Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study.

BACKGROUND: Fetal growth restriction is a major determinant of adverse perinatal outcome. Screening procedures for fetal growth restriction need to identify small babies and then differentiate between those that are healthy and those that are pathologically small. We sought to determine the diagnostic effectiveness of universal ultrasonic fetal biometry in the third trimester as a screening test for small-for-gestational-age (SGA) infants, and whether the risk of morbidity associated with being small differed in the presence or absence of ultrasonic markers of fetal growth restriction. METHODS: The Pregnancy Outcome Prediction (POP) study was a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan. Women participating had clinically indicated ultrasonography in the third trimester as per routine clinical care and these results were reported as usual (selective ultrasonography). Additionally, all participants had research ultrasonography, including fetal biometry at 28 and 36 weeks' gestational age. These results were not made available to participants or treating clinicians (universal ultrasonography). We regarded SGA as a birthweight of less than the 10th percentile for gestational age and screen positive for SGA an ultrasonographic estimated fetal weight of less than the 10th percentile for gestational age. Markers of fetal growth restriction included biometric ratios, utero-placental Doppler, and fetal growth velocity. We assessed outcomes for consenting participants who attended research scans and had a livebirth at the Rosie Hospital (Cambridge, UK) after the 28 weeks' research scan. FINDINGS: Between Jan 14, 2008, and July 31, 2012, 4512 women provided written informed consent of whom 3977 (88%) were eligible for analysis. Sensitivity for detection of SGA infants was 20% (95% CI 15-24; 69 of 352 fetuses) for selective ultrasonography and 57% (51-62; 199 of 352 fetuses) for universal ultrasonography (relative sensitivity 2·9, 95% CI 2·4-3·5, p<0·0001). Of the 3977 fetuses, 562 (14·1%) were identified by universal ultrasonography with an estimated fetal weight of less than the 10th percentile and were at an increased risk of neonatal morbidity (relative risk [RR] 1·60, 95% CI 1·22-2·09, p=0·0012). However, estimated fetal weight of less than the 10th percentile was only associated with the risk of neonatal morbidity (pinteraction=0·005) if the fetal abdominal circumference growth velocity was in the lowest decile (RR 3·9, 95% CI 1·9-8·1, p=0·0001). 172 (4%) of 3977 pregnancies had both an estimated fetal weight of less than the 10th percentile and abdominal circumference growth velocity in the lowest decile, and had a relative risk of delivering an SGA infant with neonatal morbidity of 17·6 (9·2-34·0, p<0·0001). INTERPRETATION: Screening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of SGA infants. Combined analysis of fetal biometry and fetal growth velocity identified a subset of SGA fetuses that were at increased risk of neonatal morbidity. FUNDING: National Institute for Health Research, Medical Research Council, Sands, and GE Healthcare.This work was supported by the National Institute for Health Research (NIHR) Cambridge Comprehensive Biomedical Research Centre and the Stillbirth and Neonatal Death Society. DP was supported by a Medical Research Council (MRC) Clinical Training Fellowship. IRW is supported by a MRC Unit Programme (number U105260558). GE Healthcare (Fairfield, CT, USA) donated two Voluson i ultrasound systems for this study. This study was also supported by the NIHR Cambridge Clinical Research Facility, where all visits at about 20, 28, and 36 weeks took place. No direct or indirectly supporting bodies for the project were involved in any aspect of preparation of this paper for publication. We thank the Perinatal Institute for providing a bulk calculator for customised percentiles of estimated fetal weight. We thank all the women who participated in the study, and all the staff in the Rosie Hospital (Cambridge, UK) and NIHR Cambridge Clinical Research Facility who provided direct or indirect assistance for the study.This is the final published version of the article. It was originally published in The Lancet (Sovio U, White IR, Dacey A, Pasupathy D, Smith GCS, The Lancet, 2015, doi:10.1016/S0140-6736(15)00131-2). The final version is available at http://dx.doi.org/10.1016/S0140-6736(15)00131-2

The relationship between human placental morphometry and ultrasonic measurements of utero-placental blood flow and fetal growth.

INTRODUCTION: Ultrasonic fetal biometry and arterial Doppler flow velocimetry are widely used to assess the risk of pregnancy complications. There is an extensive literature on the relationship between pregnancy outcomes and the size and shape of the placenta. However, ultrasonic fetal biometry and arterial Doppler flow velocimetry have not previously been studied in relation to postnatal placental morphometry in detail. METHODS: We conducted a prospective cohort study of nulliparous women in The Rosie Hospital, Cambridge (UK). We studied a group of 2120 women who had complete data on uterine and umbilical Doppler velocimetry and fetal biometry at 20, 28 and 36 weeks' gestational age, digital images of the placenta available, and delivered a liveborn infant at term. Associations were expressed as the difference in the standard deviation (SD) score of the gestational age adjusted ultrasound measurement (z-score) comparing the lowest and highest decile of the given placental morphometric measurement. RESULTS: The lowest decile of placental surface area was associated with 0.87 SD higher uterine artery Doppler mean pulsatility index (PI) at 20 weeks (95% CI: 0.68 to 1.07, P < 0.001). The lowest decile of placental weight was associated with 0.73 SD higher umbilical artery Doppler PI at 36 weeks (95% CI: 0.54 to 0.93, P < 0.001). The lowest decile of both placental weight and placental area were associated with reduced growth velocity of the fetal abdominal circumference between 20 and 36 weeks (both P < 0.001). CONCLUSION: Placental area and weight are associated with uterine and umbilical blood flow, respectively, and both are associated with fetal growth rate.This study was funded by the NIHR Cambridge Comprehensive Biomedical Research Centre (grant number A019057) and Stillbirth and Neonatal Death Society (SANDS). GE donated two ultrasound machines for use in the project.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.placenta.2015.12.00

The pregnancy outcome prediction (POP) study: Investigating the relationship between serial prenatal ultrasonography, biomarkers, placental phenotype and adverse pregnancy outcomes

Placental dysfunction is implicated in many major complications of pregnancy associated with adverse maternal and infant outcome, such as preeclampsia, fetal growth restriction and stillbirth. Yet, despite years of intensive research, screening for these complications is still largely based upon clinical grounds rather than ultrasonic and/or biochemical assessment of placental function. One of the few widely employed methods for assessment of risk, low first trimester levels of PAPP-A (Pregnancy Associated Plasma Protein A), was identified through secondary analysis of data collected to identify new methods of screening for Down's syndrome rather than as a purposeful search for screening tests for abnormal placentation. Development of improved methods for population screening requires better mechanistic understanding of the pathways leading to placentally-related complications of human pregnancy. This is in addition to a need for identification of biomarkers which reflect the underlying pathology, while predicting associated disease with high sensitivity and specificity. In this paper, we outline some of the challenges and opportunities in this area. Furthermore, we illustrate how some of these can be addressed in research studies using the example of the Pregnancy Outcome Prediction (POP) study, a prospective cohort study conducted in Cambridge, UK.This study was funded by the NIHR Cambridge Comprehensive Biomedical Research Centre [grant number A019057], the Medical Research Council [grant number MR/K021133/1] and the Stillbirth and Neonatal Death Society (SANDS)

A Fast Hash Family for Memory Integrity

We give a first construction of an ϵ-balanced hash family based on linear transformations of vectors in $\mathbb{F}_2$, where ϵ = 1/(2n − 1) for n-bit hash values, regardless of the message size. The parameter n is also the bit length of the input blocks and the internal state, and can be chosen arbitrarily without design changes, This hash family is fast, easily parallelized, and requires no initial setup. A secure message authentication code can be obtained by combining the hash family with a pseudo random function. These features make the hash family attractive for memory integrity protection, while allowing generic use cases

Blinded ultrasonic fetal biometry at 36 weeks and the risk of emergency caesarean delivery: A prospective cohort study of 3,047 low risk nulliparous women

OBJECTIVES: We studied the risk of emergency caesarean delivery (CD) using blinded ultrasonographic estimated fetal weight (EFW) at 36 weeks of gestational age (wkGA): (1) to compare the association for customised and non-customised EFW, (2) to determine whether adding ultrasonic EFW improved prediction based on maternal characteristics alone, and (3) to determine whether women at high predicted risk of emergency CD had higher risks of maternal and perinatal morbidity than other women. METHODS: We studied 3,047 low risk women (no pre-existing medical conditions or acquired complications of pregnancy) from the Pregnancy Outcome Prediction study (Cambridge UK) who had ultrasonic EFW at ~36 weeks gestational age, where women and clinicians were blinded to the result. RESULTS: Blinded EFW was strongly associated with the risk of emergency CD (coefficient for a 1 standard deviation increase in EFW = 0.39 [95% CI 0.30 to 0.48], odds ratio [OR] = 1.48 [95% CI 1.35 to 1.62]). The coefficient for customised EFW was similar (0.42 [95% CI 0.33 to 0.51], OR = 1.53 [95% CI 1.39 to 1.67]), hence, for simplicity, non-customised EFW was subsequently employed. Maternal characteristics (age, height, body mass index, and weight gain between 12 and 36 weeks) when combined in a multivariate logistic regression model were moderately predictive for emergency CD (AUROCC = 0.68). Adding blinded EFW to the model increased the AUROCC to 0.71 and this model was more predictive (P < 0.0001). When using this model and defining screen positive as a predicted risk of emergency CD ≥40%, 189 (6.2%) women screened positive and the proportion delivered by caesarean was 48%. Compared with screen negative women, they had elevated risks (relative risk [95% CI]) of severe postpartum hemorrhage (2.49 [1.83 to 3.38]), any adverse neonatal outcome (1.86 [1.22 to 2.82]), and severe adverse neonatal outcome (4.03 [1.35 to 12.03]). The risks of these events were also higher compared to women who had a term CD for breech presentation. The model was similarly predictive of the risk of emergency CD and perinatal morbidity when evaluated using routinely collected data from 55,337 births in Scotland between 2003 and 2008. CONCLUSIONS: Ultrasonic EFW at 36 weeks, combined with maternal characteristics, identifies women who are at increased risk of subsequent emergency CD. These women were at increased risk of maternal and perinatal morbidity compared with women at low risk of emergency CD and with women having CD for breech presentation at term

Size, Speed, and Security: An Ed25519 Case Study

Ed25519 has significant performance benefits compared to ECDSA using Weierstrass curves such as NIST P-256, therefore it is considered a good digital signature algorithm, specially for low performance IoT devices. However, such devices often have very limited resources and thus, implementations for these devices need to be as small and as performant as possible while being secure. In this paper we describe a scenario in which an obvious strategy to aggressively optimize an Ed25519 implementation for code size leads to a small memory footprint that is functionally correct but vulnerable to side-channel attacks. This strategy serves as an example of aggressive optimizations that might be considered by cryptography engineers, developers, and practitioners unfamiliar with the power of Side-Channel Analysis (SCA). As a solution to the flawed implementation example, we use a computer-aided cryptography tool generating formally verified finite field arithmetic to generate two secure Ed25519 implementations fulfilling different size requirements. After benchmarking and comparing these implementations to other widely used implementations our results show that computer-aided cryptography is capable of generating competitive code in terms of security, speed, and size

A Lower Maternal Cortisol-to-Cortisone Ratio Precedes Clinical Diagnosis of Preterm and Term Preeclampsia by Many Weeks.

CONTEXT: Previous studies have shown reduced placental levels of 11-β-hydroxysteroid dehydrogenase type 2 (11βHSD2) in preeclampsia (PE). However, it is unknown if the maternal cortisol-to-cortisone ratio is predictive of placental complications of pregnancy. OBJECTIVE: To determine the relationship between the maternal serum cortisol-to-cortisone ratio at different stages of pregnancy and the risk of PE or fetal growth restriction (FGR). DESIGN: Women from the Pregnancy Outcome Prediction Study experiencing PE (n = 194) or FGR (n = 185), plus a random sample of healthy controls (n = 279), were studied. Steroids were measured at ∼12, ∼20, ∼28, and ∼36 weeks of gestational age (wkGA). Separate analyses were performed for outcomes with term or preterm delivery. Associations were modeled using logistic regression. RESULTS: At 28 wkGA, the cortisol-to-cortisone ratio was negatively associated (OR per 1 SD increase, 95% CI)] with preterm PE (OR 0.33, 95% CI 0.19 to 0.57), term PE (OR 0.61, 95% CI 0.49 to 0.76), and preterm FGR (OR 0.50, 95% CI 0.29 to 0.85). At 36 wkGA, the cortisol-to-cortisone ratio was negatively associated with term PE (OR 0.42, 95% CI 0.32 to 0.55) but not term FGR (OR 1.07, 95% CI 0.87 to 1.31). Associations were not materially affected by adjustment for maternal characteristics. CONCLUSIONS: A lower maternal serum cortisol-to-cortisone ratio precedes clinical manifestation of PE and preterm FGR by many weeks, despite previous reports of reduced levels of placental 11βHSD2 in these conditions. Our observations implicate enhanced maternal 11βHSD2 activity or reduced 11βHSD type 1 activity in the pathophysiology of PE.The POP study was funded by the National Institute for Health Research (NIHR) Cambridge Comprehensive Biomedical Research Centre (Women’s Health theme), and a project grant from the Medical Research Council (United Kingdom; G1100221). The study was also supported by GE Healthcare (donation of two Voluson i ultrasound systems for the POP study), and by the NIHR Cambridge Clinical Research Facility, where all research visits took place. A.E.H. was an Academic Clinical Fellow funded by NIHR

Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers.

Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational-age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening

Trusted Hart for Mobile RISC-V Security

The majority of mobile devices today are based on Arm architecture that supports the hosting of trusted applications in Trusted Execution Environment (TEE). RISC-V is a relatively new open-source instruction set architecture that was engineered to fit many uses. In one potential RISC-V usage scenario, mobile devices could be based on RISC-V hardware. We consider the implications of porting the mobile security stack on top of a RISC-V system on a chip, identify the gaps in the open-source Keystone framework for building custom TEEs, and propose a security architecture that, among other things, supports the GlobalPlatform TEE API specification for trusted applications. In addition to Keystone enclaves the architecture includes a Trusted Hart -- a normal core that runs a trusted operating system and is dedicated for security functions, like control of the device's keystore and the management of secure peripherals. The proposed security architecture for RISC-V platform is verified experimentally using the HiFive Unleashed RISC-V development board.Comment: This is an extended version of a paper that has been published in Proceedings of TrustCom 202

Fetal Growth and the Risk of Spontaneous Preterm Birth in a Prospective Cohort Study of Nulliparous Women.

Previous studies have suggested an association between fetal growth restriction and the risk of spontaneous preterm birth (sPTB). However, addressing this association is methodologically challenging. We conducted a prospective cohort study of nulliparous women with a singleton pregnancy in Cambridge, United Kingdom (2008-2012). Ultrasonic fetal biometry was performed at 20 weeks of gestation as per routine clinical care. Participants also had blinded research ultrasonography performed at approximately 28 weeks. Biometric measurements were expressed as gestational-age-adjusted z scores. Fetal growth velocity was quantified by change in z score between 20 weeks and 28 weeks. Risk of sPTB, defined as delivery at ≥28 weeks and <37 weeks associated with labor in the absence of induction, was analyzed using cause-specific Cox regression. Of 3,892 women, 98 (2.5%) had sPTB. When compared with the other decile groups, the lowest decile of growth velocity of the fetal femur between 20 and 28 weeks was associated with increased risk of sPTB (hazard ratio = 2.37, 95% confidence interval: 1.43, 3.93; P < 0.001). Adjustment for maternal characteristics had no material effect (hazard ratio = 2.50, 95% confidence interval: 1.50, 4.14; P < 0.001). There were no significant associations between other fetal measurements and risk of sPTB. To conclude, slow growth velocity of the fetal femur is associated with an increased risk of sPTB.This study was funded by the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre (grant number A019057) and Stillbirth and Neonatal Death Society (SANDS). UP was funded by the Dr. Herchel Smith Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. GE donated two ultrasound machines for use in the project.This is the author accepted manuscript. It is currently embargoed pending publication by Oxford University Press