Publications

Abstract

Intestinal immunity defends against enteric pathogens, mediates symbiotic relationships with the resident microbiota, and provides tolerance to food antigens, safeguarding critical nutrient absorption and barrier functions of this mucosal tissue. Despite the abundance of tissue resident activated T cells, their contributions to these various roles remain poorly understood. Here, we identify a dominant population of IL-10 producing, T-bet-expressing Tr1 T cells, residing in the small intestinal lamina propria at homeostasis. Remarkably, these intestinal Tr1 cells emerge at the time of weaning and accumulate independently of the microbiota displaying similar abundance, function, and TCR repertoire under germ-free conditions. Instead, the small intestinal T-bet⁺ Tr1 program is driven and shaped by dietary antigens, and accumulates in a cDC1-IL-27-dependent manner. Upon activation, these cells robustly express IL-10 and multiple inhibitory receptors, establishing a distinct suppressive profile. Altogether, this work uncovers a previously unappreciated dominant player in homeostatic small intestinal immunity with the potential to play critical suppressive roles in this tissue, raising important implications for the understanding of immune regulation in the intestine.

Abstract

Background: To assess whether administering hydrocortisone in the perinatal period is associated with subsequent adverse cardiovascular outcomes.

Methods: The children/adolescents enrolled in the PREMILOC trial underwent resting blood pressure (BP) measurement, tonometry evaluation (pulse wave velocity (PWV), aortic systolic BP), continuous BP and ECG measurements (supine and standing), and ambulatory BP monitoring. Heart rate variability (HRV) indices, baroreflex sensitivity (BRS), and orthostatic systolic BP (SBP) response were calculated.

Results: Fifty-two subjects (median [25th; 75th percentile] birth weight: 892 g [750; 982]; gestational age: 26⁺³ [25⁺¹; 27⁺⁴]; age at assessment: 11.7 years [10.5; 12.7]; z-score of body mass index: 0.23 [-0.65; 1.27]; 27 girls) who received hydrocortisone (n = 28) or placebo (n = 24) were enrolled. The PWV was not different (hydrocortisone: 4.84 m/s [4.40; 5.48] vs. placebo: 5.00 m/s [4.48; 5.34], p = 0.969), and similar results were observed for HRV and BP measurements. Overweight/obese children (n = 17) vs. other children (n = 35) were characterized by higher office SBP, lower supine descending BRS, and higher orthostatic SBP response.

Conclusion: Early hydrocortisone administration after extremely preterm birth in a randomized trial is not associated with detrimental cardiovascular indices in children/adolescents, while overweight/obesity is already associated with cardiovascular morbidity. The study has been registered, ClinicalTrials.gov ID NCT05451264: https://clinicaltrials.gov/study/NCT05451264?cond=NCT05451264&rank=1 .

Impact: A meta-analysis on the effects of early postnatal administration of corticosteroids concluded that the hypertensive risk was increased in infants, but that long-term studies should be carried out. We show that early hydrocortisone administration after extremely preterm birth in a randomized trial is not associated with detrimental cardiovascular indices in children/adolescents, at least in one center of the trial Thus, our study suggests that early markers of the risk of hypertension are not altered by hydrocortisone.

Abstract

Introduction: Children born preterm often have anatomical and functional visual abnormalities, even in the absence of retinopathy of prematurity. This includes suboptimal visual acuity (VA), defined as binocular VA between 5-6.3/10 and 8/10. We examine relationships between suboptimal VA and neurodevelopment in children born preterm.

Methods: Secondary analysis of the French EPIPAGE-2 cohort with children born between 24+0 weeks and 31+6 weeks of gestation, eligible for follow-up at 5.5 years. Children were classified into three VA groups: 5-6.3/10, 8/10 and 10/10 as reference group. Neurodevelopment was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition, the Movement Assessment Battery for Children-II (MABC-2) and the Strengths and Difficulties Questionnaire (SDQ). Comparisons between groups were adjusted for neonatal and socioeconomic characteristics using generalised estimating equations models.

Results: Among 1787 included children, 62% had suboptimal VA. Compared with the 10/10 VA group, the mean full-scale IQ decreased by -3.09 (95 % CI -4.75 to -1.42) and -4.97 (95 % CI -6.47 to -3.46) points, the mean MABC-2 total score by -0.66 (95 % CI -0.71 to -0.61) and -1.06 (95 % CI -1.09 to -1.00), and the mean total SDQ scores increased by 0.40 (95 % CI -0.16 to 0.94) and 0.60 (95 % CI 0.10 to 1.1) in groups with VA groups at 8/10 and 5-6.3/10, respectively.

Discussion: In this French population-based cohort of children born preterm, suboptimal VA was frequent and associated with increased risk of neurodevelopmental difficulties. A comprehensive neurodevelopmental and neurovisual assessment is warranted in children born preterm with suboptimal VA.

Abstract

Cesarean delivery is a common route of delivery before term, but the benefits or harms for preterm infants are still unknown. This review aimed to gather information on the current epidemiology of preterm cesarean delivery using data from international collaborations and on neonatal outcomes concerning the mode of delivery. Of note, 4 obstetrical scenarios were reviewed: preterm births with cephalic or noncephalic fetal presentations, preterm preeclampsia, and preterm birth of multiple pregnancies. In addition, cesarean delivery for preterm birth and its association with later child health was briefly discussed. In Europe, the highest cesarean delivery rates were reported in very preterm births (66%) and moderately preterm births (58%), with marked between-country variations. Among very preterm infants, international cesarean delivery rates averaged 70% at 28 to 31 weeks of gestation, with declining and more variable rates at lower gestational ages, especially at 22 and 23 weeks of gestation. In moderate preterm births (32-33 weeks of gestation) and late preterm births (34-36 weeks of gestation), country-specific cesarean delivery rates mirrored practice in the full-term population. In low-risk, singletons in cephalic position, primary cesarean delivery before term has been associated with a higher risk of neonatal respiratory morbidity than vaginal delivery, particularly among moderate-late preterm infants. However, preterm cesarean delivery for breech presentation (singleton and multiple pregnancies with the first fetus in noncephalic presentation) has been associated with lower neonatal mortality than vaginal delivery, particularly among very extremely preterm infants. The literature provided no clear and consistent support for the neonatal benefits of cesarean delivery vs a trial of induction of labor in preterm preeclampsia. The same was true for twin pregnancies, except for monoamniotic twin pregnancies that were recommended for primary cesarean delivery in moderately preterm gestations. There are associations between preterm cesarean delivery and adverse childhood health outcomes, but causality has not been established. With the exception of moderate and late preterm births, in which unnecessary, policy-dictated cesarean delivery could be reduced, there are usually strong medical indications for cesarean delivery in very or extremely preterm gestations. In such situations, the immediate benefits for the infant of increased chances of survival without severe neonatal morbidity should outweigh any long-term health issues. In conclusion, there is insufficient evidence to support routine delivery of preterm infants by cesarean delivery except for breech presentation, maternal or fetal emergencies, and monoamniotic twins.

Abstract

Background: Lower gestational age (GA) is linked to higher mortality and morbidity. Long-term health and developmental difficulties of individuals born moderate (MPT, 32-33 GA) and late (LPT, 34-36 GA) preterm, and early term (ET, 37-38 GA) are less explored than those of their very preterm peers.

Objectives: To test how being born MPT, LPT, or ET affects health and development at age 10, compared to full-term (FT, 39-40 GA) births.

Methods: Data from two ongoing French nationwide birth cohorts, initiated in 2011, were collected at 10 years via telephone interview (n = 8372) and home visit (n = 6418). Weighting procedures accounted for study design, non-inclusion, and participation. Outcome-wide regressions (modified Poisson, linear), adjusted for socioeconomic situation and pregnancy complications, were used to calculate adjusted relative risks (aRR) and beta-coefficients (β).

Results: No increased risk of asthma/atopy was observed for our MPT, LPT, and ET populations, except for allergic rhinitis in MPT. Strabismus was more prevalent among MPT, LPT, and ET (2.3%-3.0%) than FT (1.3%), corresponding to aRR of 1.99 (95% CI 0.91, 4.39), 1.67 (95% CI 0.85, 3.28), and 2.18 (95% CI 1.37, 3.47), respectively. MPT and LPT had increased risk of balance problems, with aRR of 1.63 (95% CI 0.81, 3.32) and 1.80 (95% CI 1.14, 2.82), respectively. MPT scored on average lower on the WISC-V full-scale IQ Matrix β -0.6 (95% CI -1.17, -0.11) and performance IQ Puzzle β -0.7 (95% CI -1.23, -0.26) subtests, compared to FT, and had an increased risk of dental malposition, aRR 1.42 (95% CI 1.15, 1.75).

Conclusions: While most outcomes (respiratory, anthropometry, cardiometabolic) did not differ between MPT, LPT, ET, and their FT peers, others, including strabismus, were more prevalent among preterm and ET. Some outcomes were specific to MPT, including lower WISC-V average scores and dental issues.

No abstract available

Abstract

Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.

Abstract

Lipid nanoparticles (LNPs) have gained significant attention thanks to their ability to encapsulate and deliver mRNA. Exploring a variety of lipid compositions and different preparation processes is essential for a better understanding of the mRNA encapsulation and the LNPs assembly. In this study, we investigated the development of mRNA-LNPs through microfluidic PFVs production followed by a postencapsulation approach. A library of preformed vesicles (PFVs) was produced by microfluidics using a full factorial design by varying 4 formulation and process parameters: main lipid type, sterol type, flow rate ratio, and chip design. The Size and polydispersity index (PDI) of PFVs were measured and compiled into a data set. A subset of formulations was subsequently postencapsulated with mRNA, after which the size, PDI, and EE% of the resulting mRNA-LNPs were quantified to generate a labeled data set. The results showed the effects of chip design and lipid composition on the size and PDI of PFVs, with smaller PFVs obtained with the chip design that provides a higher mixing efficiency. Postencapsulated formulations showed consistent increases in nanoparticle size and decreases in PDI values, compared to the corresponding PFVs. An XGBoost model was trained and validated on the labeled data set for predicting size and EE%, and was further optimized through semisupervised learning by incorporating pseudolabeled data derived from the PFVs data set. The model demonstrated an ability to predict the size and the EE% of LNPs based on the composition, the process parameters, and the physicochemical properties of PFVs. The use of microfluidics and machine learning allowed the obtaining of relevant information with limited resources and time. Integrating machine learning and advanced data analysis in nanomedicine research could unveil its full potential and accelerate the development of innovative formulation strategies.

Abstract

Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.

Abstract

The newborn infant, particularly those born preterm, is vulnerable to brain injury resulting in lifelong neurodevelopmental sequalae. Conventional structural brain imaging correlates poorly with later individual neurodevelopmental trajectories. Therefore, assessing brain integrity with functional (particularly functional connectivity (FC)) neuroimaging, would be beneficial, as studies showed correlation between early FC assessment and later neurodevelopmental outcomes. However, these tools are absent of neonatal clinical settings, probably either due to lack of portability or restricted access to the deep structures. In this proof of concept (poc) work, we show that functional ultrasound imaging (fUS) has key characteristics for this challenge: including portability, sensitivity and spatiotemporal resolution. fUS can monitor fine grain brain activity in deep cerebral nuclei, detect changes in FC dynamics at different developmental stages, with capabilities for 3D imaging. Furthermore, we present a multimodal poc combining fUS with high-density diffuse optical tomography (HD-DOT). The results demonstrate correlation between fUS and HD-DOT signals in spatially overlapping areas of the brain. The complementary fields of view of fUS (in depth) and HD-DOT (shallow cortex) could enable for the first time cot-side whole brain assessment of FC. In the future, a system combining fUS and HD-DOT could be developed as a clinical tool to monitor the developing brain in high-risk infants.