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

Physico-chemical characterization and biocompatibility of hydroxyapatite derived from fish waste

The aim of this study was to synthesize hydroxyapatite (HAP) powder from fish waste. The powder was characterized through X-ray diffraction, Fourier transform infrared spectroscopy, ion exchange chromatography, scanning electron microscopy and plasma emission spectrometry. The cyto- and genotoxicity was carried out to demonstrate biocompatibility in vivo by means of rat subcutaneous tissue test. The results showed that the visible crystalline nature of typical apatite crystal structure when they were calcined at 800 degrees C. Infrared spectroscopy analysis showed similar composition to HAP standard with the presence of carbonate ion demonstrated by wave number values of 871 cm(-1) and 1420 cm(-1) for calcinations at 800 degrees C. The scanning electronmicrographies depicted the crystal morphology and porous nature with average pore size of similar to 10 mu m. Plasma emission spectrometry and ion exchange chromatography confirmed the presence of Ca and P in the samples. The mean of calcium content was 36.8Mg was 0.8, Na was 0.7 and K was 0.5. Rat subcutaneous tissue test revealed that HAP presented biocompatibility. Furthermore, the lack of cyto- and genotoxicity in blood, liver, kidney and lung were noticed after 30 days of HAP implantation. Taken together, our results demonstrated that HAP from fish waste exhibits a great potential for using as biomaterial since is represents a simple, effective, low-cost process and satisfactory degree of biocompatibility.CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)Fed Univ Sao Paulo UNIFESP, Dept Biosci, Av Ana Costa 95, BR-11060001 Santos, SP, BrazilIPEN, Nucl & Energy Res Inst, Sao Paulo, SP, BrazilFed Univ Sao Paulo UNIFESP, Dept Biosci, Av Ana Costa 95, BR-11060001 Santos, SP, BrazilCNPq: 442149/2014-0Web of Scienc

LFA-1 Mediates Cytotoxicity and Tissue Migration of Specific CD8+ T Cells after Heterologous Prime-Boost Vaccination against Trypanosoma cruzi Infection

Integrins mediate the lymphocyte migration into an infected tissue, and these cells are essential for controlling the multiplication of many intracellular parasites such as Trypanosoma cruzi, the causative agent of Chagas disease. Here, we explore LFA-1 and VLA-4 roles in the migration of specific CD8(+) T cells generated by heterologous prime-boost immunization during experimental infection with T. cruzi. To this end, vaccinated mice were treated with monoclonal anti-LFA-1 and/or anti-VLA-4 to block these molecules. After anti-LFA-1, but not anti-VLA-4 treatment, all vaccinated mice displayed increased blood and tissue parasitemia, and quickly succumbed to infection. In addition, there was an accumulation of specific CD8(+) T cells in the spleen and lymph nodes and a decrease in the number of those cells, especially in the heart, suggesting that LFA-1 is important for the output of specific CD8(+) T cells from secondary lymphoid organs into infected organs such as the heart. The treatment did not alter CD8(+) T cell effector functions such as the production of pro-inflammatory cytokines and granzyme B, and maintained the proliferative capacity after treatment. However, the specific CD8(+) T cell direct cytotoxicity was impaired after LFA-1 blockade. Also, these cells expressed higher levels of Fas/CD95 on the surface, suggesting that they are susceptible to programmed cell death by the extrinsic pathway. We conclude that LFA-1 plays an important role in the migration of specific CD8(+) T cells and in the direct cytotoxicity of these cells.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)FAPESPCNPqCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)UFRJUS National Institutes of Health (NIAID)Ctr Mol & Cellular Therapy, Mol Immunol Lab, Sao Paulo, BrazilFed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Biosci, Sao Paulo, BrazilFiocruz MS, Rene Rachou Res Ctr, Belo Horizonte, MG, BrazilUniv Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA USAUniv Fed Santa Catarina, Dept Microbiol Immunol & Parasitol, Florianopolis, SC, BrazilFiocruz MS, Oswaldo Cruz Inst, Biol Interact Lab, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Rio De Janeiro, BrazilFed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Biosci, Sao Paulo, BrazilFAPESP: 2012/22514-3FAPESP: 2015/08814-2FAPESP: 2017/11499-7FAPESP: 2014/19422-5Web of Scienc

LFA-1 Mediates Cytotoxicity and Tissue Migration of Specific CD8+ T Cells after Heterologous Prime-Boost Vaccination against Trypanosoma cruzi Infection

Integrins mediate the lymphocyte migration into an infected tissue, and these cells are essential for controlling the multiplication of many intracellular parasites such as Trypanosoma cruzi, the causative agent of Chagas disease. Here, we explore LFA-1 and VLA-4 roles in the migration of specific CD8+ T cells generated by heterologous prime-boost immunization during experimental infection with T. cruzi. To this end, vaccinated mice were treated with monoclonal anti-LFA-1 and/or anti-VLA-4 to block these molecules. After anti-LFA-1, but not anti-VLA-4 treatment, all vaccinated mice displayed increased blood and tissue parasitemia, and quickly succumbed to infection. In addition, there was an accumulation of specific CD8+ T cells in the spleen and lymph nodes and a decrease in the number of those cells, especially in the heart, suggesting that LFA-1 is important for the output of specific CD8+ T cells from secondary lymphoid organs into infected organs such as the heart. The treatment did not alter CD8+ T cell effector functions such as the production of pro-inflammatory cytokines and granzyme B, and maintained the proliferative capacity after treatment. However, the specific CD8+ T cell direct cytotoxicity was impaired after LFA-1 blockade. Also, these cells expressed higher levels of Fas/CD95 on the surface, suggesting that they are susceptible to programmed cell death by the extrinsic pathway. We conclude that LFA-1 plays an important role in the migration of specific CD8+ T cells and in the direct cytotoxicity of these cells