Impaired lung function and associated risk factors in children born prematurely: a systematic review and meta-analysis.

BACKGROUND: Immature lung development and respiratory morbidity place preterm-born children at high risk of long-term pulmonary sequelae. This systematic review and meta-analysis aims to quantify lung function in preterm-born children and identify risk factors for a compromised lung function. METHODS: We searched MEDLINE, Embase, Cochrane Library, Web of Science and Scopus for relevant studies published on preterm cohorts born since 1990. Studies comparing forced expiratory volume in 1 s (FEV1) in preterm-born children aged ≥5 years to term-born controls or normative data were included. Study quality was assessed using the Newcastle-Ottawa Scale for cohort studies. Standardised mean differences in FEV1 and secondary spirometry outcomes per study were pooled using meta-analysis. The impact of different demographic and neonatal variables on studies' FEV1 effect sizes was investigated by meta-regression analyses. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: We identified 42 studies with unique cohorts including 4743 preterm children and 9843 controls. Median gestational age in the studies was 28.0 weeks and age at assessment ranged from 6.7 to 16.7 years. Preterm children had lower FEV1 than controls (-0.58 sd, 95% CI -0.69- -0.47 sd, p<0.001) resulting in a relative risk of 2.9 (95% CI 2.4-3.4) for abnormal outcome, with high certainty of evidence. FEV1 was significantly associated with gestational age, birthweight, bronchopulmonary dysplasia and invasive mechanical ventilation in univariate meta-regression analyses (R2=36-96%). CONCLUSION: This systematic review shows robust evidence of impaired lung function in preterm-born children with a high certainty of evidence.

Neurodevelopmental outcomes of school-age children conceived after hysterosalpingography with oil-based or water-based iodinated contrast: long-term follow-up of a nationwide randomized controlled trial.

STUDY QUESTION: Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER: Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY: HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION: This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012-2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study included 69 children aged 6-9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE: School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION: The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05168228.

Long-Term Neurodevelopmental Outcome of Children With Mild Traumatic Brain Injury.

BACKGROUND: To investigate the long-term outcome of pediatric mild traumatic brain injury (mTBI) in terms of neurocognitive, behavioral, and school functioning and to identify clinical risk factors for adverse outcomes. METHODS: This study describes the follow-up of a prospective multicenter sample of 89 children with mTBI 3.6 years postinjury and 89 neurologically healthy children matched for sex, age, and socioeconomic status. Neurodevelopmental outcomes were assessed using an intelligence test, behavioral questionnaires, computerized neurocognitive tests, and longitudinal (pre- and postinjury) standardized school performance data. RESULTS: Children with mTBI exhibited intelligence in the average range but had more behavioral problems related to inattentiveness (P = 0.004, d = 0.47) and hyperactive impulsivity (P = 0.01, d = 0.40) and showed poorer neurocognitive performance in information processing stability (P = 0.003, d = -0.55) and Visual Working Memory (P = 0.04, d = -0.39) compared with matched peers. Longitudinal school performance data revealed poorer performance in Technical Reading up to two years postinjury (P = 0.005, d = -0.42) when compared with normative data. Clinical risk factors did not reveal predictive value for adverse outcomes in children with mTBI. CONCLUSIONS: This study indicates that children with mTBI are at risk of long-term deficits in neurocognitive and behavioral functioning, with longitudinal evidence suggesting shortfalls in school performance up to two years postinjury. Clinical risk factors do not provide a solid basis for long-term neurodevelopmental prognosis. Findings emphasize the importance of, and challenges for, early identification of children at risk for adverse neurodevelopmental outcome after mTBI.

Placebo-related improvement with methylphenidate treatment in children with ADHD.

