Quantitative Analysis of the Cervical Texture by Ultrasound and Correlation with Gestational Age

Objectives: Quantitative texture analysis has been proposed to extract robust features from the ultrasound image to detect subtle changes in the textures of the images. The aim of this study was to evaluate the feasibility of quantitative cervical texture analysis to assess cervical tissue changes throughout pregnancy. Methods: This was a cross-sectional study including singleton pregnancies between 20.0 and 41.6 weeks of gestation from women who delivered at term. Cervical length was measured, and a selected region of interest in the cervix was delineated. A model to predict gestational age based on features extracted from cervical images was developed following three steps: data splitting, feature transformation, and regression model computation. Results: Seven hundred images, 30 per gestational week, were included for analysis. There was a strong correlation between the gestational age at which the images were obtained and the estimated gestational age by quantitative analysis of the cervical texture (R = 0.88). Discussion: This study provides evidence that quantitative analysis of cervical texture can extract features from cervical ultrasound images which correlate with gestational age. Further research is needed to evaluate its applicability as a biomarker of the risk of spontaneous preterm birth, as well as its role in cervical assessment in other clinical situations in which cervical evaluation might be relevant

Quantitative ultrasound texture analysis of fetal lungs to predict neonatal respiratory morbidity

Objective To develop and evaluate the performance of a novel method for predicting neonatal respiratory morbidity based on quantitative analysis of the fetal lung by ultrasound. Methods More than 13¿000 non-clinical images and 900 fetal lung images were used to develop a computerized method based on texture analysis and machine learning algorithms, trained to predict neonatal respiratory morbidity risk on fetal lung ultrasound images. The method, termed ‘quantitative ultrasound fetal lung maturity analysis’ (quantusFLM™), was then validated blindly in 144 neonates, delivered at 28¿+¿0 to 39¿+¿0¿weeks' gestation. Lung ultrasound images in DICOM format were obtained within 48¿h of delivery and the ability of the software to predict neonatal respiratory morbidity, defined as either respiratory distress syndrome or transient tachypnea of the newborn, was determined. Results Mean (SD) gestational age at delivery was 36¿+¿1 (3¿+¿3) weeks. Among the 144 neonates, there were 29 (20.1%) cases of neonatal respiratory morbidity. Quantitative texture analysis predicted neonatal respiratory morbidity with a sensitivity, specificity, positive predictive value and negative predictive value of 86.2%, 87.0%, 62.5% and 96.2%, respectively. Conclusions Quantitative ultrasound fetal lung maturity analysis predicted neonatal respiratory morbidity with an accuracy comparable to that of current tests using amniotic fluid.Peer ReviewedPostprint (published version

Association of neurexin 3 polymorphisms with smoking behavior.

The Neurexin 3 gene (NRXN3) has been associated with dependence on various addictive substances, as well as with the degree of smoking in schizophrenic patients and impulsivity among tobacco abusers. To further evaluate the role of NRXN3 in nicotine addiction, we analyzed single nucleotide polymorphisms (SNPs) and a copy number variant (CNV) within the NRXN3 genomic region. An initial study was carried out on 157 smokers and 595 controls, all of Spanish Caucasian origin. Nicotine dependence was assessed using the Fagerstrom index and the number of cigarettes smoked per day. The 45 NRXN3 SNPs genotyped included all the SNPs previously associated with disease, and a previously described deletion within NRXN3. This analysis was replicated in 276 additional independent smokers and 568 controls. Case-control association analyses were performed at the allele, genotype and haplotype levels. Allelic and genotypic association tests showed that three NRXN3 SNPs were associated with a lower risk of being a smoker. The haplotype analysis showed that one block of 16 Kb, consisting of two of the significant SNPs (rs221473 and rs221497), was also associated with lower risk of being a smoker in both the discovery and the replication cohorts, reaching a higher level of significance when the whole sample was considered [odds ratio = 0.57 (0.42-0.77), permuted P = 0.0075]. By contrast, the NRXN3 CNV was not associated with smoking behavior. Taken together, our results confirm a role for NRXN3 in susceptibility to smoking behavior, and strongly implicate this gene in genetic vulnerability to addictive behaviors

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Objective To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU ) population as part of an application for European Medicines Agency (EMA ) orphan designation. Design Incidence estimation based on literature review and published national and EU statistics. Setting and population European Union. Methods Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. Results The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93–3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07–3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. Conclusions Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life‐threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits

Research Letter: Is neuroticism a risk factor for postpartum depression?

Although the relationship between personality and depressive illness is complex (Shea, 2005), there is empirical evidence that some personality features such as neuroticism, harm avoidance, introversion, dependency, self-criticism or perfectionism are related to depressive illness risk (Gunderson et al. 1999).This work was supported by the Instituto Carlos III (Spanish Ministry of Health; grant numbers P1041635, PI041783, PI041779, PI0411761, PI041791, PI041766 and PI041782), as well as the Spanish Psychiatric Genetics and Genotyping network G03/184, RTA (RD06/001/1009), and Generalitat de Catalunya, SGR2009/1435).Ye

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood

Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson's two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates

Loss of Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter-dependency between Akt-1 and heme oxygenase-1

Aims - Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-ß (TGF-ß) signalling, which is known to be elevated in preeclampsia. Methods and results - Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Aktdn) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Aktmyr) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Aktmyr to mice significantly reduced circulating sEng, whereas Aktdn promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Aktmyr failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng. Conclusion - The loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction