Publications

Abstract

The emergence of aztreonam-avibactam resistance among NDM-producing Escherichia coli represents a major therapeutic and infection control concern. Four cases of aztreonam-avibactam-resistant (AZAR) NDM-producing E. coli, recovered from three blood cultures and one rectal surveillance culture in a hospital of Paris, prompted an investigation based on whole-genome sequencing. The three isolates responsible for bloodstream infection, which were clonally related, belonged to the ST405 and produced NDM-5, DHA-1, CTX-M-15, and TEM-1 β-lactamases. They also had a penicillin-binding protein 3 (PBP3) modified by the insertion of four amino acids (YRIK). On the other hand, the isolate recovered from the rectal swab belonged to another sequence type (ST2083). It produced NDM-5, CMY-42, and TEM-1 β-lactamases and had an altered PBP3 by the insertion of four other residues (YRIN). Epidemiological investigation identified endoscopic retrograde cholangiopancreatography as a potential risk factor, leading to the detection of three additional patients infected with the ST405 clone after exposure to the same duodenoscope. The outcome of the bloodstream infections was favorable except for one patient. In total, seven patients infected or colonized by AZAR NDM-5-producing E. coli were identified over a 5-month period in 2025, six with duodenoscope exposure.
IMPORTANCE : This study underlines the emergence of aztreonam-avibactam resistance among NDM-producing Escherichia coli isolates in France. To our knowledge, this report describes the first clonal outbreak due to aztreonam-avibactam-resistant NDM-producing E. coli.

Keywords: DHA; ERCP; Escherichia coli; NDM-5; PBP3; ST405; avibactam; aztreonam; carbapenem; cefiderocol; duodenoscope; outbreak; resistance

Abstract

Poor aqueous solubility is a major drawback of modern drug candidates, affecting their biopharmaceutical performance. Solvent-antisolvent methods involving rapid mixing, such as Flash Nanoprecipitation and Sequential Nanoprecipitation, have advanced the field. However, these remain restricted to compounds with relatively high hydrophobicity (minimum LogP ≥4.5-6). To address this limitation, we introduce Hydrodynamically Decoupled Nanoprecipitation (HDNP). The approach enables decoupling supersaturation, nucleation, and stabilization by controlling the hydrodynamic environments. Dexamethasone (DEX, LogP: 1.83) was used as a model drug. A mechanistically and physics-informed framework was developed, integrating in-line dynamic light scattering for count rate evolution assessment, Computational Fluid Dynamics (CFD), and Design of Experiments for design space establishment. CFD revealed periodic shear stress, high turbulent dissipation rates, and local flow reversal during pulsatile flow under various Womersley numbers, providing favorable hydrodynamic conditions for controlled delayed nucleation. HDNP of DEX successfully produced mainly amorphous nanoparticles (DEX-NPs) stabilized with P407. DEX-NPs exhibited a hydrodynamic diameter of 241 nm, PdI of 0.246, loading efficiency of 77%, enhanced dissolution relative to the micronized drug, and physicochemical stability for at least two weeks. The approach was further evaluated using prednisolone (LogP: 1.62). These findings demonstrate the applicability of HDNP to the nanoprecipitation of the used corticosteroids and highlights its potential as a promising platform for other poorly water-soluble compounds with low LogP.

Keywords: Amorphous nanoparticles; CIJ mixer; Computational fluid dynamics; Hydrodynamics; Microfluidics; Nanocrystals; Pulsatile flow; Solvent-antisolvent nanoprecipitation.

Abstract

Preterm birth continues to affect 5 to 12% of all live births in Europe and remains a leading cause of neonatal mortality and short- and long-term morbidity. Despite decades of research and clinical innovation, the overall burden has not substantially declined, and in several European settings rates are rising. This paper is a European Association of Perinatal Medicine (EAPM) Good Practice Recommendation which synthesises current evidence on spontaneous PTB (sPTB) risk and management, and examines why preterm birth persists as a clinical and public health challenge. We review the epidemiology, classification, and aetiology of sPTB; the role of the maternal microbiome; evidence-based preventive strategies; perinatal management; and neonatal care. We highlight the importance of a multicomponent and evidence-based approach, focusing on primary, secondary and tertiary prevention, to reduce the human and societal cost of preterm birth across Europe.

