Explorative study on the value of hepcidin in predicting iron non-responsiveness in paediatric inflammatory bowel disease.

BACKGROUND: In a considerable proportion of anaemic children with inflammatory bowel disease (IBD), haemoglobin (Hb) does not normalise after iron therapy. We evaluated the added value of novel iron markers (hepcidin and soluble transferrin receptor [sTfR]) as compared to traditional iron markers (ferritin and transferrin saturation [TSAT]) to determine the best strategy for the prediction of non-responsiveness to iron suppletion. METHODS: In this secondary analysis of prospectively collected data, we measured iron markers in anaemic children (Hb Z-score < -2.0) with IBD at baseline and one month after the initiation of iron therapy. Non-responsiveness was defined as an increase in Hb Z-score of less than 1 within a month. Logistic regression analysis was used to construct multi-biomarker prognostic models. RESULTS: Of 40 anaemic paediatric IBD patients, sixteen (40%) were non-responsive to iron therapy after one month. Hb Z-score and hepcidin Z-score had the highest predictive ability (area under the ROC curve [AUROC] 0.80) providing sensitivity of 69% and specificity 92%. In a post-hoc analysis we defined hepcidin cut-off values to predict iron non-responsiveness. CONCLUSION: A diagnostic strategy that involves baseline Hb Z-score and hepcidin Z-score in anaemic children with IBD reliably identifies those who will not respond to iron therapy. IMPACT: Non-response to oral and intravenous iron suppletion therapy is high in paediatric IBD and should be identified early. Prediction models using baseline hepcidin demonstrated higher sensitivity and specificity to predict iron non-response compared to models using baseline traditional iron indicators (ferritin and transferrin saturation). In a post hoc analysis, we defined cut-off values for hepcidin to facilitate the correct timing of iron treatment in young anaemic patients with chronic inflammatory bowel disease.

Infliximab in paediatric inflammatory bowel disease: External evaluation of population pharmacokinetic models.

AIMS: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations. METHODS: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements). RESULTS: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations. CONCLUSION: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels.

Waitlist mortality of young patients with biliary atresia: Impact of allocation policy and living donor liver transplantation.

Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre-post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST ( p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization ( p = 0.001), whereas LDLT increased from 55% to 74% ( p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST ( p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT.

Ferric Carboxymaltose Versus Ferrous Fumarate in Anemic Children with Inflammatory Bowel Disease: The POPEYE Randomized Controlled Clinical Trial.

OBJECTIVE: To determine whether intravenous (IV) or oral iron suppletion is superior in improving physical fitness in anemic children with inflammatory bowel disease (IBD). STUDY DESIGN: We conducted a clinical trial at 11 centers. Children aged 8-18 with IBD and anemia (defined as hemoglobin [Hb] z-score < -2) were randomly assigned to a single IV dose of ferric carboxymaltose or 12 weeks of oral ferrous fumarate. Primary end point was the change in 6-minute walking distance (6MWD) from baseline, expressed as z-score. Secondary outcome was a change in Hb z-score from baseline. RESULTS: We randomized 64 patients (33 IV iron and 31 oral iron) and followed them for 6 months. One month after the start of iron therapy, the 6MWD z-score of patients in the IV group had increased by 0.71 compared with -0.11 in the oral group (P = .01). At 3- and 6-month follow-ups, no significant differences in 6MWD z-scores were observed. Hb z-scores gradually increased in both groups and the rate of increase was not different between groups at 1, 3, and 6 months after initiation of iron therapy (overall P = .97). CONCLUSION: In this trial involving anemic children with IBD, a single dose of IV ferric carboxymaltose was superior to oral ferrous fumarate with respect to quick improvement of physical fitness. At 3 and 6 months after initiation of therapy, no differences were discovered between oral and IV therapies. The increase of Hb over time was comparable in both treatment groups. TRIAL REGISTRATION: NTR4487 [Netherlands Trial Registry].

Fatigue and Physical Activity Patterns in Children With Inflammatory Bowel Disease.

OBJECTIVES: Fatigue is a common symptom in children with inflammatory bowel disease (IBD). Diagnostic tests to evaluate biological causes of fatigue commonly include markers of inflammation and hemoglobin (Hb), yet functional parameters have been inadequately studied in pediatric IBD. In this study, we compared fatigued and non-fatigued children with IBD from both a biological and functional point of view. METHODS: A cross-sectional study of 104 pediatric IBD patients with mild to moderately active IBD was conducted. Fatigued children were defined as those with a Pediatric Quality of Life Inventory Multidimensional Fatigue Scale z score <-2.0. Non-fatigued children had a z score ≥-2.0. Disease-specific quality of life (measured with IMPACT-III score), C-reactive protein (CRP), fecal calprotectin (FC), hemoglobin z score (Hb z score), and physical activity tests including 6-minute walking distance z score (6MWD z score) and triaxial accelerometry (TA) were evaluated. RESULTS: Fatigued children (n = 24) had a significant lower IMPACT-III score than non-fatigued children (n = 80). Hb z scores, CRP, FC, and 6MWD z scores were not significantly different between groups. TA was performed in 71 patients. Wear time validation requirements were met in only 31 patients. Fatigued patients spent significant shorter median time in moderate-to-vigorous activity than non-fatigued patients (18.3 vs 37.3 minutes per day, P = 0.008). CONCLUSION: Biological parameters did not discriminate fatigued from non-fatigued patients. TA possibly distinguishes fatigued from non-fatigued patients; the potential association may provide a target for interventions to combat fatigue and improve quality of life.

First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.

OBJECTIVE: In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN: In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS: 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS: FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02517684).

Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

OBJECTIVES: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.

Exome sequencing in patient-parent trios suggests new candidate genes for early-onset primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole-exome sequencing (WES) has contributed to understanding the molecular basis of very early-onset IBD, but rare protein-altering genetic variants have not been identified for early-onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early-onset PSC. METHODS: In this multicentre study, WES was performed on 87 DNA samples from 29 patient-parent trios with early-onset PSC. We selected rare (minor allele frequency < 2%) coding and splice-site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in-house developed algorithm (GAVIN), and PSC-relevant variants were selected using gene expression data and gene function. RESULTS: In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function. CONCLUSIONS: The 36 candidate genes for early-onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants.

Managing abnormal liver tests in children with inflammatory bowel disease.

PURPOSE OF REVIEW: Liver test abnormalities in children with inflammatory bowel disease (IBD) are usually insidious in onset. By the time that symptoms referable to liver disease have appeared, the liver injury may be well advanced. It is, therefore, important that children with an incidental finding of abnormal liver tests are investigated in an appropriate and timely manner. RECENT FINDINGS: The most prevalent cause of liver test elevations in paediatric IBD is immune-related liver disease, including primary sclerosing cholangitis, autoimmune sclerosing cholangitis, and autoimmune hepatitis. Although less common, drugs used in the treatment of IBD can also cause liver injury. The diagnosis of drug-induced liver injury relies largely on excluding other causes of liver injury, such as viral hepatitis, nonalcoholic fatty liver disease, and biliary and vascular complications. SUMMARY: This review highlights an avenue to a step-wise approach for investigating children with IBD and silent liver test elevations. Central to the timing of diagnostic actions is grading the severity of liver test elevations.

A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial.

BACKGROUND: Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase. METHODS AND FINDINGS: In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite. CONCLUSIONS: Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM. TRIAL REGISTRATION: ClinicalTrials.gov NCT02246296.

Disease progression in paediatric- and adult-onset sclerosing cholangitis: Results from two independent Dutch registries.

BACKGROUND & AIMS: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. METHODS: Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. RESULTS: Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. CONCLUSION: Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.

Impact of Paediatric Versus Adult Care Setting on Health Care Utilization in Adolescents With Inflammatory Bowel Disease.

OBJECTIVE: Paediatric-onset inflammatory bowel disease (IBD) is different from adult-onset IBD with respect to disease severity and its effect on growth and development. Care of paediatric IBD patients in some countries is dispersed among paediatricians and adult care providers, which may result in different outcomes. This study aims to assess the effect of care setting (paediatric vs adult-oriented) on health care utilization in adolescent IBD patients. METHODS: This is a Dutch population-based cohort study based on an insurance claims database covering 4.2 million insurees (approximately 25% of the Dutch population). We identified IBD patients ages 16 to 18 years and followed them until the age of 19 years or transfer to adult care, whichever came first. We categorized patients according to care setting: paediatric versus adult-oriented. We defined outcomes as corticosteroid use, IBD-related hospital admission, IBD-related surgery, and biological use. We estimated Cox proportional hazards regression models to control for confounding by indication. RESULTS: Among 626 patients, 380 (61%) were in paediatric and 246 (39%) in adult-oriented care. In paediatric care, patients were less likely to be treated with corticosteroids (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.52-0.99) or biologicals (HR 0.57, 95% CI 0.34-0.97), and had fewer IBD-related hospital admissions (HR 0.58, 95% CI 0.37-0.92). CONCLUSION: In a large and representative community cohort of adolescents with IBD, treatment in paediatric care setting was associated with significantly lower steroid and biological use, without increase in hospital admissions. These results might be used to optimize clinical care for adolescents with IBD.

Time-to-reach Target Calprotectin Level in Newly Diagnosed Patients With Inflammatory Bowel Disease.

OBJECTIVES: Treatment targets in inflammatory bowel disease (IBD) move away from controlling symptoms towards complete recovery of the intestinal mucosa. Currently, the most frequently used noninvasive surrogate marker of mucosal healing is a faecal calprotectin concentration in the target range. This study tested if there was a relation between time-to-reach target calprotectin and first flare. METHODS: We prospectively included new-onset IBD patients ages 17 and younger in a cloud-based registry (FastForwardCare) and followed them for at least 52 weeks. They were treated according to Dutch national guidelines that advocate a step-up approach. Time-to-reach target was defined as the first calprotectin measurement below 250 µg/g after the start of induction therapy. Time-to-first flare was the time from the first calprotectin measurement below 250 µg/g until reappearance of symptoms with calprotectin values above 250 µg/g. RESULTS: We included 76 patients (luminal Crohn disease [CD] 43); ulcerative colitis [UC] 33). Median age at diagnosis was, respectively 14.5 and 14.1 years. Median time-to-reach target calprotectin was 37 weeks in CD and 11 weeks in UC patients (Log-rank test, P = 0.001). Once the calprotectin target was reached, time-to-first flare was significantly longer in CD than in UC patients (Log-rank test, P = 0.001). CD patients with time-to-reach target calprotectin ≤12 weeks after conventional induction therapy (ie, exclusive enteral nutrition or steroids) had a more favorable disease course in the first year than those with time-to-reach target calprotectin >12 weeks (Log-rank test, P = 0.057). In UC patients, time-to-reach target calprotectin ≤12 weeks is not associated with a favorable disease course in the first year. CONCLUSIONS: The findings of this prospective registry suggest that a quick response to conventional therapy predicts a favorable disease course in new-onset paediatric CD, but not in UC. The concept "time-to-reach target calprotectin level" rationalizes the indefinite term "response to treatment" and is well suited for studying treatment effectiveness in real-world practices.

Quality of life and colorectal function in Crohn's disease patients that underwent ileocecal resection during childhood.

Psychosocial and functional outcomes after intestinal resection in pediatric Crohn's disease (CD) are lacking. Therefore, we (I) assessed health-related quality of life (HRQOL), colorectal function, and satisfaction with surgery and (II) investigated their relationship with surgical outcomes, after ileocecal resection for CD. Crohn's patients that underwent ileocecal resection during childhood were included. HRQOL and colorectal function were assessed using SF-36 and COREFO, respectively, and compared with reference values. Satisfaction was scored on a 5-point Likert scale. In total, 80 patients (50% male, median age 23.0 years) were included. Physical HRQOL was impaired (SF-36 [mean]: CD, 47 vs. general, 54; p < 0.001), while mental HRQOL was similar to that in the general population. Overall colorectal function was impaired (COREFO [mean]: CD, 12.6 vs. normal, 7.2; p < 0.001). Worse colorectal function was associated with increasing clinical disease activity and longer interval since resection. Majority of patients was satisfied with surgery (81% satisfied/very satisfied, 11% neither satisfied nor dissatisfied, 8% dissatisfied/very dissatisfied). Decreased satisfaction with surgery was associated with increased clinical disease activity but not related to colorectal function.Conclusions: Physical HRQOL and colorectal function in CD patients who underwent ileocecal resection during childhood seem impaired and related to adverse surgical outcomes. This emphasizes the need for post-operative monitoring and prophylactic therapies. What is Known: • Up to 25% of pediatric-onset Crohn's disease (CD) patients undergo an intestinal resection within 5 years from diagnosis. • Many children and adults with CD experience disruption of their daily activities and health-related quality of life (HRQOL). What is New: • Physical HRQOL and colorectal function are impaired in patient with CD that underwent ileocecal resection during childhood. • Increasing clinical disease activity, a longer interval since surgery, severe complications related to surgery, and recurrent surgeries are all associated with worse colorectal function.

Exploring the Challenges of Implementing a Web-Based Telemonitoring Strategy for Teenagers With Inflammatory Bowel Disease: Empirical Case Study.

BACKGROUND: We designed a telemonitoring strategy for teenagers with inflammatory bowel disease to prevent an anticipated disease flare and avert unplanned office visits and day care procedures. The strategy was evaluated in a randomized controlled trial that involved 11 Dutch pediatric gastroenterology centers, each using repeated symptom scores and stool calprotectin measurements. In the telemonitoring arm of the trial, teenagers (n=84) as well as their health providers were alerted to out-of-range results, and suggestions for change in therapy were offered. We demonstrated that the technology was a safe and cost saving alternative to health checks by the specialist at fixed intervals. OBJECTIVE: The aim of this study was to evaluate whether we could move our telemonitoring strategy from a demonstration project to one that is sustained within existing sites. METHODS: In this empirical case study, we used the nonadoption, abandonment, scale-up, spread, and sustainability (NASSS) framework to explore the challenges to implementing our strategy. The framework distinguishes 7 domains: (1) the illness, (2) the technology, (3) the value proposition, (4) the adopter system, (5) the organization, (6) the societal system, and (7) the time dimension. We summarized the challenges across all 7 domains and classified them as simple (+++), complicated (++), or complex (+). Technologies in which multiple domains are complicated have proven difficult to implement, whereas those with multiple complex domains may not even become mainstreamed. RESULTS: The technology that we used and the linked program (IBD-live) allowed us to select and target the teenagers who were most likely to benefit from a face-to-face encounter with their specialist (+++). The value proposition of the technology was clear, with a distinct benefit for patients and an affordable service model, but health providers had plausible personal reasons to resist (double data entry, ++). The organization was not yet ready for the innovation, as it requires a shift to new ways of working (+). We had no concerns about reimbursement, as Dutch health insurers agreed that screen-to-screen consultations will be reimbursed at a rate equivalent to face-to-face consultations (+++). Finally, the technology was considered easy to adapt and evolve over time to meet the needs of its users (+++). CONCLUSIONS: The challenges to be addressed are merely complicated (++) rather than complex (+), which means that our program may be difficult but not impossible to sustain within existing sites. After integrating the technology and its use with local workflows first, we believe that our telemonitoring strategy will be ready for sustained adoption. In contrast with what we did ourselves, we recommend others to use the NASSS framework prospectively and in real time to predict and explore the challenges to implementing new technologies.

Wait-list mortality of young patients with Biliary atresia: Competing risk analysis of a eurotransplant registry-based cohort.

Liver transplantation (LT) is the standard treatment for biliary atresia (BA) patients with end-stage liver disease. The prognosis after LT has steadily improved, but overall prognosis of BA patients is also determined by mortality before LT. We aimed to quantify mortality in young BA patients on the Eurotransplant waiting list and to determine the effect of disease severity and age at time of listing on pretransplant mortality. We used a cohort study design, which incorporated data from the Eurotransplant registry. Participants were 711 BA patients who were below 5 years of age from 5 countries and listed for LT between 2001 and 2014. We applied a competing risk analysis to evaluate simultaneously the outcomes death, LT, and still waiting for a suitable organ. We used Cox proportional hazards regression to assess 2-year mortality. In a subcohort of 416 children, we performed multivariate analyses between 2-year mortality and disease severity or age, each at listing. Disease severity at listing was quantified by the Model for End-Stage Liver Disease (MELD) score, which assesses bilirubin, creatinine, albumin, and international normalized ratio as continuous variables. Two-year wait-list mortality was 7.9%. Age below 6 months and MELD score above 20 points, each at listing, were strongly and independently associated with 2-year mortality (each P < 0.001). A total of 21% of infants who fulfilled both criteria did not survive the first 6 months on the waiting list. In conclusion, our findings quantify mortality among young BA patients on the waiting list and the relative importance of risk factors (age and severity of disease at listing). Our results provide both an evidence base to rationally address high mortality in subgroups and a methodology to assess effects of implemented changes, for example, in allocation rules. Liver Transplantation 24 810-819 2018 AASLD.

