Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial

OBJECTIVE: We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. DESIGN: Parallel-group, non-masked, randomised controlled trial SETTING: 46 UK maternity units POPULATION: Women with pre-eclampsia between 34+0 and 36+6 weeks' gestation, without severe disease, were randomised to planned delivery or expectant management. PRIMARY LONG-TERM OUTCOME: Infant neurodevelopmental outcome at 2 years of age, using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. RESULTS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were enrolled in the trial, with 450 allocated to planned delivery and 451 to expectant management. At 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) to expectant management. The mean composite standardised PARCA-R scores were 89.5 (standard deviation (SD) 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of -2.4 (95% CI -5.4 to 0.5) points. CONCLUSION: In infants of women with late preterm pre-eclampsia, average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management is pursued. Because of lower than anticipated follow-up, there was limited power to demonstrate these scores were not different, but the small between-group difference in PARCA-R scores is unlikely to be clinically important

Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway

The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFNinduced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N-(methylcarbamoyl)-2-([5-(4- methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl)-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse geneticsbased loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection

Cost-Utility Analysis of Planned Early Delivery or Expectant Management for Late Preterm Pre-eclampsia (PHOENIX)

Aim: There is currently limited evidence on the costs associated with late preterm pre-eclampsia beyond antenatal care and post-natal discharge from hospital. The aim of this analysis is to evaluate the 24-month cost-utility of planned delivery for women with late preterm pre-eclampsia at 34+0–36+6 weeks’ gestation compared to expectant management from an English National Health Service perspective using participant-level data from the PHOENIX trial. Methods: Women between 34+0 and 36+6 weeks’ gestation in 46 maternity units in England and Wales were individually randomised to planned delivery or expectant management. Resource use was collected from hospital records between randomisation and primary hospital discharge following birth. Women were followed up at 6 months and 24 months following birth and self-reported resource use for themselves and their infant(s) covering the previous 6 months. Women completed the EQ-5D 5L at randomisation and follow-up. Results: A total of 450 women were randomised to planned delivery, 451 to expectant management: 187 and 170 women, respectively, had complete data at 24 months. Planned delivery resulted in a significantly lower mean cost per woman and infant(s) over 24 months (− £2711, 95% confidence interval (CI) − 4840 to − 637), with a mean incremental difference in QALYs of 0.019 (95% CI − 0.039 to 0.063). Short-term and 24-month infant costs were not significantly different between the intervention arms. There is a 99% probability that planned delivery is cost-effective at all thresholds below £37,000 per QALY gained. Conclusion: There is a high probability that planned delivery is cost-effective compared to expectant management. These results need to be considered alongside clinical outcomes and in the wider context of maternity care. Trial registration: ISRCTN registry ISRCTN01879376. Registered 25 November 2013

4 '-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4 '-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4 '-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4 '-phosphopantetheine as a candidate therapeutic for PKAN

A multiorganism pipeline for antiseizure drug discovery:Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant

OBJECTIVE:Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS:We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS:Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE:These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions

Planned delivery or expectant management for late preterm pre-eclampsia:study protocol for a randomised controlled trial (PHOENIX trial)

Abstract Background Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks’ gestation, without increasing problems related to infant immaturity or complications, remains unclear. Methods/design The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks’ gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Discussion Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. Trial registration ISRCTN01879376. Registered on 25 November 2013

Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): A randomised controlled trial

ObjectiveWe evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes.DesignParallel-group, non-masked, randomised controlled trial.SettingForty-six maternity units in the UK.PopulationWomen with pre-eclampsia between 34+0 and 36+6 weeks of gestation, without severe disease, were randomised to planned delivery or expectant management.Main outcome measuresInfant neurodevelopmental outcome at 2 years of age, using the Parent Report of Children’s Abilities – Revised (PARCA-R) composite score.ResultsBetween 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 women allocated to planned delivery and 451 women allocated to expectant management. At the 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) allocated to expectant management. The mean composite standardised PARCA-R scores were 89.5 (SD 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of −2.4 points (95% CI −5.4 to 0.5 points).ConclusionsIn infants of women with late preterm pre-eclampsia, the average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management was pursued. With the lower than anticipated follow-up rate there was limited power to demonstrate that these scores did not differ, but the small between-group difference in PARCA-R scores is unlikely to be clinically important

Controls on subaerial erosion rates in Antarctica

Erosion rates offer insight on landscape development and the relative importance of chemical and physical processes of weathering. Minimal chemical weathering makes Antarctica an ideal location in which to compare the physical weathering of carbonate rocks to other lithologies. Here we report the first cosmogenic nuclide-derived erosion rates for carbonate rocks in Antarctica. Carbonate samples collected in the southernmost Ellsworth Mountains reflect a 36Cl erosion rate of 0.22 ± 0.02 mm/ka. This erosion rate is consistent with other reported Antarctic erosion rates, but is lower than 36Cl erosion rates derived from other arid regions in the world. These results are integrated with a continent-wide reanalysis of 28 erosion rate studies (>200 measurements), which comprise numerous rock types and other cosmogenic nuclides. By combining cosmogenic nuclide-derived erosion rates across studies, the larger trends provide insight into factors (e.g. lithology, glacial history, and availability of abrasive material) affecting subaerial erosion rates in Antarctica. Statistical analysis of the compiled data set shows differences based on lithology, with sandstone having the largest range of erosion rates. The compiled data also reveals higher erosion rates in areas with a large potential sediment supply, like the Dry Valleys. Samples collected from boulders yield lower erosion rates than those collected from bedrock, likely due to a combination of physical processes that affect boulders and bedrock differently, and glacial history, which can affect the apparent cosmogenic-nuclide derived erosion rate

Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial

© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. Methods: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. Findings: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79–0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08–1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. Interpretation: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. Funding: National Institute for Health Research Health Technology Assessment Programme