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

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 middle-income 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 low-income 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 low-income, 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

The VSL#3 treatment prevents the CBDL-induced A) up-regulation eNOS and down-regulation of SK_ca and IK_ca, and B) down-regulation of connexins (Cx37, Cx40 and Cx43) in the mesenteric artery.

<p>Upper panels show representative immunofluorescence staining, and lower panels corresponding cumulative data. C) Expression of eNOS and SK_Ca protein levels as assessed by Western blot analysis. Results are shown as mean±SEM of 4 different rats for A and B, and 3 for C. *<i>P</i><0.05 for CBDL vs sham, and ^#<i>P</i><0.05 CBDL+VSL#3 vs CBDL.</p

The VSL#3 treatment prevents the CBDL-induced up-regulation of several components of the local angiotensin system in the aorta.

<p>The expression level of angiotensin II (Ang II), AT1 receptors (AT1R) and angiotensin-converting enzyme (ACE) was determined by immunofluorescence staining. Upper panels show representative immunofluorescence staining; Lower panels corresponding cumulative data. Results are shown as mean±SEM of 4 different rats. *<i>P</i><0.05 CBDL vs sham, and ^#<i>P</i><0.05 CBDL+VSL#3 vs CBDL.</p

The VSL#3 treatment prevents the CBDL-induced oxidative stress in the aorta.

<p>(A) <i>In situ</i> determination of the formation of ROS, peroxynitrite (nitrotyrosine), and eNOS in aortic sections. Top: representative immunofluorescence staining; bottom: corresponding cumulative data for 4 to 5 rats/group. (B) To study the cellular sources of ROS, aortic sections were exposed either to apocynin (NADPH oxidase inhibitor and antioxidant), L-NA (NO synthase inhibitor), sulfaphenazol (Sulfa, cytochrome P450 inhibitor), indomethacin (Indo, cyclooxygenase inhibitor) or the combination KCN, myxothiazol and rotenone (KCN+MY+Rot, inhibitors of the mitochondrial respiration chain) for 30 min before DHE staining. Top of each panel: DHE staining; bottom: corresponding cumulative data for 4 rats. Results are shown as mean±SEM. The lumen is on the right side of each image. A) *<i>P</i><0.05 CBDL vs sham, and ^#<i>P</i><0.05 CBDL+VSL#3 vs CBDL; B) *<i>P</i><0.05 versus control.</p

Ingestion of VSL#3 improves the CBDL-induced blunted EDH but not NO-mediated relaxations in mesenteric artery rings.

<p>Concentration-relaxation curves to acetylcholine in mesenteric artery rings with endothelium in sham, CBDL, sham+VSL#3 and CBDL+VSL#3 rats. A) The NO component of the relaxation was assessed in the presence of indomethacin (10 µM) and apamin plus charybdotoxin (100 nM each), and B) the EDH component in the presence of indomethacin and N^G-nitro-L-arginine (300 µM). C) Relaxations to sodium nitroprusside (an exogenous donor of NO) and D) levcromakalim (an ATP-sensitive K⁺ channel opener) in mesenteric artery rings without endothelium are also shown. Results are shown as mean±SEM of 5-7 different rats; *<i>P</i><0.05 CBDL vs sham, and ^#<i>P</i><0.05 CBDL+VSL#3 vs CBDL.</p

The VSL#3 treatment prevents the CBDL-induced up-regulation of the NAPDH oxidase subunits p22phox and p47phox, and COX-2 but not COX-1 in aortic sections.

<p>A) Representative immunofluorescence staining and corresponding cumulative data. B) Expression levels of target proteins as assessed by Western blot analysis in aortic segments. Results are shown as mean±SEM of 4 different rats. *<i>P</i><0.05 CBDL vs sham, and ^#<i>P</i><0.05 CBDL+VSL# 3 vs CBDL.</p

Local or global commons? Application of framework for analysing SES for soil biodiversity at EU level

Defect in apoptosis has been implicated as a major cause of resistance to chemotherapy observed in B cell chronic lymphocytic leukaemia (B CLL). This study evaluated the pro-apoptotic effect of an anthocyanin-rich dietary bilberry extract (Antho 50) on B CLL cells from 30 patients and on peripheral blood mononuclear cells (PBMCs) from healthy subjects, and determined the underlying mechanism. Antho 50 induced concentration- and time-dependent pro-apoptotic effects in B CLL cells but little or no effect in PBMCs. Among the main phenolic compounds of the bilberry extract, delphinidin-3-O-glucoside and delphinidin-3-O-rutinoside induced a pro-apoptotic effect. Antho 50-induced apoptosis is associated with activation of caspase 3, down-regulation of UHRF1, a rapid dephosphorylation of Akt and Bad, and down-regulation of Bcl-2. Antho 50 significantly induced PEG-catalase-sensitive formation of reactive oxygen species in B CLL cells. PEG-catalase prevented the Antho 50-induced induction of apoptosis and related signaling. The present findings indicate that Antho 50 exhibits strong pro-apoptotic activity through redox-sensitive caspase 3 activation-related mechanism in B CLL cells involving dysregulation of the Bad/Bcl-2 pathway. This activity of Antho 50 involves the glucoside and rutinoside derivatives of delphinidin. They further suggest that Antho 50 has chemotherapeutic potential by targeting selectively B CLL cells