Impact of postoperative necrotizing enterocolitis after neonatal cardiac surgery on neurodevelopmental outcome at 1 year of age.

Objectives: We analyzed the impact of postoperative necrotizing enterocolitis (NEC) after cardiac surgery in neonatal age on neurodevelopmental (ND) outcome at 1 year of age. Methods: Using data from the Swiss Neurodevelopmental Outcome Registry for Children with Congenital Heart Disease (ORCHID), we analyzed perioperative variables including postoperative NEC (Bell's stage ≥2) and 1-year ND outcome (Bayley III). Results: The included patients (n = 101) had congenital heart disease (CHD), categorized as follows: 77 underwent biventricular repair for CHD with two functional chambers, 22 underwent staged palliation until the Fontan procedure for CHD with single ventricle physiology (n = 22), or 4 underwent single ventricle palliation or biventricular repair for borderline CHD (n = 4). Neonatal cardiopulmonary bypass (CBP) surgery was performed at a median age (IQR) of 8 (6) days. NEC occurred in 16 patients. Intensive care unit (ICU) length of stay (LOS) and the total duration of the hospitalization were longer in children with NEC than those in others (14 with vs. 8 days without NEC, p < 0.05; 49 with vs. 32 days without NEC, p < 0.05). The Bayley III scores of the analyzed patients determined at an age of 11.5 ± 1.5 months showed cognitive (CCS) (102.2 ± 15.0) and language scores (LCS) (93.8 ± 13.1) in the normal range and motor composite scores (MCS) (88.7 ± 15.9) in the low-normal range. After adjusting for socioeconomic status and CHD type, patients with NEC had lower CCS scores [ß = -11.2 (SE 5.6), p = 0.049]. Using a cumulative risk score including NEC, we found a higher risk score to be associated with both lower CCS [ß = -2.8 (SE 1.3), p = 0.030] and lower MCS [ß = -3.20 (SE 1.3), p = 0.016]. Conclusions: Postoperative NEC is associated with longer ICU and hospital LOS and contributes together with other complications to impaired ND outcome at 1 year of age. In the future, national and international patient registries may provide the opportunity to analyze large cohorts and better identify the impact of modifiable perioperative risk factors on ND outcome. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT05996211.

ORCHID (Outcome Registry for CHIldren with severe congenital heart Disease) a Swiss, nationwide, prospective, population-based, neurodevelopmental paediatric patient registry: framework, regulations and implementation.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent birth defect. As survival has significantly improved, attention has turned to neurodevelopmental outcomes of children undergoing heart surgery in early infancy. Since multiple risk factors contribute to neurodevelopmental alterations, a nationwide registry collecting data on medical characteristics, interventions, clinical course and neurodevelopment until school-age is needed to improve the quality of management, identify risk- and protective factors affecting neurodevelopment, and facilitate multicentre trials. METHODS AND ANALYSIS: The Swiss Outcome Registry for CHIldren with severe congenital heart Disease (ORCHID) is a nationwide, prospective, population-based patient registry developed (1) to collect baseline characteristics and clinical data of CHD patients operated with bypass-surgery or hybrid procedures in the first 6 weeks of life in Switzerland, (2) to monitor long-term neurodevelopment, and (3) to relate clinical characteristics and neurodevelopment to identify risk and protective factors in these children. This registry started data collection relating to pregnancy, birth, preoperative course, catheter-based and surgical treatment, postoperative course and reinterventions in 2019. The primary outcome includes standardised neurodevelopmental assessments at 9 to 12 months, 18 to 24 months and 5.5 to 6 years. We expect to include 80 to 100 children per year. Correlation and regression analyses will be used to investigate risk- and protective factors influencing neurodevelopment. ETHICS AND DISSEMINATION OF RESULTS: Swiss ORCHID received support by the Accentus Charitable Foundation, the Anna Mueller Grocholoski Stiftung, the Swiss Society of Paediatric Cardiology, the Verein Kinderherzforschung, and the Corelina - Stiftung für das Kinderherz, and was approved by the cantonal ethics committees. Findings will be presented at national and international scientific meetings, and published in peer-reviewed journals. Results will also be shared with patient organizations, primary health care providers, and public health stakeholders to ensure a widespread dissemination of the results.

Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic.

FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.