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Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality. Current methods for evaluation of patients with suspected PE do not reliably predict which patients will later develop PE nor distinguish between PE with and without severe features. The objective of this study was to identify candidate extracellular miRNA (ex-miRNA) biomarkers for early diagnosis and prognosis of PE in a cohort of subjects presenting for evaluation of suspected PE. Small RNA-seq libraries were created from maternal serum samples, prospectively collected from participants undergoing evaluation for suspected PE between 20-40 weeks gestational age. Measurements for bivariate biomarkers, consisting of ratios of pairs of ex-miRNAs were performed. 110 bivariate ex-miRNA biomarkers passed both discovery (48 cases, 34 controls) and verification (23 cases, 18 controls) criteria. Specific biomarkers differed in their patterns of expression among different categories of hypertensive disorders in pregnancy (HDP). An iterative machine learning method was then used to identify 3 bivariate miRNA biomarkers that, when applied serially, differentiated cases from controls with a sensitivity of 93% and a positive predictive value (PPV) of 55%, and additionally distinguished between PE cases of different severity. In an independent validation cohort of 11 cases and 7 controls, these three biomarkers had a sensitivity of 91% and a PPV of 85%. We have discovered, verified, and validated 3 bivariate ex-miRNA biomarkers, which, when applied serially, enable accurate early diagnosis of preeclampsia. Bivariate ex-miRNA biomarkers can distinguish between different subtypes of HDP.

Blood culture (BC) often fails to detect bloodstream microorganisms in sepsis. However, molecular diagnostics hold great potential. The molecular method PCR/electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect DNA from hundreds of different microorganisms in whole blood. The aim of the present study was to evaluate the performance of this method in a multicenter study including 16 teaching hospitals in the USA (n=13) and Europe (n=3). First, on 2,754 contrived whole blood samples, with or without spiked microorganisms, PCR/ESI-MS produced 99.1% true positive and 97.2% true negative results. Secondly, among 1,460 patients with suspected sepsis (sepsis-2 definition), BC and PCR/ESI-MS on whole blood were positive in 14.6% and 25.6% of cases, respectively, with the following result combinations: BC+/PCR/ESI-MS-, 4.3%; BC+/PCR/ESI-MS+, 10.3%; BC-/PCR/ESI-MS+, 15.3%; and BC-/PCR/ESI-MS-, 70.1%. Compared with BC, PCR/ESI-MS showed the following sensitivities (coagulase-negative staphylococci not included): Gram-positive bacteria, 58%; Gram-negative bacteria, 78%; and Candida species, 83%. The specificities were > 94% for all individual species. Patients treated with prior antimicrobial medications (n=603) had significantly increased PCR/ESI-MS positivity rates compared with patients without prior antimicrobial treatment, 31% vs 22% (p<0.0001), with pronounced differences for Gram-negative bacteria and Candida species. In conclusion, PCR/ESI-MS showed excellent performance on contrived samples. On clinical samples, it showed high specificities, moderately high sensitivities for Gram-negative bacteria and Candida species, and elevated positivity rates during antimicrobial treatment. These promising results encourage further development of molecular diagnostics on whole blood for detection of bloodstream microorganisms in sepsis., Funding Agencies:Ibis Biosciences, a division of Abbott Abbott LaboratoriesCepheid ContraFect Nabriva Therapeutics AG Lajolla Pharmaceuticals Alere Corporation Spectral Diagnostics Ferring Pharmaceuticals Inflammix VICTASm Sanofi Pasteur Inc. Curetis GmbH PfizerMerck & CompanyCidara Therapeutics Inc. Shire Aridis Pharmaceuticals Inc. Epigenomics Inc. Roche Holding GenentechFinch Therapeutics Seres Therapeutics Inc. Diasorin Molecular Janssen Research and Development NeuMoDx Molecular Iterum Therapeutics International