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature.

KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together.

Agreement Between Home-Based Measurement of Stool Calprotectin and ELISA Results for Monitoring Inflammatory Bowel Disease Activity.

BACKGROUND & AIMS: An increasing number of physicians use repeated measurements of stool calprotectin to monitor intestinal inflammation in patients with inflammatory bowel diseases (IBDs). A lateral flow-based rapid test allows patients to measure their own stool calprotectin values at home. The test comes with a software application (IBDoc; Bühlmann Laboratories AG, Schönenbuch, Switzerland) that turns a smartphone camera into a results reader. We compared results from this method with those from the hospital-based reader (Quantum Blue; Bühlmann Laboratories AG) and enzyme-linked immunosorbent assay (ELISA) analysis. METHODS: In a single-center comparison study, we asked 101 participants (10 years of age or older) in the Netherlands to perform the IBDoc measurement on stool samples collected at home, from June 2015 to October 2016. Participants then sent the residual extraction fluid and a fresh specimen from the same bowel movement to our pediatric and adult IBD center at the University Medical Center Groningen, where the level of calprotectin was measured by the Quantum Blue reader and ELISA analysis, respectively. The primary outcome was the agreement of results between IBDoc and the Quantum Blue and ELISA analyses, determined by Bland-Altman plot analysis. RESULTS: We received 152 IBDoc results, 138 samples of residual extraction fluid for Quantum Blue analysis, and 170 fresh stool samples for ELISA analysis. Spearman's rank correlation coefficient was 0.94 for results obtained by IBDoc vs Quantum Blue and 0.85 for results obtained by IBDoc vs ELISA. At the low range of calprotectin level (<500 µg/g), 91% of IBDoc-Quantum Blue results were within the predefined limits of agreement (±100 µg/g), and 71% of IBDoc-ELISA results were in agreement. At the high range of calprotectin level (≥500 µg/g), 81% of IBDoc-Quantum Blue results were within the predefined limits of agreement (±200 µg/g) and 64% of IBDoc-ELISA results were in agreement. CONCLUSIONS: Measurements of fecal levels of calprotectin made with home-based lateral flow method were in agreement with measurements made by Quantum Blue and ELISA, as long as concentrations were <500 µg/g. For patients with concentrations of fecal calprotectin above this level, findings from IBDoc should be confirmed by another method. (Netherlands Trial Registration Number: NTR5133).

Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents.

BACKGROUND: Calgranulin C (S100A12) is an emerging marker of inflammation. It is exclusively released by activated neutrophils which makes this marker potentially more specific for inflammatory bowel disease (IBD) compared to established stool markers including calprotectin and lactoferrin. We aimed to establish a reference value for S100A12 in healthy children and investigated whether S100A12 levels can discriminate children with IBD from healthy controls. METHODS: In a prospective community-based reference interval study we collected 122 stool samples from healthy children aged 5-19 years. Additionally, feces samples of 41 children with suspected IBD (who were later confirmed by endoscopy to have IBD) were collected. Levels of S100A12 were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) (Inflamark®). The limit of detection was 0.22 µg/g. RESULTS: The upper reference limit in healthy children was 0.75 µg/g (90% confidence interval: 0.30-1.40). Median S100A12 levels were significantly higher in patients with IBD (8.00 µg/g [interquartile range (IQR) 2.5-11.6] compared to healthy controls [0.22 µg/g (IQR<0.22); p<0.001]). The best cutoff point based on receiver operating characteristic curve was 0.33 µg/g (sensitivity 93%; specificity 97%). CONCLUSIONS: Children and teenagers with newly diagnosed IBD have significantly higher S100A12 results compared to healthy individuals. We demonstrate that fecal S100A12 shows diagnostic promise under ideal testing conditions. Future studies need to address whether S100A12 can discriminate children with IBD from non-organic disease in a prospective cohort with chronic gastrointestinal complaints, and how S100A12 performs in comparison with established stool markers.