Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

The redox-active drug metronidazole and thiol-depleting garlic compounds act synergistically in the protist parasite Spironucleus vortens.

Spironucleus vortens is a protozoan parasite associated with significant mortalities in the freshwater angelfish, Pterophyllum scalare. Control of this parasite is especially problematic due to restrictions on the use of the drug of choice, metronidazole (MTZ), on fish farms. Use of garlic (Allium sativum) is undergoing a renaissance following experimental validations of its antimicrobial efficiency. Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), is a stable transformation product of allicin, the primary biologically active component of garlic. In the current study, an ajoene oil crude extract had a minimum inhibitory concentration (MIC) of 40µg/ml against S. vortens. GC-MS and NMR spectroscopy revealed this ajoene extract contained a mixture of the (E) and (Z)-ajoene isomers along with diallyl disulphide (DADS) and diallyl trisulphide (DATS). The only component of the ajoene crude oil found to substantially inhibit S. vortens growth by optical density monitoring (Bioscreen C Reader) was (Z)-ajoene (MIC 16µg/ml). Ajoene oil acted in synergy with MTZ in vitro, reducing the individual MIC of this drug (4µg/ml) by 16-fold, and that of ajoene oil by 200-fold with a fractional inhibitory concentration (FIC) index of 0.263. This synergistic interaction was confirmed in vivo. S. vortens-infected Pterophyllum scalare angelfish dosed orally with 0.5% (v/w) MTZ combined with 0.05% (v/w) ajoene displayed a significant reduction in faecal trophozoite count, whilst those fed on 0.5% MTZ flakes (half the recommended oral dose) alone did not. This study demonstrates for the first time the synergistic interaction between the synthetic drug MTZ and natural ajoene oil both in vitro and in vivo. Future work should evaluate the potential synergy of ajoene and MTZ against MTZ-resistant bacteria and protists.

Evolution of T1 Relaxation, ADC, and Fractional Anisotropy during Early Brain Maturation: A Serial Imaging Study on Preterm Infants.

BACKGROUND AND PURPOSE: The alteration of brain maturation in preterm infants contributes to neurodevelopmental disabilities during childhood. Serial imaging allows understanding of the mechanisms leading to dysmaturation in the preterm brain. The purpose of the present study was to provide reference quantitative MR imaging measures across time in preterm infants, by using ADC, fractional anisotropy, and T1 maps obtained by using the magnetization-prepared dual rapid acquisition of gradient echo technique. MATERIALS AND METHODS: We included preterm neonates born at <30 weeks of gestational age without major brain lesions on early cranial sonography and performed 3 MRIs (3T) from birth to term-equivalent age. Multiple measurements (ADC, fractional anisotropy, and T1 relaxation) were performed on each examination in 12 defined white and gray matter ROIs. RESULTS: We acquired 107 MRIs (35 early, 33 intermediary, and 39 at term-equivalent age) in 39 cerebral low-risk preterm infants. Measures of T1 relaxation time showed a gradual and significant decrease with time in a region- and hemispheric-specific manner. ADC values showed a similar decline with time, but with more variability than T1 relaxation. An increase of fractional anisotropy values was observed in WM regions and inversely a decrease in the cortex. CONCLUSIONS: The gradual change with time reflects the progressive maturation of the cerebral microstructure in white and gray matter. Our study provides reference trajectories from 25 to 40 weeks of gestation of T1 relaxation, ADC, and fractional anisotropy values in low-risk preterm infants. We speculate that deviation thereof might reflect disturbed cerebral maturation; the correlation of this disturbed maturation with neurodevelopmental outcome remains to be addressed.

[Detection of executive function disorders with a standard neurodevelopmental follow-up of premature children]. / Suivi neurodéveloppemental à 5 ans des extrêmes prématurés et détection des difficultés sur le plan des fonctions exécutives.

INTRODUCTION: A significant proportion of prematurely born children encounter behavioral difficulties, such as attention deficit or hyperactivity, which could be due to executive function disorders. AIMS: To examine whether the standard neurodevelopmental assessment offered to premature children in Switzerland recognizes executive function disorders. METHODS: The study population consisted of 49 children born before 29 weeks of gestation who were examined between 5 and 6 years of age with a standard assessment, with additional items to assess executive functioning. Children with severe neurodevelopmental impairment were excluded (mental retardation, cerebral palsy, autism). Standard assessment consisted in the Kaufman Assessment Battery for Children (K-ABC), which comprises three subscales: sequential processes (analysis of sequential information), simultaneous processes (global analysis of visual information), and composite mental processes (CMP) (result of the other two scales), as well as a behavioral evaluation using the standardized Strengths and Difficulties Questionnaire (SDQ). Executive functioning was assessed with tasks evaluating visual attention, divided attention, and digit memory as well as with a specialized questionnaire, the Behavior Rating Index of Executive Functions (BRIEF), which evaluates several aspects of executive function (regulation, attention, flexibility, working memory, etc). RESULTS: Children were divided according to their results on the three K-ABC scales (< or >85), and the different neuropsychological tasks assessing executive function were compared between the groups. The CMP did not differentiate children with executive difficulties, whereas a score < 85 on the sequential processes was significantly associated with worse visual and divided attention. There was a strong correlation between the SDQ and the BRIEF questionnaires. For both questionnaires, children receiving psychotherapy had significantly higher results. Children who presented behavioral problems assessed with the SDQ presented significantly higher scores on the BRIEF. CONCLUSION: A detailed analysis of the standard neurodevelopmental assessment allows the identification of executive function disorders in premature children. Children who performed below 85 on the sequential processes of the K-ABC had significantly more attentional difficulties on the neuropsychological tasks and therefore have to be recognized and carefully followed. Emotional regulation had a strong correlation with behavioral difficulties, which were suitably assessed with the SDQ, recognized by the families, and treated.