Non-specific effects of methylphenidate treatment, including expectancy and regression to the mean effects, contribute to the overall effect of methylphenidate on attention-deficit/hyperactivity disorder (ADHD) symptoms. Knowledge on the extent to which non-specific effects contribute to the overall effect and whether regression to the mean explains part of the non-specific effects, is currently lacking. A double-blind, randomized, placebo-controlled, cross-over trial was used to compare parent and teacher ratings of child ADHD symptoms at baseline and during treatment with placebo and 5, 10, 15 and 20 mg of methylphenidate, twice daily. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). The extent to which non-specific effects contributed to the effects of methylphenidate was determined by ADHD symptom reductions observed with placebo versus reductions observed with active doses of methylphenidate. The influence of regression to the mean was examined by estimating the contribution of baseline ADHD symptom severity to the effects observed with placebo treatment. Data were analyzed using multilevel analyses. We observed significant non-specific effects of methylphenidate for parent-rated ADHD symptoms, but not for teacher-rated symptoms. For parent reported hyperactive/impulsive symptoms, higher baseline symptoms predicted larger effects with placebo, indicating regression to the mean effects. For parent-reports, a significant part of the overall effect of methylphenidate treatment is explained by non-specific effects. Our findings stress the importance of taking non-specific effects into account when evaluating methylphenidate treatment, by including teacher-reports and using a double baseline assessment during titration. Comparing active medication with a placebo in the titration trial has the potential to identify non-specific effects.

Team functioning in Neurorehabilitation: a mixed methods study.

The objective of this study was to enhance understanding of team functioning in a neurorehabilitation team by identifying the factors that impede and facilitate effective interprofessional team collaboration. We focused on team identification, psychological safety, and team learning, and conducted the research at a neurorehabilitation center treating young patients with severe acquired brain injury in the Netherlands. A mixed-methods approach was employed, integrating quantitative data from questionnaires (N = 40) with qualitative insights from a focus group (n = 6) and in-depth interviews (n = 5) to provide a comprehensive perspective on team dynamics. Findings revealed strong team identification among participants, denoting a shared sense of belonging and commitment. However, limited psychological safety was observed, which negatively affected constructive conflict and team learning. Qualitative analysis further identified deficiencies in shared mental models, especially in shared decision-making and integrated care. These results highlight the crucial role of psychological safety in team learning and the development of shared mental models in neurorehabilitation settings. Although specific to neurorehabilitation, the insights gained may be applicable to enhancing team collaboration in various healthcare environments. The study forms a basis for future research to investigate the impact of improvements in team functioning on patient outcomes in similar settings.

Improving Methylphenidate Titration in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): A Randomized Controlled Trial Using Placebo-Controlled Titration Implemented in Clinical Practice.

BACKGROUND AND OBJECTIVES: Concerns exist regarding the rising use of methylphenidate. A double-blind, placebo-controlled methylphenidate titration (PCT) for children with attention-deficit/hyperactivity disorder (ADHD) has shown potential to improve titration (i.e., detection of placebo responders and larger ADHD symptom improvement) in experimental settings. This study aims to determine if these advantages can be transferred to clinical settings. METHOD: Children (aged 5-13 years) with an ADHD diagnosis and an indication to start methylphenidate (MPH) treatment were recruited. Participants were randomized to PCT or care as usual (CAU) in a 1:1 ratio followed by a 7-week randomized controlled trial (T1) and 6-month, naturalistic, open-label follow-up (T2). Parents, teachers, and physicians rated ADHD symptoms, ADHD medication use, MPH dosing, and treatment satisfaction using questionnaires. RESULTS: A total of 100 children were enrolled and randomized to PCT (n = 49) or CAU (n = 51). In the PCT group, we found 8.2% placebo responders, 16.3% non-responders, and 65.3% responders to MPH. With PCT compared with CAU, a significantly larger number of children discontinued MPH (T1: 24.5 vs 5.9%, p = 0.009; T2: 41.7 vs 10.4%, p < 0.001) and refrained from using other pharmacological treatment (T1: 20.4 vs 3.9%, p = 0.013; T2: 20.83 vs 6.25%, p = 0.002). At both timepoints, there were no significant differences between the groups in the average dose of MPH, ADHD symptoms, or treatment satisfaction. CONCLUSIONS: PCT can be used to improve detection of children who do not benefit from MPH, and may therefore potentially reduce overtreatment of ADHD with MPH.

Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression.

Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Embase, Medline Ovid, and Cochrane Controlled Trials Register databases for randomized controlled and crossover trials. Meta-analytic effects were calculated for each pharmaceutical agent and targeted neuromodulator system. Cognitive outcome measures were aggregated across cognitive domains. Of 8,216 articles, 41 studies (4,434 patients) were included. The noradrenergic agent methylphenidate showed a small, significant positive effect on cognitive functioning in patients with traumatic brain injury (TBI; k = 14, d = 0.34, 95% confidence interval: 0.12-0.56, P = 0.003). Specifically, methylphenidate was found to improve cognitive functions related to executive memory, baseline speed, inhibitory control, and variability in responding. The cholinergic drug donepezil demonstrated a large effect size, albeit based on a limited number of studies (k = 3, d = 1.68, P = 0.03). No significant effects were observed for other agents. Additionally, meta-regression analysis did not identify significant sources of heterogeneity in treatment response. Our meta-analysis supports the use of methylphenidate for enhancing cognitive functioning in patients with TBI. Although donepezil shows potential, it warrants further research. These results could guide clinical decision making, inform practice guidelines, and direct future pharmacotherapeutic research in ABI.

Predicting long-term neurocognitive outcome after pediatric intensive care unit admission for bronchiolitis-preliminary exploration of the potential of machine learning.

PURPOSE: For successful prevention and intervention, it is important to unravel the complex constellation of factors that affect neurocognitive functioning after pediatric intensive care unit (PICU) admission. This study aims (1) to elucidate the potential relevance of patient and PICU-related characteristics for long-term adverse neurocognitive outcome after PICU admission for bronchiolitis, and (2) to perform a preliminary exploration of the potential of machine learning as compared to linear regression to improve neurocognitive outcome prediction in a relatively small sample of children after PICU admission. METHODS: This cross-sectional observational study investigated 65 children aged 6-12 years with previous PICU admission for bronchiolitis (age ≤ 1 year). They were compared to demographically comparable healthy peers (n = 76) on neurocognitive functioning. Patient and PICU-related characteristics used for the prediction models were as follows: demographic characteristics, perinatal and disease parameters, laboratory results, and intervention characteristics, including hourly validated mechanical ventilation parameters. Neurocognitive outcome was measured by intelligence and computerized neurocognitive testing. Prediction models were developed for each of the neurocognitive outcomes using Regression Trees, k-Nearest Neighbors, and conventional linear regression analysis. RESULTS: The patient group had lower intelligence than the control group (p < .001, d = -0.59) and poorer performance in neurocognitive functions, i.e., speed and attention (p = .03, d = -0.41) and verbal memory (p < .001, d = -0.60). Lower intelligence was predicted by lower birth weight and lower socioeconomic status (R2 = 25.9%). Poorer performance on the speed and attention domain was predicted by younger age at follow-up (R2 = 53.5%). Poorer verbal memory was predicted by lower birth weight, younger age at follow-up, and greater exposure to acidotic events (R2 = 50.6%). The machine learning models did not reveal added value in terms of model performance as compared to linear regression. CONCLUSION: The findings of this study suggest that in children with previous PICU admission for bronchiolitis, (1) lower birth weight, younger age at follow-up, and lower socioeconomic status are associated with poorer neurocognitive outcome; and (2) greater exposure to acidotic events during PICU admission is associated with poorer verbal memory outcome. The findings of this study provide no evidence for the added value of machine learning models as compared to linear regression analysis in the prediction of long-term neurocognitive outcome in a relatively small sample of children. WHAT IS KNOWN: • Adverse neurocognitive outcomes are described in PICU survivors, which are known to interfere with development in other major domains of functioning, such as mental health, academic achievement, and socioeconomic success, highlighting neurocognition as an important outcome after PICU admission. • Machine learning is a rapidly growing field of artificial intelligence that is increasingly applied in health care settings, with great potential to capture the complexity of outcome prediction. WHAT IS NEW: • This study shows that lower birth weight, lower socioeconomic status, and greater exposure to acidotic events during PICU admission for bronchiolitis are associated with poorer long-term neurocognitive outcome after PICU admission. Results provide no evidence for the added value of machine learning models in a relatively small sample of children. • As bronchiolitis seldom manifests neurologically, the relation between acidotic events and neurocognitive outcome may reflect either potentially harmful effects of acidosis itself or related processes such as hypercapnia or hypoxic and/or ischemic events during PICU admission. This study further highlights the importance of structured follow-up to monitor long-term outcome of children after PICU admission.

Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

The mediating role of neurocognitive functions in the relation between physical competencies and academic achievement of primary school children.

Previous studies into associations between physical, neurocognitive and academic skills have reported inconsistent results. This study aimed to get more insight into these relations by examining all three domains simultaneously, testing a complete mediational model including measures of physical competencies (cardiovascular fitness and motor skills), neurocognitive skills (attention, information processing, and core executive functions), and academic achievement (reading, mathematics, and spelling). Dutch primary school students (n = 891, 440 boys, mean age 9.17 years) were assessed on the Shuttle Run Test (cardiovascular fitness), items of the Körperkoordinationstest für Kinder and Bruininks-Oseretsky Test-II (fundamental motor skills), computerized neurocognitive tests, and standardized academic achievement tests. A multilevel structural equation model showed that physical competencies were only indirectly related to academic achievement, via specific neurocognitive functions depending on the academic domain involved. Results provide important implications, highlighting the importance of well-developed physical competencies in children.

The Prevalence and Clinical Impact of Transition Zone Anastomosis in Hirschsprung Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Hirschsprung disease (HD) is characterized by absent neuronal innervation of the distal colonic bowel wall and is surgically treated by removing the affected bowel segment via pull-through surgery (PT). Incomplete removal of the affected segment is called transition zone anastomosis (TZA). The current systematic review aims to provide a comprehensive overview of the prevalence and clinical impact of TZA. METHODS: Pubmed, Embase, Cinahl, and Web of Sciences were searched (last search: October 2020), and studies describing histopathological examination for TZA in patients with HD were included. Data were synthesized into aggregated Event Rates (ER) of TZA using random-effects meta-analysis. The clinical impact was defined in terms of obstructive defecation problems, enterocolitis, soiling, incontinence, and the need for additional surgical procedures. The quality of studies was assessed using the Newcastle-Ottawa Scale. KEY RESULTS: This systematic review included 34 studies, representing 2207 patients. After excluding series composed of only patients undergoing redo PT, the prevalence was 9% (ER = 0.09, 95% CI = 0.05-0.14, p < 0.001, I2 = 86%). TZA occurred more often after operation techniques other than Duhamel (X2 = 19.21, p = <0.001). Patients with TZA often had obstructive defecation problems (62%), enterocolitis (38%), soiling (28%), and fecal incontinence (24%) in follow-up periods ranging from 6 months to 13 years. Patients with TZA more often had persistent obstructive symptoms (X2 = 7.26, p = 0.007). CONCLUSIONS AND INFERENCES: TZA is associated with obstructive defecation problems and redo PT and is thus necessary to prevent.

Somatic symptoms, pain, catastrophizing and the association with disability among children with heritable connective tissue disorders.

The aim of the present study was to investigate the nature and prevalence of nonspecific somatic symptoms, pain and catastrophizing in children with Heritable Connective Tissue Disorders (HCTD), and to determine their association with disability. This observational, multicenter study included 127 children, aged 4-18 years, with Marfan syndrome (MFS) (59%), Loeys-Dietz syndrome (LDS) (8%), Ehlers-Danlos syndromes (EDS) (12%) and hypermobile Ehlers-Danlos syndrome (hEDS) (23%). The assessments included the Children's Somatization Inventory or parent proxy (CSI, PCSI), pain visual-analogue scale (VAS), SUPERKIDZ body diagram, Pain Catastrophizing Scale Child or parent proxy (PCS-C, PCS-P) and Childhood Health Assessment Questionnaire (CHAQ-30). Data from children aged ≥8 years were compared to normative data. In children ≥ 8 years (n = 90), pain was present in 59%, with a median of 4 (IQR = 3-9) pain areas. Compared to normative data, the HCTD group reported significantly higher on the CSI (p ≤ 0.001, d = 0.85), VAS pain intensity (p ≤ 0.001, d = 1.22) and CHAQ-30 (p ≤ 0.001, d = 1.16) and lower on the PCS-C (p = 0.017, d = -0.82) and PCS-P (p ≤ 0.001, d = -0.49). The intensity of nonspecific somatic symptoms and pain explained 45% of the variance in disability (r2 = 0.45 F(2,48) = 19.70, p ≤ 0.001). In children ≤ 7 years (n = 37), pain was present in 35% with a median of 5(IQR = 1-13) pain areas. The mean(SD) VAS scores for pain intensity was 1.5(2.9). Functional disability was moderately correlated to the number of pain areas (r = 0.56, p ≤ 0.001), intensity of nonspecific somatic symptoms (r = 0.63, p ≤ 0.001) and pain (r = 0.83, p ≤ 0.001). In conclusion, this study supports the need for comprehensive assessment of nonspecific somatic symptoms, pain, and disability in children with HCTD to allow tailored treatment.

Long-Term Follow-Up of Daily Life Functioning After Pediatric Intensive Care Unit Admission.

OBJECTIVE: To investigate the long-term impact of pediatric intensive care unit (PICU) admission on daily life functioning while exploring the potential mediating role of neurocognitive outcome. STUDY DESIGN: This cross-sectional observational study compared children aged 6-12 years with previous PICU admission (age ≤1 year) for bronchiolitis requiring mechanical ventilation ("patient group," n = 65) to demographically comparable healthy peers ("control group," n = 76). The patient group was selected because bronchiolitis is not expected to affect neurocognitive functioning in itself. Assessed daily life outcome domains were behavioral and emotional functioning, academic performance, and health-related quality of life (QoL). The role of neurocognitive outcomes in the relationship between PICU admission and daily life functioning was assessed by mediation analysis. RESULTS: The patient group did not differ from the control group regarding behavioral and emotional functioning but performed poorer on academic performance and school-related QoL (Ps ≤ .04, d = -0.48 to -0.26). Within the patient group, lower full-scale IQ (FSIQ) was associated with poorer academic performance and school-related QoL (Ps ≤ .02). Poorer verbal memory was associated with poorer spelling performance (P = .002). FSIQ mediated the observed effects of PICU admission on reading comprehension and arithmetic performance. CONCLUSIONS: Children admitted to the PICU are at risk for long-term adverse daily life outcomes in terms of academic performance and school-related QoL. Findings suggest that lower intelligence may contribute to academic difficulties after PICU admission. Findings underline the importance of monitoring daily life and neurocognitive functioning after PICU admission.

Physical activity and physical fitness in children with heritable connective tissue disorders.

