Mortality and Sequential Organ Failure Assessment Score in Patients With Suspected Sepsis: The Impact of Acute and Preexisting Organ Failures and Infection Likelihood.

Unlabelled: The Sequential Organ Failure Assessment (SOFA) was chosen in the definition of sepsis due to superior validity in predicting mortality. However, few studies have assessed the contributions of acute versus chronic organ failures to SOFA for mortality prediction.

Objectives: The main objective in this study was to assess the relative importance of chronic and acute organ failures in mortality prediction in patients with suspected sepsis at hospital admission.

DIAGNOSTIC ACCURACY AND ADDED VALUE OF INFECTION BIOMARKERS IN PATIENTS WITH POSSIBLE SEPSIS IN THE EMERGENCY DEPARTMENT.

Background: Biomarkers for early recognition of infection are warranted. The hypothesis of this study was that calprotectin, C-reactive protein (CRP), IL-6 and procalcitonin (PCT), alone or in combination, provide clinically useful information to the clinicians for early identification of infection in patients with possible sepsis in the emergency department (ED). Biomarker dynamics in the first week of hospitalization were explored.

Probiotics to HIV-Infected Immunological Nonresponders: Altered Mucosal Immunity and Microbial Diversity Restricted to Ileum.

Background: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon.

A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients.

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls.

Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients.

Introduction: Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes.

Methods: Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56.

Prognostic Value of Nucleated RBCs for Patients With Suspected Sepsis in the Emergency Department: A Single-Center Prospective Cohort Study.

Objectives: Increase of nucleated RBCs in peripheral blood has been shown to be predictive of mortality in ICU patients. The aim of this study was to explore the prognostic value of nucleated RBCs in the first blood sample taken at admission to the emergency department from patients with suspected sepsis.

Design: Single-center prospective cohort study.

A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics.

Here, we randomized 53 patients hospitalized with coronavirus disease 2019 (COVID-19) to hydroxychloroquine therapy (at a dose of 400 mg twice daily for seven days) in addition to standard care or standard care alone (ClinicalTrials.gov Identifier, NCT04316377). All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission.

Norwegian Coronavirus Disease 2019 (NO COVID-19) Pragmatic Open label Study to assess early use of hydroxychloroquine sulphate in moderately severe hospitalised patients with coronavirus disease 2019: A structured summary of a study protocol for a randomised controlled trial.

Objectives: The hypothesis of the study is that treatment with hydroxychloroquine sulphate in hospitalised patients with coronavirus disease 2019 (Covid-19) is safe and will accelerate the virological clearance rate for patients with moderately severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when compared to standard care. Furthermore, we hypothesize that early treatment with hydroxychloroquine sulphate is associated with more rapid resolve of clinical symptoms as assessed by the National Early Warning Score 2 (NEWS2), decreased admission rate to intensive care units and mortality, and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide).

Trial Design: The study is a two-arm, open label, pragmatic randomised controlled group sequential adaptive trial designed to assess the effect on viral loads and clinical outcome of hydroxychloroquine sulphate therapy in addition to standard care compared to standard care alone in patients with established Covid-19.

Estimating the Public Health Impact of Air Pollution for Informing Policy in the Twin Cities: A Minnesota Tracking Collaboration.

Objective: The Minnesota Department of Health and the Minnesota Pollution Control Agency used local air pollution and public health data to estimate the impacts of particulate matter and ozone on population health, to identify disparities, and to inform decisions that will improve health.

Setting: While air quality in Minnesota currently meets federal standards, urban communities are concerned about the impact of air pollution on their health. The Twin Cities (Minneapolis-St Paul) metropolitan area includes 7 counties where fine particulate levels and rates of asthma exacerbations are elevated in some communities.

Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.

Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL.

The therapeutic HIV Env C5/gp41 vaccine candidate Vacc-C5 induces specific T cell regulation in a phase I/II clinical study.

Background: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41 as well as the effects on pre-existing AB levels to C5/gp41, immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation.

T Cell Responses and Regulation and the Impact of In Vitro IL-10 and TGF-β Modulation During Treatment of Active Tuberculosis.

Mycobacterium tuberculosis (Mtb) is particularly challenging for the immune system being an intracellular pathogen, and a variety of T cell subpopulations are activated by the host defence mechanism. In this study, we investigated T cell responses and regulation in active TB patients with drug-sensitive Mtb (N = 18) during 24 weeks of efficient anti-TB therapy. T cell activation, differentiation, regulatory T cell (Treg) subsets, Mtb-induced T cell proliferation and in vitro IL-10 and TGF-β modulation were analysed by flow cytometry at baseline and after 8 and 24 weeks of therapy, while soluble cytokines in culture supernatants were analysed by a 9-plex Luminex assay.

The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection.

Background: Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens. Host-directed immune modulating therapies have been suggested as adjunctive treatment to TB antibiotics. Upregulated cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) signaling pathway may cause a dysfunctional immune response that favors survival and replication of Mycobacterium tuberculosis (Mtb).

Plasma IP-10 Is Increased in Immunological NonResponders and Associated With Activated Regulatory T Cells and Persisting Low CD4 Counts.

Objective: To explore immune mechanisms and identify biomarkers associated with an inadequate immune recovery in patients with HIV with efficient antiretroviral therapy.

Design: A cross-sectional study of 67 HIV-infected patients on antiretroviral therapy for ≥24 months with HIV RNA ≤20 copies per milliliter; 41 were defined as immunological nonresponders (INR) (CD4 < 400 cells per microliter) and 26 as immunological responders (CD4 > 600 cells per microliter). CD4 counts were also registered 2 years after inclusion.

Regulation of Gag- and Env-Specific CD8+ T Cell Responses in ART-Naïve HIV-Infected Patients: Potential Implications for Individualized Immunotherapy.

Strategies to develop a functional cure for HIV infection will likely require boosting of effector T cell responses to eliminate reactivated, latently infected cells. We have recently explored an assay for assessing antigen-specific regulation of T cell proliferation, which was related to clinical progression in untreated patients and to vaccine efficacy in two trials of therapeutic Gag-based vaccines. We here expand the same assay to further investigate regulation mediated by various inhibitory pathways.

Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors.

Human regulatory T cells (Tregs) are essential in maintaining immunological tolerance and suppress effector T cells. Tregs are commonly up-regulated in chronic infectious diseases such as tuberculosis (TB) and human immunodeficiency virus (HIV) infection and thereby hamper disease-specific immune responses and eradication of pathogens. The MEK/ERK signaling pathway is involved in regulation of the FoxP3 transcription factor, which directs a lineage-specific transcriptional program to define Tregs and control their suppressive function.

Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART.

Background: Microbial translocation and chronic inflammation may contribute to non-AIDS morbidity in patients with HIV. This study assessed the impact of probiotic intervention on microbial translocation and inflammation in patients on antiretroviral therapy with viral suppression and subnormal CD4 count.

Methods: Thirty-two patients receiving antiretroviral therapy (CD4 <500 cells/μL) were randomized in a double-blind fashion to multistrain daily probiotics (n = 15), placebo (n = 9), or controls (n = 8) for 8 weeks.

High MIP-1β Levels in Plasma Predict Long-Term Immunological Nonresponse to Suppressive Antiretroviral Therapy in HIV Infection.

Background: HIV-infected patients who fail to reconstitute their CD4 T-cell counts during suppressive antiretroviral therapy (ART) have increased risk of both AIDS-related and non-AIDS-related morbidity and mortality. Improved understanding of immunological nonresponse (INR) is necessary to enable earlier clinical intervention.

Methods: In a cohort of 112 HIV-infected patients starting ART, we performed a serial analysis of 32 plasma-soluble markers, assessed by multiplex cytokine and enzyme immunoassay.

Traffic, air pollution, minority and socio-economic status: addressing inequities in exposure and risk.

Higher levels of nearby traffic increase exposure to air pollution and adversely affect health outcomes. Populations with lower socio-economic status (SES) are particularly vulnerable to stressors like air pollution. We investigated cumulative exposures and risks from traffic and from MNRiskS-modeled air pollution in multiple source categories across demographic groups.

IP-10 measured by Dry Plasma Spots as biomarker for therapy responses in Mycobacterium Tuberculosis infection.

Tuberculosis (TB) has huge impact on human morbidity and mortality and biomarkers to support rapid TB diagnosis and ensure treatment initiation and cure are needed, especially in regions with high prevalence of multi-drug resistant TB. Soluble interferon gamma inducible protein 10 (IP-10) analyzed from dry plasma spots (DPS) has potential as an immunodiagnostic marker in TB infection. We analyzed IP-10 levels in plasma directly and extracted from DPS in parallel by ELISA from 34 clinically well characterized patients with TB disease before and throughout 24 weeks of effective anti-TB chemotherapy.

IP-10 differentiates between active and latent tuberculosis irrespective of HIV status and declines during therapy.

Objectives: Biomarkers for diagnosis and therapy efficacy in tuberculosis (TB) are requested. We have studied biomarkers that may differentiate between active and latent TB infection (LTBI), the influence of HIV infection and changes during anti-TB chemotherapy.

Methods: Thirty-eight plasma cytokines, assessed by multiplex and enzyme immunoassays, were analyzed in patients with active TB before and during 24 weeks of anti-TB chemotherapy (n = 65), from individuals with LTBI (n = 34) and from QuantiFERON-TB (QFT) negative controls (n = 65).