Search

Background Pneumocystis pneumonia (PCP) severely menaces modern chemotherapy and immunosuppression. Detailed description of the epidemiology of Pneumocystis jirovecii today is needed to identify candidates for PCP-prophylaxis. Methods We performed a 12-year retrospective study of patients with P. jirovecii detected by polymerase chain reaction in Central Norway. In total, 297 patients were included. Comprehensive biological, clinical and epidemiological data were abstracted from patients’ medical records. Regional incidence rates and testing trends were also assessed. Results From 2007 to 2017 we found a 3.3-fold increase in testing for P. jirovecii accompanied by a 1.8-fold increase in positive results. Simultaneously, regional incidence rates doubled from 5.0 cases per 100,000 person years to 10.8. A majority of the study population had predisposing conditions other than human immunodeficiency virus (HIV). Hematological (36.0%) and solid cancers (25.3%) dominated. Preceding corticosteroids were a common denominator for 72.1%. Most patients (74.4%) presented with at least two cardinal symptoms; cough, dyspnea or fever. Main clinical findings were hypoxia, cytopenias and radiological features consistent with PCP. A total of 88 (29.6%) patients required intensive care and 121 (40.7%) suffered at least one complication. In-hospital mortality was 21.5%. Three patients (1.0%) had received prophylaxis. Conclusions P. jirovecii is re-emerging; likely due to increasing immunosuppressants use. This opportunistic pathogen threatens the life of heterogenous non-HIV immunosuppressed populations currently at growth. Corticosteroids seem to be a major risk factor. A strategy to increase prophylaxis is called for.

Background - Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. Objectives - This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. Methods - The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. Results - We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. Conclusions - Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703)

Background Bloodstream infection and sepsis are major causes of health loss worldwide, and it is important to identify patients at risk of developing and dying from these conditions. The single-nucleotide polymorphism most strongly associated with sepsis mortality is FER rs4957796. However, it is not known how this variant is associated with bloodstream infection incidence and mortality. Methods We used prospective data from 1995–2017 from the population-based HUNT Study. Genotypes were ascertained from blood samples, and additional genotypes were imputed. Information on bloodstream infection and diagnosis codes at hospitalization were collected through record linkage with all hospitals in the area. Results A total of 69 294 patients were included. Patients with the rs4957796 CC genotype had an increased risk of developing a bloodstream infection compared with the TT genotype (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.00–1.43). However, there was a protective additive effect of the C allele in terms of mortality in the total study population (HR, 0.77; 95% CI, .64–.92 per copy of the C allele) and among bloodstream infection patients (odds ratio, 0.70; 95% CI, .58–.85 per copy of the C allele). The results did not appear to be affected by selection bias. Conclusions The rs4957796 CC genotype was associated with an increased risk of contracting a bloodstream infection but with a reduced risk of dying from one. The latter finding is in line with studies of sepsis case fatality, while the former expands our understanding of the immunoregulatory role of this polymorphism., The C allele of FER rs4957796 has been associated with reduced sepsis case fatality. In this prospective study of 69 294 patients, the C allele increases the risk of developing bloodstream infection but reduces the risk of dying from one.

Purpose Studies on aetiology of community-acquired pneumonia (CAP) vary in terms of microbial sampling methods, anatomical locations, and laboratory analyses, since no gold standard exists. In this large, multicentre, retrospective, regional study from Norway, our primary objective was to report the results of a strategic diagnostic stewardship intervention, targeting diagnostic yield from lower respiratory tract sampling. The secondary objective was to report hospitalized CAP aetiology and the diagnostic yield of various anatomical sampling locations. Methods Medical records from cases diagnosed with hospitalized CAP were collected retrospectively from March throughout May for three consecutive years at six hospitals. Between year one and two, we launched a diagnostic stewardship intervention at the emergency room level for the university teaching hospital only. The intervention was multifaceted aiming at upscaling specimen collection and enhancing collection techniques. Year one at the interventional hospital and every year at the five other emergency hospitals were used for comparison. Results Of the 1280 included cases of hospitalized CAP, a microbiological diagnosis was established for 29.1% among 1128 blood cultures and 1444 respiratory tract specimens. Blood cultures were positive for a pathogenic respiratory tract microbe in 4.9% of samples, whereas upper and lower respiratory tract samples overall provided a probable microbiological diagnosis in 21.3% and 47.5%, respectively. Expectorated or induced sputum overall provided aetiology in 51.7% of the samples. At the interventional hospital, the number of expectorated or induced sputum samples were significantly increased, and diagnostic yield from expectorated or induced sputum was significantly enhanced from 41.2 to 62.0% after the intervention (p = 0.049). There was an over-representation of samples from the interventional hospital during the study period. Non-typeable Haemophilus influenza and Streptococcus pneumoniae accounted for 25.3% and 24.7% of microbiologically confirmed cases, respectively. Conclusion Expectorated or induced sputum outperformed other sampling methods in providing a reliable microbiological diagnosis for hospitalized CAP. A diagnostic stewardship intervention significantly improved diagnostic yield of lower respiratory tract sampling.

ObjectiveTo examine the effect of sex on risk of bloodstream infections (BSI) and BSI mortality and to assess to what extent known risk factors for BSI mediate this association in the general population.ParticipantsThe prospective, population-based HUNT2 Survey (1995-97) in Norway invited 93,898 inhabitants ≥20 years in the Nord-Trøndelag region, whereof 65,237 (69.5%) participated. 46.8% of the participants were men.ExposuresSex and potential mediators between sex and BSI; health behaviours (smoking, alcohol consumption), education attainment, cardiovascular risk factors (systolic blood pressure, non-HDL cholesterol, body mass index) and previous or current comorbidities.Main outcome measuresSex differences in risk of first-time BSI, BSI mortality (death within first 30 days after a BSI), BSI caused by the most frequent bacteria, and the impact of known BSI risk factors as mediators.ResultsWe documented a first-time BSI for 1,840 (2.9%) participants (51.3% men) during a median follow-up of 14.8 years. Of these, 396 (0.6%) died (56.6% men). Men had 41% higher risk of any first-time BSI (95% confidence interval (CI), 28 to 54%) than women. An estimated 34% of the excess risk of BSI in men was mediated by known BSI risk factors. The hazard ratio (HR) with 95% CI for BSI due to S. aureus was 2.09 (1.28 to 2.54), S. pneumoniae 1.36 (1.05 to 1.76), and E. coli 0.97 (0.84 to 1.13) in men vs women. BSI related mortality was higher in men compared to women with HR 1.87 (1.53 to 2.28).ConclusionsThis large population-based study show that men have higher risk of BSI than women. One-third of this effect was mediated by known risk factors for BSI. This raises important questions regarding sex specific approaches to reduce the burden of BSI.

[No Abstract]

Background Peripheral intravenous catheters (PIVCs) account for a mean of 38% of catheter associated bloodstream infections (CABSI) with Staphylococcus aureus, which are preventable if deficiencies in best practice are addressed. There exists no feasible and reliable quality surveillance tool assessing all important areas related to PIVC quality. Thus, we aimed to develop and test feasibility and reliability for an efficient quality assessment tool of overall PIVC quality. Methods The Peripheral Intravenous Catheter- mini Questionnaire, PIVC-miniQ, consists of 16 items calculated as a sum score of problems regarding the insertion site, condition of dressing and equipment, documentation, and indication for use. In addition, it contains background variables like PIVC site, size and insertion environment. Two hospitals tested the PIVC-miniQ for feasibility and inter-rater agreement. Each PIVC was assessed twice, 2–5 min apart by two independent raters. We calculated the intraclass correlation coefficient (ICC) for each hospital and overall. For each of the 16 items, we calculated negative agreement, positive agreement, absolute agreement, and Scott’s pi. Results Sixty-three raters evaluated 205 PIVCs in 177 patients, each PIVC was assessed twice by independent raters, in total 410 PIVC observations. ICC between raters was 0.678 for hospital A, 0.577 for hospital B, and 0.604 for the pooled data. Mean time for the bedside assessment of each PIVC was 1.40 (SD 0.0007) minutes. The most frequent insertion site symptom was “pain and tenderness” (14.4%), whereas the most prevalent overall problem was lack of documentation of the PIVC (26.8%). Up to 50% of PIVCs were placed near joints (wrist or antecubital fossae) or were inserted under suboptimal conditions, i.e. emergency department or ambulance. Conclusions Our study highlights the need for PIVC quality surveillance on ward and hospital level and reports the PIVC-miniQ to be a reliable and time efficient tool suitable for frequent point-prevalence audits. © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

ObjectiveBeyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties.MethodsIn a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase–DNA (MPO–DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1–3).ResultsOur major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all pConclusionsIn patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.

Objective: Lower respiratory tract infections (LRTIs) are a leading cause of morbidity and mortality worldwide. Few studies have previously investigated the genetic susceptibility and potential risk factors for LRTI. Methods: We used data from UK Biobank, HUNT, and FinnGen, to conduct a genome-wide association study (GWAS). Cases were subjects hospitalized with LRTI, and controls were subjects with no such hospitalization. We conducted stratification and interaction analyses to evaluate if the genetic effect of LRTI differed by sex or smoking. Mendelian randomization [MR] analyses were conducted to identify the unconfounded relationship between cardiometabolic risk factors and LRTI. Results: A total of 25,320 cases and 575,294 controls were included. The 15q25.1 locus reached genome-wide significance in the meta-analysis (rs10519203: OR = 0.94, P = 3.87e-11). The protective effect of effect allele of rs10519203 was present among smokers (OR = 0.90 [95% CI = 0.87 - 0.92, P = 1.38e-15]) but not among never-smokers (OR = 1.01 [95% CI = 0.97 - 1.06, P = 5.20e-01]). In MR analyses, we found that increasing body mass index (OR = 1.31 [95% CI = 1.24 - 1.40, P = 3.78e-18]), lifetime smoking (OR = 2.83 [95% CI = 2.34 - 3.42, P = 6.56e-27]), and systolic blood pressure robustly increased the risk of LRTIs (OR = 1.11 [95% CI = 1.02 - 1.22, P = 1.48e-02]). Conclusion: A region in 15q25.1 was strongly associated with LRTI susceptibility. Reduction of the prevalence of smoking, overweight, obesity, and hypertension may reduce the disease burden of LRTIs. Keywords: body mass index, genome-wide association study, lowerrespiratory tract infection, mendelianrandomization, pneumonia, respiratory infection, smoking

Background Whole body ischemia and reperfusion injury after cardiac arrest leads to the massive inflammation clinically manifested in the post-cardiac arrest syndrome. Previous studies on the inflammatory effect on circulatory failure after cardiac arrest have either investigated a selected patient group or a limited part of the inflammatory mechanisms. We examined the association between cardiac arrest characteristics and inflammatory biomarkers, and between inflammatory biomarkers and circulatory failure after cardiac arrest, in an unselected patient cohort. Methods This was a prospective study of 50 consecutive patients with out-of-hospital cardiac arrest. Circulation was invasively monitored from admission until day five, whereas inflammatory biomarkers, i.e. complement activation, cytokines and endothelial injury, were measured daily. We identified predictors for an increased inflammatory response, and associations between the inflammatory response and circulatory failure. Results We found a marked and broad inflammatory response in patients after cardiac arrest, which was associated with clinical outcome. Long time to return of spontaneous circulation and high lactate level at admission were associated with increased complement activation (TCC and C3bc), pro-inflammatory cytokines (IL-6, IL-8) and endothelial injury (syndecan-1) at admission. These biomarkers were in turn significantly associated with lower mean arterial blood pressure, lower cardiac output and lower systemic vascular resistance, and increased need of circulatory support in the initial phase. High levels of TCC and IL-6 at admission were significantly associated with increased 30-days mortality. Conclusion Inflammatory biomarkers, including complement activation, cytokines and endothelial injury, were associated with increased circulatory failure in the initial period after cardiac arrest.

Pneumocystis jirovecii is a threat to iatrogenically immunosuppressed individuals, a heterogeneous population at rapid growth. We assessed the ability of an in-house semiquantitative real-time PCR assay to discriminate Pneumocystis pneumonia (PCP) from colonization and identified risk factors for infection in these patients. Retrospectively, 242 PCR-positive patients were compared according to PCP status, including strata by immunosuppressive conditions, human immunodeficiency virus (HIV) infection excluded. Associations between host characteristics and cycle threshold (CT) values, semiquantitative real-time PCR correlates of fungal loads in lower respiratory tract specimens, were investigated. CT values differed significantly according to PCP status. Overall, a CT value of 36 allowed differentiation between PCP and colonization with sensitivity and specificity of 71.3% and 77.1%, respectively. A CT value of less than 31 confirmed PCP, whereas no CT value permitted exclusion. A considerable diversity was uncovered; solid organ transplant (SOT) recipients had significantly higher fungal loads than patients with hematological malignancies. In SOT recipients, a CT cutoff value of 36 resulted in sensitivity and specificity of 95.0% and 83.3%, respectively. In patients with hematological malignancies, a higher CT cutoff value of 37 improved sensitivity to 88.5% but reduced specificity to 66.7%. For other conditions, assay validity appeared inferior. Corticosteroid usage was an independent predictor of PCP in a multivariable analysis and was associated with higher fungal loads at PCP expression. Semiquantitative real-time PCR improves differentiation between PCP and colonization in immunocompromised HIV-negative individuals with acute respiratory syndromes. However, heterogeneity in disease evolution requires separate cutoff values across intrinsic and iatrogenic predisposition for predicting non-HIV PCP. IMPORTANCE Pneumocystis jirovecii is potentially life threatening to an increasing number of individuals with compromised immune systems. This microorganism can cause severe pneumonia in susceptible hosts, including patients with cancer and autoimmune diseases and people undergoing solid organ transplantation. Together, these patients constitute an ever-diverse population. In this paper, we demonstrate that the heterogeneity herein has important implications for how we diagnose and assess the risk of Pneumocystis pneumonia (PCP). Specifically, low loads of microorganisms are sufficient to cause infection in patients with blood cancer compared to those in solid organ recipients. With this new insight into host versus P. jirovecii biology, clinicians can manage patients at risk of PCP more accurately. As a result, we take a significant step toward offering precision medicine to a vulnerable patient population. One the one hand, these patients have propensity for adverse effects from antimicrobial treatment. On the other hand, this population is susceptible to life-threatening infections, including PCP.

Background: Hepatitis C is highly prevalent among people who use drugs (PWUD), and the hepatitis C virus (HCV) epidemic is less characterised in Norway. The aims of the study were to assess the prevalence and treatment willingness in high-risk populations by reaching out to frequently visited sites for high-risk populations. Methods: Individuals from high-risk populations were included from September 2015 to March 2017. Two dedicated study nurses frequently visited the local opioid substitution clinic, outpatient clinics, PWUD day centres, local prison, and refugee centre in Trondheim, Norway. Demographic data, risk behaviour, and clinical symptoms were obtained by study questionnaire. Subjects with anti-HCV+ rapid test were subsequently tested for HCV RNA and genotyped. Viraemic patients were offered referral for HCV treatment evaluation. Results: A total of 381 participants were included in the study: 52 immigrants, 62 prisoners, and 267 PWUD. The anti-HCV prevalence rates were 0% ( n = 0) in immigrants, 40% ( n = 25) in prisoners, and 61% ( n = 164) in PWUD, with 24% ( n = 15) of prisoners and 42% ( n = 108) of PWUD being viraemic. Of those qualifying for treatment ( n = 31), 30 wished to be evaluated. Conclusion: This study showed high HCV prevalence in prisoners and PWUD and that infected high-risk patients were interested in treatment evaluation.

Objectives Bloodstream infection is an important cause of death worldwide. The main objective of this study was to identify genetic loci linked to risk of contracting a bloodstream infection. Design Genome-wide linkage analysis. Setting Population-based, Norwegian cohort, followed between 1995 and 2017. Subjects Among 69,423 genotyped subjects, there were 47 families with two or more second-degree relatives with bloodstream infection in the follow-up period. There were 365 subjects in these families, of which 110 were affected. Interventions None. Measurements and main results The cohort was genotyped using Illumina HumanCoreExome (Illumina, San Diego, CA) arrays. Before linkage analysis, single-nucleotide polymorphisms were pruned and clumped. In nonparametric linkage analysis using an exponential model, we found three loci with a suggestive linkage to bloodstream infection, all on chromosome 4, at 46.6 centimorgan (logarithm of odds, 2.3), 57.7 centimorgan (logarithm of odds, 3.2), and 70.0 centimorgan (logarithm of odds, 2.1). At the peak of the lead region are three genes: TLR10, TLR1, and TLR6. Conclusions Variations in the TLR10/1/6 locus appear to be linked with the risk of contracting a bloodstream infection.

BackgroundSkin and soft tissue infections (SSTIs) are common worldwide, but little is known about the genetic susceptibility and the causal effect of cardiometabolic risk factors. We therefore conducted the first genome-wide association study (GWAS) of SSTIs, with downstream analyses including Mendelian randomization analyses.MethodsThe GWAS was conducted using the UK Biobank as discovery cohort, with 6,107 cases and 399,239 controls, and the Trøndelag Health Study (HUNT) as replication cohort with 1,657 cases and 67,522 controls. Cases and controls were those who had or had not been hospitalized with an SSTI diagnosis, respectively.FindingsOne locus, lead single-nucleotide polymorphism rs3749748 in LINC01184/SLC12A2, was associated with SSTIs in the UK Biobank (odds ratio [OR] 1.19, p-value = 7.6e-16) and replicated in HUNT (OR 1.15, p-value = 6.3e-4). Meta-analysis confirmed the lead variant (OR 1.18, p-value = 4.4e-18), as well as suggested two additional loci close to genome-wide significance (rs2007361 in PSMA1, OR 0.91, p-value = 5.1e-8; and rs78625038 in GAN, OR 1.86, p-value = 5.9e-8). Gene-based association tests identified four genes linked to SSTIs: SLC12A2, PSMA1, GAN, and IL6R. The minor allele of rs3749748 reduced the gene expression of SLC12A2 primarily in monocytes and macrophages. Mendelian randomization analyses showed that increasing body mass index and lifetime smoking habits increased risk of SSTIs.InterpretationLINC0118/SLC12A2 was robustly associated with SSTI incidence and may exert its effect through reduced gene expression in monocytes and macrophages. Reducing tobacco smoking, overweight and obesity in the population may reduce the incidence of SSTIs.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. Published version available at https://doi.org/10.1016/j.ijcard.2018.04.136. Aim: To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI). Methods: 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay. Results: Using a mixed between-within subjects analysis of variance, we observed a significant (p Δ), placebo: 3 (−60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1β mΔ, placebo: 5 (−2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1β was inversely correlated to troponin T (r = −0.28, p Conclusions: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074.

Infective endocarditis (IE) is associated with severe complications and a high mortality rate. Identification of the causative pathogen is crucial to optimise treatment. We present a case of prosthetic valve endocarditis caused by Corynebacterium freneyi, a very rare cause of human infection and not previously reported as a cause of IE. Despite proper antibiotic therapy, the patient eventually needed surgery after progression of the infection. After surgery, he quickly recovered without evidence of relapse during an 8-month follow-up period. This report highlights critical decision making in a complex and potentially life-threatening situation, where neither guidelines nor previous clinical or microbiological experience were able to give clear treatment recommendations.

Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI).This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months.Tocilizumab did not affect CFR during hospitalisation (tocilizumab: 3.4±0.8 vs placebo: 3.3±1.2, p=0.80). CFR improved significantly in both groups at 6 months. Patients in the tocilizumab group had significantly higher area under the curve for VCAM-1 (median 622 vs 609 ng/mL/hour, tocilizumab and placebo respectively, p=0.003). There were inverse correlations between VCAM-1 and CFR in the placebo (hospitalisation: r=-0.74, p0.01, 6 months: r=-0.59, p0.01), but not in the tocilizumab group (hospitalisation: r=0.20, p=0.37, 6 months r=-0.28, p=0.20).Tocilizumab did not affect CFR during hospitalisation or after 6 months. Tocilizumab increased VCAM-1 levels during hospitalisation, but this was not associated with reduced CFR in these patients.

Aims Extracellular matrix remodelling may influence atherosclerotic progression and plaque stability. We hypothesized that evaluation of extracellular matrix markers, with potentially different roles during atherogenesis, could provide information on underlying mechanisms and risk of myocardial infarction (MI) in apparently healthy individuals. Methods We conducted a case-control study nested within the population-based HUNT2 cohort in Norway. A total of 58,761 men and women, free of known cardiovascular disease, were followed for a first MI. During 11.3 years of follow-up, 1587 incident MIs were registered, and these cases were compared with 3959 age- and sex-matched controls. Circulating levels of the ECM proteins CD147 (ECM metalloproteinase inducer; EMMPRIN), cartilage oligomeric matrix protein (COMP: thrombospondin-5) and YKL-40 (chitinase-3-like-1) were measured by enzyme immunoassays. Results We found an inverse association between COMP (quartile (Q) 4 vs. Q1: hazard ratio 0.81 (95% confidence interval: 0.67-0.98)) and YKL-40 (Q4 vs. Q1: hazard ratio 0.77 (0.62-0.95)) with incidence of MI after full multivariable adjustment. Serum CD147 was not associated with MI risk in adjusted analysis. Conclusion High levels of COMP and YKL-40 were associated with lower risk of incident MI, suggesting a potential beneficial role in promoting plaque stability in individuals without incident cardiovascular disease.

An amendment to this paper has been published and can be accessed via the original article.

Background The IL-6 receptor antagonist tocilizumab has been shown to attenuate the proatherogenic lipoprotein a [Lp(a)] in rheumatoid arthritis. We evaluated if a single dose of tocilizumab reduced Lp(a) in patients with non-ST-elevation myocardial infarction (NSTEMI). Methods Lp(a) was assessed by immunoassay (n = 117 patients) at 7 consecutive time-points between day 1 and 3 and at 3 and 6 months follow-up. Results Tocilizumab did not affect Lp(a) at any time-point during the study and was not associated with cardiovascular risk factors. Conclusions Short-time inhibition of IL-6 with tocilizumab in patients with NSTEMI did not influence Lp(a) levels.

