Study protocol for the randomised controlled trial: combined multimarker screening and randomised patient treatment with ASpirin for evidence-based PREeclampsia prevention (ASPRE)

This is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.INTRODUCTION: Pre-eclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. Prophylactic use of low-dose aspirin in women at risk for PE may substantially reduce the prevalence of the disease. Effective screening for PE requiring delivery before 37 weeks (preterm PE) can be provided by a combination of maternal factors, uterine artery Doppler, mean arterial pressure, maternal serum pregnancy-associated plasma protein A and placental growth factor at 11-13 weeks' gestation, with a detection rate of 75% at a false-positive rate of 10%. We present a protocol (V.6, date 25 January 2016) for the ASpirin for evidence-based PREeclampsia prevention (ASPRE) trial, which is a double-blinded, placebo-controlled, randomised controlled trial (RCT) that uses an effective PE screening programme to determine whether low-dose aspirin given to women from 11 to 13 weeks' gestation will reduce the incidence of preterm PE. METHODS AND ANALYSIS: All eligible women attending for their first trimester scan will be invited to participate in the screening study for preterm PE. Those found to be at high risk of developing preterm PE will be invited to participate in the RCT. Further scans will be conducted for assessment of fetal growth and biomarkers. Pregnancy and neonatal outcomes will be collected and analysed. The first enrolment for the pilot study was in April 2014. As of April 2016, 26 670 women have been screened and 1760 recruited to the RCT. The study is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry. TRIAL REGISTRATION NUMBER: ISRCTN13633058.This study is supported by grants from the European Union 7th Framework Programme—FP7-HEALTH-2013-INNOVATION-2 (ASPRE Project # 601852) and the Fetal Medicine Foundation (FMF) (Charity No: 1037116)

ROX Index to Guide Management of COVID-19 Pneumonia

Coronavirus disease 2019 (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged from China in December 2019 leading to a global pandemic (1). Approximately 17% of patients admitted to hospital require critical care, the majority of whom undergo mechanical ventilation (MV) for pneumonia complicated by hypoxaemia (2)

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

Ultraluminous Infrared Galaxies

At luminosities above ~10^{11} L_sun, infrared galaxies become the dominant population of extragalactic objects in the local Universe (z < 0.5), being more numerous than optically selected starburst and Seyfert galaxies, and QSOs at comparable bolometric luminosity. At the highest luminosities, ultraluminous infrared galaxies (ULIGs: L_ir > 10^{12} L_sun), outnumber optically selected QSOs by a factor of ~1.5-2. All of the nearest ULIGs (z < 0.1) appear to be advanced mergers that are powered by both a circumnuclear starburst and AGN, both of which are fueled by an enormous concentration of molecular gas (~10^{10} M_sun) that has been funneled into the merger nucleus. ULIGs may represent a primary stage in the formation of massive black holes and elliptical galaxy cores. The intense circumnuclear starburst that accompanies the ULIG phase may also represent a primary stage in the formation of globular clusters, and the metal enrichment of the intergalactic medium by gas and dust expelled from the nucleus due to the combined forces of supernova explosions and powerful stellar winds.Comment: LaTex, 6 pages with 4 embedded .eps figures. Postscript version plus color plates available at http://www.ifa.hawaii.edu/users/sanders/astroph/s186/plates.html To appear in "Galaxy Interactions at Low and High Redshift" IAU Symposium 186, Kyoto, Japan, eds. J.E. Barnes and D.B. Sander

Integration of genetic and physical maps of the Primula vulgaris S locus and localization by chromosome in situ hybridization

•Heteromorphic flower development in Primula is controlled by the S locus. The S locus genes, which control anther position, pistil length and pollen size in pin and thrum flowers, have not yet been characterized. We have integrated S-linked genes, marker sequences and mutant phenotypes to create a map of the P. vulgaris S locus region that will facilitate the identification of key S locus genes. We have generated, sequenced and annotated BAC sequences spanning the S locus, and identified its chromosomal location. •We have employed a combination of classical genetics and three-point crosses with molecular genetic analysis of recombinants to generate the map. We have characterized this region by Illumina sequencing and bioinformatic analysis, together with chromosome in situ hybridization. •We present an integrated genetic and physical map across the P. vulgaris S locus flanked by phenotypic and DNA sequence markers. BAC contigs encompass a 1.5-Mb genomic region with 1 Mb of sequence containing 82 S-linked genes anchored to overlapping BACs. The S locus is located close to the centromere of the largest metacentric chromosome pair. •These data will facilitate the identification of the genes that orchestrate heterostyly in Primula and enable evolutionary analyses of the S locus

Deceptive body movements reverse spatial cueing in soccer

This article has been made available through the Brunel Open Access Publishing Fund.The purpose of the experiments was to analyse the spatial cueing effects of the movements of soccer players executing normal and deceptive (step-over) turns with the ball. Stimuli comprised normal resolution or point-light video clips of soccer players dribbling a football towards the observer then turning right or left with the ball. Clips were curtailed before or on the turn (-160, -80, 0 or +80 ms) to examine the time course of direction prediction and spatial cueing effects. Participants were divided into higher-skilled (HS) and lower-skilled (LS) groups according to soccer experience. In experiment 1, accuracy on full video clips was higher than on point-light but results followed the same overall pattern. Both HS and LS groups correctly identified direction on normal moves at all occlusion levels. For deceptive moves, LS participants were significantly worse than chance and HS participants were somewhat more accurate but nevertheless substantially impaired. In experiment 2, point-light clips were used to cue a lateral target. HS and LS groups showed faster reaction times to targets that were congruent with the direction of normal turns, and to targets incongruent with the direction of deceptive turns. The reversed cueing by deceptive moves coincided with earlier kinematic events than cueing by normal moves. It is concluded that the body kinematics of soccer players generate spatial cueing effects when viewed from an opponent's perspective. This could create a reaction time advantage when anticipating the direction of a normal move. A deceptive move is designed to turn this cueing advantage into a disadvantage. Acting on the basis of advance information, the presence of deceptive moves primes responses in the wrong direction, which may be only partly mitigated by delaying a response until veridical cues emerge

Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus

Supported by the Dutch Cancer Society (KWF) and Cancer Research UK (CR-UK). This work was supported by Cancer Research UK (grant number A14895

Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour.

AIMS/HYPOTHESIS: Hypothalamic glucose-excited (GE) neurons contribute to whole-body glucose homeostasis and participate in the detection of hypoglycaemia. This system appears defective in type 1 diabetes, in which hypoglycaemia commonly occurs. Unfortunately, it is at present unclear which molecular components required for glucose sensing are produced in individual neurons and how these are functionally linked. We used the GT1-7 mouse hypothalamic cell line to address these issues. METHODS: Electrophysiological recordings, coupled with measurements of gene expression and protein levels and activity, were made from unmodified GT1-7 cells and cells in which AMP-activated protein kinase (AMPK) catalytic subunit gene expression and activity were reduced. RESULTS: Hypothalamic GT1-7 neurons express the genes encoding glucokinase and ATP-sensitive K(+) channel (K(ATP)) subunits K ( ir ) 6.2 and Sur1 and exhibit GE-type glucose-sensing behaviour. Lowered extracellular glucose concentration hyperpolarised the cells in a concentration-dependent manner, an outcome that was reversed by tolbutamide. Inhibition of glucose uptake or metabolism hyperpolarised cells, showing that energy metabolism is required to maintain their resting membrane potential. Short hairpin (sh)RNA directed to Ampkα2 (also known as Prkaa2) reduced GT1-7 cell AMPKα2, but not AMPKα1, activity and lowered the threshold for hypoglycaemia-induced hyperpolarisation. shAmpkα1 (also known as Prkaa1) had no effect on glucose-sensing or AMPKα2 activity. Decreased uncoupling protein 2 (Ucp2) mRNA was detected in AMPKα2-reduced cells, suggesting that AMPKα2 regulates UCP2 levels. CONCLUSIONS/INTERPRETATION: We have demonstrated that GT1-7 cells closely mimic GE neuron glucose-sensing behaviour, and reducing AMPKα2 blunts their responsiveness to hypoglycaemic challenge, possibly by altering UCP2 activity. These results show that suppression of AMPKα2 activity inhibits normal glucose-sensing behaviour and may contribute to defective detection of hypoglycaemia.This study was funded by: grants from the Wellcome Trust (grant numbers 068692 and 086989) and Diabetes UK (grant number RD08/0003681) to M.L.J. Ashford; a Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellowship to C. Beall (grant number 3-576-2010); grants from JDRF and European Foundation for the study of Diabetes to R.J. McCrimmon, and from the British Heart Foundation to A. Jovanović