Publications

Abstract

The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new bactericidal strategies to combat Gram-negative infections that would address these specific issues. In this study, we report and characterize one such approach, an antibody-drug conjugate (ADC) that combines (i) targeting the surface of a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of an antimicrobial peptide. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa. To target this organism, we designed an ADC by fusing an antimicrobial peptide to the C-terminal end of the VH and/or VL-chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide. This ADC demonstrates appropriately minimal levels of toxicity against mammalian cells, rapidly kills P. aeruginosa strains, and protects mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study might result in a broadly useful strategy for targeting specific pathogenic microorganisms without further augmenting antibiotic resistance.

Abstract

Background: The skin is the largest organ in the human body. It provides multiple barrier functions, tactile or defensive, and acts as a mediator allowing for the attachment of vital monitoring devices with medical adhesives. Adhesives consist of several layers with varying compositions and properties. We aimed to provide recommendations for their use in the care of hospitalized neonates on the basis of a systematic literature review.

Methods: We searched PubMed for English or French articles published before May 29, 2020, using the keywords « adhesive, » « tape, », « skin, » and « neonat*. » Recommendations were developed after review by a multidisciplinary group including 15 professionals and parent representatives.

Results: We identified 295 studies, and from 30 eligible studies we developed six recommendations according to four perspectives: assessment of the skin condition to improve the methods of application of the different adhesives and their removal; use of adhesives as a platform; and discouraging the regular use of semi-permeable dressings to compensate for the immaturity of the skin barrier.

Conclusion: Skin lesions are common for hospitalized neonates. Use of adhesives may increase the occurrence of such lesions. Adhesives should be subject to good clinical practice guidelines. Health professionals caring for newborns should know the tools for screening and preventing skin lesions.

Abstract

Objective: To develop and validate a clinical prediction model for outcomes at 5 years of age for children born extremely preterm and receiving active perinatal management.

Design: The EPIPAGE-2 national prospective cohort.

Setting: France, 2011.

Population: Live-born neonates between 24⁺⁰ and 26⁺⁶ weeks of gestation who received active perinatal management (i.e. birth in a tertiary-level hospital, with antenatal steroids and resuscitation at birth).

Methods: A prediction model using logistic modelling, including gestational age, small-for gestational-age (SGA) status and sex, was developed. Model performance was assessed through calibration and discrimination, with bootstrap internal validation.

Main outcome measures: Survival without moderate or severe neurodevelopmental disability (NDD) at 5 years.

Results: Among the 557 neonates included, 401 (72%) survived to 5 years, of which 59% survived without NDD (95% CI 54% to 63%). Predicted rates of survival without NDD ranged from 45% (95% CI 33% to 57%), to 56% (95% CI 49% to 64%) to 64% (95% CI 57% to 70%) for neonates born at 24, 25 and 26 weeks of gestation, respectively. Predicted rates of survival without NDD were 47% (95% CI 18% to 76%) and 62% (95% CI 49% to 76%) for SGA and non-SGA children, respectively. The model showed good calibration (calibration slope 0.85, 95% CI 0.54 to 1.16; calibration-in-the-large -0.0123, 95% CI -0.25 to 0.23) and modest discrimination (C-index 0.59, 95% CI 0.53 to 0.65).

Conclusions: A simple prediction model using three factors easily known antenatally may help doctors and families in their decision-making for extremely preterm neonates receiving active perinatal management.

No abstract available

Abstract

Objective

To determine the prevalence, short-term prognosis and pharmacologic management of pulmonary hypertension (PH) among very preterm infants born before 32 weeks gestation (WG).

Study design

In the EPIPAGE-2 French national prospective population-based cohort of preterm infants born in 2011, those presenting with PH were identified and prevalence was estimated using multiple imputation. The primary outcome was survival without severe morbidity at discharge and was compared between infants with or without PH after adjusting for confounders, using generalized estimating equations models. Subgroup analysis was performed according to gestational age (GA) groups.

