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Introduction: Non-consensual condom removal (NCCR) refers to the act of removing a condom during sex without the other person's permission. It poses physical and psychological risks to women's health. Views and attitudes regarding this sexual practice are not well understood in the UK. This study aimed to explore young people's views on the morality and criminality of NCCR and how their views are affected by negative health outcomes, relationship status, and socio-demographic characteristics., Methods: A quantitative online survey of people aged 18-25 living in the UK was conducted. The survey consisted of two NCCR scenarios, varied by health outcome and relationship status, followed by questions about the morality and criminality of NCCR and respondents' socio-demographic characteristics. Statistical analysis included Chi-square testing and logistic regression modelling., Results: Most of the 1729 respondents considered NCCR to be a violation of consent to sex (97.4%-98.1%), to be wrong (99.3%-99.5%), and to be sexual assault (86.3%-89.2%). Respondents were more likely to support prison time for NCCR if the victim got pregnant (52.1%) (rather than depressed (41.6%)) or was part of a casual hook-up (53.9%) (as opposed to a long-term dating relationship (47.2%). Respondents who were female or non-heterosexual were more likely to view NCCR as sexual assault and support prison as a penalty for NCCR., Conclusion: The majority of young UK adults in this survey considered condom removal during sex without the other person's permission to be a violation of consent, morally wrong, and a form of sexual assault. Support for prison as a penalty was lower. These findings can inform future campaigns on consent in sexual relationships and legislation to provide support for women affected by NCCR., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ezzat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: AS is a member of PLOS Medicine’s editorial board. The authors have declared that no other competing interests exist., (Copyright: © 2024 Hezelgrave et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: It is widely accepted that maternal healthcare is vital for improving maternal and neonatal mortality rates. Furthermore, the continuum of care-the integrated delivery of antenatal, delivery and postnatal care-has been shown to be particularly important. Sub-Saharan Africa has the highest neonatal and maternal mortality rates in the world; significant improvements in the provision and utilisation of the continuum are urgently needed, therefore the barriers preventing access need to be better understood. This study aimed to identify key factors associated with the utilisation of maternal healthcare, in the Mchinji District of Malawi., Methods: 4,244 pregnant women from the Mchinji District of Malawi were interviewed between March and December 2013. The overall utilisation of maternal healthcare was calculated by combining the use of antenatal, delivery and postnatal care into one variable-continuum of care. Univariate and multivariate logistic regressions were performed to determine the factors associated with utilisation of maternal healthcare., Results: Utilisation of maternal healthcare in the Mchinji District was inadequate; only 24% of women received the recommended package. Being further from a healthcare facility (OR = 0.2, 95%CI = 0.04-0.96), having at least one live child (OR = 0.87, 95%CI = 0.84-0.99), previous experience of miscarriage (OR = 0.64, 95%CI = 0.50-0.82) or abuse (OR = 0.81, 95%CI = 0.69-0.95) reduced utilisation, whereas being in the richest 20% (OR = 1.33 95%CI = 1.08-1.65), having a planned pregnancy (OR = 1.3, 95%CI = 1.11-1.51) or more control over decisions (OR = 1.09, 95%CI = 0.80-1.49) increased utilisation., Conclusion: Seven groups of women were identified as having an increased risk of low utilisation of maternal healthcare; women living >5km from a healthcare facility, within the poorest socio-economic group, experiencing an unplanned pregnancy, with at least one live child, experience of a previous miscarriage, no control over their healthcare decisions or experience of abuse. Policy makers should pay extra attention to these high-risk groups when designing and delivering strategies to improve maternal healthcare utilisation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Stewart, Hall. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To determine whether the participation of consultant gynaecologists in delivering early pregnancy care results in a lower rate of acute hospital admissions., Design: Prospective cohort study and emergency hospital care audit; data were collected as part of the national prospective mixed-methods VESPA study on the "Variations in the organization of EPAUs in the UK and their effects on clinical, Service and PAtient-centred outcomes"., Setting: 44 Early Pregnancy Assessment Units (EPAUs) across the UK randomly selected in balanced numbers from eight pre-defined mutually exclusive strata., Participants: 6606 pregnant women (≥16 years old) with suspected first trimester pregnancy complications attending the participating EPAUs or Emergency Departments (ED) from December 2016 to July 2017., Exposures: Planned and actual senior clinician presence, unit size, and weekend opening., Main Outcome Measures: Unplanned admissions to hospital following any visit for investigations or treatment for first trimester complications as a proportion of women attending EPAUs., Results: 205/6397 (3.2%; 95% CI 2.8-3.7) women were admitted following their EPAU attendance. The admission rate among 44 units ranged from 0% to 13.7% (median 2.8). Neither planned senior clinician presence (p = 0.874) nor unit volume (p = 0.247) were associated with lower admission rates from EPAU, whilst EPAU opening over the weekend resulted in lower admission rates (p = 0.027). 1445/5464 (26.4%; 95%CI 25.3 to 27.6) women were admitted from ED. There was little evidence of an association with planned senior clinician time (p = 0.280) or unit volume (p = 0.647). Keeping an EPAU open over the weekend for an additional hour was associated with 2.4% (95% CI 0.1% to 4.7%) lower odds of an emergency admission from ED., Conclusions: Involvement of senior clinicians in delivering early pregnancy care has no significant impact on emergency hospital admissions for early pregnancy complications. Weekend opening, however, may be an effective way of reducing emergency admissions from ED., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MM, VG, GA, ZA, NK, JH, GB, RBA, JS, DJ has nothing to disclose. Peter Brocklehurst reports grants and personal fees from MRC, grants from MRC, NIHR HS&DR, NIHR HJTA, Wellcome Trust, personal fees from AG Biotest, outside the submitted work. Edna Keeney reports personal fees from Novartis Pharma, personal fees from Pfizer Inc., outside the submitted work. Sergio A. Silverio (King’s College London) is supported by the National Institute for Health Research Applied Research Collaboration South London [NIHR ARC South London] at King’s College Hospital NHS Foundation Trust. Jeff Round reports grants from NIHR, during the conduct of the study; and Dr Round is currently employed by the Insitute of Health Economics (IHE). The IHE receives funding from, and collaborates with, government, academic, not-for-profit and private sector organisations. The IHE does not currently receive funds for research related to the submitted work.

Background: Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix., Methods and Findings: We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses., Conclusions: These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out., Trial Registration: ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. JEN has received grants from government and charitable bodies for research into understanding the mechanism of term and preterm labour and understanding treatments. Within the last 3 years she has acted on a Data Safety and Monitoring Board for a study involving a preterm birth therapeutic agent for Glaxo Smith Kline, and has provided consultancy for Dilafor on drugs to alter labour progress. PRB reports personal fees from ObsEva Geneva, other from ObsEva Geneva, outside the submitted work; In addition, PRB has a patent PCT/GB1997/000529 WO1997031631 A1 Cox-2 selective inhibitors for managing labour and uterine contractions issued, a patent PCT/GB2004/001380 WO2005053705 A1 Use of a cyclopentenone prostaglandin for delaying the onset and/or preventing the continuation of labour (Priority Date Dec 2, 2003). issued, a patent PCT/GB2016/050618 Circulating miRNAs predictive of cervical shortening and preterm birth (Pending UK filing 6th March 2015 /Full international filing completed 7th March 2016). issued, a patent PCT/GB2016/050621 Rapid evaporative ionisation mass spectroscopy (REIMS) and Desorbtion Electrospray Ionisation Mass Spectroscopy (DESI-MS) analysis of swabs and biopsy samples. (Pending UK filing 6th March 2015 /Full international filing completed 7th March 2016 pending, a patent PCT/GB2019 Desorbtion Electrospray Ionisation Mass Spectroscopy (DESI-MS) analysis of swabs to predict vaginal microbiota. (Pending UK filing March 2019) pending, and a patent PCT/GB2019/Circulating miRNAs predictive of IUGR (Pending UK filing March 2019) pending. SCB reports grants from other from NIHR, NETSCC, HTA during the conduct of the study and personal fees and other from University of Copenhagen, Wellcome Trust, NIHR Global Health Research and French Cancer Institute outside the submitted work. SJS reports grants from NIHR HTA during the conduct of the study; being a member of the NIHR HTA General committee and receiving received other research funding from the NIHR (14/32/01 QUIDS), Wellcome Trust (209560/Z/17/Z) and CSO During the course of the study. SJS is a member of PLOS Medicine’s Editorial Board. NM reports personal fees from Shire-Takeda, personal fees from Novartis, personal fees from Glaxo-Smith-Klein, outside the submitted work. JN reports grants from University of Aberdeen and University of Edinburgh during the conduct of the study; and Membership of the following NIHR boards: CPR decision making committee; HTA Commissioning Board; HTA Commissioning Sub-Board (EOI); HTA Funding Boards Policy Group; HTA General Board; HTA Post-Board funding teleconference; NIHR CTU Standing Advisory Committee; NIHR HTA & EME Editorial Board; Pre-exposure Prophylaxis Impact Review Panel. ST has received grant funding from NIHR, other government and charity organisations. He provides commercial consultancy advice which has received financial compensation.

The time-critical 'can't intubate, can't oxygenate' [CICO] emergency post-induction of anaesthesia is rare, but one which, should it occur, requires Anaesthetists to perform rapid emergency front of neck access [FONA] to the trachea, restoring oxygenation, and preventing death or brain hypoxia. The UK Difficult Airway Society [DAS] has directed all Anaesthetists to be trained with surgical cricothyroidotomy [SCT] as the primary emergency FONA method, sometimes referred to as 'Cric' as a shorthand. We present a longitudinal analysis using a classical approach to Grounded Theory methodology of ten Specialist Trainee Anaesthetists' data during a 6-month training programme delivered jointly by Anaesthetists and Surgeons. We identified with a critical realist ontology and an objectivist epistemology meaning data interpretation was driven by participants' narratives and accepted as true accounts of their experience. Our theory comprises three themes: 'Identity as an Anaesthetist'; 'The Role of a Temporary Surgeon'; and 'Training to Reconcile Identities', whereby training facilitated the psychological transition from a 'bloodless Doctor' (Anaesthetist) to becoming a 'temporary Surgeon'. The training programme enabled Specialist Trainees to move between the role of control and responsibility (Identity as an Anaesthetist), through self-described 'failure' and into a role of uncertainty about one's own confidence and competence (The Role of a Temporary Surgeon), and then return to the Anaesthetist's role once the airway had been established. Understanding the complexity of an intervention and providing a better insight into the training needs of Anaesthetic trainees, via a Grounded Theory approach, allows us to evaluate training programmes against the recognised technical and non-technical needs of those being trained., Competing Interests: Sergio A. Silverio (King’s College London) is supported by the National Institute for Health Research Applied Research Collaboration South London [NIHR ARC South London] at King’s College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors have declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Jaundice is a major cause of mortality and morbidity in the newborn. Globally, early identification and home monitoring are significant challenges in reducing the incidence of jaundice-related neurological damage. Smartphone cameras are promising as colour-based screening tools as they are low-cost, objective and ubiquitous. We propose a novel smartphone method to screen for neonatal jaundice by imaging the sclera. It does not rely on colour calibration cards or accessories, which may facilitate its adoption at scale and in less economically developed regions. Our approach is to explicitly address three confounding factors in relating colour to jaundice: (1) skin pigmentation, (2) ambient light, and (3) camera spectral response. (1) The variation in skin pigmentation is avoided by imaging the sclera. (2) With the smartphone screen acting as an illuminating flash, a flash/ no-flash image pair is captured using the front-facing camera. The contribution of ambient light is subtracted. (3) In principle, this permits a device- and ambient-independent measure of sclera chromaticity following a one-time calibration. We introduce the concept of Scleral-Conjunctival Bilirubin (SCB), in analogy with Transcutaneous Bilirubin (TcB). The scleral chromaticity is mapped to an SCB value. A pilot study was conducted in the UCL Hospital Neonatal Care Unit (n = 37). Neonates were imaged using a specially developed app concurrently with having a blood test for total serum bilirubin (TSB). The better of two models for SCB based on ambient-subtracted sclera chromaticity achieved r = 0.75 (p<0.01) correlation with TSB. Ambient subtraction improved chromaticity estimates in proof-of-principle laboratory tests and screening performance within our study sample. Using an SCB decision threshold of 190μmol/L, the sensitivity was 100% (specificity 61%) in identifying newborns with TSB>250μmol/L (area under receiver operating characteristic curve, AUROC, 0.86), and 92% (specificity 67%) in identifying newborns with TSB>205μmol/L (AUROC 0.85). These results are comparable to modern transcutaneous bilirubinometers., Competing Interests: The authors have declared that no competing interests exist.

Facial somatosensory feedback is critical for breastfeeding in the first days of life. However, its development has never been investigated in humans. Here we develop a new interface to measure facial somatosensation in newborn infants. The novel system allows to measure neuronal responses to touching the face of the subject by synchronously recording scalp electroencephalography (EEG) and the force applied by the experimenter. This is based on a dedicated force transducer that can be worn on the finger underneath a clinical nitrile glove and linked to a commercial EEG acquisition system. The calibrated device measures the pressure applied by the investigator when tapping the skin concurrently with the resulting brain response. With this system, we were able to demonstrate that taps of 192 mN (mean) reliably elicited facial somatosensory responses in 7 pre-term infants. These responses had a time course similar to those following limbs stimulation, but more lateral topographical distribution consistent with body representations in primary somatosensory areas. The method introduced can therefore be used to reliably measure facial somatosensory responses in vulnerable infants., Competing Interests: The authors have declared that no competing interests exist.

We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes.

Background: Stroke is the second most common cause of seizures in term neonates and is associated with abnormal long-term neurodevelopmental outcome in some cases., Objective: To aid diagnosis earlier in the postnatal period, our aim was to describe the characteristic EEG patterns in term neonates with perinatal arterial ischaemic stroke (PAIS) seizures., Design: Retrospective observational study., Patients: Neonates >37 weeks born between 2003 and 2011 in two hospitals., Method: Continuous multichannel video-EEG was used to analyze the background patterns and characteristics of seizures. Each EEG was assessed for continuity, symmetry, characteristic features and sleep cycling; morphology of electrographic seizures was also examined. Each seizure was categorized as electrographic-only or electroclinical; the percentage of seizure events for each seizure type was also summarized., Results: Nine neonates with PAIS seizures and EEG monitoring were identified. While EEG continuity was present in all cases, the background pattern showed suppression over the infarcted side; this was quite marked (>50% amplitude reduction) when the lesion was large. Characteristic unilateral bursts of theta activity with sharp or spike waves intermixed were seen in all cases. Sleep cycling was generally present but was more disturbed over the infarcted side. Seizures demonstrated a characteristic pattern; focal sharp waves/spike-polyspikes were seen at frequency of 1-2 Hz and phase reversal over the central region was common. Electrographic-only seizure events were more frequent compared to electroclinical seizure events (78 vs 22%)., Conclusions: Focal electrographic and electroclinical seizures with ipsilateral suppression of the background activity and focal sharp waves are strong indicators of PAIS. Approximately 80% of seizure events were the result of clinically unsuspected seizures in neonates with PAIS. Prolonged and continuous multichannel video-EEG monitoring is advocated for adequate seizure surveillance.

Background: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development., Methods and Findings: Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression., Conclusions: HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

Aberrant DNA methylation is an important cancer hallmark, yet the dynamics of DNA methylation changes in human carcinogenesis remain largely unexplored. Moreover, the role of DNA methylation for prediction of clinical outcome is still uncertain and confined to specific cancers. Here we perform the most comprehensive study of DNA methylation changes throughout human carcinogenesis, analysing 27,578 CpGs in each of 1,475 samples, ranging from normal cells in advance of non-invasive neoplastic transformation to non-invasive and invasive cancers and metastatic tissue. We demonstrate that hypermethylation at stem cell PolyComb Group Target genes (PCGTs) occurs in cytologically normal cells three years in advance of the first morphological neoplastic changes, while hypomethylation occurs preferentially at CpGs which are heavily Methylated in Embryonic Stem Cells (MESCs) and increases significantly with cancer invasion in both the epithelial and stromal tumour compartments. In contrast to PCGT hypermethylation, MESC hypomethylation progresses significantly from primary to metastatic cancer and defines a poor prognostic signature in four different gynaecological cancers. Finally, we associate expression of TET enzymes, which are involved in active DNA demethylation, to MESC hypomethylation in cancer. These findings have major implications for cancer and embryonic stem cell biology and establish the importance of systemic DNA hypomethylation for predicting prognosis in a wide range of different cancers., Competing Interests: The authors have declared that no competing interests exist.