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

Impaired hypothalamic mTOR activation in the adult rat offspring born to mothers fed a low-protein diet.

Several epidemiological and experimental studies have clearly established that maternal malnutrition induces a high risk of developing obesity and related metabolic diseases in the offspring. To determine if altered nutrient sensing might underlie this enhanced disease susceptibility, here we examined the effects of perinatal protein restriction on the activation of the nutrient sensor mTOR in response to acute variations in the nutritional status of the organism. Female Wistar rats were fed isocaloric diets containing either 17% protein (control) or 8% protein (PR) throughout pregnancy and lactation. At weaning offspring received standard chow and at 4 months of age the effects of fasting or fasting plus re-feeding on the phosphorylation levels of mTOR and its downstream target S6 ribosomal protein (rpS6) in the hypothalamus were assessed by immuno-fluorescence and western blot. Under ad libitum feeding conditions, PR rats exhibited decreased mTOR and rpS6 phosphorylation in the arcuate (ARC) and ventromedial (VMH) hypothalamic nuclei. Moreover, the phosphorylation of mTOR and rpS6 in these hypothalamic nuclei decreased with fasting in control but not in PR animals. Conversely, PR animals exhibited enhanced number of pmTOR imunostained cells in the paraventricular nucleus (PVN) and fasting decreased the activation of mTOR in the PVN of malnourished but not of control rats. These alterations occurred at a developmental stage at which perinatally-undernourished animals do not show yet obesity or glucose intolerance. Collectively, our observations suggest that altered hypothalamic nutrient sensing in response to an inadequate foetal and neonatal energetic environment is one of the basic mechanisms of the developmental programming of metabolic disorders and might play a causing role in the development of the metabolic syndrome induced by malnutrition during early life

Effect of early protein restriction on the mTOR signaling pathway.

<p>Graphs illustrate the activation of AKT (A), mTOR (B) and S6 ribosomal protein (C) in the hypothalamus in response to variations in nutrient supply in adult rats born to control or protein-restricted dams as determined by western blot analysis. The figures above each histogram correspond to representative western blots of the phosphorylated and non phosphorylated forms of the indicated proteins as well as of β-actin which was used as internal control of protein loading. Animals were sacrificed under ad libitum feeding conditions, after a fasting period of 48 h or after fasting followed by re-feeding for 3 h. ^§P<0.05 compared to <i>ad libitum</i> fed controls animals.</p

Effects of early protein-restriction on body weight characteristics.

<p>Graphs illustrate post-weaning growth pattern (A) and body fat mass at adulthood (B) of offspring born to control or protein-restricted dams. Growth pattern is expressed as the amount of body weight gain in grams between the indicated periods of time. Abdominal fat refers to the summed weight of bilateral fat depots from 3 regions (inguinal, retroperitoneal and epididymal) and the mesenteric fat pad at 4 months of age expressed in percentage of body weight. ***P<0.001 (Student's t-test with n = 18 animals per group).</p

Changes in mTOR phosphorylation within the paraventricular nucleus of the hypothalamus in response to variations in nutrient supply in adult rats born to control or protein-restricted dams.

<p>Top panels correspond to representative images of pmTOR labeling in hypothalamic slices from control (A,B,C) or perinatally undernourished rats (D,E,F) sacrificed under <i>ad libitum</i> feeding conditions, after a fast of 48 h or after fasting followed by 3 h of re-feeding. Bottom graph (G) corresponds to the mean number of immune-positive pmTOR cells in the fed state or after fasting and fasting plus re-feeding. 3 V, third ventricle. ^§p<0.05 as compared to <i>ad libitum</i> fed control animals (Student's t-test). *P<0.05 in relation to <i>ad libitum</i> fed animals from the same group (One way ANOVA followed by Dunnett's test). n = 5 for all groups. Scale bar  = 300 µm for all pictures.</p

Changes in food intake, body weight and serum hormone and metabolite levels in response to variations in nutrient supply in adult rats born to control or protein-restricted dams.

<p>Animals were sacrificed under <i>ad libitum</i> feeding conditions or food-deprived with free access to water for a period of 48 h after which they were either sacrificed or fed for 3 h and sacrificed immediately after. *P<0.05; **P<0.01; ***P<0.001 in comparison to <i>ad libitum</i> fed animals of the same experimental group as determined by One way ANOVA followed by Dunnett's test. ^§§p<0.01 in comparison to <i>ad libitum</i> fed control animals as determined by Student's t-test. A minimum of 5 animals per group was used for the determinations.</p

Effect of early protein restriction on mTOR phosphorylation within hypothalamic POMC-expressing neurons.

<p>Panels correspond to representative images of pmTOR and POMC labeling in the PVN (A, B and C), or the mediobasal hypothalamus (D, E and F), of <i>ad libitum</i> fed control rats. The bottom graphs correspond to the mean number of POMC cells (G) or POMC/pmTOR colabelled cells (H) in the fed state or after fasting and fasting plus re-feeding. 3 V, third ventricle. ^§P<0.05 compared to <i>ad libitum</i> fed control animals (Student's t test). *P<0.05; **P<0.01 in relation to <i>ad libitum</i> fed animals from the same group (One way ANOVA followed by Dunnett's test). n = 3 for all groups. Scale bar  = 300 µm for all pictures.</p

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids