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Abstract Background Congenital gastrointestinal malformation (CGIM) require neonatal surgical treatment and may lead to disease-specific sequelae, which have a potential psychological impact on parents. The aim of this study is to assess distress and symptoms of post-traumatic stress disorder (PTSD) in parents of patients with CGIM. In this cross-sectional study, seventy-nine parents (47 mothers and 32 fathers) of 53 patients with CGIM completed the Distress Thermometer for Parents (DT-P) and the Self Rating Scale for Posttraumatic Stress Disorders (SRS-PTSD) as part of the multidisciplinary follow-up of their children (aged 5–35 months). Group differences were tested between parents and representative Dutch reference groups with regard to rates of (clinical) distress and PTSD, and severity of overall distress and PTSD, for mothers and fathers separately. Mixed model regression models were used to study factors associated with the risk of (clinical) distress, PTSD and with severity of symptoms of PTSD (intrusion, avoidance and hyperarousal). Results Prevalence of clinical distress was comparable to reference groups for mothers (46%) and fathers (34%). There was no difference in severity of overall distress between both mothers as well as fathers and reference groups. Prevalence of PTSD was significantly higher in mothers (23%) compared to the reference group (5.3%) (OR = 5.51, p

Background: Congenital gastrointestinal malformation (CGIM) require neonatal surgical treatment and may lead to disease-specific sequelae, which have a potential psychological impact on parents. The aim of this study is to assess distress and symptoms of post-traumatic stress disorder (PTSD) in parents of patients with CGIM. In this cross-sectional study, seventy-nine parents (47 mothers and 32 fathers) of 53 patients with CGIM completed the Distress Thermometer for Parents (DT-P) and the Self Rating Scale for Posttraumatic Stress Disorders (SRS-PTSD) as part of the multidisciplinary follow-up of their children (aged 5-35 months). Group differences were tested between parents and representative Dutch reference groups with regard to rates of (clinical) distress and PTSD, and severity of overall distress and PTSD, for mothers and fathers separately. Mixed model regression models were used to study factors associated with the risk of (clinical) distress, PTSD and with severity of symptoms of PTSD (intrusion, avoidance and hyperarousal).Results: Prevalence of clinical distress was comparable to reference groups for mothers (46%) and fathers (34%). There was no difference in severity of overall distress between both mothers as well as fathers and reference groups. Prevalence of PTSD was significantly higher in mothers (23%) compared to the reference group (5.3%) (OR = 5.51, p < 0.001), not in fathers (6.3% vs 2.2.%). Symptoms of intrusion were commonly reported by all the parents (75%). Longer total length of child's hospital stay was associated with more severe symptoms of intrusion, avoidance and hyperarousal. Child's length of follow-up was negatively associated with severity of intrusion.Conclusions: Having a child with CGIM has a huge impact on parents, demonstrated by a higher prevalence of PTSD in mothers, but not fathers, compared to parents in the general population. Monitoring of symptoms of PTSD of parents in follow-up is necessary. [ABSTRACT FROM AUTHOR]

Background: Functional constipation is common in children and accurate diagnostic methods are essential for early diagnosis and effective management. The diagnostic accuracy of transabdominal ultrasound to diagnose functional constipation is unclear., Objective: To evaluate the diagnostic accuracy of transverse rectal diameter measurement via transabdominal ultrasound in diagnosing children with functional constipation and in identifying fecal impaction., Materials and Methods: Electronic databases were searched from inception to March 2023. Original studies investigating the diagnostic accuracy of measuring transverse rectal diameter via transabdominal ultrasound, including children with and without functional constipation, or with and without fecal impaction were included. Data extraction and quality assessment were performed independently by two reviewers., Results: Sixteen studies were included (n = 1,801 children, 0-17 years). Thirteen studies investigated the diagnostic accuracy for functional constipation, and five for fecal impaction. High risk of bias was found across the majority of studies mainly due to un-blinded case-control designs. Cut-off transverse rectal diameter values to diagnose functional constipation ranged from 2.4 cm to 3.8 cm. Meta-analysis (seven studies, n = 509 children) estimated mean sensitivity and specificity to diagnose functional constipation were 0.68 (95% confidence interval (CI) 0.55-0.78) and 0.81 (95% CI 0.71-0.88), respectively. Meta-analysis of diagnostic accuracy of identifying fecal impaction was not feasible. Studies reported a sensitivity and specificity ranging between 68-100% and 83-100%, respectively., Conclusion: Transabdominal ultrasound may be a valuable non-invasive diagnostic tool to diagnose functional constipation by measuring transverse rectal diameter and identifying fecal impaction in children. Heterogeneous study methods and lack of age-dependent normal values impair current clinical recommendations. Future research should focus on separating age groups and developing a standardized protocol., Competing Interests: Declarations Competing interests Marc A. Benninga is consultant for Mallinckrodt, Shire, Danone, FrieslandCampina, HIPP, Norgine, Coloplast, United Pharmaceuticals, and Wellspect. All honoraria were paid to the hospital (Amsterdam UMC). Ilan J.N. Koppen received research funding from Wellspect Healthcare and The EuroQol Research Foundation. All other authors declare no conflict of interest., (© 2024. The Author(s).)

Transducin β-like 1 X-linked receptor 1 (mouse Tbl1xr1) or TBL1X/Y related 1 (human TBL1XR1), part of the NCoR/SMRT corepressor complex, is involved in nuclear receptor signaling. Variants in TBL1XR1 cause a variety of neurodevelopmental disorders including Pierpont syndrome caused by the p.Tyr446Cys variant. We recently reported a mouse model carrying the Tbl1xr1 Y446C/Y446C variant as a model for Pierpont syndrome. To obtain insight into mechanisms involved in altered brain development we studied gene expression patterns in the cortex of mutant and wild type (WT) mice, using RNA-sequencing, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene correlation network analysis (WGCNA) and hub gene analysis. We validated results in mutated mouse cortex, as well as in BV2 and SK-N-AS cell lines, in both of which Tbl1xr1 was knocked down by siRNA. Two DEGs (adj.P. Val < 0.05) were found in the cortex, Mpeg1 (downregulated in mutant mice) and 2900052N01Rik (upregulated in mutant mice). GSEA, WGCNA and hub gene analysis demonstrated changes in genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1 Y446C/Y446C mice. The lowered expression of ion channel genes Kcnh3 and Kcnj4 mRNA was validated in the mutant mouse cortex, and increased expression of TRIM9, associated with neuroinflammation, was confirmed in the SK-N-AS cell line. Conclusively, our results show altered expression of genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1 Y446C/Y446C mice. These may partly explain the impaired neurodevelopment observed in individuals with Pierpont syndrome and related TBL1XR1-related disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Osteogenesis Imperfecta (OI), known as "brittle bone disease," presents a rare genetic disorder characterized by bone fragility, often accompanied by skeletal deformities and extraskeletal complications. OI is primarily associated with collagen type I defects, responsible for the syndromic nature of the disease affecting a broad range of tissues. As such, its multisystemic complexity necessitates multidisciplinary care approaches in all patient life stages. OI treatment remains largely supportive, commonly including bisphosphonates and orthopedic surgeries, which show promise in children. Although rehabilitation programs for children exist, guidelines for adult care and especially the transition from pediatric to adult care, are lagging behind in OI care and research. The current systematic review summarizes the literature on OI patient pediatric to adult care transition experiences and compares OI transition approaches to other chronic diseases. The review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were conducted across multiple databases. Search terms encompassed synonyms and closely related phrases relevant to "OI" and "Transition to adult care". The initial screening involved the evaluation of article titles, followed by a thorough review of abstracts to assess relevance for the purpose of the current review. Programs aimed at easing the transition from pediatric to adult OI care necessitate a multifaceted approach. Collaborative efforts between different medical disciplines including pediatricians, endocrinologists, orthopedics, cardiology, pulmonology, ophthalmology, otolaryngologists, maxillofacial specialists, psychologists and medical genetics, are crucial for addressing the diverse needs of OI patients during this critical life phase. Comprehensive education, readiness assessments, personalized transition plans, and further follow-up are essential components of a structured transition framework. Further research is warranted to evaluate the feasibility and efficacy of sequential stepwise transition systems tailored to individuals with OI., Competing Interests: Declarations Conflict of interest Luca, Mark R. Garrelfs, Ralph J. B. Sakkers, Mariet W. Elting, Mauro Celli, Arend Bökenkamp, Cas Smits, Thadé Goderie, Jan Maerten Smit, Lothar A. Schwarte, Patrick R. Schober, Wouter D. Lubbers, Marieke C. Visser, Arthur J. Kievit, Barend J. van Royen, Marjolijn Gilijamse, Willem H. Schreuder, Thomas Rustemeyer, Angela Pramana, Jan-Jaap Hendrickx, Max R. Dahele, Peerooz Saeed, Annette C. Moll, Katie R. Curro–Tafili, Ebba A. E. Ghyczy, Chris Dickhoff, Robert A. de Leeuw, Jaap H. Bonjer, Jakko A. Nieuwenhuijzen, Thelma C. Konings, Anton F. Engelsman, Augustinus M. Eeckhout, Joost G. van den Aardweg, Patrick J. Thoral, David P. Noske, Leander Dubois, Berend P. Teunissen, Oliver Semler, Lena Lande Wekre, Katre Maasalu, Aare Märtson, Luca Sangiorgi, Paolo Versacci, Mara Riminucci, Paola Grammatico, Anna Zambrano, Lorena Martini, Marco Castori, Esmee Botman, Ingunn Westerheim, Lidiia Zhytnik, Dimitra Micha, Elisabeth Marelise W. Eekhoff have no competing interests to declare that are relevant to the content of this article. Ethical Approval Not applicable., (© 2024. The Author(s).)

