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Objective: : To develop an international Core Outcome Set (COS), a minimal collection of outcomes that should be measured and reported in all future clinical trials evaluating treatments of acute simple appendicitis in children.Summary Background Data: A previous systematic review identified 115 outcomes in 60 trials and systematic reviews evaluating treatments for children with appendicitis, suggesting the need for a COS.Methods: The development process consisted of four phases: (1) an updated systematic review identifying all previously reported outcomes, (2) a two-stage international Delphi study in which parents with their children and surgeons rated these outcomes for inclusion in the COS, (3) focus groups with young people to identify missing outcomes, and (4) international expert meetings to ratify the final COS.Results: The systematic review identified 129 outcomes which were mapped to 43 unique outcome terms for the Delphi survey. The first-round included 137 parents (eight countries) and 245 surgeons (10 countries), the second-round response rates were 61% and 85% respectively, with ten outcomes emerging with consensus. After two young peoples’ focus groups, two additional outcomes were added to the final COS (12): mortality, bowel obstruction, intra-abdominal abscess, recurrent appendicitis, complicated appendicitis, return to baseline health, readmission, reoperation, unplanned appendectomy, adverse events related to treatment, major and minor complications.Conclusion: An evidence-informed COS based on international consensus, including patients and parents has been developed. This COS is recommended for all future studies evaluating treatment of simple appendicitis in children, to reduce heterogeneity between studies and facilitate data synthesis and evidence-based decision-making.

Currently, accurate biomarkers differentiating simple (phlegmonous) from complex (gangrenous and/or perforated) appendicitis in children are lacking. However, both types may potentially require different treatment strategies, and the search for diagnostic modalities remains warranted. Previously, we demonstrated a distinct microbiota (both an increased bacterial diversity and abundance) in the appendix of children with complex compared to simple appendicitis. From the same cohort of patients we have collected 35 rectal swabs under general anesthesia prior to appendectomy and microbiota analysis was performed by IS-pro, a 16S-23S rDNA–based clinical microbiota profiling technique. Using the obtained IS-profiles, we performed cluster analyses (UPGMA), comparison of diversity (Shannon Diversity Index) and intensity (abundance in relative fluorescence units) on phylum level, and comparison on species level of bacteria between simple and complex appendicitis. Regarding these analyses, we observed no clear differences between simple and complex appendicitis. However, increased similarity of the microbial composition of the appendix and rectal swab was found within children with complex compared to simple appendicitis. Furthermore, PLS-DA regression analysis provided clear visual differentiation between simple and complex appendicitis, but the diagnostic power was low (highest AUC 0.65). Conclusion: Microbiota analysis of rectal swabs may be viable to differentiate between simple and complex appendicitis prior to surgery as a supervised classification model allowed for discrimination of both types. However, the current diagnostic power was low and further validation studies are needed to assess the value of this method. What is Known:• Simple and complex appendicitis in children may require different treatment strategies, but accurate preoperative biomarkers are lacking.• Clear differentiation can be made between both types in children based upon the microbial composition in the appendix. What is New:• Increased similarity was found between the microbial composition of the appendix and rectal swab within children with complex compared to simple appendicitis.• Using a supervised classification model rectal swabs may be viable to discriminate between simple and complex appendicitis, but the diagnostic power was low.

To determine the perception of children with inflammatory bowel disease (IBD) regarding monitoring tests, we first compared the reported discomfort and patient perspective during gastro-intestinal (GI)-endoscopy, magnetic resonance entrography (MRE), and ultrasound (US) and, in a second comparison, patient preference on non-invasive tests (venipuncture, sampling stool and US). A cross-sectional study in children 8–18 years undergoing an US, MRE, and GI-endoscopy for diagnosis or follow-up of IBD. After each procedure, the children filled out the Discomfort during research procedures questionnaire (DISCO-RC). Items of the DISCO-RC are as follows: nervousness, annoyance, pain, fright, boredom, and tiredness. Answers range from “not” (= 0 points) to “extremely” (= 4 points) (range total score: 0–24). Differences between the procedures were assessed with Friedman test, with subsequent Wilcoxon signed-rank test. The children were also asked which non-invasive test they preferred not to undergo regularly (venipuncture, stool-sampling, or US). Answers were analyzed with χ2-test. Forty-nine patients (27 (55%) female, median age 15 (range 9–17)) were included. The children reported to be most nervous, frightened, and tired after GI-endoscopy (median: 1, 1, 2 points, respectively), equally annoyed by MRE and GI-endoscopy (median 1 point), and equally bored by MRE and US. GI-endoscopy was ranked as most discomfortable, followed by MRE and US (total DISCO-RC scores: 7 vs. 5 vs. 2, p n = 20 (41%, both) (p Conclusion: Our results suggest that the children with IBD report low discomfort after US, MRE, and GI-endoscopy. US is preferred as a monitoring tool, also among non-invasive monitoring tests. GI-endoscopy was most discomfortable. What is Known:• Children with inflammatory bowel disease need to be monitored frequently for disease activity.• Adult studies — including a systematic review — on acceptability of monitoring tools among IBD patients showed mixed results. What is New:• Children in our study ranked gastro-intestinal endoscopy as most discomfortable, followed by MRE and US.• With regard to non-invasive monitoring, most children preferred not to sample stool or perform venipuncture regularly, and preferred US.

Aim: To assess whether infants with colic (IC) demonstrate persisting developmental dysregulation into childhood, manifested as behavioural problems, and to determine if these behavioural problems are associated with parenting factors. Methods: Preschool children with a history of IC at the age of 0–3 months, as defined by the Wessel criteria, were invited to participate in an observational follow-up study, in which their caregivers completed the Child Behaviour Checklist (CBCL). Raw scores and clinical-range scores on the internalising, externalising and total behavioural problems scales were compared with a Dutch normative sample using independent t-tests and Chi-square tests. For the clinical-range scores, multivariable logistic regressions (odds ratios [99% confidence interval, CI]) were used to adjust for confounders and to identify variables associated with behavioural problems. Results: Two hundred and fifty-eight children with a history of IC (median age 5.1 (interquartile range, IQR 4.6–5.5) years, 51.9% boys) were included. The cases had a significantly higher adjusted risk (adjusted odds ratios (aORs) [99% CI]) of scoring in the clinical range of the emotionally reactive, internalising and total problems scale (2.96 [1.24–7.06]; 2.50 [1.35–4.62]; 2.98 [1.46-6.07], respectively). Internalising (P < 0.001), externalising (P < 0.001) and total (P < 0.001) behavioural problems in children with a history of IC were associated with higher parenting stress scores. Conclusions: Children with a history of IC demonstrated significantly more internalising behavioural problems at preschool age compared to the norm sample. Specific advice and support need to be available for parents to understand and regulate the behaviour of their child, from infancy to childhood.

There is an increasing need for suitable tools to evaluate body composition in paediatrics. The Body Composition Monitor (BCM) shows promise as a method, but reference values in children are lacking. Twenty children were included and measured twice by 4 different raters to asses inter- and intra-rater reproducibility of the BCM. Reliability was assessed using the Bland-Altman method and by calculating intraclass correlation coefficients (ICCs). The intra-rater ICCs were high (≥ 0.97) for all parameters measured by BCM as were the inter-rater ICCs for all parameters (≥ 0.98) except for overhydration (0.76). Consequently, a study was set up in which BCM measurements were performed in 2058 healthy children aged 3–18.5 years. The age- and gender-specific percentile values and reference curves for body composition (BMI, waist circumference, fat mass and lean tissue mass) and fluid status (extracellular and intracellular water and total body water) relative to age were produced using the GAMLSS method for growth curves.Conclusion: A high reproducibility of BCM measurements was found for fat mass, lean tissue mass, extracellular water and total body water. Reference values for these BCM parameters were calculated in over 2000 children and adolescents aged 3 to 18 years. What is Known• The 4-compartment model is regarded as the ‘gold standard’ of body composition methods, but is inappropriate for regular follow-up or screening of large groups, because of associated limitations. • Body Composition Monitor® is an inexpensive field method that has the potential to be an adequate monitoring tool.What is New• Good reproducibility of BCM measurements in children provides evidence to use the device in longitudinal follow-up, multicentre and comparative studies.• Paediatric reference values relative to age and sex for the various compartments of the body are provided.

Background Appendiceal mass and abscess and its treatment are associated with significant morbidity and high costs. Still, the optimal treatment strategy is the point of debate. Therefore, this systematic review and meta-analysis aimed to compare overall complications between initial non-operative treatment (NOT) and early appendectomy (EA) in children with appendiceal mass and/or abscess. Methods Pubmed and Embase were searched. Only randomized controlled trials and prospective or historical cohort studies that compared NOT with EA in children with appendiceal mass or abscess in terms of complications were eligible for inclusion. Risk of bias was assessed. Primary outcome was the overall complication rate. Secondary, length of stay and readmission rate were investigated. A meta-analysis of overall complications associated with both treatment strategies was performed. Results 14 of 7083 screened studies were selected, including 1022 children in the NOT group and 333 in the EA group. Duration of follow-up ranged between four weeks and 12 years. Risk of bias was moderate in four and serious in 10 studies. NOT was associated with a lower overall complication rate (risk ratio (RR) 0.37 [95% confidence interval (CI) 0.21–0.65]). However, NOT led to increased length of stay (mean difference varied between 0.2 and 8.4 days) and higher readmission rate (RR 1.75 [95%CI 0.79–3.89]), although not significantly. Interval appendectomy after NOT was performed as a routine procedure in all but one study. This study found a recurrence rate of 34% in a group of 38 patients during a follow-up period of 3.4 ± 1.7 years. Conclusion NOT may reduce the overall complication rate compared to EA, but the evidence is very uncertain. As evidence is scarce, and of low level, and heterogeneity between studies is substantial, the results should be interpreted with caution. Large prospective studies are needed to determine the optimal treatment strategy for children with appendiceal mass and/or abscess.

Investigator-initiated clinical trials are crucial for improving quality of care for children and pregnant women as they are often excluded from industry-initiated trials. However, trials have become increasingly time-consuming and costly since the EU Clinical Trial Directive entered into force in 2001. This directive made compliance with ICH-Good Clinical Practice Guidelines (ethical and quality standard for conducting human subject research) mandatory for all clinical trials, regardless of its risk-classification. By discussing two investigator-initiated, ‘low-risk’ drug trials, we aim to illustrate that compliance with all GCP requirements makes trials very laborious and expensive, while a clear rationale is missing. This discourages clinical researchers to start and carry out investigator-initiated research. However, the forthcoming EU Clinical Trial Regulation (No 536/2014) seems to provide a solution as it allows for less stringent rules for low-risk trials. We want to raise awareness for these developments in both the clinical research community and the European and national regulatory authorities. Implementation of this forthcoming Regulation regulatory policies should be done in such a way that investigator-initiated trials evaluating standard care interventions will become more feasible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research. What is Known• Investigator-initiated trials are indispensable for improving care for children and pregnant women as they are often excluded from industry-initiated trials• Trials have become increasingly time-consuming and costly because of mandatory compliance with ICH-GCP guidelines What is New• The forthcoming EU Clinical Trial Regulation allows less stringent rules for low-risk trials• The national legislator and regulatory authorities should recognize the importance of this opportunity and implement the Regulation in such a way that investigator-initiated trials will become more feasible

BACKGROUND Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of

IntroductionIn daily practice large heterogeneity in the treatment of children with complex appendicitis exists. Complex appendicitis can be divided into two subtypes; complex appendicitis with and without appendiceal mass and/or abscess. As complex appendicitis is associated with high morbidity and costs, identification of the optimal treatment strategy is essential. In this article, we present the study protocol for the CAPP (Complex Appendicitis in the Pediatric Population) study.Methods and analysisThis nation-wide, multi-centre, comparative, non-randomised prospective cohort study includes all children Ethics and disseminationThe Medical Ethics Review Committee of the Amsterdam UMC, location AMC, declared that the Medical Research involving Human Subjects Act (WMO) did not apply to this study. Therefore, no official approval was required by national law. Study results will be presented in peer-reviewed scientific journals and at (inter)national conferences.Trial registration numbersNCT04755179; NL9371.