Abstract

Importance: The consistency of nirsevimab effectiveness across consecutive seasons and its broader clinical protective effects remain to be fully characterized.

Objective: To assess whether first-season effectiveness of nirsevimab against respiratory syncytial virus (RSV)-lower respiratory tract infection (LRTI)-related hospitalizations is maintained during a new RSV season, whether the effectiveness persists beyond the first season, and whether nirsevimab exposure is associated with hospitalizations for non-RSV infections and asthma during the first and second years of follow-up.

Design, setting, and participants: This cohort study analyzed 2 nationwide matched cohorts using the French National Health Data System, including infants born in metropolitan France before the 2023 and 2024 immunization campaigns. Infants receiving nirsevimab were matched 1:1 to unimmunized infants. Both cohorts were followed up for 1 year after immunization, with an additional second year of follow-up for the 2023 cohort. Data analysis was performed from February 2023 to August 2025.

Exposures: Single dose of nirsevimab.

Main outcomes and measures: RSV-LRTI-related, non-RSV infection, and asthma hospitalizations were assessed using weighted Cox proportional hazards models.

Results: This cohort study included 74 672 infants in 2023 and 175 526 in 2024. At baseline, the mean (SD) age of immunized infants was 4.5 (2.0) months in the 2023 cohort; 19 633 (52.6%) were male and 17 703 (47.4%) were female. The mean (SD) age of the 2024 cohort was 4.8 (2.2) months; 44 863 immunized infants (51.1%) were male and 42 900 (48.9%) were female. Among 37 366 infant pairs in 2023 and 87 763 pairs in 2024, RSV-LRTI-related hospitalizations during the first year of follow-up occurred in 299 (0.8%) immunized vs 899 (2.4%) unimmunized infants in 2023 and 456 (0.5%) vs 1711 (1.9%), respectively, in 2024. Nirsevimab was associated with a lower rate of RSV-LRTI-related hospitalization in both the 2023 and 2024 cohort during the first year of follow-up, with effectiveness estimates of 66% (95% CI, 61%-70%) and 72% (95% CI, 69%-75%), respectively. An association with higher rates of hospitalization for ear, nose, and throat (ENT) bacterial infections was observed (2023 cohort: weighted hazard ratio [wHR], 1.36; 95% CI, 1.00-1.84; 2024 cohort: wHR, 1.43; 95% CI, 1.15-1.78). No significant association was observed for other outcomes. During the second year of follow-up, no protective association was observed for RSV-LRTI-related hospitalization (wHR, 1.03; 95% CI, 0.73-1.43). An association with higher rates of hospitalization for ENT (wHR, 1.56; 95% CI, 1.10-2.22) and asthma (wHR, 1.24; 95% CI, 1.05-1.46) was observed.

Conclusions and relevance: This study found that nirsevimab was associated with a substantial reduction in RSV-LRTI-related hospitalizations during the first year across both the 2023-2024 and 2024-2025 seasons. It was not associated with reduced hospitalizations due to non-RSV infections or asthma, nor during the second year of follow-up.

Abstract

Critical care involves the management of organismal stress by sedation. Benzodiazepines remain widely used for anxiolysis and sedation in critical care, including in septic shock. Yet converging mechanistic, preclinical and clinical evidence suggests that benzodiazepines and the endogenous ligand of benzodiazepine-binding sites, the « endozepine » acyl-CoA binding protein/diazepam binding inhibitor (ACBP/DBI), may impair host immune defenses, exacerbate organ dysfunction and contribute to long-term morbidity after intensive care. A unifying framework is that benzodiazepines may accelerate « iatrogenic aging » by antagonizing adaptive stress responses (notably autophagy) and favoring cellular senescence, chronic inflammation, immunosuppression and neurocognitive perturbations. Here, we synthesize evidence supporting benzodiazepine avoidance in sepsis-heavy intensive care populations. We propose that replacing benzodiazepines with alternative sedative strategies may improve both short-term outcomes and long-term trajectories of post-sepsis disability. We hypothesize that post-intensive-care syndrome (PICS), including -as a specific case- post-sepsis syndrome (PSS), is caused by premature aging of the organism and that PICS/PSS might be attenuated by the avoidance of benzodiazepine administration during and after critical care.

Abstract

Microglia play dynamic roles in the developing brain and are central mediators of injury responses in perinatal brain injury. In mice, microglial gene regulatory and transcriptional programes reveal progression through early, pre-mature and mature stages. In contrast, microglial maturation has not been systematically characterised in the large-brained species most widely used to model human perinatal brain injury, particularly sheep and pigs. These large-animal models are indispensable as they share gyrencephaly, an expanded subplate, and clinically relevant physiology with the human infant brain. Here, we integrate established mouse and human frameworks of microglial maturation with a critical re-analysis of available sheep and pig datasets to assess whether rodent-derived insights into microglial development extend to large-animal models. Current sheep datasets lack sufficient resolution to infer maturation states, whereas pig data, although limited, reveal stage-dependent patterns consistent with late-gestation human development. This review also briefly considers emerging data on microglial development in non-human primates and the extent to which microglial gene expression programes appear conserved across species. Overall, microglial transitions are most dynamic during fetal and early postnatal life, underscoring the importance of developmentally aligned benchmarks for interpreting injury responses and informing microglia-targeted neuroprotective strategies. IMPACT: This article provides the first structured comparison of microglial maturation across human and mouse and uses these frameworks to benchmark large-brain animal models of perinatal brain injury, addressing a key translational gap. It shows that while existing sheep datasets lack sufficient resolution to define microglial maturation states, available pig data align closely with human late-gestation microglial development, supporting their use for developmental benchmarking. The work highlights that failure to account for microglial developmental stage risks misinterpretation of injury responses and underscores the need for developmentally aligned microglial markers in large-animal and non-human primate models to guide microglia-targeted neuroprotective strategies.

Abstract

Background: Infant mortality has recently increased in France, especially in deprived areas. Congenital anomalies (CA) are a major cause of infant mortality and could contribute to these trends.

Objectives: This study aimed to investigate socio-spatial inequalities in infant mortality associated with CA. It also examined socio-spatial differences in antenatal detection.

Methods: We included all live births ≥ 22 weeks with CA from the Paris Registry of CA (remaPAR). Births are linked to infant deaths < 1 year using vital statistics records. A case-population design was applied to assess the association between an area-based deprivation score, assigned at the smallest census tract level (IRIS) of the mother’s place of residence, and risks of infant death and live birth with CA. In the absence of data on births at the IRIS level, we used an aggregated population comparison group of children < 2 years old in 2019-2022 census data. We computed unadjusted odds ratios (OR) by comparing the distribution of the area-based score in quartiles in the case and census comparison populations. We also compared antenatal detection of CA by deprivation quartile.

Results: The study included 2539 live births, resulting in 81 infant deaths. The proportions of infant deaths with CA were 39.5% and 16.0% in the most and least deprived quartiles, respectively, yielding an OR of 2.43 (95% confidence interval [CI] 1.28, 4.63). For live births with CA, these percentages were 29.7% and 22.0% with an OR of 1.34 (95% CI 1.20, 1.49). No variation across quartiles was observed in antenatal detection of CA, with a detection rate of 56.0% for live births and 85.2% for infant deaths. First-trimester ultrasound use was high (90.5%) but was lower in the most compared to the least deprived quartile (87.8% and 93.9%, respectively); however, second-trimester ultrasound use was similar across quartiles.

