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Prediction of preeclampsia risk is key to informing effective maternal care. Current screening for preeclampsia at 11 -13 weeks' gestation using maternal demographic characteristics and medical history with measurements of mean arterial pressure, uterine artery pulsatility index and serum placental growth factor can identify about 75% of women who develop preterm preeclampsia with delivery at37 weeks' gestation. Further improvements to preeclampsia screening tests will likely require integrating additional biomarkers. Recent research suggests the existence of distinct maternal risk profiles. Biomarker evaluation should therefore account for the possibility that a biomarker only predicts preeclampsia in a specific maternal phenotype.Verification of metabolite biomarkers as preterm preeclampsia predictors early in pregnancy in all women and across body mass index (BMI) groups.Observational case-control study drawn from a large prospective study on the early prediction of pregnancy complications in women attending their routine first hospital visit at King's College Hospital, London, UK, in 2010-2015. Pregnant women underwent a complete first-trimester assessment, including the collection of blood samples for biobanking. In 11-13 weeks' plasma samples of 2501 singleton pregnancies levels of pre-selected metabolites implicated in the prediction of pregnancy complications were determined using a targeted liquid chromatography-mass spectrometry method, yielding high-quality quantification data on 50 metabolites. Ratios of amino acid levels involved in arginine biosynthesis and nitric oxide synthase pathways were added to the list of biomarkers. Placental growth factor and pregnancy-associated plasma protein-A were also available for all study subjects, serving as comparator risk predictors. Data on 1635 control and 106 preterm preeclampsia pregnancies were considered for this analysis, normalized using multiples of medians. Prediction analyses were performed across the following patient strata: all subjects, and the BMI classes25 kg/mLevels of 13 metabolites were associated with preterm preeclampsia in the entire study population (p0.05) with particularly significant associations found for five of them, namely 2-hydroxy-(2/3)-methylbutyric acid, 25-hydroxyvitamin D3, 2-hydroxybutyric acid, alanine, dodecanoylcarnitine and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine (p0.01). Fold changes in seven amino acid ratios, all involving glutamine or ornithine, were also significantly different between cases and controls (p0.01). The predictive performance of some metabolites and ratios differed according to BMI classification; for example, ornithine (p0.001) and several ornithine-related ratios (p0.0001 - p0.01) were only strongly associated with preterm preeclampsia in the BMI25 kg/mSingle metabolites and ratios of amino acids related to arginine bioavailability and nitric oxide synthase pathways were associated with preterm preeclampsia risk at 11 -13 weeks' gestation. Differential prediction was observed across BMI classes, supporting the existence of distinct maternal risk profiles. Future studies in preeclampsia prediction should account for the possibility of different maternal risk profiles to improve etiological and prognostic understanding and, ultimately, clinical utility of screening tests.

OBJECTIVE To estimate the chorionic villus sampling (CVS)-related risk of fetal loss in twin pregnancy after adjustment for chorionicity, nuchal translucency thickness (NT), intertwin discordance in crown-rump length (CRL), maternal demographic characteristics and serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG). METHODS This was a multicenter study from eight fetal medicine units in which the leadership were trained at the Harris Birthright Research Centre for Fetal Medicine in London, UK, and in which the protocols for screening, invasive testing and pregnancy management are similar. Data were obtained prospectively from women with twin pregnancy undergoing routine ultrasound examination at 11-13 weeks' gestation. Multivariable logistic regression analysis with backward stepwise elimination was used to examine whether CVS provided a significant independent contribution to the prediction of risk of fetal loss after adjusting for maternal and pregnancy characteristics, including maternal age, racial origin and weight, method of conception, smoking status, parity, chorionicity, intertwin discordance in CRL, fetal NT ≥ 95th percentile and free β-hCG and PAPP-A multiples of the median. Similarly, within the CVS group, multivariable logistic regression analysis was used to investigate the effect of the number of intrauterine needle insertions and size of the needle on the risk of fetal loss. RESULTS The study population of 8581 twin pregnancies undergoing ultrasound examination at 11-13 weeks' gestation included 316 dichorionic and 129 monochorionic twins that had CVS. First, in twin pregnancies undergoing CVS, compared to those not undergoing CVS, there was a 2-fold increased risk of fetal loss at

To develop further a competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate by including sonographically estimated fetal weight (EFW) and biomarkers of impaired placentation at 36 weeks' gestation, and to compare the performance of the new model with that of the traditional EFW 10This was a prospective observational study in 29 035 women with a singleton pregnancy undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. A competing-risks model for the prediction of a SGA neonate was used. The parameters included in the prior-history model were provided in previous studies. An interaction continuous model was used for the EFW likelihood. A folded plane regression model was fitted to describe likelihoods of biomarkers of impaired placentation. Stratification plans were also developed. The new model was evaluated and compared with EFW percentile cut-offs.The performance of the model was better for predicting SGA neonates delivered closer to the point of assessment. The prediction provided by maternal factors alone was improved significantly by the addition of EFW, uterine artery pulsatility index (UtA-PI) and placental growth factor (PlGF) but not by mean arterial pressure or soluble fms-like tyrosine kinase-1. At a 10% false-positive rate, maternal factors and EFW predicted 77.6% and 65.8% of SGA neonates 10A competing-risks model provides effective risk stratification for a SGA neonate at 35 + 0 to 36 + 6 weeks' gestation and is superior to EFW percentile cut-offs. The use of biomarkers of impaired placentation in addition to maternal factors and fetal biometry results in small improvement of the predictive performance for a neonate with severe SGA. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

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.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.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%.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.

Preeclampsia is associated with increased risks of life-threatening, -altering, and -ending complications. Assessment of risk for preeclampsia at 35 to 36 weeks' gestation by the Fetal Medicine Foundation 36-week competing-risk model identifies approximately 75% of women who will develop term preeclampsia, at a 10% screen-positive rate.This study aimed to assess whether the Fetal Medicine Foundation 36-week model can provide personalized guidance to women about the probable timing of their delivery, whether or not they develop pregnancy hypertension.In this prospective nonintervention screening study at 2 maternity hospitals in England, women who did not have preeclampsia (American College of Obstetricians and Gynecologists definition) and were attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment of risk for preeclampsia, including maternal demographic characteristics, medical history, mean arterial pressure, and serum placental growth factor and soluble fms-like tyrosine kinase-1. Fetal Medicine Foundation 36-week model risk categories for subsequent preeclampsia were defined as: A, ≥0.500; B, 0.20 to 0.499; C, 0.05 to 0.199; D, 0.020 to 0.049; and E,0.020. Obstetrical records were examined for all women to identify their gestational age at delivery, and whether they experienced a spontaneous onset of labor (irrespective of mode of delivery) or had a medically indicated birth (either induction of labor or unlabored cesarean delivery). The cumulative incidence of delivery and risk ratios, for all deliveries and for spontaneous deliveries, was assessed.Among 29,035 women with singleton pregnancies, 1.0%, 2.9%, 3.3%, 5.0%, 9.9%, and 77.9% were in A, B, C, D, and E risk strata, respectively. In the A (vs E) stratum, 71.95% (vs 33.52%) of births were medically indicated. Compared with women in stratum E, women in higher risk strata were more likely to deliver, and to deliver following spontaneous labor, before their due date. For example, of the women in stratum A (vs E), 14.2% (vs 1.1%; risk ratio, 12.5 [95% confidence interval, 9.45-15.35]), 48.5% (vs 5.1%; risk ratio, 8.47 [7.48-9.35]), 69.6% (vs 15.5%; risk ratio, 3.86 [3.59-4.08]), and 90.1% (vs 44.8%; risk ratio, 6.72 [4.53-9.95]) gave birth before 37 0/7, 38 0/7, 39 0/7, and 40 0/7 weeks, respectively. For women in stratum A (vs E), when censored for medically indicated births, spontaneous labor occurred more commonly before 37 0/7 (risk ratio, 4.31 [1.99-6.57]), 38 0/7 (risk ratio, 3.71 [2.48-4.88]), 39 0/7 (risk ratio, 2.87 [2.22-3.46]), and 40 0/7 (risk ratio, 1.42 [1.14-1.77]) weeks.Women in higher-risk strata gave birth earlier, and more frequently following medically indicated delivery, compared with those in lower-risk strata. Importantly, the proportion of women who gave birth following spontaneous onset of labor before their due date was also greater in higher-risk than in lower-risk women. The Fetal Medicine Foundation 36-week competing-risk model incorporates biomarkers of placental aging, including angiogenic imbalance; these results imply that a fetoplacental response to placental aging may be an important trigger for the onset of labor at term.

BACKGROUND Several cross-sectional studies have investigated the incidence of urinary Congo-red dye positivity in women with preeclampsia (PE), compared to unaffected pregnancies, and reported very high sensitivity and low false positive rate in the diagnosis of PE. OBJECTIVE To determine the performance of the urinary Congo-red dot paper test at 35-37 weeks' gestation in the prediction of delivery with PE at ≤2 and >2 weeks after assessment. METHODS This was a prospective observational study in women attending for a routine hospital visit at 35+0 to 36+6 weeks' gestation in a maternity hospital in England. Urine samples were collected and the Congo-red dot paper test was used to assess the degree of Congo-red dye positivity. The test uses a scoring system from 1 to 8 and the higher the score the greater the degree of Congo-red dye positivity. We examined and compared the degree of Congo-red dye positivity in the groups that delivered with PE at ≤2 and >2 weeks with those that remained normotensive. Reproducibility was assessed by examining the inter- and intra-observer reliability of scoring on stored images with the researchers blinded to previous results. RESULTS The study population of 2140 women included 46 (2.1%) that subsequently developed PE (2.1%). The urinary Congo-red dot test was positive in 8.3% (1/12) and 2.9% (1/34) that delivered with PE at ≤2 and >2 weeks from assessment and in 0.2% (4/2094) of the unaffected pregnancies when the cutoff for Congo-red dye positivity was ≥5. The respective values when the cutoff used was ≥3 were 66.7%, 23.5%, and 16.5%, respectively. The intraclass correlation coefficient for the inter-observer reliability was 0.926 (95% CI 0.890-0.953, p

OBJECTIVE To develop further a new competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate, by including second-trimester ultrasonographic estimated fetal weight (EFW). METHODS This was a prospective observational study in 96 678 women with singleton pregnancy undergoing routine ultrasound examination at 19-24 weeks' gestation. All pregnancies had ultrasound biometry assessment, and EFW was calculated according to the Hadlock formula. We refitted in this large dataset a previously described competing-risks model for the joint distribution of gestational age (GA) at delivery and birth-weight Z-score, according to maternal demographic characteristics and medical history, to obtain the prior distribution. The continuous likelihood of the EFW was fitted conditionally to GA at delivery and birth-weight Z-score and modified the prior distribution, according to Bayes' theorem, to obtain individualized distributions for GA at delivery and birth-weight Z-score and therefore patient-specific risks for any cut-offs for GA at delivery and birth-weight Z-score. We assessed the discriminative ability of the model for predicting SGA with, without or independently of pre-eclampsia occurrence. A calibration study was carried out. Performance of screening was evaluated for SGA defined according to the Fetal Medicine Foundation birth-weight charts. RESULTS The distribution of EFW, conditional to both GA at delivery and birth-weight Z-score, was best described by a regression model. For earlier gestations, the association between EFW and birth weight was steeper. The prediction of SGA by maternal factors and EFW improved for increasing degree of prematurity and greater severity of smallness but not for coexistence of pre-eclampsia. Screening by maternal factors predicted 31%, 34% and 39% of SGA neonates with birth weight