Objective: Human milk composition is dynamic. While extensive research has focused on its macronutrient concentrations during the first 6 months of lactation, limited research exists for extended lactation periods. This study aims to examine the nutritional composition of human milk during these longer lactation phases., Design: A retrospective longitudinal cohort study performed within the National Dutch Human Milk Bank., Participants: We selected donors who had provided milk donations at least once after the 6-month postpartum mark., Main Outcome Measures: The Miris Human Milk Analyser was used to analyse macronutrient concentrations in the milk samples. Linear mixed models were used for longitudinal analysis of these concentrations, factoring in time variables established for six sequential lactation periods., Results: We analysed 820 milk samples from 86 women, collected between 5 weeks and 28 months postpartum. Initially, milk protein concentrations dropped over the first 8 months of lactation (diff = -0.19 g/dL, p<0.001) and stabilised between 8 and 18 months before increasing again by 0.21 (95% CI 0.06-0.21) g/dL. Carbohydrate concentrations remained steady throughout the study period. Fat concentrations were stable for the first 8 months but saw an increase afterwards. Post 18 months, the fat content saw a rise of 1.90 (95% CI 1.59-2.21) g/dL. The caloric density mirrored the pattern of the fat concentrations., Conclusion: The nutritional content of human milk does not decrease after 6 months of lactation. Therefore, human milk banks may accept donations from mothers up to 2 years post-birth., Competing Interests: Competing interests: JM, JIAL, JWRT, BJvK, AS: All report no conflict of interest. JBvG: Member of the Dutch National Health Institute and founder and director of the Dutch National Human Milk Bank. CHPVDA: Reports receipt of speakers and consultancy honoraria from Nestlé Nutrition Institute, Nutricia Early Life Nutrition and Baxter., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Prenatal detection of cardiac abnormalities has increased significantly over the past few decades, such that fetal cardiology has developed into a sub-specialty of paediatric and congenital cardiology. As this speciality develops further and extends across Europe and more globally, it is important to standardize the requirements for training and subsequent practice, to optimize prenatal diagnosis and perinatal care. In addition to the knowledge and technical skills required to make a correct diagnosis, the counseling of families after diagnosis and the planning of appropriate perinatal management is equally important. The aim of these recommendations is to provide a framework for both basic and advanced training for paediatric cardiologists wishing to practice as fetal cardiologists, as well as highlighting requisites for a fetal cardiology service. All aspects regarding training in fetal cardiology and service provision are addressed including diagnosis, counseling and management.

Purpose: The purpose of this study was to understand the provision and distribution of esophageal atresia (EA) follow-up (FU) and transition services across European Reference Network for rare Inherited and Congenital Anomalies (ERNICA) member and affiliate centers., Methods: A REDCap questionnaire was sent to clinical leads of 18 ERNICA members and 14 affiliate centers., Results: 29 of 32 centers responded (91%), the majority of which were highly specialized. Two-thirds had a dedicated EA clinic with a specialist multi-disciplinary team (MDT), offered to selected/complex patients only in 40% of centers. ERNICA centers were more likely to offer an MDT FU clinic than affiliates, with lack of resources most cited as a barrier to uptake (67%). Delivery of routine investigations was heterogeneous, particularly provision of three endoscopies over the course of FU (24%). Only 55% had a dedicated transition pathway, more prevalent in ERNICA centers (81% vs. 30%; p < 0.01). Self-reported awareness of ERNICA and European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidance for FU and transition was poor (28%)., Conclusion: Despite the existence of European follow-up and transition guidelines, their delivery is not uniform and may be limited by lack of awareness of the guidelines and a lack of resources., (© 2024. The Author(s).)

The use of archival formalin-fixed paraffin-embedded (FFPE) tissue samples for biochemical analyses is problematic because of the formation of a Schiff base, leading to low protein and metabolite yields during analytical extractions. Here, we overcome this issue using a unified protocol on FFPE tissue for metabolomics and proteomics analyses. Using 20 mg of wet mass tissue, this protocol consistently extracted more than 50 metabolites (across 11 classes of metabolites) and over 900 proteins., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest None.

Background: We have previously developed Core Outcome Measures sets for Severe Asthma (COMSA) by multi-stakeholder consensus. There are no patient-centred tools to quantify response to biologics for severe asthma. We aimed to develop paediatric and adult CompOsite iNdexes For Response in asthMa (CONFiRM) incorporating clinical parameters and patient-reported quality of life (QoL)., Methods: International expert healthcare professionals (HCPs) and patients with severe asthma were invited to: 1) develop consensus levels of clinically relevant changes for each outcome measure within COMSA; 2) use multicriteria decision analysis to develop the CONFiRM scores and 3) assess their internal validity. A separate group of HCPs evaluated CONFiRM's external validity., Results: Five levels of change for each COMSA outcome were agreed. Severe exacerbations and maintenance oral corticosteroids use were rated as most important in determining both paediatric and adult CONFiRM scores. There was strong agreement between HCPs and patients, although patients assigned greater importance to QoL. The CONFiRM score quantified response to a biological from -31 (deterioration) to 69 (best possible response). Paediatric and adult CONFiRMs had good discriminative ability for a sufficient (AUC≥0.92) and a substantial (AUC≥0.95) response to biologics. Both CONFiRMs demonstrated excellent external validity (Spearman correlation coefficients 0.9 and 0.8 for paediatric and adult respectively (p<0.0001))., Conclusions: We have developed novel patient-centred paediatric and adult CONFiRMs which include QoL measures. CONFiRMs should allow a more holistic understanding of response for the patient and a standardised assessment of the effectiveness of biologics between studies. Further research is needed to prospectively validate CONFiRM scores., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction., Competing Interests: Declaration of interests All authors were former employees of AVROBIO, Inc., Cambridge, MA, USA during the conception and writing of the manuscript, except V.M., M.R., and A.S. N.P.v.T. and C.M. are inventors on patents in the field of HSC gene therapy. AVROBIO, Inc., has a preclinical gene therapy program for Pompe disease (AVR-RD-03) based on a genetically modified HSPC platform using lentiviral vectors. Collection of data and analysis was performed as part of the program. This research received no external funding and was sponsored by AVROBIO, Inc., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects of VWF. The p.M771V VWF variant leads to a severe bleeding phenotype in homozygous patients. However, the exact molecular mechanism remains unclear, which prevents personalized treatment of those VWD patients., Objective: This study aims to characterize the underlying molecular mechanisms of the p.M771V variant in multiple representative ex-vivo cell models., Methods: ECFCs were isolated from venous blood of VWD patients from the Willebrand in the Netherlands (WiN) cohort carrying homozygous and heterozygous p.M771V VWF variants. The p.M771V variant was also introduced in cord-blood derived ECFCs (CB-ECFCs) through adenine base editing and was overexpressed in HEK293 cells. Biosynthesis, storage, and secretion of VWF was studied using biochemical methods and confocal microscopy., Results: Two unrelated homozygous p.M771V patients presented with very low VWF activity and antigen levels in plasma. Patient ECFCs showed impaired proVWF processing into mature VWF with secreted VWF being severely reduced when compared to ECFCs of healthy donors. Multimer analysis of p.M771V ECFCs showed a deficiency of high molecular weight VWF multimers. Immunofluorescent staining revealed VWF retention in the endoplasmic reticulum (ER); this was confirmed in various populations of base edited CB-ECFCs harboring the p.M771V variant., Conclusion: The severe endothelial phenotype observed in patient-derived p.M771V ECFCs, HEK293 cells, and an original base-edited CB-ECFC modelling system, show that ER retention of VWF and failure to undergo subsequent proteolytic processing underpins the severe bleeding phenotype of patients with homozygous variants at M771., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neurodevelopmental disorder with or without autism or seizures (NEDAUS; OMIM #619239) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase; OMIM #603136) haploinsufficiency. We collected clinical and molecular data from twenty-six individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including twenty previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge into the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we preformed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying twenty new individuals and confirming five previously reported cases of NEDAUS., (Copyright © 2024. Published by Elsevier Inc.)

Background: Intestinal ultrasound (IUS) is an emerging modality in monitoring disease activity in ulcerative colitis (UC). Here, we aimed to identify early IUS predictors of treatment response as evaluated by endoscopy and assessed the kinetics of IUS changes., Methods: This prospective, longitudinal study included UC patients with endoscopic disease activity (endoscopic Mayo score [EMS] ≥2) starting anti-inflammatory treatment. Clinical scores, biochemical parameters and IUS were assessed at baseline (W0), at week 2 (W2), at W6(W6), and at the time of second endoscopy (W8-W26). Per colonic segment, endoscopic remission (EMS = 0), improvement (EMS ≤1), response (decrease in EMS ≥1), and clinical remission (Lichtiger score ≤3) were assessed and correlated with common IUS parameters. Additionally, drug-specific responsiveness of bowel wall thickness (BWT) was assessed., Results: A total of 51 patients were included and followed, and 33 patients underwent second endoscopy. BWT was lower from W6 onward for patients reaching endoscopic improvement (3.0 ± 1.2 mm vs 4.1 ± 1.3 mm; P = .026), remission (2.5 ± 1.2 mm vs 4.1 ± 1.1 mm; P = .002), and clinical remission (3.01 ± 1.34 mm vs 3.85 ± 1.20 mm; P = .035). Decrease in BWT was more pronounced in endoscopic responders (-40 ± 25% vs -4 ± 28%; P = .001) at W8 to W26. At W6, BWT ≤3.0 mm (odds ratio [OR], 25.13; 95% confidence interval, 2.01-3.14; P = .012) and color Doppler signal (OR, 0.35; 95% confidence interval, 0.14-0.88; P = .026) predicted endoscopic remission and improvement, respectively. Submucosal layer thickness at W6 predicted endoscopic remission (OR, 0.09; P = .018) and improvement (OR, 0.14; P = .02). Furthermore, BWT decreased significantly at W2 for infliximab and tofacitinib and at W6 for vedolizumab., Conclusions: BWT and color Doppler signal predicted endoscopic targets already after 6 weeks of treatment and response was drug specific. IUS allows close monitoring of treatment in UC and is a surrogate marker of endoscopy., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

The metabolic profile of dendritic cells (DCs) shapes their phenotype and functions. The carboxylesterase 1 (CES1) enzyme is highly expressed in mononuclear myeloid cells; however, its exact role in DCs is elusive. We used a CES1 inhibitor (WWL113) and genetic overexpression to explore the role of CES1 in DC differentiation in inflammatory models. CES1 expression was analyzed during CD14+ monocytes differentiation to DCs (MoDCs) using quantitative polymerase chain reaction. A CES1 inhibitor (WWL113) was applied during MoDC differentiation. Surface markers, secreted cytokines, lactic acid production, and phagocytic and T cell polarization capacity were analyzed. The transcriptomic and metabolic profiles were assessed with RNA sequencing and mass spectrometry, respectively. Cellular respiration was assessed using seahorse respirometry. Transgenic mice were used to assess the effect of CES1 overexpression in DCs in inflammatory models. CES1 expression peaked early during MoDC differentiation. Pharmacological inhibition of CES1 led to higher expression of CD209, CD86 and MHCII. WWL113 treated MoDCs secreted higher quantities of interleukin (IL)-6, IL-8, tumor necrosis factor, and IL-10 and demonstrated stronger phagocytic ability and a higher capacity to polarize T helper 17 differentiation in an autologous DC-T cell coculture model. Transcriptomic profiling revealed enrichment of multiple inflammatory and metabolic pathways. Functional metabolic analysis showed impaired maximal mitochondrial respiration capacity, increased lactate production, and decreased intracellular amino acids and tricarboxylic acid cycle intermediates. Transgenic human CES1 overexpression in murine DCs generated a less inflammatory phenotype and increased resistance to T cell-mediated colitis. In conclusion, CES1 inhibition directs DC differentiation toward a more inflammatory phenotype that shows a stronger phagocytic capacity and supports T helper 17 skewing. This is associated with a disrupted mitochondrial respiration and amino acid depletion., Competing Interests: Conflict of interest statement: W.J.d.J. is co-founder and share holder of AIBiomics B.V., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

