital Medical Center, Cincinnati, Ohio, and contributors from 28 other institutionsFlavour highlight – Does maralixibat alter incidence of hepatobiliary malignancy or only postpone malignant transformation ?  

Dr Alex Knisely today speaks with Prof Yvan Vandenplas of Brussels, where he was chief of paediatrics for many years. He’s a hollow-viscus gastroenterologist rather than a “liver man”, and he has made many contributions in his chosen field, particularly in feeding disorders of infancy and in cows’-milk allergy, a topic on which he has selected three articles for us, all published in 2023 : From JPGN, “An ESPGHAN position paper on the diagnosis, management and prevention of cow's milk allergy”, with him as lead author, and (both by Meyer R et al.) from World Allergy Organization Journal, “World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) Guideline update – VII – Milk elimination and reintroduction in the diagnostic process of cow’s milk allergy” and from Pediatric Allergy and Immunology, “The role of online symptom questionnaires to support the diagnosis of cow's milk allergy in children for healthcare professionals – A Delphi consensus study”. What is known about cows’-milk allergy, how to decide if cows’-milk allergy is a strong consideration in a particular patient, how to approach diagnosis and treatment in such a patient, and what may come next – all taken up in this podcast, which we hope you will enjoy.

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 in JPGN Journal Club is bantering happily with Dr Andreas Jenke, who for discussion has chosen two articles and a pair of Letters to the Editor, thrust and parry, attack and defence. He believes that correspondence of this sort often affords insight into what is at issue in the matter addressed – and he may well be right. Along with those, we have a contribution from Dr S Bonilla of Boston Children’s Hospital – Helicobacter pylori Antimicrobial Resistance Using Next-Generation Sequencing in Stool Samples in a Pediatric Population – and another from Dr B Özer Bekmez of Ankara City Hospital – Antenatal Neuroprotective Magnesium Sulfate in Very Preterm Infants and Its Association With Feeding Intolerance. Dr Özer Bekmez and her team compared the courses of pre-term infants who received magnesium sulfate (MgSO4) for neuroprotective purposes and pre-term infants who did not receive MgSO4. Findings included “a significant difference in intrauterine growth retardation (IUGR), preterm premature rupture of membranes, and the usage of antenatal steroids between the groups” – those receiving MgSO4 had worse IUGR, were more likely to have suffered from rupture of membranes, and were more likely to have been exposed to steroids ; they also went on to have more bronchopulmonary dysplasia and to require longer mechanical ventilation, with greater incidences of necrotising enterocolitis, feeding intolerance, and delay in enteral feeding. The authors posit these adverse outcomes as consequent on MgSO4 exposure. Were the dice loaded, though, given the more troubled antenatal course of those receiving MgSO4 ? Might MgSO4 administration have made no difference to outcome ? The study design with Dr Bonilla and team was less questionable, perhaps. Although few patients were studied, when stool yielded enough microbial DNA for evaluation, results of next-generation sequencing correlated well with those of antibiotic sensitivity testing in cultured gastric-biopsy material. Regrettable, though, that the authors made so little of potential benefits of speed – if DNA test results were in hand substantially before results of standard culture, selective antibiotic therapy might begin more quickly than possible at present, a boon to all. Now for the letter pair, with Ms A Aloysius and colleagues writing in regard to the recent ESPGHAN Preterm Enteral Nutrition Position Paper (2022)—Issues of Oral Feeding on CPAP and Dr N Embleton offering a response on behalf of the position-paper authorial team. The initial letter says, in effect, “We as speech and language therapists believe that this position paper does not adequately address transition to oral feeding ! ” – the response says, “Erm, we rather think that we did, and here are the parts of our text in which we did, but whatever – yes, this is an important aspect of care, and one best approached in a multidisciplinary manner.” Fewer fireworks than in the best correspondential wars, and one must read the position paper to see if the speech and language therapists’ discipline truly was shortchanged. As always, happy listening – and happy reading !

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.