Conclusions: Area-based deprivation was associated with higher risks of infant mortality and live birth with CA, but not antenatal detection of CA. These results raise questions about differences in CA aetiology and decision-making about termination of pregnancy after CA detection.

Summary

Background & Aims

Body mass index (BMI) is used to identify high-risk groups in childhood and to target early interventions to prevent later metabolic disorders. This is a priority area for research among children born very preterm (VPT) given growing concern with their long-term risks of adverse metabolic outcomes. Two principal international BMI classifications exist for underweight, overweight and obesity (OWOB) in children (International Obesity Task Force (IOTF) and World Health Organization (WHO)), but how the choice of reference affects results of research in children born VPT is unknown. Our objective was to compare the prevalence and risk factors for underweight and OWOB using these two references among five-year-old children born VPT.

Methods

Data comes from a population-based cohort of children born VPT in 11 European countries in 2011–12 with information from medical records during the neonatal hospitalization and parental questionnaires at age five. BMI at five years of age was classified into underweight and OWOB using IOTF and WHO references (n = 2654 children). Conversion algorithms were also applied to prevalence estimates. Associations with sociodemographic, perinatal and neonatal characteristics were assessed using multinomial logistic regression with multiple imputation and inverse probability weighting to account for missing data and attrition.

Results

After applying a cutoff of −1SD to define mild underweight for WHO – since this category exists only for IOTF – the estimated prevalence of total underweight was similar between IOTF and WHO references (27.8% vs 27.0%, respectively). IOTF classified a higher proportion of children as having severe underweight (4.1% vs 1.6%). For OWOB, prevalence estimates were lower using IOTF, particularly among boys (8.6% vs 14.1%). The algorithms provided good conversion (1–2% absolute difference) of prevalence between references for underweight and obesity overall, and overweight for girls, but had a larger error for overweight in boys. Risk factors were similar for underweight and OWOB for both references, with the exception of sex and maternal country of birth. Notably, the IOTF reference identified a lower risk of OWOB among boys, a result not found using WHO references.

Conclusion

Clinicians and researchers should be aware of the difference in prevalence of suboptimal BMI when interpreting findings from studies using different classifications and IOTF should be used with caution for investigating sex differences. Given the high prevalence of mild underweight in children born VPT, the cutoff of −1SD should be used with the WHO references in studies of BMI in this population.

No abstract available

Abstract

Objective: To assess the association between late-onset sepsis (LOS) and neurodevelopmental disorders (NDD) at 5 years of age among children born very preterm.

Methods: We included children from the EPIPAGE-2 cohort study, born before 32 weeks of gestation and followed at 5 years. LOS was defined as one positive blood culture after 72 hours of life, associated with antibiotic therapy ≥5 days. At 5 years, NDD were evaluated as a composite outcome including cerebral palsy, neurosensory impairment and/or coordination, cognitive and behavioural disorders. NDD were categorised as: none, mild or moderate-to-severe disorders. We used multivariable multinomial regressions after multiple imputations of missing data to assess the association between LOS and NDD at 5 years.

Results: Among the 3186 children born very preterm, 697 (20.6%) had at least one episode of LOS and 1927 (60.5%) had a complete assessment at 5 years. Among children who had an LOS, 42.2% had no NDD, 38.2% had mild NDD and 19.6% had moderate-to-severe NDD. The proportion of children with three episodes of LOS was higher in the mild NDD group and in the moderate to severe NDD group than in the none NDD group (1.3% vs 0.6% and 2.8 vs 0.6%, respectively). No association was found between the occurrence of at least one episode of LOS and NDD (mild NDD adjusted OR (aOR) 1.06 (95% CI 0.82 to 1.36); moderate-to-severe NDD aOR 1.18 (95% CI 0.90 to 1.55)).

Conclusion: We found no significant association between LOS and mild, moderate or severe NDD at five in children born very preterm.

Keywords: Child Development; Epidemiology; Follow-Up Studies; Neonatology; Sepsis.