Views and Uses of Sepsis Digital Alerts in National Health Service Trusts in England: Qualitative Study With Health Care Professionals.

Background: Sepsis is a common cause of serious illness and death. Sepsis management remains challenging and suboptimal. To support rapid sepsis diagnosis and treatment, screening tools have been embedded into hospital digital systems to appear as digital alerts.

Deep multiomic profiling reveals molecular signatures that underpin preschool wheeze and asthma.

Background: Wheezing in childhood is prevalent, with over one-half of all children experiencing at least 1 episode by age 6. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear.

Objectives: This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multiomic profiling.

Conventional and unconventional T-cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients.

Sepsis is characterized by a dysfunctional host response to infection culminating in life-threatening organ failure that requires complex patient management and rapid intervention. Timely diagnosis of the underlying cause of sepsis is crucial, and identifying those at risk of complications and death is imperative for triaging treatment and resource allocation. Here, we explored the potential of explainable machine learning models to predict mortality and causative pathogen in sepsis patients.

Low levels of small HDL particles predict but do not influence risk of sepsis.

Background: Low levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling.

Phenotypic Associations With the HMOX1 GT(n) Repeat in European Populations.

Heme oxygenase 1 is a key enzyme in the management of heme in humans. A GT(n) repeat length in the heme oxygenase 1 gene (HMOX1) has been widely associated with a variety of phenotypes, including susceptibility to and outcomes in diabetes, cancer, infections, and neonatal jaundice. However, studies have generally been small and results inconsistent.

Prevalence of electronic screening for sepsis in National Health Service acute hospitals in England.

Unlabelled: Sepsis is a worldwide public health problem. Rapid identification is associated with improved patient outcomes-if followed by timely appropriate treatment.

Objectives: Describe digital sepsis alerts (DSAs) in use in English National Health Service (NHS) acute hospitals.

Gene filtering strategies for machine learning guided biomarker discovery using neonatal sepsis RNA-seq data.

Machine learning (ML) algorithms are powerful tools that are increasingly being used for sepsis biomarker discovery in RNA-Seq data. RNA-Seq datasets contain multiple sources and types of noise (operator, technical and non-systematic) that may bias ML classification. Normalisation and independent gene filtering approaches described in RNA-Seq workflows account for some of this variability and are typically only targeted at differential expression analysis rather than ML applications.

Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study.

Introduction: Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system's biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases.

Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease.

ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity.

An observational and Mendelian randomisation study on iron status and sepsis.

Iron deficiency is associated with a substantial burden of morbidity. However, supplementation of iron has been linked to increased rates of serious infection in randomised trials of children in sub-Saharan Africa. Randomised trials in other settings have been inconclusive and it is unknown if changes in levels of iron biomarkers are linked to sepsis in these other settings.

The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis.

Objectives: Severe malaria remains a deadly disease for many young children in low- and middle-income countries. Levels of interleukin (IL)-6 have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal.

Methods: A single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor was chosen as a genetic variant that is known to alter IL-6 signaling.

Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study.

IL-6 responses are ubiquitous in () infections, but their role in determining human tuberculosis (TB) disease risk is unknown. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor () gene, focusing on the non-synonymous variant, rs2228145, associated with reduced classical IL-6 signalling, to assess the effect of altered IL-6 activity on TB disease risk. We identified 16 genome wide association studies (GWAS) of TB disease collating 17,982 cases of TB disease and 972,389 controls across 4 continents.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.

Background: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.

Immune-metabolic adaptations in pregnancy: A potential stepping-stone to sepsis.

Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cellular, and molecular systems-level in the context of sepsis.

HMOX1 STR polymorphism and malaria: an analysis of a large clinical dataset.

Background: Inducible expression of heme oxygenase-1 (encoded by the gene HMOX1) may determine protection from heme released during malaria infections. A variable length, short tandem GT(n) repeat (STR) in HMOX1 that may influence gene expression has been associated with outcomes of human malaria in some studies. In this study, an analysis of the association between variation at the STR in HMOX1 on severe malaria and severe malaria subtypes is presented in a large, prospectively collected dataset (MalariaGEN).

CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.

Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import.

Evaluation of perturbed iron-homeostasis in a prospective cohort of patients with COVID-19.

Marked reductions in serum iron concentrations are commonly induced during the acute phase of infection. This phenomenon, termed hypoferremia of inflammation, leads to inflammatory anemia, but could also have broader pathophysiological implications. In patients with coronavirus disease 2019 (COVID-19), hypoferremia is associated with disease severity and poorer outcomes, although there are few reported cohorts.

Patients with transplantation have reduced mortality in bacteraemia: Analysis of data from a randomised trial.

Objectives: Infection remains a major complication of organ transplantation. Paradoxically, epidemiological studies suggest better survival from serious infection. We analysed the relationship between organ transplantation and short -term mortality of patients with bloodstream infection.

HMOX1 genetic polymorphisms and outcomes in infectious disease: A systematic review.

Introduction: Heme-oxygenase 1 (HMOX1) is a critical stress response gene that catalyzes the multistep oxidation of heme. A GT(n) repeat of variable length in the promoter in has been associated with a wide range of human diseases, including infections. This paper aims to summarise and systematically review associations between the length of the HMOX1 GT(n) promoter and infectious disease in humans.