Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer.

OBJECTIVE: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ). METHODS: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms. RESULTS: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3). SIGNIFICANCE: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation.

Predicting spontaneous preterm birth in asymptomatic high-risk women with cervical cerclage.

OBJECTIVE: To determine the performance of the predictive markers of spontaneous preterm birth, cervicovaginal quantitative fetal fibronectin (fFN) and cervical length, in asymptomatic high-risk women with transabdominal, history-indicated or ultrasound-indicated cervical cerclage. METHODS: This was a secondary analysis of a prospective cohort of asymptomatic high-risk women with cervical cerclage and no other prophylactic intervention (including progesterone), who attended the preterm birth clinic at a central London teaching hospital between October 2010 and September 2016. Women had either transabdominal cerclage, placed prior to conception, history-indicated cerclage, placed before 14 weeks' gestation, or ultrasound-indicated cerclage for a short cervix (< 25 mm), placed before 24 weeks. All women underwent serial cervical length assessment on transvaginal ultrasound in the second trimester (16-28 weeks), and quantitative fFN testing from 18 weeks onward. Test performance was analyzed for the prediction of spontaneous preterm birth before 30 weeks (cerclage failure), 34 weeks and 37 weeks, using receiver-operating-characteristics (ROC)-curve analysis. RESULTS: Overall, 181 women were included in the analysis. Cervical length and fFN were strong predictors of spontaneous preterm birth before 30 weeks in women with cerclage, with areas under the ROC curve (AUC) of 0.86 (95% CI, 0.79-0.94) and 0.84 (95% CI, 0.75-0.92), respectively. Cervical length was a better predictor of preterm birth before 30 weeks in women with history-indicated compared to those with ultrasound-indicated cerclage, although both showed clinical utility (AUC, 0.96 (95% CI, 0.91-1.00) vs 0.79 (95% CI, 0.66-0.91); P = 0.01). Quantitative fFN was a strong predictor of spontaneous preterm birth before 30 weeks in women with history-indicated cerclage (AUC, 0.91 (95% CI, 0.75-1.00)) and retained clinical utility in those with ultrasound-indicated cerclage (AUC, 0.76 (95% CI, 0.64-0.89)). There were no spontaneous deliveries before 34 weeks in women with a transabdominal cerclage, so AUC was not calculated. Delivery was delayed significantly in this group (P < 0.01). CONCLUSIONS: Cervical length and quantitative fFN retain clinical utility for the prediction of spontaneous preterm birth in women with cervical cerclage, and prediction is best in women with a history-indicated stitch. These tests can be relied upon to discriminate risk and have utility when planning clinical management with regard to treatment failure. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Characteristics associated with antenatally unidentified small-for-gestational-age fetuses: prospective cohort study nested within DESiGN randomized controlled trial.

OBJECTIVE: To identify the clinical characteristics and patterns of ultrasound use amongst pregnancies with an antenatally unidentified small-for-gestational-age (SGA) fetus, compared with those in which SGA is identified, to understand how to design interventions that improve antenatal SGA identification. METHODS: This was a prospective cohort study of singleton, non-anomalous SGA (birth weight < 10th centile) neonates born after 24 + 0 gestational weeks at 13 UK sites, recruited for the baseline period and control arm of the DESiGN trial. Pregnancy with antenatally unidentified SGA was defined if there was no scan or if the final scan showed estimated fetal weight (EFW) at the 10th centile or above. Identified SGA was defined if EFW was below the 10th centile at the last scan. Maternal and fetal sociodemographic and clinical characteristics were studied for associations with unidentified SGA using unadjusted and adjusted logistic regression models. Ultrasound parameters (gestational age at first growth scan, number and frequency of ultrasound scans) were described, stratified by presence of indication for serial ultrasound. Associations of unidentified SGA with absolute centile and percentage weight difference between the last scan and birth were also studied on unadjusted and adjusted logistic regression, according to time between the last scan and birth. RESULTS: Of the 15 784 SGA babies included, SGA was not identified antenatally in 78.7% of cases. Of pregnancies with unidentified SGA, 47.1% had no recorded growth scan. Amongst 9410 pregnancies with complete data on key maternal comorbidities and antenatal complications, the risk of unidentified SGA was lower for women with any indication for serial scans (adjusted odds ratio (aOR), 0.56 (95% CI, 0.49-0.64)), for Asian compared with white women (aOR, 0.80 (95% CI, 0.69-0.93)) and for those with non-cephalic presentation at birth (aOR, 0.58 (95% CI, 0.46-0.73)). The risk of unidentified SGA was highest among women with a body mass index (BMI) of 25.0-29.9 kg/m2 (aOR, 1.15 (95% CI, 1.01-1.32)) and lowest in those with underweight BMI (aOR, 0.61 (95% CI, 0.48-0.76)) compared to women with BMI of 18.5-24.9 kg/m2 . Compared to women with identified SGA, those with unidentified SGA had fetuses of higher SGA birth-weight centile (adjusted odds for unidentified SGA increased by 1.21 (95% CI, 1.18-1.23) per one-centile increase between the 0th and 10th centiles). Duration between the last scan and birth increased with advancing gestation in pregnancies with unidentified SGA. SGA babies born within a week of the last growth scan had a mean difference between EFW and birth-weight centiles of 19.5 (SD, 13.8) centiles for the unidentified-SGA group and 0.2 (SD, 3.3) centiles for the identified-SGA group (adjusted mean difference between groups, 19.0 (95% CI, 17.8-20.1) centiles). CONCLUSIONS: Unidentified SGA was more common amongst women without an indication for serial ultrasound, and in those with cephalic presentation at birth, BMI of 25.0-29.9 kg/m2 and less severe SGA. Ultrasound EFW was overestimated in women with unidentified SGA. This demonstrates the importance of improving the accuracy of SGA screening strategies in low-risk populations and continuing performance of ultrasound scans for term pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Delta oscillation coupled propagating fast ripples precede epileptiform discharges in patients with focal epilepsy.

Epileptiform spikes are used to localize epileptogenic brain tissue. The mechanisms that spontaneously trigger epileptiform discharges are not yet elucidated. Pathological fast ripple (FR, 200-600 Hz) are biomarkers of epileptogenic brain, and we postulated that FR network interactions are involved in generating epileptiform spikes. Using macroelectrode stereo intracranial EEG (iEEG) recordings from a cohort of 46 patients we found that, in the seizure onset zone (SOZ), propagating FR were more often followed by an epileptiform spike, as compared with non-propagating FR (p < 0.05). Propagating FR had a distinct frequency and larger power (p < 1e-10) and were more strongly phase coupled to the peak of iEEG delta oscillation, which likely correspond with the DOWN states during non-REM sleep (p < 1e-8), than non-propagating FR. While FR propagation was rare, all FR occurred with the highest probability within +/- 400 msec of epileptiform spikes with superimposed high-frequency oscillations (p < 0.05). Thus, a sub-population of epileptiform spikes in the SOZ, are preceded by propagating FR that are coordinated by the DOWN state during non-REM sleep.

Temporal lobe interictal spikes disrupt encoding and retrieval of verbal memory: A subregion analysis.

OBJECTIVE: The medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall. METHODS: Seventy-eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre-encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed-effects logistic regression. RESULTS: IS in the left hippocampus (odds ratio [OR] = .73, 95% confidence interval [CI] = .63-.84, p < .001) and left middle temporal gyrus (OR = .46, 95% CI = .27-.78, p < .05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR = .76, 95% CI = .66-.88, p < .01) and dentate gyrus (OR = .74, 95% CI = .62-.89, p < .05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p > .05). IS during retrieval in right hippocampal (OR = .22, 95% CI = .08-.63, p = .01) and parahippocampal regions (OR = .24, 95% CI = .07-.8, p < .05) reduced the probability of recalling a word. SIGNIFICANCE: IS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory.

Improving antenatal detection of small-for-gestational-age fetus: economic evaluation of Growth Assessment Protocol.

OBJECTIVE: To determine whether the Growth Assessment Protocol (GAP), as implemented in the DESiGN trial, is cost-effective in terms of antenatal detection of small-for-gestational-age (SGA) neonate, when compared with standard care. METHODS: This was an incremental cost-effectiveness analysis undertaken from the perspective of a UK National Health Service hospital provider. Thirteen maternity units from England, UK, were recruited to the DESiGN (DEtection of Small for GestatioNal age fetus) trial, a cluster randomized controlled trial. Singleton, non-anomalous pregnancies which delivered after 24 + 0 gestational weeks between November 2015 and February 2019 were analyzed. Probabilistic decision modeling using clinical trial data was undertaken. The main outcomes of the study were the expected incremental cost, the additional number of SGA neonates identified antenatally and the incremental cost-effectiveness ratio (ICER) (cost per additional SGA neonate identified) of implementing GAP. Secondary analysis focused on the ICER per infant quality-adjusted life year (QALY) gained. RESULTS: The expected incremental cost (including hospital care and implementation costs) of GAP over standard care was £34 559 per 1000 births, with a 68% probability that implementation of GAP would be associated with increased costs to sustain program delivery. GAP identified an additional 1.77 SGA neonates per 1000 births (55% probability of it being more clinically effective). The ICER for GAP was £19 525 per additional SGA neonate identified, with a 44% probability that GAP would both increase cost and identify more SGA neonates compared with standard care. The probability of GAP being the dominant clinical strategy was low (11%). The expected incremental cost per infant QALY gained ranged from £68 242 to £545 940, depending on assumptions regarding the QALY value of detection of SGA. CONCLUSION: The economic case for replacing standard care with GAP is weak based on the analysis reported in our study. However, this conclusion should be viewed taking into account that cost-effectiveness analyses are always limited by the assumptions made. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Contribution of left supramarginal and angular gyri to episodic memory encoding: An intracranial EEG study.

The role of the left ventral lateral parietal cortex (VPC) in episodic memory is hypothesized to include bottom-up attentional orienting to recalled items, according to the dual-attention model (Cabeza et al., 2008). However, its role in memory encoding could be further clarified, with studies showing both positive and negative subsequent memory effects (SMEs). Furthermore, few studies have compared the relative contributions of sub-regions in this functionally heterogeneous area, specifically the anterior VPC (supramarginal gyrus/BA40) and the posterior VPC (angular gyrus/BA39), on a within-subject basis. To elucidate the role of the VPC in episodic encoding, we compared SMEs in the intracranial EEG across multiple frequency bands in the supramarginal gyrus (SmG) and angular gyrus (AnG), as twenty-four epilepsy patients with indwelling electrodes performed a free recall task. We found a significant SME of decreased theta power and increased high gamma power in the VPC overall, and specifically in the SmG. Furthermore, SmG exhibited significantly greater spectral tilt SME from 0.5 to 1.6 s post-stimulus, in which power spectra slope differences between recalled and unrecalled words were greater than in the AnG (p = 0.04). These results affirm the contribution of VPC to episodic memory encoding, and suggest an anterior-posterior dissociation within VPC with respect to its electrophysiological underpinnings.

Spatial and temporal profile of high-frequency oscillations in posttraumatic epileptogenesis.

We studied the role of temporal and spatial changes in high-frequency oscillation (HFO, 80-500 Hz) generation in epileptogenesis following traumatic brain injury (TBI). Experiments were conducted on adult male Sprague Dawley rats. For the TBI group, fluid percussion injury (FPI) on the left sensorimotor area was performed to induce posttraumatic epileptogenesis. For the sham control group, only the craniotomy was performed. After TBI, 8 bipolar micro-electrodes were implanted bilaterally in the prefrontal cortex, perilesional area and homotopic contralateral site, striatum, and hippocampus. Long-term video/local field potential (LFP) recordings were performed for up to 21 weeks to identify and characterize seizures and capture HFOs. The electrode tip locations and the volume of post TBI brain lesions were further estimated by ex-vivo MRI scans. HFOs were detected during slow-wave sleep and categorized as ripple (80-200 Hz) and fast ripple (FR, 250-500 Hz) events. HFO rates and the HFO peak frequencies were compared in the 8 recording locations and across 8-weeks following TBI. Data from 48 rats (8 sham controls and 40 TBI rats) were analyzed. Within the TBI group, 22 rats (55%) developed recurrent spontaneous seizures (E+ group), at an average of 62.2 (+17.1) days, while 18 rats (45%) did not (E- group). We observed that the HFOs in the E+ group had a higher mean peak frequency than the E- group and the sham group (P < 0.05). Furthermore, the FR rate of the E+ group showed a significant increase compared to the E-group (P < 0.01) and sham control group (P < 0.01), specifically in the perilesional area, homotopic contralateral site, bilateral hippocampus, and to a lesser degree bilateral striatum. When compared across time, the increased FR rate in the E+ group occurred immediately after the insult and remained stable across the duration of the experiment. In addition, lesion size was not statistically different in the E+ and E- group and was not correlated with HFO rates. Our results suggest that TBI results in the formation of a widespread epileptogenic network. FR rates serve as a biomarker of network formation and predict the future development of epilepsy, however FR are not a temporally specific biomarker of TBI sequelae responsible for epileptogenesis. These results suggest that in patients, future risk of post-TBI epilepsy can be predicted early using FR.

Clinicians' experiences of using and implementing a medical mobile phone app (QUiPP V2) designed to predict the risk of preterm birth and aid clinical decision making.

BACKGROUND: As the vast majority of women who present in threatened preterm labour (TPTL) will not deliver early, clinicians need to balance the risks of over-medicalising the majority of women, against the potential risk of preterm delivery for those discharged home. The QUiPP app is a free, validated app which can support clinical decision-making as it produces individualised risks of delivery within relevant timeframes. Recent evidence has highlighted that clinicians would welcome a decision-support tool that accurately predicts preterm birth. METHODS: Qualitative interviews were undertaken as part of the EQUIPTT study (The Evaluation of the QUiPP app for Triage and Transfer) (REC: 17/LO/1802) which aimed to evaluate the impact of the QUiPP app on management of TPTL. Individual semi-structured telephone interviews were used to explore clinicians' (obstetricians' and midwives') experiences of using the QUiPP app and how it was implemented at their hospital sites. Thematic analysis was chosen to explore the meaning of the data, through a framework approach. RESULTS: Nineteen participants from 10 hospital sites in England took part. Data analysis revealed three overarching themes which were: 'experience of using the app', 'how QUiPP risk changes practice' and 'successfully adopting QUiPP: context is everything'. With these final themes we appeared to have achieved our aim of exploring the clinicians' experiences of using and implementing the QUiPP app. CONCLUSION: This study explored different clinician's experiences of implementing the app. The organizational and cultural context at different sites appeared to have a large impact on how well the QUiPP app was implemented. Future work needs to be undertaken to understand how best to embed the intervention within different settings. This will inform scale up of QUiPP app use across the UK and ensure that clinicians have access to this free, easy-to-use tool which can positively aid clinical decision making when caring for women in TPTL. CLINICAL TRIAL REGISTRY AND REGISTRATION NUMBER: ISRCTN 17846337, registered 08th January 2018, https://doi.org/10.1186/ISRCTN17846337 .

Placental growth factor in suspected preterm pre-eclampsia: a review of the evidence and practicalities of implementation.

Despite extensive research, the pathophysiology and prevention of pre-eclampsia remain elusive, diagnosis is challenging, and pre-eclampsia remains associated with adverse maternal and perinatal outcomes. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing is increasingly being implemented in clinical practice in several countries. This review provides healthcare providers with an understanding of the evidence for PlGF-based testing and describes the practicalities and challenges to implementation. TWEETABLE ABSTRACT: Placental growth factor in pre-eclampsia: evidence and implementation of testing.

Incidence and characteristics of pregnancy-related death across ten low- and middle-income geographical regions: secondary analysis of a cluster randomised controlled trial.

OBJECTIVE: The aim of this article is to describe the incidence and characteristics of pregnancy-related death in low- and middle-resource settings, in relation to the availability of key obstetric resources. DESIGN: This is a secondary analysis of a stepped-wedge cluster randomised controlled trial. SETTING: This trial was undertaken at ten sites across eight low- and middle-income countries in sub-Saharan Africa, India and Haiti. POPULATION: Institutional-level consent was obtained and all women presenting for maternity care were eligible for inclusion. METHODS: Pregnancy-related deaths were collected prospectively from routine data sources and active case searching. MAIN OUTCOME MEASURES: Pregnancy-related death, place, timing and age of maternal death, and neonatal outcomes in women with this outcome. RESULTS: Over 20 months, in 536 233 deliveries there were 998 maternal deaths (18.6/10 000, range 28/10 000-630/10 000). The leading causes of death were obstetric haemorrhage (36.0%, n = 359), hypertensive disorders of pregnancy (20.6%, n = 206), sepsis (14.1%, n = 141) and other (26.5%, n = 264). Approximately a quarter of deaths occurred prior to delivery (28.4%, n = 283), 35.7% (n = 356) occurred on the day of delivery and 35.9% (n = 359) occurred after delivery. Half of maternal deaths (50.6%; n = 505) occurred in women aged 20-29 years, 10.3% (n = 103) occurred in women aged under 20 years, 34.5% (n = 344) occurred in women aged 30-39 years and 4.6% (n = 46) occurred in women aged ≥40 years. There was no measured association between the availability of key obstetric resources and the rate of pregnancy-related death. CONCLUSIONS: The large variation in the rate of pregnancy-related death, irrespective of resource availability, emphasises that inequality and inequity in health care persists. TWEETABLE ABSTRACT: Inequality and inequity in pregnancy-related death persists globally, irrespective of resource availability.

Development and validation of predictive models for QUiPP App v.2: tool for predicting preterm birth in asymptomatic high-risk women.

OBJECTIVES: Accurate mid-pregnancy prediction of spontaneous preterm birth (sPTB) is essential to ensure appropriate surveillance of high-risk women. Advancing the QUiPP App prototype, QUiPP App v.2 aimed to provide individualized risk of delivery based on cervical length (CL), quantitative fetal fibronectin (qfFN) or both tests combined, taking into account further risk factors, such as multiple pregnancy. Here we report development of the QUiPP App v.2 predictive models for use in asymptomatic high-risk women, and validation using a distinct dataset in order to confirm the accuracy and transportability of the QUiPP App, overall and within specific clinically relevant time frames. METHODS: This was a prospective secondary analysis of data of asymptomatic women at high risk of sPTB recruited in 13 UK preterm birth clinics. Women were offered longitudinal qfFN testing every 2-4 weeks and/or transvaginal ultrasound CL measurement between 18 + 0 and 36 + 6 weeks' gestation. A total of 1803 women (3878 visits) were included in the training set and 904 women (1400 visits) in the validation set. Prediction models were created based on the training set for use in three groups: patients with risk factors for sPTB and CL measurement alone, with risk factors for sPTB and qfFN measurement alone, and those with risk factors for sPTB and both CL and qfFN measurements. Survival analysis was used to identify the significant predictors of sPTB, and parametric structures for survival models were compared and the best selected. The estimated overall probability of delivery before six clinically important time points (< 30, < 34 and < 37 weeks' gestation and within 1, 2 and 4 weeks after testing) was calculated for each woman and analyzed as a predictive test for the actual occurrence of each event. This allowed receiver-operating-characteristics curves to be plotted, and areas under the curve (AUC) to be calculated. Calibration was performed to measure the agreement between expected and observed outcomes. RESULTS: All three algorithms demonstrated high accuracy for the prediction of sPTB at < 30, < 34 and < 37 weeks' gestation and within 1, 2 and 4 weeks of testing, with AUCs between 0.75 and 0.90 for the use of qfFN and CL combined, between 0.68 and 0.90 for qfFN alone, and between 0.71 and 0.87 for CL alone. The differences between the three algorithms were not statistically significant. Calibration confirmed no significant differences between expected and observed rates of sPTB within 4 weeks and a slight overestimation of risk with the use of CL measurement between 22 + 0 and 25 + 6 weeks' gestation. CONCLUSIONS: The QUiPP App v.2 is a highly accurate prediction tool for sPTB that is based on a unique combination of biomarkers, symptoms and statistical algorithms. It can be used reliably in the context of communicating to patients the risk of sPTB. Whilst further work is required to determine its role in identifying women requiring prophylactic interventions, it is a reliable and convenient screening tool for planning follow-up or hospitalization for high-risk women. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Development and validation of predictive models for QUiPP App v.2: tool for predicting preterm birth in women with symptoms of threatened preterm labor.

OBJECTIVE: To develop enhanced prediction models to update the QUiPP App prototype, a tool providing individualized risk of spontaneous preterm birth (sPTB), for use in women with symptoms of threatened preterm labor (TPTL), incorporating risk factors, transvaginal ultrasound assessment of cervical length (CL) and cervicovaginal fluid quantitative fetal fibronectin (qfFN) test results. METHODS: Participants were pregnant women between 23 + 0 and 34 + 6 weeks' gestation with symptoms of TPTL, recruited as part of four prospective cohort studies carried out at 16 UK hospitals between October 2010 and October 2017. The training set comprised all women whose outcomes were known in May 2017 (n = 1032). The validation set comprised women whose outcomes were gathered between June 2017 and March 2018 (n = 506). Parametric survival models were developed for three combinations of predictors: risk factors plus qfFN test results alone, risk factors plus CL alone, and risk factors plus both qfFN and CL. The best models were selected using the Akaike and Bayesian information criteria. The estimated probability of sPTB < 30, < 34 or < 37 weeks' gestation and within 1 or 2 weeks of testing was calculated and receiver-operating-characteristics (ROC) curves were created to demonstrate the diagnostic ability of the prediction models. RESULTS: Predictive statistics were similar between the training and the validation sets at most outcome time points and for each combination of predictors. Areas under the ROC curves (AUC) demonstrated that all three algorithms had good accuracy for the prediction of sPTB at < 30, < 34 and < 37 weeks' gestation and within 1 and 2 weeks' post-testing in the validation set, particularly the model combining risk factors plus qfFN alone (AUC: 0.96 at < 30 weeks; 0.85 at < 34 weeks; 0.77 at < 37 weeks; 0.91 at < 1 week from testing; and 0.92 at < 2 weeks from testing). CONCLUSIONS: Validation of the new prediction models suggests that the QUiPP App v.2 can reliably calculate risk of sPTB in women with TPTL. Use of the QUiPP App in practice could lead to better targeting of intervention, while providing reassurance and avoiding unnecessary intervention in women at low risk. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Desarrollo y validación de modelos predictivos para la Aplicación QUiPP v.2: herramienta para predecir el parto pretérmino en mujeres con síntomas de amenaza de parto prematuro OBJETIVO: Desarrollar modelos de predicción mejorados para actualizar el prototipo de la Aplicación QUiPP, una herramienta que proporciona el riesgo individualizado de parto pretérmino espontáneo (PPTE), para su uso en mujeres con síntomas de amenaza de parto pretérmino (APPT), mediante la incorporación de los factores de riesgo, la evaluación de la longitud cervical (LC) mediante ecografía transvaginal y los resultados de la prueba de fibronectina fetal cuantitativa (qfFN, por sus siglas en inglés) del líquido cérvico-vaginal. MÉTODOS: Las participantes fueron mujeres embarazadas entre 23 + 0 y 34 + 6 semanas de gestación con síntomas de APPT, reclutadas como parte de cuatro estudios de cohorte prospectivos llevados a cabo en 16 hospitales del Reino Unido entre octubre de 2010 y octubre de 2017. El grupo de entrenamiento comprendía a todas las mujeres cuyos resultados se conocían en mayo de 2017 (n = 1032). El grupo de validación estaba compuesto por mujeres cuyos resultados se recogieron entre junio de 2017 y marzo de 2018 (n = 506). Se desarrollaron modelos paramétricos de supervivencia para tres combinaciones de predictores: factores de riesgo más resultados de pruebas de qfFN solamente, factores de riesgo más LC solamente, y factores de riesgo más tanto qfFN como LC. Los mejores modelos fueron seleccionados utilizando los criterios de información de Akaike y Bayesiano. Se calculó la probabilidad estimada de PPTE a <30, <34 o <37 semanas de gestación y dentro de 1 o 2 semanas de la prueba y se crearon curvas de la característica operativa del receptor (ROC, por sus siglas en inglés) para demostrar la capacidad de diagnóstico de los modelos de predicción. RESULTADOS: Las estadísticas de predicción fueron similares entre los grupos de entrenamiento y de validación en la mayoría de los puntos de tiempo de los resultados y para cada combinación de predictores. Las áreas bajo las curvas (ABC) ROC demostraron que los tres algoritmos tuvieron una buena precisión para la predicción del PPTE a <30, <34 y <37 semanas de gestación y dentro de 1 a 2 semanas después de la prueba en el grupo de validación, en particular el modelo que combina los factores de riesgo más qfFN por si solo (ABC: 0,96 a <30 semanas; 0,85 at <34 semanas; 0,77 at <37 semanas; 0,91 at <1 semana de la prueba; y 0,92 a <2 semanas de la prueba CONCLUSIONES: La validación de los nuevos modelos de predicción sugiere que la Aplicación QUiPP v.2 puede calcular de manera fiable el riesgo de PPTE en mujeres con APPT. El uso de la Aplicación QUiPP en la práctica podría llevar a un mejor cribado para la intervención, a la vez que daría seguridad y evitaría intervenciones innecesarias en mujeres con bajo riesgo.

Low-voltage fast seizures in humans begin with increased interneuron firing.

OBJECTIVE: Intracellular recordings from cells in entorhinal cortex tissue slices show that low-voltage fast (LVF) onset seizures are generated by inhibitory events. Here, we determined whether increased firing of interneurons occurs at the onset of spontaneous mesial-temporal LVF seizures recorded in patients. METHODS: The seizure onset zone (SOZ) was identified using visual inspection of the intracranial electroencephalogram. We used wavelet clustering and temporal autocorrelations to characterize changes in single-unit activity during the onset of LVF seizures recorded from microelectrodes in mesial-temporal structures. Action potentials generated by principal neurons and interneurons (ie, putative excitatory and inhibitory neurons) were distinguished using waveform morphology and K-means clustering. RESULTS: From a total of 200 implanted microelectrodes in 9 patients during 13 seizures, we isolated 202 single units; 140 (69.3%) of these units were located in the SOZ, and 40 (28.57%) of them were classified as inhibitory. The waveforms of both excitatory and inhibitory units remained stable during the LVF epoch (p > > 0.05). In the mesial-temporal SOZ, inhibitory interneurons increased their firing rate during LVF seizure onset (p < 0.01). Excitatory neuron firing rates peaked 10 seconds after the inhibitory neurons (p < 0.01). During LVF spread to the contralateral mesial temporal lobe, an increase in inhibitory neuron firing rate was also observed (p < 0.01). INTERPRETATION: Our results suggest that seizure generation and spread during spontaneous mesial-temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution. Ann Neurol 2018;84:588-600.

Placental growth factor testing for suspected pre-eclampsia: a cost-effectiveness analysis.

OBJECTIVE: To calculate the cost-effectiveness of implementing PlGF testing alongside a clinical management algorithm in maternity services in the UK, compared with current standard care. DESIGN: Cost-effectiveness analysis. SETTING: Eleven maternity units participating in the PARROT stepped-wedge cluster-randomised controlled trial. POPULATION: Women presenting with suspected pre-eclampsia between 20+0 and 36+6  weeks' gestation. METHODS: Monte Carlo simulation utilising resource use data and maternal adverse outcomes. MAIN OUTCOME MEASURES: Cost per maternal adverse outcome prevented. RESULTS: Clinical care with PlGF testing costs less than current standard practice and resulted in fewer maternal adverse outcomes. There is a total cost-saving of UK£149 per patient tested, when including the cost of the test. This represents a potential cost-saving of UK£2,891,196 each year across the NHS in England. CONCLUSIONS: Clinical care with PlGF testing is associated with the potential for cost-savings per participant tested when compared with current practice via a reduction in outpatient attendances, and improves maternal outcomes. This economic analysis supports a role for implementation of PlGF testing in antenatal services for the assessment of women with suspected pre-eclampsia. TWEETABLE ABSTRACT: Placental growth factor testing for suspected pre-eclampsia is cost-saving and improves maternal outcomes.

Comparison of three commercially available placental growth factor-based tests in women with suspected preterm pre-eclampsia: the COMPARE study.

OBJECTIVE: To compare the performance of three placental growth factor (PlGF)-based tests in predicting delivery within 14 days from testing in women with suspected preterm pre-eclampsia before 35 weeks' gestation. METHODS: This was a retrospective analysis of samples collected from three prospective pregnancy cohort studies. Participants were pregnant women with suspected preterm pre-eclampsia recruited in tertiary maternity units in the UK and Ireland. Samples were analyzed simultaneously according to the manufacturers' directions. The tests compared were the DELFIA Xpress PlGF 1-2-3 test, the Triage PlGF test and the Elecsys immunoassay soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio. Areas under receiver-operating characteristics curves (AUCs) were compared. The main outcome measure was detection of a difference of 0.05 in AUC between tests for delivery within 14 days of testing. RESULTS: Plasma samples from 396 women and serum samples from 244 women were assayed. In predicting delivery within 14 days secondary to suspected pre-eclampsia prior to 35 weeks' gestation, no significant differences were observed in AUCs (P = 0.795), sensitivities (P = 0.249), positive predictive values (P = 0.765) or negative predictive values (P = 0.920) between the three tests. The specificity of the Elecsys sFlt-1/PlGF ratio test was higher than that of the other two tests (P < 0.001). CONCLUSIONS: The tests perform similarly in their prediction of need for delivery within 14 days in women with suspected pre-eclampsia. The high negative predictive values support the role of PlGF-based tests as 'rule-out' tests for pre-eclampsia. © 2018 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Predicting delivery of a small-for-gestational-age infant and adverse perinatal outcome in women with suspected pre-eclampsia.

OBJECTIVE: To evaluate the test performance of 47 biomarkers and ultrasound parameters for the prediction of delivery of a small-for-gestational-age (SGA) infant and adverse perinatal outcome in women presenting with suspected pre-eclampsia. METHODS: This was a prospective, multicenter observational study in which 47 biomarkers and ultrasound parameters were measured in 397 women with a singleton pregnancy presenting with suspected preterm pre-eclampsia between 20 + 0 and 36 + 6 weeks' gestation, with the objective of evaluating them as predictors of subsequent delivery of a SGA infant and adverse perinatal outcome. Women with confirmed pre-eclampsia at enrollment were excluded. Factor analysis and stepwise logistic regression were performed in two prespecified groups stratified according to gestational age at enrollment. The primary outcome was delivery of a SGA infant with a birth weight < 3rd customized centile (SGA-3), and secondary outcomes were a SGA infant with a birth weight < 10th customized centile and adverse perinatal outcome. RESULTS: In 274 women presenting at 20 + 0 to 34 + 6 weeks' gestation, 96 (35%) delivered a SGA-3 infant. For prediction of SGA-3, low maternal placental growth factor (PlGF) concentration had a sensitivity of 93% (95% CI, 84-98%) and negative predictive value (NPV) of 90% (95% CI, 76-97%) compared with a sensitivity of 71% (95% CI, 58-82%) and a NPV of 79% (95% CI, 68-87%) for ultrasound parameters (estimated fetal weight or abdominal circumference < 10th centile). No individual biomarker evaluated had a better performance than did PlGF, and marker combinations made only small improvements to the test performance. Similar results were found in 123 women presenting between 35 + 0 and 36 + 6 weeks' gestation. CONCLUSION: In women presenting with suspected preterm pre-eclampsia, measurement of PlGF offers a useful adjunct for identifying those at high risk of delivering a SGA infant, allowing appropriate surveillance and timely intervention. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Ripple oscillations in the left temporal neocortex are associated with impaired verbal episodic memory encoding.

BACKGROUND: We sought to determine if ripple oscillations (80-120 Hz), detected in intracranial electroencephalogram (iEEG) recordings of patients with epilepsy, correlate with an enhancement or disruption of verbal episodic memory encoding. METHODS: We defined ripple and spike events in depth iEEG recordings during list learning in 107 patients with focal epilepsy. We used logistic regression models (LRMs) to investigate the relationship between the occurrence of ripple and spike events during word presentation and the odds of successful word recall following a distractor epoch and included the seizure onset zone (SOZ) as a covariate in the LRMs. RESULTS: We detected events during 58,312 word presentation trials from 7630 unique electrode sites. The probability of ripple on spike (RonS) events was increased in the SOZ (p < 0.04). In the left temporal neocortex, RonS events during word presentation corresponded with a decrease in the odds ratio (OR) of successful recall, however, this effect only met significance in the SOZ (OR of word recall: 0.71, 95% confidence interval (CI): 0.59-0.85, n = 158 events, adaptive Hochberg, p < 0.01). Ripple on oscillation (RonO) events that occurred in the left temporal neocortex non-SOZ also correlated with decreased odds of successful recall (OR: 0.52, 95% CI: 0.34-0.80, n = 140, adaptive Hochberg, p < 0.01). Spikes and RonS that occurred during word presentation in the left middle temporal gyrus (MTG) correlated with the most significant decrease in the odds of successful recall, irrespective of the location of the SOZ (adaptive Hochberg, p < 0.01). CONCLUSION: Ripples and spikes generated in the left temporal neocortex are associated with impaired verbal episodic memory encoding. Although physiological and pathological ripple oscillations were not distinguished during cognitive tasks, our results show an association of undifferentiated ripples with impaired encoding. The effect was sometimes specific to regions outside the SOZ, suggesting that widespread effects of epilepsy outside the SOZ may contribute to cognitive impairment.

Bimodal coupling of ripples and slower oscillations during sleep in patients with focal epilepsy.

OBJECTIVE: Differentiating pathologic and physiologic high-frequency oscillations (HFOs) is challenging. In patients with focal epilepsy, HFOs occur during the transitional periods between the up and down state of slow waves. The preferred phase angles of this form of phase-event amplitude coupling are bimodally distributed, and the ripples (80-150 Hz) that occur during the up-down transition more often occur in the seizure-onset zone (SOZ). We investigated if bimodal ripple coupling was also evident for faster sleep oscillations, and could identify the SOZ. METHODS: Using an automated ripple detector, we identified ripple events in 40-60 min intracranial electroencephalography (iEEG) recordings from 23 patients with medically refractory mesial temporal lobe or neocortical epilepsy. The detector quantified epochs of sleep oscillations and computed instantaneous phase. We utilized a ripple phasor transform, ripple-triggered averaging, and circular statistics to investigate phase event-amplitude coupling. RESULTS: We found that at some individual recording sites, ripple event amplitude was coupled with the sleep oscillatory phase and the preferred phase angles exhibited two distinct clusters (p < 0.05). The distribution of the pooled mean preferred phase angle, defined by combining the means from each cluster at each individual recording site, also exhibited two distinct clusters (p < 0.05). Based on the range of preferred phase angles defined by these two clusters, we partitioned each ripple event at each recording site into two groups: depth iEEG peak-trough and trough-peak. The mean ripple rates of the two groups in the SOZ and non-SOZ (NSOZ) were compared. We found that in the frontal (spindle, p = 0.009; theta, p = 0.006, slow, p = 0.004) and parietal lobe (theta, p = 0.007, delta, p = 0.002, slow, p = 0.001) the SOZ incidence rate for the ripples occurring during the trough-peak transition was significantly increased. SIGNIFICANCE: Phase-event amplitude coupling between ripples and sleep oscillations may be useful to distinguish pathologic and physiologic events in patients with frontal and parietal SOZ.