Maternal iron status in early pregnancy and birth outcomes : insights from the Baby's Vascular health and Iron in Pregnancy study

Date of Acceptance: 16/03/2015 Acknowledgements N. A. A. was funded by a Wellcome Trust Research Training Fellowship (WT87789). H. J. M. and H. E. H. are supported by the Scottish Government’s Rural and Environment Science and Analytical Services. N. A. B. S. is supported by Cerebra. The authors’ contributions are as follows: N. A. A. was responsible for organising the study conduct, data collection and database management, performed the statistical analysis, interpreted the results and drafted the paper. N. A. A., N. A. B. S., J. E. C., H. J. M. and D. C. G. contributed to the study concept and design, and interpretation of results. H. J. M. and H. E. H. analysed the laboratory samples. J. E. C. and D. C. G. provided advice on statistical strategy and analysis. All authors have fully participated in the reporting stage and have critically reviewed and approved the final draft of the paper. The authors declare no conflict of interestPeer reviewedPublisher PD

Prediction of Small for Gestational Age Infants in Healthy Nulliparous Women Using Clinical and Ultrasound Risk Factors Combined with Early Pregnancy Biomarkers

Objective Most small for gestational age pregnancies are unrecognised before birth, resulting in substantial avoidable perinatal mortality and morbidity. Our objective was to develop multivariable prediction models for small for gestational age combining clinical risk factors and biomarkers at 15±1 weeks’ with ultrasound parameters at 20±1 weeks’ gestation. Methods Data from 5606 participants in the Screening for Pregnancy Endpoints (SCOPE) cohort study were divided into Training (n = 3735) and Validation datasets (n = 1871). The primary outcomes were All-SGA (small for gestational age with birthweight <10th customised centile), Normotensive-SGA (small for gestational age with a normotensive mother) and Hypertensive-SGA (small for gestational age with an hypertensive mother). The comparison group comprised women without the respective small for gestational age phenotype. Multivariable analysis was performed using stepwise logistic regression beginning with clinical variables, and subsequent additions of biomarker and then ultrasound (biometry and Doppler) variables. Model performance was assessed in Training and Validation datasets by calculating area under the curve. Results 633 (11.2%) infants were All-SGA, 465(8.2%) Normotensive-SGA and 168 (3%) Hypertensive-SGA. Area under the curve (95% Confidence Intervals) for All-SGA using 15±1 weeks’ clinical variables, 15±1 weeks’ clinical+ biomarker variables and clinical + biomarkers + biometry /Doppler at 20±1 weeks’ were: 0.63 (0.59–0.67), 0.64 (0.60–0.68) and 0.69 (0.66–0.73) respectively in the Validation dataset; Normotensive-SGA results were similar: 0.61 (0.57–0.66), 0.61 (0.56–0.66) and 0.68 (0.64–0.73) with small increases in performance in the Training datasets. Area under the curve (95% Confidence Intervals) for Hypertensive-SGA were: 0.76 (0.70–0.82), 0.80 (0.75–0.86) and 0.84 (0.78–0.89) with minimal change in the Training datasets. Conclusion Models for prediction of small for gestational age, which combine biomarkers, clinical and ultrasound data from a cohort of low-risk nulliparous women achieved modest performance. Incorporation of biomarkers into the models resulted in no improvement in performance of prediction of All-SGA and Normotensive-SGA but a small improvement in prediction of Hypertensive-SGA. Our models currently have insufficient reliability for application in clinical practice however, they have potential utility in two-staged screening tests which include third trimester biomarkers and or fetal biometry

Use of metabolomics for the identification and validation of clinical biomarkers for preterm birth:Preterm SAMBA

Made available in DSpace on 2018-12-11T17:29:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-08-08Background: Spontaneous preterm birth is a complex syndrome with multiple pathways interactions determining its occurrence, including genetic, immunological, physiologic, biochemical and environmental factors. Despite great worldwide efforts in preterm birth prevention, there are no recent effective therapeutic strategies able to decrease spontaneous preterm birth rates or their consequent neonatal morbidity/mortality. The Preterm SAMBA study will associate metabolomics technologies to identify clinical and metabolite predictors for preterm birth. These innovative and unbiased techniques might be a strategic key to advance spontaneous preterm birth prediction. Methods/design: Preterm SAMBA study consists of a discovery phase to identify biophysical and untargeted metabolomics from blood and hair samples associated with preterm birth, plus a validation phase to evaluate the performance of the predictive modelling. The first phase, a case-control study, will randomly select 100 women who had a spontaneous preterm birth (before 37 weeks) and 100 women who had term birth in the Cork Ireland and Auckland New Zealand cohorts within the SCOPE study, an international consortium aimed to identify potential metabolomic predictors using biophysical data and blood samples collected at 20 weeks of gestation. The validation phase will recruit 1150 Brazilian pregnant women from five participant centres and will collect blood and hair samples at 20 weeks of gestation to evaluate the performance of the algorithm model (sensitivity, specificity, predictive values and likelihood ratios) in predicting spontaneous preterm birth (before 34 weeks, with a secondary analysis of delivery before 37 weeks). Discussion: The Preterm SAMBA study intends to step forward on preterm birth prediction using metabolomics techniques, and accurate protocols for sample collection among multi-ethnic populations. The use of metabolomics in medical science research is innovative and promises to provide solutions for disorders with multiple complex underlying determinants such as spontaneous preterm birth.University of Campinas (UNICAMP) School of Medical Sciences Department of Obstetrics and Gynecology, R. Alexander Fleming, 101University of Auckland Gravida: National Centre for Growth and Development Liggins InstituteUniversity College Cork Irish Centre for Fetal and Neonatal Translational Research (INFANT) Department of Obstetrics and GynaecologyUniversity of Auckland South Auckland Clinical School Faculty of Medical and Health SciencesUniversity of Auckland School of Biological SciencesUniversity of Campinas (UNICAMP) LNBio-Brazilian Biosciences National Laboratory and School of Medical SciencesSchool of Medical Sciences University of CampinasLNBioSchool of Medicine of Botucatu UNESPSchool of Medicine Federal University of Rio Grande do SulSchool of Medicine Federal University of PernambucoSchool of Medicine Federal University of CearáKing's College London and King's Health PartnersMaternal and Fetal Health Research Centre University of ManchesterUniversity of LeedsUniversity of AdelaideSchool of Medicine of Botucatu UNES