OBJECTIVE To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis. DESIGN Case-control, retrospective cohort studies. SETTING Antenatal clinics, clinical research facilities. POPULATION Women with ICP or uncomplicated pregnancies. METHODS Serial TSBA measurements were performed pre-/postprandially in 42 women with ICP or uncomplicated pregnancy. Third-trimester non-fasting TSBA reference ranges were calculated from 561 women of black, south Asian and white ethnicity. Rates of adverse perinatal outcomes for women with ICP but peak non-fasting TSBA below the upper reference range limit were compared with those in healthy populations. MAIN OUTCOME MEASURES Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA. RESULTS Concentrations of TSBA increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA

To investigate whether first-trimester maternal plasma fetal fraction is altered in women that subsequently develop preeclampsia (PE) or gestational hypertension (GH) and to examine its potential value in improving the performance of screening for PE and GH by maternal factors and maternal serum pregnancy associated plasma protein-A (PAPP-A), mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI).The study population of 10,131 pregnancies undergoing cell free fetal DNA testing at 11-13 weeks' gestation included 91 (0.9%) cases with preterm-PE, 222 (2.2%) cases with term-PE, 360 (3.6%) with GH and 9,458 (93.4%) cases unaffected by hypertensive disorders. Maternal plasma fetal fraction levels were expressed as multiples of the median (MoM) after adjustment for maternal factors and crown-rump length. The performance of screening for preterm-PE, term PE and GH by maternal factors and MoM values of fetal fraction, PAPP-A, UtA-PI and MAP was evaluated by receiver operating characteristic (ROC) curves.The median fetal fraction MoM was significantly lower in the preterm-PE (0.825; IQR 0.689-1.115 MoM,First trimester maternal plasma fetal fraction is not useful in screening for hypertensive disorders of pregnancy.

Introduction Pre-eclampsia (PE) affects 2–8% of pregnancies worldwide. Despite identification of numerous possible biomarkers, accurate prediction and early diagnosis of PE remain challenging. We examined the potential of leukotriene B4 (LTB4) and 15-hydroxyeicosatetraenoic acid (15(S)-HETE) as biomarkers of PE by comparing serum levels at three gestational age (GA) groups between normotensive pregnancies and asymptomatic women who subsequently developed preterm or term-PE. Methods This is a case-control study drawn from a prospective study of adverse pregnancy outcomes with serum samples collected at 19–24 weeks (n = 48), 30–34 weeks (n = 101) and 35–37 weeks (n = 54) GA. LTB4 and 15(S)-HETE levels were determined by ELISA. Serum level multiples of the median (MoM) were compared between normal and PE-pregnancies. Association between LTB4 and 15(S)-HETE and GA at delivery was investigated with Cox proportional-hazards models. Results Serum LTB4 levels were lower in women of East-Asian ethnicity, higher in women with PE history, and increased with GA in normotensive pregnancies, but not in PE. LTB4 was elevated at 19–24 weeks in women who developed preterm-PE. There was a negative association between LTB4 MoM and interval between sampling and delivery with PE at 19–24 weeks only. Serum 15(S)-HETE levels were not influenced by GA at testing and were elevated in women of South-Asian ethnicity. Median 15(S)-HETE levels were unchanged in preterm and term-PE at any GA. Discussion LTB4 was higher at 19–24 weeks in pregnancies that developed preterm-PE versus unaffected pregnancies, suggesting it is a potentially useful predictive marker of preterm PE in the second trimester.

OBJECTIVE To develop a new competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate, based on maternal factors and biophysical and biochemical markers at 11-13 weeks' gestation. METHODS This was a prospective observational study in 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. All pregnancies had pregnancy-associated plasma protein-A and placental growth factor (PlGF) measurements, 59 001 had uterine artery pulsatility index (UtA-PI) measurements and 58 479 had mean arterial pressure measurements; 57 131 cases had complete data for all biomarkers. We used a previously developed competing-risks model for the joint distribution of gestational age (GA) at delivery and birth-weight Z-score, according to maternal demographic characteristics and medical history. The likelihoods of the biophysical markers were developed by fitting folded-plane regression models, a technique that has already been used in previous studies for the likelihoods of biochemical markers. The next step was to modify the prior distribution by the likelihood, according to Bayes' theorem, to obtain individualized distributions for GA at delivery and birth-weight Z-score. We used the 57 131 cases with complete data to assess the discrimination and calibration of the model for predicting SGA with, without or independently of pre-eclampsia, by different combinations of maternal factors and biomarkers. RESULTS The distribution of biomarkers, conditional to both GA at delivery and birth-weight Z-score, was best described by folded-plane regression models. These continuous two-dimensional likelihoods update the joint distribution of birth-weight Z-score and GA at delivery that has resulted from a competing-risks approach; this method allows application of user-defined cut-offs. The best biophysical predictor of preterm SGA was UtA-PI and the best biochemical marker was PlGF. The prediction of SGA was consistently better for increasing degree of prematurity, greater severity of smallness, coexistence of PE and increasing number of biomarkers. The combination of maternal factors with all biomarkers predicted 34.3%, 48.6% and 59.1% of all cases of a SGA neonate with birth weight

