Developmental outcome of children with Robin sequence treated with the current Paris protocol.

AIM: We aimed to investigate the developmental outcome of children with Robin sequence (RS) for whom continuous positive airway pressure was the main strategy to release upper airway obstruction. METHODS: We included children with isolated RS or RS associated with Stickler syndrome who were aged 15 months to 6 years. We used the French version of the Child Development Inventory and calculated the developmental quotient (DQ) for eight different domains and the global DQ (DQ-global). We searched for determinants of risk of delay. RESULTS: Of the 87 children, for 71%, the developmental evolution was within the norm (DQ-global ≥86 or ≥-1 SD), 29% were at high risk of delay (DQ-global <86 or <-1 SD), and only 3% were at very high risk of delay (DQ-global <70 or <-2 SD). The DQs for expressive language and language comprehension were lower in our study population than the general population, but an improvement was noticed with the children's growth. CONCLUSION: Risk of a developmental delay was not greater for children with the most severe respiratory phenotype than the others. Children whose mothers had low education levels were more at risk than the others.

Early Mortality in Infants Born with Neonatally Operated Congenital Heart Defects and Low or Very-Low Birthweight: A Systematic Review and Meta-Analysis.

Mortality outcomes of children with isolated neonatally operated congenital heart defects (CHDs) born with a low (LBW), moderately low (MLBW) or very-low birthweight (VLBW) remain ambiguous. We searched Medline and Embase (inception until October 2021) and included studies that evaluated early mortality. The risk of bias was assessed using the Critical Appraisal Skills Program cohort checklist. Meta-analysis involved random-effects models. We explored variability in mortality across birthweight subgroups, CHD types, and study designs. From 2035 reports, we included 23 studies in qualitative synthesis, and the meta-analysis included 11 studies (1658 CHD cases), divided into 30 subcohorts. The risk of bias was low in 4/11 studies included in the meta-analysis. Summary mortality before discharge or within one month after surgery was 37% (95%CI 27-47). Early mortality varied by birthweight (VLBW 56%, MLBW 15%, LBW 16%; p = 0.003) and CHD types (hypoplastic left heart syndrome (HLHS) 50%, total anomalous pulmonary venous return (TAPVR) 47%, transposition of the great arteries (TGA) 34%, coarctation of the aorta (CoA) 16%; p = 0.13). Mortality was higher in population-based studies (49% vs. 10%; p = 0.006). One-third of infants born with neonatally operated isolated CHDs and LBW, MLBW, or VLBW died within 30 days after surgery. Mortality varied across infant and study characteristics. These results may help clinicians assess neonatal prognosis. PROSPERO registration CRD42020170289.

Recent historic increase of infant mortality in France: A time-series analysis, 2001 to 2019.

BACKGROUND: The infant mortality rate (IMR) serves as a key indicator of population health. METHODS: We used data from the French National Institute of Statistics and Economic Studies on births and deaths during the first year of life from 2001 to 2019 to calculate IMR aggregated by month. We ran joinpoint regressions to identify inflection points and assess the linear trend of each segment. Exploratory analyses were performed for overall IMR, as well as by age at death subgroups (early neonatal [D0-D6], late neonatal [D7-27], and post-neonatal [D28-364]), and by sex. We performed sensitivity analyses by excluding deaths at D0 and using other time-series modeling strategies. RESULTS: Over the 19-year study period, 53,077 infant deaths occurred, for an average IMR of 3·63/1000 (4·00 in male, 3·25 in female); 24·4% of these deaths occurred during the first day of life and 47·8% during the early neonatal period. Joinpoint analysis identified two inflection points in 2005 and 2012. The IMR decreased sharply from 2001 to 2005 (slope: -0·0167 deaths/1000 live births/month; 95%CI: -0·0219 to -0·0116) and then decreased slowly between 2005 and 2012 (slope: -0·0041; 95%CI: -0·0065 to -0·0016). From 2012 onwards, a significant increase in IMR was observed (slope: 0·0033; 95%CI: 0·0011 to 0·0056). Subgroup analyses indicated that these trends were driven notably by an increase in the early neonatal period. Sensitivity analyses provided consistent results. INTERPRETATION: The recent historic increase in IMR since 2012 in France should prompt urgent in-depth investigation to understand the causes and prepare corrective actions. FUNDING: No financial relationships with any organizations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Variations in Guidelines for Diagnosis of Child Physical Abuse in High-Income Countries: A Systematic Review.

