Publications

Abstract

Background: Cerebral malaria (CM) is a neuropathology which remains one of the deadliest forms of malaria among African children. The kinetics of the pathophysiological mechanisms leading to neuroinflammation and the death or survival of patients during CM are still poorly understood. The increasing production of cytokines, chemokines and other actors of the inflammatory and oxidative response by various local actors in response to neuroinflammation plays a major role during CM, participating in both the amplification of the neuroinflammation phenomenon and its resolution. In this study, we aimed to identify risk factors for CM death among specific variables of inflammatory and oxidative responses to improve our understanding of CM pathogenesis.

Methods: Children presenting with CM (n = 70) due to P. falciparum infection were included in southern Benin and divided according to the clinical outcome into 50 children who survived and 20 who died. Clinical examination was complemented by fundoscopic examination and extensive blood biochemical analysis associated with molecular diagnosis by multiplex PCR targeting 14 pathogens in the patients’ cerebrospinal fluid to rule out coinfections. Luminex technology and enzyme immunoassay kits were used to measure 17 plasma and 7 urinary biomarker levels, respectively. Data were analysed by univariate analysis using the nonparametric Mann‒Whitney U test and Pearson’s Chi2 test. Adjusted and multivariate analyses were conducted separately for plasma and urinary biomarkers to identify CM mortality risk factors.

Results: Univariate analysis revealed higher plasma levels of tumour necrosis factor (TNF), interleukin-1beta (IL-1β), IL-10, IL-8, C-X-C motif chemokine ligand 9 (CXCL9), granzyme B, and angiopoietin-2 and lower urinary levels of prostanglandine E2 metabolite (PGEM) in children who died compared to those who survived CM (Mann-Whitney U-test, P-values between 0.03 and < 0.0001). The multivariate logistic analysis highlighted elevated plasma levels of IL-8 as the main risk factor for death during CM (adjusted odd ratio = 14.2, P-value = 0.002). Values obtained during follow-up at D3 and D30 revealed immune factors associated with disease resolution, including plasma CXCL5, C-C motif chemokine ligand 17 (CCL17), CCL22, and urinary 15-F2t-isoprostane.

Conclusions: The main risk factor of death during CM was thus elevated plasma levels of IL-8 at inclusion. Follow-up of patients until D30 revealed marker profiles of disease aggravation and resolution for markers implicated in neutrophil activation, endothelium activation and damage, inflammatory and oxidative response. These results provide important insight into our understanding of CM pathogenesis and clinical outcome and may have important therapeutic implications.

Abstract

Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks’ of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th-10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4-8 mmol/L in the absence of hypo or hyperglycemic episodes with 2-3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side.

Abstract

Background: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis.

Methods: Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization.

Results: We selected for further study the conserved surface polysaccharide Poly-β-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen.

Interpretation: Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections.

Abstract

Background: Motor impairment is common after extremely preterm (EPT, <28 weeks’ gestational age (GA)) birth, with cerebral palsy (CP) affecting about 10% of children and non-CP movement difficulties (MD) up to 50%. This study investigated the sociodemographic, perinatal and neonatal risk factors for CP and non-CP MD.

Methods: Data come from a European population-based cohort of children born EPT in 2011-2012 in 11 countries. We used multinomial logistic regression to assess risk factors for CP and non-CP MD (Movement Assessment Battery for Children – 2nd edition ≤5th percentile) compared to no MD (>15th percentile) among 5-year-old children.

Results: Compared to children without MD (n = 366), young maternal age, male sex and bronchopulmonary dysplasia were similarly associated with CP (n = 100) and non-CP MD (n = 224) with relative risk ratios (RRR) ranging from 2.3 to 3.6. CP was strongly related to severe brain lesions (RRR >10), other neonatal morbidities, congenital anomalies and low Apgar score (RRR: 2.4-3.3), while non-CP MD was associated with primiparity, maternal education, small for GA (RRR: 1.6-2.6) and severe brain lesions, but at a much lower order of magnitude.

Conclusion: CP and non-CP MD have different risk factor profiles, with fewer clinical but more sociodemographic risk factors for non-CP MD.

Impact: Young maternal age, male sex and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties. Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors. These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention.

Abstract

In order to inform patients undergoing ART regarding their chances for motherhood, it seems useful to describe “freeze all” outcomes according to the different potential indications. The goal of this study was to examine the impact of a “freeze-all approach” on the cumulative live birth rate (cLBR) according to the indication. It is a cohort study including women who had undergone ovarian stimulation (OS) using an antagonist protocol with GnRH agonist triggering between 09.2016 and 09.2018 followed by a freeze-all cycle of blastocyst embryos. The ART outcomes were compared between the two main indications of the freeze-all strategy which were in our cohort: risk of ovarian hyperstimulation syndrome (OHSS) and endometriosis. The ART outcomes were also described for the others indications (inadequate endometrium and/or premature progesterone elevation at trigger day, two or more previous ART failures, and autoimmune disease and/or a high risk of thromboembolic disease (AI and/or TE risk)). In total, 658 women were included. The cLBR in the total population was 37.7% (248/658). The cLBR was significantly higher in the “OHSS risk” group (133/281, 47.3%) than in the “endometriosis” group (69/190, 36.3%) (p = 0.017). No significant differences were noted regarding perinatal outcomes, except a significantly higher risk of placenta praevia (PP) observed in the “endometriosis” group (10.1%) (p = 0.002). The “freeze-all approach” yielded good results in terms of the cLBR and especially in case of OHSS risk. These data should be taken into account when informing patients about the ART strategy and their chances of motherhood.

Abstract

Introduction: Embryo transfer(ET) is one of the main procedures to become pregnant by assisted reproductive technology(ART). Simulation training is a way to improve the skills of clinicians. The objective of this study was to evaluate the interest of trainees in learning embryo transfer using simulators.

Material and methods: An observational study was conducted at the University hospital-based research center. Trainees, comprising midwives and resident or graduated gynecologists, who attended the medical training for infertility and ART in June 2019, were included. They trained on two ET simulators (Simulator A and B) and complete an anonymously online questionnaire. A sub-group analysis focusing on graduated gynecologists not performing ET in current practice, was performed.

Results: Thirty-two trainees were included. Trainees felt that ET simulators should be used in medical education to promote learning how to perform the ET procedure (n=26, 81.3% for Simulator A and n=21, 65.5% for Simulator B; p=0.31). The use of both simulators improved the level of self-confidence (81.3% and 75.0% respectively; p=0.55). Significant differences in the global and in the subgroup analysis (n=24) in favor of Simulator A were observed regarding learning the precision of the ET procedure (p<0.01), the pathway to introduce the catheter into the uterine cavity (p<0.05), and the guidance for proper placement of the catheter into the uterine cavity (p=0.03). In the subgroup analysis of graduated gynecologists not performing ET in current practice, Simulator A was found more realistic for the visualization of the introduction of the catheter into the uterine cavity (p=0.01) and more useful to learn about difficult cases (p=0.03).

Conclusion: Students expressed a high level of interest in ET simulators to improve their skills. Although the simulators displayed some differences regarding learning the precision of the ET procedure, both improved the level of self-confidence. This new learning method needs to be further developed in order to offer to trainees the most realistic simulators.

Trial registration: This study was approved for publication by the Ethics Review Committee of the Cochin University Hospital (CLEP) (n° AAA-2020-08016) retrospectively registered.

Abstract

Objective: To investigate the management and survival of very preterm singletons born because of fetal growth restriction (FGR) with or without maternal hypertensive disorders in France.

Study design: From a population-based cohort of very preterm births between 22 and 31 weeks in France in 2011, the study population included all non-anomalous singleton pregnancies delivered because of detected FGR with or without maternal hypertensive disorders. Antenatal detection of FGR was defined as an estimated fetal weight <10th percentile with or without fetal Doppler abnormalities or growth arrest. All fetuses were alive at the time of detection of FGR. Indicators of active perinatal management (antenatal steroids, pre-labor cesarean and birth in level 3 maternity unit) and fetal/neonatal outcomes (terminations of pregnancy (TOP), stillbirths, neonatal deaths and survival to discharge) were compared by gestational age between FGR associated with maternal hypertensive disorders and isolated FGR.

Results: Overall, 398 pregnancies delivered before 32 weeks for FGR associated with hypertensive disorders and 234 for isolated FGR. Active perinatal care was rare before 26 weeks in both groups and about one in five cases associated with maternal hypertensive disorders received steroids and was born by prelabor cesarean compared to none for isolated FGR. Before 25 weeks of gestation age, more pregnancies resulted in TOP when FGR was associated with hypertensive disorders compared to isolated FGR (respectively, 76.2 % vs 28.0 % at 22-23 weeks, P = 0.002 and 57.9 % vs 21.1 % at 24 weeks, P = 0.028) whereas stillbirths were more common among isolated FGR (respectively, 23.8 % vs 72.0 % at 22-23 weeks, P = 0.002 and 36.8 % vs 73.7 % at 24 weeks, P = 0.030). Survival to discharge was higher at any gestational age when the cause of birth was FGR associated with hypertensive disorders compared to isolated FGR.

Conclusion: The management and pregnancy outcomes differed when FGR was associated with maternal hypertensive disorders or isolated. The proportion of TOP was higher when FGR was associated with hypertensive disorders and the proportion of stillbirths was higher in isolated FGR.

Abstract

Objective: To assess the association between gestational age at delivery and postpartum severe acute maternal morbidity (SAMM) in twin pregnancies.

Methods: Secondary analysis of the JUMODA cohort, a national, prospective, population-based study of twin pregnancies in France. We excluded women with delivery before 32 weeks, with a fetal death or medical termination, with antepartum SAMM, or with antepartum conditions responsible for postpartum SAMM. The primary outcome was a composite of postpartum SAMM. We assessed the association between gestational age at delivery and SAMM by using multivariable multilevel modified Poisson regression modeling.

Results: Among the 7,713 women included, 410 (5.3%) developed postpartum SAMM. Compared with the reference category of 37 weeks, the risk of postpartum SAMM was significantly lower for all categories of earlier gestational age at delivery (from an adjusted RR of 0.34, 95% CI 0.17, 0.68 at 32 weeks to an adjusted RR of 0.71, 95% CI 0.54, 0.94 at 36 weeks), and did not differ for later gestational ages.

Conclusion: In twin pregnancies, compared with delivery at 37 weeks, delivery at earlier gestational ages is associated with a lower risk of postpartum SAMM. Continuing pregnancy beyond 37 weeks is not associated with an increased risk of postpartum SAMM.

Abstract

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Abstract

Since the beginning of the Coronavirus disease (COVID)-19 pandemic in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for more than 600 million infections and 6.5 million deaths worldwide. Given the persistence of SARS-CoV-2 and its ability to develop new variants, the implementation of an effective and long-term herd immunity appears to be crucial to overcome the pandemic. While a vast field of research has focused on the role of humoral immunity against SARS-CoV-2, a growing body of evidence suggest that antibodies alone only confer a partial protection against infection of reinfection which could be of high importance regarding the strategic development goals (SDG) of the United Nations (UN) and in particular UN SDG3 that aims towards the realization of good health and well being on a global scale in the context of the COVID-19 pandemic.In this review, we highlight the role of humoral immunity in the host defense against SARS-CoV-2, with a focus on highly neutralizing antibodies. We summarize the results of the main clinical trials leading to an overall disappointing efficacy of convalescent plasma therapy, variable results of monoclonal neutralizing antibodies in patients with COVID-19 but outstanding results for the mRNA based vaccines against SARS-CoV-2. Finally, we advocate that beyond antibody responses, the development of a robust cellular immunity against SARS-CoV-2 after infection or vaccination is of utmost importance for promoting immune memory and limiting disease severity, especially in case of (re)-infection by variant viruses.