Whole blood gene expression profiling of neonates with confirmed bacterial sepsis

peer-reviewedNeonatal infection remains a primary cause of infant morbidity and mortality worldwide and yet our understanding of how human neonates respond to infection remains incomplete. Changes in host gene expression in response to infection may occur in any part of the body, with the continuous interaction between blood and tissues allowing blood cells to act as biosensors for the changes. In this study we have used whole blood transcriptome profiling to systematically identify signatures and the pathway biology underlying the pathogenesis of neonatal infection. Blood samples were collected from neonates at the first clinical signs of suspected sepsis alongside age matched healthy control subjects. Here we report a detailed description of the study design, including clinical data collected, experimental methods used and data analysis workflows and which correspond with data in Gene Expression Omnibus (GEO) data sets (GSE25504). Our data set has allowed identification of a patient invariant 52-gene classifier that predicts bacterial infection with high accuracy and lays the foundation for advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Making of Britain’s European Foreign Policy

Few commentators would contest that Britain’s relationship with the European Union (EU) has been one of the most consistent and troublesome issues to have influenced British politics during the last fifty years. This has been reflected in the number of publications devoted to this subject, and in particular to the question of the reluctance of successive British governments to commit to Europe. Much of this scholarship has analysed Britain’s relationship with the EU in a historical context, citing the various phases that this debate has passed through (Greenwood, 1992; George, 1991 and 1994; Gowland and Turner, 2000; J. Young, 1984 and 2000; H. Young, 1998). This book offers a new contribution to debates by examining the making of British European policy. It focuses on the dynamics of policy-making in a European context, using a case study approach to analyse a wide range of issues more closely. More broadly it also analyses the changing nature of the foreign policy process itself, and so to remedy the gap of 25 years since the last major study of the process of making British foreign policy was published (W. Wallace, 1975). In line with the Political Dynamics of the European Union series, the book has three key aims. The first is to examine the extent to which Britain’s relationship with the EU is changing. The second is to determine where power lies in the construction of what we term ‘Britain’s European policy’. The third is to examine the extent to which existing structures are adequate to meet the current demands and future challenges to the making of British European policy

A Cholesterol Biosensor Based on the NIR Electrogenerated-Chemiluminescence (ECL) of Water-Soluble CdSeTe/ZnS Quantum Dots

This contribution examines the application of near infra-red (NIR) quantum dot (QD) containing films for cholesterol detection. Water-soluble, 2-(dimethylamino) ethanthiol (DAET) protected 800 nm CdSeTe/ZnS core-shell QDs were prepared and incorporated into a chitosan film. The NIR electrogenerated chemiluminescence (ECL) of the QD/chitosan films upon reaction with H2O2 co-reactant (produced as a by-product of cholesterol oxidase-catalysed oxidation of cholesterol) gave a strong ECL signal at −1.35 V vs. Ag/AgCl. The sensor displayed a linear response over the clinically relevant range (0.25 ≤ [cholesterol] ≤ 5 mM) allowing the rapid detection of cholesterol and providing a platform for future development. Significantly, this NIR emission has been shown to exhibit excellent penetrability through biological samples, and will likely be at the forefront of development in the biosensing and imaging fields for the foreseeable future

Whole blood gene expression profiling of neonates with confirmed bacterial sepsis

Neonatal infection remains a primary cause of infant morbidity and mortality worldwide and yet our understanding of how human neonates respond to infection remains incomplete. Changes in host gene expression in response to infection may occur in any part of the body, with the continuous interaction between blood and tissues allowing blood cells to act as biosensors for the changes. In this study we have used whole blood transcriptome profiling to systematically identify signatures and the pathway biology underlying the pathogenesis of neonatal infection. Blood samples were collected from neonates at the first clinical signs of suspected sepsis alongside age matched healthy control subjects. Here we report a detailed description of the study design, including clinical data collected, experimental methods used and data analysis workflows and which correspond with data in Gene Expression Omnibus (GEO) data sets (GSE25504). Our data set has allowed identification of a patient invariant 52-gene classifier that predicts bacterial infection with high accuracy and lays the foundation for advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis

Differential abundance of host miRNAs in mouse serum during <i>S. mansoni</i> infection.

<p>miRNAs were quantified by qRT-PCR and normalized to a synthetic RNA spike-in. Each symbol represents data from one individual mouse. Fold changes are defined as the ratio of abundance in infected versus naïve serum; the signal from naïve was set as 1. (***p<0.001, ****p<0.0001).</p

Differential expression of host miRNAs in the livers of mice at 4–12 weeks post infection with <i>S. mansoni</i>.

<p>miRNAs were quantified by qRT-PCR, normalized to miR-16 and fold changes calculated as the ratio of values from infected versus naïve mice (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).</p

Small RNA classification in serum of naïve and infected mice.

1<p>This does not include 42 reads identical to sja-miR-277 that contain 1 nucleotide mismatch to <i>S. mansoni</i> draft genome.</p

Chiredzi study participants.

<p>Chiredzi study participants.</p

Piida study participants.

<p>Piida study participants.</p