Results

Among 3383 eligible infants, 3222 were analyzed. The prevalence of PH was 6.0 % (95 % CI, 5.2–6.9), 14.5 % in infants born at 22–27⁺⁶ WG vs 2.7 % in infants born at 28–31⁺⁶ WG (P < .001). The primary outcome (survival without severe morbidity at discharge) occurred in 30.2 % of infants with PH vs 80.2 % of infants without PH (P < .001). Adjusted incidence rate ratios for survival without severe morbidity among infants with PH were 0.42 (0.32–0.57) and 0.52 (0.39–0.69) in infants born at 22–27⁺⁶ weeks gestation and those born at 28–31⁺⁶ weeks, respectively. Among infants with PH, 92.2 % (95 % CI, 87.7–95.2) received sedation and/or analgesia, 63.5 % (95 % CI, 56.6–69.9) received inhaled NO and 57.6 % (95 % CI, 50.9–64.0) received hemodynamic treatments.

Conclusion

In this population-based cohort of very preterm infants, the prevalence of PH was 6 %. PH was associated with a significant decrease of survival without severe morbidity in this population.

Abstract

The vaginal microbiota refers to the microorganisms that reside in the vagina. These microorganisms contribute significantly to a woman’s reproductive and general health. A healthy vaginal microbiota is typically a low-diversity environment with a predominance of lactic acid-producing Lactobacillus species. Factors such as antibiotic use, sexual activity, and hormonal changes can disrupt the balance of the vaginal microbiota, leading to conditions such as bacterial vaginosis. The composition of the vaginal microbiota changes and takes on added importance during pregnancy, serving as a barrier against infection for both mother and fetus. Despite the importance of the microorganisms that colonize the vagina, details of how changes in composition and diversity can impact pregnancy outcomes is poorly understood. This is especially true for woman with a high prevalence of Gardnerella vaginalis. Here we report on a diverse cohort of 749 women, enrolled in the InSPIRe cohort, during their final trimester of pregnancy. We show that Lactobacilli, including L. crispatus are important in maintaining low diversity, and that depletion in this critical community is linked with preterm delivery. We further demonstrate that it is overall diversity of the vaginal microbiota, not specific species, which provides the best indicator of risk.

No abstract available

Abstract

The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother-child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.

Abstract

Aim: To describe the circumstances, causes and timing of death in extremely preterm infants.

Methods: We included from the EPIPAGE-2 study infants born at 24-26 weeks in 2011 admitted to neonatal intensive care units (NICU). Vital status and circumstances of death were used to define three groups of infants: alive at discharge, death with or without withholding or withdrawing life-sustaining treatment (WWLST). The main cause of death was classified as respiratory disease, necrotizing enterocolitis, infection, central nervous system (CNS) injury, other or unknown.

Results: Among 768 infants admitted to NICU, 224 died among which 89 died without WWLST and 135 with WWLST. The main causes of death were respiratory disease (38%), CNS injury (30%) and infection (12%). Among the infants who died with WWLST, CNS injury was the main cause of death (47%), whereas respiratory disease (56%) and infection (20%) were the main causes in case of death without WWLST. Half (51%) of all deaths occurred within the first 7 days of life, and 35% occurred within 8 and 28 days.

Conclusion: The death of extremely preterm infants in NICU is a complex phenomenon in which the circumstances and causes of death are intertwined.

Abstract

Sperm fertilization ability mainly relies on proper sperm progression through the female genital tract and capacitation, which involves phosphorylation signaling pathways triggered by calcium and bicarbonate. We performed exome sequencing of an infertile asthenozoospermic patient and identified truncating variants in MAP7D3, encoding a microtubule-associated protein, and IQCH, encoding a protein of unknown function with enzymatic and signaling features. We demonstrate the deleterious impact of both variants on sperm transcripts and proteins from the patient. We show that, in vitro, patient spermatozoa could not induce the phosphorylation cascades associated with capacitation. We also provide evidence for IQCH association with calmodulin, a well-established calcium-binding protein that regulates the calmodulin kinase. Notably, we describe IQCH spatial distribution around the sperm axoneme, supporting its function within flagella. Overall, our work highlights the cumulative pathological impact of gene mutations and identifies IQCH as a key protein required for sperm motility and capacitation.