Phytoplankton responses to dust addition in the Fe-Mn co-limited eastern Pacific sub-Antarctic differ by source region.

The seasonal availability of light and micronutrients strongly regulates productivity in the Southern Ocean, restricting biological utilization of macronutrients and CO2 drawdown. Mineral dust flux is a key conduit for micronutrients to the Southern Ocean and a critical mediator of multimillennial-scale atmospheric CO2 oscillations. While the role of dust-borne iron (Fe) in Southern Ocean biogeochemistry has been examined in detail, manganese (Mn) availability is also emerging as a potential driver of past, present, and future Southern Ocean biogeochemistry. Here, we present results from fifteen bioassay experiments along a north-south transect in the undersampled eastern Pacific sub-Antarctic zone. In addition to widespread Fe limitation of phytoplankton photochemical efficiency, we found further responses following the addition of Mn at our southerly stations, supporting the importance of Fe-Mn co-limitation in the Southern Ocean. Moreover, addition of different Patagonian dusts resulted in enhanced photochemical efficiency with differential responses linked to source region dust characteristics in terms of relative Fe/Mn solubility. Changes in the relative magnitude of dust deposition, combined with source region mineralogy, could hence determine whether Fe or Mn limitation control Southern Ocean productivity under future as well as past climate states.

Deuterium MRI of serine metabolism in mouse models of glioblastoma.

PURPOSE: Serine is a major source of one-carbon units needed for the synthesis of nucleotides and the production of intramitochondrial nicotinamide adenine dinucleotide phosphate (NADPH), and it plays an important role in cancer cell proliferation. The aim of this study was to develop a deuterium (2H) MRS imaging method for imaging tumor serine metabolism. METHODS: Sequential (2H) spectra and spectroscopic images were used to monitor the metabolism of [2,3,3-2H3]serine in patient-derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain. RESULTS: [14,14-2H2] 5,10-methylene-tetrahydrofolate, [2H]glycine, [2H]formate, and labeled water were detected in cell suspensions and water labeling in spectroscopic images of tumors. Studies in cells and tumors with variable mitochondrial content and inhibitor studies in cells demonstrated that most of the labeled serine was metabolized in the mitochondria. Water labeling in the cell suspensions was correlated with formate labeling; therefore, water labeling observed in tumors could be used to provide a surrogate measure of flux in the pathway of one-carbon metabolism in vivo. CONCLUSION: The method has the potential to be used clinically to select patients for treatment with inhibitors of one-carbon metabolism and subsequently to detect their early responses to such treatment.

Maternal vascular indices at 36 weeks' gestation in the prediction of preeclampsia.

BACKGROUND: Epidemiological studies have shown that women with preeclampsia (PE) are at increased long term cardiovascular risk. This risk might be associated with accelerated vascular ageing process but data on vascular abnormalities in women with PE are scarce. OBJECTIVE: This study aimed to identify the most discriminatory maternal vascular index in the prediction of PE at 35 to 37 weeks' gestation and to examine the performance of screening for PE by combinations of maternal risk factors and biophysical and biochemical markers at 35 to 37 weeks' gestation. STUDY DESIGN: This was a prospective observational nonintervention study in women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices, and hemodynamic parameters obtained by a noninvasive operator-independent device (pulse wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressures, total peripheral resistance, and fetal heart rate), mean arterial pressure, uterine artery pulsatility index, and serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1. The performance of screening for delivery with PE at any time and at <3 weeks from assessment using a combination of maternal risk factors and various combinations of biomarkers was determined. RESULTS: The study population consisted of 6746 women with singleton pregnancies, including 176 women (2.6%) who subsequently developed PE. There were 3 main findings. First, in women who developed PE, compared with those who did not, there were higher central systolic and diastolic blood pressures, pulse wave velocity, peripheral vascular resistance, and augmentation index. Second, the most discriminatory indices were systolic and diastolic blood pressures and pulse wave velocity, with poor prediction from the other indices. However, the performance of screening by a combination of maternal risk factors plus mean arterial pressure was at least as high as that of a combination of maternal risk factors plus central systolic and diastolic blood pressures; consequently, in screening for PE, pulse wave velocity, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and soluble fms-like tyrosine kinase-1 were used. Third, in screening for both PE within 3 weeks and PE at any time from assessment, the detection rate at a false-positive rate of 10% of a biophysical test consisting of maternal risk factors plus mean arterial pressure, uterine artery pulsatility index, and pulse wave velocity (PE within 3 weeks: 85.2%; 95% confidence interval, 75.6%-92.1%; PE at any time: 69.9%; 95% confidence interval, 62.5%-76.6%) was not significantly different from a biochemical test using the competing risks model to combine maternal risk factors with placental growth factor and soluble fms-like tyrosine kinase-1 (PE within 3 weeks: 80.2%; 95% confidence interval, 69.9%-88.3%; PE at any time: 64.2%; 95% confidence interval, 56.6%-71.3%), and they were both superior to screening by low placental growth factor concentration (PE within 3 weeks: 53.1%; 95% confidence interval, 41.7%-64.3%; PE at any time: 44.3; 95% confidence interval, 36.8%-52.0%) or high soluble fms-like tyrosine kinase-1-to-placental growth factor concentration ratio (PE within 3 weeks: 65.4%; 95% confidence interval, 54.0%-75.7%; PE at any time: 53.4%; 95% confidence interval, 45.8%-60.9%). CONCLUSION: First, increased maternal arterial stiffness preceded the clinical onset of PE. Second, maternal pulse wave velocity at 35 to 37 weeks' gestation in combination with mean arterial pressure and uterine artery pulsatility index provided effective prediction of subsequent development of preeclampsia.

Calcium supplementation for the prevention of pre-eclampsia: Challenging the evidence from meta-analyses.

OBJECTIVE: To investigate the validity of the conclusion from Cochrane reviews and meta-analyses that treatment with calcium supplementation during pregnancy reduces the risk for pre-eclampsia by 55%, which has been influential in international guidelines and future research. DESIGN: Sensitivity analysis of data from Cochrane reviews of trials evaluating high-dose calcium supplementation (of at least 1 g/day) for reduction of pre-eclampsia risk. SETTING: Systematic review and meta-analysis. POPULATION: The Cochrane reviews and meta-analyses included 13 trials enrolling a total of 15 730 women. Random-effects meta-analysis of these studies resulted in a mean risk ratio (RR, calcium/placebo) of 0.45 (95% confidence interval [CI] 0.31-0.65; p < 0.0001). METHODS: We carried out a sensitivity analysis of evidence from the relevant Cochrane review, to examine the impact of study size. MAIN OUTCOME MEASURES: pre-eclampsia. RESULTS: In the three largest studies, accounting for 13 815 (88%) of total recruitment, mean RR was 0.92 (95% CI 0.80-1.06) and there was no evidence of heterogeneity between studies (I2 = 0). With inclusion of the smaller studies, mean RR decreased to 0.45 and I2 increased to 70%. CONCLUSIONS: In assessment of the effect of calcium supplementation on pre-eclampsia risk, the naive focus on the mean of the random-effects meta-analysis in the presence of substantial heterogeneity is highly misleading.

First-trimester prediction of preterm pre-eclampsia and prophylaxis by aspirin: Effect on spontaneous and iatrogenic preterm birth.

OBJECTIVE: To report the predictive performance for preterm birth (PTB) of the Fetal Medicine Foundation (FMF) triple test and National Institute for health and Care Excellence (NICE) guidelines used to screen for pre-eclampsia and examine the impact of aspirin in the prevention of PTB. DESIGN: Secondary analysis of data from the SPREE study and the ASPRE trial. SETTING: Multicentre studies. POPULATION: In SPREE, women with singleton pregnancies had screening for preterm pre-eclampsia at 11-13 weeks of gestation by the FMF method and NICE guidelines. There were 16 451 pregnancies that resulted in delivery at ≥24 weeks of gestation and these data were used to derive the predictive performance for PTB of the two methods of screening. The results from the ASPRE trial were used to examine the effect of aspirin in the prevention of PTB in the population from SPREE. METHODS: Comparison of performance of FMF method and NICE guidelines for pre-eclampsia in the prediction of PTB and use of aspirin in prevention of PTB. MAIN OUTCOME MEASURE: Spontaneous PTB (sPTB), iatrogenic PTB for pre-eclampsia (iPTB-PE) and iatrogenic PTB for reasons other than pre-eclampsia (iPTB-noPE). RESULTS: Estimated incidence rates of sPTB, iPTB-PE and iPTB-noPE were 3.4%, 0.8% and 1.6%, respectively. The corresponding detection rates were 17%, 82% and 25% for the triple test and 12%, 39% and 19% for NICE guidelines, using the same overall screen positive rate of 10.2%. The estimated proportions prevented by aspirin were 14%, 65% and 0%, respectively. CONCLUSION: Prediction of sPTB and iPTB-noPE by the triple test was poor and poorer by the NICE guidelines. Neither sPTB nor iPTB-noPE was reduced substantially by aspirin.

Monitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging.

2H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that 2H MR spectroscopy and spectroscopic imaging measurements of [2,3-2H2]malate production from [2,3-2H2]fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of [2,3-2H2]malate, following injection of [2,3-2H2]fumarate (1 g/kg) into tumor-bearing mice, was measured in a murine lymphoma (EL4) treated with etoposide, and in human breast (MDA-MB-231) and colorectal (Colo205) xenografts treated with a TRAILR2 agonist, using surface-coil localized 2H MR spectroscopy at 7 T. Malate production was also imaged in EL4 tumors using a fast 2H chemical shift imaging sequence. The malate/fumarate ratio increased from 0.016 ± 0.02 to 0.16 ± 0.14 in EL4 tumors 48 h after drug treatment (P = 0.0024, n = 3), and from 0.019 ± 0.03 to 0.25 ± 0.23 in MDA-MB-231 tumors (P = 0.0001, n = 5) and from 0.016 ± 0.04 to 0.28 ± 0.26 in Colo205 tumors (P = 0.0002, n = 5) 24 h after drug treatment. These increases were correlated with increased levels of cell death measured in excised tumor sections obtained immediately after imaging. 2H MR measurements of [2,3-2H2]malate production from [2,3-2H2]fumarate provide a potentially less expensive and more sensitive method for detecting cell death in vivo than 13C MR measurements of hyperpolarized [1,4-13C2]fumarate metabolism, which have been used previously for this purpose.

Assessment of the sensitivity of 2 H MR spectroscopy measurements of [2,3-2 H2 ]fumarate metabolism for detecting tumor cell death.

Imaging the metabolism of [2,3-2 H2 ]fumarate to produce malate can be used to detect tumor cell death post-treatment. Here, we assess the sensitivity of the technique for detecting cell death by lowering the concentration of injected [2,3-2 H2 ]fumarate and by varying the extent of tumor cell death through changes in drug concentration. Mice were implanted subcutaneously with human triple negative breast cancer cells (MDA-MB-231) and injected with 0.1, 0.3, and 0.5 g/kg [2,3-2 H2 ]fumarate before and after treatment with a multivalent TRAlL-R2 agonist (MEDI3039) at 0.1, 0.4, and 0.8 mg/kg. Tumor conversion of [2,3-2 H2 ]fumarate to [2,3-2 H2 ]malate was assessed from a series of 13 spatially localized 2 H MR spectra acquired over 65 min using a pulse-acquire sequence with a 2-ms BIR4 adiabatic excitation pulse. Tumors were then excised and stained for histopathological markers of cell death: cleaved caspase 3 (CC3) and DNA damage (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]). The rate of malate production and the malate/fumarate ratio plateaued at tumor fumarate concentrations of 2 mM, which were obtained with injected [2,3-2 H2 ]fumarate concentrations of 0.3 g/kg and above. Tumor malate concentration and the malate/fumarate ratio increased linearly with the extent of cell death determined histologically. At an injected [2,3-2 H2 ]fumarate concentration of 0.3 g/kg, 20% CC3 staining corresponded to a malate concentration of 0.62 mM and a malate/fumarate ratio of 0.21. Extrapolation indicated that there would be no detectable malate at 0% CC3 staining. The use of low and nontoxic fumarate concentrations and the production of [2,3-2 H2 ]malate at concentrations that are within the range that can be detected clinically suggest this technique could translate to the clinic.

Prediction of recurrence from metabolites and expression of TOP2A and EZH2 in prostate cancer patients treated with radiotherapy.

BACKGROUND: The dual upregulation of TOP2A and EZH2 gene expression has been proposed as a biomarker for recurrence in prostate cancer patients to be treated with radical prostatectomy. A low tissue level of the metabolite citrate has additionally been connected to aggressive disease and recurrence in this patient group. However, for radiotherapy prostate cancer patients, few prognostic biomarkers have been suggested. The main aim of this study was to use an integrated tissue analysis to evaluate metabolites and expression of TOP2A and EZH2 as predictors for recurrence among radiotherapy patients. METHODS: From 90 prostate cancer patients (56 received neoadjuvant hormonal treatment), 172 transrectal ultrasound-guided (TRUS) biopsies were collected prior to radiotherapy. Metabolic profiles were acquired from fresh frozen TRUS biopsies using high resolution-magic angle spinning MRS. Histopathology and immunohistochemistry staining for TOP2A and EZH2 were performed on TRUS biopsies containing cancer cells (n = 65) from 46 patients, where 24 of these patients (n = 31 samples) received hormonal treatment. Eleven radical prostatectomy cohorts of a total of 2059 patients were used for validation in a meta-analysis. RESULTS: Among radiotherapy patients with up to 11 years of follow-up, a low level of citrate was found to predict recurrence, p = 0.001 (C-index = 0.74). Citrate had a higher predictive ability compared with individual clinical variables, highlighting its strength as a potential biomarker for recurrence. The dual upregulation of TOP2A and EZH2 was suggested as a biomarker for recurrence, particularly for patients not receiving neoadjuvant hormonal treatment, p = 0.001 (C-index = 0.84). While citrate was a statistically significant biomarker independent of hormonal treatment status, the current study indicated a potential of glutamine, glutamate and choline as biomarkers for recurrence among patients receiving neoadjuvant hormonal treatment, and glucose among patients not receiving neoadjuvant hormonal treatment. CONCLUSION: Using an integrated approach, our study shows the potential of citrate and the dual upregulation of TOP2A and EZH2 as biomarkers for recurrence among radiotherapy patients.

The implications of the Fetal Medicine Foundation 35- to 36-week preeclampsia prediction competing-risk model on timing of birth.

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Risks and pregnancy outcome after fetal reduction in dichorionic twin pregnancies: a Danish national retrospective cohort study.

BACKGROUND: Twin pregnancies carry a higher risk of congenital and structural malformations, and pregnancy complications including miscarriage, stillbirth, and intrauterine fetal death, compared with singleton pregnancies. Carrying a fetus with severe malformations or abnormal karyotype places the remaining healthy fetus at an even higher risk of adverse outcome and pregnancy complications. Maternal medical conditions or complicated obstetrical history could, in combination with twin pregnancy, cause increased risks for both the woman and the fetuses. To our knowledge, no previous studies have evaluated and compared the outcomes of all dichorionic twin pregnancies and compared the results of reduced twins with those of nonreduced and primary singletons in a national cohort. These data are important for clinicians when counseling couples about fetal reduction and its implications. OBJECTIVE: This study aimed to describe and compare the risks of adverse pregnancy outcomes, including the risk of pregnancy loss, in a national cohort of all dichorionic twins-reduced, nonreduced, and primary singletons. In addition, we examined the implications of gestational age at fetal reduction on gestational age at delivery. STUDY DESIGN: This was a retrospective cohort study of all Danish dichorionic twin pregnancies, including pregnancies undergoing fetal reduction and a large proportion of randomly selected primary singleton pregnancies with due dates between January 2008 and December 2018. The primary outcome measures were adverse pregnancy outcomes (defined as miscarriage before 24 weeks, stillbirth from 24 weeks, or single intrauterine fetal death in nonreduced twin pregnancies), preterm delivery, and obstetrical pregnancy complications. Outcomes after fetal reduction were compared with those of nonreduced dichorionic twins and primary singletons. RESULTS: In total, 9735 dichorionic twin pregnancies were included, of which 172 (1.8%) were reduced. In addition, 16,465 primary singletons were included. Fetal reductions were performed between 11 and 23 weeks by transabdominal needle-guided injection of potassium chloride, and outcome data were complete for all cases. Adverse pregnancy outcome was observed in 4.1% (95% confidence interval, 1.7%-8.2%) of reduced twin pregnancies, and 2.4% (95% confidence interval, 0.7%-6.1%) were delivered before 28 weeks, and 4.2% (95% confidence interval, 1.7%-8.5%) before 32 weeks. However, when fetal reduction was performed before 14 weeks, adverse pregnancy outcomes occurred in only 1.4% (95% confidence interval, 0.0%-7.4%), and delivery before 28 and 32 weeks diminished to 0% (95% confidence interval, 0.0%-5.0%) and 2.8% (95% confidence interval, 0.3%-9.7%), respectively. In contrast, 3.0% (95% confidence interval, 2.7%-3.4%) of nonreduced dichorionic twins had an adverse pregnancy outcome, and 1.9% (95% confidence interval, 1.7%-2.1%) were delivered before 28 weeks, and 7.3% (95% confidence interval, 6.9%-7.7%) before 32 weeks. Adverse pregnancy outcomes occurred in 0.9% (95% confidence interval, 0.7%-1.0%) of primary singletons, and 0.2% (95% confidence interval, 0.1%-0.3%) were delivered before 28 weeks, and 0.7% (95% confidence interval, 0.6%-0.9%) before 32 weeks. For reduced twins, after taking account of maternal factors and medical history, it was demonstrated that the later the fetal reduction was performed, the earlier the delivery occurred (P<.01). The overall risk of pregnancy complications was significantly lower among reduced twin pregnancies than among nonreduced dichorionic twin pregnancies (P=.02). CONCLUSION: In a national 11-year cohort including all dichorionic twin pregnancies, transabdominal fetal reduction by needle guide for fetal or maternal indication was shown to be safe, with good outcomes for the remaining co-twin. Results were best when the procedure was performed before 14 weeks.

Triple trouble: uncovering the risks and benefits of early fetal reduction in trichorionic triplets in a large national Danish cohort study.

BACKGROUND: Triplet pregnancies are high risk for both the mother and the infants. The risks for infants include premature birth, low birthweight, and neonatal complications. Therefore, the management of triplet pregnancies involves close monitoring and may include interventions, such as fetal reduction, to prolong the pregnancy and improve outcomes. However, the evidence of benefits and risks associated with fetal reduction is inconsistent. OBJECTIVE: This study aimed to compare the outcomes of trichorionic triplet pregnancies with and without fetal reduction and with nonreduced dichorionic twin pregnancies and primary singleton pregnancies. STUDY DESIGN: All trichorionic triplet pregnancies in Denmark, including those with fetal reduction, were identified between 2008 and 2018. In Denmark, all couples expecting triplets are informed about and offered fetal reduction. Pregnancies with viable fetuses at the first-trimester ultrasound scan and pregnancies not terminated were included. Adverse pregnancy outcome was defined as a composite of miscarriage before 24 weeks of gestation, stillbirth at 24 weeks of gestation, or intrauterine fetal death of 1 or 2 fetuses. RESULTS: The study cohort was composed of 317 trichorionic triplet pregnancies, of which 70.0% of pregnancies underwent fetal reduction to a twin pregnancy, 2.2% of pregnancies were reduced to singleton pregnancies, and 27.8% of pregnancies were not reduced. Nonreduced triplet pregnancies had high risks of adverse pregnancy outcomes (28.4%), which was significantly lower in triplets reduced to twins (9.0%; difference, 19.4%, 95% confidence interval, 8.5%-30.3%). Severe preterm deliveries were significantly higher in nonreduced triplet pregnancies (27.9%) than triplet pregnancies reduced to twin pregnancies (13.1%; difference, 14.9%, 95% confidence interval, 7.9%-21.9%). However, triplet pregnancies reduced to twin pregnancies had an insignificantly higher risk of miscarriage (6.8%) than nonreduced twin pregnancies (1.1%; difference, 5.6%; 95% confidence interval, 0.9%-10.4%). CONCLUSION: Triplet pregnancies reduced to twin pregnancies had significantly lower risks of adverse pregnancy outcomes, severe preterm deliveries, and low birthweight than nonreduced triplet pregnancies. However, triplet pregnancies reduced to twin pregnancies were potentially associated with a 5.6% increased risk of miscarriage.