Maternal alcohol intake prior to and during pregnancy and risk of adverse birth outcomes: evidence from a British cohort

Background: Evidence is conflicting regarding the relationship between low maternal alcohol consumption and birth outcomes. This paper aimed to investigate the association between alcohol intake before and during pregnancy with birth weight and gestational age and to examine the effect of timing of exposure. Methods: A prospective cohort in Leeds, UK, of 1303 pregnant women aged 18–45 years. Questionnaires assessed alcohol consumption before pregnancy and for the three trimesters separately. Categories of alcohol consumption were divided into ≤2 units/week and >2 units/week with a non-drinking category as referent. This was related to size at birth and preterm delivery, adjusting for confounders including salivary cotinine as a biomarker of smoking status. Results: Nearly two-thirds of women before pregnancy and over half in the first trimester reported alcohol intakes above the Department of Health (UK) guidelines of ≤2 units/week. Associations with birth outcomes were strongest for intakes >2 units/week before pregnancy and in trimesters 1 and 2 compared to non-drinkers. Even women adhering to the guidelines in the first trimester were at significantly higher risk of having babies with lower birth weight, lower birth centile and preterm birth compared to non-drinkers, after adjusting for confounders (p<0.05). Conclusions: We found the first trimester to be the period most sensitive to the effect of alcohol on the developing fetus. Women adhering to guidelines in this period were still at increased risk of adverse birth outcomes. Our findings suggest that women should be advised to abstain from alcohol when planning to conceive and throughout pregnanc

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes

Monitoring Flower Visitation Networks and Interactions between Pairs of Bumble Bees in a Large Outdoor Flight Cage

This research was supported by a combined grant from the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, and the Engineering and Physical Sciences Research Council (BB/F52765X/1). While writing, ML was supported by the IDEX of the Federal University of Toulouse (Starting and Emergence grants), the Fyssen foundation and the CNRS. NER was supported as the Rebanks Family Chair in Pollinator Conservation by The W. Garfield Weston Foundation. LC was supported by ERC Advanced Grant SpaceRadarPollinator and by a Royal Society Wolfson Research Merit Award

Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort

Abstract: Background: Severe iodine insufficiency in pregnancy has significant consequences, but there is inadequate evidence to indicate what constitutes mild or moderate insufficiency, in terms of observed detrimental effects on pregnancy or birth outcomes. A limited number of studies have examined iodine status and birth outcomes, finding inconsistent evidence for specific outcomes. Methods: Maternal iodine status was estimated from spot urine samples collected at 26–28 weeks’ gestation from 6971 mothers in the Born in Bradford birth cohort. Associations with outcomes were examined for both urinary iodine concentration (UIC) and iodine-to-creatinine ratio (I:Cr). Outcomes assessed included customised birthweight (primary outcome), birthweight, small for gestational age (SGA), low birthweight, head circumference and APGAR score. Results: There was a small positive association between I:Cr and birthweight in adjusted analyses. For a typical participant, the predicted birthweight centile at the 25th percentile of I:Cr (59 μg/g) was 2.7 percentage points lower than that at the 75th percentile of I:Cr (121 μg/g) (99% confidence interval (CI) 0.8 to 4.6), birthweight was predicted to be 41 g lower (99% CI 13 to 69) and the predicted probability of SGA was 1.9 percentage points higher (99% CI 0.0 to 3.7). There was no evidence of associations using UIC or other birth outcomes, including stillbirth, preterm birth, ultrasound growth measures or congenital anomalies. Conclusion: Lower maternal iodine status was associated with lower birthweight and greater probability of SGA. Whilst small, the effect size for lower iodine on birthweight is comparable to environmental tobacco smoke exposure. Iodine insufficiency is avoidable, and strategies to avoid deficiency in women of reproductive age should be considered. Trial registration: ClinicalTrials.gov NCT03552341. Registered on June 11, 2018

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy