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BACKGROUND. Severe, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth. METHODS. Women with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data. RESULTS. The most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94). CONCLUSION. Ultrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians. TRIAL REGISTRATION. ClinicalTrials.gov NCT02097667. FUNDING. The European Union, Rosetrees Trust, Mitchell Charitable Trust., Introduction The survival and growth of a fetus depends on placental provision of nutrients and waste exchange with the mother. When this system is impaired by inadequate transformation of the [...]

Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19–9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers. Using a selected patient cohort with benign pancreatic and biliary tract conditions we aimed to develop a data analysis protocol leading to a biomarker signature capable of distinguishing patients with non-specific yet concerning clinical presentations, from those with PDAC. Methods: 539 patient serum samples collected under the Accelerated Diagnosis of neuro Endocrine and Pancreatic TumourS (ADEPTS) study (benign disease controls and PDACs) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, healthy controls) were screened using the Olink Oncology II panel, supplemented with five in-house markers. 16 specialized base-learner classifiers were stacked to select and enhance biomarker performances and robustness in blinded samples. Each base-learner was constructed through cross-validation and recursive feature elimination in a discovery set comprising approximately two thirds of the ADEPTS and UKCTOCS samples and contrasted specific diagnosis with PDAC. Results: The signature which was developed using diagnosis-specific ensemble learning demonstrated predictive capabilities outperforming CA19-9, the only biomarker currently accepted by the FDA and the National Comprehensive Cancer Network guidelines for pancreatic cancer, and other individual biomarkers and combinations in both discovery and held-out validation sets. An AUC of 0.98 (95% CI 0.98–0.99) and sensitivity of 0.99 (95% CI 0.98–1) at 90% specificity was achieved with the ensemble method, which was significantly larger than the AUC of 0.79 (95% CI 0.66–0.91) and sensitivity 0.67 (95% CI 0.50–0.83), also at 90% specificity, for CA19-9, in the discovery set (p = 0.0016 and p = 0.00050, respectively). During ensemble signature validation in the held-out set, an AUC of 0.95 (95% CI 0.91–0.99), sensitivity 0.86 (95% CI 0.68–1), was attained compared to an AUC of 0.80 (95% CI 0.66–0.93), sensitivity 0.65 (95% CI 0.48–0.56) at 90% specificity for CA19-9 alone (p = 0.0082 and p = 0.024, respectively). When validated only on the benign disease controls and PDACs collected from ADEPTS, the diagnostic-specific signature achieved an AUC of 0.96 (95% CI 0.92–0.99), sensitivity 0.82 (95% CI 0.64–0.95) at 90% specificity, which was still significantly higher than the performance for CA19-9 taken as a single predictor, AUC of 0.79 (95% CI 0.64–0.93) and sensitivity of 0.18 (95% CI 0.03–0.69) (p = 0.013 and p = 0.0055, respectively). Conclusion: Our ensemble modelling technique outperformed CA19-9, individual biomarkers and indices developed with prevailing algorithms in distinguishing patients with non-specific but concerning symptoms from those with PDAC, with implications for improving its early detection in individuals at risk. Author summary: Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates among cancers, primarily due to its complex biology and late-stage diagnosis. Early symptoms often mimic benign gastrointestinal conditions, complicating timely detection. The standard biomarker, carbohydrate antigen (CA) 19–9, is not reliable due to its suboptimal performance and elevation in benign conditions, highlighting the need for better diagnostic tools. In our study, we aimed to develop a biomarker signature to distinguish between benign pancreatic/biliary conditions and PDAC using serum samples from the Accelerated Diagnosis of neuro Endocrine and Pancreatic Tumours and UK Collaborative Trial of Ovarian Cancer Screening studies. We screened 539 patient serum samples with state-of-the-art biomarker panels and developed a robust predictive signature by applying specialized machine learning methods. This new signature significantly outperformed CA19-9 and other panels reported in the literature. Our findings suggest that this new biomarker signature can improve early detection of PDAC in patients with ambiguous clinical symptoms, potentially leading to better outcomes for those at risk. [ABSTRACT FROM AUTHOR]

Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1‐36 and PYY3‐36, with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1‐36 and PYY3‐36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux‐en‐Y gastric bypass (RYGB) on fasting and postprandial PYY1‐36 and PYY3‐36 secretion using a newly developed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay. Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1‐36 and PYY3‐36 concentrations. Results: Presurgery, the fasting and postprandial levels of PYY1‐36 and PYY3‐36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1‐36 and PYY3‐36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1‐36 and PYY3‐36, which may account for long‐term differences in efficacy and adverse effects between the two types of surgery. [ABSTRACT FROM AUTHOR]

Motivation Database searching of isotopically labelled PTMs can be problematic and we frequently find that only one, or neither in a heavy/light pair are assigned. In such cases, having a pair of MS/MS spectra that differ due to an isotopic label can assist in identifying the relevant m / z values that support the correct peptide annotation or can be used for de novo sequencing. Results We have developed an online application that identifies matching peaks and peaks differing by the appropriate mass shift (difference between heavy and light PTM) between two MS/MS spectra. Furthermore, the application predicts, from the exact-match peaks, the mass of their complementary ions and highlights these as high confidence matches between the two spectra. The result is a tool to visually compare two spectra, and downloadable peaks lists that can be used to support de novo sequencing. Availability and implementation HiLight-PTM is released using shinyapps.io by RStudio, and can be accessed from any internet browser at https://harrywhitwell.shinyapps.io/hilight-ptm/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY 1-36 and PYY 3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY 1-36 and PYY 3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY 1-36 and PYY 3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay., Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY 1-36 and PYY 3-36 concentrations., Results: Presurgery, the fasting and postprandial levels of PYY 1-36 and PYY 3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY 1-36 and PYY 3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG., Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY 1-36 and PYY 3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Streptococcus pyogenes genotype emm 1 is a successful, globally distributed epidemic clone that is regarded as inherently virulent. An emm 1 sublineage, M1 UK , that produces increased levels of SpeA toxin was associated with increased scarlet fever and invasive infections in England in 2015/2016. Defined by 27 SNPs in the core genome, M1 UK is now dominant in England. To more fully characterize M1 UK , we undertook comparative transcriptomic and proteomic analyses of M1 UK and contemporary non-M1 UK emm 1 strains (M1 global ). Just seven genes were differentially expressed by M1 UK compared with contemporary M1 global strains. In addition to speA , five genes in the operon that includes glycerol dehydrogenase were upregulated in M1 UK ( gldA, mipB/talC, pflD , and phosphotransferase system IIC and IIB components), while aquaporin ( glpF2 ) was downregulated. M1 UK strains have a stop codon in gldA . Deletion of gldA in M1 global abrogated glycerol dehydrogenase activity, and recapitulated upregulation of gene expression within the operon that includes gldA , consistent with a feedback effect. Phylogenetic analysis identified two intermediate emm 1 sublineages in England comprising 13/27 (M1 13SNPs ) and 23/27 SNPs (M1 23SNPs ), respectively, that had failed to expand in the population. Proteomic analysis of invasive strains from the four phylogenetic emm 1 groups highlighted sublineage-specific changes in carbohydrate metabolism, protein synthesis and protein processing; upregulation of SpeA was not observed in chemically defined medium. In rich broth, however, expression of SpeA was upregulated ~10-fold in both M1 23SNPs and M1 UK sublineages, compared with M1 13SNPs and M1 global . We conclude that stepwise accumulation of SNPs led to the emergence of M1 UK . While increased expression of SpeA is a key indicator of M1 UK and undoubtedly important, M1 UK strains have outcompeted M1 23SNPs and other emm types that produce similar or more superantigen toxin. We speculate that an accumulation of adaptive SNPs has contributed to a wider fitness advantage in M1 UK on an inherently successful emm 1 streptococcal background.

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care., Competing Interests: The authors declare no competing interests. Author John F. Timms was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge., (Copyright: © 2022 Demichev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

When biomolecules attach to engineered nanoparticle (ENP) surfaces, they confer the particles with a new biological identity. Physical format may also radically alter, changing ENP stability and agglomeration state within seconds. In order to measure which biomolecules are associated with early ENP growth, we studied ENPs in conditioned medium from A549 cell culture, using dynamic light scattering (DLS) and linear trap quadrupole electron transfer dissociation mass spectrometry. Two types of 100 nm polystyrene particles (one uncoated and one with an amine functionalized surface) were used to measure the influence of surface type. In identically prepared conditioned medium, agglomeration was visible in all samples after 1 h, but was variable, indicating inter-sample variability in secretion rates and extracellular medium conditions. In samples conditioned for 1 h or more, ENP agglomeration rates varied significantly. Agglomerate size measured by DLS was well correlated with surface sequestered peptide number for uncoated but not for amine coated polystyrene ENPs. Amine-coated ENPs grew much faster and into larger agglomerates associated with fewer sequestered peptides, but including significant sequestered lactose dehydrogenase. We conclude that interference with extracellular peptide balance and oxidoreductase activity via sequestration is worthy of further study, as increased oxidative stress via this new mechanism may be important for cell toxicity., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)