Validation of machine-learning model for first-trimester prediction of pre-eclampsia using cohort from PREVAL study.

OBJECTIVE: Effective first-trimester screening for pre-eclampsia (PE) can be achieved using a competing-risks model that combines risk factors from the maternal history with multiples of the median (MoM) values of biomarkers. A new model using artificial intelligence through machine-learning methods has been shown to achieve similar screening performance without the need for conversion of raw data of biomarkers into MoM. This study aimed to investigate whether this model can be used across populations without specific adaptations. METHODS: Previously, a machine-learning model derived with the use of a fully connected neural network for first-trimester prediction of early (< 34 weeks), preterm (< 37 weeks) and all PE was developed and tested in a cohort of pregnant women in the UK. The model was based on maternal risk factors and mean arterial blood pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A). In this study, the model was applied to a dataset of 10 110 singleton pregnancies examined in Spain who participated in the first-trimester PE validation (PREVAL) study, in which first-trimester screening for PE was carried out using the Fetal Medicine Foundation (FMF) competing-risks model. The performance of screening was assessed by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% screen-positive rate (SPR). These indices were compared with those derived from the application of the FMF competing-risks model. The performance of screening was poor if no adjustment was made for the analyzer used to measure PlGF, which was different in the UK and Spain. Therefore, adjustment for the analyzer used was performed using simple linear regression. RESULTS: The DRs at 10% SPR for early, preterm and all PE with the machine-learning model were 84.4% (95% CI, 67.2-94.7%), 77.8% (95% CI, 66.4-86.7%) and 55.7% (95% CI, 49.0-62.2%), respectively, with the corresponding AUCs of 0.920 (95% CI, 0.864-0.975), 0.913 (95% CI, 0.882-0.944) and 0.846 (95% CI, 0.820-0.872). This performance was achieved with the use of three of the biomarkers (MAP, UtA-PI and PlGF); inclusion of PAPP-A did not provide significant improvement in DR. The machine-learning model had similar performance to that achieved by the FMF competing-risks model (DR at 10% SPR, 82.7% (95% CI, 69.6-95.8%) for early PE, 72.7% (95% CI, 62.9-82.6%) for preterm PE and 55.1% (95% CI, 48.8-61.4%) for all PE) without requiring specific adaptations to the population. CONCLUSIONS: A machine-learning model for first-trimester prediction of PE based on a neural network provides effective screening for PE that can be applied in different populations. However, before doing so, it is essential to make adjustments for the analyzer used for biochemical testing. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Change in prevalence of preterm birth in Israel following publication of national guidelines recommending routine sonographic cervical-length measurement at 19-25 weeks' gestation.

OBJECTIVE: To compare the prevalence of preterm birth (PTB) (delivery before 37 weeks) in Israel before and after publication of national guidelines recommending second-trimester sonographic cervical-length (CL) measurement. METHODS: The Israeli Society of Obstetrics and Gynecology (ISOG) guidelines, issued on 1 January 2012, specified that CL should be measured transabdominally or, if this is not possible, transvaginally, at the 19-25-week ultrasound anomaly scan and that CL < 25 mm should indicate further work-up and treatment, although the type of treatment was unspecified. In 2000, the Israel Ministry of Health issued a legal requirement for the submission of delivery records to a national registry. These data were used to compare PTB prevalence in the period before (2000-2011) and that after (2012-2020) publication of the guidelines, as well as trends within each time period. Information was available on singleton and multiple pregnancy and maternal age and parity, as well as low birth weight (< 2500 g). RESULTS: During the period 2000-2020, there were 3 403 976 infants liveborn in Israel: 1 797 657 before and 1 606 319 after publication of the ISOG guidelines. There were 247 187 PTBs overall, with a prevalence of 7.64% (95% CI, 7.52-7.77%) before publication of the guidelines and 6.84% (95% CI, 6.43-7.24%) afterwards (P < 0.0002, two-tailed). The annual PTB prevalence was static in the first time period but declined by 0.18% per annum during the second period, after publication of the guidelines. The proportionate reduction in PTB prevalence after compared with before publication of the guidelines was 10% overall, 9% for PTB at 33-36 weeks, 18% for PTB at 28-32 weeks and 24% for PTB at < 28 weeks. After publication of the guidelines, reduced prevalence of PTB was observed among singletons (5.49% before vs 4.83% after, P < 0.0001), but not among infants in twin or higher-order multiple pregnancy. There was a statistically significant reduction in the rate of PTB following publication of the guidelines in both nulliparous and parous women and in the 19-39-year-old maternal-age group. Although reductions in PTB prevalence were also noted in high-risk age groups (maternal age < 19 years and ≥ 40 years), these did not reach statistical significance. Following publication of the guidelines, there was a statistically significant reduction in the prevalence of birth weight under 2500 g, of a magnitude similar to that for PTB prevalence. CONCLUSIONS: The publication of national guidelines recommending routine CL measurement at the time of the second-trimester anomaly scan was associated with a fall in PTB prevalence in singleton pregnancies. Whilst direct evidence linking screening with this fall in prevalence is lacking, it is likely that implementation of routine CL screening played an important role in the reduction of PTB rate. Our experience indicates that screening can be incorporated into the second-trimester anomaly scan. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Machine-learning-based prediction of pre-eclampsia using first-trimester maternal characteristics and biomarkers.

OBJECTIVE: To evaluate the accuracy of predicting the risk of developing pre-eclampsia (PE) according to first-trimester maternal demographic characteristics, medical history and biomarkers using artificial-intelligence and machine-learning methods. METHODS: The data were derived from prospective non-interventional screening for PE at 11-13 weeks' gestation at two maternity hospitals in the UK. The data were divided into three subsets. The first set, including 30 437 subjects, was used to develop the training process, the second set of 10 000 subjects was utilized to optimize the machine-learning hyperparameters and the third set of 20 352 subjects was coded and used for model validation. An artificial neural network was used to predict from the demographic characteristics and medical history the prior risk that was then combined with biomarker values to determine the risk of PE and preterm PE with delivery at < 37 weeks' gestation. An additional network was trained without including race as input. Biomarkers included uterine artery pulsatility index (UtA-PI), mean arterial blood pressure (MAP), placental growth factor (PlGF) and pregnancy-associated plasma protein-A. All markers were entered using raw values without conversion into standardized multiples of the median. The prediction accuracy was estimated using the area under the receiver-operating-characteristics curve (AUC). We further computed the detection rate at 10%, 20% and 40% false-positive rates (FPR). The impact of taking aspirin was also added. Shapley values were calculated to evaluate the contribution of each parameter to the prediction of risk. We used a non-parametric test to compare the expected AUC with the one obtained when we randomly scrambled the labels and kept the predictions. For the general prediction, we performed 10 000 permutations of the labels. When the AUC was higher than the one obtained in all 10 000 permutations, we reported a P-value of < 0.0001. For the race-specific analysis, we performed 1000 permutations. When the AUC was higher than the AUC in permutations, we reported a P-value of < 0.001. RESULTS: The detection rate for preterm PE vs no PE, at a 10% FPR, was 53.3% when screening by maternal factors only, and the corresponding AUC was 0.816; these increased to 75.3% and 0.909, respectively, with the addition of biomarkers into the model. Information on race was important for the prediction accuracy; when race was not used to train the model, at a 10% FPR, the detection rate of preterm PE vs no PE decreased to 34.5-45.5% (for different races) when screening by maternal factors only and to 55.0-62.1% when biomarkers were added. The major predictors of PE were high MAP and UtA-PI, and low PlGF. The accuracy of prediction of all PE cases was lower than that for preterm PE. Aspirin use was recommended for cases who were at high risk of preterm PE. The AUC of all PE vs no PE was 0.770 when screening by maternal factors and 0.817 when the biomarkers were added; the respective detection rates, at a 10% FPR, were 41.3% and 52.9%. CONCLUSIONS: Screening for PE using a non-linear machine-learning-based approach does not require a population-based normalization, and its performance is similar to that of logistic regression. Removing race information from the model reduces its prediction accuracy, especially for the non-white populations when only maternal factors are considered. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester markers for the prediction of pre-eclampsia in women with a-priori high risk.

OBJECTIVE: To investigate the predictive value of the combination of first-trimester serum placental protein 13 (PP13), uterine artery Doppler pulsatility index (PI) and pulse wave analysis (augmentation index at a heart rate of 75 beats per min (AIx-75)), and to evaluate concurrent and contingent strategies using this combination for assessing the risk of pre-eclampsia in high-risk women. METHODS: In this nested case-control study, serum PP13, uterine artery mean PI and AIx-75 were measured at between 11 + 0 and 13 + 6 weeks' gestation in women at increased risk of pre-eclampsia. For each case of pre-eclampsia (n = 42), five matched controls were randomly selected from the study group. Gestation specific multiples of the median (MoMs) were adjusted for body mass index, ethnicity, smoking, age and parity. MoMs were compared between cases and controls using the Wilcoxon rank sum test. Sensitivities and specificities were derived from receiver-operating characteristics curves. RESULTS: Compared with controls, women who developed pre-eclampsia had lower PP13, higher uterine artery mean PI and higher AIx-75 (P < 0.001). For a 10% false-positive rate, the best detection rate for pre-eclampsia (85.7% (95% CI, 71.5-94.6%)) and pre-eclampsia requiring delivery before 34 weeks (92.9% (95% CI, 66.1-99.8%)) was achieved by concurrent testing with all three markers. The best contingency screening sequences for pre-eclampsia were (AIx-75 --> PP13 --> mean PI) and (PP13 --> AIx-75 --> mean PI), with an 86% detection rate for false-positive rates of 9 and 10%, respectively. These two sequences would require 410 and 414 tests, respectively, compared with 756 tests in concurrent testing. CONCLUSION: Combination of first-trimester PP13, uterine artery mean PI and pulse-wave analysis is promising for the prediction of pre-eclampsia in women at increased a-priori risk and may be useful in clinical practice. Contingency screening achieved similar detection rates to concurrent testing, but required almost 50% fewer tests, making it a more cost-effective option.

IFPA meeting 2008 workshops report.

Workshops are an important part of the IFPA annual meeting. At the IFPA meeting 2008 diverse topics were discussed in 12 themed workshops. Topics covered included: immunology of placentation; galectins and trophoblast invasion; signaling in implantation and invasion; markers to identify trophoblast subpopulations; placental pathology; placental toxicology; stereology; placental transport of fatty acids; placental mesenchymal stem cells; comparative placentation; trophoblast and neoplasia; trophoblast differentiation. This report is a summary of the various topics covered.

Membrane conductance and action potential of a regenerating axonal tip.

The electrical membrane properties of axotomized and regenerating giant axons from the nerve cord of the cockroach Periplaneta americana were studied. Immediately after axotomy there was a decrease in resting potential, input resistance, and action potential amplitude near the cut end. This decrease was followed by the disappearance of the sodium-dependent action potential; an increase in the resting membrane conductance to K+, Na+, and Ca2+; and the appearance of a calcium-dependent action potential.

Adrenocorticotropic hormone causes long-lasting potentiation of transmitter release from frog motor nerve terminals.

Exposure of frog neuromuscular preparations to adrenocorticotropic hormone for several minutes increased both nerve-evoked and spontaneous transmitter release for several hours. No changes in postsynaptic sensitivity to transmitter were detected. The long-lasting potentiation shows little sensitivity to changes in extracellular calcium concentration and seems to be entirely presynaptic in origin.

Placental protein 13 as an early marker for pre-eclampsia: a prospective longitudinal study.

OBJECTIVE: To assess the value of placental protein 13 (PP13) as an early marker of pre-eclampsia. DESIGN: Sequential blood samples were obtained from women with singleton viable pregnancies at 6-10, 16-20 and 24-28 weeks of gestation. Samples were tested for PP13 using a solid-phase sandwich enzyme-linked immunosorbent assay. Levels were expressed as multiples of the medians (MoM) of the unaffected population. The slope or rate of change in PP13 concentration per week of gestation was also calculated. SETTING: Thirty-five prenatal care community clinics. SAMPLE: In total, 1,366 women were recruited, and subsequently, 20 were diagnosed with pre-eclampsia, 41 with gestational hypertension and 1,178 were unaffected. MAIN OUTCOME MEASURES: Sensitivity and specificity of screening with PP13 at each gestational period and of PP13 level combined with the slope of PP13 between two testing periods. RESULTS: At 6-10 gestational weeks, PP13 levels were significantly lower among the pre-eclampsia group with a median 0.28 MoM (95% CI 0.15-0.39, P < 0.004). Using a cutoff of 0.40 MoM, the sensitivity was 80%, false-positive rate (FPR) was 20% and odds ratio was 16.0 (95% CI 5.3-48.4). Combining MoM of 6-10 weeks and slope between 6-10 and 16-20 weeks, the sensitivity was 78%, the FPR was 6% and odds ratio was 55.5 (95% CI 18.2-169.2). The gestational hypertension group was not different from the normal group. CONCLUSIONS: PP13 in the first trimester alone or in combination with the slope between the first and the second trimesters may be a promising marker for assessing the risk of pre-eclampsia.

The fusogenic substance dimethyl sulfoxide enhances exocytosis in motor nerve endings.

Fusion of synaptic vesicles with the surface membrane of the nerve terminal is a key step in synaptic transmission, which normally requires the entry of calcium ions into the cell. We report that this fusion and the subsequent liberation of transmitter can also be induced by the fusogenic substances DMSO (dimethyl sulfoxide) and PEG (poly(ethylene glycol)). Calcium ions and DMSO exhibit a synergistic effect in the fusion of synaptic vesicles with the axolemma, resembling their action on fusion phenomena in liposomes.

Toxic effects of alumino-silicates on nerve cells.

The recently reported presence of alumino-silicates in the core of Alzheimer's senile plaques raises a number of questions concerning the little studied area of interactions between solid particles and neuronal tissue. In this preliminary study we report that contact between crystalline alumino-silicates and cultured neuroblastoma cells selectively caused a rapid increase in membrane electrical conductance and loss of excitable activity. Severe morphological deterioration was subsequently evident within 30 min of exposure. Similar effects were induced by a magnesium silicate mineral but not by aluminum hydroxides or by silicon in the form of quartz. Homogeneously charged synthetic particles did not induce changes in electrical function of the cells. These results suggest that a layout incorporating both negative and positive charges, as can be found on the broken edges of platy clay metallo-silicates, and the non-isodiametrical geometry of the particles may be necessary for the acute neurotoxic interaction observed.

Effects of aluminium on electrical and mechanical properties of frog atrial muscle.

1. The effects of aluminium on membrane ionic currents were studied in single cardiac myocytes. Most of the work was done on frog atrial cells, but some experiments were also carried out on single cells isolated from rabbit ventricles and atria. 2. The effects of aluminium on the force of contraction of frog atrial trabeculae were also investigated. 3. Aluminium was prepared from AlCl3 as a stock 0.5 M solution which has a pH of 3.5. Before each experiment, this solution was added to the control solution, to give a final concentration of 20-100 micrograms ml-1 aluminium (0.75-3.75 mM AlCl3). The solutions were brought to a pH of 7.4 or 7.6. at which they consist of a mixture of amorphous aluminium hydroxides and a very small amount of soluble ionic aluminium complexes: free aluminium cations (less than 10 pM), aluminohydroxide anions (less than 8 microM). The addition of this suspension reduced the peak inward calcium currents in single rabbit atrial and ventricular cells and in frog atrial cells. In the latter, the peak current was reduced (at + 10 mV) to 45% of control (mean of 9 cells). This effect was reversible upon washout, and was obtained at all membrane potentials, with no shift of the calcium current voltage relationship along the voltage axis. 4. Aluminium also reduced the time-dependent potassium current IK. This reduction was observed at all membrane potentials. For example, at + 10 mV, the mean reduction of IK (n = 9) was to 69% of the control amplitude. This effect, which was very difficult to reverse, was not due to IK rundown. The fully activated current-voltage relationships (obtained by standard 'tail' analysis) showed that the effect of aluminium was due mainly to a decrease in conductance and not to a shift in the activation range of IK. The mean voltage of half activation was shifted by 8 mV in the depolarizing direction (n = 5). 5. The background potassium current IK1 was also slightly but consistently changed in a complex fashion, with an outward shift at membrane potentials positive to -60 mV. For example, at a membrane potential of -40mV, the mean shift was by 22 + 4pA. At more negative potentials, there was an inward shift in the current amplitudes. For example, for steps to -I00 mV the current elicited was larger (more inward) by 53 pA (mean value, n = 10). The reversal potential was slightly shifted (<10 mV) in the hyperpolarizing direction. 6. The force of contraction of frog atrial trabeculae was altered by aluminium in a complex manner, which showed marked seasonal variation. During most of the year, 50-100,ug ml-1 aluminium caused a biphasic change, with an early small and consistent decrease, followed by a large increase in twitch amplitude. For a short period corresponding to the (local) winter months the sensitivity to aluminium was greatly enhanced. Aluminium lOOupgml-1 totally abolished contraction (n = 5), while a lower concentration (20,ug ml- 1) produced a sustained reduction in the force of contraction. Similar biphasic and seasonal responses have been reported to be induced by lanthanum. 7. The biphasic changes in twitch amplitude were independent of the transmembrane sodium gradient. Aluminium produced the same effects when 90% of the extracellular sodium was replaced by lithium. Caffeine (5 mM) attenuated or even inverted the positive inotropic effect of aluminium. These results imply that aluminium alters the release of calcium from intracellular, caffeine-sensitive stores. This could be effected either by augmenting the amount released during each activation, and/or by increasing the loading of stores prior to release.

Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies.

Placental tissue protein 13 (PP-13), one of the 56 known placental proteins identified till today, was purified from placentas obtained from women at delivery, and used to evoke antibodies against it. The purified PP-13 was lysed to peptides, which were sequenced, leading to the full-length cDNA sequencing and its expression in Escherichia coli. Sequence analysis in databases showed homology to the galectin family. Of the various antibody preparations developed, a pair of monoclonal antibodies (MAbs) coupled to the recombinant PP-13 (PP-13-R) was used for the immunodetection of PP-13 in pregnant women's serum with the solid-phase ELISA format. With a dynamic range of 25-500 pg/mL with no background in non-pregnant women's serum and men's serum, the ELISA test was suitable for the detection of PP-13 in the 1st, 2nd, and 3rd trimesters. PP-13 levels slowly increase during pregnancy. In the 1st trimester, lower than normal PP-13 levels were found in fetal growth restriction (IUGR), preeclampsia (PE), and particularly in early PE (<34 weeks of gestation). In the 2nd and 3rd trimesters, higher than normal concentrations were found in PE, IUGR and in preterm delivery (PTD). Application of PP-13 to cultured trophoblasts elicited depolarization carried by calcium ions, followed by liberation of linoleic and arachidonic acids from the trophoblast membrane, and a subsequent elevation of prostacyclin and thromboxane. These effects were negligible when PP-13 derived from the placentas of patients with IUGR, PE or PTD was used. The results are discussed in view of the potential utilization of PP-13 for early serum screening to assess the risk to develop placental insufficiency, coupled to a differential analysis of the various pathologies by analyzing cultured trophoblasts.

Intracellular and extracellular calcium ions in transmitter release at the neuromuscular synapse.

The theme of this presentation has been to show that the control of transmitter release at the neuromuscular synapse is achieved by extracellular and intracellular calcium. For the fast information transfer represented by the end-plate potential, the electrochemical gradient for calcium across the presynaptic membrane and the associated calcium conductance seem to play the primary role. For slower processes such as tetanic and posttetanic potentiation, the combined effect of both sources for calcium determine the amount of transmitter liberated.

Detection of cell surface sodium channels by monoclonal antibodies--could the channels become exposed to the external surface and 'down regulated' by binding to antibodies?

Different domains of the sodium channel were characterized in rat sciatic nerve according to the binding of antibodies to their antigenic determinants. An extracellular domain, accessible to antibodies, modulates channel conductance. Another domain, which is not involved in the physiological activity, becomes accessible to externally applied antibodies only after prolonged exposure. This study also revealed mobile antigenic determinants whose internalization can be detected by immunofluorescence.

Is synaptic transmission modulated by progesterone?

The influence of the gonadosteroid hormone progesterone on synaptic transmission was studied using the frog neuromuscular preparation. Intracellular recording of synaptic potentials revealed enhanced release of acetylcholine from motor nerve terminals exposed to progesterone (3 nM-3 mM). The following effects were observed. An augmented quantal content of evoked release of transmitter; an elevation in synaptic facilitation; and a substantial increase in the rate of spontaneously occurring miniature endplate potentials. It is suggested that synaptic transmission at the neuromuscular junction may be naturally modulated by the physiologically oscillating level of progesterone.

Impaired control of information transfer at an isolated synapse treated by aluminum: is it related to dementia?

Information transfer across an isolated cholinergic synapse exposed to aluminum was investigated using conventional electrophysiological techniques and computer-assisted analysis. Spontaneous and stimulation-induced release of neurotransmitter from frog motor nerve endings was augmented in the presence of aluminum (6-200 micrograms/ml). The release-enhancing effect of aluminum was dose-dependent and it was independent of the concentration of calcium ions in the extracellular solution. These results indicate that aluminum at concentrations similar to those found in the diseased brain of demented patients modulates synaptic transmission.

Colchicine prevents recovery of nerve conduction at chronic demyelination.

A colchicine cuff was applied to rat sciatic nerve proximal to a demyelinating region produced by a focal injection of lysophosphatidylcholine (LPC). The colchicine cuff prevented the recovery of function normally seen within 6-8 days after LPC-induced demyelination. Colchicine blocked the delivery of sodium channels to the demyelinated region and induced their accumulation proximal to the cuff. The dual effect of colchicine in blocking both the recovery of impulse propagation through the demyelinated region and the delivery of sodium channels suggests a central role for fast axonal transport of sodium channels in the recovery of function at demyelination.

Modification of the Na-dependent action potential in myelinated fibers of rat sciatic nerve exposed to phorbol ester.

Exposure of rat sciatic nerve to the active phorbol 1,2-beta-myristate-13-acetate (b-PMA), but not to the active analogue 4-alpha-phorbol-12,13-didecanoate (a-PDD), is followed by a decrease of the compound action potential amplitude, rate of rise, and conduction velocity, and an increase of the threshold, and of the duration of the refractory period. The effect is concentration-dependent, the Kd being 250 nM. The attenuated Na-dependent action potential is tetrodotoxin (TTX)-sensitive, but after exposure to b-PMA the sensitivity to TTX is decreased from Kd = 45 nM to 400 nM. Action potential depression is larger when Ca is replaced by Mg (but not by Ba), or when Na is replaced by Li. The replacement of K by Cs, or exposure to potassium channel blockers such as 4-aminopyridine (4AP) and tetra-ethyl ammonium (TEA) has no effect. The results indicate that in the myelinated axons of rat sciatic nerve, exposure to b-PMA induces modification of Na channels.

Postsynaptic effects of DMSO at the frog neuromuscular junction.

Postsynaptic effects of dimethylsulfoxide (DMSO) were studied at the frog cutaneous pectoris neuromuscular junction using electrophysiological techniques and computer assisted analysis. It was found that the average amplitude of extracellularly recorded miniature end-plate potentials (meppse) as well as the time constant of their monoexponential decay (tau) were both elevated in the presence of DMSO. In spite of increased scatter of individual values, amplitude and tau of meppse highly correlated with each other. These results imply that DMSO partially blocked the activity of acetylcholine esterase in addition to its already known presynaptic action of acetylcholine release enhancement. Inhibitory action of DMSO on activity of isolated acetylcholine esterase was previously demonstrated by biochemical methods.

Distribution and possible abnormality in antigenic composition of sodium channels in peripheral axons of dystrophic mice.

In some dystrophic mice (Bar-Harbour 129 dy/dy), axons of the sciatic nerve are a-myelinated but are capable of carrying action potentials. In this study, we showed by immunofluorescence that such excitability is supported by the presence of voltage-gated sodium channels along the a-myelinated axon. In addition, the number of sodium channels measured by radioimmunoassay in sciatic nerves of these dystrophic mice is significantly higher. Furthermore, the composition of sodium channel epitopes is abnormal. This suggested a link between the disease and the biogenesis of the sodium channels.