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Background: A previous Australia-wide pilot study identified pain as a significant burden in people with CF (pwCF). However, the prevalence, frequency and severity have not been evaluated using validated tools., Methods: Australian adults, pwCF and healthy controls (HC) were invited to complete an online questionnaire from July 2023 - February 2024, consisting of four validated tools: Brief Pain Inventory, Pain Catastrophising Scale, PAGI-SYM and PAC-SYM. The questionnaire, disseminated via Cystic Fibrosis Australia, CF Together and online social media groups, explored experiences surrounding pain and its management using closed and free text entries., Results: There were 206 respondents, consisting of 117 CF patients and 89 HC. Over 70 % (n = 69) of pwCF reported pain compared to 28 % (n = 21) of HC (p = <0.001). Further, significantly higher pain frequency per month was reported for pwCF than HC (40 % vs. 10 %; p < 0.001). Symptom clustering was also observed where at least three other locations of pain were reported, and pain was reported to trigger other physiological and psychological symptoms. Notably, there was no significant difference in the locations, occurrence, frequency or severity of pain between those on a CFTR modulator or not (p = 0.625). PwCF also reported significantly lower relief from over-the-counter therapies (p = 0.002) and expressed themes of unmet symptom and management needs., Conclusions: This study identified a high prevalence of pain affecting multiple body parts in pwCF compared to HC and suggests that pain is sub-optimally managed, impairing their quality of life. Increased awareness and early recognition within the CF clinics and the development of clinical pathways are critically needed to better manage and monitor pain in pwCF, leading to improved quality of life and health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Objective: To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP., Study Design: Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed., Results: In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days., Conclusions: Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP., Competing Interests: Declaration of Competing Interest Z.M.S. is currently an employee of 4D Molecular Therapeutics Inc and a consultant for BridgeBio Pharma and Renexxion. M.A.H. is the president of CAPER, a board member of CAPER, and a board member of the National Pancreas Foundation. T.G. received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). C.Y.O. is a consultant for and has received research grant from Vertex Pharmaceuticals. E.R.P. is a consultant for BridgeBio and Ultragenyx. S.J.S. is a consultant for UpToDate, Nestle, Abbvie, Renexxion, and the CFF. A.J.F. is a consultant for Takeda and AbbVie, CFF, and is a member of the CAPER board. V.D.M. is an Associate Editor for JPGN Reports. D.M.T. is an Associate Editor for JPGN. M.W. is a consultant for and has received research grants from Vertex Pharmaceuticals. M.E.L. receives royalties from Millipore Inc and UpToDate and consults for CFF. A.U. is a consultant for CFF and Abbvie Inc. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aim: The COVID-19 pandemic necessitated the transition to online medical education. This study evaluated the efficacy of online case-based tutorials using a serious game tutorial [PlayMed™ (PM)], as compared to a traditional slideshow tutorial (TT)., Methods: We performed a prospective, mixed-methods, randomised controlled trial on undergraduate medical students during the COVID-19 pandemic, from May 2020 to January 2021. Students were block randomised into the PM or TT groups. Tutors conducted online teaching on bronchiolitis and gastroenteritis cases using PM or TT to facilitate the presentation. Educational experience was assessed using a continuous interval scale (0-100; with pre-defined categories) and free text responses. Immediate and long-term knowledge acquisition was assessed using 6 multiple-choice questions (MCQ) for each case (total of 12 MCQ). A modified intention-to-treat mixed methods and a sensitivity per-protocol analysis were performed to compare outcomes between PM and TT groups., Results: In total, 80 PM and 73 TT participants attended at least one tutorial. Sixty-five (81%) PM and 52 (71%) TT participants completed at least one survey and were included for analysis. PlayMed™ students had an increased likelihood of completing the surveys, which included the MCQ [odds ratio (95% CI) of 2.4 (1.6-3.8), p  < 0.00006]. Regarding the immediate reactions post bronchiolitis and gastroenteritis cases, several responses were significantly more positive in the PM group compared to the TT group; e.g. 'The learning activity was engaging' [medium effect size: d (95% CI) = 0.58 (0.32-0.85), p  < 0.0001]. Higher proportions of participants in the PM group reported feeling safe in the gastroenteritis and bronchiolitis tutorials (96 and 89%), compared to the TT group (76 and 74%). PlayMed™ participants significantly outperformed TT participants on the bronchiolitis MCQs done immediately post tutorial, 4.1 (1.0) vs. 3.5 (1.0), respectively, p  = 0.004 [medium effect size: d (95% CI) = 0.54 (0.16-0.91)]., Conclusion: This study demonstrates the utility of a serious game (PlayMed™) as an online teaching tool for medical education. Students exposed to PM demonstrated superior engagement and feelings of safety. Utilisation of serious games may also facilitate knowledge acquisition, at least in the short term., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tan, Coffey, Blazek, Sitaram, Dobrescu, Motta, Chuang and Ooi.)

Introduction: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP., Methods: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors., Results: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001)., Discussion: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP., (Copyright © 2024 by The American College of Gastroenterology.)

Highly effective modulator therapy (HEMT), particularly the triple combination elexacaftor-tezacaftor-ivacaftor (ETI), significantly improved clinical outcomes and quality of life in people with Cystic Fibrosis (pwCF). This review analyzes current knowledge on the impact of HEMTs on gastrointestinal (GI) symptoms and features in pwCF. A descriptive review of English literature until February 29, 2024, was conducted using medical databases. Observational studies and clinical trials addressing GI reflux disease (GERD), lower GI symptoms and pancreatic disease were considered. Studies report positive effects of HEMTs on pH levels and bicarbonate secretion as well as improvement on intestinal inflammation. HEMTs also demonstrated positive effects on GERD and lower GI symptoms or conditions CF related such as dysbiosis. Taking ETI during pregnancy could also allow resolution of meconium ileus in fetuses with CF. The best benefits were observed in pancreatic function, potentially delaying CF-related diabetes and recovering pancreatic function in some children on ETI. Larger trials, particularly in pediatric populations, need to confirm these findings and explore long-term effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

People with cystic fibrosis (pwCF) have an altered gastrointestinal microbiome. These individuals also demonstrate propensity toward developing small intestinal bacterial overgrowth (SIBO). The dysbiosis present has intestinal and extraintestinal implications, including potential links with the higher rates of gastrointestinal malignancies described in CF. Given these implications, there is growing interest in therapeutic options for microbiome modulation. Alternative therapies, including probiotics and prebiotics, and current CF transmembrane conductance regulator gene modulators are promising interventions for ameliorating gut microbiome dysfunction in pwCF. This article will characterize and discuss the current state of knowledge and expert opinions on gut dysbiosis and SIBO in the context of CF, before reviewing the current evidence supporting gut microbial modulating therapies in CF., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF., Competing Interests: Declaration of competing interest All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

To support investigation of the etiology and psychophysiology of medical traumatic stress, we developed a standardized set of emotionally-salient medical images, called the 'MEDical Image Collection' (MEDIC), for use in neuroimaging or psychological research. This study aimed to establish internal consistency, test re-test reliability, and congruent validity of the image set. A representative sample of 300 adults in the United States were recruited via research recruitment platform, Prolific. Participants rated 124 images depicting medical stimuli on one of two dimensions: emotional arousal (i.e., how strongly an evoked emotion is felt) or affective valence (i.e., how positive or negative the evoked emotion is). Sociodemographic and health-related characteristics, including experiences during the COVID-19 pandemic, were also assessed. To assess test re-test reliability, a subset (n = 200) rated the images on the same dimension a second time, 3 months later. The MEDIC image set was found to: (a) elicit a range of emotional arousal and valence ratings, (b) have excellent inter-rater reliability, (c) moderate test-retest reliability, and (d) good face validity. Results indicate the new MEDIC 124-image set is a reliable and valid instrument, enabling researchers to provide context-specific and emotionally-salient stimuli to individuals when studying affective responses in relation to health and medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Children with chronic kidney disease (CKD) experience many obstacles to achieving optimal dietary intake. Dietary intake patterns remain unexplored or poorly described. This study compares nutritional intake and diet quality of Australian children with CKD to controls., Methods: A food frequency questionnaire captured intake data and was compared to controls. Nutritional intake was determined using individualized nutrient reference values, and diet quality described using the Australian Guide to Healthy Eating and the Australian Child and Adolescent Recommended Food Score., Results: Children with CKD (n = 36) and controls (n = 82) were studied. Children with CKD had lower weight and height z scores, but higher body mass index (P < .0001 for all parameters). Children with CKD had adequate energy intake, and excessive protein and sodium intake (336% and 569%). They were significantly less likely to meet requirements for vitamin A (P < .001), thiamine (P = .006), folate (P = .01), vitamin C (P = .008), calcium (P < .0001), iron (P = .01), magnesium (P = .0009), and potassium (P = .002). No child met recommended vegetable intake; however, less than half of children with CKD met fruit (44%), grains (31%), and dairy serves (31%). They were also less likely to meet recommended fruit and dairy serves (P = .04 and P = .01, respectively). Non-core foods provided 36% of energy, and although comparable to controls, was contributed more by takeaway foods (P = .01)., Conclusion: Children with CKD have reduced nutritional intake of key nutrients and consume more takeaways than controls. Attention to increasing core foods, limiting sodium intake, and managing restrictions while promoting nutrient density appears necessary., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Cystic fibrosis liver disease (CFLD) is characterised by a wide heterogenity of manifestations and severity. It represents a major cause of morbidity in people with cystic fibrosis (PwCF), which will be of increasing relevance as survival increases in the new era of cystic fibrosis care. No medical therapy currently available has evidence to treat or prevent progression of liver disease. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators may be transformative on pulmonary, nutritional and quality of life, but direct effect on long term liver disease outcomes is not yet established. Drug-associated hepatic adverse effects may be common, and clinician familiarity with drug-monitoring recommendations is essential. Longitudinal studies are required to understand the effect of CFTR modulators on the incidence and natural history of CFLD, including with early treatment initiation, in established advanced liver disease, and post liver transplantation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The global incidence of acute pancreatitis (AP) is increasing, but little information exists about trends in Australia. This study aimed to describe incidence trends, along with clinical and socio-demographic associations, in the state of Tasmania over a recent 12-year period., Methods: The study cohort was obtained by linking clinical and administrative datasets encompassing the whole Tasmanian population between 2007 and 2018, inclusive. Pancreatitis case definition was based on relevant ICD-10 hospitalization codes, or elevated serum lipase or amylase in pathology data. Age-standardised incidence rates were estimated, overall and stratified by sex, aetiology, and Index of Relative Socio-economic Disadvantage (IRSD)., Results: In the study period, 4905 public hospital AP episodes were identified in 3503 people. The age-standardised person-based incidence rate across the entire period was 54 per 100,000 per year. Incidence was inversely related to IRSD score; 71 per 100,000 per year in the most disadvantaged quartile compared to 32 in the least disadvantaged. Biliary AP incidence was higher than that of alcohol-related AP, although the greatest incidence was in "unspecified" cases. There was an increase in incidence for the whole cohort (average annual percent change 3.23 %), largely driven by the two most disadvantaged IRSD quartiles; the least disadvantaged quartile saw a slight overall decrease., Conclusion: This is the first Australian study providing robust evidence that AP incidence is increasing and is at the upper limit of population-based studies worldwide. This increased incidence is greatest in socio-economically disadvantaged areas, meriting further research to develop targeted, holistic management strategies., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Parents of a child with a chronic illness can experience greater distress than the average population, yet little is understood about differences between illness groups. This cross-sectional survey study aimed to compare parents' psychological distress and perceived wellbeing across five chronic illnesses. Parents from one Australian pediatric hospital completed the Kessler Psychological Distress Scale and seven purpose-designed items about their wellbeing. Data from 106 parents (cancer = 48, cystic fibrosis [CF] = 27, kidney disease = 12, gastrointestinal condition/disorder = 9, developmental and epileptic encephalopathy [DEE] = 10) was analysed using bivariate Pearson's Correlation and linear mixed-effects models. Parents' distress scores differed between groups ( F (4,80) = 2.50, p = .049), with the DEE group reporting higher distress than the CF group ( mean difference = 6.76, 95% CI [0.11, 13.42]). Distress scores were moderately correlated to parents' perceptions of their child's health and their own wellbeing. Parents' self-reported coping with their child's condition/treatments differed ( F (4,81) = 3.24, p = .016), with the DEE group rating their coping as poorer than the CF group ( mean difference = -25.32, 95% CI [-46.52, 4.11]). Across all groups, parents reported unmet needs, particularly for psychosocial support and practical/financial assistance. Support interventions may be most effective if tailored to the child's illness, with greater support potentially needed for parents who have a child with DEE and/or severe comorbidities., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

Aim: This study addresses the absence of a definition of care for children with feeding disorders, limited agreement on key performance indicators (KPIs), and the lack of data linked to those KPIs., Methods: Clinicians, consumers and researchers involved in outpatient feeding care in New South Wales (NSW), Australia were invited to participate in a two-Phase study. In Phase 1, a modified Delphi method was used. Two rounds of voting resulted in a new consensus definition of a multidisciplinary paediatric feeding clinic. Three further rounds voting determined relevant KPIs. In Phase 2, the KPIs were piloted prospectively in 10 clinics., Results: Twenty-six clinicians, consumers and researchers participated in Phase 1. Participation across five voting rounds declined from 92% to 60% and a valid definition and KPI set were created. In Phase 2, the definition and KPIs were piloted in 10 clinics over 6 weeks. Data for 110 patients were collected. The final KPI set of 28 measures proposed covers clinical features, patient demographics and medical issues, parent-child interaction and outcome measures., Conclusions: A new definition of a multidisciplinary paediatric feeding clinic is now available, linked to a standardised KPI set covering relevant performance measures. These proved viable in baseline data collection for 10 clinics across NSW. This sets a foundation for further data collection, systematic measurement of care provision and outcomes, and research needed to deliver care improvement for children with paediatric feeding disorder., (© 2024 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: Gastrointestinal symptoms and inflammatory gastrointestinal diseases exist at higher rates in the autistic population. It is not clear however whether autism is associated with elevated gastrointestinal inflammation as studies examining non-invasive faecal biomarkers report conflicting findings. To understand the research landscape and identify gaps, we performed a systematic review and meta-analysis of studies measuring non-invasive markers of gastrointestinal inflammation in autistic and non-autistic samples. Our examination focused on faecal biomarkers as sampling is non-invasive and these markers are a direct reflection of inflammatory processes in the gastrointestinal tract., Methods: We extracted data from case-control studies examining faecal markers of gastrointestinal inflammation. We searched PubMed, Embase, Cochrane CENTRAL, CINAHL, PsycINFO, Web of Science Core Collection and Epistemonikos and forward and backwards citations of included studies published up to April 14, 2023 (PROSPERO CRD42022369279)., Results: There were few studies examining faecal markers of gastrointestinal inflammation in the autistic population, and many established markers have not been studied. Meta-analyses of studies examining calprotectin (n = 9) and lactoferrin (n = 3) were carried out. A total of 508 autistic children and adolescents and 397 non-autistic children and adolescents were included in the meta-analysis of calprotectin studies which found no significant group differences (ROM: 1.30 [0.91, 1.86]). Estimated differences in calprotectin were lower in studies with siblings and studies which did not exclude non-autistic controls with gastrointestinal symptoms. A total of 139 autistic participants and 75 non-autistic controls were included in the meta-analysis of lactoferrin studies which found no significant group differences (ROM: 1.27 [0.79, 2.04])., Limitations: All studies included in this systematic review and meta-analysis examined children and adolescents. Many studies included non-autistic controls with gastrointestinal symptoms which limit the validity of their findings. The majority of studies of gastrointestinal inflammation focused on children under 12 with few studies including adolescent participants. Most studies that included participants aged four or under did not account for the impact of age on calprotectin levels. Future studies should screen for relevant confounders, include larger samples and explore gastrointestinal inflammation in autistic adolescents and adults., Conclusions: There is no evidence to suggest higher levels of gastrointestinal inflammation as measured by calprotectin and lactoferrin are present in autistic children and adolescents at the population level. Preliminary evidence suggests however that higher calprotectin levels may be present in a subset of autistic participants, who may be clinically characterised by more severe gastrointestinal symptoms and higher levels of autistic traits., (© 2024. Crown.)

Objectives: This study aims to compare the intestinal microbiota and intestinal inflammation of children with esophageal atresia (EA) to matched healthy controls, and to investigate the relationship between these factors and clinical outcomes., Methods: A cross-sectional study of 35 children with EA and 35 matched healthy controls (HC) from a single tertiary pediatric hospital in Australia was conducted. Demographic and dietary data were collected using surveys. Stool samples were analyzed using 16S rRNA sequencing, and fecal calprotectin measurements were used to measure intestinal inflammation. Comparisons were made between the groups, and correlations between the microbiota and clinical factors were investigated in the EA cohort., Results: Compared to HC, children with EA had similar alpha diversity, but beta diversity analysis revealed clustering of EA and HC cohorts. Children with EA had a significantly higher relative abundance of the order Lactobacillales, and a lower abundance of the genus uncultured Bacteroidales S24-7. Fecal calprotectin was significantly higher in children with EA compared to HC. In the EA cohort, children taking proton pump inhibitors (PPI's) had lower alpha diversity and higher calprotectin levels compared to those not taking PPI's. There was a negative correlation between calprotectin and length/height-for-age z scores, and children with higher calprotectin levels had a greater burden of gastrointestinal symptoms., Conclusions: Children with EA have an altered intestinal microbiota compared to HC, which is likely related to PPI use, and may be impacting on growth and quality of life. It is important to rationalize PPI use in this cohort., (© 2023 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: Gastrointestinal (GI) symptoms are common in individuals with Cystic Fibrosis (CF). International research has highlighted that GI care for this group of patients is lacking. Gastroenterology services to CF clinics across Australasia are yet to be examined. This study aimed to describe the current service delivery model and identify areas for improvement that may lead to positive patient outcomes., Materials and Methods: CF clinicians (dietitians, clinical nurse consultants, respiratory consultants), gastroenterologists (GE), and patients or their carers from Australia and New Zealand (NZ) were surveyed online to gather their opinions on CF gastroenterology services provided in their region. Data were analysed using descriptive statistics (frequencies and percentages). Likert scale questions were analysed by grouping responses 1-5 and 6-10, presented alongside the median and interquartile range (IQR). Mann-Whitney U and chi-square tests were used to look at differences between stakeholder groups., Results: One hundred and fifty-six health professionals and 172 patients or their carers completed the survey. Results showed that the current GI model of care is predominantly a publicly funded service delivered outside of CF clinic time. GE are largely not integrated into the CF team and report a lack of training opportunities. There is a higher level of dissatisfaction with the current service model in NZ than Australia., Discussion: No stakeholder group deemed the current CF gastroenterology service model as adequate, leaving opportunity for transformations in this field. Ideally this study will invigorate the need for promotion and integration of GI services that would ultimately benefit the whole CF community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Katz, Wakefield, Signorelli, Day, Vernon-Roberts and Ooi.)

Background/objectives: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied., Methods: This retrospective study was performed at three sites and included data from INSPPIRE-2., Results: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < -2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < -2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively)., Conclusion: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objectives: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children., Methods: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode., Results: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores., Conclusions: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP., Competing Interests: Dr Lowe is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. Dr Gonska received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). Dr Uc is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology , and consultant for CFF. Dr Schwarzenberg is a consultant for UpToDate, Nestle, AbbVie, and the CFF, and she has a grant from Gilead. Dr Troendle is an Associate Editor for JPGN . Dr Morinville is an Associate Editor for JPGN Reports . The remaining authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Historically, body mass index (BMI) >50th percentile has represented optimal nutritional status in children with cystic fibrosis (CF) due to its positive association with lung function. Body composition parameters including fat-free mass index (FFMI) have been suggested as a more physiological nutrition benchmark., Aims: (1) describe changes in body composition with age and gender; (2) assess the correlation between measures of nutritional status (FFMI-z, FMI-z, BMI-z) and lung function (forced expiratory volume in one second predicted; FEV1pp)., Methods: This retrospective, mixed cross-sectional and serial measures study consisted of children with CF (8 to 18 years) attending Sydney Children's Hospital (2007-2020). FFMI and fat mass index (FMI) were taken from biennial dual energy x-ray absorptiometry (DXA) scans. Z-scores were derived using Well's reference population [1]. Repeated measures correlation analyses assessed correlations between FFMI-z, FMI-z, and BMI-z with FEV1pp., Results: 339 DXA reports were analysed from 137 patients. There were slight downwards trends in BMI-z and FMI-z, and an upwards trend in FFMI-z with increasing age and across both genders. Females had higher FMI-z and FFMI-z than males from 12.5 years. There was a weak, positive correlation between FEV1pp and BMI-z (r = 0.14, p = 0.04), and FFMI-z (r = 0.25, p<0.001). FMI-z had no correlation with FEV1pp (r=-0.06, p = 0.41)., Conclusion: Deficits in FFMI exist despite increasing trends with age. FFMI-z and BMI-z had a weak, positive correlation with FEV1pp. In contemporary cohorts, nutritional status (reflected by surrogate markers such as FFMI and BMI) may be less influential upon lung function than in previous decades. [1]: Wells, J.C., et al. Body-composition reference data for simple and reference techniques and a 4-component model: a new UK reference child. Am. J. Clin. Nutr.96, 1316-1326 (2012)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: The objective of this study was to conduct a web-based questionnaire to investigate self-reported phenotypes and disease burdens of individuals living in Australia and diagnosed with cystic fibrosis (CF) using a case-control study design., Methods: An online questionnaire was distributed to individuals with CF and healthy control subjects. Overall health rating, medications, family history, education, clinical indicators of disease, and symptoms, including their severity and frequency, were evaluated., Results: There was a total of 119 respondents consisting of 59 people living with CF and 60 controls. The CF cohort had significantly lower tertiary educational levels compared to controls. The analysis specific to the CF cohort depicted a significant correlation between the frequency of hospitalizations and the level of education in the CF cohort. Of the 26 self-reported symptoms of CF that were analyzed, 14 were significantly higher in the people living with CF. The CF cohort reporting symptoms of chronic pain (25%) described an increase in the burden of disease, depicting a 30% longer mean hospitalization, increased consumption of medications and significant relationships with four other symptoms, including muscle aches, digestive issues, pancreatic insufficiency, and abdominal swelling., Conclusions: The nationwide survey identified a diverse range of clinical manifestations experienced by the Australian CF population. Chronic pain, linked to aging and the changing landscape of disease, was a significant indicator of the burden of disease. A comprehensive understanding of the phenotypic profiles and symptom variability will contribute to future research and provide insights into the impacts of disease and the burden of therapy, particularly in children, at the start of their health journey., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Cystic-fibrosis-related liver disease (CFLD) is a variable phenotype of CF. The severe CFLD variant with cirrhosis or portal hypertension has a poor prognosis and life expectancy. CFTR modulator therapies are now available for people with CF and eligibility for such treatment is based on their CFTR genotype. We evaluated the genetic eligibility for elexacaftor, tezacaftor, ivacaftor (ETI), and ivacaftor (IVA) monotherapy in a previously reported CF cohort of 1591 people with CF of whom 171 with severe CFLD. Based on their CFTR mutations, 13% (N=184/1420) of subjects without CFLD and 11% (N=19/171) of those with severe CFLD are not eligible for either ETI or IVA therapy. The non-eligible patients without CFLD or with severe CFLD can currently not take advantage of the potential benefits of these new treatments. Although this study cannot provide any data regarding the effect of ETI or IVA on the progression of severe CFLD, the consequences for ineligibility of patients with extreme liver phenotype may be even more significant because of their poorer disease risk profile., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Cystic fibrosis (CF) is a multisystem, autosomal, recessive disease primarily affecting the lungs, pancreas, gastrointestinal tract, and liver. Whilst there is increasing evidence of a microbial 'gut-lung axis' in chronic respiratory conditions, there has been limited analysis of such a concept in CF. We performed a comprehensive dietary and microbiota analysis to explore the interactions between diet, gastrointestinal microbiota, respiratory microbiota, and clinical outcomes in children with CF. Our results demonstrate significant alterations in intestinal inflammation and respiratory and gastrointestinal microbiota when compared to age and gender matched children without CF. We identified correlations between the gastrointestinal and respiratory microbiota, lung function, CF pulmonary exacerbations and anthropometrics, supporting the concept of an altered gut-lung axis in children with CF. We also identified significant differences in dietary quality with CF children consuming greater relative proportions of total, saturated and trans fats, and less relative proportions of carbohydrates, wholegrains, fiber, insoluble fiber, starch, and resistant starch. Our findings position the CF diet as a potential modulator in gastrointestinal inflammation and the proposed gut-lung axial relationship in CF. The dietary intake of wholegrains, fiber and resistant starch may be protective against intestinal inflammation and should be explored as potential therapeutic adjuvants for children with CF.

Aim: To explore the perceptions and practices of Australasian paediatric gastroenterologists in diagnosing coeliac disease (CD) before and during the COVID-19 pandemic., Methods: Paediatric gastroenterologists in Australasia were invited via email to complete an anonymous online questionnaire over a 2-week period in 2021., Results: The questionnaire was completed by 39 respondents: 33 from Australia and six from New Zealand (NZ) equating to a 66% response rate. Thirty-four (87%) of the 39 respondents reported they currently practised non-biopsy diagnosis of CD in eligible children, while the rest diagnosed CD using biopsy confirmation only. All NZ respondents practised non-biopsy CD diagnosis. A majority of responders (76%) who practised non-biopsy CD diagnosis followed the 2020 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines. Twenty-two (56%) respondents reported that they started using a non-biopsy CD diagnosis protocol before the pandemic and did not change their practice during the pandemic, 10 (26%) started diagnosing non-biopsy CD during the pandemic, 5 (13%) stated their practices of CD were not impacted by the pandemic and 2 (5%) did not respond on whether the pandemic changed their practice., Conclusion: The majority of Australasian gastroenterologist respondents reported they routinely utilised the 2020 ESPGHAN diagnostic criteria in eligible children; half of them started prior to the pandemic and another quarter started this approach due to the pandemic. A minority of practitioners routinely rely only on biopsy confirmation to diagnose CD., (© 2022 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Siblings of young people with chronic illness commonly undertake caring responsibilities for their affected brother/sister, which may encourage maturation, yet may also be perceived as a burden. Our study determined (1) siblings' caring responsibilities, (2) siblings' current emotional distress and psychosocial functioning, and (3) how siblings' caring responsibilities and psychosocial functioning related to familial relationships and coping strategies. Siblings completed questionnaires which contained Sibling Inventory of Behavior, Sibling Inventory of Differential Experiences, PedsQL, emotion thermometers, Brief COPE, and a checklist of caregiving responsibilities. We analyzed the data with t -tests and multi-level models. Forty-five siblings (mean age = 15.40 years, SD = 3.31 years; 60.0% female) participated. Siblings who had caring responsibilities ( n = 26, 57.8%) reported lower anxiety symptoms, lower need for help, greater use of problem-focused coping, and more companionship and teaching/directiveness with their affected brother/sister than siblings without caring responsibilities. Siblings reported lower psychosocial and physical functioning when they perceived their parents provided them with less affection than their affected brother/sister. Family-based psychosocial interventions may aim to improve the sibling-parent relationship (including expressing affection) and the sibling-sibling relationship. Future interventions may also focus on increasing siblings' use of problem-focused coping strategies.

Objectives: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP)., Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP., Results: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP., Conclusions: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP., Competing Interests: M.E.L. is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. T.G. received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology, and consultant for CFF. S.J.S. is a consultant for UpToDate, Nestle, Abbvie, and the Cystic Fibrosis Foundation, and she has a grant from Gilead. V.D.M. is an Associate Editor for JPGN Reports. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Diets of children and adolescents on the autism spectrum often differ when compared to their non-autistic peers. Most dietary studies have been limited by small sample sizes and rarely assess the heterogeneity of autism. Addressing this gap, this study compared the anthropometrics, dietary composition, dietary quality, and food variety of 154 Australian children and adolescents on the spectrum and 213 non-autistic children (71 siblings and 142 unrelated controls). Beyond the case-control approach, within-group comparisons assessed the influence of autism clinical presentations and sensory processing styles on body mass index (BMI) and measures of dietary intake among those on the spectrum. In this word first study of diet that included between-group comparisons with non-autistic peers (siblings and an unrelated comparison group) and within-autism group comparisons, we found that children on the spectrum consumed limited variety and lower quality of food and non-autistic siblings also ate comparably higher levels of energy-dense, nutrient poor food, and less diary. This may be due to autistic traits influencing family's diets or shared sensory sensitivities driving dietary intake. Within the autism group, higher autistic traits were associated with lower BMIs and a specific dietary pattern higher in simple carbohydrates and lower in unprocessed protein. Contrastingly, greater sensitivity to sensory stimuli was associated with a healthier diet. Increased age was linked to more varied diets but also diets higher in saturated fats and energy-dense, nutrient poor foods. Overall, this research highlights that potential mediators of dietary intake, such as familial influences, autistic traits, sensory processing styles, age and sex, need to be considered when assessing diet in the autistic population. LAY SUMMARY: In this study of dietary differences linked to autism, children, and teenagers on the spectrum ate fewer different foods and were less likely to eat recommended amounts of fruits and vegetables when compared to non-autistic siblings and unrelated children and teenagers. There were also family differences, in that those on the spectrum and their siblings ate more unhealthy foods and less dairy. Among those on the spectrum, dietary differences were linked to age, sex, autistic traits and sensory processing styles., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Objectives: Children with esophageal atresia (EA) often have feeding difficulties and dysphagia, which may compromise their nutritional status. This study aimed to compare dietary intake between children with EA and matched healthy controls (HC) and to investigate the relationship between dietary factors, growth, dysphagia, and feeding difficulties in the EA cohort., Methods: This cross-sectional cohort study recruited children with EA and HC aged 2-17 years from a tertiary pediatric hospital in Australia. Growth parameters were measured. Dietary intake was assessed using the validated Australian Child and Adolescent Eating Survey. Dysphagia and feeding difficulties were assessed using objective questionnaires., Results: Twenty-one children with EA were matched for age and sex with 21 HC. Compared to HC, children with EA had lower mean z scores for height-for-age, but mean weight-for-age and body mass index-for-age z scores were similar. Energy intake was similar between the groups. The diet of children with EA consisted of a higher proportion of fats and lower proportion of carbohydrates compared to matched HC. Dysphagia severity in children with EA positively correlated with proportion of energy from fats and saturated fats., Conclusions: Children with EA have similar energy intake and growth parameters to HC, but their diet consists of a higher proportion of fats and lower proportion of carbohydrates compared to HC. Targeted dietary interventions and parental education are necessary., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Although chitinase-3-like-1 (CHI3L1), predominately produced by epithelial cells and macrophages, is relevant to pulmonary disease in cystic fibrosis (CF), fecal levels have not yet been assessed in children with CF. Fecal CHI3L1 was measured with a commercial immunoassay using fecal samples provided by children with CF and healthy control (HC) children. Higher median (interquartile range) fecal CHI3L1 levels were seen in the 52 children with CF than in the 35 controls: 15.97 (3.34-50.53) ng/g versus 2.93 (2.13-9.27) ng/g ( P = 0.001). Fecal CHI3LI did not differ according to sex. In the children with CF, fecal CHI3L1 levels did not correlate with growth parameters nor were the levels affected by pancreatic insufficiency. Children with CF had higher fecal CHI3L1 levels, suggesting underlying gut inflammation. Further work is required to confirm the current findings and to ascertain the longer-term significance of elevated CHI3L1., Competing Interests: C.Y.O. has consulted and served on advisory boards for Vertex Pharmaceuticals (unrelated to this manuscript). A.S.D. has served on advisory boards for Janssen, Abbvie, and Nestle (all unrelated to this manuscript). The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

A significant challenge to making targeted cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies accessible to all individuals with cystic fibrosis (CF) are many mutations in the CFTR gene that can cause CF, most of which remain uncharacterized. Here, we characterized the structural and functional defects of the rare CFTR mutation R352Q, with a potential role contributing to intrapore chloride ion permeation, in patient-derived cell models of the airway and gut. CFTR function in differentiated nasal epithelial cultures and matched intestinal organoids was assessed using an ion transport assay and forskolin-induced swelling assay, respectively. CFTR potentiators (VX-770, GLPG1837, and VX-445) and correctors (VX-809, VX-445, with or without VX-661) were tested. Data from R352Q-CFTR were compared with data of 20 participants with mutations with known impact on CFTR function. R352Q-CFTR has residual CFTR function that was restored to functional CFTR activity by CFTR potentiators but not the corrector. Molecular dynamics simulations of R352Q-CFTR were carried out, which indicated the presence of a chloride conductance defect, with little evidence supporting a gating defect. The combination approach of in vitro patient-derived cell models and in silico molecular dynamics simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine.

Cystic fibrosis (CF) is a common disorder of autosomal recessive inheritance, that once conferred a life expectancy of only a few months. Over recent years, significant advances have been made to CF therapeutic approaches, changing the face of the disease, and facilitating the partial restoration of pancreatic function. This mini review summarizes the current landscape of exocrine pancreatic management in CF and explores areas for future direction and development., Competing Interests: CO has served as a consultant and received research funding (unrelated to the content of this manuscript) from Vertex Pharmaceuticals. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McKay and Ooi.)

Objectives: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL., Methods: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment., Results: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001)., Conclusions: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children., Competing Interests: M.L. is on the Board of Directors of the National Pancreas Association; receives royalties from Millipore Inc and UpToDate. T.G. received a research grant from Vertex Pharmaceuticals and she is a consultant for Cystic Fibrosis Foundation. M.B. is a consultant for AbbVie Inc and ARIEL Precision Medicine. C.Y.O. is a consultant for Vertex Pharmaceuticals. A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology and a consultant for Cystic Fibrosis Foundation. The other authors declare no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA., Methods: We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model., Results: Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12)., Conclusions: CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Cystic fibrosis (CF) is a life-limiting autosomal recessive multisystem disease. While its burden of morbidity and mortality is classically associated with pulmonary disease, CF also profoundly affects the gastrointestinal (GI) tract. Chronic low-grade inflammation and alterations to the gut microbiota are hallmarks of the CF intestine. The etiology of these manifestations is likely multifactorial, resulting from cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, a high-fat CF diet, and the use of antibiotics. There may also be a bidirectional pathophysiological link between intestinal inflammation and changes to the gut microbiome. Additionally, a growing body of evidence suggests that these GI manifestations may have significant clinical associations with growth and nutrition, quality of life, and respiratory function in CF. As such, the potential utility of GI therapies and long-term GI outcomes are areas of interest in CF. Further research involving microbial modulation and multi-omics techniques may reveal novel insights. This article provides an overview of the current evidence, pathophysiology, and future research and therapeutic considerations pertaining to intestinal inflammation and alterations in the gut microbiota in CF.

Cystic fibrosis (CF) is a life-shortening genetic disorder that affects the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the gastrointestinal (GI) tract, CFTR dysfunction results in low intestinal pH, thick and inspissated mucus, a lack of endogenous pancreatic enzymes, and reduced motility. These mechanisms, combined with antibiotic therapies, drive GI inflammation and significant alteration of the GI microbiota (dysbiosis). Dysbiosis and inflammation are key factors in systemic inflammation and GI complications including malignancy. The following review examines the potential for probiotic and prebiotic therapies to provide clinical benefits through modulation of the microbiome. Evidence from randomised control trials suggest probiotics are likely to improve GI inflammation and reduce the incidence of CF pulmonary exacerbations. However, the highly variable, low-quality data is a barrier to the implementation of probiotics into routine CF care. Epidemiological studies and clinical trials support the potential of dietary fibre and prebiotic supplements to beneficially modulate the microbiome in gastrointestinal conditions. To date, limited evidence is available on their safety and efficacy in CF. Variable responses to probiotics and prebiotics highlight the need for personalised approaches that consider an individual's underlying microbiota, diet, and existing medications against the backdrop of the complex nutritional needs in CF.

Characterization of I37R, a mutation located in the lasso motif of the CFTR chloride channel, was conducted by theratyping several CFTR modulators from both potentiator and corrector classes. Intestinal current measurements in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids, and short circuit current measurements in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype demonstrated that the I37R-CFTR results in a residual function defect amenable to treatment with potentiators and type III, but not type I, correctors. Molecular dynamics of I37R using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavorable strengthening of the interactions between the lasso motif, the regulatory (R) domain, and the transmembrane domain 2 (TMD2). Structural and functional characterization of the I37R- CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to expand drug access to CF patients with ultra-rare genotypes., Competing Interests: SAW is the recipient of a Vertex Innovation Grant (2018) and a TSANZ/Vertex Research Award (2020). Both are unrelated and outside of the submitted manuscript. AJ has received consulting fees from Vertex on projects unrelated to this study. CYO has acted as consultant and is on advisory boards for Vertex pharmaceuticals. These works are unrelated to this project and manuscript. All other authors declare no conflict of interest., (© 2021 The Author(s).)

Abstract: We reviewed INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in five (1.2%); two had ARP, three CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in four, mild AP in one. Venous thrombosis occurred in four, arterial pseudoaneurysm (left gastric artery) in one. Two patients with venous thrombosis were treated with anticoagulant, one achieved recanalization (splenic vein). In two patients who did not receive anticoagulants, one re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated., Competing Interests: Dr Mark Lowe is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. Dr Tanja Gonska received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation. Dr Aliye Uc is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology and Consultant for Cystic Fibrosis Foundation. The remaining authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose of Review: Approximately 20-30% of children who experience one episode of acute pancreatitis will have at least one additional episode. For some children, pancreatitis recurs multiple times and in a few years is followed by the diagnosis of chronic pancreatitis. Identifying risk factors for recurrent episodes and disease progression is critical to developing therapeutic interventions., Recent Findings: Obesity is driving an increase in biliary stone disease and severe acute pancreatitis. Recurrent acute pancreatitis (RAP) may lead to the development of diabetes through autoimmune mechanisms. Cystic fibrosis or CFTR-related disorders may present as RAP and CFTR modulator therapy can increase or decrease the risk of acute pancreatitis in these populations. Children with Crohn disease have a three-fold risk of acute pancreatitis over the general population while children with ulcerative colitis are at increased risk for pediatric autoimmune pancreatitis, a disorder that may be distinct from autoimmune pancreatitis described in adults. Obstructive jaundice in the absence of identified mechanical factors may be a presenting sign of pediatric autoimmune pancreatitis., Summary: Pediatric RAP is a painful condition that leads to gland destruction and functional insufficiency. Risk factors are being clarified but preventive treatments remain elusive., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: FUNDING STATEMENT This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. We also acknowledge the funding support of the Sydney Children's Hospital Foundation, and the Australian Government Department of Education and Training.

Over the past two decades there has been considerable progress with the evaluation and management of infants with an inconclusive diagnosis following Newborn Screening (NBS) for cystic Fibrosis (CF). In addition, we have an increasing amount of evidence on which to base guidance on the management of these infants and, importantly, we have a consistent designation being used across the globe of CRMS/CFSPID. There is still work to be undertaken and research questions to answer, but these infants now receive more consistent and appropriate care pathways than previously. It is clear that the majority of these infants remain healthy, do not convert to a diagnosis of CF in childhood, and advice on management should reflect this. However, it is also clear that some will convert to a CF diagnosis and monitoring of these infants should facilitate their early recognition. Those infants that do not convert to a CF diagnosis have some potential of developing a CFTR-RD later in life. At present, it is not possible to quantify this risk, but families need to be provided with clear information of what to look out for. This paper contains a number of changes from previous guidance in light of developing evidence, but the major change is the recommendation of a detailed assessment of the child with CRMS/CFSPID in the sixth year of age, including respiratory function assessment and imaging. With these data, the CF team can discuss future care arrangements with the family and come to a shared decision on the best way forward, which may include discharge to primary care with appropriate information. Information is key for these families, and we recommend consideration of a further appointment when the individual is a young adult to directly communicate the implications of the CRMS/CFSPID designation., (Copyright © 2020 European Cystic Fibrosis Society. All rights reserved.)

Background: Simulation-based technologies are emerging to enhance medical education in the digital era. However, there is limited data for the use of virtual reality simulation in pediatric medical education. We developed Virtual Doc as a highly immersive virtual reality simulation to teach pediatric cardiopulmonary resuscitation skills to medical students., Objective: The primary objectives of this study were to evaluate participant satisfaction and perceived educational efficacy of Virtual Doc. The secondary aim of this study was to assess the game play features of Virtual Doc., Methods: We conducted a prospective closed beta-testing study at the University of New South Wales (Sydney, Australia) in 2018. All medical students from the 6-year undergraduate program were eligible to participate and were recruited through voluntary convenience sampling. Participants attended a 1-hour testing session and attempted at least one full resuscitation case using the virtual reality simulator. Following this, participants were asked to complete an anonymous postsession questionnaire. Responses were analyzed using descriptive statistics., Results: A total of 26 participants were recruited, consented to participate in this study, and attended a 1-hour in-person closed beta-testing session, and 88% (23/26) of participants completed the anonymous questionnaire and were included in this study. Regarding participant satisfaction, Virtual Doc was enjoyed by 91% (21/23) of participants, with 74% (17/23) intending to recommend the simulation to a colleague and 66% (15/23) intending to recommend the simulation to a friend. In assessment of the perceived educational value of Virtual Doc, 70% (16/23) of participants agreed they had an improved understanding of cardiopulmonary resuscitation, and 78% (18/23) agreed that Virtual Doc will help prepare for and deal with real-life clinical scenarios. Furthermore, 91% (21/23) of participants agreed with the development of additional Virtual Doc cases as beneficial for learning. An evaluation of the game play features as our secondary objective revealed that 70% (16/23) of participants agreed with ease in understanding how to use Virtual Doc, and 74% (17/23) found the game play elements useful in understanding cardiopulmonary resuscitation. One-third (7/23, 30%) found it easy to work with the interactive elements. In addition, 74% (17/23) were interested in interacting with other students within the simulation., Conclusions: Our study demonstrates a positive response regarding trainee satisfaction and perceived educational efficacy of Virtual Doc. The simulation was widely accepted by the majority of users and may have the potential to improve educational learning objectives., (©Janaya Elizabeth Perron, Michael Jonathon Coffey, Andrew Lovell-Simons, Luis Dominguez, Mark E King, Chee Y Ooi. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.07.2021.)

Aim: To determine whether combined multichannel intraluminal impedance and pH (MII-pH) testing led to a change in management of children with gastro-oesophageal reflux disease (GORD)., Methods: Retrospective chart review was done in all patients who underwent MII-pH testing for GORD symptoms at Sydney Children's Hospital between 2008 and 2016. Changes to anti-reflux medications and referral for anti-reflux surgery were evaluated., Results: There were 365 patients, 260 (71.2%) of whom were on acid-suppressing therapy. The median age was 4.1 ± 4.8 years, 205 patients (56%) were males, 83 (22.7%) were infants (<1 year of age) and 145 (39.7%%) had comorbid conditions. We found 72.1% had abnormal MII-pH results, of which 17.5% had abnormal acid reflux, 8.2% had abnormal number of retrograde bolus movements and 46.3% had hypersensitive oesophagus (positive symptom association only). Infants were significantly more likely to have abnormal MII-pH results compared to older children (P = .04). Results of MII-pH testing led to medication changes in 44.7% and referral for anti-reflux surgery in 6.8% of patients., Conclusion: Combined multichannel intraluminal impedance and pH testing is clinically useful in the management of children with symptoms of GORD and over half the patients had changes to their medical treatment or referral for anti-reflux surgery based on the results of MII-pH testing. It resulted in a treatment change in an additional 32% of patients over traditional pH-metry., (© 2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Paediatric pancreatic diseases are often under-recognised and may be associated with severe diseases and significant clinical consequences. In recent years, advances have been made in key areas, particularly with the contributions from international societies and study groups focused on paediatric pancreatic disease research. This review focuses on the two key manifestations of pancreatic disorders in childhood, pancreatitis and exocrine pancreatic dysfunction., (© 2019 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objectives: The aim of the study was to investigate the role of combined multichannel intraluminal impedance and pH (MII-pH) testing in clinical management of children with gastroesophageal reflux disease (GERD) by exploring the impact of treatment changes made based on MII-pH testing results on symptoms and quality of life outcomes., Methods: All patients (<18 years) referred to the Sydney Children's Hospital for MII-pH testing were recruited. Patients were classified by acid suppression therapy (AST) status (on AST and off AST) and changes in medical and surgical management were evaluated. Validated questionnaires (Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire and Infant Gastroesophageal Reflux Questionnaire Revised) were administered at baseline at the time of MII-pH testing, and 4 weeks after treatment changes were made and questionnaire scores were compared., Results: Of the 45 patients recruited, 24 patients (53.3%) were off AST and 21 patients (46.7%) were on AST. MII-pH testing led to medication changes in 30 patients (66.7%). This included 15 of 24 (62.5%) in those off AST and 15 of 21 (71.4%) in those on AST. More than 98% of patients who had treatment changes showed a significant improvement in both symptoms and quality of life scores., Conclusions: Our study is one of the first pediatric studies to evaluate the clinical validity of MII-pH testing in the pediatric population referred for suspected GERD, and its ability in guiding clinical management. Our study has shown that treatment decisions guided by and based on results of MII-pH testing led to a significant improvement in symptoms and quality of life in infants and children with GERD.

Background: Studies have increasingly challenged the traditional management of acute pancreatitis (AP) with bowel rest. However, these studies used a low-fat diet or transgastric feeding and only included adults. Aiming to generate higher-quality prospective pediatric data, we compared the traditional approach of fasting and intravenous fluids and early enteral feeding with standard diet or formula., Methods: Randomized controlled trial of children (2-18 years) with mild-moderate AP. Patients were randomly assigned 1:1 to initial fasting and intravenous fluids or an immediate, unrestricted diet. Pain scores, blood measures, and cross-sectional imaging were recorded throughout admission and follow-up. The primary outcome was time to discharge, and secondary outcomes were clinical and biochemical resolution and local and systemic complication rates., Results: Of 33 patients (17 [52%] boys, mean age of 11.5 [±4.8] years), 18 (55%) were randomly assigned to early feeding and 15 (45%) were randomly assigned to initial fasting. We recorded the median (interquartile range [IQR]) time to discharge (2.6 [IQR 2.0 to 4.0] vs 2.9 [IQR 1.8 to 5.6]; P = .95), reduction in serum lipase levels by day 2 (58% [IQR 2% to 85%] vs 48% [IQR 3% to 71%]; P = .65), and readmission rates (1 of 18 [6%] vs 2 of 15 [13%]; P = .22) between the early feeding and fasting cohorts, respectively. Immediate or delayed complication rates did not differ. Patients randomly assigned to early feeding had weight gain of 1.3 kg (IQR 0.29 to 3.6) at follow-up, compared with weight loss of 0.8 kg (IQR -2.1 to 0.7) in fasted patients ( P = .028)., Conclusions: This is the first randomized controlled trial in pediatric AP. There was no difference between early commencement of a standard oral diet and initial fast in any of the major outcome measures., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test. Young children with CF have glucose abnormalities detected by CGM that fluctuate over time., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2020. Published by Elsevier B.V.)

Objective: The aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites., Study Design: Data were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test., Results: Out of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P < 0.0001); white race in Northeast (P = 0.009). CP was less common and time from diagnosis of first acute pancreatitis to CP was longer in children at non-US sites (P = 0.0002 and P = 0.011, respectively). Genetic mutations were most common among all groups; PRSS1 variants predominated in Midwest (P = 0.002). Gallstones were more frequent in South (P = 0.002). Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) imaging were more commonly utilized in United States compared with non-United States (P < 0.0001), but there were no differences in the use of MRI/MRCP. Disease burden was highest in the West and Midwest, possibly as total pancreatectomy and islet autotransplantation (TPIAT) referral sites were located in these regions. All therapies were less commonly administered in non-US sites (P < 0.0001)., Conclusions: This is the first study to describe geographical variations in the INSPPIRE cohort, which possibly reflect variations in practice and referral patterns. The underlying reason behind the lower frequency of CP and fewer treatments in non-United States sites need to be further explored.

Background: Cystic fibrosis-related liver disease (CFLD) is the leading nonpulmonary cause of mortality in cystic fibrosis (CF). We evaluated and compared the burden of disease and nonrespiratory comorbidities of those with severe CFLD and those without (noCFLD)., Methods: A retrospective nationwide (Australia) longitudinal review (from 1998 to 2016) of severe CFLD patients compared with noCFLD controls (matched 1 : 1 for age, genotype, pancreatic insufficiency, and center)., Results: One hundred sixty-six patients with severe CFLD and 166 with noCFLD were identified. Forced expiratory volume in 1 second percentage of predicted (FEV1%) was significantly lower in CFLD than noCFLD across all ages (estimate [SE] -6.05% [2.12]; P = 0.004). Median (IQR) hospitalizations per patient per year were higher in CFLD than noCFLD for: respiratory indications (0.6 [0.2-1.3] vs 0.4 [0.1-0.9]; P = 0.002); gastrointestinal indications (0.09 [0-0.2] vs 0 [0-0.05]; P < 0.001); and other indications (0.05 [0-0.2] vs 0 [0-0.1]; P = 0.03). In the CFLD cohort, there was increased use of nasogastric (12.6% vs 5.4%; OR 2.51 [95% CI 1.06-6.46]; P = 0.03) and gastrostomy nutritional supplementation (22.9% vs 13.2%; OR 1.93 [95% CI 1.05-3.63]; P = 0.03). Additionally, the CFLD cohort had a higher frequency of bone diseases, osteopenia (26.5% vs 16.8%; OR 1.77 [95%CI 1.01-3.15]; P = 0.04) and osteoporosis (16.2% vs 8.4%; OR 2.1 [95% CI 1.01-4.52]; P = 0.04), as well as CF-related diabetes (38.5% vs 19.2%; OR 2.61 [95% CI 1.55-4.47]; P = 0.001)., Conclusions: Patients with severe CFLD have greater disease burden, with higher number of hospitalizations (both respiratory and nonrespiratory indications), nutritional interventions, and are at higher risk of CF-related bone disease and diabetes.