Publications

Abstract

Early microscopic-scale pericyte dysfunction contributes to the initial stages of many neurological diseases and represents a strong candidate target for therapeutic intervention. A non-invasive imaging modality able to image microvascular alterations induced by pericyte dysfunction is needed. In addition, the development of pericyte-focused therapies remains challenging due to the lack of early biomarkers of disease progression. Here we show that cerebral microvascular alterations induced by pericyte dysfunction can be characterized non-invasively in mice using functional ultrasound localization microscopy (fULM). Depletion of endothelial endoglin in adult mice as a model of hereditary haemorrhagic telangiectasia, leads to pericyte detachment in the arteriole-capillary transition (ACT) zone. Imaging reveals that arteriolar capillaries have irregular shapes, increased diameters, reduced blood speed and neurovascular uncoupling mainly localized in the ACT zone. Transforming growth factor-β signalling activator C381 restores pericyte coverage and neurovascular response. Our study underscores the potential of fULM in characterizing early microvascular alterations. As super-resolution ultrasound transitions to the clinic, our data support its future use in monitoring pericyte-focused therapies in humans.

Abstract

Importance: In randomized trials, early prophylactic hydrocortisone improved survival without bronchopulmonary dysplasia (BPD) with few adverse effects in extremely preterm infants. Large scale implementation data are needed to evaluate clinical effects and safety.

Objective: To examine the association between early prophylactic hydrocortisone and survival without BPD at 36 weeks’ postmenstrual age (PMA) in extremely preterm infants in Sweden after guideline implementation and to assess treatment safety.

Design, setting, and participants: A national historical cohort study with prospectively collected data from the Swedish Neonatal Quality register from 4 Swedish centers where hydrocortisone prophylaxis was implemented. The study included infants born between 22 and 27 weeks’ gestation between 2018 and 2023. Infants were divided into exposed and nonexposed groups according to the intention-to-treat principle.

Exposure: Hydrocortisone, 1 mg/kg/d, for the first 7 days of life, followed by 0.5 mg/kg/d from days 8 through 10.

Main outcomes and measures: The primary outcome was survival without BPD at 36 weeks’ PMA. A predefined statistical analysis plan with logistic regression was used to calculate unadjusted and adjusted odds ratios.

Results: Among 1106 infants (median [IQR] gestational age, 25 weeks, 6 days [24 weeks, 3 days to 27 weeks]; median [IQR] birth weight, 780 [610-964] g), 474 received hydrocortisone prophylaxis and 632 did not. Survival without BPD occurred in 154 of 474 exposed (32.5%) and 185 of 632 nonexposed (29.3%) infants (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27). BPD occurred in 233 exposed (49.2%) and 345 nonexposed (54.6%) infants (adjusted odds ratio, 0.65; 95% CI, 0.49-0.86). Death before 36 weeks’ PMA occurred in 87 exposed (18.4%) and 102 nonexposed (16.1%) infants. Late-onset bacterial infection was more common in exposed infants, but not significant after adjustment. No other severe neonatal morbidities differed significantly between the 2 groups.

Conclusions and relevance: In this cohort study of extremely preterm infants, the introduction of prophylactic hydrocortisone was associated with increased survival without BPD, after adjusting for covariates. There was no significant increase in severe neonatal morbidities, except that late-onset bacterial infection was more common in the exposed group before adjustments.

Abstract

Background: Very preterm birth (<32 weeks gestation, VP), immigrant background, and language barriers are all independently associated with a high risk for mental health problems in childhood, but research has neglected the long-term development of immigrant children born VP. We assessed whether behavioural and socio-emotional problems of 5-year-old children born VP growing up across different language contexts in the European Union are associated with an immigrant background and linguistic distance of families’ mother tongue (L1) to the host countries’ official languages.

Methods: Data are from a population-based cohort including all VP births in 2011/12 in 11 European countries; a total of 3,067 children were followed up at 2 and 5 years of age. Behavioural and socio-emotional difficulties were assessed using the parent-reported Strengths and Difficulties Questionnaire (SDQ).

Results: Mixed-effects models showed that a larger linguistic distance of children’s L1 to the host countries’ official language was associated with higher SDQ total scores (0.02 [0.01, 0.03]), after adjusting for a wide range of social risks, biological, and perinatal clinical factors.

Conclusion: Language barriers in the form of linguistic distance between VP children’s L1 and countries’ official languages play a critically important role for the behavioural and socio-emotional development of immigrant children born VP.

Impact: Immigrant children born very preterm across Europe face systemic inequalities such as language barriers. Language barriers can be operationalised as a continuous linguistic distance score between children’s mother tongues and countries’ official languages. Linguistic distance plays an important role for the behavioural and socio-emotional development of immigrant children born VP. Research, policy, and practice need to better account for language barriers to increase equity in health and education.

Abstract

Objective: Existing predictive models for bronchopulmonary dysplasia (BPD) often lack external validation, limiting their clinical use. This study aimed to externally validate recent BPD prediction models using baseline variables, in a population-based cohort.

Design: This was an external validation study conducted on data collected from 2014 to 2021.

Setting: This was a retrospective, multicentre, population-level cohort with prospectively collected data.

Participants: Extremely low gestational age neonates recorded in the SwissNeoNet registry across all nine level III neonatal care units in Switzerland (n=1748) were included.

Interventions: Recent BPD prediction models estimating the risk of BPD or death at 36 weeks postmenstrual age, based on predictors available within the first 24 hours of life.

Main outcome measures: The primary outcome was survival without BPD. A systematic literature search identified five eligible models, which were externally validated and recalibrated for the Swiss cohort. The most performant model was further optimised to improve local applicability.

Results: Among 693 screened studies, five models based solely on perinatal variables were included. Without recalibration, models showed fair discrimination (area under the curve (AUC) 0.70-0.76) but variable calibration (observed/expected (O/E) 0.58-0.80). After recalibration, AUCs ranged from 0.69 to 0.76, and calibration improved (O/E 0.58-1.61). The optimised version of the best-performing model demonstrated improved calibration (O/E 1.03) and was validated in the Swiss population.

Conclusion: By comparing and externally validating existing BPD prediction models, we propose an optimised model using baseline variables at birth, enhancing its applicability to both the Swiss population and similar clinical contexts.

Abstract

Background: The characteristics of listeriosis in children beyond the neonatal period are unknown.

Methods: MONALISA is a prospective cohort study of listeriosis in France. All children aged 1 month to 18 years with microbiologically confirmed infection were enrolled.

Findings: We included 48 children among the 1,646 MONALISA patients (3%): 29/48 (60%) with neurolisteriosis, 12/48 (25%) with bacteremia, 6/48 (13%) with abdominal infection (gastroenteritis [n = 4] and appendicitis [n = 2]), and 1 with skin abscess. The median age was 4 years (interquartile range [IQR]: 25-75, range: 1-10), 23 were male (23/48, 48%), and 16 (16/48, 33%) reported at least one past medical event: 8/12 (67%) of those with bacteremia but only 8/29 (28%) of those with neurolisteriosis (p = 0.034) and none of the seven children with other forms. Diarrhea was reported in 21/48 children (44%) and was equally distributed among the different forms. Neurolisteriosis presented as meningoencephalitis (13/29, 45%) or isolated meningitis (16/29, 55%). Twenty-three children with neurolisteriosis presented without known immunosuppression (23/29, 79%), including 20 of the 22 children younger than 5 years (90%). Fourteen patients (14/48, 29%) required intensive care unit management. There were four in-hospital deaths (4/48, 8%), two attributed to listeriosis. All surviving children with neurolisteriosis recovered without permanent disability.

Conclusion: Listeriosis in children has specificities: neurolisteriosis in younger children most often occurs in the absence of immunosuppression and often presents as isolated meningitis, abdominal forms are more common than in adults, and the outcome is much better than in adults.

Funding: This work was funded by Institut Pasteur, INSERM, Santé Publique France, and Program Hospitalier de Recherche Clinique.

Abstract

Objective: Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in infants, whose neurodevelopmental consequences currently lack effective treatment. Since TBI is associated with neuroinflammation, modulation of the post-injury neuroinflammatory response is a promising strategy. Oxytocin is suggested to possess anti-inflammatory properties, and seems to play a role in clinical interventions that improve brain development in neonates. However, the underlying mechanisms remain unclear, as does its applicability to acute brain injury.

Methods: Here, we assess the effects of chemogenetic activation of oxytocinergic neurons on acute neuroinflammation and on long-term brain development after TBI in postnatal day 7 (P7) male mice. Immunohistochemistry, RNA sequencing, ex-vivo MRI-diffusion tensor imaging, in-vivo functional ultrasound imaging and behavioral assays are used for assessment. Oxytocinergic neurons were chemogenetically activated daily between P7 and P10.

Results: We show that chemogenetic activation of oxytocinergic neurons mitigates the acute neuroinflammatory response to TBI 24 h post-injury, where it reduces the expression of inflammation-related genes, and promotes brain repair and development gene pathways in microglia. In the long-term, early-life oxytocinergic neuron activation improves subcortical and cortical white matter damage after TBI, prevents hyperactivity and loss of social behavior, and restores TBI-induced alterations in resting-state functional connectivity of the isocortex. These effects were found 35 days after the last treatment session.

Conclusions: Our findings enhance the understanding of neuroinflammation modulation by oxytocin, reveal its long-term effects, and support intervention associated with endogenous oxytocin release as a promising neuroprotective strategy in pediatric TBI.

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.