Dr Jake Mann, of the Children’s Hospital of Birmingham and the University of Birmingham is our guest today – 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 !

Todays guests are 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 in JPGN Journal Club is – as usual ! -- speaking with Dr Andreas Jenke, who for discussion has chosen the three articles Budd-Chiari Syndrome – A Single-Centre Experience from the United Kingdom, contributed by the Birmingham paediatric team ; Body Composition and Physical Activity in Pediatric Intestinal Failure, from London’s Great Ormond Street ; and Thiopurines Maintenance Therapy in Children with Ulcerative Colitis, the work of several medical centres in Israel. Budd-Chiari syndrome in children . . . a quarter of a century and 25 cases, but as soon as you think “I’ll never see that” you’ll be called to Accident & Emergency for your first patient with, yes, you guessed it. Good to have this review to read on your mobile telephone as you walk down to A&E. Our London mates remind us that the body-composition shifts-to-fat so usual in intestinal failure do not go away on their own once parenteral feeding no longer is required : One take-home message may be that children who never could develop a habit of exercise when they were catheter-tethered need to be prodded into physical activity (and their parents to learn to see the children as suited for physical activity). Finally, from Israel, a confirmation that the old ways may still be the best ways : Whilst the tendency nowadays is to carpet-bomb ulcerative colitis into submission, calling out the F16s (uhm, those are the biological agents) at presentation, traditional tactics of ground warfare (those are the thiopurines) both regain and hold territory very adequately indeed – less expensively and with far greater knowledge of What To Expect. Happy listening – and reading !

Our todays guest is Prof. Anil Dhawan of King’s College Hospital in London, leader of the paediatric liver service there, about Prof. Dhawan’s lifelong especial interest within paediatric hepatology: Acute liver failure. In May, 2023, at the annual meeting of ESPGHAN, he sketched – from his personal vantage point – the horrorshow with which this clinical diagnosis confronted caregivers thirty-plus years ago; what steps have been taken to improve the prognosis of children with acute liver failure (they’re doing better now); and what remains to be accomplished for these children in both the near term and the longer term. He believes that “bridge transplantation”, using hepatocytes administered intraperitoneally, holds out particular promise for many patients, maintaining them until liver recovery or liver transplantation more definitively resolves the crisis situation that acute liver failure still represents. In this podcast he shares anecdotes, perspectives, and hard data on acute liver failure and what can be, what should be, done for patients with that disorder. This mix is refracted through a unique and commanding personality – both informative and entertaining ? Well, have a listen, see what you think!

Dr Alex Knisely today in JPGN Journal Club is – as usual ! -- speaking with Dr Andreas Jenke, who for discussion has chosen two full-size articles, call them “mains”, and a pair of linked items from among the “starters”, that is, a letter to the editors of the journal and a response from ESPGHAN. The two “mains” are Efficacy and Safety of Teduglutide in Infants and Children With Short Bowel Syndrome Dependent on Parenteral Support, from a coalition of Japanese, British, and Finnish centres supported by Takeda Yakuhin, makers of teduglutide, and, from Boston Children’s Hospital (USA), Gastric Intestinal Metaplasia in Children – Natural History and Clinicopathological Correlation. The “starters” ? Liver Histology Before Treatment Withdrawal in Autoimmune Hepatitis – Is It Time to Review the ESPGHAN Recommendations ?, a Franco-Italian défi, and, réponse à cette provocation, Liver Biopsy is Indicated Before Attempting Treatment Withdrawal in Children with AIH – Commentary by the ESPGHAN HepCom. The mains may leave you wanting a bit more ; the teduglutide data draw on very few patients, the intestinal-metaplasia data yield no very firm conclusions ; but both offer at least reassurance. Mind you, if you are about to spend €100.000,00 on a year of teduglutide for one of your patients, you’ll be well-advised to do it in a manufacturer-supported study with firm guidelines for use and assessment – yes, a registry is needed. And the starters ? Highly spiced ! But, with a J Hepatol article from the Franco-Italian group (summarised in the Commentary, but which you must seek out on your own), they certainly fill the plate. Whose arguments are more convincing ? What will you say to the next teenager with treated AIH and “good numbers” who is desperate to abandon steroids and the like ? Prudence seems in order . . .

Today we are talking to Prof. (and Dr.) Richard Thompson, of London’s King’s College Hospital, who there for twenty-five years has broadened and heightened his leading role in studies of the genetics, physiology, and treatment of forms of intrahepatic cholestasis, disorders that come to clinical attention principally in childhood. Richard and Alex for fifteen years were on the same team at King’s, sometimes shoulder to shoulder, sometimes pushmi-pullyu, but always having fun. Their chat today, after rather a lot of reciprocal congratulation, touches on clinicogenetic correlations in Wilson disease, moving thence to bile salt export pump deficiency – first, with its spectrum of manifestations, as a paradigm of the falsity of Mendelian genetics ; second, with its responses to drugs that inhibit ileal bile acid transport, as a paradigm of how without fixing a programme’s basic code one can apply patches that substantially improve the programme’s utility (that is, how knowledge of clinicogenetic correlations permits patient-tailored choices among surgical and pharmacologic therapies, with earlier and more satisfactory improvements in health). Be warned : You won’t take on board in one hearing what Richard has to share. Make time, then, for a couple of listen-throughs. They will reward you well.

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.

Today we are talking to Prof. Dr. Tobias Cantz, of Hanover / Hannover, Germany, on a topic that offers the chance to re-work many approaches to both acquired and inborn disease not just of the liver but also of the biliary tree. Prof. Cantz is a regenerative hepatologist, conducting research into how hepatocellular or cholangiocellular organoids – or, more complexly, organoids that include all the components of the differentiated and polarised and vascularised hepatic lobule – can be used to examine and to dissect how gene variants contribute to clinical disease, and how administration of organoids can contribute to repair of hepatobiliary injury. His presentation in Vienna this May, at the annual meeting of ESPGHAN, was a wonder ; the things that can be done already using these “organoids”, these miniature versions of components of an organ, are mind-boggling, and the feats to date really are only the start of what Prof. Cantz envisions. Perhaps his intensity, his devotion, and his determination to take our field forward can be appreciated, at least in part, in this conversation. Not easy listening, better suited for a quarter-hour in a lay-by during which you can concentrate on the abundance of information that he presents than for dodging delivery- van traffic – well, if you have to get to work, then listen to it not just on the way in but also again on the way home, to be sure you grasp it all.

Dr Alex Knisely today is speaking with Dr Andreas Jenke – it’s Journal Club again. Skipping over the June, 2023, number of JPGN, Dr Jenke has chosen from the July number not two but three articles for discussion – from a Scandinavian consortium, Risk Factors of Cancer in Pediatric-Onset Inflammatory Bowel Disease in Denmark and Finland ; from a group in California, Prevalence of Elevated ALT in Adolescents in the US 2011-2018; and from a group in Birmingham, England, Liver Disease inGLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology. Interviewer and interviewee alike consider the Danish / Finnish study a lovely piece of work, the Californian study rather risky in respect of over-medicalisation of a questionably abnormal biomarker value, and the English study as  . . well, as questionable. What will your opinions be?