Rare and severe adverse events in children with inflammatory bowel disease: analysis of data from the PIBD-SETQuality Safety Registry.

BACKGROUND: Rare and severe adverse events can occur in children with inflammatory bowel disease (IBD), and the relationship with disease or drug treatment is often uncertain. We aimed to establish a method of reporting adverse events of interest in children with IBD, allowing for estimates of incidence rates with comparison between different regions, and, if possible, to compare with published data on rates of adverse events in children overall. METHODS: For this analysis, we used data from the Paediatric Inflammatory Bowel Disease Network for Safety, Efficacy and Treatment and Quality improvement of care (PIBD-SETQuality) Safety Registry, which collects data on multiple rare and severe adverse events in children younger than 19 years with IBD. Overall, the registry collected data on ten prespecified rare and severe adverse events in children with IBD, as established by a panel of paediatric IBD experts, via reports from paediatric gastroenterologists at participating hospitals between Nov 1, 2016, and March 31, 2023. Reporting physicians, who could only be paediatric gastroenterologists or IBD nurses reporting on behalf of paediatric gastroenterologists, were recruited through invitations sent to both national and international IBD networks and at conferences. Once per month, participating paediatric gastroenterologists received an email with an anonymous and unique link to an online survey asking them to report whether any of ten rare and severe adverse events had occurred in a patient in their paediatric-IBD population in the previous month. Prevalent or retrospective rare and severe adverse events were excluded, as were events occurring in children with an unconfirmed diagnosis of IBD or for whom inflammatory colitis was part of a monogenic immunodeficiency disorder. Duplicates and events that did not meet the definitions and criteria were excluded. Physicians could also report other, non-categorised adverse events if they considered them rare and severe. In case of no response, up to two reminders were sent for each per-month survey. Annual denominator data surveys were sent to obtain the total number of person-years for the estimation of incidence rates, which were calculated via Poisson regression models. FINDINGS: Responses were gathered from 220 paediatric gastroenterologists from 167 centres. 121 centres were in Europe, 23 centres were in North America, 17 centres were in Asia, and six centres were in Oceania. Combined, the total population with paediatric IBD consisted of an estimated 30 193 children with 114 528 person-years of follow-up. 451 adverse events were initially reported. After excluding and reorganising adverse events, 402 were eligible; 261 (65%) were categorised and 141 (35%) were non-categorised. The most frequently reported adverse events were venous-thromboembolic events (n=66), renal failure (n=43), opportunistic infections (n=42), and cancer (n=33). Haemophagocytic lymphohistiocytosis (n=4) and liver failure (n=3) were the least frequently reported adverse events. Incidence rates per 10 000 person-years were 5·50 (95% CI 4·25-6·97) for venous-thromboembolic events, 3·75 (2·74-4·99) for renal failure, 3·67 (2·67-4·89) for opportunistic infection, and 2·88 (2·01-3·98) for cancer. Of 66 venous-thromboembolic events, 31 (47%) involved cerebral venous sinus thrombosis at an incidence rate of 2·71 (95% CI 1·86-3·77). INTERPRETATION: The PIBD-SETQuality Safety Registry enabled us to identify incidence rates of rare and severe adverse events in children with IBD. Our findings can guide physicians and enhance awareness of the incidence of adverse events in children with IBD that are considered to be rare. FUNDING: EU Horizon 2020 Research and Innovation Programme.

Biomarkers predicting the effect of anti-TNF treatment in paediatric and adult inflammatory bowel disease.

OBJECTIVES: Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-TNF treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients. METHODS: In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD. RESULTS: During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response. CONCLUSION: Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.

Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease.

BACKGROUND: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. AIM: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. METHODS: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. RESULTS: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). CONCLUSIONS: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. TRIAL REGISTRATION NUMBER: NCT02517684.

The Rhinoplasty Rosetta Stone: using Rasch analysis to create and validate crosswalks between the NOSE and SCHNOS functional subscale.

BACKGROUND: The NOSE and SCHNOS functional subscale are widely used PROMs to measure functional outcomes of rhinoplasty. However, as different instruments produce scores on different metrics, results of these instruments cannot be linked directly. This hinders comparing and aggregating rhinoplasty outcome data from practices using either instrument. The aim of this study was to develop and validate crosswalks between the NOSE and SCHNOS-O. METHODS: In a sample of 552 rhinoplasty patients who completed both instruments, the NOSE and SCHNOS-O scales were co-calibrated onto a common interval-scaled metric using Rasch analysis. Separate Rasch models were run per instrument and the latent constructs were estimated using the calibrated item parameters. By anchoring original PROM scores of both instruments to this Rasch computed measurement scale, the scores of both instruments were linked. A second independent sample was used to validate the created crosswalks. RESULTS: Total scores on the NOSE and SCHNOS-O were strongly correlated. The Rasch-based co-calibration of the NOSE and SCHNOS-O items resulted in a model that adequately fitted the data. Back-and-forth crosswalk tables were created from the NOSE to the SCHNOS-O. For patients with moderate nasal obstruction, predicted SCHNOS-O scores were slightly higher for a given level of the NOSE. Intraclass correlation coefficients between predicted and actual scores were 0.93 for both directions, indicating adequate agreement for group-level comparisons. CONCLUSION: This study developed and validated Rasch-based crosswalks from the NOSE to the SCHNOS-O and vice-versa. The provided crosswalks enhance comparison and harmonization of functional rhinoplasty outcomes.

Using joint models for longitudinal and time-to-event data to investigate the causal effect of salvage therapy after prostatectomy.

Prostate cancer patients who undergo prostatectomy are closely monitored for recurrence and metastasis using routine prostate-specific antigen measurements. When prostate-specific antigen levels rise, salvage therapies are recommended in order to decrease the risk of metastasis. However, due to the side effects of these therapies and to avoid over-treatment, it is important to understand which patients and when to initiate these salvage therapies. In this work, we use the University of Michigan Prostatectomy Registry Data to tackle this question. Due to the observational nature of this data, we face the challenge that prostate-specific antigen is simultaneously a time-varying confounder and an intermediate variable for salvage therapy. We define different causal salvage therapy effects defined conditionally on different specifications of the longitudinal prostate-specific antigen history. We then illustrate how these effects can be estimated using the framework of joint models for longitudinal and time-to-event data. All proposed methodology is implemented in the freely-available R package JMbayes2.

Exploring the relation of active surveillance schedules and prostate cancer mortality.

BACKGROUND: Active surveillance (AS), where treatment is deferred until cancer progression is detected by a biopsy, is acknowledged as a way to reduce overtreatment in prostate cancer. However, a consensus on the frequency of taking biopsies while in AS is lacking. In former studies to optimize biopsy schedules, the delay in progression detection was taken as an evaluation indicator and believed to be associated with the long-term outcome, prostate cancer mortality. Nevertheless, this relation was never investigated in empirical data. Here, we use simulated data from a microsimulation model to fill this knowledge gap. METHODS: In this study, the established MIcrosimulation SCreening Analysis model was extended with functionality to simulate the AS procedures. The biopsy sensitivity in the model was calibrated on the Canary Prostate Cancer Active Surveillance Study (PASS) data, and four (tri-yearly, bi-yearly, PASS, and yearly) AS programs were simulated. The relation between detection delay and prostate cancer mortality was investigated by Cox models. RESULTS: The biopsy sensitivity of progression detection was found to be 50%. The Cox models show a positive relation between a longer detection delay and a higher risk of prostate cancer death. A 2-year delay resulted in a prostate cancer death risk of 2.46%-2.69% 5 years after progression detection and a 10-year risk of 5.75%-5.91%. A 4-year delay led to an approximately 8% greater 5-year risk and an approximately 25% greater 10-year risk. CONCLUSION: The detection delay is confirmed as a surrogate for prostate cancer mortality. A cut-off for a "safe" detection delay could not be identified.

Establishing how much improvement in lung function and distance walked is clinically important for adult patients with Pompe disease.

BACKGROUND AND PURPOSE: Pompe disease is a rare, inheritable, progressive metabolic myopathy. This study aimed to estimate the minimal clinically important difference (MCID) for an improvement in forced vital capacity in the upright seated position (FVCup) and the 6-min walk test (6MWT) after a year of treatment with enzyme replacement therapy. METHODS: Data were obtained from two prospective follow-up studies. Between-group and within-group MCIDs were estimated using anchor-based methods. Additionally, a distribution-based method was used to generate supportive evidence. As anchors, self-reported change in health and in physical functioning, shortness of breath and a categorization of the Short-Form 36 Physical Component Summary score were used. Anchor appropriateness was assessed using Spearman correlations (absolute values ≥0.29) and a sufficient number of observations in each category. RESULTS: In all, 102 patients had at least one FVCup or 6MWT measurement during enzyme replacement therapy. Based on the anchors assessed as appropriate, the between-group MCID for an improvement in FVCup ranged from 2.47% to 4.83% points. For the 6MWT, it ranged from 0.35% to 7.47% points which is equivalent to a distance of 2.18-46.61 m and 1.97-42.13 m for, respectively, a man and a woman of age 50, height 1.75 m and weight 80 kg. The results of the distribution-based method were within these ranges when applied to change in the outcome values. CONCLUSION: The MCIDs for FVCup and 6MWT derived in this study can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort studies.

