Individual and composite adverse pregnancy outcomes in a randomized trial on isoniazid preventative therapy among women living with human immunodeficiency virus

CITATION: Theron, G. et al. 2021. Individual and Composite Adverse Pregnancy Outcomes in a Randomized Trial on Isoniazid Preventative Therapy Among Women Living With Human Immunodeficiency Virus. Clinical infectious diseases, 72(11):e784–e790. doi:10.1093/cid/ciaa1482The original publication is available at https://academic.oup.com/cid/Background: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1078, a randomized noninferiority study designed to compare the safety of starting isoniazid preventive therapy (IPT) in women living with human immunodeficiency virus (HIV) either during pregnancy or after delivery, showed that IPT during pregnancy increased the risk of composite adverse pregnancy outcomes, but not individual outcomes. Many known factors are associated with adverse pregnancy outcomes: these factors' associations and effect modifications with IPT and pregnancy outcomes were examined. Methods: Pregnant women living with HIV from 8 countries with tuberculosis incidences >60/100 000 were randomly assigned to initiate 28 weeks of IPT either during pregnancy or at 12 weeks after delivery. Using univariable and multivariable logistic regression and adjusting for factors associated with pregnancy outcomes, composite and individual adverse pregnancy outcome measures were analyzed. Results: This secondary analysis included 925 mother-infant pairs. All mothers were receiving antiretrovirals. The adjusted odds of fetal demise, preterm delivery (PTD), low birth weight (LBW), or a congenital anomaly (composite outcome 1) were 1.63 times higher among women on immediate compared to deferred IPT (95% confidence interval [CI], 1.15-2.31). The odds of fetal demise, PTD, LBW, or neonatal death within 28 days (composite outcome 2) were 1.62 times higher among women on immediate IPT (95% CI, 1.14-2.30). The odds of early neonatal death within 7 days, fetal demise, PTD, or LBW (composite outcome 3) were 1.74 times higher among women on immediate IPT (95% CI, 1.22-2.49). Conclusions: We confirmed higher risks of adverse pregnancy outcomes associated with the initiation of IPT during pregnancy, after adjusting for known risk factors for adverse pregnancy outcomes.https://academic.oup.com/cid/article/72/11/e784/5913421?login=truePublishers versio

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Contribution à l'étude d'une plante haploïde de pommier (Malus pumila Mill.). Etude descriptive et comparaison avec des clones de ploïdie différente. I. — Caractères végétatifs : entre- noeuds, feuilles et stomates

National audienceA first haploid plant of apple has been studied and compared with related clones at diploid, triploid and tetraploid level. After a general description of the plant, the comparative study concerned internode length, leaf size, and stomatal size and density. The internodes of the haploid were distinctly shorter than those of the diploid and triploid. The very pointed leaves of the haploid had a leaf height/width ratio statistically different from those of the other clones ; there was a regular decrease in this ratio, i.e. wider less pointed leaves , with increasing ploidy. Stomatal size gave the most clear-cut distinction between the clones compared.La première plante haploïde découverte chez le pommier est étudiée et comparée à des clones de filiation proche, diploïde, triploïde et tétraploïde. Après avoir décrit l’aspect général de la plante, l’étude comparative concerne la longueur des entre-nœuds, les dimensions des feuilles ainsi que la taille et la densité des stomates. Les entre-nœuds du clone haploïde sont nettement plus courts que ceux des clones diploïde et triploïde. Les feuilles de la plante haploïde, de forme très allongée, ont un rapport hauteur sur largeur significativement différent de ceux des autres clones comparés ; on note une diminution régulière de ce rapport, soit un arrondissement du limbe, quand le taux de ploïdie augmente. La taille des stomates est le caractère qui permet de distinguer le plus clairement les clones appartenant aux divers niveaux de ploïdie

Contribution à l’étude d’une plante haploïde de pommier (Malus pumila, Mill.). Etude descriptive et comparaison avec des clones de ploïdie différente. II. - Aptitude à la reprise au greffage

National audienceGreenhouse propagation of a haploid apple by grafting on diploid seedlings proved rather difficult. Accordingly, bud-take of this valuable haplcid clone was compared with that of related diploid and tetraploid clones. Histological study of the union process clearly showed the following points : 1) there was no abnormality in stem structure of the haploid plant ; 2) there was no incompatibility related to the difference of ploidy level between scion and rootstock. However, the large difference in diameter between scion and rootstock seemed to delay the union process, possibly resulting in poor nutrition of the haploid scion. Comparative trials with rootstocks inducing different vigors in the scion have confirmed these observations. The dwarfing rootstock, ’Mailling 9’, is now being used for propagation of the apple haploid clone.La multiplication en serre de la plante haploïde de pommier par greffage sur des porte-greffes diploïdes issus de semis pose de nombreux problèmes. L’originalité du clone haploïde nous a conduits à comparer ses réactions au greffage avec celles de clones apparentés diploïde et tétraploïde. L’étude histologique des phénomènes de cicatrisation a permis d’écarter, d’une part, la possibilité de l’existence d’une anomalie dans la structure de la tige du sujet haploïde et, d’autre part, l’hypothèse d’une incompatibilité due à la différence de niveau de ploïdie entre le porte-greffe et le greffon. Par contre, la grande inégalité entre les diamètres des deux symbiotes semble retarder les processus d’union et pourrait être à l’origine d’une mauvaise nutrition du greffon haploïde. Des essais comparatifs portant sur des porte-greffes conférant différentes vigueurs ont confirmé ces observations. Le porte-greffe « Malling 9 », de vigueur faible et d’un diamètre proche de celui du greffon, est désormais utilisé pour la multiplication du clone haploïde

Contribution à l’étude d’une plante haploïde de pommier (Malus pumila, Mill.). Etude descriptive et comparaison avec des clones de ploïdie différente. II. - Aptitude à la reprise au greffage

National audienceGreenhouse propagation of a haploid apple by grafting on diploid seedlings proved rather difficult. Accordingly, bud-take of this valuable haplcid clone was compared with that of related diploid and tetraploid clones. Histological study of the union process clearly showed the following points : 1) there was no abnormality in stem structure of the haploid plant ; 2) there was no incompatibility related to the difference of ploidy level between scion and rootstock. However, the large difference in diameter between scion and rootstock seemed to delay the union process, possibly resulting in poor nutrition of the haploid scion. Comparative trials with rootstocks inducing different vigors in the scion have confirmed these observations. The dwarfing rootstock, ’Mailling 9’, is now being used for propagation of the apple haploid clone.La multiplication en serre de la plante haploïde de pommier par greffage sur des porte-greffes diploïdes issus de semis pose de nombreux problèmes. L’originalité du clone haploïde nous a conduits à comparer ses réactions au greffage avec celles de clones apparentés diploïde et tétraploïde. L’étude histologique des phénomènes de cicatrisation a permis d’écarter, d’une part, la possibilité de l’existence d’une anomalie dans la structure de la tige du sujet haploïde et, d’autre part, l’hypothèse d’une incompatibilité due à la différence de niveau de ploïdie entre le porte-greffe et le greffon. Par contre, la grande inégalité entre les diamètres des deux symbiotes semble retarder les processus d’union et pourrait être à l’origine d’une mauvaise nutrition du greffon haploïde. Des essais comparatifs portant sur des porte-greffes conférant différentes vigueurs ont confirmé ces observations. Le porte-greffe « Malling 9 », de vigueur faible et d’un diamètre proche de celui du greffon, est désormais utilisé pour la multiplication du clone haploïde