Integrated lipidomics and proteomics point to early blood-based changes in childhood preceding later development of psychotic experiences: evidence from the Avon Longitudinal Study of Parents and Children

Background The identification of early biomarkers of psychotic experiences (PEs) is of interest as early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. Methods Plasma of 115 children (age 12) who were first identified as experiencing PEs at age 18 (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semi-targeted proteomics approaches. We assessed the lipids, LPCs (n=11) and PCs (n=61), and the protein members of the coagulation pathway (n=22) and integrated this data with complement pathway protein data already available on these subjects. Results Twelve PCs, four LPCs and the coagulation protein plasminogen were altered between the control and PE group after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated to PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters with one of the clusters presenting the highest ratio cases:controls (P < 0.01) and associated with a higher concentration of smaller LDL cholesterol particles. Conclusions Our findings indicate that the lipidome and proteome of subjects who report PEs at age 18 is already altered at age 12 indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting cross-talk between these LPCs, PCs and coagulation and complement proteins

Environment and land use in the Lower Lea Valley c.12,500 BC – c.600 AD: Innova Park and the former Royal Ordnance Factory, Enfield

Excavations revealed aspects of the changing environment of the floodplain of the Lower Lea Valley from the Late Glacial to the early historic periods. Evidence for land use mostly related to activity along the western bank of a former stream. Wooden revetments (the earliest dated one being Early Bronze Age), ditches, gullies, pits, a droveway, land surfaces and associated ‘midden-like’ deposits provided evidence for seasonal or periodic use and, arguably, habitation, dating principally from the Middle to Late Bronze Age. The economy of the site was focused on stock rearing, grazing and the exploitation of river resources. The ‘midden-like’ deposits, identified as interleaved layers of silt, sand and gravel containing pottery, human and animal bone, as well as flint and bone tools, and other objects, may be compared with similar, more extensive deposits from sites such as Runnymede Bridge, Surrey. There was no evidence of further activity until the Late Iron Age to early Romano-British period, when a series of fish-traps, pits and a structure within an enclosure indicate renewed, again possibly seasonal, use of the area. An evaluation on the site of the former Royal Ordnance Factory produced evidence for the continuing importance of waterfront management in this floodplain environment, in the form of the wooden revetment of another stream channel, radiocarbon dated to the late or post-Roman period

Integrated lipidomics and proteomics point to early blood-based changes in childhood preceding later development of psychotic experiences: evidence from the Avon Longitudinal Study of Parents and Children

Background: The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort.Methods: Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects.Results: Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p Conclusions: Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.</p

Effect of lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal vs standard care ventilation on 90-day mortality in patients with acute hypoxemic respiratory failure

Importance In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, −7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, −2.1 [95% CI, −3.8 to −0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference