Clinic for Special Children

Skin diseases can greatly impair quality of life (QoL) of pediatric patients and their families. The Infants and Toddlers Dermatology Quality of Life questionnaire (InToDermQoL) is the first skin-generic instrument assessing QoL in children ≤4years, as reported by their caregiver. This study aimed to psychometrically validate the German version of the InToDermQoL. The psychometric properties of the InToDermQoL were examined in a sample of 148 children with various skin diseases (age groups [n]: <1 [44]; 1-2 [68]; 3-4 [36]). Exploratory factor analysis suggested a unidimensional structure of the version for children <1year, and a two- and three-factor structure for the two older age groups, respectively. Internal consistency was excellent (Cronbach's alpha, 0.904-0.922). Two-week test-retest reliability was good, except in children aged 1-2 years (intraclass correlation coefficient [ICC], 0.430). The InToDermQoL demonstrated good convergent validity with other QoL questionnaires. The German InToDermQoL is a valid and reliable QoL measure in children ≤4years with any skin disease. Application of the tool in research and clinical practice will contribute to a better understanding of the impact of pediatric dermatoses, and optimize care and support for affected families.

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in GPR156 (c.1599G>T, p.Glu533Asp) associated with a two-fold increase in the relative risk of MDD. GPR156 is an orphan G protein-coupled receptor localized in the medial habenula, a region implicated in mood regulation. Insertion of a human sequence containing c.1599G>T into the murine Gpr156 locus induced medial habenula hyperactivity and abnormal stress-related behaviors. This work reveals a human variant that is associated with depression, implicates GPR156 as a target for mood regulation, and introduces informative murine models for investigating the pathophysiology and treatment of affective disorders.

Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA-/- HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha-/- and Bckdhb-/- mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.

IntroductionAdverse perinatal outcomes (APO) pose a significant global challenge, particularly in low- and middle-income countries (LMICs). This study aims to analyse two cohorts of high-risk pregnant women for APO to comprehend risk factors and improve prediction accuracy.MethodsWe considered an LMIC and a high-income country (HIC) population to derive XGBoost classifiers to predict low birth weight (LBW) from a comprehensive set of maternal and fetal characteristics including socio-demographic, past and current pregnancy information, fetal biometry and fetoplacental Doppler measurements. Data were sourced from the FeDoC (Fetal Doppler Collaborative) study (Pakistan, LMIC) and theIMPACT (Improving Mothers for a Better PrenAtal Care Trial) study (Spain, HIC), and included 520 and 746 pregnancies assessed from 28 weeks gestation, respectively. The models were trained on varying subsets of the mentioned characteristics to evaluate their contribution in predicting LBW cases. For external validation, and to highlight potential differential risk factors for LBW, we investigated the generalisation of these models across cohorts. Models’ performance was evaluated through the area under the curve (AUC), and their interpretability was assessed using SHapley Additive exPlanations.ResultsIn FeDoC, Doppler variables demonstrated the highest value at predicting LBW compared with biometry and maternal clinical data (AUCDoppler, 0.67; AUCClinical, 0.65; AUCBiometry, 0.63), and its combination with maternal clinical data yielded the best prediction (AUCClinical+Doppler, 0.71). In IMPACT, fetal biometry emerged as the most predictive set (AUCBiometry, 0.75; AUCDoppler, 0.70; AUCClinical, 0.69) and its combination with Doppler and maternal clinical data achieved the highest accuracy (AUCClinical+Biometry+Doppler, 0.81). External validation consistently indicated that biometry combined with Doppler data yielded the best prediction.ConclusionsOur findings provide new insights into the predictive role of different clinical and ultrasound descriptors in two populations at high risk for APO, highlighting that different approaches are required for different populations. However, Doppler data improves prediction capabilities in both settings, underscoring the value of standardising ultrasound data acquisition, as practiced in HIC, to enhance LBW prediction in LMIC. This alignment contributes to bridging the health equity gap.

Introduction: Childhood Opportunity Index (COI) measures access to quality education, safe housing, and healthcare based on zip codes. These scores can influence patient behaviors, such as no-shows (NS), which can affect resource utilization and health outcomes. Objective: To quantify the correlation between COI and NS through odds ratio (OR) in a pediatric cardiology clinic. Methods: Patient data was collected from a single, independent pediatric cardiology practice for all visits between 2019 to 2021. COI was categorized into 3 subdomains; education, health and environment, social and economic according to zipcode from Diversitydatakids. The COI was split into low (&lt;40), moderate (40-60U), and high (&gt;60U). Additional variables included age, insurance type, lead time (time from scheduling to appointment date), and telehealth status. Multiple logistic mixed-effect models, both unadjusted (single predictor) and adjusted (multiple predictors), were used to obtain OR for NS. Results: There were 11,474 total encounters. 92% were completed appointments and 8% were NS. Unadjusted model showed statistical significance (p&lt;.05) with increased odds of NS for low COI education, low COI social and economic, and low COI, compared to high COI as the reference category (Table 1). Adjusted model 2 showed similar significant results for the low COI overall category, while for adjusted models 1 and 3, none of the COI categories were statistically significant. In all 4 models, OR for all age categories, all lead times, and public and mixed insurance types were significant. Conclusion: The unadjusted and adjusted model 2 showed that patients with lower COIs were more likely to NS. Public insurance and longer lead times were indicators of NS while higher ages were indicators for completed appointments. Therefore, efforts need to be made to identify vulnerable patients; younger patients, and those with lower COIs and public insurance; and address barriers such as arranging transport and sending reminders that can help decrease NS. Interestingly, the NS rate was lower than the national average. Future research is needed to assess the impact of NS on patient outcomes.