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Pregestational diabetes mellitus (PGDM) confers an increased risk of adverse maternal and neonatal outcomes [1,2]. Glycaemic control in the medium and long term is commonly evaluated by examining glycosylated haemoglobin (HbA1c) levels. However, the value of HbA1c in pregnancy may be diminished by increased level of red cell turnover characteristic of pregnancy [3,4]. We sought to examine the impact of HbA1c in the first trimester and pre-delivery, and the within-patient change throughout gestation on mode of delivery and birthweight in pregnancies complicated by a pre-pregnancy diagnosis of type I or type II diabetes.A 10-year consecutive cohort of pregnancies complicated by PGDM, from Jan 2010 until Dec 2019, was examined for HbA1c data in the first trimester and within 6 weeks of delivery. Perinatal outcome data, including gestational age at delivery, mode of delivery and birthweight centile, were obtained from hospital records. The Spearman Rank correlation was used to correlate HcA1c levels in the first trimester with birthweight centiles. Non-parametric summaries and rank-based tests, Signed-rank test and Kruskal-Wallis test, were used to compare Hba1c levels.During the 10-year study period, a consecutive cohort of 396 pregnancies that attained a viable gestational age (24 weeks' gestation) and complicated by pregestational diabetes was identified; representing 81 % of the population of pregestational diabetic pregnancies managed by this service during the study period. The median [IQR] HbA1c levels (mmol/mol) in the first trimester, pre-delivery and the differential across gestation were 51 [19] mmol/mol, 43 [11] mmol/mol and -8 [13] mmol/mol, respectively. A statistically significant reduction in HbA1c levels throughout gestation was observed (p 0.001). The median [IQR] birthweight centile was 69 [50 - 96]. The distributions in HbA1c levels and birthweight centiles were heavily skewed. No correlation was identified between HbA1c levels and mode of delivery.Neither baseline HbA1c levels, pre-delivery values, nor trends across gestation appear to impact birthweight centile or mode of delivery in PGDM. While optimising glycaemic control can affect the long term health of the mother, these indices cannot be relied upon to reflect the impact of glycaemic control on fetal growth aberrations that influence mode of delivery.

Purpose:Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers.Experimental Design:Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment.Results:Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance.Conclusions:Subtype classification systems represent canonical “termini a quo” (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.

Supplementary Figures S1 - S8 and Table S1. Fig S1: Analysis of copy number burden in a PDX population trial of REG treated mCRC PDXs. Fig S2: Effect of REG on microvessel density and proliferation according to CNA cluster. Fig S3 - S6: BCL-2 family profiling of mCRC PDX models via quantitative Western blotting. Fig S7: RPPA protein scores indicating proteins' association with the PDX models' response to REG. Fig S8: Western blot validation of differential EPHA2 protein expression between REG post- and pre-treatment progressor and non-progressor PDX models. Table S1: List of antibodies and dilution factors used against desired targets in RPPA analysis.

Background Induction of labour (IOL) at 39 weeks has been shown to decrease maternal and neonatal adverse outcomes. Given the growing demand for 39-week IOL, it is imperative that effective methods be assessed for induction in the outpatient setting. The aim of this study is to answer the clinical question as to whether Dilapan-S® vs Propess® as a method of cervical ripening is non-inferior in the outpatient setting at 39 weeks and to ascertain whether Dilapan-S® 12 h is non-inferior to Dilapan-S® 24 h. Methods This study is an open-label parallel group single-centre randomised trial. Participants are normal risk nulliparous women who have no pregnancy-related or medical contraindication to IOL. Women will be randomised to one of three induction groups—Dilapan-S® (12-h insertion or 24-h insertion) or Propess. Induction will be initiated between 39+0 and 39+4 weeks’ gestation and participants will return home for either 12 or 24 h. They will be readmitted 12/24 h later in order to continue with induction of labour. Patient recruitment will take place over 30 months within a single centre. The study will recruit a maximum 109 women for each study arm. Total duration of participants’ involvement in the trial will be 8 weeks to allow for postpartum follow-up. Discussion This study will definitively answer whether Dilapan-S is non-inferior to Propess® as a method of induction of labour in the outpatient setting and whether cervical ripening with Dilapan-S over a 12-h timeframe is non-inferior to cervical ripening with Dilapan-S over a 24-h timeframe. Trial registration EudraCT Number 2019-004697-25 Registered 14 September 2020

To describe the growth dynamics of fetuses with initial fetal growth restriction (FGR) later outgrowing the 10th centile for estimated fetal weight with respect to perinatal outcomes and maternal factors.A multicenter prospective study recruited 1116 patients for ultrasound surveillance between 2010 and 2012. All pregnancies were growth-restricted singleton gestations between 24 + 0 and 36 + 0 weeks. Biometry and Doppler analysis were carried out, and delivery and adverse perinatal outcomes were recorded.A total of 193 (17%) fetuses outgrew their diagnosis of initial FGR (surpassed the 10th centile) on their last sonogram before delivery. These fetuses were termed "growers," to compare with the true FGR group. The mothers of "growers" were less likely to be smokers (14% vs 25%, P = 0.0001) or affected by hypertensive pregnancy complications (5.2% vs 15%, P = 0.001). Of the growers, 49 (25%) had an abnormal umbilical artery Doppler; however, in most cases (33/49, 67%), this was a single episode of raised umbilical artery pulsatility index, which subsequently normalized.There were dynamic growth changes in FGR fetuses, with 17% outgrowing their original diagnosis. Positive growth spurts more commonly occurred in healthy mothers. Once a fetus had outgrown the 10th centile, antenatal surveillance could be decreased.

Smoking cessation improves pregnancy outcomes, yet there is uncertainty around the efficacy of models of antenatal intervention for smoking cessation in pregnancy.This study aimed to test the Smoking cessation Through Optimization of clinical care in Pregnancy (STOP) clinic as an antenatal care pathway for smoking cessation in pregnancy. The STOP intervention is a smoking cessation clinic staffed by a dedicated multidisciplinary team of obstetricians, midwives, and smoking cessation practitioners, who provide motivational and psychological support and intensive clinical monitoring of pregnancy.This was a pragmatic randomized controlled trial of the STOP clinic compared with routine antenatal care at a tertiary urban maternity hospital delivering8000 infants per year. The primary outcome measured was continuous abstinence from smoking before 28+0 weeks' gestation, sustained throughout the duration of the pregnancy, and validated using biological measures. The secondary outcomes included maternal and fetal morbidity, delivery and neonatal outcomes, smoking outcomes, and qualitative measures.A total of 436 women were randomized, with 430 women included in the primary outcome analysis. Women attending the STOP antenatal clinic were more likely to quit smoking compared with those in routine care (odds ratio, 3.62; 95% confidence interval, 1.43-9.17). In addition, women who continued to smoke in the STOP clinic smoked fewer cigarettes daily at the time of delivery compared with controls: 5±4 in the STOP clinic and 7±5 in the control group (odds ratio, 0.28; 95% confidence interval, 0.13-0.59). However, this intervention did not alter postpartum relapse rates (4.3% intervention arm vs 1.5% control arm, not significant) at 4 to 6 months following delivery. The mean birthweight was similar in the intervention and control arms; however, quitters in both groups had infants with significantly higher birthweights compared with those of continued smokers.The STOP antenatal model of care leads to higher smoking cessation rates among pregnant smokers and lower daily cigarette consumption at time of delivery. Currently, there is no defined or dedicated antenatal pathway for pregnant smokers, despite the high-risk nature of their pregnancies. Our findings suggest that improved smoking cessation rates in pregnancy may be achieved using the holistic approach of the STOP model of care.

The ability to predict the need for emergency Cesarean delivery holds the potential to facilitate birth choices. The objective of the RECIPE study (Reducing Emergency Cesarean delivery and Improving the Primiparous Experience) was to externally validate a Cesarean delivery risk prediction model. This model, developed by the Genesis study, identified five key predictive factors for emergency Cesarean delivery: maternal age, maternal height, BMI, fetal head circumference (HC) and fetal abdominal circumference (AC).This prospective, observational study was conducted in two tertiary referral perinatal centers. Inclusion criteria were as follows: primiparous women with a singleton, cephalic presentation fetus in the absence of fetal growth restriction (FGR), oligohydramnios, pre-eclampsia, pre-existing diabetes mellitus or an indication for planned Cesarean delivery. Between 38 + 0 and 40 + 6 weeks' gestational age, participants attended for prenatal assessment that enabled the determination of an individualized risk calculation for emergency Cesarean delivery during labour based on maternal height, BMI, fetal HC and AC, with crucially both participants and care providers being blinded to the resultant risk prediction score. Labor, delivery and postnatal outcomes were ascertained. Calibration and receiver operator curves were generated to determine the predictive capacity for emergency Cesarean delivery of the Genesis risk prediction model in this cohort.559 primiparous participants were enrolled from May 2017 to April 2019, of whom 142 (25 %) had an emergency Cesarean delivery during labour. Participants with a low predicted risk score (10 %) had a mean predicted rate of 8% (+/- standard deviation of 2%) and a similarly low actual observed rate of Cesarean delivery (8%). Participants with a high predicted risk (50 %) had a mean predicted Cesarean delivery rate of 64 % (+/- standard deviation of 9%) and also had a high actual observed Cesarean delivery rate (62 %). The calibration curve and receiver operating characteristic curve demonstrated that this validation study had comparable discriminatory power for emergency Cesarean delivery to that described in the original Genesis study. The Area Under the Curve (AUC) in Genesis was 0.69, whereas the AUC in RECIPE was 0.72, which reflects good predictive capacity of the risk prediction model.The accuracy of the Genesis Cesarean delivery prediction tool is supported by this validation study.

To characterize abnormal growth processes and their associated cardiovascular abnormalities in SGA fetuses using Individualized Growth Assessment (IGA).This longitudinal investigation utilized a SGA cohort [EFW and BW10th percentile] derived from the PORTO study. Fetuses categorized by their Fetal Growth Pathology Score [FGPS1] patterns [Pattern 2 {Pattern 2 was usually characterized by a single, growth abnormality (67% of cases) of variable magnitude that occurred within two weeks of delivery {median onset age: 37.6 weeks}. The incidence of UA abnormalities was low (25%) while those of MCA and DV/MPI were high {60%, 42%}. Most neonates were of normal size (67%) and delivered at term (67%).Pattern 3 had an initial progressive growth restriction phase, followed by constant but abnormally low growth. Growth pathology had an early onset (median age: 31.6 weeks), was moderate but persistently abnormal. The incidences of cardiovascular abnormalities were moderate [30-50%]. Most neonates were abnormally small (80%) but delivered at term (90%).Pattern 5 had an initial progressive phase with an early onset [onset age {median}: 31.6 weeks]. However, this process was arrested and returned toward normal. Growth pathology magnitudes were minor as were the incidences of cardiovascular abnormalities. Neonatal size was usually normal and all fetuses delivered at term.Characteristics of SGA Growth Restricted, Patterns 2, 3 and 5 are clearly different from those found in SGA Normal or SGA Growth Restricted Pattern 1 groups. They also differed from one another, indicating that growth restriction can manifest itself in several different ways. Pattern 2 is similar to "late" growth restriction reported previously. Patterns 3 and 5 are novel and have been designated as "adaptive" and "recovering" types of growth restriction.

To characterize growth processes and their associated cardiovascular abnormalities in SGA fetuses with normal growth and progressive growth restriction patterns as defined by Individualized Growth Assessment (IGA).A SGA cohort (EFW and BW10th percentile) was derived from the PORTO study that included 47 fetuses with normal growth outcome (SGA Normal) and 34 fetuses with progressive growth restriction (SGA Growth Restricted, Pattern 1). Composite fetal size parameters were used to quantify growth pathology at individual third trimester time points (individual composite Prenatal Growth Assessment Score {icPGAS}) and calculated cumulatively during the third trimester (Fetal Growth Pathology Score 1{FGPS1}). Paired Doppler evaluations of the umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and myocardial performance index (MPI) were used to detect cardiovascular anomalies. Outcome variables were birth age and birth weight.Ranking fetuses with respect to the severity of the 3rd trimester growth pathology (-FGPS1) revealed three subgroups in each of these two groups. In SGA Normal, no (51%), minimal (19%) or minor (30%) growth abnormalities were present. Although vascular flow abnormalities occurred without growth abnormalities (UA: 38%; MCA: 35%), they increased with minor growth disturbances (UA: 64%; MCA: 50%). All fetuses delivered at term and in only 7 cases (minor growth abnormalities subgroup) were the neonates abnormally small based on IGA criteria. In SGA Growth Restricted, Pattern 1, the progression of growth restriction was slow (47%), moderate (21%) and rapid (32%). Corresponding median -FGPS1 values were -1.34%, -2.67% and -4.88%, respectively. The median age of onset was 33.6, 29.7 and 29.7 weeks in these three subgroups. UA abnormalities occurred infrequently in the first two subgroups but were found in all cases of rapidly progressing pathology. Similar results were found for the MCA and DV + MPI Doppler parameters (rapid progression: MCA = 50%; DV + MPI = 50%). Premature delivery occurred less frequently with slow progression but was nearly 100% in the moderately and rapidly progressive subgroups.Negative FGPS1 growth restriction patterns can be used to classify SGA fetuses. Subgroups, based on ranked -FGPS1 values in both SGA Normal and SGA Growth Restricted Pattern 1 groups had marked differences in cardiovascular abnormalities and neonatal outcomes. The characteristics of these two groups are consistent with small, normally growing fetuses and fetuses with "early" growth restriction, respectively.

Screening for developmental hip dysplasia (DDH) continues to evolve with the use of ultrasound (US) in either selective or universal screening methods. The possibility of delayed evidence of DDH, and thus the need for radiographic follow-up at a later stage of development have been suggested by some authors. The aim of this review was to evaluate the number of patients in our hospital network with a normal screening US at 6 weeks with evidence of DDH at the time of radiographic review at 6 months. Secondary aim; to determine the outcomes for these patients. A retrospective review was done to infants undergoing DDH ultrasound screening between January and December 2015. Initial US and radiographs at 6 months were reviewed. Patients with normal screening US who had subsequent radiographs were included for analysis. In total, there were 829 patients included for analysis. Sixty-three patients (8%) had evidence of DDH at 6 months, representing 34% of all DDH diagnoses for the study period. Five of the 63 patients were lost to follow-up. The remaining 58 babies were treated in Boston bracing. Four patients with evidence of persistent DDH were referred for tertiary review. The osteotomy rate in the radiograph diagnosed group was 2%, versus 6% and 3% in the unstable and US diagnosed groups, respectively. Eight percent of patients with a normal screening US had evidence of DDH at time of radiograph at 6 months, reflecting 34% of all our DDH cases for the year. Based on these findings, patients in our hospital network undergo radiographic evaluation at 6 months even if the initial screening US is normal.

OBJECTIVE To compare the obstetric outcomes and socio-demographic factors in electronic cigarette (EC) users with cigarette smokers and non-smokers in pregnancy. DESIGN Prospective observational cohort study. SETTING A large urban maternity hospital delivering almost 8500 infants per year. POPULATION Pregnant women attending for antenatal care. METHODS Electronic cigarette users at time of booking history were prospectively identified. Maternal and neonatal outcomes were compared with those of pregnant smokers and non-smokers. Multiple logistic regression analysis was performed to estimate the association between the explanatory variables and birthweight. MAIN OUTCOMES MEASURES Infant birthweight, gestation at delivery, incidence of low birthweight. RESULTS A total of 218 women with exclusive EC use and 195 women with dual use of both cigarettes and EC, had a live birth during the study period. EC users were of higher socio-economic status than smokers. Infants born to EC users had a mean birthweight of 3470 g (± 555 g), which was similar to that of non-smokers (3471 ± 504 g, P = 0.97) and significantly greater than that of smokers (3166 ± 502 g, P

The objective of this study was to: 1. Establish the median gestational age of spontaneous labour for low-risk nulliparas. 2. Examine the variation in mode of delivery and short-term neonatal outcomes with gestation at onset of spontaneous labour.This is a retrospective observational cohort study conducted at a tertiary obstetric unit. The study population was 12, 323 low risk nulliparous women with singleton pregnancies who experienced spontaneous onset of labour. The study period was over seven years, from Jan 1st 2011 to 31st Dec 2017. Exclusion criteria were multiparity, multi-fetal pregnancy, booking after 14 weeks gestation, antepartum or intrapartum death, or any obstetric or fetal indication for delivery with the exception of post-maturity. Gestation of onset of spontaneous labour, demographic variables and maternal and neonatal outcomes were collected. The primary outcome was median gestational age at onset of spontaneous labour and its distribution at term. Secondary outcomes were mode of delivery and neonatal outcomes including low-apgar score and NICU admission.12, 323 patients were eligible for inclusion. Median gestation for onset of labour was 40.1 weeks gestation, with 80.5% of spontaneous labour occurs by 41 + 0 weeks gestation. The risk of assisted delivery (RR 1.32, 95% CI 1.23 - 1.42), caesarean section (RR 2.17, 95% CI 1.88-2.51) and low-apgar scores (RR 3.13 95% CI 1.50-6.55) increased significantly with spontaneous labour after 41 weeks' gestation.Nulliparous women with low-risk pregnancies are most likely to experience spontaneous labour between 40 + 0 and 40 + 6. 80.5% of spontaneous labour occurred by 41 + 0 weeks gestation. Assisted vaginal delivery, caesarean section and low-apgar scores were significantly more likely with spontaneous labour after 41 weeks' gestation.

There exists uncertainty surrounding the most effective and efficient means of inducing labour, particularly in the setting of an unfavourable cervix. This study aims to determine the merit of repeating dinoprostone administration when a single application has failed to render the cervix favourable for amniotomy.Retrospective analysis of a consecutive cohort of nulliparous women who underwent term induction of labour in a tertiary referral centre in Ireland was conducted over a 12- month period (December 2019 to January 2021). The time-interval from dinoprostone administration to delivery and the incidence of complicated birth, associated with single and sequential dinoprostone dosing, were determined. Comparisons were made using the Chi-square test and logistic regression adjusting for gestational age delivery.586 nulliparous women underwent term induction of labour during the study period. Administration of a single dose of dinoprostone or amniotomy alone were associated with the greatest prospect of an uncomplicated vaginal birth when compared to sequential dinoprostone dosing. Nonetheless, just one in four nulliparous women undergoing induction of labour experienced an unassisted and uncomplicated vaginal birth. The median [interquartile range] for time interval from induction to delivery or decision for caesarean delivery was 0.4 [0.3-0.6] days in those who underwent amniotomy alone, compared to 1.1 [0.7-1.5] days, 1.8 [1.4-2.2] days and 2.2 [2.0-2.6] days for those with 1, 2 or 3 doses of dinoprostone, respectively (p 0.001 between all groups; Figure 1).These contemporaneous data indicate that in circumstances where more than a single dose of dinoprostone is required for cervical priming in a nulliparous woman, the incidence of an uncomplicated vaginal delivery decreased from more than half of women to less than one third. Over one third of women who were administered either a single dose of dinoprostone or more than one dose experienced an emergency intrapartum Caesarean delivery or a complicated vaginal birth. These findings are relevant to nulliparous women undergoing induction of labour in the setting of an unfavourable cervix and should be incorporated into shared decision-making consultations, particularly when repeat administration of dinoprostone is being considered.

Purpose: Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers. Experimental Design: Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment. Results: Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance. Conclusions: Subtype classification systems represent canonical “termini a quo” (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.

New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles, have failed to direct treatment strategies. We hypothesized that interrogation of the GBM tumor microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision treatment strategies. To this end, a refined and validated microenvironment cell population (MCP)-counter method was applied to > 800 GBM patient tumours and validated by multiplex-immunohistochemistry. The MCP-counter deconvolution method interrogates the TME composition from transcriptomic data. Using this refined method, we classified the GLIOTRAIN(www.gliotrain.eu) IDHwt GBM cohort (n=123) into 3 novel clusters characterised by differences in TME composition and subsequently validated findings in the TCGA (n=69), CGGA (n=72) and DUKE (unpublished)(n=162) cohorts. TMEHigh tumours (30%) displayed elevated immune populations, functional orientation markers, immune checkpoint genes, and upregulated immunoregulatory pathways. Moreover, tertiary lymphoid structures were a feature of TMEHigh/mesenchymal+ patients. TMEMed (46%) tumours displayed heterogeneous immune populations and upregulated neuronal signalling pathways. TMELow (24%) tumours represented an ‘immune-desert’ group, high EGFR mutation frequency and upregulated EGFR signalling pathways. Longitudinal analysis of the GLASS cohort revealed TME-subtype transitions upon recurrence, influenced by TME composition changes. Finally, assessment of three GBM immunotherapy clinical trial cohorts revealed that TMEHigh patients treated with neo-adjuvant anti-PD1 have a significantly improved survival (P=0.04). Moreover, TMEHigh patients treated with anti-PD1 and an oncolytic virus (PVSRIPO) in the adjuvant setting, showed a trend towards improved survival (P=0.15 and P=0.056 respectively). Overall, we have established a novel TME-based classification system for application in intracranial malignancies. This system may be used to better inform a precision targeting approach in the brain tumour setting. For example, we hypothesise that patients bearing TMELow tumours may be amenable to neoadjuvant anti-TIM3 + EGFR inhibitor, TMEMed to anti-angiogenic immunotherapy, and TMEHigh patients to neoadjuvant anti-PD1 + anti-CTLA4.

Background Cigarette smoking negatively impacts on maternal and fetal health. Smoking cessation is one of the few interventions capable of improving pregnancy outcomes. Despite the risks, the most effective antenatal model of care for smokers is still unclear, and specific recommendations for screening for fetal growth restriction are absent. Methods This is a pragmatic randomised controlled trial of a dedicated smoking cessation clinic versus routine antenatal care as an intervention to reduce cigarette smoking behaviour. Smoking mothers randomised to the Smoking cessation Through Optimisation of clinical care in Pregnancy (STOP) clinic will have all antenatal care provided by a team comprising an obstetrician, a midwife, and a smoking cessation practitioner. This intervention includes ultrasound screening for fetal growth restriction. The control arm comprises two groups: one receiving standard care with ultrasound screening for fetal growth restriction, and one receiving standard care with ultrasound screening for growth restriction only if clinically indicated by their healthcare provider. Four hundred and fifty women will be recruited and randomised to either intervention or control arms stratifying for age, parity, and history of fetal growth restriction. Results The primary outcome is self-reported, continuous abstinence from smoking between the quit date and end of pregnancy, validated by exhaled carbon monoxide or urinary cotinine. The quit date is targeted as being at or before 16 weeks’ gestation and no further than 28 weeks’ gestation. The secondary outcomes are a set of variables including maternal and fetal morbidity and mortality, neonatal complications and delivery outcomes, smoking and psychological outcomes, and qualitative measures. Conclusions Despite much research into cigarette smoking in pregnancy, the optimal model of care for these women is still unknown. This study has the potential to improve the model of antenatal care provided to pregnant women who smoke and to improve outcomes for both mother and infant. Trial registration ISRCTN11214785. Registered on 8 February 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3653-4) contains supplementary material, which is available to authorized users.

peer-reviewed Objective Increased fetal size is associated with shoulder dystocia during labor and subsequent need for assisted delivery. We sought to investigate if increased fetal adiposity diagnosed sonographically in late pregnancy is associated with increased risk of operative delivery. Methods This secondary analysis of the Genesis Study recruited 2392 nulliparous women with singleton pregnancy in cephalic presentation, in a prospective, multicenter study, to examine prenatal and intrapartum predictors of Cesarean delivery. Participants underwent ultrasound and clinical evaluation between 39 + 0 and 40 + 6 weeks' gestation. Data on fetal biometry were not revealed to patients or to their managing clinicians. A fetal adiposity composite of fetal thigh adiposity and fetal abdominal wall thickness was compiled for each infant in order to determine whether fetal adiposity > 90th centile was associated with an increased risk of Cesarean or operative vaginal delivery. Results After exclusions, data were available for 2330 patients. Patients with a fetal adiposity composite > 90th centile had a higher maternal body mass index (BMI) (25 ± 5 kg/m2 vs 24 ± 4 kg/m2; P = 0.005), birth weight (3872 ± 417 g vs 3585 ± 401 g; P 90th centile were more likely to require Cesarean delivery than were those with adiposity composite ≤ 90th centile (P 90th centile remained a risk factor for Cesarean delivery (P 90th centile was more predictive of the need for unplanned Cesarean delivery than was an estimated fetal weight > 90th centile (odds ratio, 2.20 (95% CI, 1.65–2.94; P 90th centile was not associated with an increased likelihood of operative vaginal delivery when compared with having an adiposity composite ≤ 90th centile (P = 0.37). Conclusions Fetuses with increased adipose deposition are more likely to require Cesarean delivery than are those without increased adiposity. Consideration should, therefore, be given to adding fetal thigh adiposity and abdominal wall thickness to fetal sonographic assessment in late pregnancy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. ACCEPTED peer-reviewed

The objective was to evaluate whether routine aspirin 75 mg is more cost-effective than the Fetal Medicine Foundation screen-and-treat approach for preeclampsia prevention in low-risk nulliparous women. A health economic decision analytical model was devised to estimate the discounted net health and cost outcomes of routine aspirin versus Fetal Medicine Foundation screening test–indicated aspirin for a cohort of 100 000 low-risk nulliparous women. Both strategies were compared with no intervention. A subanalysis also compared disaggregated components of the algorithm. The analysis used data from hospital administration, literature, and a randomized controlled trial. Sensitivity analyses assessed the impact of aspirin adherence, test cost, and accuracy on study results. Presumed rates of preeclampsia were 3.75% with no intervention versus 0.45% with aspirin use. Results found that routine aspirin was the preferred strategy, in terms of greater health gains and larger cost savings. It provided 163 quality-adjusted life-years relative to no intervention, whereas the screen-and-treat policy achieved 108 quality-adjusted life-years. Routine aspirin would result in an estimated cost saving of €14.9 million annually relative to no intervention, whereas screen-and-treat approach would result in a smaller cost saving of €3.1 million. When the analysis was extended to consider alternative screen-and-treat strategies, routine aspirin remained the optimally cost-effective approach. In conclusion, routine aspirin use in low-risk nulliparous women has a greater health gain and cost saving compared with both the Fetal Medicine Foundation and other screen-and-treat approaches.

OBJECTIVE We have shown previously that third-trimester growth in small fetuses (estimated fetal weight (EFW) 10th percentile are also variable but in different ways. METHODS This was a study of 191 cases with EFW 10th percentile (appropriate-for-gestational-age (AGA) cohort), derived from the PORTO study. Composite size parameters were used to quantify growth pathology at individual third-trimester timepoints (individual composite prenatal growth assessment score (-icPGAS)). The fetal growth pathology score 1 (-FGPS1), calculated cumulatively from serial -icPGAS values, was used to characterize third-trimester growth patterns. Vascular-system evaluation included umbilical artery (UA) and middle cerebral artery (MCA) Doppler velocimetry. Outcome variables were birth age (preterm/term delivery) and BW (expressed as growth potential realization index for weight (GPRIWT ) and percentile). The findings from the AGA cohort were compared with those from small fetuses (EFW

peer-reviewed The full text of this article will not be available in ULIR until the embargo expires on the 08/01/2022 Objective To evaluate the correlation between Umbilical Artery (UA) Doppler and its feasibility across categories of maternal BMI in the presence of foetal growth restriction (FGR). Methods 1074 Singleton pregnancies with suspected FGR on ultrasound examination between 24+0 and 36+0 weeks' gestation were reviewed. Evaluation of the UA Doppler was performed at 1‐2 weekly intervals. Abnormal UA Doppler findings and delivery outcomes were compared between the different maternal BMI categories. Results Increased UA pulsatility index (PI > 95th centile) was reported in 81% of obese category 2 patients (BMI

Pre-eclampsia (PET) affects 2-3% of all pregnancies, rising to 5-7% in nulliparous women. This study aimed to investigate the prevalence of PET over a 13-year period.A retrospective review was performed over a 13-year period (2004-2016) via interrogation of the annual clinical reports of The Rotunda Hospital, Dublin.There was a fall in the overall incidence of PET (nulliparous and multiparous), from a peak of 3.8% in 2007 to 1.5% in 2015. Comparing the first and second halves of the study time-period this decrease was statistically significant (In our institution, we have shown a decrease in preeclampsia rates over a 13-year period. While the reason for this trend remains unclear, a similar trend has been observed in another tertiary unit and additional research is required to explain the etiology behind these observations.

Contemporary approaches to monitoring quality of care in obstetrics often focus on comparing Cesarean Delivery rates. Varied rates can complicate interpretation of quality of care. We previously developed a risk prediction tool for nulliparous women who may require intrapartum Cesarean delivery which identified five key predictors. Our objective with this study was to ascertain if patient heterogeneity can account for much of the observed variation in Cesarean delivery rates, thereby enabling Cesarean delivery rates to be a better marker of quality of care.This is a secondary analysis of the Genesis study. This was a large prospective study of 2336 nulliparous singleton pregnancies recruited at seven hospitals. A heterogeneity score was calculated for each hospital. An adjusted Cesarean delivery rate was also calculated incorporating the heterogeneous risk score.A cut-off at the 90th percentile was determined for each predictive factor. Above the 90th percentile was considered to represent 'high risk' (with the exception of maternal height which identified those below the 10th percentile). The patient heterogeneous risk score was defined as the number of risk factors90th percentile (10th percentile for height). An unequal distribution of high-risk patients between centers was observed (p 0.001). The correlation between the Cesarean delivery rate and the patient heterogeneous risk score was high (0.76, p 0.05). When adjusted for patient heterogeneity, Cesarean delivery rates became closer aligned.Inter-institutional diversity is common. We suggest that crude comparison of Cesarean delivery rates between different hospitals as a marker of care quality is inappropriate. Allowing for marked differences in patient characteristics is essential for correct interpretation of such comparisons.

Resistance to chemotherapy often results from dysfunctional apoptosis, however multiple proteins with overlapping functions regulate this pathway. We sought to determine whether an extensively validated, deterministic apoptosis systems model, &lsquo, DR_MOMP&rsquo, could be used as a stratification tool for the apoptosis sensitiser and BCL-2 antagonist, ABT-199 in patient-derived xenograft (PDX) models of colorectal cancer (CRC). Through quantitative profiling of BCL-2 family proteins, we identified two PDX models which were predicted by DR_MOMP to be sufficiently sensitive to 5-fluorouracil (5-FU)-based chemotherapy (CRC0344), or less responsive to chemotherapy but sensitised by ABT-199 (CRC0076). Treatment with ABT-199 significantly improved responses of CRC0076 PDXs to 5-FU-based chemotherapy, but showed no sensitisation in CRC0344 PDXs, as predicted from systems modelling. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were performed to investigate possible early biomarkers of response. In CRC0076, a significant post-treatment decrease in mean standard uptake value was indeed evident only in the combination treatment group. Radiomic CT feature analysis of pre-treatment images in CRC0076 and CRC0344 PDXs identified features which could phenotypically discriminate between models, but were not predictive of treatment responses. Collectively our data indicate that systems modelling may identify metastatic (m)CRC patients benefitting from ABT-199, and that 18F-FDG-PET could independently support such predictions.

Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF &beta, Pix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of &beta, Pix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of &beta, Pix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover &beta, Pix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with &beta, Pix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF &beta, Pix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.

Objective This article evaluates the effect of low-dose aspirin on uterine artery (UtA) Doppler, placental volume, and vascularization flow indices in low-risk pregnancy. Study Design In this secondary analysis of the TEST randomized controlled trial, low-risk nulliparous women were originally randomized at 11 weeks to: (1) routine aspirin 75 mg; (2) no aspirin; and (3) aspirin based upon the preeclampsia Fetal Medicine Foundation screening test. UtA Doppler, three-dimensional (3D) placental volume, and vascularization flow indices were assessed prior to and 6 weeks postaspirin commencement. Results A total of 546 women were included (aspirin n = 192, no aspirin n = 354). Between first and second trimesters, aspirin use was not associated with a change in UtA Doppler, placental volume, or vascular flow indices. There was no significant difference in the change in UtA Doppler pulsatility index (PI) Z-scores or notching (PI Z-score –0.2 vs. –0.2, p = 0.17), nor was there a significant change in placental volume Z-score and vascular flow indices (volume Z-score change: 0.74 vs. 0.62, p = 0.34). Conclusion Low-dose aspirin commenced at 11 weeks in low-risk women does not appear to improve uterine and placental perfusion or placental volume. Any perceived effect on uteroplacental vasculature is not reflected in changes in placental volume nor uteroplacental flow as assessed by two-dimensional and 3D ultrasound.

To evaluate the capacity of the current system of obstetric risk stratification at the outset of pregnancy to predict severe adverse perinatal outcome.This retrospective cohort study of singleton pregnancies over a five year period (2009-2013) was performed at the Rotunda Hospital, Dublin, Ireland. High-risk or low-risk status was assigned retrospectively to a large consecutive cohort of women with a normally-formed singleton pregnancy on the basis of factors analyzed at the first prenatal hospital visit. The incidence of severe perinatal morbidity and mortality were compared between high- and low-risk groups to determine the predictive utility of risk stratification at the outset of pregnancy for severe perinatal morbidity.During the study period, 41,044 patients registered for prenatal care. 25,702;(63%) were deemed low-risk and 15,342;(37%) high-risk. Low-risk women were statistically more likely to be nulliparous (p 0.0001) and to have a spontaneous or operative vaginal delivery (p 0.0001). High-risk women were more likely to be multiparous and to undergo Caesarean delivery (p 0.0001). The perinatal mortality rate was 3.8 per-1000 in low-risk pregnancies and 6.1 per-1000 in the a priori high-risk group (p = 0.012). The incidence of severe neonatal encephalopathy (NNE) was 1.8 and 0.65 per-1000 in the low and high-risk groups respectively (p = 0.0025).Where low-risk status is assigned at registration, neonatal encephalopathy is more prevalent. This data is relevant for the design of prenatal care models and demonstrates that assignment of low obstetric risk on the basis of maternal or pre-pregnancy factors alone may erroneously be interpreted as conferring low-risk status to the fetus.

Background: Preeclampsia, preterm birth and low birth weight represent key contributing factors to perinatal morbidity and mortality. Pregnancies complicated by type 1 and type 2 diabetes are at increased risk of these complications, which are purported to be largely attributed to placental dysfunction. Studies investigating a potential role for aspirin therapy in optimizing perinatal outcome have consistently failed to demonstrate a benefit among women with pre-existing diabetes, and yet widespread aspirin administration has become common practice in many centres. This study seeks to examine the effect of aspirin therapy, administered from the first trimester until 36 weeks gestation, on perinatal outcome in women with established pre-pregnancy diabetes. Our hypothesis is that aspirin therapy will reduce complications mediated by placental dysfunction, and improve perinatal outcomes. Methods: This phase III double-blinded, placebo-controlled randomized clinical trial will be conducted in seven tertiary-level perinatology centres in Ireland. Consenting participants who meet all eligibility criteria will be allocated randomly to either aspirin 150 mg once daily or matching placebo, commenced between 11 + 0 and 13 + 6 weeks. Allocation will take place electronically using software by Clininfo with randomization tables provided by the trial biostatistician. The primary outcome will be a composite clinical measure of placental dysfunction (preeclampsia, preterm birth before 34 weeks, birthweight below the 10th centile or perinatal mortality). This trial has been set up such that it is parallel in design and is a superiority study. No participants have been recruited yet. The trial has been registered with Eudra Clinical Trials - EudraCT Number 2018-000770-29. Funding for this trial was granted by the Health research Board (HRB) 1/9/2017(DIFA-2017-026). Discussion: Aspirin therapy has been investigated for the prevention of preeclampsia owing to its reduction on thromboxane production. Previous studies have failed to demonstrate a beneficial effect of aspirin on perinatal outcome amongst women with type I or type II diabetes. It is plausible that the failure to observe benefit to date, among the limited aspirin studies that have included participants with diabetes, may be a consequence of aspirin initiation too late in pregnancy to exert any effect on placentation. We believe that if aspirin is to be used for the prevention of placental dysfunction, it must be initiated before the second active phase of trophoblast invasion, which takes place from 14 weeks’ gestation onwards. No randomized trials investigating the role of aspirin in prevention of preeclampsia in pregnancies complicated by diabetes have previously initiated treatment in the first trimester, the gestational period at which it is most likely to exert an effect on placentation. Keywords: Aspirin, Pregnancy, Diabetes, Pre-eclampsia

Although two-dimensional (2D) and three-dimensional videos have traditionally provided foundations for reviewing operative procedures, the recent 360º format may provide new dimensions to surgical education. This study sought to describe the production of a high quality 360º video for an index-operation (augmented with educational material), while evaluating for variances in attentiveness, information retention, and appraisal compared to 2D.A 6-camera synchronised array (GoPro Omni, [California, United States]) was suspended inverted and recorded an elective laparoscopic cholecystectomy in 2016. A single-blinded randomised cross-over study was performed to evaluate this video in 360º vs 2D formats. Group A experienced the 360º video using Samsung (Suwon, South-Korea) GearVR virtual-reality headsets, followed by the 2D experience on a 75-inch television. Group B were reversed. Each video was probed at designated time points for engagement levels and task-unrelated images or thoughts. Alternating question banks were administered following each video experience. Feedback was obtained via a short survey at study completion.The New Academic and Education Building (NAEB) in Dublin, Royal College of Surgeons in Ireland, July 2017.Preclinical undergraduate students from a medical university in Ireland.Forty students participated with a mean age of 23.2 ± 4.5 years and equal sex involvement. The 360º video demonstrated significantly higher engagement (p0.01) throughout the experience and lower task-unrelated images or thoughts (p0.01). Significant variances in information retention between the 2 groups were absent (p = 0.143) but most (65%) reported the 360º video as their learning platform of choice. Mean appraisal levels for the 360º platform were positive with mean responses of8/10 for the platform for learning, immersion, and entertainment.This study describes the successful development and evaluation of a 360º operative video. This new video format demonstrated significant engagement and attentiveness benefits compared to traditional 2D formats. This requires further evaluation in the field of technology enhanced learning.

Video gaming demands elements of visual attention, hand–eye coordination and depth perception which may be contiguous with laparoscopic skill development. General video gaming has demonstrated altered cortical plasticity and improved baseline/acquisition of minimally invasive skills. The present study aimed to evaluate for skill acquisition associated with a commercially available dedicated laparoscopic video game (Underground) and its unique (laparoscopic-like) controller for the Nintendo®Wii U™ console. This single-blinded randomised controlled study was conducted with laparoscopically naive student volunteers of limited (

Consumer-available virtual-reality technology was launched in 2016 with strong foundations in the entertainment-industry. We developed an innovative medical-training simulator on the Oculus™ Gear-VR platform. This novel application was developed utilising internationally recognised Advanced Trauma Life Support (ATLS) principles, requiring decision-making skills for critically-injured virtual-patients.Participants were recruited in June, 2016 at a single-centre trauma-course (ATLS, Leinster, Ireland) and trialled the platform. Simulator performances were correlated with individual expertise and course-performance measures. A post-intervention questionnaire relating to validity-aspects was completed.Eighteen(81.8%) eligible-candidates and eleven(84.6%) course-instructors voluntarily participated. The survey-responders mean-age was 38.9(±11.0) years with 80.8% male predominance. The instructor-group caused significantly less fatal-errors (p 0.050) and proportions of incorrect-decisions (p 0.050). The VR-hardware and trauma-application's mean ratings were 5.09 and 5.04 out of 7 respectively. Participants reported it was an enjoyable method of learning (median-6.0), the learning platform of choice (median-5.0) and a cost-effective training tool (median-5.0).Our research has demonstrated evidence of validity-criteria for a concept application on virtual-reality headsets. We believe that virtual-reality technology is a viable platform for medical-simulation into the future.

Objectives We aimed to firstly identify the different haemodynamic profiles amongst nulliparous women who develop either gestational hypertension (GH), pre-eclampsia (PE), normotensive fetal growth restriction (FGR) versus unaffected pregnancies using non-invasive cardiac output monitoring (NICOM®). Our second primary objective was to assess the ability of NICOM® derived variables to predict the evolution of PE, GH and FGR. Study design Low risk nulliparous women were enrolled in a single center prospective observational study. NICOM® assessments were performed at 14, 20 and 28 weeks’ gestation and data was obtained on cardiac output (CO), total peripheral resistance (TPR), indexed TPR (adjusted for maternal body surface area; TPRi), stroke volume (SV), indexed SV (adjusted for maternal body surface area; SVi) and heart rate (HR). Logistic regression was used to model GH, PE and FGR with NICOM® measurements as predictors. Linear, non-linear and interaction terms were assessed using the Akaike Information Criterion. Results The haemodynamic profile of pregnancies complicated by uteroplacental disease- GH (n = 18), PE (n = 6) and FGR (n = 24) were compared to 318 healthy unaffected pregnant controls. Women with evolving PE have a different haemodynamic profile to those developing either GH or FGR. The best independent predictors for the evolution of uteroplacental disease at 14 weeks’ gestation were CO in the prediction of FGR (AUC = 0.61; p 0.002), TPR in the prediction of GH (AUC = 0.63; p Conclusions NICOM® derived maternal haemodynamic profile at 14 weeks’ gestation has the novel potential to identify pregnancies which will ultimately develop uteroplacental disease.

The identification of early biological changes associated with the psychotic disorder (PD) is important as it may provide clues to the underlying pathophysiological mechanisms. We undertook the first proteomic profiling of blood plasma samples of children who later develop a PD. Participants were recruited from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who also participated in psychiatric assessment interviews at age 18. Protein expression levels at age 11 were compared between individuals who developed PD at age 18 (n = 37) with population-based age-matched controls (n = 38). Sixty out of 181 plasma proteins profiled were found to be differentially expressed (P < .05) in children with an outcome of the PD. Thirty-four of these proteins were found to be differentially expressed following correction for multiple comparisons. Pathway analysis implicated the complement and coagulation cascade. A second, targeted proteomic approach was used to verify these findings in age 11 plasma from subjects who reported psychotic experiences at age 18 (n = 40) in comparison to age-matched controls (n = 66). Our findings indicate that the complement and coagulation system is dysregulated in the blood during childhood before the development of the PD.

Background Fetal growth restriction (FGR) accounts for a significant proportion of perinatal morbidity and mortality. The cerebroplacental ratio (CPR) is gaining much interest as a useful tool in differentiating the “at-risk” fetus in both FGR and appropriate for gestational age (AGA) pregnancies. The Prospective Observational Trial to Optimize Pediatric Health in FGR (PORTO) group, have previously demonstrated that the presence of this ‘brain-sparing’ effect is significantly associated with adverse perinatal outcomes in the FGR cohort. However, data about neurodevelopment in children from pregnancies complicated by FGR are sparse and conflicting. Objective The aim of the PORTO NeuroDevelopmental Assessment Study (PANDA) was to determine whether children born after FGR pregnancies are at additional risk of adverse early childhood developmental outcomes compared to children born small for gestational age (SGA). The objective of this secondary analysis was to describe the role of CPR in the prediction of adverse early childhood neurodevelopmental outcome. Materials and Methods Participants were prospectively recruited from the Perinatal Ireland multicenter observational PORTO study cohort. FGR was defined as birth weight Results Assessments were performed on 198 SGA children; 136 FGR children with abnormal UA Doppler and normal CPR and 41 FGR children with both abnormal UA Doppler and CPR. At three years of age, while there were no differences in head circumference, children who also had an abnormal CPR had persistently shorter stature (p=0.005) and lower weight (p=0.18). Children from FGR affected pregnancies demonstrated poorer neurodevelopmental outcome than their SGA counterparts. FGR pregnancies with an abnormal CPR had significantly poorer neurological outcome at three years of age across all measured variables (Tables 1 & 2). Conclusion We have demonstrated that growth restricted pregnancies with a CPR