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

Analysis of the advancements in real-life performance of highly automated vehicles' with regard to the road traffic safety

The article presents the analysis of the performance of the vehicles equipped with automated driving systems (ADS) which were tested in real-life road conditions from 2015 to 2017 in the state of California. It aims at the effort to assess the impact on the road safety the continuous technological advancements in driving automation might have, based on of the first large-scale, real-life test deployments. Vehicle manufacturers and other stakeholders testing the highly automated vehicles in California are obliged to issue yearly reports which provide an insight on the test scale as well as the technology maturity. The so-called 'disengagement reports' highlight the range and number of control takeovers between the ADS and driver, which are made either based on driver's decision or information provided by the vehicle itself. The analysis of these reports allowed to investigate the development made in automated driving technology throughout the years of tests, as well as the direct or indirect influence of the external factors (e.g. various weather conditions) on the ADS performance. The results show that there is still a significant gap in reliability and safety between human drivers and highly automated vehicles which has been yet steadily decreasing due to technology advancements made while driving in the specific infrastructure and traffic conditions of California

The impact of the interfaces of the driving automation system on a driver with regard to road traffic safety

The article presents the results of the road safety-targeted research on the influence of driving automation system interfaces, regarding the highway chauffeur scenario. The verification of multisensory test stand operation was planned through the research targeting transfer of control in a driving simulator. Such examination on one hand allowed to verify its efficiency as a whole (as well as its modules), while on the other hand it helped to answer a significant question regarding the efficient and time-minimizing communication form with driver through the HMI. One of the main analyzed, road safety-targeted parameters was time needed for taking over the control of the vehicle. The results of conducted experiment show that providing the RtI information using all interfaces available in the vehicle may not to be the most effective way. The examinees achieved the best results when informed through visual and auditory interfaces (t=3,84 s). The next stage of the research will cover the analysis of the maneuvers made after the control takeover

The impact of the interfaces of the driving automation system on a driver with regard to road traffic safety

The article presents the results of the road safety-targeted research on the influence of driving automation system interfaces, regarding the highway chauffeur scenario. The verification of multisensory test stand operation was planned through the research targeting transfer of control in a driving simulator. Such examination on one hand allowed to verify its efficiency as a whole (as well as its modules), while on the other hand it helped to answer a significant question regarding the efficient and time-minimizing communication form with driver through the HMI. One of the main analyzed, road safety-targeted parameters was time needed for taking over the control of the vehicle. The results of conducted experiment show that providing the RtI information using all interfaces available in the vehicle may not to be the most effective way. The examinees achieved the best results when informed through visual and auditory interfaces (t=3,84 s). The next stage of the research will cover the analysis of the maneuvers made after the control takeover

IKAP Deficiency in an FD Mouse Model and in Oligodendrocyte Precursor Cells Results in Downregulation of Genes Involved in Oligodendrocyte Differentiation and Myelin Formation

<div><p>The splice site mutation in the <i>IKBKAP</i> gene coding for IKAP protein leads to the tissue-specific skipping of exon 20, with concomitant reduction in IKAP protein production. This causes the neurodevelopmental, autosomal-recessive genetic disorder - Familial Dysautonomia (FD). The molecular hallmark of FD is the severe reduction of IKAP protein in the nervous system that is believed to be the main reason for the devastating symptoms of this disease. Our recent studies showed that in the brain of two FD patients, genes linked to oligodendrocyte differentiation and/or myelin formation are significantly downregulated, implicating IKAP in the process of myelination. However, due to the scarcity of FD patient tissues, these results awaited further validation in other models. Recently, two FD mouse models that faithfully recapitulate FD were generated, with two types of mutations resulting in severely low levels of IKAP expression. Here we demonstrate that IKAP deficiency in these FD mouse models affects a similar set of genes as in FD patients' brains. In addition, we identified two new IKAP target genes involved in oligodendrocyte cells differentiation and myelination, further underscoring the essential role of IKAP in this process. We also provide proof that IKAP expression is needed cell-autonomously for the regulation of expression of genes involved in myelin formation since knockdown of IKAP in the Oli-neu oligodendrocyte precursor cell line results in similar deficiencies. Further analyses of these two experimental models will compensate for the lack of human postmortem tissues and will advance our understanding of the role of IKAP in myelination and the disease pathology.</p></div

Reduced expression of IKAP target genes in FD mouse models.

<p>Quantitative real-time PCR (qPCR) analysis of APOD, EDG2, Ermin, GTX, KLK6, MAG, MAL, MBP, PLP1, PP1R14A, TMEM10, Transferrin, and TTYH2 in brain RNA from control (CTRL, n = 8) and FD (n = 7). Analysis was repeated 2 to 3 times for each gene. Expression levels were normalized over internal control (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094612#s4" target="_blank">Materials and Methods</a>) and are expressed as percentage of CTRL. Data are represented as Mean ±SD. **P<0.01, ***P<0.001, ****P<0.0001.</p

IKAP is expressed in oligodendrocytes in vivo.

<p>Sagittal mouse brain cryosection at the level of dentate gyrus immunostained for IKAP (green) and the oligodendrocyte marker GALC (red), counterstained with DAPI (blue). (<b>A</b>) Arrow shows an oligodendrocyte, which stains for GALC and IKAP simultaneously (yellow). (<b>B</b>) IKAP expression (green channel), (<b>C</b>) GALC expression (red channel), and (<b>D</b>) DAPI staining (blue channel).</p

IKAP protein levels are highly reduced in FD mutant mice and after lentiviral ShIKAP administration in Oli-neu cells.

<p>(<b>A</b>) Western blot analyses of total protein lysates from brain cortex of control (N1, N2, N3) and age-matched FD (FD1, FD2, FD3) littermates. Upper panel shows detection of IKAP with the polyclonal anti-IKAP antibody (AnaSpec), and lower panel shows anti-β-actin for loading control. Note that IKAP protein expression is highly reduced in FD1, FD2, and FD3, relative to controls. Quantitative analysis of the Western blot was performed using Image J software. IKAP expression levels over β-actin levels are presented. (<b>B</b>) Western blot analyses of total protein lysates from control scrambled (ShSCR) and <i>IKAP</i> knockdown (ShIKAP) Oli-neu cells. Upper panel shows detection of IKAP with the polyclonal anti-IKAP antibody (AnaSpec), and lower panel shows anti-β-actin for loading control. Note that IKAP is significantly expressed in ShSCR Oli-neu cells. Quantitative analysis of the Western blot was performed using Image J software. IKAP expression levels over β-actin levels and are presented.</p

IKAP knockdown in Oli-neu cells results in reduced expression of myelin-related genes.

<p>Quantitative real-time PCR (qPCR) analysis of APOD, EDG2, Ermin, GTX, KLK6, MAG, MAL, MBP, PLP1, PP1R14A, SST, TMEM10, Transferrin, and TTYH2 in RNA from control (ShSCR) and Ikbkap knockdown (ShIKAP) Oli-neu cells. Analysis was repeated 2 to 3 times for each gene. Expression levels were normalized over internal control (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094612#s4" target="_blank">Materials and Methods</a>) and are expressed as percentage of CTRL. Data are represented as Mean ±SD. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.</p