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

Toxoplasma gondii : identification by inverse docking on the molecular targets of active compounds derived from natural products

Les écorces d’arbres, co-produit de la sylviculture, constituent une source abondante et durable de substances naturelles. Toxoplasma gondii est le parasite responsable de la toxoplasmose, présentant une menace chez les fœtus, les nouveau-nés et les personnes immunodéprimées. Les thérapies actuelles, limitées et mal tolérées, font désormais face à des phénomènes de chimiorésistance. Ce travail de thèse a pour but d’explorer l’espace chimique associé aux écorces d’essences champardennaises, et les cibles protéiques essentielles à T. gondii. Une première évaluation in silico par docking inverse (AMIDEv2.0) a été réalisée afin d’identifier la cible biologique de triterpènes dérivés de la bétulone, isolés de l’Aulne glutineux ayant montré une activité anti-toxoplasmose in vitro. La CDPK3 a été identifiée comme étant la cible la plus probable parmi 87 protéines de T. gondii. Puis, une protéothèque de 25 structures protéiques 3D essentielles à la survie du parasite, 19 ayant été modélisées par homologie, a été constituée. Les composés de la Chimiothèque Nationale Essentielle ont été évalués ensuite sur cette protéothèque en utilisant AMIDEv2.0. Deux protéines ont été identifiées comme de potentielles cibles, dont ATG3, une structure reconstruite à partir d'homologues avec un pourcentage d'identité inférieur à 50%. Deuxièmement, les écorces du Mélèze d'Europe, dont l’extrait n-heptane avait démontré une activité significative (58 % d’inhibition de croissance parasitaire à 100 µg/ml), ont été soumises à un profilage chimique impliquant un fractionnement par Chromatographie de Partage Centrifuge et de déréplication combinant les données issues de la résonance magnétique nucléaire et de la spectrométrie de masse. Les outils VersaDB et CATHEDRAL ont été développés pour faciliter la création de bases de données modulables et l’évaluation du niveau de confiance des annotations. 52 molécules ont ainsi pu être annotées et associées à un score de confiance. En parallèle, des tests in vitro ont démontré que 2 des 12 fractions CPC, majoritairement composées de terpènes, inhibaient à plus de 40% la survie du parasite à 25 µg/ml. Les composés annotés chez L. decidua ont été soumis à AMIDEv2.0. Le croisement des résultats in vitro et in silico, reposant sur le calcul d'un score d'activité biologique, a mis en évidence l'acide 7-oxo-déhydroabiétique et l'acide daniellique, fortement corrélés à l'activité inhibitrice in vitro des écorces. La CDPK1 et la protéine SET containing Protein ont été identifiées comme leurs cibles protéiques probables, fournissant ainsi de premières informations sur leurs mécanismes d'action. Ces deux hits font actuellement l’objet d’une évaluation in vitro afin d’attester l’efficacité de la démarche développée au cours de ces travaux de thèse.Tree barks, by-product of forestry industry, constitute an abundant and sustainable source of natural compounds. Toxoplasma gondii is the parasite responsible for toxoplasmosis, posing a threat to fetuses, newborns, and immunocompromised individuals. The current therapeutics, limited and poorly tolerated, are now confronted to chemoresistant phenomena. This doctoral project aims to explore the chemical space associated with tree barks from the Champagne-Ardenne region, as relevant protein targets to fight T. gondii. An initial in silico evaluation using reverse docking (AMIDEv2.0) was carried out to identify biological target for triterpenes derived from betulone, isolated from the European alder, which had exhibited in vitro anti-toxoplasmosis activity. Among 87 proteins of T. gondii, CDPK3 was identified as the most probable target. Subsequently, a bank of 25 essential 3D protein structures for parasite survival, including 19 homology-modeled structures, was compiled. Thereafter, compounds from the Essential National Chemical Library were screened against this protein bank, using AMIDEv2.0. Two proteins were identified as potential targets; one of them was ATG3, a protein structure modeled from homologs with less than 50% identity. Subsequently, the barks of European Larch, whose n-heptane extract had shown significant activity (58% inhibition of parasitic growth at 100 µg/ml), were subjected to a chemical profiling. First, through a fractionation process using Centrifugal Partition Chromatography, and then a dereplication approach combining data from nuclear magnetic resonance and mass spectrometry. Tools like VersaDB and CATHEDRAL were developed to facilitate the creation of custom-databases and assess the confidence level of annotations. 52 molecules were annotated and associated with a confidence score. Simultaneously, in vitro tests demonstrated that 2 out of the 12 CPC fractions, primarily composed of terpenic derivatives, inhibited the parasite's survival by more than 40% at 25 µg/ml. Ultimately, the annotated compounds from L. decidua were subjected to AMIDEv2.0. The overlap between in vitro and in silico results highlighted 7-oxo-dehydroabietic acid and daniellic acid, strongly correlated with the in vitro inhibitory activity of the barks. CDPK1 and the SET-containing Protein are likely protein targets for these two ligands, thereby providing initial insights into their mechanism of action. These two hits are currently undergoing in vitro evaluation to verify the efficiency of developed approach during this doctoral project

3D environment on human mesenchymal stem cells differentiation for bone tissue engineering

International audienc

matreex: Simulation IPM for forest dynamic depending on climatic variables from Kunstler et al (2020)

The goal of this package is to run integrated projection models of tree species in single or multi-specific density dependence context. The simulations return the size distribution dynamics along time. These models can be completed with different harvest and disturbance models and be runned untile equilibrium.L'objectif de ce package R est d'exécuter des modèles de projection intégrés d'espèces d'arbres dans un contexte de compétition spécifique ou multi-spécifique. Les simulations retournent la dynamique de la distribution des tailles au fil du temps. Ces modèles peuvent être complétés par différents modèles de coupe et de perturbation et être exécutés jusqu'à l'équilibre

Five-year risk of major ischemic and hemorrhagic events after intracerebral hemorrhage

International audienceBackground and Purpose- We aimed to determine incidences and predictors of major vascular events in intracerebral hemorrhage (ICH) survivors. Methods- We did a prospective observational cohort study in patients with spontaneous ICH from the Prognosis of Intracerebral Hemorrhage cohort in Lille, France. We studied incidences and predictors of long-term vascular events (cerebral and extracerebral, ischemic and hemorrhagic) in patients alive at 30 days with a prespecified subgroup analysis according to ICH location. We performed multivariable analyses (competing risk analyses, with death during follow-up as a competing event). Results- From the 560 patients with spontaneous ICH enrolled between November 2004 and March 2009, we included 310 patients (median age, 70 years). Eighty-two patients presented at least 1 major vascular event leading to an incidence rate of 20.0% (95% CI, 15.7-24.7) at 5 years after ICH. In the overall cohort, ischemic events were more frequent than hemorrhagic events. However, the incidence strikingly differed according to ICH location: deep ICH was associated with future ischemic events (subhazard ratio, 1.85; 95% CI, 1.01-3.40), whereas lobar ICH with hemorrhagic events (subhazard ratio, 2.38; 95% CI, 1.17-4.86). In deep ICH, the incidence of ischemic events at 5 years was 6× higher than the incidence of hemorrhagic events. Conclusions- ICH survivors are at high risk of both cerebral and extracerebral vascular events. The ischemic or hemorrhagic risk profile varies according to the index ICH location with a stronger ischemic risk in deep ICH. Secondary prevention, tailored on ICH location, should target not only cerebral recurrences but also extracerebral vascular events

Pathways to antigen expression after oral delivery of an Adenovirus-based vaccine

National audienc

Pathways to antigen expression after oral delivery of an Adenovirus-based vaccine

National audienc

Which factors influence the resort to surrogate consent in stroke trials, and what are the patient outcomes in this context?

International audienceBACKGROUND:The provision of informed consent is a prerequisite for inclusion of a patient in a clinical research project. In some countries, the legislation on clinical research authorizes a third person to provide informed consent if the patient is unable to do so directly (i.e. surrogate consent). This is the case during acute stroke, when the symptoms may prevent the patient from providing informed consent and thus require a third party to be approached. Identification of factors associated with the medical team's decision to resort to surrogate consent may (i) help the care team during the inclusion process and (ii) enable the patient's family circle to be better informed (and thus feel less guilty) about providing surrogate consent.METHODS:Patients included in the BIOSTROKE cohort (initially dedicated to the analysis of factors influencing stroke severity) were divided into two groups: those having provided informed consent directly and those for whom a third party (such as a family member) had provided surrogate consent. We compared the groups in terms of the initial clinical characteristics (age, gender, type of stroke, severity on the National Institutes of Health Stroke Scale (NIHSS), pre-stroke cognitive status according to the Informant Questionnaire on Cognitive Decline in the Elderly, and the stroke's aetiology) and the functional and cognitive impairments (according to the NIHSS, the modified Rankin score (mRS) and the Mini Mental State Examination) on post-stroke days 8 and 90.RESULTS:Three hundred and ninety five patients were included (mean ± SD age: 67 ± 15 years; 53% males). Surrogate consent had been obtained in 228 cases, and 167 patients had provided consent themselves. The patients included with surrogate consent were likely to be older and more aphasic, with a pre-existing cognitive disorder and more severe stroke (relative to the patients having provided consent). In terms of recovery, the patients included with surrogate consent had a worse functional prognosis (day 90 mRS ≥3: 57.6%, compared with 16.8% in patients having provided consent themselves; p < 0.0001) and a worse cognitive prognosis (day 90 MMS < 24: 15.4% and 4.8%, respectively; p < 0.002). The mortality rate was significantly higher in the surrogate consent group.CONCLUSIONS:We found that in addition to age, aphasia and stroke severity, pre-stroke cognitive status is a factor that should prompt the care team to consider requesting surrogate consent for participation in a clinical study. Given that the unfavourable outcome in patients with surrogate consent is often due to their initial clinical state (rather than inclusion in a trial per se), the issue of the family's feelings of guilt (and how to avoid these feelings) should be further addressed

Adverse Cardiovascular Events in Non-Traumatic Intracranial Hemorrhage and Ischemic Stroke Survivors

Background: We aimed to evaluate different measures of adverse cardiovascular events between non-traumatic intracranial hemorrhage (ICrH) and ischemic stroke (IS) survivors with and without atrial fibrillation (AF). Methods: Using a national hospitalization database we compared incidences and risks of all-cause in-hospital death, cardiovascular death, non-cardiovascular death, MACE-HF (in-hospital cardiovascular death, myocardial infarction, IS or new-onset heart failure [HF]) between ICrH and IS survivors with and without AF. Propensity-score matching was also performed. Results: We identified 40,523 survivors of IS and 12,028 survivors of an ICrH without AF, and 20,449 IS survivors and 3574 ICrH survivors with AF. In unadjusted, adjusted and matched analyses, ICrH patients without AF had a higher risk of all-cause in-hospital death (Hazard Ratio (HR; for matched analyses) 1.80; 95% confidence interval (CI) 1.74–1.86), cardiovascular death (HR; 2.79; CI 2.64–2.94), MACE-HF (HR 1.97; CI 1.89–2.06) and new cerebrovascular events (HR 1.75; CI 1.57–1.96) but with lower risk of myocardial infarction (HR 0.81; CI 0.70–0.94), major bleeding (HR 0.92; CI 0.87–0.98) and new onset HF (HR 0.85; CI 0.79–0.91) compared to IS survivors without AF. Similar results were found for ICrH and IS survivors with AF except for myocardial infarction (HR 1.05; CI 0.79–1.34) and new onset HF (HR 0.94; CI 0.84–1.06) that were similar between the two groups. Conclusions: Adverse cardiovascular events are more frequent in ICrH survivors compared to IS survivors. New onset HF is a relatively frequent event after ICrH, especially in those patients with comorbid atrial fibrillation