Importance: The highly variable practices observed regarding the early detection and diagnostic workup of suspected child physical abuse contribute to suboptimal care and could be partially related to discrepancies in clinical guidelines. Objective: To systematically evaluate the completeness, clarity, and consistency of guidelines for child physical abuse in high-income countries. Evidence Review: For this systematic review, national or regional guidelines that were disseminated from 2010 to 2020 related to the early detection and diagnostic workup of child physical abuse in infants aged 2 years or younger by academic societies or health agencies in high-income countries were retrieved. The definitions of sentinel injuries and the recommended diagnostic workup (imaging and laboratory tests) for child physical abuse were compared. Data were analyzed from July 2020 to February 2021. Findings: Within the 20 included guidelines issued in 15 countries, 168 of 408 expected statements (41%) were missing and 10 statements (4%) were unclear. Among 16 guidelines characterizing sentinel injuries, all of them included skin injuries, such as bruises, hematoma, or burns, but only 8 guidelines (50%) included intraoral injuries and fractures. All 20 guidelines agreed on the indication for radiological skeletal survey, head computed tomography, and head magnetic resonance imaging but differed for those of bone scintigraphy, follow-up skeletal survey, spinal magnetic resonance imaging, cranial ultrasonography, chest computed tomography, and abdominal ultrasonography and computed tomography. Additionally, 16 guidelines agreed on exploring primary hemostasis and coagulation but not on the tests to perform, and 8 guidelines (50%) mentioned the need to investigate bone metabolism. Conclusions and Relevance: These findings suggest that guidelines for the diagnosis of child physical abuse in infants were often clear but lacked completeness and were discrepant on major issues. These results may help identify priorities for well-designed original diagnostic accuracy studies, systematic reviews, or an international consensus process to produce clear and standardized guidelines to optimize practices and infant outcomes.

Functional rescue of an ABCB11 mutant by ivacaftor: A new targeted pharmacotherapy approach in bile salt export pump deficiency.

BACKGROUND & AIM: The canalicular bile salt export pump (BSEP/ABCB11) of hepatocytes is the main adenosine triphosphate (ATP)-binding cassette (ABC) transporter responsible for bile acid secretion. Mutations in ABCB11 cause several cholestatic diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) often lethal in absence of liver transplantation. We investigated in vitro the effect and potential rescue of a BSEP mutation by ivacaftor, a clinically approved cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) potentiator. METHODS: The p.T463I mutation, identified in a PFIC2 patient and located in a highly conserved ABC transporter motif, was studied by 3D structure modelling. The mutation was reproduced in a plasmid encoding a rat Bsep-green fluorescent protein. After transfection, mutant expression was studied in Can 10 cells. Taurocholate transport activity and ivacaftor effect were studied in Madin-Darby canine kidney (MDCK) clones co-expressing the rat sodium-taurocholate co-transporting polypeptide (Ntcp/Slc10A1). RESULTS: As the wild-type protein, BsepT463I was normally targeted to the canalicular membrane of Can 10 cells. As predicted by 3D structure modelling, taurocholate transport activity was dramatically low in MDCK clones expressing BsepT463I . Ivacaftor treatment increased by 1.7-fold taurocholate transport activity of BsepT463I (P < .0001), reaching 95% of Bsepwt activity. These data suggest that the p.T463I mutation impairs ATP-binding, resulting in Bsep dysfunction that can be rescued by ivacaftor. CONCLUSION: These results provide experimental evidence of ivacaftor therapeutic potential for selected patients with PFIC2 caused by ABCB11 missense mutations affecting BSEP function. This could represent a significant step forward for the care of patients with BSEP deficiency.