Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial

Background Previous prospective cohort studies have shown that angiogenic factors have a high diagnostic accuracy in women with suspected pre-eclampsia, but we remain uncertain of the effectiveness of these tests in a real-world setting. We therefore aimed to determine whether knowledge of the circulating concentration of placental growth factor (PlGF), an angiogenic factor, integrated with a clinical management algorithm, decreased the time for clinicians to make a diagnosis in women with suspected pre-eclampsia, and whether this approach reduced subsequent maternal or perinatal adverse outcomes. Methods We did a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial in 11 maternity units in the UK, which were each responsible for 3000–9000 deliveries per year. Women aged 18 years and older who presented with suspected pre-eclampsia between 20 weeks and 0 days of gestation and 36 weeks and 6 days of gestation, with a live, singleton fetus were invited to participate by the clinical research team. Suspected pre-eclampsia was defined as new-onset or worsening of existing hypertension, dipstick proteinuria, epigastric or right upper-quadrant pain, headache with visual disturbances, fetal growth restriction, or abnormal maternal blood tests that were suggestive of disease (such as thrombocytopenia or hepatic or renal dysfunction). Women were approached individually, they consented for study inclusion, and they were asked to give blood samples. We randomly allocated the maternity units, representing the clusters, to blocks. Blocks represented an intervention initiation time, which occurred at equally spaced 6-week intervals throughout the trial. At the start of the trial, all units had usual care (in which PlGF measurements were also taken but were concealed from clinicians and women). At the initiation time of each successive block, a site began to use the intervention (in which the circulating PlGF measurement was revealed and a clinical management algorithm was used). Enrolment of women continued for the duration of the blocks either to concealed PlGF testing, or after implementation, to revealed PlGF testing. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia in women enrolled in the trial who received a diagnosis of pre-eclampsia by their treating clinicians. This trial is registered with ISRCTN, number 16842031. Findings Between June 13, 2016, and Oct 27, 2017, we enrolled and assessed 1035 women with suspected pre-eclampsia. 12 (1%) women were found to be ineligible. Of the 1023 eligible women, 576 (56%) women were assigned to the intervention (revealed testing) group, and 447 (44%) women were assigned to receive usual care with additional concealed testing (concealed testing group). Three (1%) women in the revealed testing group were lost to follow-up, so 573 (99%) women in this group were included in the analyses. One (99%) women in this group were included in the analyses. The median time to pre-eclampsia diagnosis was 4·1 days with concealed testing versus 1·9 days with revealed testing (time ratio 0·36, 95% CI 0·15–0·87; p=0·027). Maternal severe adverse outcomes were reported in 24 (5%) of 447 women in the concealed testing group versus 22 (4%) of 573 women in the revealed testing group (adjusted odds ratio 0·32, 95% CI 0·11–0·96; p=0·043), but there was no evidence of a difference in perinatal adverse outcomes (15% vs 14%, 1·45, 0·73–2·90) or gestation at delivery (36·6 weeks vs 36·8 weeks; mean difference −0·52, 95% CI −0·63 to 0·73). Interpretation We found that the availability of PlGF test results substantially reduced the time to clinical confirmation of pre-eclampsia. Where PlGF was implemented, we found a lower incidence of maternal adverse outcomes, consistent with adoption of targeted, enhanced surveillance, as recommended in the clinical management algorithm for clinicians. Adoption of PlGF testing in women with suspected pre-eclampsia is supported by the results of this study

Placental growth fActor Repeat sampling for Reduction of adverse perinatal Outcomes in women with suspecTed pre-eclampsia: study protocol for a randomised controlled trial (PARROT-2)

Background Pre-eclampsia is a complex pregnancy disorder, characterised by new or worsening hypertension associated with multi-organ dysfunction. Adverse outcomes include eclampsia, liver rupture, stroke, pulmonary oedema, and acute kidney injury in the mother, and stillbirth, foetal growth restriction, and iatrogenic preterm delivery for the foetus. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing for suspected preterm pre-eclampsia has been incorporated into national guidance. The role of repeat PlGF-based testing and its effect on maternal and perinatal adverse outcomes have yet to be evaluated. Methods The PARROT-2 trial is a multi-centre randomised controlled trial of repeat revealed PlGF-based testing compared to repeat concealed testing, in women presenting with suspected pre-eclampsia between 22+0 and 35+6 weeks’ gestation. The primary objective is to establish whether repeat PlGF-based testing decreases a composite of perinatal severe adverse outcomes (stillbirth, early neonatal death, or neonatal unit admission). All women prior to enrolment in the trial will have an initial revealed PlGF-based test. Repeat PlGF-based tests will be performed weekly or two-weekly, depending on the initial PlGF-based test result, with results randomised to revealed or concealed. Discussion National guidance recommends that all women presenting with suspected preterm pre-eclampsia should have a single PlGF-based test when disease is first suspected, to help rule out pre-eclampsia. Clinical and cost-effectiveness of repeat PlGF-based testing has yet to be investigated. This trial aims to address whether repeat PlGF-based testing reduces severe maternal and perinatal adverse outcomes and whether repeat testing is cost-effective. Trial registration ISRCTN 85912420. Registered on 25 November 201

Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism

Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with “protein glycosylation” and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda

BACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success

Evaluation of a novel device for the management of high blood pressure and shock in pregnancy in low-resource settings: study protocol for a stepped-wedge cluster-randomised controlled trial (CRADLE-3 trial).

BackgroundObstetric haemorrhage, sepsis and pregnancy hypertension account for more than 50% of maternal deaths worldwide. Early detection and effective management of these conditions relies on vital signs. The Microlife® CRADLE Vital Sign Alert (VSA) is an easy-to-use, accurate device that measures blood pressure and pulse. It incorporates a traffic-light early warning system that alerts all levels of healthcare provider to the need for escalation of care in women with obstetric haemorrhage, sepsis or pregnancy hypertension, thereby aiding early recognition of haemodynamic instability and preventing maternal mortality and morbidity. The aim of the trial was to determine whether implementation of the CRADLE intervention (the Microlife® CRADLE VSA device and CRADLE training package) into routine maternity care in place of existing equipment will reduce a composite outcome of maternal mortality and morbidity in low- and middle-income country populations.MethodsThe CRADLE-3 trial was a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care. Each cluster crossed from routine maternity care to the intervention at 2-monthly intervals over the course of 20 months (April 2016 to November 2017). All women identified as pregnant or within 6 weeks postpartum, presenting for maternity care in cluster catchment areas were eligible to participate. Primary outcome data (composite of maternal death, eclampsia and emergency hysterectomy per 10,000 deliveries) were collected at 10 clusters (Gokak, Belgaum, India; Harare, Zimbabwe; Ndola, Zambia; Lusaka, Zambia; Free Town, Sierra Leone; Mbale, Uganda; Kampala, Uganda; Cap Haitien, Haiti; South West, Malawi; Addis Ababa, Ethiopia). This trial was informed by the Medical Research Council guidance for complex interventions. A process evaluation was undertaken to evaluate implementation in each site and a cost-effectiveness evaluation will be undertaken.DiscussionAll aspects of this protocol have been evaluated in a feasibility study, with subsequent optimisation of the intervention. This trial will demonstrate the potential impact of the CRADLE intervention on reducing maternal mortality and morbidity in low-resource settings. It is anticipated that the relatively low cost of the intervention and ease of integration into existing health systems will be of significant interest to local, national and international health policy-makers.Trial registrationISCRTN41244132. Registered on 2 February 2016. Prospective protocol modifications have been recorded and were communicated to the Ethics Committees and Trials Committees. The adapted Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist and the SPIRIT Checklist are attached as Additional file 1

Decision-making, cognitive distortions and alcohol use in adolescent problem and non-problem gamblers: an experimental study

In the psychological literature, many studies have investigated the neuropsychological and behavioral changes that occur developmentally during adolescence. These studies have consistently observed a deficit in the decision-making ability of children and adolescents. This deficit has been ascribed to incomplete brain development. The same deficit has also been observed in adult problem and pathological gamblers. However, to date, no study has examined decision-making in adolescents with and without gambling problems. Furthermore, no study has ever examined associations between problem gambling, decision-making, cognitive distortions and alcohol use in youth. To address these issues, 104 male adolescents participated in this study. They were equally divided in two groups, problem gamblers and non-problem gamblers, based on South Oaks Gambling Screen Revised for Adolescents scores. All participants performed the Iowa Gambling Task and completed the Gambling Related Cognitions Scale and the Alcohol Use Disorders Identification Test. Adolescent problem gamblers displayed impaired decision-making, reported high cognitive distortions, and had more problematic alcohol use compared to non-problem gamblers. Strong correlations between problem gambling, alcohol use, and cognitive distortions were observed. Decision-making correlated with interpretative bias. This study demonstrated that adolescent problem gamblers appear to have the same psychological profile as adult problem gamblers and that gambling involvement can negatively impact on decision-making ability that, in adolescence, is still developing. The correlations between interpretative bias and decision-making suggested that the beliefs in the ability to influence gambling outcomes may facilitate decision-making impairment

The gene structure and expression of human ABHD1: overlapping polyadenylation signal sequence with Sec12

BACKGROUND: Overlapping sense/antisense genes orientated in a tail-to-tail manner, often involving only the 3'UTRs, form the majority of gene pairs in mammalian genomes and can lead to the formation of double-stranded RNA that triggers the destruction of homologous mRNAs. Overlapping polyadenylation signal sequences have not been described previously. RESULTS: An instance of gene overlap has been found involving a shared single functional polyadenylation site. The genes involved are the human alpha/beta hydrolase domain containing gene 1 (ABHD1) and Sec12 genes. The nine exon human ABHD1 gene is located on chromosome 2p23.3 and encodes a 405-residue protein containing a catalytic triad analogous to that present in serine proteases. The Sec12 protein promotes efficient guanine nucleotide exchange on the Sar1 GTPase in the ER. Their sequences overlap for 42 bp in the 3'UTR in an antisense manner. Analysis by 3' RACE identified a single functional polyadenylation site, ATTAAA, within the 3'UTR of ABHD1 and a single polyadenylation signal, AATAAA, within the 3'UTR of Sec12. These polyadenylation signals overlap, sharing three bp. They are also conserved in mouse and rat. ABHD1 was expressed in all tissues and cells examined, but levels of ABHD1 varied greatly, being high in skeletal muscle and testis and low in spleen and fibroblasts. CONCLUSIONS: Mammalian ABHD1 and Sec12 genes contain a conserved 42 bp overlap in their 3'UTR, and share a conserved TTTATTAAA/TTTAATAAA sequence that serves as a polyadenylation signal for both genes. No inverse correlation between the respective levels of ABHD1 and Sec12 RNA was found to indicate that any RNA interference occurred