Protocol for an international multicenter randomized controlled trial assessing treatment success and safety of peroral endoscopic myotomy vs endoscopic balloon dilation for the treatment of achalasia in children.

INTRODUCTION: Achalasia is a rare neurodegenerative esophageal motility disorder characterized by incomplete lower esophageal sphincter (LES) relaxation, increased LES tone and absence of esophageal peristalsis. Achalasia requires invasive treatment in all patients. Conventional treatment options include endoscopic balloon dilation (EBD) and laparoscopic Heller's myotomy (LHM). Recently, a less invasive endoscopic therapy has been developed; Peroral Endoscopic Myotomy (POEM). POEM integrates the theoretical advantages of both EBD and LHM (no skin incisions, less pain, short hospital stay, less blood loss and a durable myotomy). Our aim is to compare efficacy and safety of POEM vs. EBD as primary treatment for achalasia in children. METHODS AND ANALYSIS: This multi-center, and center-stratified block-randomized controlled trial will assess safety and efficacy of POEM vs EBD. Primary outcome measure is the need for retreatment due to treatment failure (i.e. persisting symptoms (Eckardt score > 3) with evidence of recurrence on barium swallow and/or HRM within 12 months follow-up) as assed by a blinded end-point committee (PROBE design). DISCUSSION: This RCT will be the first one to evaluate which endoscopic therapy is most effective and safe for treatment of naïve pediatric patients with achalasia.

The potential of rectal swabs to differentiate simple and complex appendicitis in children with a microbiota-based test.

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.

Follow-up of infants with colic into childhood: Do they develop behavioural problems?

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.

Implementing Nonoperative Treatment Strategy for Simple Pediatric Appendicitis: A Qualitative Study.

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.

Prevalence of suspected child abuse in children with constipation: a case-control study.

BACKGROUND: 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 CAN in children with FC as compared with their healthy peers. METHODS: 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 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. RESULTS: 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 (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. CONCLUSION: 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.

Identification of the optimal treatment strategy for complex appendicitis in the paediatric population: a protocol for a multicentre prospective cohort study (CAPP study).

INTRODUCTION: In 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 ANALYSIS: This nation-wide, multi-centre, comparative, non-randomised prospective cohort study includes all children <18 years old with a preoperative suspicion of complex appendicitis, which is based on imaging confirmed acute appendicitis and predefined criteria regarding the severity of appendicitis. Eligible patients are recruited in more than 30 hospitals. Open appendectomy will be compared with laparoscopic appendectomy for children without appendiceal mass and/or abscess and initial non-operative treatment (ie, intravenous antibiotics with or without percutaneous drainage) to direct appendectomy for children with appendiceal mass and/or abscess. Based on historical data supplied by the participating hospitals and an inclusion period of 2 years and 9 months, a sample size of 1308 patients is aimed. Primary outcome is the proportion of patients experiencing any complication at 3 months follow-up. Reported complications will be assessed by an independent adjudication committee. Secondary outcomes include, but are not limited to, quality of life, and (in)direct costs. To adjust for baseline differences and selection bias, outcomes will be compared after propensity score analysis (inverse probability weighting and stratification). ETHICS AND DISSEMINATION: The 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 NUMBERS: NCT04755179; NL9371.

International Core Outcome Set for Acute Simple Appendicitis in Children: Results of a Systematic Review, Delphi Study, and Focus Croups With Young People.

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 OF 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 4 phases: (1) an updated systematic review identifying all previously reported outcomes, (2) a 2-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 (8 countries) and 245 surgeons (10 countries), the second-round response rates were 61% and 85% respectively, with 10 outcomes emerging with consensus. After 2 young peoples' focus groups, 2 additional outcomes were added to the final COS (12): mortality, bowel obstruction, intraabdominal 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 ofsimple appendicitis in children, to reduce heterogeneity between studies and facilitate data synthesis and evidence-based decision-making.

The child's perception on monitoring inflammatory bowel disease activity.

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 < 0.001). Most of the children preferred not to sample stool or perform venipuncture regularly (n = 20 (41%, both) (p < 0.001)).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.

Reactions of non-abused children aged 3-9 years to the Sexual Knowledge Picture Instrument: an interview-based study.

Background: The 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 analysis: Subject 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. Results: Of 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. Conclusion: Non-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.

Diagnostic accuracy of fibrosis tests in children with non-alcoholic fatty liver disease: A systematic review.

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.

The Value of Early Tumor Size Response to Chemotherapy in Pediatric Rhabdomyosarcoma.

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.

Body composition monitoring in children and adolescents: reproducibility and reference values.

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.

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints.

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers.

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI's demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

Management of appendiceal mass and abscess in children; early appendectomy or initial non-operative treatment? A systematic review and meta-analysis.

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.

Hospitalising preterm infants in single family rooms versus open bay units: A systematic review and meta-analysis of impact on parents.

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<0·004, I2=46%), specifically NICU-related stress (n = 573, SMD-0·42,95%CI -0·61;-0·23, p<0·0001, I2=0%). In majority of studies higher levels of empowerment, family-centred care, and satisfaction was present with SFRs. No differences were found for anxiety, parent-infant bonding, or self-efficacy. Depression was high (up to 29%) but not different between settings. No studies described post-traumatic stress. INTERPRETATION: Single family rooms seem to facilitate parental presence, involvement, skin-to-skin care, and reduce NICU-related parental stress.

Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?

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.

Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

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 <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group. RESULTS: Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death. CONCLUSIONS: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).

Bone mineral density is within normal range in most adult phenylketonuria patients.

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 <-2) was at maximum 5.5%. No risk factors for low BMD in PKU patients could be identified. Low BMD occurs only in a small subset of PKU patients. DXA scans should be considered for well controlled patients from age 35-40 years and up and on indication in those PKU patients considered to be at increased risk for fractures.