[Neurodevelopmental outcome of very premature infants]. / Devenir et prise en charge des enfants grands prématurés.

Very preterm infants are at risk of neurodevelopmental impairments, which may affect motor development, intelligence and behavior. Neurodevelopmental follow-up is offered to these children who represent 1% of Swiss births, and may show abnormal motor tone, which sometimes resolves spontaneously or evolves in cerebral palsy. Standardized tests explore intellectual functioning and may allow the diagnosis of specific learning impediments. Finally, behavior is assessed with standardized questionnaires which can reveal hyperactivity with or without attention deficit, impaired social relations, psychiatric troubles or autism, all more frequent amongst preterm children.

Emotional reactivity at 12 months in very preterm infants born at <29 weeks of gestation.

The present study evaluated the socio-emotional development of very preterm born infants at 12 months corrected age. Forty-one infants born very preterm (<29 weeks of gestation) were compared to 22 infants born full term on a standardized behavioral assessment and a parental temperament questionnaire, both measuring emotional reactivity to joy, anger and fear, as well as sustained attention. The behavioral assessment showed that very preterm infants exhibited as much joy as full term infants during a joy-eliciting episode. However, they expressed a significantly higher reactivity in anger-eliciting situations and a reduced reactivity toward fear-eliciting situations. For all three emotion-eliciting situations, the preterm infants reacted with a higher level of motor activity. The preterm infants also exhibited a distinct attention pattern with a significantly higher initial attention level which declined rapidly throughout the episode. The questionnaire did not show any group differences. The clinical relevance of these results in terms of preliminary hallmarks of later behavioral difficulties such attention deficit/hyperactivity disorder are discussed as well as the inconsistencies observed between the questionnaire and the behavioral assessment.

[Neurodevelopmental follow-up of premature children in Lausanne and Geneva]. / Suivi neurodéveloppemental de l'enfant né prématuré dans l'Arc lémanique.

Preterm children born before 32 weeks of gestation represent 1% of the annual births in Switzerland, and are the most at risk of neurodevelopmental disabilities. A neurological surveillance is thus implemented in the neonatal units, and multidisciplinary neurodevelopmental follow-up is offered to all our preterm patients. The follow-up clinics of the University hospitals in Lausanne and Geneva follow the Swiss guidelines for follow-up. An extended history and neurological examination is taken at each appointment, and a standardized test of development is performed. These examinations, which take place between the ages of 3 months and 9 years old, allow the early identification and treatment of developmental disorders frequent in this population, such as motor, cognitive or behavioral disorders, as well as the monitoring of the quality of neonatal care.

[Pediatrics. Developmental care in neonatology]. / Pédiatrie. 1. Les soins de soutien au développement en néonatologie.

Developmental care is a multidisciplinary approach aiming at improving the premature newborn's well-being through individualized observation and care, and at limiting environmental nociceptive stimuli. The aim is to lessen neonatal morbidity and enhance long-term psychomotor development in this population of high-risk newborns.

Severe postnatally acquired cytomegalovirus infection presenting with colitis, pneumonitis and sepsis-like syndrome in an extremely low birthweight infant.

Few cases of severe postnatally acquired cytomegalovirus (CMV) infection are reported in premature infants. We report on an extremely low birthweight (ELBW) preterm infant who presented with a sepsis-like syndrome and multiple organ involvement, notably pneumonitis and colitis. The course of infection was assessed by repeated analysis of urine, tracheal aspirates and blood. The patient was given intravenous ganciclovir. The clinical course was rapidly favorable. Development of neutropenia led to the discontinuation of the antiviral treatment after 28 days. Follow-up showed moderate white matter anomalies on cerebral MRI, a transient hypoacusis and a mild developmental delay at 18 months of corrected age. To the best of our knowledge, this is the first description of a severe combination of pneumonitis and colitis in postnatal CMV infection. Many issues remain controversial and are discussed. We propose that antiviral treatment should be considered in severe postnatal CMV infection in ELBW patients.

Antimicrobial activity of selected cyclic dipeptides.

Cyclic dipeptides are products of rational drug design, which may exhibit both antimicrobial and antitumor properties. The aim of this study was to investigate both the antimicrobial effects of the cyclic dipeptides cyclo(L-phenylalanyl-L-prolyl), cyclo(L-tyrosyl-L-prolyl), cyclo(L-tryptophanyl-L-prolyl) and cyclo(L-tryptophanyl-L-tryptophanyl) and the effects of these cyclic dipeptides on the gastrointestinal epithelium in vitro. Furthermore, a relevant solvent for the possible pharmaceutical application of the products was sought concurrently. The antimicrobial effect of the cyclic dipeptides was assayed using the Kirby-Bauer disc diffusion assay against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Bacillus subtilis, Streptococcus pneumoniae, Candida albicans, Aspergillus niger and Penicillium notatum. The effect of the cyclic dipeptides on the gastrointestinal epithelium was assessed by changes in alkaline phosphatase expression of HT-29 cells. Cyclo(Pro-Trp) and cyclo(Phe-Pro) show broad spectrum antibacterial properties and cyclo(Trp-Pro) and cyclo(Trp-Trp) show broad spectrum antifungal properties. The maturation of the gastrointestinal cells was enhanced by cyclo(Phe-Pro), cyclo(Tyr-Pro), cyclo(Trp-Trp) and cyclo(Trp-Pro). The activity of these cyclic dipeptides thus indicates potential application of these compounds as pharmacological agents.