Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) – precursors for dyes and drugs

Anthraquinone (AQ) derivatives play a prominent role in medicine and also in textile industry. Bromaminic acid (1-amino-4-bromoanthraquinone-2-sulfonic acid) is an important precursor for obtaining dyes as well as biologically active compounds through the replacement of the C4-bromo substituent with different (ar)alkylamino residues. Here we report methods for the synthesis of bromaminic acid analogues bearing different substituents at the 2-position of the anthraquinone core. 1-Aminoanthraquinone was converted to its 2-hydroxymethyl-substituted derivative which, under different reaction conditions, yielded the corresponding carbaldehyde, carboxylic acid, and nitrile derivatives. The latter was further reacted to obtain 1-amino-2-tetrazolylanthraquinone. Subsequent bromination using bromine in DMF led to the corresponding bromaminic acid derivatives in excellent isolated yields (>90%) and high purities. Alternatively, 1-amino-4-bromo-2-hydroxymethylanthraquinone could be directly converted to the desired 2-substituted bromaminic acid analogues in high yields (85–100%). We additionally report the preparation of bromaminic acid sodium salt and 1-amino-2,4-dibromoanthraquinone directly from 1-aminoanthraquinone in excellent yields (94–100%) and high purities. The synthesized brominated AQs are valuable precursors for the preparation of AQ drugs and dyes

Eco-friendly synthesized few layered graphene: main physico-chemical nanocharacterizations for optical quenching applications

The importance of green process in the synthesis of nanomaterials becomes universally known. In this study, we report on the efficiency of Aspalathus linearis's plant extract known as Rooibos tea on the synthesis of graphene via a bio-active process. Using several nanocharcterization techniques, our investigations on the main physico-chemical properties confirmed the ability of this plant extract as a reducing and capping agent on performing an effective reducing process leading to a wide and flat FLrGO sheets without folds along their length and of a mean size of 265 nm. Furthermore, this eco-friendly cost-effective process allows the control and modulation of the optical and the electrical properties of the prepared graphene. Moreover, this material was positively tested as silver NPs fluorescence quencher. Hence, Rooibos shows its ability as an effective chelating agent in the production of graphene sheets which serves electronic and optoelectronic related quenching applications

Molecular Recognition of Agonists and Antagonists by the Nucleotide-Activated G Protein-Coupled P2Y₂ Receptor

A homology model of the nucleotide-activated P2Y₂R was created based on the X-ray structures of the P2Y₁ receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP. Significant reduction in agonist potency was observed for all other receptor mutants (Phe111, His184, Ser193, Phe261, Tyr268, Tyr269) predicted to be involved in agonist recognition. An ionic lock between Asp185 and Arg292 that is probably involved in receptor activation interacts with the phosphate groups. The antagonist AR-C118925 and anthraquinones likely bind to the orthosteric site. The updated homology models will be useful for virtual screening and drug design

Development of Potent and Selective Antagonists for the UTP-Activated P2Y₄ Receptor

P2Y₄ is a G_q protein-coupled receptor activated by uridine-5′-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y₄ receptor antagonist has been described so far. Therefore, we developed and optimized P2Y₄ receptor antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y₄ receptor. The most potent compound of the present series, sodium 1-amino-4-[4-(2,4-dimethylphenylthio)­phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-16133, <b>61</b>) exhibited an IC₅₀ value of 233 nM, selectivity versus other P2Y receptor subtypes, and is thought to act as an allosteric antagonist. A receptor homology model was built and docking studies were performed to analyze ligand–receptor interactions. Compound <b>64</b> (PSB-1699, sodium 1-amino-4-[4-(3-pyridin-3-ylmethylthio)­phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate) represents the most selective P2Y₄ receptor antagonist known to date. Compounds <b>61</b> and <b>64</b> are therefore anticipated to become useful tools for studying this scarcely investigated receptor

Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription

Caffeine is the most consumed psychoactive substance worldwide. Strikingly, molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal-omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus, at the epigenomic, proteomic and metabolomic levels. Caffeine lowers metabolic-related processes in the bulk tissue, while it induces neuronal-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through a fine-tuning of metabolic genes while boosting the salience of information processing during learning in neuronal circuits.This work was supported by grants from Hauts-de-France (PARTEN-AIRR, COGNADORA; START-AIRR, INS-SPECT) and Programs d’Investissements d’Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease) and EGID (European Genomic Institute for Diabetes ANR-10LABX-46). Our laboratories are also supported by ANR (GRAND to LB, ADORATAU, ADORASTrAU, METABOTAU to DB and BETAPLASTICITY to JSA), COEN (5008), Fondation pour la Recherche Médicale, France Alzheimer/Fondation de France, FHU VasCog research network (Lille, France), Fondation Vaincre Alzheimer (ADOMEMOTAU), European Foundation for the Study of Diabetes (EFSD to JSA), Fondation Plan Alzheimer as well as Inserm, CNRS, Université Lille, Lille Métropole Communauté Urbaine, DN2M. KC hold a doctoral grant from Lille University. VG-M was supported by Fondation pour la Recherche Médicale (SPF20160936000). CM was supported by Région Hauts753 30 754 de-France. ALB is supported by CNRS, Unistra (Strasbourg, France), ANR-16-CE92-0031 755 756 757 758 759 760 761 762 (EPIFUS), ANR-18-CE16-0008-02 (ADORASTrAU), Alsace Alzheimer 67, France Alzheimer (AAP SM 2017 #1664). IP is supported by Fondation pour la Recherche Médicale (SPF201909009162). CEM is grateful for the support by the Alzheimer Forschung Initiative e.V. (AFI, Düsseldorf, Germany). LC was funded by SIF Italian Society of Pharmacology. RAC was supported by LaCaixa Foundation (LCF/PR/HP17/52190001) and FCT (POCI-01-0145-FEDER-03127). Santa Casa da Misericórdia (MB-7-2018) and CEECIND/01497/2017 to LVL