Objective: Pre-eclampsia (PE) is a significant contributor to adverse maternal and perinatal outcome; however, accurate prediction and early diagnosis of this condition remain a challenge. The aim of this study was to compare serum levels of growth-differentiation factor-15 (GDF-15) at three different gestational ages between asymptomatic women who subsequently developed preterm or term PE and healthy controls. Methods: This was a case–control study drawn from a prospective observational study on adverse pregnancy outcomes in women attending for their routine second- and third-trimester hospital visits. Serum GDF-15 was determined in 300 samples using a commercial GDF-15 enzyme-linked immunosorbent assay: 120 samples at 19–24 weeks of gestation, 120 samples at 30–34 weeks and 60 samples at 35–37 weeks. Multiple linear regression was applied to logarithmically transformed GDF-15 control values to evaluate the influence of gestational age at blood sampling and maternal characteristics on GDF-15 results. GDF-15 multiples of the normal median (MoM) values, adjusted for gestational age and maternal characteristics, were compared between pregnancies that subsequently developed preterm or term PE and healthy controls. Results: Values of GDF-15 increased with gestational age. There were no significant differences in GDF-15 MoM values between cases of preterm or term PE and normotensive pregnancies at 19–24 or 35–37 weeks of gestation. At 30–34 weeks, GDF-15 MoM values were significantly increased in cases of preterm PE, but not in those who later developed term PE. Elevated GDF-15 MoM values were associated significantly with a shorter interval between sampling at 30–34 weeks and delivery with PE (P = 0.005). Conclusion: Serum GDF-15 levels at 19–24 or 35–37 weeks of gestation are not predictive of preterm or term PE. At 30–34 weeks, GDF-15 levels are higher in women who subsequently develop preterm PE; however, this difference is small and GDF-15 is unlikely to be useful in clinical practice when used in isolation. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Objectives: To examine the association between racial origin and preeclampsia(PE) and gestational hypertension(GH) after adjustment for factors in maternal characteristics and medical history in screening study from the Fetal Medicine Foundation (FMF) in England, and to perform a systematic review and meta-analysis of studies on PE. Methods: In the FMF data regression analysis was performed to examine the association between racial origin and PE or GH. Literature search to December 2021 was carried out to identify peer-reviewed publications on race and PE. Main outcome measure: Relative risk of PE and GH in women of black, South Asian and East Asian racial origin by comparison to white women. Results: In the FMF study there were 168,966 singleton pregnancies without major abnormalities delivering at ≥24 weeks’ gestation. In black women the respective risk of total-PE and preterm-PE was 2-fold and 2.5-fold higher and risk of GH was 25% higher, in South Asian women there was a 1.5-fold higher risk of preterm-PE but not total-PE, and in East Asian women there was no significant difference in risk of hypertensive disorders. The literature search identified 19 studies that provided data on several million of pregnancies, but 17 were at moderate or high-risk of bias and only three provided risks adjusted for some maternal characteristics; consequently, these studies did not provide accurate contribution of different racial groups to the prediction of PE. Conclusion: In women of black and South Asian origin the risk of PE, after adjustment for confounders, is higher than in white women

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography–tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11–13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m2 with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m2 (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.