Objectives: Health problems in patients with heritable connective tissue disorders (HCTD) are diverse and complex and might lead to lower physical activity (PA) and physical fitness (PF). This study aimed to investigate the PA and PF of children with heritable connective tissue disorders (HCTD). Methods: PA was assessed using an accelerometer-based activity monitor (ActivPAL) and the mobility subscale of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). PF was measured in terms of cardiovascular endurance using the Fitkids Treadmill Test (FTT); maximal hand grip strength, using hand grip dynamometry (HGD) as an indicator of muscle strength; and motor proficiency, using the Bruininks-Oseretsky Test of Motor Proficiency-2 (BOTMP-2). Results: A total of 56 children, with a median age of 11.6 (interquartile range [IQR], 8.8-15.8) years, diagnosed with Marfan syndrome (MFS), n = 37, Loeys-Dietz syndrome (LDS), n = 6, and genetically confirmed Ehlers-Danlos (EDS) syndromes, n = 13 (including classical EDS n = 10, vascular EDS n = 1, dermatosparaxis EDS n = 1, arthrochalasia EDS n = 1), participated. Regarding PA, children with HCTD were active for 4.5 (IQR 3.5-5.2) hours/day, spent 9.2 (IQR 7.6-10.4) hours/day sedentary, slept 11.2 (IQR 9.5-11.5) hours/day, and performed 8,351.7 (IQR 6,456.9-1,0484.6) steps/day. They scored below average (mean (standard deviation [SD]) z-score -1.4 (1.6)) on the PEDI-CAT mobility subscale. Regarding PF, children with HCTD scored well below average on the FFT (mean (SD) z-score -3.3 (3.2)) and below average on the HGD (mean (SD) z-score -1.1 (1.2)) compared to normative data. Contradictory, the BOTMP-2 score was classified as average (mean (SD) z-score.02 (.98)). Moderate positive correlations were found between PA and PF (r(39) = .378, p < .001). Moderately sized negative correlations were found between pain intensity and fatigue and time spent actively (r(35) = .408, p < .001 and r(24) = .395 p < .001, respectively). Conclusion: This study is the first to demonstrate reduced PA and PF in children with HCTD. PF was moderately positively correlated with PA and negatively correlated with pain intensity and fatigue. Reduced cardiovascular endurance, muscle strength, and deconditioning, combined with disorder-specific cardiovascular and musculoskeletal features, are hypothesized to be causal. Identifying the limitations in PA and PF provides a starting point for tailor-made interventions.

The Relation Between Classroom Setting and ADHD Behavior in Children With ADHD Compared to Typically Developing Peers.

OBJECTIVE: More knowledge on the impact of classroom setting on behavior of children with ADHD may help us to better adjust classroom settings to the needs of this group. METHOD: We observed ADHD behaviors of 55 children with ADHD and 34 typically developing peers (6-12 years) during classroom transitions, group lessons, and individual seatwork. RESULTS: Multivariate analyses revealed that levels of motor and verbal hyperactivity increased during classroom transitions compared to group lessons and individual seatwork. Children in the ADHD group were more off-task, across settings. There were no interactions between group and setting. CONCLUSIONS: Children with ADHD were similarly affected by classroom setting compared to typically developing peers, despite being more off-task across settings. Further research into whether the observed increase in hyperactivity during classroom transitions may be problematic or possibly even beneficial for children with ADHD is recommended.

Transition Zone Pull-through in Patients with Hirschsprung Disease: Is Redo Surgery Beneficial for the Long-term Outcomes?

INTRODUCTION: Transition zone pull-through (TZPT) is incomplete removal of the aganglionic bowel/transition zone (TZ) in patients with Hirschsprung disease (HD). Evidence on which treatment generates the best long-term outcomes is lacking. The aim of this study was to compare the long-term occurrence of Hirschsprung associated enterocolitis (HAEC), requirement of interventions, functional outcomes and quality of life between patients with TZPT treated conservatively to patients with TZPT treated with redo surgery to non-TZPT patients. METHODS: We retrospectively studied patients with TZPT operated between 2000 and 2021. TZPT patients were matched to two control patients with complete removal of the aganglionic/hypoganglionic bowel. Functional outcomes and quality of life was assessed using Hirschsprung/Anorectal Malformation Quality of Life questionnaire and items of Groningen Defecation & Continence together with occurrence of Hirschsprung associated enterocolitis (HAEC) and requirement of interventions. Scores between the groups were compared using One-Way ANOVA. The follow-up duration lasted from time at operation until follow-up. RESULTS: Fifteen TZPT-patients (six treated conservatively, nine receiving redo surgery) were matched with 30 control-patients. Median duration of follow-up was 76 months (range 12-260). No significant differences between groups were found in the occurrence of HAEC (p = 0.65), laxatives use (p = 0.33), rectal irrigation use (p = 0.11), botulinum toxin injections (p = 0.06), functional outcomes (p = 0.67) and quality of life (p = 0.63). CONCLUSION: Our findings suggest that there are no differences in the long-term occurrence of HAEC, requirement of interventions, functional outcomes and quality of life between patients with TZPT treated conservatively or with redo surgery and non-TZPT patients. Therefore, we suggest to consider conservative treatment in case of TZPT.

Diagnosing Hirschsprung Disease in Children Younger than 6 Months of Age: Insights in Incidence of Complications of Rectal Suction Biopsy and Other Final Diagnoses.

BACKGROUND: The gold standard for diagnosing Hirschsprung disease (HD) in patients younger than 6 months is pathological examination of rectal suction biopsy (RSB). The aim of this study was to gain insight into the following: (1) complications following RSB, (2) final diagnosis of patients referred for RSB, and (3) factors associated with HD. METHODS: Patients suspected of HD referred for RSB at our center were analyzed retrospectively. Severity of complications of RSB was assessed using Clavien-Dindo (CD) grading. Factors associated with HD were tested using multivariate logistic regression analysis. RESULTS: From 2000 to 2021, 371 patients underwent RSB because of infrequent defecation, at a median age of 44 days. Three patients developed ongoing rectal bleeding (0.8%) graded CD1. Most frequent final diagnoses were: HD (n = 151, 40.7%), functional constipation (n = 113, 31%), idiopathic meconium ileus (n = 11, 3%), and food intolerance (n = 11, 3%). Associated factors for HD were male sex (odds ratio [OR], 3.19; confidence interval [CI], 1.56-6.53), presence of syndrome (OR, 7.18; CI, 1.63-31.69), younger age at time of RSB (OR, 0.98; CI, 0.85-0.98), meconium passage for more than 48 hours (OR, 3.15; CI, 1.51-6.56), distended abdomen (OR, 2.09; CI, 1.07-4.07), bilious vomiting (OR, 6.39; CI, 3.28-12.47), and failure to thrive (OR, 8.46; CI, 2.11-34.02) (model R 2 = 0.566). CONCLUSION: RSB is a safe procedure with few and only minor complications. In the majority of patients referred for RSB under the age of 6 months, HD was found followed by a functional cause for the defecation problems. RSB should be obtained on a low threshold in all patients under the age of 6 months with the suspicion of HD.

Structured Multidisciplinary Follow-Up After Pediatric Intensive Care: A Model for Continuous Data-Driven Health Care Innovation.

OBJECTIVES: Morbidity after PICU admission for critical illness is a growing concern. Sequelae may occur in various domains of functioning and can only appropriately be determined through structured follow-up. Here, we describe the process of designing and implementing a structured multidisciplinary follow-up program for patients and their parents after PICU admission and show the first results illustrating the significance of our program. DESIGN: Prospective observational cohort study. SETTING: Outpatient PICU follow-up clinic. PATIENTS: Patients 0-18 years old admitted to our PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In our structured multidisciplinary follow-up program, follow-up care is provided by a pediatric intensivist and psychologist and in addition, depending on patient's critical illness and received PICU treatment(s), by a pediatric pulmonologist, cardiologist, neurologist, and/or neuropsychologist. All consultations are scheduled consecutively. Collected data are stored in a hospital-wide data warehouse and used for yearly health care evaluation sessions as well as scientific research. Challenges in organizing this follow-up program include technological challenges, providing time-efficient care, participation rate, and completeness of questionnaires. In our experience, a dedicated team is essential to tackle these challenges. Our first results, obtained in 307 of 388 referred patients (79.1%), showed the diversity of problems arising after PICU discharge, including physical, neurocognitive, and psychosocial sequelae. In addition, our data also reflected the risk of psychosocial problems among parents. Within the limited operation time of our follow-up program, the program has evolved based on our experiences and the data collected. CONCLUSIONS: We successfully developed and implemented a structured multidisciplinary follow-up program for patients and their parents after PICU admission. This program may help to timely initiate appropriate interventions, improve the standard of care during and after PICU admission, and facilitate scientific research on outcome and prognosis after PICU admission.

Genomic patterns linked to gray matter alterations underlying working memory deficits in adults and adolescents with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD.