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

Buffalo cheese whey proteins, identification of a 24 kda protein and characterization of their hydrolysates: in vitro gastrointestinal digestion

Milk whey proteins are well known for their high biological value and versatile functional properties, characteristics that allow its wide use in the food and pharmaceutical industries. In this work, a 24 kDa protein from buffalo cheese whey was analyzed by mass spectrometry and presented homology with Bos taurus beta-lactoglobulin. In addition, the proteins present in buffalo cheese whey were hydrolyzed with pepsin and with different combinations of trypsin, chymotrypsin and carboxypeptidase-A. When the TNBS method was used the obtained hydrolysates presented DH of 55 and 62% for H1 and H2, respectively. Otherwise for the OPA method the DH was 27 and 43% for H1 and H2, respectively. The total antioxidant activities of the H1 and H2 samples with and without previous enzymatic hydrolysis, determined by DPPH using diphenyl-p-picrylhydrazyl radical, was 4.9 and 12 mM of Trolox equivalents (TE) for H2 and H2Dint, respectively. The increased concentrations for H1 and H2 samples were approximately 99% and 75%, respectively. The in vitro gastrointestinal digestion efficiency for the samples that were first hydrolyzed was higher compared with samples not submitted to previous hydrolysis. After in vitro gastrointestinal digestion, several amino acids were released in higher concentrations, and most of which were essential amino acids. These results suggest that buffalo cheese whey is a better source of bioavailable amino acids than bovine cheese whey.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Amino acid sequence for β-Lg from <i>Bos taurus</i> (gi/229460).

<p>The tryptic peptides obtained for 24 kDa protein from buffalo cheese way were identical to the red sequence. It was obtained 37% of coverage.</p

Protein, lactose and fat concentrations of the <i>in natura</i> and treated buffalo milk whey.

<p>*reduction of lactose</p><p>**dialyzed, defatted and centrifuged</p><p>Protein, lactose and fat concentrations of the <i>in natura</i> and treated buffalo milk whey.</p

Relative concentration (nmol. L^-1) of the amino acids from buffalo milk whey before and after dialyzability.

<p>1 Hydrolysis with pepsin, trypsin, chymotrypsin and carboxypeptidase-A</p><p>2 Total of released amino acids by dialyzability (Dext + Dint) NH = non-hydrolyzed; H1 = low degree of hydrolysis; H2 = high degree of hydrolysis; GD = gastric digest; Dext = external intestinal digest, samples collected inside of the membrane; Dint = internal intestinal digest, samples collected outside of the membrane</p><p>3 Essential amino acids</p><p>4 Non-essential amino acids</p><p>Relative concentration (nmol. L^-1) of the amino acids from buffalo milk whey before and after dialyzability.</p

SDS-PAGE patterns for the H1 and H2 hydrolysates.

<p>In the both figures the Lane 1: molecular mass standards; Lane 2: treated bovine milk whey; Lane 3: treated buffalo milk whey. The lanes 4–12 are showing hydrolysates produced using the M1 method (Fig 5a) with incubation between 0–180 min, whereas the lanes 4–16 are showing hydrolysates produced using the M2 method (Fig 5b) with incubation between 0–1440 min.</p

Electrophoretic profile of the buffalo cheese whey.

<p>a) Ten percent PAGE silver stained protein profile of treated bovine (1) and buffalo (2) whey. b) Twelve percent SDS-PAGE of the bovine and buffalo milk whey proteins. (1) Molar mass standards; (2) bovine milk whey; (3) buffalo milk whey. Ig: immunoglobulin; BSA: bovine serum albumin; α-La: alpha-lactalbumin; β-Lg: beta-lactoglobulin.</p

Determination of the hydrolysis degree for buffalo cheese whey hydrolysates.

<p>The values of DH were obtained by TNBS and OPA methods for hydrolysis using the M1 and M2 methods.</p

The HPLC chromatographic of the buffalo cheese whey hydrolysates.

<p>a) non-hydrolyzed (NH), b) with a medium degree of hydrolysis (H1), and c) with a high degree of hydrolysis (H2). Reverse phase chromatography using column Kromasil C18 (250 x 4.6 mm) Φ = 5 μm, 300 Ǻ porosity with a 5–95% linear gradient (solvent A: water with 0.045% TFA and solvent B: acetonitrile containing 0.036% TFA, 30 min), a flow rate of 1.0 mL min^-1 and with detection at 220 nm.</p