Effect of race on the measurement of angiogenic factors for prediction and diagnosis of pre-eclampsia.

OBJECTIVE: To examine the effect of self-declared race on serum placental growth factor (PlGF) and sFlt-1/PlGF ratio and the impact on pre-eclampsia (PE) prediction. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: 29 035 women with singleton pregnancies attending a routine 35+0 to 36+6 weeks' gestation hospital visit, including 654 (2.3%) who subsequently developed PE. METHODS: The predictive performance of PlGF and sFlt-1/PlGF for PE in minority racial groups (versus white) was examined. MAIN OUTCOME MEASURE: Delivery with PE. RESULTS: Compared with white women, mean PlGF was higher and sFlt-1/PlGF ratio lower in black, South Asian, East Asian and mixed race women. In white women at a PlGF concentration cut-off corresponding to a screen-positive rate (SPR) of 10%, detection rates (DRs) were 49.1% for PE at any time and 72.3% for PE within 2 weeks after screening. In black women, at the same PlGF concentration cut-off for white women, the SPR was 5.5%, and DRs 33.6% and 55.0%, respectively; the number of PE cases was too small to evaluate screening performance in other racial groups. Using a fixed cut-off in sFlt-1/PlGF ratio to identify women at risk of developing PE, similarly diagnostically disadvantaged black women. Bias was overcome by adjusting metabolite concentrations for maternal characteristics and use of the competing risks model to estimate patient-specific risks. CONCLUSION: Screening for PE with fixed cut-offs in PlGF or sFlt-1/PlGF diagnostically disadvantages black women. It is essential that measured levels of PlGF be adjusted for race as well as other maternal characteristics.

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.

Absolute choline tissue concentration mapping for prostate cancer localization and characterization using 3D 1 H MRSI without water-signal suppression.

PURPOSE: Until now, 1 H MRSI of the prostate has been performed with suppression of the large water signal to avoid distortions of metabolite signals. However, this signal can be used for absolute quantification and spectral corrections. We investigated the feasibility of water-unsuppressed MRSI in patients with prostate cancer for water signal-mediated spectral quality improvement and determination of absolute tissue levels of choline. METHODS: Eight prostate cancer patients scheduled for radical prostatectomy underwent multi-parametric MRI at 3 T, including 3D water-unsuppressed semi-LASER MRSI. A postprocessing algorithm was developed to remove the water signal and its artifacts and use the extracted water signal as intravoxel reference for phase and frequency correction of metabolite signals and for absolute metabolite quantification. RESULTS: Water-unsuppressed MRSI with dedicated postprocessing produced water signal and artifact-free MR spectra throughout the prostate. In all patients, the absolute choline tissue concentration was significantly higher in tumorous than in benign tissue areas (mean ± SD: 7.2 ± 1.4 vs 3.8 ± 0.7 mM), facilitating tumor localization by choline mapping. Tumor tissue levels of choline correlated better with the commonly used (choline + spermine + creatine)/citrate ratio (r = 0.78 ± 0.1) than that of citrate (r = 0.21 ± 0.06). The highest maximum choline concentrations occurred in high-risk cancer foci. CONCLUSION: This report presents the first successful water-unsuppressed MRSI of the whole prostate. The water signal enabled amelioration of spectral quality and absolute metabolite quantification. In this way, choline tissue levels were identified as tumor biomarker. Choline mapping may serve as a tool in prostate cancer localization and risk scoring in multi-parametric MRI for diagnosis and biopsy procedures.

Deuterium MRSI of tumor cell death in vivo following oral delivery of 2 H-labeled fumarate.

PURPOSE: There is an unmet clinical need for direct and sensitive methods to detect cell death in vivo, especially with regard to monitoring tumor treatment response. We have shown previously that tumor cell death can be detected in vivo from 2 H MRS and MRSI measurements of increased [2,3-2 H2 ]malate production following intravenous injection of [2,3-2 H2 ]fumarate. We show here that cell death can be detected with similar sensitivity following oral administration of the 2 H-labeled fumarate. METHODS: Mice with subcutaneously implanted EL4 tumors were fasted for 1 h before administration (200 µl) of [2,3-2 H2 ]fumarate (2 g/kg bodyweight) via oral gavage without anesthesia. The animals were then anesthetized, and after 30 min, tumor conversion of [2,3-2 H2 ]fumarate to [2,3-2 H2 ]malate was assessed from a series of 13 2 H spectra acquired over a period of 65 min. The 2 H spectra and 2 H spectroscopic images were acquired using a surface coil before and at 48 h after treatment with a chemotherapeutic drug (etoposide, 67 mg/kg). RESULTS: The malate/fumarate signal ratio increased from 0.022 ± 0.03 before drug treatment to 0.12 ± 0.04 following treatment (p = 0.023, n = 4). Labeled malate was undetectable in spectroscopic images acquired before treatment and increased in the tumor area following treatment. The increase in the malate/fumarate signal ratio was similar to that observed previously following intravenous administration of labeled fumarate. CONCLUSION: Orally administered [2,3-2 H2 ]fumarate can be used to detect tumor cell death noninvasively following treatment with a sensitivity that is similar to that obtained with intravenous administration.

Genetic algorithm-based optimization of pulse sequences.

PURPOSE: The performance of pulse sequences in vivo can be limited by fast relaxation rates, magnetic field inhomogeneity, and nonuniform spin excitation. We describe here a method for pulse sequence optimization that uses a stochastic numerical solver that in principle is capable of finding a global optimum. The method provides a simple framework for incorporating any constraint and implementing arbitrarily complex cost functions. Efficient methods for simulating spin dynamics and incorporating frequency selectivity are also described. METHODS: Optimized pulse sequences for polarization transfer between protons and X-nuclei and excitation pulses that eliminate J-coupling modulation were evaluated experimentally using a surface coil on phantoms, and also the detection of hyperpolarized [2-13 C]lactate in vivo in the case of J-coupling modulation-free excitation. RESULTS: The optimized polarization transfer pulses improved the SNR by ~50% with a more than twofold reduction in the B1 field, and J-coupling modulation-free excitation was achieved with a more than threefold reduction in pulse length. CONCLUSION: This process could be used to optimize any pulse when there is a need to improve the uniformity and frequency selectivity of excitation as well as to design new pulses to steer the spin system to any desired achievable state.

Ophthalmic artery Doppler in the prediction of preeclampsia.

The ophthalmic artery is an easily accessible vessel for Doppler assessment that provides information on the less accessible intracranial circulation. In women with preeclampsia, compared with normotensive pregnant women, there is a decrease in impedance to flow and an increase in velocities in the flow velocity waveforms from the ophthalmic arteries. This study aimed to report the methodology for ophthalmic artery Doppler and summarize findings from the clinical implementation of such assessment in the prediction of preeclampsia. The Embase and MEDLINE were searched from inception to November 2020 to identify studies reporting on the use of ophthalmic artery Doppler in the prediction of preeclampsia. Of note, 2 small studies in high-risk pregnancies, one at 11 to 14 weeks' gestation and another at 20 to 28 weeks' gestation, reported differences between women who developed preeclampsia, compared with unaffected pregnancies, in ophthalmic artery Doppler and suggested that this is a useful biomarker for screening for preeclampsia. Another small study in high-risk pregnancies at 18 to 23 weeks' gestation reported that there was no marked difference in ophthalmic artery Doppler indices between the preeclampsia and unaffected groups. In addition, 2 recent, large observational studies in unselected pregnancies at 19 to 23 and 35 to 37 weeks' gestation, respectively, reported that, first, it is necessary to record waveforms from both eyes to get reproducible results; second, the waveform from the ophthalmic arteries is characterized by 2 systolic peaks and the ratio of the second to the first peak systolic velocity was increased in women who developed preeclampsia; third, in the study at 19 to 23 weeks' gestation, the peak systolic velocity ratio was superior to the uterine artery pulsatility index, mean arterial pressure, serum placental growth factor, and soluble fms-like tyrosine kinase-1 as individual biomarkers in the prediction of both preterm and term preeclampsia and the peak systolic velocity ratio improved the prediction of preeclampsia provided by all the other biomarkers; and fourth, in the study at 35 to 37 weeks' gestation, the peak systolic velocity ratio improved the prediction of subsequent development of preeclampsia provided by maternal factors alone and combinations of maternal factors with mean arterial pressure, uterine artery pulsatility index, placental growth factor, and serum placental growth factor. The ophthalmic artery Doppler provides a useful biomarker for the prediction of preeclampsia.

