Comparing cervical cerclage, pessary and vaginal progesterone for prevention of preterm birth in women with a short cervix (SuPPoRT): A multicentre randomised controlled trial.

BACKGROUND: Cervical cerclage, cervical pessary, and vaginal progesterone have each been shown to reduce preterm birth (PTB) in high-risk women, but to our knowledge, there has been no randomised comparison of the 3 interventions. The SuPPoRT "Stitch, Pessary, or Progesterone Randomised Trial" was designed to compare the rate of PTB <37 weeks between each intervention in women who develop a short cervix in pregnancy. METHODS AND FINDINGS: SuPPoRT was a multicentre, open label 3-arm randomised controlled trial designed to demonstrate equivalence (equivalence margin 20%) conducted from 1 July 2015 to 1 July 2021 in 19 obstetric units in the United Kingdom. Asymptomatic women with singleton pregnancies with transvaginal ultrasound cervical lengths measuring <25 mm between 14+0 and 23+6 weeks' gestation were eligible for randomisation (1:1:1) to receive either vaginal cervical cerclage (n = 128), cervical pessary (n = 126), or vaginal progesterone (n = 132). Minimisation variables were gestation at recruitment, body mass index (BMI), and risk factor for PTB. The primary outcome was PTB <37 weeks' gestation. Secondary outcomes included PTB <34 weeks', <30 weeks', and adverse perinatal outcome. Analysis was by intention to treat. A total of 386 pregnant women between 14+0 and 23+6 weeks' gestation with a cervical length <25 mm were randomised to one of the 3 interventions. Of these women, 67% were of white ethnicity, 18% black ethnicity, and 7.5% Asian ethnicity. Mean BMI was 25.6. Over 85% of women had prior risk factors for PTB; 39.1% had experienced a spontaneous PTB or midtrimester loss (>14 weeks gestation); and 45.8% had prior cervical surgery. Data from 381 women were available for outcome analysis. Using binary regression, randomised therapies (cerclage versus pessary versus vaginal progesterone) were found to have similar effects on the primary outcome PTB <37 weeks (39/127 versus 38/122 versus 32/132, p = 0.4, cerclage versus pessary risk difference (RD) -0.7% [-12.1 to 10.7], cerclage versus progesterone RD 6.2% [-5.0 to 17.0], and progesterone versus pessary RD -6.9% [-17.9 to 4.1]). Similarly, no difference was seen for PTB <34 and 30 weeks, nor adverse perinatal outcome. There were some differences in the mild side effect profile between interventions (vaginal discharge and bleeding) and women randomised to progesterone reported more severe abdominal pain. A small proportion of women did not receive the intervention as per protocol; however, per-protocol and as-treated analyses showed similar results. The main study limitation was that the trial was underpowered for neonatal outcomes and was stopped early due to the COVID-19 pandemic. CONCLUSIONS: In this study, we found that for women who develop a short cervix, cerclage, pessary, and vaginal progesterone were equally efficacious at preventing PTB, as judged with a 20% equivalence margin. Commencing with any of the therapies would be reasonable clinical management. These results can be used as a counselling tool for clinicians when managing women with a short cervix. TRIAL REGISTRATION: EU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.

"I had given up on being a mother": a survey of 183 women's experience of transabdominal cerclage (TAC).

BACKGROUND: Transabdominal cerclage (TAC) is a relatively uncommon intervention for preventing preterm birth. This study aimed to investigate the experience of women who had undergone this procedure. METHODS: The survey was designed in collaboration with a preterm birth studies public and patient involvement (PPI) group and ethical approval was granted by KCL BDM Research Ethics Panel (LRS-19/20-13205). Members of closed Facebook group, UK TAC Support, were invited to complete an online questionnaire about their experience of TAC, and pregnancies before and after having it placed. The survey was open between December 2019 and May 2020. Open and closed questions provided both qualitative and quantitative data for analysis, which was carried out using NVivo Pro 2020 v.1.4.1 qualitative data management software and SPSS Statistics 27 (IBM). RESULTS: One hundred eighty-three participants completed the survey, having had TAC procedures carried out in 36 hospitals. Altogether, participants had experienced 287 preterm births (PTB) and late miscarriages (LM), equating to an average of 1.6 each (range 0-5), including 18 stillbirths. TAC was indicated in 123 (67%) for previous PTB and/or LM, 29 (16%) for cervical surgery and 31 (17%) for both. 151 (83%) TAC procedures were open, 32 (17%) laparoscopic. 86% (n = 157) were placed outside pregnancy. Of those placed in pregnancy, gestation at TAC ranged from 7 to 16 weeks. When comparing earliest pre- and post-TAC pregnancy gestation (excluding first trimester losses), median gestational weeks gained following TAC was 15.5 weeks (SD 6.89). Qualitative themes included: the struggle to get treatment; lack of TAC knowledge amongst clinicians; gratitude, hope and feeling protected; possible detrimental effects of TAC. CONCLUSIONS: This very high-risk group found having a TAC gave great reassurance and hope, and were very grateful to have found the care they needed. However, they often struggled to get this support, frequently due to lack of clinician awareness. This may improve following roll-out of NHS England's Saving Babies Live Care Bundle and NHS commissioning guidelines for care of women at risk of PTB.