Optimizing dynamic predictions from joint models using super learning.

Joint models for longitudinal and time-to-event data are often employed to calculate dynamic individualized predictions used in numerous applications of precision medicine. Two components of joint models that influence the accuracy of these predictions are the shape of the longitudinal trajectories and the functional form linking the longitudinal outcome history to the hazard of the event. Finding a single well-specified model that produces accurate predictions for all subjects and follow-up times can be challenging, especially when considering multiple longitudinal outcomes. In this work, we use the concept of super learning and avoid selecting a single model. In particular, we specify a weighted combination of the dynamic predictions calculated from a library of joint models with different specifications. The weights are selected to optimize a predictive accuracy metric using V-fold cross-validation. We use as predictive accuracy measures the expected quadratic prediction error and the expected predictive cross-entropy. In a simulation study, we found that the super learning approach produces results very similar to the Oracle model, which was the model with the best performance in the test datasets. All proposed methodology is implemented in the freely available R package JMbayes2.

An illness-death multistate model to implement delta adjustment and reference-based imputation with time-to-event endpoints.

With a treatment policy strategy, therapies are evaluated regardless of the disturbance caused by intercurrent events (ICEs). Implementing this estimand is challenging if subjects are not followed up after the ICE. This circumstance can be dealt with using delta adjustment (DA) or reference-based (RB) imputation. In the survival field, DA and RB imputation have been researched so far using multiple imputation (MI). Here, we present a fully analytical solution. We use the illness-death multistate model with the following transitions: (a) from the initial state to the event of interest, (b) from the initial state to the ICE, and (c) from the ICE to the event. We estimate the intensity function of transitions (a) and (b) using flexible parametric survival models. Transition (c) is assumed unobserved but identifiable using DA or RB imputation assumptions. Various rules have been considered: no ICE effect, DA under proportional hazards (PH) or additive hazards (AH), jump to reference (J2R), and (either PH or AH) copy increment from reference. We obtain the marginal survival curve of interest by calculating, via numerical integration, the probability of transitioning from the initial state to the event of interest regardless of having passed or not by the ICE state. We use the delta method to obtain standard errors (SEs). Finally, we quantify the performance of the proposed estimator through simulations and compare it against MI. Our analytical solution is more efficient than MI and avoids SE misestimation-a known phenomenon associated with Rubin's variance equation.

Sex-specific cardiovascular protein levels and their link with clinical outcome in heart failure.

AIMS: This study aims to provide insight into sex-specific cardiovascular protein profiles and their associations with adverse outcomes, which may contribute to a better understanding of heart failure (HF) pathophysiology and the optimal use of circulating proteins for prognostication in women and men. METHODS AND RESULTS: In 250 stable patients with HF with reduced ejection fraction (HFrEF), we performed trimonthly blood sampling (median follow-up: 26 [17-30] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or one sample closest to censoring and applied the Olink Cardiovascular III panel. We used linear regression to study sex-based differences in baseline levels and joint models to study differences in the prognostic value of serially measured proteins. In 66 women and 184 men (mean age of 66 and 67 years, respectively), 21% and 28% reached the PEP, respectively. Mean baseline levels of fatty acid-binding protein 4, secretoglobin family 3A member 2, paraoxonase 3, and trefoil factor 3 were higher in women (Pinteraction : 0.001, 0.007, 0.018, and 0.049, respectively), while matrix metalloproteinase-3, interleukin 1 receptor-like 1, and myoglobin were higher in men (Pinteraction : <0.001, 0.001, and 0.049, respectively), independent of clinical characteristics. No significant differences between sexes were observed in the longitudinal associations of proteins with the PEP. Only peptidoglycan recognition protein 1 showed a suggestive interaction with sex for the primary outcome (Pinteraction  = 0.028), without multiple testing correction, and was more strongly associated with adverse outcome in women {hazard ratio [HR] 3.03 [95% confidence interval (CI), 1.42 to 6.68], P = 0.008} compared with men [HR 1.18 (95% CI, 0.84 to 1.66), P = 0.347]. CONCLUSIONS: Although multiple cardiovascular-related proteins show sex differences at baseline, temporal associations with the adverse outcome do not differ between women and men with HFrEF.

Machine learning-based biomarker profile derived from 4210 serially measured proteins predicts clinical outcome of patients with heart failure.

Aims: Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF. Methods and results: In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated c-index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a c-index of 0.85 upon internal validation and c-indices up to 0.80 upon external validation. The c-index was higher than that of a model containing established risk factors (P = 0.021). Conclusion: Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24.

Medical Imaging Decision And Support (MIDAS): Study protocol for a multi-centre cluster randomized trial evaluating the ESR iGuide.

OBJECTIVES: Medical imaging plays an essential role in healthcare. As a diagnostic test, imaging is prone to substantial overuse and potential overdiagnosis, with dire consequences to patient outcomes and health care costs. Clinical decision support systems (CDSSs) were developed to guide referring physicians in making appropriate imaging decisions. This study will evaluate the effect of implementing a CDSS (ESR iGuide) with versus without active decision support in a physician order entry on the appropriate use of imaging tests and ordering behaviour. METHODS: A protocol for a multi-center cluster-randomized trial with departments acting as clusters, combined with a before-after-revert design. Four university hospitals with eight participating departments each for a total of thirty-two clusters will be included in the study. All departments start in control condition with structured data entry of the clinical indication and tracking of the imaging exams requested. Initially, the CDSS is implemented and all physicians remain blinded to appropriateness scores based on the ESR imaging referral guidelines. After randomization, half of the clusters switch to the active intervention of decision support. Physicians in the active condition are made aware of the categorization of their requests as appropriate, under certain conditions appropriate, or inappropriate, and appropriate exams are suggested. Physicians may change their requests in response to feedback. In the revert condition, active decision support is removed to study the educational effect. RESULTS/CONCLUSIONS: The main outcome is the proportion of inappropriate diagnostic imaging exams requested per cluster. Secondary outcomes are the absolute number of imaging exams, radiation from diagnostic imaging, and medical costs. TRIAL REGISTRATION NUMBER: Approval from the Medical Ethics Review Committee was obtained under protocol numbers 20-069 (Augsburg), B 238/21 (Kiel), 20-318 (Lübeck) and 2020-15,125 (Mainz). The trial is registered in the ClinicalTrials.gov register under registration number NCT05490290.

Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Gastrointestinal Biomarkers and Their Association with Feeding in the First Five Days of Pediatric Critical Illness.

OBJECTIVES: Predicting the patients' tolerance to enteral nutrition (EN) would help clinicians optimize individual nutritional intake. This study investigated the course of several gastrointestinal (GI) biomarkers and their association with EN advancement (ENA) longitudinally during pediatric intensive care unit (PICU) admission. METHODS: This is a secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial. EN was started early and increased gradually. The cholecystokinin (CCK), leptin, glucagon, intestinal fatty acid-binding protein 2 (I-FABP2), and citrulline plasma concentrations were measured upon PICU admission, day 3 and day 5. ENA was defined as kcal EN provided as % of predicted resting energy expenditure. The course of the biomarkers and ENA was examined in patients with samples on all time points using Friedman and Wilcoxon signed-rank tests. The association of ENA with the biomarkers was examined using a 2-part mixed-effects model with data of the complete population, adjusted for possible confounders. RESULTS: For 172 patients, median age 8.6 years (first quartile; third quartile: 4.2; 13.4), samples were available, of which 55 had samples on all time points. The median ENA was 0 (0; 0) on admission, 14.5 (0.0; 43.8) on day 3, and 28.0 (7.6; 94.8) on day 5. During PICU stay, CCK and I-FABP2 concentrations decreased significantly, whereas glucagon concentrations increased significantly, and leptin and citrulline remained stable. None of the biomarkers was longitudinally associated with ENA. CONCLUSIONS: Based on the current evidence, CCK, leptin, glucagon, I-FABP2, and citrulline appear to have no added value in predicting ENA in the first 5 days of pediatric critical illness.

Intermittent feeding with an overnight fast versus 24-h feeding in critically ill neonates, infants, and children: An open-label, single-centre, randomised controlled trial.

BACKGROUND & AIMS: Critically ill children are fed day and night, assuming this improves enteral tolerance and the probability of achieving nutritional goals. It was previously shown that a fasting response, reflected by increased ketosis, at least partly explained the beneficial outcome of delayed initiation of supplemental parenteral nutrition. This study aims to investigate whether an overnight fast increases ketosis and is feasible and safe in critically ill children. METHODS: The Continuousversus Intermittent Nutrition in Paediatric Intensive Care (ContInNuPIC) study is a randomised controlled trial in a tertiary referral Paediatric Intensive Care Unit (PICU) in the Netherlands. Critically ill children (term newborn-18 years) with an expected PICU stay ≥48 h, dependent on artificial nutrition, were eligible. Participants were randomly assigned (1:1, stratified for age group) to intermittent feeding, with interruption of feedings during an age-dependent overnight period of eight to 12 h, or to continuous feeding, with the administration of feedings day and night. In both groups, similar daily caloric targets were pursued. For children younger than one year, mandatory minor glucose infusions were provided during fasting. The primary outcome was the feasibility, defined as two conditions (1): a significant difference in the patients' highest daily ketone (3-ß-hydroxybutyrate, BHB) levels during each overnight period, and (2): non-inferiority regarding daily caloric intake, examined using a two-part mixed-effects model with a predefined non-inferiority margin of 33%, in an intention-to-treat analysis. The study is registered in the Netherlands Trial Register (NL7877). RESULTS: Between May 19, 2020, and July 13, 2022, 140 critically ill children, median (first quartile; third quartile) age 0.3 (0.1; 2.7) years, were randomised to intermittent (n = 67) or continuous feeding (n = 73). In the intermittent feeding group, BHB levels were significantly higher (median 0.4 (0.2; 1.0) vs. 0.3 (0.1; 0.7) mmol/L, p < 0.001). The ratio of total caloric intake in the intermittent feeding group to the intake in the continuous feeding group was not consistently significantly more than 0.67, thus not proving non-inferiority. No severe, resistant hypoglycaemic events, nor severe gastrointestinal complications related to the intervention occurred, and feeding intolerance did not occur more often in the intermittent than in the continuous feeding group. CONCLUSION: Compared with day and night feeding, intermittent feeding with an overnight fast and mandatory glucose infusion for children younger than one year marginally increased ketosis and did not lead to more hypoglycaemic incidents in critically ill children. Because non-inferiority regarding daily caloric intake was not proven, the feasibility of an overnight fast could not be shown in the current study. However, as feeding intolerance did not increase during the condensed feeding periods, the nutritional intake was probably limited by the prescription of nutrition and interruptions. More research is needed to determine the optimal level and duration of clinically relevant ketosis and the best method to achieve this.

Neurofilament Light and Its Association With CNS Involvement in Patients With Classic Infantile Pompe Disease.

BACKGROUND AND OBJECTIVES: Enzyme replacement therapy (ERT) has substantially improved the outcome of classic infantile Pompe disease, an inheritable muscle disease previously fatal at infancy. However, under treatment, patients develop white matter abnormalities and neurocognitive problems. Therefore, upcoming therapies also target the brain. Currently, biomarkers reflecting CNS involvement are lacking. We aimed to study the association of neurofilament light (NfL) and CNS involvement. METHODS: To investigate the potential of NfL, we analyzed serum samples of patients with classic infantile Pompe disease who were treated with ERT. The samples were collected at ages of <1, 5, and 10 years, as well as around MRI scans. We compared the outcomes with levels in age- and sex-matched peers. Control samples were originally collected as part of routine blood work in children who underwent small surgeries and stored in the biobank of the Erasmus MC/Sophia Children's Hospital. RESULTS: We analyzed 74 serum samples of 17 patients collected at ages ranging from 22 days to 21.2 years (1-8 samples per patient) and compared these with outcomes of 71 matched peers. In the first year of age, NfL levels in patients and controls were similar (10.3 vs 11.0 pg/mL), but mixed linear model analysis showed a yearly increase of NfL of 6.0% in patients, compared with a decrease of 8.8% in controls (p < 0.001). Higher NfL was associated with lower IQ scores (p = 0.009) and lower processing speed scores (p = 0.001). DISCUSSION: We found significant differences in NfL levels between patients and controls and a good association between NfL and cognition. NfL deserves further exploration as a biomarker for CNS involvement in patients with classic infantile Pompe disease.

HFrEF subphenotypes based on 4210 repeatedly measured circulating proteins are driven by different biological mechanisms.

BACKGROUND: HFrEF is a heterogenous condition with high mortality. We used serial assessments of 4210 circulating proteins to identify distinct novel protein-based HFrEF subphenotypes and to investigate underlying dynamic biological mechanisms. Herewith we aimed to gain pathophysiological insights and fuel opportunities for personalised treatment. METHODS: In 382 patients, we performed trimonthly blood sampling during a median follow-up of 2.1 [IQR:1.1-2.6] years. We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, LVAD implantation, and heart transplantation) or censoring, and applied an aptamer-based multiplex proteomic approach. Using unsupervised machine learning methods, we derived clusters from 4210 repeatedly measured proteomic biomarkers. Sets of proteins that drove cluster allocation were analysed via an enrichment analysis. Differences in clinical characteristics and PEP occurrence were evaluated. FINDINGS: We identified four subphenotypes with different protein profiles, prognosis and clinical characteristics, including age (median [IQR] for subphenotypes 1-4, respectively:70 [64, 76], 68 [60, 79], 57 [47, 65], 59 [56, 66]years), EF (30 [26, 36], 26 [20, 38], 26 [22, 32], 33 [28, 37]%), and chronic renal failure (45%, 65%, 36%, 37%). Subphenotype allocation was driven by subsets of proteins associated with various biological functions, such as oxidative stress, inflammation and extracellular matrix organisation. Clinical characteristics of the subphenotypes were aligned with these associations. Subphenotypes 2 and 3 had the worst prognosis compared to subphenotype 1 (adjHR (95%CI):3.43 (1.76-6.69), and 2.88 (1.37-6.03), respectively). INTERPRETATION: Four circulating-protein based subphenotypes are present in HFrEF, which are driven by varying combinations of protein subsets, and have different clinical characteristics and prognosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01851538https://clinicaltrials.gov/ct2/show/NCT01851538. FUNDING: EU/EFPIA IMI2JU BigData@Heart grant n°116074, Jaap Schouten Foundation and Noordwest Academie.

Validation and Reference Scores of the Transition Readiness Assessment Questionnaire in Adolescent and Young Adult IBD Patients.

OBJECTIVES: Transition readiness can predict a successful transition from pediatric to adult care. This study aimed to validate and develop age-dependent reference scores for the (Dutch version of) Transition Readiness Assessment Questionnaire (TRAQ), in adolescents and young adults (AYAs) with inflammatory bowel disease (IBD). METHODS: TRAQ has 20 items (score 1-5) distributed over 5 domains (total sum score 100) and is completed by AYAs. Following the COnsensus-based Standards for the selection of health Measurement INstruments methodology, we conducted the translation, back-to back translation, pretesting, and validation of the final Dutch version of TRAQ (TRAQ-NL) questionnaire. We used a Rasch model for structural validation, hypothesis testing for construct validity, and Cronbach alpha to demonstrate reliability. Reference scores were calculated using percentiles. RESULTS: Two hundred fifty TRAQ questionnaires were evaluated in 136 AYAs with IBD [56% Crohn disease, 58% male, median age 17.5 years (range 15.7-20.4)]. The overall mean item score was 3.87 (range 1.45-5). With good reliability (Cronbach alpha 0.87), TRAQ-NL discriminated well between knowledge levels, especially in the lower levels. Transition readiness was defined as low, moderate, adequate, or excellent in patients with TRAQ percentile scores (PC) <25th (<3.375 mean item score), 25th-50th (3.375-3.9), 50th-90th (3.91-4.7), or >90th (>4.7). Younger patients, concomitant illness, fewer visits to the transition clinic, and parental dependence were associated with significantly lower TRAQ scores. CONCLUSION: TRAQ(-NL) is reliable and valid, with age-dependent PC to identify (in)adequate transfer readiness. TRAQ can now be more easily used as a patient-reported outcome measure to monitor transition readiness longitudinally in routine care for AYAs IBD patients.

Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure.

BACKGROUND: Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes. METHODS: In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13-31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing. RESULTS: In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (Pinteraction < 0.001) and somatostatin (Pinteraction = 0.040) with the PEP was modified by sex, independent of clinical characteristics. Endothelin-1 was more strongly associated with the PEP in men (HR 2.62 [95%CI, 1.98, 3.46], p < 0.001) compared to women (1.14 [1.01, 1.29], p = 0.036). Somatostatin was positively associated with the PEP in men (1.23 [1.10, 1.38], p < 0.001), but inversely associated in women (0.33 [0.12, 0.93], p = 0.036). CONCLUSION: Baseline cardiovascular protein levels differ between women and men. However, the predictive value of repeatedly measured circulating proteins does not seem to differ except for endothelin-1 and somatostatin.