A5061304904- Sepsis Diagnosis and Treatment
- Immune Response and Inflammation
- Bacterial Identification and Susceptibility Testing
- Adrenal Hormones and Disorders
- Genomics and Phylogenetic Studies
- Pharmacological Effects of Natural Compounds
- COVID-19 Clinical Research Studies
- Antibiotic Resistance in Bacteria
- NF-κB Signaling Pathways
- Antimicrobial Resistance in Staphylococcus
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- interferon and immune responses
- S100 Proteins and Annexins
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Respiratory viral infections research
- SARS-CoV-2 and COVID-19 Research
- Intensive Care Unit Cognitive Disorders
- Stress Responses and Cortisol
- Adenosine and Purinergic Signaling
- Vitamin K Research Studies
- Meta-analysis and systematic reviews
- Data-Driven Disease Surveillance
- Immune responses and vaccinations
- Lipoproteins and Cardiovascular Health
- Immune cells in cancer
Stanford University
2015-2023
Boston Children's Hospital
2023
University of British Columbia
2009-2018
St. Paul's Hospital
2009-2018
Stanford Medicine
2017
St. Paul's Hospital
2012-2013
Lung Institute
2011
Inhibition of PCSK9 function is associated with an increase in pathogen lipid clearance, a decrease the innate immune inflammatory response, and improvement septic shock clinical outcome.
Clinical trials in septic shock continue to fail due, part, inequitable and sometimes unknown distribution of baseline mortality risk between study arms. Investigators advocate that interventional require effective outcome stratification. We derived tested a multibiomarker-based approach estimate adults with shock.
The pandemic 2019 novel coronavirus disease (COVID-19) shares certain clinical characteristics with other acute viral infections. We studied the whole-blood transcriptomic host response to severe respiratory syndrome 2 (SARS-CoV-2) using RNAseq from 24 healthy controls and 62 prospectively enrolled patients COVID-19. then compared these data non-COVID-19 infections, curated 23 independent studies profiling 1,855 blood samples covering six viruses (influenza, syncytial virus (RSV), human...
Rationale: The CysGlyGln haplotype of the β2-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in patients asthma. Whether this alters outcome receiving septic shock unknown.Objectives: To determine whether genetic variation ADRB2 influences shock.Methods: Two cohorts were studied: a single center (St. Paul's Hospital [SPH]) cohort (n = 589) Vasopressin Septic Shock Trial (VASST) 616). A allele rs1042717 G/A polymorphism complete...
Rationale: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change early septic shock.Objectives: Our hypotheses were that changes over 24 hours differ between survivors nonsurvivors, there are different effects of vasopressin norepinephrine on shock.Methods: We studied 394 patients a randomized, controlled trial shock. used hierarchical clustering principal components analysis the baseline concentrations to subgroup cytokines;...
Angiotensin II and its postreceptor signaling are crucial in regulating vasomotor tone. The objective of this study was to test the hypothesis that single nucleotide polymorphisms angiotensin pathway genes alter outcome septic shock.Genetic association vitro experiment.Intensive care units at academic teaching centers.Derivation validation shock cohorts (n = 589 n 616, respectively) a coronary artery bypass surgery cohort 551).Patients with derivation were genotyped for tag polymorphisms:...
Introduction Inflammatory response during sepsis is incompletely understood due to small sample sizes and variable timing of measurements following the onset symptoms. The vasopressin in septic shock trial (VASST) compared addition norepinephrine alone patients with shock. During this study plasma was collected 39 cytokines measured a 363 at both baseline (before treatment) 24 hours. Clinical features relating underlying health acute organ dysfunction induced by severe infection were first...
Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription antibiotics. Host-response-based could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries patients with bacterial or viral infections representing a broad spectrum biological, clinical, technical heterogeneity, we show host-response-based gene signatures have lower accuracy distinguish intracellular than extracellular infections. Using...
We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of NF-κB pathway are associated with altered clinical outcome septic shock patients. genotyped 59 SNPs in a discovery cohort patients (St. Paul's Hospital [SPH], N = 589), which identified C allele rs7222094 T/C MAP3K14 (NF-κB inducing kinase; NIK) increased 28-d mortality (uncorrected p 0.00024, Bonferroni corrected 0.014). This result was replicated second (Vasopressin and Septic Shock Trial [VASST; 616]) CC...
Abstract There is still an ongoing demand for a simple broad-spectrum molecular diagnostic assay pathogenic bacteria. For this purpose, we developed single-plex High Resolution Melt (HRM) that generates complex melt curves bacterial identification. Using internal transcribed spacer (ITS) region as the phylogenetic marker HRM, observed curve signatures compared to 16S rDNA amplicons with enhanced interspecies discrimination. We also novel Naïve Bayes classification algorithm statistical...
Objectives: Mortality from septic shock is highly heritable. The identification of causal genetic factors insufficient. To discover key contributors, we first identified nonsynonymous single-nucleotide polymorphisms in conserved genomic regions that are predicted to have significant effects on protein function. We then test the hypothesis these across genome alter clinical outcome shock. Design: Genetic-association study plus vitro experiment using primary cells silico analysis DNA and...
Background Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) life-threatening and fatal complication severe influenza infection. Methods We measured RNA expression 469 biologically plausible candidate genes children admitted to North American pediatric intensive care units with infection without MODS. Whole blood samples from 191 influenza-infected (median age 6.4 years, IQR: 2.2, 11) were collected median...
During septic shock, tumor necrosis factor alpha (TNFα) is an early response gene and induces a plethora of genes signaling pathways. To identify robust signals in reliably upregulated by TNFα, we first measured microarray expression vitro searched methodologically comparable, publicly available data sets to concordant signals. Using tag single-nucleotide polymorphisms the common all sets, identified genetic variant TNFAIP2 gene, rs8126, associated with decreased 28-day survival increased...
OBJECTIVES: Early diagnosis of infections is pivotal in critically ill patients. Innovative gene expression–based approaches promise to deliver precise, fast, and clinically practicable diagnostic tools bedside. This study aimed validate the SepsisMetaScore, an 11-gene signature previously reported by our group, a representative longitudinal cohort trauma DESIGN: Prospective observational study. SETTING: Surgical ICUs University Medical Center Goettingen, Germany. PATIENTS: Critically...
Sepsis, sequela of bloodstream infections and dysregulated host responses, is a leading cause death globally. Neutrophils tightly regulate responses to pathogens prevent organ damage. Profiling early epigenetic in neutrophils may aid disease recognition. We performed assay for transposase-accessible chromatin (ATAC)-seq human challenged with six toll-like receptor ligands two organisms; RNA-seq after Escherichia coli exposure 1 4 h along ATAC-seq. ATAC-seq facilitates detection pathogen DNA....
Indiscriminate use of antimicrobials and antimicrobial resistance is a public health threat. IMX-BVN-1, 29-host mRNA classifier, provides two separate scores that predict likelihoods bacterial viral infections in patients with suspected acute infections. We validated the performance IMX-BVN-1 adults attending care settings influenza.We amplified response genes RNA extracted from blood by NanoString nCounter. calculated to probabilities Results were compared against infection status (no...
Abstract Background Sepsis is a leading cause of death and can be caused by wide range potential pathogens. In up to 40% cases, causative pathogen never identified. There need for improved diagnostic tests that accurately identify the breadth pathogens inform effective antimicrobial therapy. Methods We enrolled prospective cohort patients presenting hospital with signs symptoms sepsis. Plasma samples were collected NGS testing at time initial blood culture. Extracted plasma cell-free DNA was...
<b><i>Background:</i></b> The <i>IL10</i> family of genes includes crucial immune regulators.<b> </b>We tested the hypothesis that single nucleotide polymorphisms (SNPs) in <i>IL10</i>, <i>IL19</i>, <i>IL20</i>, and <i>IL24</i> gene cluster alter clinical outcome septic shock. <b><i>Methods:</i></b> Patients with shock (<i>n</i> = 1,193) were genotyped for 13...
<b><i>Background:</i></b> Genetic variations contribute to septic shock mortality. To discover a novel locus, we performed in vitro genome-wide association studies (GWAS) and further tested the result cohort of patients. <b><i>Methods:</i></b> Two GWAS using quantitative trait locus analysis stimulated IL-6 production lymphoblastoid cells from 60 individuals European ancestry were performed. <i>VPS13D</i> rs6685273 was genotyped...
ABSTRACT Background Current diagnostic techniques are inadequate for rapid microbial diagnosis and optimal management of patients with suspected sepsis. We assessed the clinical impact three powerful molecular methods. Methods With blood samples from 200 consecutive sepsis, we evaluated 1) metagenomic shotgun sequencing together a Bayesian inference approach contaminant sequence removal, detecting bacterial DNA; 2) viral capture sequencing; 3) transcript-based host response profiling...