BackgroundA possible association between child abuse and neglect (CAN) and functional constipation (FC) has been described in adults, however, limited data are available in children. Our objective was to determine the prevalence of suspected CAN in children with FC as compared with their healthy peers.MethodsA case–control study was carried out in children aged 3–10 years. Children with FC were recruited at a tertiary outpatient clinic, and healthy controls were recruited at schools. Parents were asked to fill out questionnaires about the history and behaviour of their child, children were inquired using a semistructured interview about experienced traumatic events and sexual knowledge. The interview was scored by two independent observers. The prevalence of suspected CAN was determined according to the questionnaires and interview.ResultsIn total, 228 children with FC and 153 healthy controls were included. Both groups were age and gender comparable (50% females, median age 6 years (not significant)). No significant difference in the prevalence of suspected CAN was found between children with FC and healthy controls (23.3% vs 30.1%, 95% CI 0.44 to 1.12, p=0.14), including a suspicion of sexual, emotional and physical abuse.ConclusionSuspected CAN was detected in both children with FC as in healthy controls. The possible association between CAN and FC in children could not be confirmed.

Introduction: A nonoperative treatment strategy (NOT) with antibiotics for children with simple appendicitis could reduce anesthesia and surgery-related complications. As the implementation of a new treatment in routine clinical practice may take years, this study aims to identify barriers and facilitators for implementation of NOT for children with simple appendicitis. Materials and methods: To identify barriers and facilitators for its implementation, we conducted 14 semistructured interviews and a focus group with health insurance/hospital policymakers, surgical clinicians, and young people—together with their parents—who have been treated surgically or with antibiotics. Transcripts were open coded and categorized as per the framework for healthcare innovations by Fleuren et al. Results: We identified four main themes: (1) Appendicitis is a well-known disease. Children, parents, and clinicians regard appendectomy as routine and safe, making them reluctant toward other treatment options. (2) Clinicians regard uptake of NOT in the national appendicitis guideline necessary for its implementation. (3) For identification of patients best suited for NOT more experience and scientific evidence is needed. (4) Appendectomy and NOT have different risk and benefits making the treatment choice depended on individual patient preferences. Conclusions: By addressing how NOT and operative treatment are regarded by patients and surgeons could have a substantial impact on the implementation of NOT for children with simple appendicitis. Furthermore, the individual preferences of patients need to be taken into account when choosing between operative and NOT. In other words, offering NOT in a shared decision-making model seems the first appropriate step in its implementation.

Background & Aims Non‐alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children. Even at young age, it can progress to liver fibrosis. Given the drawbacks of liver biopsy, there is a need for non‐invasive methods to accurately stage liver fibrosis in this age group. In this systematic review, we evaluate the diagnostic accuracy of non‐invasive methods for staging liver fibrosis in children with NAFLD. Methods We searched MEDLINE, Embase, Web of Science and the Cochrane Library, for studies that evaluated the performance of a blood‐based biomarker, prediction score or imaging technique in staging liver fibrosis in children with NAFLD, using liver biopsy as the reference standard. Results Twenty studies with a total of 1787 NAFLD subjects were included, which evaluated three prediction scores, five simple biomarkers, two combined biomarkers and six imaging techniques. Most studies lacked validation. Substantial heterogeneity of studies and limited available study data precluded a meta‐analysis of the few fibrosis tests evaluated in more than one study. The most consistent accuracy data were found for transient elastography by FibroScan®, ELF test and ultrasound elastography, with an area under the receiver operating characteristics curve varying between 0.92 and 1.00 for detecting significant fibrosis. Conclusion Due to the lack of validation, the accuracy and clinical utility of non‐invasive fibrosis tests in children with NAFLD remains uncertain. As studies have solely been performed in tertiary care settings, accuracy data cannot directly be translated to screening populations.

To determine the perception of children with inflammatory bowel disease (IBD) regarding monitoring tests, we first compared the reported discomfort and patient perspective during gastro-intestinal (GI)-endoscopy, magnetic resonance entrography (MRE), and ultrasound (US) and, in a second comparison, patient preference on non-invasive tests (venipuncture, sampling stool and US). A cross-sectional study in children 8-18 years undergoing an US, MRE, and GI-endoscopy for diagnosis or follow-up of IBD. After each procedure, the children filled out the Discomfort during research procedures questionnaire (DISCO-RC). Items of the DISCO-RC are as follows: nervousness, annoyance, pain, fright, boredom, and tiredness. Answers range from "not" (= 0 points) to "extremely" (= 4 points) (range total score: 0-24). Differences between the procedures were assessed with Friedman test, with subsequent Wilcoxon signed-rank test. The children were also asked which non-invasive test they preferred not to undergo regularly (venipuncture, stool-sampling, or US). Answers were analyzed with χ

A possible association between child abuse and neglect (CAN) and functional constipation (FC) has been described in adults, however, limited data are available in children. Our objective was to determine the prevalence of suspected child abuse and neglect (CAN) in children with functional constipation (FC) as compared to their healthy peers.A case-control study was carried out in children aged 3-10 years. Children with FC were recruited at a tertiary outpatient clinic, and healthy controls were recruited at schools. Parents were asked to fill out questionnaires about the history and behavior of their child, children were inquired using a semi-structured interview about experienced traumatic events and sexual knowledge. The interview was scored by two independent observers. The prevalence of suspected CAN was determined according to the questionnaires and interview. In total, 228 children with FC and 153 healthy controls were included. Both groups were age and gender comparable (50% females, median age 6 years (NS)). Significantly more parents of children with FC had a low education level as compared to parents of healthy controls (66.2% vs. 32.7%, pConclusion: Suspected CAN was detected in both children with FC as in healthy controls. The possible association between CAN and FC in children could not be confirmed.

Despite a growing interest in, and commitment to, implementing pediatric clinical trials, approximately one in every five trials in children fails because of inappropriate study design, suboptimal experiment planning, or inadequate participant enrollment. This tutorial, presented from the perspectives of seasoned pediatric investigators, an experienced research coordinator, and an established pediatric clinical trials network, is designed to provide practical guidance for successfully implementing pediatric clinical trials at an academic center or another comparable institution.

Background and Aims Currently used non-invasive tools for monitoring children with inflammatory bowel disease [IBD], such as faecal calprotectin, do not accurately reflect the degree of intestinal inflammation and do not provide information on disease location. Ultrasound [US] might be of added value. This systematic review aimed to assess the diagnostic test accuracy of transabdominal US in detecting intestinal inflammation in children with IBD in both diagnostic and follow-up settings. Methods We systematically searched PubMed, Embase [Ovid], Cochrane Library, and CINAHL [EBSCO] databases for studies assessing diagnostic accuracy of transabdominal US for detection of intestinal inflammation in patients diagnosed or suspected of IBD, aged 0–18 years, with ileo-colonoscopy and/or magnetic resonance enterography [MRE] as reference standards. Studies using US contrast were excluded. Risk of bias was assessed with QUADAS-2. Results The search yielded 276 records of which 14 were included. No meta-analysis was performed, because of heterogeneity in study design and methodological quality. Only four studies gave a clear description of their definition for an abnormal US result. The sensitivity and specificity of US ranged from 39-93% and 90–100% for diagnosing de novo IBD, and 48–93% and 83–93% for detecting active disease during follow-up, respectively. Conclusions The diagnostic accuracy of US in detecting intestinal inflammation as seen on MRE and/or ileo-colonoscopy in paediatric IBD patients remains inconclusive, and there is currently no consensus on defining an US result as abnormal. Prospective studies with adequate sample size and methodology are needed before US can be used in the diagnostics and monitoring of paediatric IBD.

ObjectiveWe aim to give an overview of the available evidence on brain structure and function in PHIV-infected patients (PHIV+) using long-term combination antiretroviral therapy (cART) and how differences change over time.MethodsWe conducted an electronic search using MEDLINE, Embase, and PsycINFO. We used the following selection criteria: cohort and cross-sectional studies that reported on brain imaging differences between PHIV+ of all ages who used cART for at least six months before neuroimaging and HIV-negative controls. Two reviewers independently selected studies, performed data extraction, and assessed quality of studies.ResultsAfter screening 1500 abstracts and 343 full-text articles, we identified 19 eligible articles. All included studies had a cross-sectional design and used MRI with different modalities: structural MRI (n = 7), diffusion tensor imaging (DTI) (n = 6), magnetic resonance spectroscopy (n = 5), arterial spin labeling (n = 1), and resting-state functional neuroimaging (n = 1). Studies showed considerable methodological limitations and heterogeneity, preventing us to perform meta-analyses. DTI data on white matter microstructure suggested poorer directional diffusion in cART-treated PHIV+ compared with controls. Other modalities were inconclusive.ConclusionEvidence may suggest brain structure and function differences in the population of PHIV+ on long-term cART compared with the HIV-negative population. Because of a small study population, and considerable heterogeneity and methodological limitations, the extent of brain structure and function differences on neuroimaging between groups remains unknown.

Background: The effect of the hospital environment on health and specifically neurodevelopment in preterm infants remains under debate. We assessed outcomes of preterm infants hospitalised in single family rooms compared with common open bay units. Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PsycInfo, CENTRAL (the Cochrane Central Register of Controlled Trials), Web of Science, and ClinicalTrials.gov from inception to Aug 13, 2018, using controlled terms (ie, MeSH terms) and text words related to prematurity and neonatal intensive care unit design. We included randomised and non-randomised studies investigating clinical outcomes of preterm infants. We assessed methodological quality using the Cochrane Collaboration's Risk of Bias Tool for randomised controlled trials and the Cochrane Risk of Bias Tool for Non-randomised Studies of Interventions. We calculated summary estimates for meta-analysis using random effects models. The primary outcome was age appropriate long-term neurodevelopment. Secondary outcomes were length of hospital stay, sepsis, breastfeeding, growth, bronchopulmonary dysplasia, intraventricular haemorrhage, retinopathy of prematurity, and mortality. This systematic review is registered with PROSPERO, number CRD42016050643. Findings: We identified 487 records. 13 study populations (n=4793) were included. No difference in cognitive neurodevelopment was found on the Bayley Scales of Infant and Toddler Development-III at 18–24 months of corrected age (680 infants analysed; mean difference 1·04 [95% CI −3·45 to 5·52], p=0·65; I 2 =42%). The incidence of sepsis was lower (4165 infants analysed; 108 035 days in hospital [hospitalisation days]; risk ratio 0·63 [95% CI 0·50 to 0·78], p

Simple Summary Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. At diagnosis, tumor and patient characteristics determine the prognosis and subsequent treatment stratification. There are currently no early biomarkers that identify good or poor responders to chemotherapy regimens, survival being the only valid endpoint. Early tumor size response, which is assessed by imaging, could be such a marker. We performed a systematic assessment of literature to November 2020. Six studies were included describing 2010 patients; quality assessment showed methodological limitations. We conclude that there is evidence that early progressive disease is associated with poorer survival compared to patients with non-progressive disease, being either stable disease, partial, or complete response. However, for the vast majority of patients with non-progressive disease, we found no evidence that the degree of response is prognostic for survival. Therefore, the value of early tumor size response as a prognostic marker, and its translation into treatment modifications on an individual patient or trial level should be reconsidered. Abstract Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Results of clinical trials, with three-year event-free and overall survival as primary outcomes, often take 7 to 10 years. Identification of an early surrogate biomarker, predictive for survival, is therefore crucial. We conducted a systematic review to define the prognostic value of early tumor size response in children with IRSG group III rhabdomyosarcoma. The search included MEDLINE/EMBASE from inception to 18 November 2020. In total, six studies were included, describing 2010 patients, and assessed by the Quality in Prognosis Studies (QUIPS) instrument. Four studies found no prognostic value for tumor size response, whereas two studies reported a prognostic effect. In these two studies, the survival rate of patients with progressive disease was not separately analyzed from patients with stable disease, potentially explaining the difference in study outcome. In conclusion, our findings support that early progression of disease is associated with poorer survival, justifying adaptation of therapy. However, in patients with non-progressive disease, there is no evidence that the degree of response is a prognostic marker for survival. Because the vast majority of patients do not have progressive disease, early tumor size response should be reconsidered for assessment of treatment efficacy. Therefore, at present, early surrogate biomarkers for survival are still lacking.

Background: Many parents develop stress-related symptoms and depression when their preterm infant is hospitalised in the neonatal intensive care unit (NICU) after birth. We reviewed the evidence of parent well-being with preterm infants hospitalised in single family rooms (SFRs) or in open bay neonatal units (OBUs). Methods: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP) databases from inception through 22 November 2019 using controlled terms and text words related to prematurity and NICU-design. We included randomised and non-randomised studies comparing outcomes in parents with preterm infants admitted to SFRs or OBUs. Methodological quality was assessed using Cochrane Collaboration's Risk of Bias Tool for randomised controlled trials and the Risk of Bias Tool for Non-Randomised Studies of Interventions (ROBINS-I). Outcomes included: parental stress, satisfaction, participation (presence/involvement/skin-to-skin care), self-efficacy, parent-infant-bonding, depression, anxiety, post-traumatic stress, empowerment, and degree of family-centred care. Summary estimates were calculated using random effects models with standardised mean differences (SMDs). PROSPERO registration: CRD42016050643. Findings: We identified 614 unique publications. Eleven study populations (1, 850 preterm infants, 1, 549 mothers and 379 fathers) were included. All but one study were at serious to critical risk of bias. SFRs were associated with higher levels of parental presence, involvement, and skin-to-skin care. Upon discharge, SFRs were associated with lower stress levels (n = 828 parents, SMD-0·30,95%CI -0·50;-0·09, p

Background Ultrasound (US) is a noninvasive method of assessing the bowel that can be used to screen for bowel pathology, such as Inflammatory Bowel Disease, in children. Knowledge about US findings of the bowel in healthy children is important for interpreting US results in cases where disease is suspected. Objective To assess the bowel wall thickness in different bowel segments in healthy children and to assess differences in bowel wall thickness among pediatric age categories. Materials and methods We conducted a systematic search in the PubMed, Embase, Cochrane, and CINAHL databases for studies describing bowel wall thickness measured by transabdominal US in healthy children. We excluded studies using contrast agent. We calculated the pooled mean and standard deviation scores and assessed differences among age categories (0–4 years, 5–9 years, 10–14 years, 15–18 years), first with analysis of variance (ANOVA) and further with subsequent Student’s t-tests for independent samples, corrected for multiple testing. Results We identified 191 studies and included 7 of these studies in the systematic review. Reported bowel wall thickness values ranged from 0.8 mm to 1.9 mm in the small bowel and from 1.0 mm to 1.9 mm in the colon. The mean colonic bowel wall thickness is larger in children ages 15–19 years compared to 0–4 years (range in difference: 0.3–0.5 mm [corrected P Conclusion The reported upper limit of bowel wall thickness in healthy children is 1.9 mm in the small bowel and the colon, and mean thickness increases slightly with age in jejunum and colon. These values can be used as guidance when screening for bowel-related pathology in children.

Low bone mineral density (BMD) as a risk factor for fractures has been a long‐standing concern in phenylketonuria (PKU). It is hypothesised that the disease itself or the dietary treatment might lead to a low BMD. Previous studies show conflicting results of BMD in PKU due to differences in age, techniques to assess BMD and criteria used. To assess the prevalence of low BMD and define possible risk factors in a large number of adult, early treated PKU (ETPKU) patients. European centres were invited for a survey, collecting retrospective data including results of dual‐energy X‐ray absorptiometry (DXA) scans of adult ETPKU patients. BMD of 183 adult ETPKU patients aged 18‐46 (median age 28, all females premenopausal) years was lower than in the general population at most skeletal sites but the frequency of low BMD (Z‐score

BACKGROUND: Early response to induction chemotherapy is used in current European guidelines to evaluate the efficacy of chemotherapy and subsequently to adapt treatment in pediatric patients with rhabdomyosarcoma (RMS). However, existing literature on the prognostic value of early radiologic response on survival is contradictory; here the prognostic value is analyzed with data from the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor 95 (MMT-95) study. METHODS: This study examined 432 Intergroup Rhabdomyosarcoma Study Grouping III (macroscopic residue) patients enrolled in the SIOP MMT-95 study with a response assessment after 3 courses of chemotherapy (a 2-dimensional assessment). Patients with progressive disease (PD) after 3 courses of chemotherapy were excluded (n57). Failure-free survival (FFS) and overall survival (OS), calculated with the Kaplan-Meier method, were compared for 3 groups (complete response [CR]/partial response [PR], objective response [OR], and no response [NR]). The prognostic impact of early response was assessed through the calculation of Cox proportional hazards. RESULTS: After 3 courses of chemotherapy, 85.2% of the patients had CR/PR, 8.6% had OR, and 6.3% had NR. For all patients, the 5-year FFS and OS rates were 60% (95% confidence interval [CI], 56%-65%) and 74% (95% CI, 70%-78%), respectively. However, a Cox proportional hazards regression analysis revealed no significant difference in FFS or OS between the response groups. The adjusted hazard ratios for an OR and NR were 1.09 (95% CI, 0.63-1.88) and 0.81 (95% CI, 0.39-1.67), respectively, for FFS and 0.91 (95% CI, 0.47-1.76) and 1.27 (95% CI, 0.61-2.64), respectively, for OS. CONCLUSIONS: No evidence was found for the idea that early radiologic response to chemotherapy is prognostic for survival for patients with RMS. Treatment adaptation based on early response (except for patients with PD) should, therefore, no longer be incorporated into future studies. (C) 2017 American Cancer Society.

BackgroundThe Sexual Knowledge Picture Instrument (SKPI) is a child-friendly picture book that was developed as a diagnostic tool for sexual abuse in young children and is currently being validated. The aim of the current study was to explore the verbal and non-verbal reactions of non-abused Dutch children, aged 3–9 years, to the SKPI and to assess differences in reactions between genders and age groups.Methods and analysisSubject recruitment took place at preschools and primary schools. All children underwent a recorded video semi-structured interview with the SKPI. Interview recordings were scored by an independent rater who used scoring lists for verbal and non-verbal reactions. Non-parametric tests were used in statistical analyses.ResultsOf the 90 children (median age 5 years) participating in the study, most correctly named the genitals and their non-sexual functions. Only 34 showed an understanding of the picture depicting adult sexuality, with just one child describing a sexual function. Girls (n=45) gave more correct answers (median 87%) than boys (n=45, median 78%; p=0.006). Giggling was the most frequently observed non-verbal reaction, with a total of 186 instances in 54 children.ConclusionNon-abused children up to 9 years of age showed only limited knowledge of the sexual function of the genitals and hardly any insight into adult sexuality.

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up. Electronic supplementary material The online version of this article (doi:10.1007/s10545-016-9990-5) contains supplementary material, which is available to authorized users.

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function inpatients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here. (C) 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Background To determine if non-operative treatment is safe in children with acute appendicitis, we evaluated the incidence of unexpected findings after an appendectomy in children, and the influence they have on subsequent treatment. Methods A historical cohort study (January 2004–December 2014) was performed including children, aged 0–17 years, who underwent an appendectomy for the suspicion of acute appendicitis. Patients were divided based upon histopathological examination. Unexpected findings were reviewed, as well as the subsequent treatment plan. Results In total 484 patients were included in this study. In the overall group, unexpected findings were noted in 10 (2.1%) patients of which two patients intra-operatively with a non-inflamed appendix (Ileitis terminalis N = 1 and ovarian torsion N = 1) and in 8 patients on histopathological examination. The latter group consisted of 4 patients with concomitant simple appendicitis (parasitic infection N = 3 and Walthard cell rest N = 1), two with concomitant complex appendicitis (carcinoid N = 1 and parasitic infection N = 1) and two patients with a non-inflamed appendix (endometriosis N = 1 and parasitic infection N = 1). Treatment was changed in 4 patients ( Conclusions Results from this study corroborate the safety of non-operative strategy for acute simple appendicitis, as the occurrence of unexpected findings was low, with extremely few necessary changes of the treatment plan because of serious findings. Type of study Prognosis study. Level of evidence Level 2 (retrospective cohort study).

Background: To compare the risk of complications between initial nonoperative treatment and appendectomy of uncomplicated (simple) appendicitis in children. Methods: Systematic literature search. Eligible for inclusion were both and randomized controlled trials and cohort studies including children inwhich the outcome of nonoperative treatment of uncomplicated appendicitis was reported with a minimum follow-up period of one year. Two authors extracted data independently and assessed quality. Primary outcome parameter was the percentage of children experiencing complications. Secondary outcomes were early failures, recurrent appendicitis and appendectomies, for all indications and on request. Results: Five of the 2051 articles screenedwere eligible for inclusion, including 147 children (nonoperative treatment) and 173 children (appendectomy) with one year follow-up. Percentage of children experiencing complications ranged from 0 to 13% versus 0-17% for nonoperative and appendectomy, respectively. Nonoperative treatment avoided an appendectomy in 62-81% of the children after one year follow-up. Conclusion: The evidence base for initial nonoperative treatment of acute uncomplicated appendicitis in children is by far insufficient. It suggests that the percentage of patients experiencing complications in the initial nonoperative treatment group is comparable to the appendectomy group, and it may avoid an appendectomy in the large majority of children after one year follow-up. Type of study: Systematic review. Level of evidence: 1. (C) 2017 Elsevier Inc. All rights reserved

BACKGROUND: Two types of appendicitis are hypothesized, simple and complex, with potential different treatment strategies. To improve differentiation, underlying pathogeneses need to be further unraveled. AIM: To determine if the microbial composition in the appendix differs between children with simple and complex appendicitis. METHODS: Two-center, prospective cohort study including 40 children (0-17 years old) undergoing appendectomy for suspected appendicitis. Appendix tissue was used for IS-pro analysis to identify bacterial species by their length of 16S-23S rDNA interspacer (IS) region. Cluster analysis, based on IS-profiles, and correspondence with type of appendicitis, using Fisher exact test, was performed. Simple and complex appendicitis were compared regarding bacterial presence, intensity and diversity, using Fisher exact test and Mann-Whitney U test, respectively. RESULTS: Appendicitis was confirmed in 36 of 40 patients (16 simple, 20 complex). Cluster analysis identified 2 clusters, encompassing 34 patients. Distribution of simple and complex appendicitis was 12 (80%) and 3 (20%) versus 3 (16%) and 16 (84%) patients for clusters 1 and 2, respectively (P < 0.001). Complex appendicitis was on phylum level characterized by an increased intensity (Bacteroidetes P = 0.001, Firmicutes, Actinobacteria, Fusobacteria and Verrucomicrobia (FAFV) P = 0.005 and Proteobacteria P < 0.001) and diversity (Bacteroidetes P = 0.001 and Proteobacteria P = 0.016) and an increased abundance of 5 species (Alistipes finegoldii P = 0.009, Bacteroides fragilis P = 0.002, Escherichia coli P = 0.014, Parvimonas micra P = 0.022 and Sutterella spp P = 0.026). CONCLUSIONS: The microbial composition of the appendix differs between children with simple and complex appendicitis, regarding both composition and diversity. Future research should focus on the role of these bacteria in the pathogenesis of both types and its implications for preoperative diagnostics.

IntroductionAppendicitis is a global disease affecting roughly 1 in every 12 people in the world, with the highest incidence between ages 10 and 19 years. To date, a wide variety of health outcomes have been reported in randomised controlled trials and meta-analyses evaluating treatments for appendicitis. This is especially the case in studies comparing non-operative treatment with operative treatment. A set of standard outcomes, to be reported in all future trials, is needed to allow for adequate comparison and interpretation of clinical trial results and to make data pooling possible. This protocol describes the development of such a global core outcome set (COS) to allow unified reporting of treatment interventions in children with acute uncomplicated appendicitis.Methods and analysisWe use current international standard methodology for the development and reporting of this COS. Its development consists of three phases: (1) an update of the most recent systematic review on outcomes reported in uncomplicated paediatric appendicitis research to identify additional outcomes, (2) a three-step global Delphi study to identify a set of core outcomes for which there is consensus between parents and (paediatric) surgeons and (3) an expert meeting to finalise the COS and its definitions. Children and young people will be involved through their parents during phase 2 and will be engaged directly using a customised face-to-face approach.Ethics and disseminationThe medical research ethics committee of the Academic Medical Center Amsterdam has approved the study. Each participating country/research group will ascertain ethics board approval. Electronic informed consent will be obtained from all participants. Results will be presented in peer-reviewed academic journals and at (international) conferences.Trial registration numberCOMET registration: 1119

Non-operative treatment of uncomplicated appendicitis in children is gaining ground. Pending definitive evidence regarding its effectiveness, there is a call to evaluate clinical recovery after non-operative treatment. In this study, we analyzed data collected during initial admission of a multicenter prospective cohort in which children, 7–17 year, were treated non-operatively for uncomplicated appendicitis. During admission clinical parameters (pain and gastro-intestinal symptoms), inflammation parameters and sequential abdominal ultrasound were recorded. In total, 45 children were included, 42(93%) were discharged without the need for appendectomy; median [IQR] pain scores on admission were 5 [4–7], decreasing to 2 [0–3] after 1 day of treatment. Initially, 28/42 (67%) reported nausea and 19/42 (45%) vomiting; after 1 day, this was 3/42 (7%) and 1/42 (2%), respectively. White blood cell count declined from a median [IQR] of 12.9 [10.7–16.7] 10E9/L on admission to 7.0 [5.8–9.9] 10E9/L on day 1. Median [IQR] C-reactive protein levels increased from 27.5 [9–69] mg/L on admission to 48 [22–80] mg/L on day 1, declining to 21.5 [11–42] mg/L on day 2. Follow-up ultrasound showed no signs of complicated appendicitis in any of the patients. Conclusion: Clinical symptoms resolved in most children after 1 day of non-operative treatment. This suggests that non-operative treatment is a viable alternative to appendectomy regarding clinical recovery. Trail registration: NCT01356641 What is Known: • Non-operative treatment of uncomplicated appendicitis in children is safe and its use around the world is gaining ground, however high quality evidence from adequately designed randomized trials is still lacking.• Concerns have been raised regarding the potentially prolonged clinical recovery associated with non-operative treatment. What is New: • Most clinical symptoms resolve after 1 day of non-operative treatment in the majority of children. Electronic supplementary material The online version of this article (10.1007/s00431-018-3277-9) contains supplementary material, which is available to authorized users.

PURPOSE: To identify available clinical prediction rules (CPRs) and investigate their ability to rule out appendicitis in children presenting with abdominal pain at the emergency department, and accordingly select CPRs that could be useful in a future prospective cohort study.METHODS: A literature search was conducted to identify available CPRs. These were subsequently tested in a historical cohort from a general teaching hospital, comprising all children (RESULTS: Twelve CPRs were tested in a cohort of 291 patients, of whom 87 (29.9%) suffered from acute appendicitis. The Ohmann score, Alvarado score, modified Alvarado score, Pediatric Appendicitis score, Low-Risk Appendicitis Rule Refinement, Christian score, and Low Risk Appendicitis Rule had a negative likelihood ratio 0.1. Three CPRs were excluded because the score could not be calculated for at least 50% of patients.CONCLUSION: This study identified seven CPRs that could be used in a prospective cohort study to compare their ability to rule out appendicitis in children and investigate if clinical monitoring and re-evaluation instead of performing additional investigations (i.e., ultrasound) is a safe treatment strategy in case there is low suspicion of appendicitis.

Background After the completion of therapy, patients with localized rhabdomyosarcoma (RMS) are subjected to intensive radiological tumor surveillance. However, the clinical benefit of this surveillance is unclear. This study retrospectively analyzed the value of off‐therapy surveillance by comparing the survival of patients in whom relapse was detected by routine imaging (the imaging group) and patients in whom relapse was first suspected by symptoms (the symptom group). Methods This study included patients with relapsed RMS after the completion of therapy for localized RMS who were treated in large pediatric oncology hospitals in France, the United Kingdom, Italy, and the Netherlands and who were enrolled in the International Society of Paediatric Oncology Malignant Mesenchymal Tumor 95 (1995‐2004) study, the Italian Paediatric Soft Tissue Sarcoma Committee Rhabdomyosarcoma 96 (1996‐2004) study, or the European Paediatric Soft Tissue Sarcoma Study Group Rhabdomyosarcoma 2005 (2005‐2013) study. The survival times after relapse were compared with a log‐rank test between patients in the imaging group and patients in the symptom group. Results In total, 199 patients with relapsed RMS were included: 78 patients (39.2%) in the imaging group and 121 patients (60.8%) in the symptom group. The median follow‐up time after relapse was 7.4 years (interquartile range, 3.9‐11.5 years) for survivors (n = 86); the 3‐year postrelapse survival rate was 50% (95% confidence interval [CI], 38%‐61%) for the imaging group and 46% (95% CI, 37%‐55%) for the symptom group (P = .7). Conclusions Although systematic routine imaging is the standard of care after RMS therapy, the majority of relapses were detected as a result of clinical symptoms. This study found no survival advantage for patients whose relapse was detected before the emergence of clinical symptoms. These results show that the value of off‐therapy surveillance is controversial, particularly because repeated imaging may also entail potential harm., This study assesses the clinical value of radiological surveillance imaging in pediatric patients with rhabdomyosarcoma, which is routinely performed after the completion of therapy. In the majority of patients, relapse is detected because of symptoms, and there is no evidence that early detection by imaging results in improved survival.

Background In all patients with mucopolysaccharidosis type I (MPS I), skeletal disease (dysostosis multiplex) is a prominent, debilitating, condition related complication that may impact strongly on activities of daily living. Unfortunately, it is not alleviated by treatment with hematopoietic cell transplantation (HCT) or enzyme replacement therapy (ERT). Although early kyphosis is one of the key features of dysostosis multiplex, there is no international consensus on the optimal management. Therefore, an international consensus procedure was organized with the aim to develop the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients. Methods A literature review was conducted to identify all available information about kyphosis and related surgery in MPS I patients. Subsequently, a modified Delphi procedure was used to develop consensus statements. The expert panel included 10 spinal orthopedic surgeons, 6 pediatricians and 3 physiotherapists, all experienced in MPS I. The procedure consisted of 2 written rounds, a face-to-face meeting and a final written round. The first 2 rounds contained case histories, general questions and draft statements. During the face-to-face meeting consensus statements were developed. In the final round, the panel had the opportunity to anonymously express their opinion about the proposed statements. Results Eighteen case series and case reports were retrieved from literature reporting on different surgical approaches and timing of thoracolumbar kyphosis surgery in MPS I. During the face-to-face meeting 16 statements were discussed and revised. Consensus was reached on all statements. Conclusion This international consensus procedure resulted in the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients, focusing on the goals and timing of surgery, as well as the optimal surgical approach, the utility of bracing and required additional assessments (e.g. radiographs). Most importantly, it was concluded that the decision for surgery depends not only on the kyphotic angle, but also on additional factors such as the progression of the deformity and its flexibility, the presence of symptoms, growth potential and comorbidities. The eventual goal of treatment is the maintenance or improvement of quality of life. Further international collaborative research related to long-term outcome of kyphosis surgery in MPS I is essential as prognostic information is lacking. Electronic supplementary material The online version of this article (10.1186/s13023-019-0997-5) contains supplementary material, which is available to authorized users.

Background: Left ventricular dysfunction is an important co-morbidity of end-stage renal disease (ESRD) and is associated with a poor prognosis in the adult population. In pediatric ESRD, left ventricular function is generally well preserved, but limited information is available on early changes in myocardial function. The aim of this study was to investigate myocardial mechanics in pediatric patients with ESRD using speckle-tracking echocardiography (STE). Methods: Echocardiographic studies, including M-mode, tissue Doppler imaging (TDI) and STE, were performed in 19 children on dialysis, 17 transplant patients and 33 age-matched controls. Strain measurements were performed from the apical four-chamber and the short axis view, respectively. Results: The interventricular and left ventricular posterior wall thickness was significantly increased in dialysis and transplant patients compared to healthy controls. No significant differences were found in shortening fraction, ejection fraction and systolic tissue Doppler velocities. Dialysis and transplant patients had a decreased mean longitudinal strain compared to healthy controls, with a mean difference of 3.1 [95 % confidence interval (CI) 2.0–4.4] and 2.7 (95 % CI 1.2–4.2), respectively. No differences were found for radial and circumferential strain. Conclusions: Speckle-tracking echocardiography may reveal early myocardial dysfunction in the absence of systolic dysfunction measured by conventional ultrasound or TDI in children with ESRD.

This study aims to provide an overview of both our own experience and the available literature on the treatment of post-appendectomy abscess (PAA) in children. We performed a historical cohort study encompassing all children aged 0–17 years old treated for a radiologically confirmed PAA between 2007 and 2013. Their medical charts were reviewed and descriptive analyses were performed. A literature search on the treatment of PAA in children was performed. In our cohort, 25 out of 372 (7 %) children developed a PAA. Thirteen were treated with a noninvasive strategy and 12 with an invasive strategy (percutaneous or surgical drainage). The immediate success rate was 9/13 (69 %) and 8/12 (67 %) for the noninvasive and invasive strategy, respectively. In both groups, four children (31 and 33 % resp.) required delayed interventions after their initial treatment. In the literature review, six studies were included which reported a median (range) frequency of persistent or recurrent abscess of 9 % (0–30 %), 50 % (0–100 %) and 24 % (0–33 %) for the antibiotic (noninvasive), percutaneous drainage (invasive) and surgical drainage strategies, respectively. Conclusion: Although confounding by indication cannot be excluded, we recommend noninvasive treatment as a safe strategy for PAA in children with stable condition. What is known: • Post-appendectomy abscess is a well-known and feared complication, occurring in up to 24 % of the children treated surgically for appendicitis.• Several strategies are available to treat this condition, all with advantages and disadvantages. What is new: • Noninvasive strategy is a safe strategy for children with a PAA in a stable condition. • An overview of the literature (the first to our knowledge) supports the above-mentioned statement.

Background: Low prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design.Results: Before and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry.Conclusions: A RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.