Traumatic subcutaneous emphysema following blood donation: A case report.

BACKGROUND: Subcutaneous emphysema is a condition where air becomes trapped under the skin, typically resulting from surgery or skin trauma. It is mostly localized and its occurrence in blood donors is exceedingly rare. Phlebotomy poses minimal risk of subcutaneous emphysema, but procedural errors may lead to such complications. STUDY DESIGN AND METHOD: This is a case report of 29-year-old repeat blood donor who experienced subcutaneous emphysema following blood donation. The donor was vigorously squeezing sponge ball during donation resulting in displacement of the needle which required readjustment. Post-donation, the donor reported a crackling sensation and mild swelling near phlebotomy site. Non-contrast computed tomography (NCCT) scans confirmed subcutaneous emphysema, attributing its development to air trapping in subcutaneous plane due to ball valve mechanism. RESULTS: Computed tomography (CT) imaging revealed subcutaneous emphysematous changes in the right cubital region and no evidence of hematoma. The swelling spontaneously subsided in 10-12 days without any intervention. The case underscores the importance of differentiating subcutaneous emphysema from common complications like hematoma. DISCUSSION: Subcutaneous emphysema in blood donors is exceptionally rare but should be managed with clear communication. Donors should be reassured that the condition, although rare, is benign and self-resolving. Healthcare providers should be equipped to handle such rare complications, offering appropriate care and documenting incidents for future prevention.

The Pediatric Crohn Disease Morbidity Index (PCD-MI): Development of a Tool to Assess Long-Term Disease Burden Using a Data-Driven Approach.

BACKGROUND/OBJECTIVE: Heterogeneity and chronicity of Crohn disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient's disease course, preventing assessment and integration into predictive modeling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score. METHODS: Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a pediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children's Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov). RESULTS: Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/fecal/radiological/endoscopic results, medication usage, surgery, growth parameters, and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration. PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/fecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5); data were normally distributed ( P = 0.2) with 25% of patients having a PCD-MI < 10. There was no difference in the mean PCD-MI when split by year of diagnosis, F -statistic 1.625, P = 0.147. CONCLUSIONS: PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimized scores, and validation on external cohorts.

Incidence and Prevalence of Paediatric Inflammatory Bowel Disease Continues to Increase in the South of England.

OBJECTIVE: The incidence of paediatric inflammatory bowel disease (IBD) has been increasing over 25 years; however, contemporary trends are not established and the impact of COVID-19 on case rates is unclear. METHODS: Data from Southampton Children's hospital prospective IBD database were retrieved for 2002-2021. Incidence rates were calculated based on referral area populations and temporal trends analysed. Disease prevalence for those aged <18 years was calculated for 2017-2021. Monoclonal prescriptions were reported. RESULTS: In total, 1150 patients were included (mean age at diagnosis 12.63 years, 40.5% female). An estimated 704 patients had Crohn's disease (61.2%), 385 had ulcerative colitis (33.5%), and 61 had IBD unclassified (5.3%). Overall IBD incidence increased, ß = 0.843, P = 3 × 10 -6 , driven by Crohn's disease, ß = 0.732, P = 0.00024 and ulcerative colitis, ß = 0.816, P = 0.000011. There was no change in IBDU incidence, ß = 0.230, P = 0.33. From 2002-2021, 51 patients were diagnosed <6 years of age, 160 patients aged 6 to <10 years and 939 patients aged 10 to <18 years of age. Increased incidence was observed in patients aged 10 to <18 years of age (ß = 0.888, P = 1.8 × 10 -7 ). There was no significant change in incidence of IBD in <6 years (ß = 0.124, P = 0.57), or 6 to <10 years (ß = 0.146, P = 0.54). IBD prevalence increased by an average of 1.71%/year from 2017 to 2021, ß = 0.979, P = 0.004. The number of new monoclonal prescriptions increased from 6 in 2007 to 111 in 2021. CONCLUSIONS: IBD incidence continues to increase in Southern England. Compounding prevalence and increased monoclonal usage has implications for service provision.

Growth failure is rare in a contemporary cohort of paediatric inflammatory bowel disease patients.

