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

Investigating the functions of low-density lipoprotein receptor-related protein 1 (LRP1) in neural stem/progenitor cells and developing mouse brain

Neurale Stammzellen (NSZ) sind, mit der Fähigkeit zur Selbsterneuerung und Differenzierung in Neurone und Gliazellen, multipotent. Die Untersuchung von Regulatoren der Eigenschaften von NSZ, könnte zur Steuerung ihrer Bestimmung beitragen. Das Low-density Lipoprotein Receptor-related Protein 1 (LRP1) ist in NSZ des sich entwickelnden zentralen Nervensystems (ZNS) angereichert, seine Funktion aber unklar. Das Ziel meines Projektes war die Untersuchung der Rolle von LRP1 in NSZ des ZNS. Durch konditionelle Deletion von LRP1 konnten LRP1-Knockout (ko) und -Wildtyp (WT)-Zellen verglichen werden. LRP1-ko-Zellen zeigten weniger Proliferation, kürzeres Überleben sowie ein verändertes Differenzierungsprofil. In vivo führt LRP-ko im sich entwickelnden Vorderhirn zu epileptischen Anfällen. Eine Hochregulierung von NMDAR auf der Neuronen-Oberfläche und ein Ungleichgewicht der Glia-Zell-Komposition könnten dabei in den ko-Tieren zum Ausbruch der Epilepsie beitragen.Neural stem cells (NSCs) are multipotent cells with a capacity to self-renew and differentiate into neurons and glia. Investigating the modulators of NCSs' properties may help to control their fate. Low-density lipoprotein receptor-related protein 1 (LRP1) is enriched in the NSCs of the developing central nervous system (CNS), however the functions of LRP1 in the development are still unclear. Therefore studying the role of LRP1 in the NSCs and developing CNS became the aim of my project. Upon conditional deletion of LRP1, I compared stem cell properties of LRP1 knockout (ko) and wild type cells. LRP1 ko had a negative effect on proliferation and survival of the NCSs. Moreover, the ko cells demonstrated a shifted differentiation profile. In vivo ko of LRP in the developing forebrain caused epileptic seizures. An upregulation of the neurotransmitter receptor NMDAR on the surface of the neurons and an imbalance in glial cell composition in the ko animals may contribute to seizure onset