When to give aspirin to prevent preeclampsia: application of Bayesian decision theory.

BACKGROUND: There is good evidence that first-trimester assessment of the risk for preterm preeclampsia and treatment of the high-risk group with aspirin reduces the incidence of preterm preeclampsia. Furthermore, there is evidence that aspirin is associated with an increased risk of maternal and neonatal hemorrhagic complications. Against this background, there are ongoing debates whether aspirin should be recommended for all women or to a subpopulation of women predicted to be at increased risk of developing preeclampsia. Moreover, if a strategy of the prediction and prevention of preterm preeclampsia is to be used, what method should be used for the prediction, and what risk cutoff should be used to decide on who to treat? OBJECTIVE: This study aimed to compare the policies of universal treatment, stratified treatment, and no treatment with aspirin. STUDY DESIGN: Decisions about aspirin prophylaxis were considered from the perspective of the Bayesian decision theory. Using this approach, the treatment policies were evaluated for risks of preterm preeclampsia, effects of aspirin, and trade-offs between the harms and benefits of the treatment. Evidence on the risk of preterm preeclampsia was taken from the Screening programme for pre-eclampsia study, which was a first-trimester screening study for the prediction of preeclampsia. Evidence of the effect of aspirin was taken from the Aspirin for Evidence-Based Preeclampsia Prevention trial, which was a trial of aspirin vs placebo in the prevention of preterm preeclampsia. The trade-off between the benefits and harms of aspirin was specified by addressing the question, "What is the maximum number of women that should be treated to prevent 1 case of preterm preeclampsia?" The number can be considered as an exchange rate between the harms and benefits of using aspirin to prevent preterm PE. Given the uncertainty about the harms associated with aspirin, the treatment policies were compared across a wide range of exchange rates. RESULTS: For exchange rates between 10 and 1000 women treated with aspirin to prevent 1 case of preterm preeclampsia, the net benefit achieved from the risk assessment and targeted treatment of women at high risk of preterm preeclampsia was higher than that from women with no treatment or women with universal treatment with aspirin. CONCLUSION: Universal treatment with aspirin should be avoided. Risk-based screening should be used, and the cutoff for taking aspirin should be determined from the consideration of the trade-off between the benefits and harms and detection, false-positive, and screen-positive rates.

Implementing personalised care planning for older people with frailty: a process evaluation of the PROSPER feasibility trial.

BACKGROUND: Personalised Care Planning (PCP) is a collaborative approach used in the management of chronic conditions. Core components of PCP are shared decision making to achieve joint goal setting and action planning by the clinician and patient. We undertook a process evaluation within the PROSPER feasibility trial to understand how best to implement PCP for older people with frailty in the community. METHODS: The trial was set in two localities in England. We observed training sessions and intervention delivery at three time points during the 12-week intervention period. We interviewed delivery teams before, during and after the intervention period, as well as primary care staff. We interviewed older people who had received, declined or withdrawn from PCP. We explored training of staff delivering PCP, structures, mechanisms and resources needed for delivery, and influences on uptake. We undertook a framework approach to data analysis. FINDINGS: We observed thirteen training sessions and interviewed seven delivery staff, five primary care staff, and twenty older people, including seven who had declined or withdrawn from the intervention. Delivery teams successfully acquired skills and knowledge, but felt underprepared for working with people with lower levels of frailty. Timing of training was critical and 'top-ups' were needed. Engagement with primary care staff was tenuous. Older people with lower frailty were unclear of the intervention purpose and benefits, goal setting and action planning. CONCLUSIONS: PCP has the potential to address the individualised needs of older people with frailty. However, training requires careful tailoring and is ideally on-going. Considerable efforts are required to integrate statutory and voluntary stakeholders, understanding the expectations and contributions of each agency from the outset. In addition, older people with frailty need time and support to adjust to new ways of thinking about their own health now and in the future so they can participate in shared decision making. These key factors will be essential when developing models of care for delivering PCP to support older people with frailty to sustain their independence and quality of life. TRIAL REGISTRATION: ISRCTN 12,363,970 - 08/11/2018.