AIM: We assessed growth in a paediatric inflammatory bowel disease (PIBD) cohort. METHODS: Paediatric inflammatory bowel disease patients were eligible if they were diagnosed at Southampton Children's Hospital from 2011 to 2018. Weight and height standard deviation scores (SDS) were retrieved. Mean SDS values, SDS change and anti-TNF status were analysed at diagnosis and during follow-up. RESULTS: Four hundred and ninety patients were included, 313 with Crohn's disease (CD). CD patients presented with mean height SDS -0.13, -0.1 at 1-year, -0.11 at 2-years and -0.03 at 5 years, reflecting preserved linear growth. There was no significant height-SDS change from diagnosis to 5-year follow-up, +0.12, 95%-CI: 0.48 to -0.24. Mean weight-SDS at diagnosis was -0.39, driven by CD patients (-0.65). Mean weight-SDS approached 0 after 1 year and remained at the 50th centile throughout follow-up. Growth in ulcerative colitis was maintained. In multivariable regression males had worse height growth from diagnosis to transition (P = .036). Anti-TNF treatment (P = .013) and surgical resection (P = .005) were also associated with poorer linear growth. Patients treated with anti-TNF therapy had lower height-SDS compared to those never treated with anti-TNF at 1 year (-0.2 vs -0.01, P = .22), 2-years (-0.27 vs -0.01, P = .07) and 5 years (-0.21 vs 0.25, P = .051). CONCLUSION: Height was generally maintained in Crohn's disease, and impaired linear growth was rare in this cohort.

Emotional Wellbeing in Parents of Children on Home Parenteral Nutrition.

OBJECTIVES: Caring for a child on home parenteral nutrition (HPN) is stressful, and its emotional impact not fully appreciated. This study explored the emotional wellbeing and coping styles of parents and children on HPN. METHODS: Questionnaire data were collected for parents of children (0-18 years) on HPN. Children 8 years and older completed the revised children's anxiety and depression scale. Parents completed the Hospital Anxiety and Depression Scale, Paediatric Inventory for Parents (PIP) and brief COPE. RESULTS: A total of 14 children were included, 20 parents (13 females) and 4 children completed the survey. Parents had mean PIP difficulty and frequency score of 117.9 and 124, respectively, higher compared to parents of children with other chronic illness. PIP scores were significantly higher where children were also enterally tube fed (P < 0.05). Thirty-five per cent parents scored above clinical threshold on anxiety subscale of Hospital Anxiety and Depression Scale and 30% in borderline range. On depression subscale 15% scored above clinical threshold range and 15% in borderline range. Mean anxiety and depression scores in parents of children with short bowel syndrome (11.8, 7.8) were significantly higher than those with neuromuscular disease (5.8, 1.6) P < 0.05. Coping styles differed according to health condition and whether child was enterally fed. CONCLUSIONS: There is a significant emotional impact of caring for a child on HPN, assessment and treatment of anxiety, depression, and stress should be a routine part of care. Individual needs of the child and parent need to be taken into account in providing the most appropriate psychological support.

Immunological Profiling of Paediatric Inflammatory Bowel Disease Using Unsupervised Machine Learning.

OBJECTIVES: The current classification of inflammatory bowel disease (IBD) is based on clinical phenotypes, which is blind to the molecular basis of the disease. The aim of this study was to stratify a treatment-naïve paediatric IBD cohort through specific innate immunity pathway profiling and application of unsupervised machine learning (UML). METHODS: In order to test the molecular integrity of biological pathways implicated in IBD, innate immune responses were assessed at diagnosis in 22 paediatric patients and 10 age-matched controls. Peripheral blood mononuclear cells (PBMCs) were selectively stimulated for assessing the functionality of upstream activation receptors including NOD2, toll-like receptor (TLR) 1-2 and TLR4, and the downstream cytokine responses (IL-10, IL-1ß, IL-6, and TNF-α) using multiplex assays. Cytokine data generated were subjected to hierarchical clustering to assess for patient stratification. RESULTS: Combined immune responses in patients across 12 effector responses were significantly reduced compared with controls (P = 0.003) and driven primarily by "hypofunctional" TLR responses (P values 0.045, 0.010, and 0.018 for TLR4-mediated IL-10, IL-1ß, and TNF-α, respectively; 0.018 and 0.015 for TLR1-2 -mediated IL-10 and IL-1ß). Hierarchical clustering generated 3 distinct clusters of patients and a fourth group of "unclustered" individuals. No relationship was observed between the observed immune clusters and the clinical disease phenotype. CONCLUSIONS: Although a clinically useful outcome was not observed through hierarchical clustering, our study provides a rationale for using an UML approach to stratify patients. The study also highlights the predominance of hypo-inflammatory innate immune responses as a key mechanism in the pathogenesis of IBD.

Endoscopic and Histological Assessment of Paediatric Inflammatory Bowel Disease Over a 3-Year Follow-up Period.

OBJECTIVES: Discrepancies between inflammatory bowel disease (IBD) endoscopic/histological extent are documented at diagnosis. It is unclear whether these differences persist through disease course, with potential impact on categorization and management. We aimed to analyze the progression of disease over a 3-year period. METHODS: Patients younger than 17 years, diagnosed between 2010 and 2013 at Southampton Children's Hospital and followed-up for 3 years were eligible. Primary outcome was disease extent at diagnosis and follow-up. Data are presented as percentage of patients undergoing endoscopy. Paris classification (PC) and PC using histological, rather than endoscopic disease, were determined. RESULTS: One hundred and twenty-five patients were included, 66 boys; Crohn's disease (CD) 74, ulcerative colitis (UC) 40, IBD unclassified (IBDU) 11. All had endoscopy at diagnosis. One hundred and two patients underwent ≥1 repeat endoscopies.Disease extent reduced from diagnosis to first follow-up endoscopy for both endoscopic and histological disease extent (CD/UC/IBDU, all P < 0.00006). Histological extent remained greater than endoscopic in CD with significant differences in stomach, ileum, and large bowel at all follow-up points (P =  < 0.045). Endoscopic matched histological extent in UC/IBDU. Applying a modified PC resulted in significant changes for CD (L3 27.4%-53.2%, P = 0.006, L3 + L4A 21%-50%, P = 0.001, and upper gastrointestinal disease 50%-80.6%, P = 0.0006) but not UC. CD height (-0.37 to -0.25) and weight (-1.09 to -0.19) standard deviation scores increased from diagnosis to follow-up. CONCLUSIONS: Histological disease is greater than endoscopic extent at diagnosis and during follow-up in CD, although not in UC/IBDU. Classification of disease extent in CD should be based on both endoscopic and histological criteria.

Hydroxyethyl starch and kidney function: A retrospective study in patients undergoing therapeutic plasma exchange.

PURPOSE: Hydroxyethyl starch (HES) and albumin are used as replacement fluids during therapeutic plasma exchange (TPE). HES solutions are no longer recommended in critically ill patients due to its effect on kidneys and coagulation. In this retrospective study, we tried to look at the association between cumulative HES administration and kidney function in patients undergoing TPE. METHODS: Transfusion medicine department register was scrutinized to identify adult patients who had completed at least 5 cycles of TPE during the period June 2014-May 2015. Patient demographics, indication for TPE, amount of plasma removed, amount of colloid administered, adverse events and vascular access details were collected. Electronic hospital database was scrutinized to retrieve lab parameters, including blood urea and serum creatinine (before and after 5 cycles of TPE) and platelet count. Baseline renal parameters were compared with post TPE values using Wilcoxon signed rank test. A p value <0.05 was kept as significant. RESULTS: Of the 593 patients who received TPE during the study period, 104 patients fulfilled the inclusion criteria. Forty-five patients out of 104 received TPE in the intensive care unit. All patients received 2500 ml of HES during the study period. Blood urea and serum creatinine values, when compared to baseline, significantly decreased after 5 cycles of TPE (p = 0.004, p = 0.001, respectively). CONCLUSION: Blood urea and serum creatinine, used as markers of renal function, improved in patients requiring multiple doses of HES solutions during TPE. Further studies using novel renal biomarkers are required to examine whether HES induces any structural damage to kidneys.

Intestinal failure: the evolving demographic and patient outcomes on home parenteral nutrition.

AIM: We performed this study to examine and understand the evolving demographics and changing outcomes of intestinal failure (IF) and its implications for healthcare delivery. METHOD: We conducted a retrospective analysis of outcome data of children on home parenteral nutrition (HPN), over a 15-year period. RESULTS: A total of 31 patients received HPN: 15 for short bowel syndrome (SBS), eight neuromuscular disease (NMD) and eight for other causes. The HPN prevalence increased from 1.54 per million children in 2000 to 21.5 in 2016. The outcomes over last 5 years were better than those of previous 10 years. The rate of catheter-related bloodstream infection (CRBSI) had fallen from 4 to 1.3 and IF liver disease (IFALD) from 20% to 7.7%. The aetiology changed over years from SBS being the main cause to NMD contributing 43% to the total in 2016. This was especially relevant as NMD was associated with greater numbers of IFALD (38% vs 6.7%), CRBSI (1.51 vs 0.64/1000 PN days) and mortality. CONCLUSION: The outcome of long-term parenteral nutrition (PN) has improved. The increasing number of patients with NMD, coupled with their higher burden of care, results in an increasing health care burden, and the planning of intestinal rehabilitation services needs to reflect this.

Endoscopic Versus Histological Disease Extent at Presentation of Paediatric Inflammatory Bowel Disease.

OBJECTIVES: The Paris classification (PC) of paediatric inflammatory bowel disease categorises disease extent and therefore affects treatment decisions. Histological (microscopic) disease extent is not incorporated, and endoscopic (macroscopic) findings may underrepresent disease extent when compared with histological findings; this study compares disease extent at presentation. METHODS: Data were obtained of patients <17 years of age diagnosed with inflammatory bowel disease from 2010 to 2013 at University Hospital Southampton. Data are presented as percentage of patients undergoing endoscopy. PC was performed alongside a modified PC by histological disease location. RESULTS: A total of 172 patients were identified (median age at diagnosis 13.5 years, 115 boys); Crohn disease (CD) 107, ulcerative colitis (UC) 50, inflammatory bowel disease unclassified (IBDU) 15; 159 had undergone upper gastrointestinal (GI) endoscopy, 163 had undergone lower GI endoscopy. Histological disease was more extensive at all points for CD, UC, and IBDU. CD--endoscopic ileal disease in 49% of patients compared with histological disease in 71.3%. Comparing PC--a 10% increase in L3 disease (ileocolonic), a 24% increase in L3 + L4a disease (ileocolonic plus upper GI), and a 27% increase in all of the upper GI involvement if histological disease extent was used. UC--the most common disease location was the rectum (endoscopic 91.5% vs histological 93.6%) and descending colon (endoscopic 89.4% vs histological 95.7%). Comparing PC--a 19% increase in E4 disease (pancolitis) if histological disease extent was used. CONCLUSIONS: These data confirm that histological disease extent is greater than endoscopic disease extent. This should be considered when the PC is used. Further study is needed to elucidate which classification would better predict disease outcome.

How to use faecal calprotectin in management of paediatric inflammatory bowel disease.

Faecal calprotectin (FC) is a neutrophil-derived protein released in stool in response to mucosal inflammation. It is a simple, cheap and non-invasive test with high sensitivity and moderate specificity, which can be useful in the diagnosis and monitoring of inflammatory bowel disease (IBD). FC levels correlate well with bowel inflammation (both macroscopic and histological activity) and are not influenced by disease location or type of IBD. Despite the shortcoming with regards to specificity, it is the high sensitivity of FC that makes it a valuable screening tool in the diagnosis of IBD. It is especially effective in identifying children with low probability of IBD who would not benefit from further investigations. The cut-off value selected has a significant impact on the diagnostic accuracy of the test, influencing its sensitivity and specificity, and must be interpreted judiciously. Its role in disease monitoring is as an add-on test to Paediatric Ulcerative Colitis Activity Index and Paediatric Crohn's Disease Activity Index scores and can be used to differentiate disease relapse from functional symptoms. High levels of FC are also seen in a number of other conditions, such as gastrointestinal infections and coeliac disease. It is recommended that infective causes affecting the gut must be excluded first, before FC is measured.

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

This study reports thiopurine-induced toxicity in pediatric patients with inflammatory bowel disease. The findings are presented in the context of genetic variations, focusing on genes implicated in thiopurine drug metabolism, thereby contributing to the missing pharmacogenomic association in patients developing toxicity.

Prediction of Crohn's Disease Stricturing Phenotype Using a NOD2-derived Genomic Biomarker.

BACKGROUND: Crohn's disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. METHODS: Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric ("GenePy"). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. RESULTS: Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged < 18-years improved performance (HR-3.164, P = 1 × 10-6). Models were modified to include disease location, such as terminal ileal (TI) disease or not. Inclusion of NOD2 risk groups added significant additional utility to prediction models. High-risk group pediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3 × 10-5) compared with the low-risk group patients without TI disease. CONCLUSIONS: A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.

NOD2 is a well-established risk gene for development of Crohn's disease and stricturing behavior. Here we demonstrate NOD2 can be utilized as a genomic biomarker, stratifying patients into 2 stricturing risk groups. Further refinement using disease location at diagnosis improved risk stratification.

Feeding children with neurodisability: challenges and practicalities.

Nutritional management for children with neurodisability can be challenging and there are an increasing number of children at risk of malnutrition. Management involves healthcare professionals in community and hospital working together with the family with the aim of optimising nutrition and quality of life. Feeding difficulties can be the result of physical causes like lack of oromotor coordination, discomfort associated with reflux oesophagitis or gastrointestinal dysmotility. Non-physical causes include parental/professional views towards feeding, altered perception of pain and discomfort, extreme sensitivity to certain textures and rigidity of feeding schedule associated with artificial feeding. Estimating nutritional needs can be difficult and is affected by comorbidities including epilepsy and abnormal movements, severity of disability and mobility. Defining malnutrition is difficult as children with neurodisability reflect a wide spectrum with disparate growth patterns and body composition and auxology is less reliable and less reproducible. Management involves selecting the type and method of feeding best suited for the patient. As artificial feeding can place a significant burden of care any decision-making should be, as much as possible, in concurrence with the family. Symptom management sometimes requires pharmacological interventions, but polypharmacy is best avoided. The article aims to discuss the pathways of identifying children at risk of malnutrition and available management options with a strong emphasis on working as a clinical team with the child and family.

Time to normalisation of tissue transglutaminase in paediatric coeliac disease is dependent on initial titre and half of patients will normalise within 12 months.

BACKGROUND: Coeliac disease (CD) is common. Response to a gluten-free diet is assessed through serial measurement of tissue transglutaminase (TTG) antibody titre. However, the relationship of TTG titres to symptoms and the speed of normalisation is poorly understood. METHODS: Patients seen in 2020, and under follow-up in the Southampton CD clinic, had blood results, growth measures and symptom data collated. Time to normalisation, predictors of normalisation and relationship of TTG to growth/symptoms were assessed. RESULTS: 57 patients were included. All had TTG results from the time of diagnosis and follow-up. All families reported dietary compliance.Median TTG at diagnosis was 100 µ/L (range 0.3-4360), 94.7% of the patients had symptoms compatible with CD. At 6-12 months after diagnosis, the median TTG was 3.8 µ/mL (range 0.3-133). In terms of response, 29 of the 57 patients (50.9%) had a TTG below 4 µ/mL (upper normal limit). A further 25 patients (43.9%) had a TTG<10 times the upper limit of normal. Ten patients (17.5%) had a persistently high TTG (median=8.55 µ/mL, range 4.1-303) after >12 months.TTG at diagnosis was correlated with TTG at 6-12 months, ß=0.542, p=0.000016. Patients with TTG<10 times the upper limit of normal at diagnosis group were more likely to have normalised at 6-12 months compared with >10 times normal (85% vs 32.4%, p=0.0015). TTG titres did not correlate with growth measures (Z-scores) at diagnosis or at follow-up. CONCLUSIONS: Normalisation of TTG levels occurs within 6-12 months for around half of patients. Higher TTG levels at diagnosis take longer to normalise. The role of compliance is unclear.

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn's disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription. METHODS: Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a "complex" score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription. RESULTS: Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (ß = -0.702, P = 4.3 × 10-5) and increased NFKBIA (ß = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (ß = 0.8, P = 3.1475 × 10-8) and TXN (ß = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (ß = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (ß = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients. CONCLUSIONS: Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

Prevalence of home parenteral nutrition in children.

BACKGROUND: Use of HPN in paediatrics in the UK has increased rapidly over the last 20 years but the prevalence of HPN has been challenging to define. Clinicians in the UK have noted an evolving complexity of cases and perceive improved outcomes and increased acceptability of long-term PN. These factors combined have the potential to increase the burden on existing paediatric gastroenterology services in the UK. METHODS: A national database was interrogated to define the prevalence of HPN in children in the UK and to explore outcomes for patients receiving HPN. RESULTS: Since 2015, 525 children were notified to the database; of these patients, mortality was <5% and intestinal transplant occurred in 1%. In 2019, 389 children received HPN in the UK; this is nearly double the number last reported in 2012 and is a prevalence of 30 per million children. Short bowel syndrome is the largest category of these patients. However, a poorly defined group including those with multisystem disease has increased 10 fold since 2012 and is now the second largest category. CONCLUSIONS: Long term HPN in childhood is safe and associated with good survival and low risk of the need for intestinal transplantation.

Short bowel syndrome in infancy: recent advances and practical management.

Short bowel syndrome (SBS) is a rare condition characterised by extensive loss of intestinal mass secondary to congenital or acquired disease. The outcomes are determined by dependency on parenteral nutrition (PN), its possible complications and factors that influence intestinal adaptation. In order to achieve the best results, patients should be managed by a specialised multidisciplinary team with the aims of promoting growth and development, stimulating intestinal adaptation and preventing possible complications. This involves timely surgical management aimed at rescuing maximum bowel length and eventually re-establishing intestinal continuity where appropriate. A combination of enteral and parenteral nutrition needs to be targeted towards maintaining a balance between fulfilling the nutritional and metabolic needs of the child while preventing or at least minimising potential complications. Enteral nutrition and establishment of oral feeding play a fundamental role in stimulating bowel adaptation and promoting enteral autonomy. Other measures to promote enteral autonomy include the chyme recycling in patients where bowel is not in continuity, autologous gastrointestinal reconstruction and pharmacological treatments, including promising new therapies like teduglutide. Strategies such as lipid reduction, changing the type of lipid emulsion and cycling PN are associated with a reduction in the rates of intestinal failure-associated liver disease. Even though vast improvements have been made in the surgical and medical management of SBS, there is still lack of consensus in many aspects and collaboration is essential.

Bioelectrical spectroscopy impedance phase angle is not associated with nutritional status in a stable cohort of paediatric inflammatory bowel disease patients.

BACKGROUND & AIMS: Nutritional assessment in paediatric inflammatory bowel disease (IBD) is key to supporting growth whilst minimising adiposity. Bedside assessment using bioelectrical impedance spectroscopy (BIS) has previous identified patients with declining cellular and nutritional health. We aimed to assess BIS measures in stable paediatric IBD patient. METHODS: Stable IBD patients were recruited at routine hospital visits. All patients underwent BIS, anthropometry and disease activity assessment. Multivariable regression and receiver operator curve (ROC) analyses were undertaken to assess the utility of BIS phase angle 50 KHz (PA-50) and 200/5 KHz impedance ratio (IR) in nutritional assessment. RESULTS: There were 140 study visits from 97 patients, mean age 14.49 years, 62.9% Crohn's disease. Mean BMI Z-score (BMIZ) was 0.31 (range -2.97 to 3.99), 33% of patients were overweight (BMIZ>1) and 13.8% of patients were underweight (BMIZ < -1). Crohn's disease patients had a lower mean BMIZ score 0.14, compared to ulcerative colitis, 0.68, p = 0.007. There was no relationship between PA-50 and BMIZ or disease activity. IR was not related to disease activity but was negatively related to BMIZ in a multivariable regression, accounting for age, sex and disease subtype (beta -0.331, p = 0.001). ROC analyses did not identify a clinically useful cut off for either PA-50 or IR to identify patients with active disease, biologic use or BMIZ>1 or < -1. CONCLUSION: BIS appears to have limited added value in nutritional assessment of stable paediatric IBD patients. Nearly 1/3 patients were overweight and personalised approach to supplementation is vital to avoid overnutrition.

Ileal Transcriptomic Analysis in Paediatric Crohn's Disease Reveals IL17- and NOD-signalling Expression Signatures in Treatment-naïve Patients and Identifies Epithelial Cells Driving Differentially Expressed Genes.

BACKGROUND AND AIMS: Crohn's disease [CD] arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD. METHODS: We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted gene co-expression network analysis [WGCNA] was performed and differentially expressed genes [DEGs] were determined. We integrated clinical data to determine co-expression modules associated with outcomes. RESULTS: In all, 27 treatment-naive CD [TN-CD], 26 established CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established CD, nor controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes, including S100A12 and the calprotectin subunit S100A9, were significantly upregulated in TN CD compared with controls [p = 2.61 x 10-15 and p = 9.13 x 10-14, respectively] and established CD [both p = 0.0055]. Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse [correlation-coefficient-0.36, p = 0.07]. Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells. CONCLUSIONS: Ileal tissue from treatment-naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.