Maternal folate, one-carbon metabolism and pregnancy outcomes

Single nucleotide polymorphisms and pre- and peri-conception folic acid (FA) supplementation and dietary data were used to identify one-carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 μg daily FA at 15-week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 μg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L-1 vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre- and early-pregnancy dietary factors, are independent risk factors for pregnancy complications.Tanja Jankovic-Karasoulos, Denise L. Furness, Shalem Y. Leemaqz, Gustaaf A. Dekker, Luke E. Grzeskowiak, Jessica A. Grieger, Prabha H. Andraweera, Dylan McCullough, Dale McAninch, Lesley M. McCowan, Tina Bianco-Miotto, Claire T. Robert

Near-intrinsic energy resolution for 30-662 keV gamma rays in a high pressure xenon electroluminescent TPC

We present the design, data and results from the NEXT prototype for Double Beta and Dark Matter (NEXT-DBDM) detector, a high-pressure gaseous natural xenon electroluminescent time projection chamber (TPC) that was built at the Lawrence Berkeley National Laboratory. It is a prototype of the planned NEXT-100 136Xe neutrino-less double beta decay (0νββ) experiment with the main objectives of demonstrating near-intrinsic energy resolution at energies up to 662 keV and of optimizing the NEXT-100 detector design and operating parameters. Energy resolutions of ∼1% FWHM for 662 keV gamma rays were obtained at 10 and 15 atm and ∼5% FWHM for 30 keV fluorescence xenon X-rays. These results demonstrate that 0.5% FWHM resolutions for the 2,459 keV hypothetical neutrino-less double beta decay peak are realizable. This energy resolution is a factor 7 to 20 better than that of the current leading 0νββ experiments using liquid xenon and thus represents a significant advancement. We present also first results from a track imaging system consisting of 64 silicon photo-multipliers recently installed in NEXT-DBDM that, along with the excellent energy resolution, demonstrates the key functionalities required for the NEXT-100 0νββ search

STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): An international consortium of randomised placebo-controlled trials

Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.  Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.  Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis

Relative importance of metabolic syndrome components for developing gestational diabetes

Published online: 16 October 2021Purpose: To assess the independent and joint contribution of the individual components of metabolic syndrome, and known risk factors for gestational diabetes (GDM), on risk of GDM. Methods: Two thousand nine hundred and fifteen women from Australia and New Zealand, who participated in The Screening for Pregnancy Endpoints Study (SCOPE), were included. Using the SCOPE clinical data set and biomarkers obtained at 14–16 weeks’ gestation, a logistic regression model was fitted to the binary outcome GDM, with individual metabolic syndrome components (waist circumference, blood pressure, glucose, HDL-C, triglycerides), recruitment site, and other established factors associated with GDM. Hierarchical partitioning was used to assess the relative contribution of each variable. Results: Of the 2915 women, 103 women (3.5%) developed GDM. The deviance explained by the logistic regression model containing all variables was 18.65% and the AUC was 0.809. Seventy percent of the independent effect was accounted for by metabolic syndrome components. The highest independent relative contribution to GDM was circulating triglycerides (17 ± 3%), followed by waist circumference (13 ± 3%). Glucose and maternal BMI contributed 12 ± 2% and 12 ± 3%, respectively. The remaining factors had an independent relative contribution of < 10%. Conclusion: Triglyceride concentrations had the highest independent relative importance for risk of GDM. Increased focus for lowering triglycerides as an important risk factor for GDM is warranted.Jessica A. Grieger, Shalem Y. Leemaqz, Emma J. Knight, Luke E. Grzeskowiak, Lesley M. McCowan, Gustaaf A. Dekker, Claire T. Robert

Metabolic syndrome and time to pregnancy: a retrospective study of nulliparous women

OBJECTIVE:To determine: (1) the association between metabolic syndrome (MetS), time to pregnancy (TTP), and infertility; (2) associations between individual and an increasing number of MetS components, TTP, and infertility; and (3) whether these relationships differ by body mass index (BMI  12 months) were compared using a generalised linear model (Poisson distribution) with robust variance estimates (relative risks, RRs; 95% CIs). All analyses (entire cohort and split by BMI) were controlled for a range of maternal and paternal confounding factors. MAIN OUTCOME MEASURES:Time to pregnancy and infertility. RESULTS:Of the 5519 women included, 12.4% (n = 684) had MetS. Compared with women without MetS, women with MetS had a longer TTP (adjusted TR 1.30; 95% CI 1.15-1.46), which was similar in women who were obese and in women who were not obese. Marginal estimates for median TTP in women with MetS versus without MetS was 3.1 months (3.0-3.3 months) versus 4.1 months (3.6-4.5 months), respectively. Women with MetS were at a 62% greater risk for infertility and were at a greater risk for infertility whether they were obese (adjusted RR 1.62; 95% CI 1.15-2.29) or not (adjusted RR 1.73; 95% CI 1.33-2.23). Reduced high-density lipoprotein cholesterol (HDL-C) and raised triglycerides (TGs) were the main individual components associated with risk for infertility. CONCLUSION:Metabolic syndrome is associated with longer TTP and infertility, independent of obesity. Additional studies, before pregnancy, are required to support our findings and to determine the applicability of which combinations of metabolic abnormalities pose the greatest risk to delayed fertility, or whether individual components are amenable to modification. TWEETABLE ABSTRACT:Metabolic syndrome is associated with longer time to pregnancy and infertility, independent of obesity.JA Grieger, LE Grzeskowiak, LG Smithers, T Bianco, Miotto, SY Leemaqz, P Andraweera, L Poston, LM McCowan, LC Kenny, J Myers, JJ Walker, RJ Norman, GA Dekker, CT Robert

Receptor density influences ligand-induced dopamine D2L receptor homodimerization

Chronic treatments with dopamine D2 receptor ligands induce fluctuations in D2 receptor density. Since D2 receptors tend to assemble as homodimers, we hypothesized that receptor density might influence constitutive and ligand-induced homodimerization. Using a nanoluciferase-based complementation assay to monitor dopamine D2L receptor homodimerization in a cellular model enabling the tetracycline-controlled expression of dopamine D2L receptors, we observed that increasing receptor density promoted constitutive dopamine D2L receptor homodimerization. Receptor full agonists promoted homodimerization, while antagonists and partial agonists disrupted dopamine D2L receptor homodimers. High receptor densities enhanced this inhibitory effect only for receptor antagonists. Taken together, our findings indicate that both receptor density and receptor ligands influence dopamine D2L receptor homodimerization, albeit excluding any strict correlation with ligands’ intrinsic activity and highlighting further complexity to dopaminergic pharmacology