In clinical practice, the glomerular filtration rate (GFR), a measurement of kidney functioning, is normally calculated using equations, such as the European Kidney Function Consortium (EKFC) equation. Despite being the most general equation, EKFC, just like previously proposed approaches, can still struggle to achieve satisfactory performance, limiting its clinical applicability. As a possible solution, recently machine learning (ML) has been investigated to improve GFR prediction, nonetheless the literature still lacks a general and multi-center study. Using a dataset with 19,629 patients from 13 cohorts, we investigate if ML can improve GFR prediction in comparison to EKFC. More specifically, we compare diverse ML methods, which were allowed to use age, sex, serum creatinine, cystatin C, height, weight and BMI as features, in internal and external cohorts against EKFC. The results show that the most performing ML method, random forest (RF), and EKFC are very competitive where RF and EKFC achieved respectively P10 and P30 values of 0.45 (95% CI 0.44;0.46) and 0.89 (95% CI 0.88;0.90), whereas EKFC yielded 0.44 (95% CI 0.43; 0.44) and 0.89 (95% CI 0.88; 0.90), considering the entire cohort. Small differences were, however, observed in patients younger than 12 years where RF slightly outperformed EKFC., (© 2024. The Author(s).)

Background and Aims: The effectiveness of transition programs from paediatric to adult healthcare in adolescents with inflammatory bowel disease is not clear, as prospective studies using validated outcome measures for transition are lacking. This study aimed to develop and validate a quantitative Transition Success Score, and to apply it in a multicenter setting to assess the effectiveness of transitional care., Methods: The Top 10 outcome items related to successful transition, identified through an international Delphi study with IBD stakeholders, were integrated into a generic questionnaire, the Transition Success Score. In a prospective, multicenter study, Transition Success Score was scored by adult healthcare providers, young adult patients and caregivers, 9-15 months after transfer of care., Results: In seven Dutch hospitals, 160 patients completed the Transition Success Score. The mean score was 25 (range 17-27), 25.6% of patients achieving maximum score. Hypothesis testing for construct validity revealed significant associations with characteristics related to transitional care, such as knowledge, independence, and quality of life (p <0.005). Structural validation indicated the score was most effective at discerning lower levels of transition success. Internal consistency was acceptable (0.64). High disease burden, exacerbation during or after transfer, and certain personality profiles were associated with lower scores., Conclusions: The Transition Success Score serves as a quantitative tool to evaluate the effectiveness of transitional care interventions and to identify inflammatory bowel disease patients at risk of encountering challenges during the transition to adult healthcare., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is a recurrent translocation in AML in infants or very young children and was recently included in the World Health Organization (WHO) Classification of Hematolymphoid Tumors. AML with t(7;12) is reported to involve MNX1 and ETV6 signaling; however, the mechanism of leukemogenesis is not well understood, and the presence of MNX1::ETV6 fusion transcripts has only been confirmed in approximately 50% of cases. In contrast, high expression of MNX1 has been seen in all investigated cases. In this study, we investigated the clinical as well as biological characteristics of 12 pediatric AML with t(7;12) and performed whole transcriptome (WTS) and whole genome sequencing (WGS) on six of these. There was no significant difference in event-free survival or overall survival of these t(7;12) AML patients compared with other AML in the same age group. Interestingly, WTS identified several fusion transcripts involving ETV6 but not together with MNX1. WGS identified the genomic breakpoints and revealed that a common fusion partner on chromosome 7 was NOM1. Principal component analysis (PCA) of the WTS data showed that all t(7;12) AML cases cluster together, separate from all other pediatric AML subtypes; all cases had high expression of MNX1, MNX1-AS1, and MNX1-AS2. Hence, t(7;12) AML, despite expressing different fusion transcripts and with varying translocation breakpoints, constitutes a phenotypically homogenous subgroup. This underlines that the leukemia-driving event most likely is ectopic expression of MNX1 and that this therefore should be the defining Classifying criteria of this type of AML., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Objectives: To describe incidence, clinical course, diagnostic and therapeutic management and long-term follow-up of paediatric intestinal pseudo-obstruction (PIPO) in the Netherlands between 2000 and 2020., Methods: Multicenter, national, retrospective, observational study including patients aged <18 years diagnosed with PIPO and treated between 2000 and 2020 in Dutch academic medical centres. Outcomes included demographics, incidence, symptoms, diagnostic- and treatment methods used during follow-up, number of hospital admissions and mortality., Results: Between 2000 and 2020, 43 children (median age 120 months, range 13 - 301, 54% female) were diagnosed with PIPO in the Netherlands. Mean incidence was 0.008/100,000/years (range 0/100 000-0.029/100 000). Twenty-six patients developed PIPO in the neonatal period. Initial symptoms were vomiting (n = 21/35, 60%) and abdominal distension (n = 14/35, 40%). Diagnostic strategies included imaging, manometry, histopathology, metabolic- and genetic screening, endoscopy and exploratory surgery. Treatment was divided in nutritional support, pharmacotherapy, colonic irrigation and surgical interventions, of which nutrition and surgery were the cornerstones for care. During the observed study period, the median number of hospital admissions was 22.5 (range 1-176) with a median of 157.5 days (range 3-840) during 20-year follow-up. Two patients (6%) died: one from sepsis and one due to a severe underlying neurological disease. Heterogeneity in diagnostic- en treatment methods existed between patients., Conclusions: PIPO is a rare, long-lasting complex disease requiring a high number of diagnostic and therapeutic interventions and hospital admissions. However, mortality rate is relatively low. Based on our results, we recommend centralization and standardization of care for this complex rare disease., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Riboflavin transporter deficiency (RTD) is an inborn error of riboflavin transport causing progressive neurological symptoms if left untreated. While infants with symptomatic RTD rapidly deteriorate, presentation later in childhood or in adulthood is more gradual. Symptoms overlap with more common diseases, carrying a risk of misdiagnosis, and given the relatively recent discovery of the genetic basis of RTD in 2010 it is likely that older patients have not been tested. Treatment with oral riboflavin (vitamin B2) halts disease progression and can be lifesaving. We hypothesized that patients may have been left unrecognized at the time of presentation and therefore we performed a datamining study to detect undiagnosed RTD patients in a tertiary referral hospital., Methods: A systematic search in Electronic Health Records (EHR) of all patients visiting the Amsterdam University Medical Centers between January 2004 and July 2021 was performed by a medical data text-mining tool. Pseudonymized patient records, matching pre-defined search terms (hearing loss or auditory neuropathy spectrum disorders combined with key clinical symptoms or riboflavin) were screened and included if no definitive alternative diagnosis for symptoms indicating possible RTD was found. Included patients were offered genetic testing. We documented total number of patients with possible RTD, number of patients that underwent genetic testing for RTD and results of genetic testing., Results: EHR of 2.288.901 patients were automatically screened. Thirteen patients with possible RTD were identified and offered genetic testing. Seven patients chose not to participate. Genetic testing was performed in 6 patients and was negative. The datamining did detect all previously known RTD patients in the hospital., Conclusions: By screening a large cohort of patients of all ages in a tertiary referral hospital in a period spanning 17 years, no new RTD patients were found. Although not all suspected patients underwent genetic testing, our findings suggest that the prevalence of RTD is low and the chance of having missed this diagnosis in a tertiary referral hospital is limited., (© 2024. The Author(s).)

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Aim: Moderate preterm (MP) birth is associated with an increased risk of developmental problems. However, post-discharge support for this group is scarce. The aim of this study was to evaluate the feasibility of a post-discharge parenting program (TOP program) for MP infants. Three feasibility dimensions were evaluated (1) recruitment capability and compliance, (2) intervention acceptability, and (3) limited efficacy testing., Methods: A group of MP infants with a gestational age (GA) between 32 0/7 -34 6/7 weeks and their parents received six home visits by a TOP interventionist until 6 months corrected age (CA). A pre-posttest intervention design with quantitative and qualitative measures was used. Recruitment capability and compliance, acceptability, and satisfaction with the intervention were evaluated using a questionnaire, checklists, interviews, and a focus group. Infant socio-emotional development, parental distress, self-efficacy, and reflective functioning were measured with questionnaires. Observation measurements were used for infant motor development and parental sensitivity., Results: Thirty-two families completed the six home visits. The satisfaction rate (scale 0-10) was remarkably high (Mean 9.4, range: 8-10). Parents reported that the program was suitable, enhanced their understanding of their infants' developmental needs, and increased their self-efficacy. The infants showed age-appropriate motor and socio-emotional development post-intervention. Parental self-efficacy, reflective functioning, and sensitivity improved from pre to post intervention, with small to large effect sizes., Conclusion: The study demonstrated high compliance, acceptability, and satisfaction with the TOP program for MP infants with promising infant and parent outcomes. This study contributes to the preparatory work prior to a larger scale evaluation and dissemination., Competing Interests: Declaration of competing interest The authors have no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Intralesional corticosteroid administration (ICA) is a first-line keloid treatment. However, it faces significant variability in current clinical and scientific practice, which hinders comparability of treatment results., Objectives: The aim of the study was to reach consensus on different aspects of ICA using hypodermic needles in keloids among an international group of dermatologists and plastic surgeons specialized in keloid treatment to provide consensus-based clinical treatment recommendations for all physicians treating keloids., Methods: The keloid expert panel of 12 dermatologists and 11 plastic surgeons rated 30 statements. Two online e-Delphi rounds were held, both with a response rate of 100%. Fifteen (65%) keloid experts participated in the final consensus meetings. Consensus was defined as ≥ 75% of the participants choosing agree or strongly agree on a 7-point Likert scale., Results: Consensus was reached on treatment goals, indication for ICA, triamcinolone acetonide (TAC) 40 mg/mL as the preferred corticosteroid administered at a maximum of 80 mg per month and at intervals of 4 weeks, minimizing pain during ICA, the use of 1 mL syringes and 25 or 27 Gauge needles, blanching as endpoint of successful infiltration, caution of not injecting subcutaneously, and the option of making multiple passes in very firm keloids prior to infiltration. Consensus could not be reached on TAC dosing, methods of prior local anesthesia, and location of injection., Conclusions: This e-Delphi study provides important clinical treatment recommendations on essential aspects of ICA in keloids. By implementing these recommendations, uniformity of ICA in keloid treatment will increase and better treatment results may be achieved., (© 2024. The Author(s).)

Background: Recurrence is a key outcome to evaluate the treatment effect of differentiated thyroid carcinoma (DTC). However, no consistent definition of recurrence is available in current literature or international guidelines. Therefore, the primary aim of this systematic review was to delineate the definitions of recurrence of DTC, categorized by total thyroidectomy with radioactive iodine ablation (RAI), total thyroidectomy without RAI and lobectomy, to assess if there is a generally accepted definition among these categories. Methods: This study adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. In December 2023, a systematic literature search in MEDLINE and EMBASE was performed for studies reporting on the recurrence of DTC, from January 2018 to December 2023. Studies that did not provide a definition were excluded. Primary outcome was the definition of recurrence of DTC. Secondary outcome was whether studies differentiated between recurrence and persistent disease. Two independent investigators screened the titles and abstracts, followed by full-text assessment and data extraction. The study protocol was registered in PROSPERO, CRD42021291753. Results: In total, 1450 studies were identified. Seventy studies met the inclusion criteria, including 69 retrospective studies and 1 randomised controlled trial (RCT). Median number of patients in the included studies was 438 (range 25-2297). In total, 17 studies (24.3%) reported on lobectomy, 4 studies (5.7%) on total thyroidectomy without RAI, and 49 studies (70.0%) with RAI. All studies defined recurrence using one or a combination of four diagnostic modalities cytology/pathology, imaging studies, thyroglobulin (-antibodies), and a predetermined minimum tumor-free time span. The most common definition of recurrence following lobectomy was cytology/pathology-proven recurrence (47.1% of this subgroup), following total thyroidectomy with RAI was cytology/pathology-proven recurrence and/or anomalies detected on imaging studies (22.4% of this subgroup). No consistent definition was found following total thyroidectomy without RAI. Nine studies (12.9%) differentiated between recurrence and persistent disease. Conclusion: Our main finding is that there is no universally accepted definition for recurrence of DTC in the current studies across any of the treatment categories. The findings of this study will provide the basis for a future, international Delphi-based proposal to establish a universally accepted definition of recurrence of DTC. A uniform definition could facilitate global discussion and enhance the assessment of treatment outcomes regarding recurrence of DTC.

Background: Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods: This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, and Beckman Coulter). Retrospective data (2008-2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2 to 20 years by 2-year categories and decade categories between 20 and 100 years. Results: We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits were higher in early childhood and decreased toward adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onward. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion: This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data are less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.