Longitudinal change in cervical length following vaginal or abdominal cervical cerclage: a randomized comparison.

BACKGROUND: Cervical cerclage has been shown to reduce the risk of recurrent spontaneous preterm birth in a high-risk patient population; however, the mechanism is not well understood. Transabdominal cerclage is superior to low and high vaginal cerclage in reducing early spontaneous preterm birth and fetal loss in women with previous failed vaginal cerclage. Cervical length measurements are commonly used to monitor high-risk women and may explain the mechanism of success. OBJECTIVE: This study aimed to evaluate the rate of change in longitudinal cervical length after randomized placement of low transvaginal, high transvaginal, or transabdominal cerclage in women with a previous failed vaginal cerclage. STUDY DESIGN: This was a planned analysis of longitudinal transvaginal ultrasound cervical length measurements from patients enrolled in the Vaginal Randomised Intervention of Cerclage trial, a randomized controlled trial comparing transabdominal cerclage or high transvaginal cerclage with low transvaginal cerclage. Cervical length measurements at specific gestational ages were compared over time and between groups, using generalized estimating equations fitted using the maximum-likelihood random-effects estimator. In addition, cervical length measurements were compared in women with transabdominal cerclage placed before and during pregnancy. The diagnostic accuracy of cervical length as a predictor of spontaneous preterm birth at <32 weeks of gestation was explored. RESULTS: This study included 78 women who underwent longitudinal cervical length assessment (70% of the analyzed cohort) with a history of failed cerclage, of whom 25 (32%) were randomized to low transvaginal cerclage, 26 (33%) to high transvaginal cerclage, and 27 (35%) to transabdominal cerclage. Abdominal cerclage was superior to low (P=.008) and high (P=.001) vaginal cerclage at maintaining cervical length over the surveillance period (14 to 26 weeks of gestation) (+0.08 mm/week, 95% confidence interval, -0.40 to 0.22; P=.580). On average, the cervical length was 1.8 mm longer by the end of the 12-week surveillance period in women with transabdominal cerclage (+1.8 mm; 95% confidence interval, -7.89 to 4.30; P=.564). High vaginal cerclage was no better than low cervical cerclage in the prevention of cervical shortening; the cervix shortened by 13.2 mm over 12 weeks in those with low vaginal cerclage (95% confidence interval, -21.7 to -4.7; P=.002) and by 20 mm over 12 weeks in those with high vaginal cerclage (95% confidence interval, -33.1 to -7.4; P=.002). Preconception transabdominal cerclage resulted in a longer cervix than those performed during pregnancy; this difference was significant after 22 weeks of gestation (48.5 mm vs 39.6 mm; P=.039). Overall, cervical length was an excellent predictor of spontaneous preterm birth at <32 weeks of gestation (receiver operating characteristic curve, 0.92; 95% confidence interval, 0.82-1.00). CONCLUSION: In women with a previous failed cervical cerclage, in the next pregnancy, the cervical length in women treated with vaginal cerclage funneled and shortened over time, whereas there was preservation of cervical length in women who receive transabdominal cerclage. Cervical length remained longer in transabdominal procedures performed before pregnancy than in transabdominal procedures performed during pregnancy. Overall, cervical length was an excellent predictor of spontaneous preterm birth in our cohort. Our findings may explain the mechanism of benefit for transabdominal cerclage, with its high placement better maintaining the structural integrity of the cervix at the level of the internal os.

The Tommy's Clinical Decision Tool, a device for reducing the clinical impact of placental dysfunction and preterm birth: protocol for a mixed-methods early implementation evaluation study.

BACKGROUND: Disparities in stillbirth and preterm birth persist even after correction for ethnicity and social deprivation, demonstrating that there is wide geographical variation in the quality of care. To address this inequity, Tommy's National Centre for Maternity Improvement developed the Tommy's Clinical Decision Tool, which aims to support the provision of "the right care at the right time", personalising risk assessment and care according to best evidence. This web-based clinical decision tool assesses the risk of preterm birth and placental dysfunction more accurately than current methods, and recommends best evidenced-based care pathways in a format accessible to both women and healthcare professionals. It also provides links to reliable sources of pregnancy information for women. The aim of this study is to evaluate implementation of Tommy's Clinical Decision Tool in four early-adopter UK maternity services, to inform wider scale-up. METHODS: The Tommy's Clinical Decision Tool has been developed involving maternity service users and healthcare professionals in partnership. This mixed-methods study will evaluate: maternity service user and provider acceptability and experience; barriers and facilitators to implementation; reach (whether particular groups are excluded and why), fidelity (degree to which the intervention is delivered as intended), and unintended consequences. Data will be gathered over 25 months through interviews, focus groups, questionnaires and through the Tommy's Clinical Decision Tool itself. The NASSS framework (Non-adoption or Abandonment of technology by individuals and difficulties achieving Scale-up, Spread and Sustainability) will inform data analysis. DISCUSSION: This paper describes the intervention, Tommy's Clinical Decision Tool, according to TiDIER guidelines, and the protocol for the early adopter implementation evaluation study. Findings will inform future scale up. TRIAL REGISTRATION: This study was prospectively registered on the ISRCTN registry no. 13498237 , on 31st January 2022.

Prior term delivery increases risk of subsequent recurrent preterm birth: An unexpected finding.

BACKGROUND: Women with a prior pregnancy at term are generally considered to be at reduced risk for subsequent spontaneous preterm birth (sPTB), whereas a previous sPTB is a major predictor for a future sPTB. AIMS: The objective of this study was to investigate the risk of recurrent sPTB in women with a prior term birth and a subsequent sPTB. MATERIALS AND METHODS: This is a retrospective cohort study conducted at St Thomas' Hospital in London, UK. There were 430 women included: 230 with a term birth (caesarean section or vaginal delivery) preceding a sPTB (term + sPTB group) and 200 with a prior sPTB only (sPTB only group). The primary outcome was sPTB, <37 weeks gestation. RESULTS: Of the term + sPTB group, 38.7% (89/230) had a recurrent sPTB compared to 20% (40/200) in the sPTB only group (P < 0.0001), with a relative risk (RR) of 1.9. Of women who had a term caesarean section and a subsequent PTB, 50% (30/60) had a further sPTB (RR 2.5 compared to the sPTB only group), while 34.7% (59/170) of women who had a term vaginal birth and subsequent sPTB, had a further sPTB (RR 1.7 compared to the sPTB only group). CONCLUSION: In women who have had a previous sPTB, the risk of a recurrence is much higher than in women with a prior term birth. The aetiology of PTB may be different in this subgroup of women and needs to be further elucidated to determine how best to identify and treat them.

Previous term emergency caesarean section is a risk factor for recurrent spontaneous preterm birth; a retrospective cohort study.

OBJECTIVES: Emergency caesarean sections (EmCS), particularly those performed in the second stage of labour, have been associated with a risk of subsequent preterm birth. More worrying is that the risk of sPTB recurrence appears to be high in women who have had a second stage EmCS and a subsequent sPTB. However, there is a paucity of evidence regarding the risk of recurrence in women who have had a prior term EmCS at any stage of labour followed by a sPTB. This study aims to investigate the relationship between all term in labour EmCS and the risk of recurrent spontaneous preterm birth (sPTB). STUDY DESIGN: This is an observational, retrospective cohort study conducted at St Thomas' Hospital, a tertiary-level maternity hospital in London, United Kingdom. 259 women were included; 59 women with a term in labour EmCS preceding a sPTB (EmCS group) and 200 women with a prior sPTB only (control group). The initial EmCS was further categorised into first stage (FS)-EmCS or second stage (SS)-EmCS. Primary outcome was sPTB in Pregnancy C < 37 weeks' gestation. Secondary outcomes included sPTB < 34 weeks' and < 24 weeks' gestation. RESULTS: 54% (32/59) of the EmCS group had a recurrent sPTB < 37 weeks compared to 20% (40/200) of the control women (p < 0.0001) with a relative risk of 2.71 [95%CI 1.87-3.87]). Of women who had a SS-EmCS and a subsequent PTB, 61.9% (13/21) had a further sPTB (RR 3.0 [95%CI, 1.8-4.5] compared to control women). In addition, there is nearly a 6-fold increased risk of a recurrent sPTB or midtrimester loss < 24 weeks' gestation in these women (RR 5.65 [95%CI2.6-12.0]). CONCLUSIONS: In women who have had a previous sPTB in which a term in labour EmCS is a risk factor, the risk of a further sPTB is much higher than in those women where a prior sPTB is the sole risk factor. Furthermore, EmCS at both the first and second stage of labour are associated with a increased risk of recurrent sPTB. Further work should ascertain which women who have had a prior term EmCS are at risk of sPTB and recurrence, and how best to identify and treat them.

Evaluating the use of the QUiPP app and its impact on the management of threatened preterm labour: A cluster randomised trial.

BACKGROUND: Preterm delivery (before 37 weeks of gestation) is the single most important contributor to neonatal death and morbidity, with lifelong repercussions. However, the majority of women who present with preterm labour (PTL) symptoms do not deliver imminently. Accurate prediction of PTL is needed in order ensure correct management of those most at risk of preterm birth (PTB) and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the majority. The QUantitative Innovation in Predicting Preterm birth (QUIPP) app aims to support clinical decision-making about women in threatened preterm labour (TPTL) by combining quantitative fetal fibronectin (qfFN) values, cervical length (CL), and significant PTB risk factors to create an individualised percentage risk of delivery. METHODS AND FINDINGS: EQUIPTT was a multi-centre cluster randomised controlled trial (RCT) involving 13 maternity units in South and Eastern England (United Kingdom) between March 2018 and February 2019. Pregnant women (n = 1,872) between 23+0 and 34+6 weeks' gestation with symptoms of PTL in the analysis period were assigned to either the intervention (762) or control (1,111). The mean age of the study population was 30.2 (+/- SD 5.93). A total of 56.0% were white, 19.6% were black, 14.2% were Asian, and 10.2% were of other ethnicities. The intervention was the use of the QUiPP app with admission, antenatal corticosteroids (ACSs), and transfer advised for women with a QUiPP risk of delivery >5% within 7 days. Control sites continued with their conventional management of TPTL. Unnecessary management for TPTL was a composite primary outcome defined by the sum of unnecessary admission decisions (admitted and delivery interval >7 days or not admitted and delivery interval ≤7 days) and the number of unnecessary in utero transfer (IUT) decisions/actions (IUT that occurred or were attempted >7 days prior to delivery) and ex utero transfers (EUTs) that should have been in utero (attempted and not attempted). Unnecessary management of TPTL was 11.3% (84/741) at the intervention sites versus 11.5% (126/1094) at control sites (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.66-1.42, p = 0.883). Control sites frequently used qfFN and did not follow UK national guidance, which recommends routine treatment below 30 weeks without testing. Unnecessary management largely consisted of unnecessary admissions which were similar at intervention and control sites (10.7% versus 10.8% of all visits). In terms of adverse outcomes for women in TPTL <36 weeks, 4 women from the intervention sites and 12 from the control sites did not receive recommended management. If the QUiPP percentage risk was used as per protocol, unnecessary management would have been 7.4% (43/578) versus 9.9% (134/1,351) (OR 0.72, 95% CI 0.45-1.16). Our external validation of the QUiPP app confirmed that it was highly predictive of delivery in 7 days; receiver operating curve area was 0.90 (95% CI 0.85-0.95) for symptomatic women. Study limitations included a lack of compliance with national guidance at the control sites and difficulties in implementation of the QUiPP app. CONCLUSIONS: This cluster randomised trial did not demonstrate that the use of the QUiPP app reduced unnecessary management of TPTL compared to current management but would safely improve the management recommended by the National Institute for Health and Care Excellence (NICE). Interpretation of qfFN, with or without the QUiPP app, is a safe and accurate method for identifying women most likely to benefit from PTL interventions. TRIAL REGISTRATION: ISRCTN Registry ISRCTN17846337.

Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms.

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

CRAFT (Cerclage after full dilatation caesarean section): protocol of a mixed methods study investigating the role of previous in-labour caesarean section in preterm birth risk.

BACKGROUND: Full dilatation caesarean sections are associated with recurrent early spontaneous preterm birth and late miscarriage. The risk following first stage caesarean sections, are less well defined, but appears to be increased in late-first stage of labour. The mechanism for this increased risk of late miscarriage and early spontaneous preterm birth in these women is unknown and there are uncertainties with regards to clinical management. Current predictive models of preterm birth (based on transvaginal ultrasound and quantitative fetal fibronectin) have not been validated in these women and it is unknown whether the threshold to define a short cervix (≤25 mm) is reliable in predicting the risk of preterm birth. In addition the efficacy of standard treatments or whether benefit may be derived from prophylactic interventions such as a cervical cerclage is unknown. METHODS: There are three distinct components to the CRAFT project (CRAFT-OBS, CRAFT-RCT and CRAFT-IMG). CRAFT-OBS: Observational Study; To evaluate subsequent pregnancy risk of preterm birth in women with a prior caesarean section in established labour. This prospective study of cervical length and quantitative fetal fibronectin data will establish a predictive model of preterm birth. CRAFT-RCT: Randomised controlled trial arm; To assess treatment for short cervix in women at high risk of preterm birth following a fully dilated caesarean section. CRAFT-IMG: Imaging sub-study; To evaluate the use of MRI and transvaginal ultrasound imaging of micro and macrostructural cervical features which may predispose to preterm birth in women with a previous fully dilated caesarean section, such as scar position and niche. DISCUSSION: The CRAFT project will quantify the risk of preterm birth or late miscarriage in women with previous in-labour caesarean section, define the best management and shed light on pathological mechanisms so as to improve the care we offer to women and their babies. TRIAL REGISTRATION: CRAFT was prospectively registered on 25th November 2019 with the ISRCTN registry ( https://doi.org/10.1186/ISRCTN15068651 ).

Efficacy of transvaginal cervical cerclage in women at risk of preterm birth following previous emergency cesarean section.

INTRODUCTION: Emergency cesarean sections (EMCS) are associated with subsequent preterm birth, particularly at full dilation (FDCS), which is a cause of both second trimester miscarriages and early, recurrent spontaneous preterm birth (sPTB). The optimal management for these women in subsequent pregnancies is currently unknown. This study aims to assess efficacy of transvaginal cervical cerclage (TVC) in prevention of preterm birth among women who have had an EMCS followed by a subsequent late miscarriage or sPTB. MATERIAL AND METHODS: A historical cohort study was performed assessing outcomes of women attending the Preterm Surveillance Clinic at St Thomas' Hospital, London, who received TVC, with a history of EMCS (pregnancy A) followed by a sPTB/late miscarriage (pregnancy B) and a subsequent pregnancy (pregnancy C). A historical reference group managed in the same clinic was identified comprising women with any risk factor for sPTB, who required TVC. Incidence of delivery >24 to <30 weeks' gestation was compared with relative risk and 95% confidence intervals (CI). Subgroup analysis was carried out assessing women who had a previous FDCS. RESULTS: 209 women with a previous EMCS during labor (50 with FDCS), followed by sPTB/late miscarriage were identified. 178 progressed beyond 24 weeks; of these, 56 received TVC and formed the study group. 905 high-risk women were identified; of these, 154 received TVC and formed the reference group. Despite TVC treatment, 17/56 (30%) of the study group delivered <30 weeks' gestation compared with 5/154 (3%) of the reference group (RR 9.4, 95% CI 3.6-24.2, P < .001). In the subset of 17 women in the study group with a previous FDCS, followed by sPTB/late miscarriage, 6/17 (35%) delivered <30 weeks' gestation, significantly higher than the reference group (P < .001) but similar to EMCS at less than full dilation (35% vs 28%, P = .596). Overall, 33/72 (46%) women receiving cerclage with prior EMCS had either a mid-trimester loss or delivery <30 weeks. CONCLUSIONS: Transvaginal cervical cerclage appears less effective in preventing preterm birth among pregnant women who have had an EMCS followed by a sPTB/late miscarriage compared with other high-risk women. The lack of efficacy in the subgroup with an FDCS was similar.

Effects of 5-HT2C, 5-HT1A receptor challenges and modafinil on the initiation and persistence of gambling behaviours.

RATIONALE: Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. OBJECTIVES: These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. RESULTS: As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. CONCLUSIONS: We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.

The relationship of self-compassion and hope with quality of life for individuals with bleeding disorders.

INTRODUCTION: Minimal research has been conducted examining the relationship of positive psychology variables with quality of life (QOL) for individuals with bleeding disorders. While many individuals manage their bleeding disorders well, some are at higher risk of developing psychosocial complications due to the daily stressors of managing illness-related symptoms. AIM: The purpose of this study is to better understand the relationships between two positive psychology variables, self-compassion and hope and QOL (overall, psychosocial and physical) among individuals diagnosed with bleeding disorders. METHODS: Participants completed a survey identifying demographic information as well as rating scales of self-compassion, hope and quality of life. We conducted Pearson correlational and standard multiple regression analyses to explore the bivariate and linear relationships between the aforementioned variables in a sample of 86 patients with bleeding disorders between the ages of 15 and 65. RESULTS: Self-compassion and hope were significantly related to QOL. Together, self-compassion and hope were predictive of overall QOL, psychosocial QOL and physical QOL. However, hope was the only individual predictor of all three QOL dimensions. CONCLUSION: Due to the significant relationships found between self-compassion, hope and QOL in this sample, it may be beneficial to incorporate positive psychology factors into the treatment of those diagnosed with bleeding disorders, especially those at higher risk for decreased QOL.

MAVRIC: a multicenter randomized controlled trial of transabdominal vs transvaginal cervical cerclage.

BACKGROUND: Vaginal cerclage (a suture around the cervix) commonly is placed in women with recurrent pregnancy loss. These women may experience late miscarriage or extreme preterm delivery, despite being treated with cerclage. Transabdominal cerclage has been advocated after failed cerclage, although its efficacy is unproved by randomized controlled trial. OBJECTIVE: The objective of this study was to compare transabdominal cerclage or high vaginal cerclage with low vaginal cerclage in women with a history of failed cerclage. Our primary outcome was delivery at <32 completed weeks of pregnancy. STUDY DESIGN: This was a multicenter randomized controlled trial. Women were assigned randomly (1:1:1) to receive transabdominal cerclage, high vaginal cerclage, or low vaginal cerclage either before conception or at <14 weeks of gestation. RESULTS: The data for 111 of 139 women who were recruited and who conceived were analyzed: 39 had transabdominal cerclage; 39 had high vaginal cerclage, and 33 had low vaginal cerclage. Rates of preterm birth at <32 weeks of gestation were significantly lower in women who received transabdominal cerclage compared with low vaginal cerclage (8% [3/39] vs 33% [11/33]; relative risk, 0.23; 95% confidence interval, 0.07-0.76; P=.0157). The number needed to treat to prevent 1 preterm birth was 3.9 (95% confidence interval, 2.32-12.1). There was no difference in preterm birth rates between high and low vaginal cerclage (38% [15/39] vs 33% [11/33]; relative risk, 1.15; 95% confidence interval, 0.62-2.16; P=.81). No neonatal deaths occurred. In an exploratory analysis, women with transabdominal cerclage had fewer fetal losses compared with low vaginal cerclage (3% [1/39] vs 21% [7/33]; relative risk, 0.12; 95% confidence interval, 0.016-0.93; P=.02). The number needed to treat to prevent 1 fetal loss was 5.3 (95% confidence interval, 2.9-26). CONCLUSION: Transabdominal cerclage is the treatment of choice for women with failed vaginal cerclage. It is superior to low vaginal cerclage in the reduction of risk of early preterm birth and fetal loss in women with previous failed vaginal cerclage. High vaginal cerclage does not confer this benefit. The numbers needed to treat are sufficiently low to justify transabdominal surgery and cesarean delivery required in this select cohort.

Mobile phone apps for clinical decision support in pregnancy: a scoping review.

BACKGROUND: The use of digital technology in healthcare has been found to be useful for data collection, provision of health information and communications. Despite increasing use of medical mobile phone applications (apps), by both clinicians and patients, there appears to be a paucity of peer-reviewed publications evaluating their use, particularly in pregnancy. This scoping review explored the use of mobile phone apps for clinical decision support in pregnancy. Specific objectives were to: 1. determine the current landscape of mobile phone app use for clinical decision support in pregnancy; 2. identify perceived benefits and potential hazards of use and 3. identify facilitators and barriers to implementation of these apps into clinical practice. METHODS: Papers eligible for inclusion were primary research or reports on the development and evaluation of apps for use by clinicians for decision support in pregnancy, published in peer-reviewed journals. Research databases included Medline, Embase, PsychoInfo, the Cochrane Database of Systematic Reviews and the online digital health journals JMIR mHealth and uHealth. Charting and thematic analysis was undertaken using NVivo qualitative data management software and the Framework approach. RESULTS: After screening for eligibility, 13 papers were identified, mainly reporting early stage development of the mobile app, and feasibility or acceptability studies designed to inform further development. Thematic analysis revealed four main themes across the included papers: 1. acceptability and satisfaction; 2. ease of use and portability; 3. multi-functionality and 4. the importance of user involvement in development and evaluation. CONCLUSIONS: This review highlights the benefits of mobile apps for clinical decision support in pregnancy and potential barriers to implementation, but reveals a lack of rigorous reporting of evaluation of their use and data security. This situation may change, however, following the issue of FDA and MHRA guidelines and implementation of UK government and other international strategies. Overall, the findings suggest that ease of use, portability and multi-functionality make mobile apps for clinical decision support in pregnancy useful and acceptable tools for clinicians.

Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility.

The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

Feeding behaviour, risk-sensitivity and response control: effects of 5-HT2C receptor manipulations.

People, like animals, tend to choose the variable option when given the choice between a fixed and variable delay to reward where, in the variable delay condition, some rewards are available immediately (Laura-Jean et al. 2019 Phil. Trans. R. Soc. B 374, 20180141. ( doi:10.1098/rstb.2018.0141 )). This bias has been suggested to reflect evolutionary pressures resulting from food scarcity in the past placing a premium on obtaining food quickly that can win out against the risks of sometimes sustaining longer delays to food. The psychologies mediating this effect may become maladaptive in the developed world where food is readily available contributing, potentially, to overeating and obesity. Here, we report our development of a novel touchscreen task in mice allowing comparisons of the impact of food delay and food magnitude across species. We show that mice exhibit the typical preference, as shown by humans, for variable over fixed delays to rewards but no preference when it comes to fixed versus variable reward amounts and further show that this bias is sensitive to manipulations of the 5-HT2C receptor, a key mediator of feeding and impulse control. We discuss the data in terms of the utility of the task to model the psychologies and underlying brain mechanisms impacting on feeding behaviours. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

EQUIPTT: The Evaluation of the QUiPP app for Triage and Transfer protocol for a cluster randomised trial to evaluate the impact of the QUiPP app on inappropriate management for threatened preterm labour.

BACKGROUND: Accurate diagnosis of preterm labour is needed to ensure correct management of those most at risk of preterm birth and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the large majority of women, who do not deliver within a week of presentation. Intervention "just-in-case" results in many avoidable admissions, women being transferred out of their local hospital unnecessarily and most women receiving unwarranted drugs, such as steroids and tocolytics. It also precludes appropriate transfers for others as neonatal cots are blocked pre-emptively, resulting in more dangerous ex-utero transfers. We have developed the QUiPP App which is a clinical decision-making aid based on previous outcomes of women, quantitative fetal fibronectin (qfFN) values and cervical length. It is hypothesised that using the QUiPP app will reduce inappropriate admissions and transfers. METHODS: A multi-site cluster randomised trial will evaluate whether the QUiPP app reduces inappropriate management for threatened preterm labour. The 13 participating centres will be randomly allocated to receive either intervention or control. If the QUiPP app calculates risk of delivery within 7 days to be is less than 5%, clinicians are advised that interventions may be withheld. Women's experience of threatened preterm labour assessment will be explored using self-completed questionnaires, with a subset of participants being invited to semi-structured interview. A health economics analysis is also planned. DISCUSSION: We hypothesise that the QUiPP app will improve identification of the most appropriate women for admission and transfer and ensure that therapies known to reduce risk of preterm neonatal morbidities are offered to those who need them. We will determine which women do not require these therapies, thereby reducing over-medicalisation and the associated maternal and fetal risks for these women. The findings will inform future national guidelines on threatened preterm labour. Beyond obstetrics, evaluating the impact of an app in an emergency setting, and our emphasis on balancing harms of over-treatment as well as under-treatment, make EQUIPTT a valuable contribution to translational medicine. TRIAL REGISTRATION: The EQUIPTT trial was prospectively registered on 16th January 2018 with the ISRCTN registry (no. 17846337 ).