Background: Prompt myocardial revascularisation with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with acute ST segment elevation myocardial infarction (STEMI). However, as much as 50 % of the loss of viable myocardium may be attributed to the subsequent reperfusion injury and the associated inflammatory response. The aim of the ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction (ASSAIL-MI) trial was to evaluate the effect of interleukin-6 (IL-6) receptor inhibition on myocardial salvage in acute STEMI. Methods: The ASSAIL-MI trial was a randomised, double blind, placebo-controlled trial performed at three high-volume PCI centres in Norway. Patients admitted with STEMI within six hours of symptom onset were eligible if they had had no prior myocardial infarction. Consenting patients were randomised in a 1:1 fashion to receive a single infusion of the IL-6 receptor inhibitor tocilizumab or placebo during PCI. The primary endpoint was the myocardial salvage index as measured by cardiac magnetic resonance imaging three to seven days after randomisation. Findings: Between 16 th March 2017 and 10 th February 2020, 101 patients were randomised to tocilizumab and 98 patients were randomised to placebo. In the intention to treat analysis, the myocardial salvage index was 69 ± 19 % in patients allocated to tocilizumab and 64 ± 21 % in the placebo group (adjusted between-group difference 5.6 percentage points, 95 % confidence interval 0·0 – 11·3 percentage points, p = 0 · 04). There were 34 serious adverse events, 19 of which occurred in patients treated with tocilizumab and 15 in patients receiving placebo.Interpretation: Treatment with tocilizumab significantly improved myocardial salvage in patients presenting with acute STEMI. Funding: The South-Eastern Norway Regional Health Authority, the Central Norway Regional Health Authority, and Roche TM supported the trial. Roche™ provided the investigational medicinal products and an unrestricted grant. Trial registration number: ClinicalTrials.gov (NCT3004703). Funding Statement: The South-Eastern Norway Regional Health Authority, the Central Norway Regional Health Authority, and RocheTM supported the trial. Roche™ provided the investigational medicinal products and an unrestricted grant. Declaration of Interests: Dr Gullestad has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis and Amgen and has been a member of local advisory board in AstraZeneca and Boehringer Ingelheim. The other authors do not have conflicts of interest pertaining to this work. Ethics Approval Statement: The trial protocol was approved by the regional ethics committee (REK Sor-Ost 2016/1223), and all participants provided written informed consent. An independent data and safety monitoring board oversaw the safety of the trial. The trial was conducted in compliance with the declaration of Helsinki and with the rules outlined in the guidelines for Good Clinical Practice.

Background: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease. Methods: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling. Findings: Transcripts of interleukin (IL)-1beta(b) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1b protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1b, IL-18 and IL-1a. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components. Interpretation: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis. © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Background Most patients in Norwegian hospitals are routinely given one or more peripheral venous catheters. A peripheral venous catheter is considered to be a benign device but may entail a risk of local infection with resulting bloodstream infection and sepsis. Good practice in the insertion and care of these catheters is essential to prevent infection. Material and method This study presents Norwegian data from the 'One Million Global Catheters Study', which evaluated practice in relation to peripheral venous catheters in 419 hospitals in 51 countries. Two Norwegian hospitals collected data from medical and surgical wards on a single day in November 2014 (Levanger Hospital) and a single day in February 2015 (St Olavs Hospital). Professional development nursing specialists recorded observations of peripheral venous catheters such as insertion site, dressing, documentation and indication. Results We evaluated 136 peripheral venous catheters in a total of 121 patients. We found 44 (32.4 %) catheters associated with various clinical problems such as pain, redness or swelling around the insertion site, catheter dislocation, or blood in the infusion set. Altogether 50 peripheral venous catheters (36.8 %) were not in use for either medications or fluid on the day in question. In 93 of 131 cases (71.0 %), there was no documentation of venous catheter assessment in the previous 24 hours. Interpretation Care and monitoring of venous catheters could be significantly improved. There was considerable incidence of unused peripheral venous catheters, and lack of documentation was widespread.

Innate immune activation has been attributed a key role in traumatic brain injury (TBI) and successive morbidity. In mild TBI (mTBI), however, the extent and persistence of innate immune activation are unknown. We determined plasma cytokine level changes over 12 months after an mTBI in hospitalized and non-hospitalized patients compared with community controls; and examined their associations to injury-related and demographic variables at admission. Prospectively, 207 patients presenting to the emergency department (ED) or general practitioner with clinically confirmed mTBI and 82 matched community controls were included. Plasma samples were obtained at admission, after 2 weeks, 3 months, and 12 months. Cytokine levels were analysed with a 27-plex beads-based immunoassay. Brain magnetic resonance imaging (MRI) was performed on all participants. Twelve cytokines were reliably detected. Plasma levels of interferon gamma (IFN-c), interleukin 8 (IL-8), eotaxin, macrophage inflammatory protein-1-beta (MIP-1b), monocyte chemoattractant protein 1 (MCP-1), IL-17A, IL-9, tumor necrosis factor (TNF), and basic fibroblast growth factor (FGFbasic) were significantly increased at all time-points in patients compared with controls, whereas IFN-c-inducing protein 10 (IP-10), platelet-derived growth factor (PDGF), and IL-1ra were not. IL-17A and FGF-basic showed significant increases in patients from admission to follow-up at 3 months, and remained increased at 12 months compared with admission. Interestingly, MRI findings were negatively associated with four cytokines: eotaxin, MIP-1b, IL-9, and IP-10, whereas age was positively associated with nine cytokines: IL-8, eotaxin, MIP-1b, MCP-1, IL-17A, IL-9, TNF, FGFbasic, and IL-1ra. TNF was also increased in those with presence of other injuries. In conclusion, mTBI activated the innate immune system consistently and this is the first study to show that several inflammatory cytokines remain increased for up to 1 year post-injury. Viktoriia Chaban et al., 2020. Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non–ST‐segment–elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction , concentration of both C‐reactive protein and troponin T were reduced in the active treatment arm. In this follow‐up study, an aptamer‐based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention– treated patients, 24 in the active intervention and 24 in the placebo‐control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMA scan assay. Employing slow off‐rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1–3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMA scan assay, and subsequently confirmed by enzyme immunoassay , were significantly altered by tocilizumab administration. The acute‐phase proteins lipopolysaccharide‐ binding protein, hepcidin, and insulin‐like growth factor‐binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C‐C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMA scan aptamer‐based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non–ST‐segment–elevation myocardial infarction .

IntroductionInterleukin-6 (IL-6) may be involved in ischaemia-reperfusion injury and myocardial remodelling after myocardial infarction (MI). We have recently shown that IL-6 inhibition by tocilizumab attenuates systemic inflammation and troponin T-release in patients with acute non-ST elevation MI (NSTEMI). Experimental studies suggest that IL-6 inhibition can limit infarct size through anti-inflammatory mechanisms, but this has not been tested in clinical studies. With the ASSessing the effect of Anti-IL-6 treatment in MI (ASSAIL-MI) trial, we aim to examine whether a single administration of the IL-6 receptor antagonist tocilizumab can increase myocardial salvage in patients with acute ST-elevation MI (STEMI).Methods and analysisThe ASSAIL-MI trial is a randomised, double blind, placebo-controlled trial, conducted at three high-volume percutaneous coronary intervention (PCI) centres in Norway. 200 patients with first-time STEMI presenting within 6 hours of the onset of chest pain will be randomised to receive tocilizumab or matching placebo prior to PCI. The patients are followed-up for 6 months. The primary endpoint is the myocardial salvage index measured by cardiac MRI (CMR) 3–7 days after the intervention. Secondary endpoints include final infarct size measured by CMR and plasma markers of myocardial necrosis. Efficacy and safety assessments during follow-up include blood sampling, echocardiography and CMR.Ethics and disseminationBased on previous experience the study is considered feasible and safe. If tocilizumab increases myocardial salvage, further endpoint-driven multicentre trials may be initiated. The ASSAIL-MI trial has the potential to change clinical practice in patients with STEMI.RegistrationClinicaltrials.gov, identifier NCT03004703.

Background The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus. Methodology/Principal findings Plasma levels of secreted Wnt antagonists (i.e. DKK-1, sFRP-3, WIF-1 and SOST) were analyzed in patients with scrub typhus (n = 129), patients with similar febrile illness without O. tsutsugamushi infection (n = 31), febrile infectious disease controls, and in healthy controls (n = 31) from the same area of South India, and were correlated to markers of inflammation, immune and endothelial cell activation as well as for their association with organ specific dysfunction and mortality in these patients. We found i) Levels of SOST and in particular sFRP-3 and WIF-1 were markedly increased and DKK-1 decreased in scrub typhus patients at admission to the hospital compared to healthy controls. ii) In recovering scrub typhus patients, SOST, sFRP-3 and WIF-1 decreased and DKK-1 increased. iii) SOST was positively correlated with markers of monocyte/macrophage and endothelial/vascular activation as well as with renal dysfunction and poor outcome iv) Finally, regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients with scrub typhus, as evaluated by gene expression studies available in public repositories, revealed markedly attenuated canonical Wnt signaling. Conclusions/Significance Our findings suggest that scrub typhus is characterized by attenuated Wnt signaling possibly involving dysregulated levels of several secreted pathway antagonists. The secreted Wnt antagonist SOST was strongly associated with renal dysfunction and poor prognosis in these patients., Author summary Scrub typhus, a systemic infection caused by Orientia tsutsugamushi is manifested by fever and multiple organ involvement with significant mortality if untreated. O. tsutsugamushi infects endothelial cells triggering inflammatory responses in endothelial and monocyte-derived macrophages. The wingless (Wnt) pathways are important regulators of the interaction between microbes and the immune system promoting inflammatory and anti-inflammatory responses. Wnt signaling is regulated by multiple extracellular secreted proteins that are readily measurable and may reflect activity in the Wnt pathways. We measured plasma levels of the secreted Wnt modulators in patients with scrub typhus and infectious controls and correlated them with markers of inflammation and immune activation. We also evaluated the regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients in microarray experiments available in public repositories. Our study suggests a pathogenic role for dysregulated Wnt signaling during acute O. tsutsugamushi infection.

Background and Aim Accurate, noninvasive biomarkers are needed to diagnose and monitor inflammatory bowel disease (IBD). Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin 2, is expressed in inflamed colonic epithelium and neutrophilic granulocytes. This study explores its properties as a biomarker in feces and plasma and, for the first time, compares fecal NGAL systematically with the existing fecal biomarker calprotectin. Methods Neutrophil gelatinase-associated lipocalin was measured in feces from 73 patients with IBD, 21 patients with infectious enterocolitis, 21 patients with irritable bowel syndrome, and 23 healthy subjects using ELISA. The results were correlated to calprotectin, clinical score, endoscopic score, and high-sensitive C-reactive protein. Plasma from 119 patients with IBD and 28 healthy controls was analyzed for NGAL. Results Fecal NGAL levels (median and interquartile range) were significantly elevated in active ulcerative colitis (UC) 6.05 (3.6–15.1) mg/kg and Crohn's disease (CD) 4.9 (1.5–7.7) mg/kg, compared with patients with inactive UC 1.3 (0.4–2.6) mg/kg, inactive CD 1.5 (0.5–1.7) mg/kg, irritable bowel syndrome 0.4 (0.2–0.6) mg/kg, and healthy controls (HC) 0.3 (0.1–0.4) mg/kg. Patients with infectious enterocolitis had significantly higher fecal-NGAL levels, 2.7 (1.4–5.6) mg/kg than HC. Sensitivity and specificity was 94.7% and 95.7%, respectively, for distinguishing between active IBD and HC. Stability of NGAL in stool was excellent for 7 days in room temperature. Plasma NGAL was significantly elevated in UC and CD compared with HC. Conclusions Fecal NGAL is a promising biomarker for IBD. As existing biomarkers are expressed mainly in granulocytes, NGAL's epithelial localization may give supplementary diagnostic information.

Aims Interleukin-6 (IL-6) contributes to atherosclerotic plaque destabilization and is involved in myocardial injury during ischaemia–reperfusion. Interleukin-6 is therefore a potential therapeutic target in myocardial infarction (MI). We hypothesized that the IL-6 receptor antagonist tocilizumab would attenuate inflammation, and secondarily reduce troponin T (TnT) release in non-ST-elevation MI (NSTEMI). Methods and results In a two-centre, double-blind, placebo-controlled trial, 117 patients with NSTEMI were randomized at a median of 2 days after symptom onset to receive placebo (n = 59) or tocilizumab (n = 58), administered as a single dose prior to coronary angiography. High sensitivity (hs) C-reactive protein and hsTnT were measured at seven consecutive timepoints between Days 1 and 3. The area under the curve (AUC) for high-sensitivity C-reactive protein was the primary endpoint. The median AUC for high-sensitivity C-reactive protein during hospitalization was 2.1 times higher in the placebo than in the tocilizumab group (4.2 vs. 2.0 mg/L/h, P < 0.001). Also, the median AUC for hsTnT during hospitalization was 1.5 times higher in the placebo group compared with the tocilizumab group (234 vs. 159 ng/L/h, P = 0.007). The differences between the two treatment groups were observed mainly in (i) patients included ≤2 days from symptom onset and (ii) patients treated with percutaneous coronary intervention (PCI). No safety issues in the tocilizumab group were detected during 6 months of follow-up. Conclusion Tocilizumab attenuated the inflammatory response and primarily PCI-related TnT release in NSTEMI patients. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2016.

Background In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. Methods and findings We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. Conclusions Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the “obesity paradox,” where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis., Tormod Rogne and colleagues investigate whether body mass index influences risk of mortality from bloodstream infection., Author summary Why was this study done? It is well-recognized that overweight and obesity are associated with increased risk of bloodstream infection (BSI) and sepsis, but it is not fully understood whether this is due to body weight in itself or factors related to body weight (such as exercise or smoking habits). While a large number of studies have observed that BSI or sepsis patients who are overweight or obese have a reduced risk of dying from those diseases, there is reason to suspect that these findings are biased. We wanted to evaluate whether genetically predicted body mass index (BMI)—which is independent of lifestyle factors—was associated with risk of developing and dying from a BSI. What did the researchers do and find? We used clinical and genetic information from the Trøndelag Health Study in Norway on 55,908 participants representative of the adult Norwegian population. Similar to what has been found in non-genetic studies, we found that increased genetically predicted BMI was associated with an increased risk of developing a BSI. Contrary to many observational studies, we found that among BSI patients, being overweight or obese was associated with an increased risk of death from bloodstream infection. What do these findings mean? The findings of many previous observational studies of an apparently protective effect of overweight or obesity among patients with BSI or sepsis may be affected by other factors, such as accompanying characteristics of overweight or obese individuals, or by who ends up participating in the studies. In this cohort, higher genetically predicted BMI was associated with an increased risk of developing and dying from a BSI, also among BSI patients, and our findings support the worldwide initiative to reduce the prevalence of overweight and obesity.

Background There is a need to develop sustainable emergency health care systems in low-resource settings, but data that analyses emergency health care needs in these settings are scarce. We aimed at assessing presenting complaints (PCs) and post-discharge mortality in a large emergency department population in Nepal. Methods Characteristics of adult patients who entered the emergency department (ED) in a hospital in Nepal were prospectively recorded in the local emergency registry from September 2013 until December 2016. To assess post-ED mortality, patient households were followed-up by telephone interviews at 90 days. Results In 21892 included adults, the major PC categories were injuries (29%), abdominal complaints (23%), and infections (16%). Median age was 40 years and sex distribution was balanced. Among 3793 patients followed at 90 days, 8% had died. For respiratory and cardiovascular PCs, 90-day mortality were 25% and 23%. The highest mortality was in individuals with known chronic lung disease, in this group 32% had died by 90 days of ED discharge, regardless of PC. In women, illiteracy compared to literacy (adjusted odds ratio (aOR) = 7.0, 95% confidence interval (CI) = 2.1-23.6) and being both exposed to tobacco-smoking and traditional cooking stove compared to no smoke (aOR = 2.8, 95% CI = 1.6-4.9) were associated with mortality. The mortality was much higher among family-initiated discharged patients (17%, aOR = 5.4, 95% CI = 3.3-8.9) compared to doctor-initiated discharged (3%). Conclusions Our report suggests that nearly one in ten patients seeking emergency health care died within 90 days. This finding is alarming and novel. Post-discharge studies need to be replicated and appropriate follow-up programs in low-resource settings where primary health care is underdeveloped are urgently needed. © Author(s) 2019. This work is distributed under the Creative Commons Attribution 4.0 License.

ObjectiveIt is unclear if activation of inflammatory pathways regulates proprotein convertase subtilisin-kexin type 9 (PCSK9) levels.ApproachWe evaluated (1) the temporal course of serum PCSK9 during hospitalisation following acute coronary syndrome and associations with markers of inflammation (leucocyte counts, interleukin (IL)-6, C-reactive protein) and lipid levels and (2) the effect of inhibition of IL-6 signalling with the IL-6 receptor antibody tocilizumab on PCSK9 levels in a randomised, double-blind, placebo-controlled trial release in patients with non-ST-elevation myocardial infarction.ResultsSerum PCSK9 increased during the acute phase and this response was modestly associated with neutrophil counts (r=0.24, p=0.009) and presence of hypercholesterolaemia (r=0.019, p=0.045), but was not modified by tocilizumab. However, a modifying effect of tocilizumab on PCSK9 levels was observed in patients with hypercholesterolaemia (p=0.024, repeated measures analysis of variance) and this effect was strongly correlated with the decrease in neutrophils (r=0.66, p=0.004).ConclusionsOur study suggests that patients with a more atherogenic profile may benefit from anti-IL-6 therapy with regard to PCSK9.Trial registration numberNCT01491074.

Objective We examined whether anxiety and depression symptoms constitute increased risk of bloodstream infection (BSI), as a proxy for sepsis. Methods A general population with self-reported anxiety and depression symptoms was followed prospectively for hospital-verified BSI. Using multivariable Cox regression analysis, we estimated hazard ratios (HR) with 95% confidence intervals (CI) of BSI and BSI mortality, with and without statistical adjustment for comorbidities, BMI, and life-style factors that may confound or mediate the associations. Results During 14.8 years median follow-up of 59,301 individuals, 1578 (2.7%) experienced BSI and 328 (0.55%) participants died within 30 days after a BSI. Severe depression symptoms were associated with a 38% increased risk of BSI, adjusted for age, sex, and education (HR = 1.38, 95% CI = 1.10-1.73). The HR was attenuated to 1.23 (0.96-1.59) after adjustment for comorbidities and to 1.15 (0.86-1.53) after additional adjustment for BMI and life-style factors. For severe anxiety symptoms, the corresponding HRs were 1.48 (1.20-1.83), 1.35 (1.07-1.70), and 1.28 (0.99-1.64). Moderate symptoms of depression and anxiety were not associated with increased BSI risk. The analysis of BSI mortality yielded imprecise results but suggested an increased risk of BSI mortality in participants with moderate depression symptoms. Conclusions Severe depression and anxiety symptoms were associated with a moderately increased risk of BSI. The association may, at least in part, be confounded or mediated by comorbidities, BMI, and life-style. Future research should investigate whether interventions targeting improved BMI and life-style may reduce the risk of BSI and sepsis in people with depression and anxiety symptoms.

The antimicrobial glycoprotein neutrophil gelatinase-associated lipocalin (NGAL) is strongly expressed in several infectious, inflammatory and malignant disorders, among these inflammatory bowel disease (IBD). Fecal and serum NGAL is elevated during active IBD and we have recently shown that fecal NGAL is a novel biomarker for IBD with a test performance comparable to the established fecal biomarker calprotectin. This study examines expression of NGAL in the healthy gut and in Crohn’s disease (CD), with emphasis on the previously unexplored small intestine. Pinch biopsies were taken from active and inactive CD in jejunum, ileum and colon and from the same sites in healthy controls. Microarray gene expression showed that the NGAL gene, LCN2, was the second most upregulated among 1820 differentially expressed genes in terminal ileum comparing active CD and controls (FC 5.86, p = 0.027). Based on immunohistochemistry and in situ hybridization findings, this upregulation most likely represented increased expression in epithelial cells. Double immunofluorescence showed NGAL expression in 49% (range 19–70) of Paneth cells (PCs) in control ileum with no change during inflammation. In healthy jejunum, the NGAL expression in PCs was weak to none but markedly increased during active CD. We further found NGAL also in metaplastic PCs in colon. Finally, we show for the first time that NGAL is expressed in enteroendocrine cells in small intestine as well as in colon.

Commentary on : Raith EP, Udy AA, Bailey M, et al . Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA 2017;317:290–300. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) has redefined sepsis, now defining sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection, with organ failure defined as a two-or-more-point change in the Sequential Organ Failure Assessment (SOFA) score.1 The new sepsis definition was determined in a retrospective cohort of both intensive care unit (ICU) and non-ICU encounters.2 The quick SOFA (qSOFA) score (altered mentation, systolic blood pressure ≤100 mm Hg and respiratory rate ≥22/min) was also introduced as a possible useful predictive tool among patients outside the ICU. This external validation study compares the discrimination …

Background We aimed to evaluate the clinical usefulness of qSOFA as a risk stratification tool for patients admitted with infection compared to traditional SIRS criteria or our triage system; the Rapid Emergency Triage and Treatment System (RETTS). Methods The study was an observational cohort study performed at one Emergency Department (ED) in an urban university teaching hospital in Norway, with approximately 20,000 visits per year. All patients >16 years presenting with symptoms or clinical signs suggesting an infection (n = 1535) were prospectively included in the study from January 1 to December 31, 2012. At arrival in the ED, vital signs were recorded and all patients were triaged according to RETTS vital signs, presenting infection, and sepsis symptoms. These admission data were also used to calculate qSOFA and SIRS. Treatment outcome was later retrieved from the patients’ electronic records (EPR) and mortality data from the Norwegian population registry. Results Of the 1535 admitted patients, 108 (7.0%) fulfilled the Sepsis2 criteria for severe sepsis. The qSOFA score ≥2 identified only 33 (sensitivity 0.32, specificity 0.98) of the patients with severe sepsis, whilst the RETTS-alert ≥ orange identified 92 patients (sensitivity 0.85, specificity 0.55). Twenty-six patients died within 7 days of admission; four (15.4%) of them had a qSOFA ≥2, and 16 (61.5%) had RETTS ≥ orange alert. Of the 68 patients that died within 30 days, only eight (11.9%) scored ≥2 on the qSOFA, and 45 (66.1%) had a RETTS ≥ orange alert. Discussion In order to achieve timely treatment for sepsis, a sensitive screening tool is more important than a specific one. Our study is the fourth study were qSOFA finds few of the sepsis cases in prehospital or at arrival to the ED. We add information on the RETTS triage system, the two highest acuity levels together had a high sensitivity (85%) for identifying sepsis at arrival to the ED - and thus, RETTS should not be replaced by qSOFA as a screening and trigger tool for sepsis at arrival. Conclusion In this observational cohort study, qSOFA failed to identify two thirds of the patients admitted to an ED with severe sepsis. Further, qSOFA failed to be a risk stratification tool as the sensitivity to predict 7-day and 30-day mortality was low. The sensitivity was poorer than the other warning scores already in use at the study site, RETTS-triage and the SIRS criteria. Electronic supplementary material The online version of this article (doi:10.1186/s13049-017-0399-4) contains supplementary material, which is available to authorized users.

Background: Bloodstream infections (BSI) cause considerable morbidity and mortality, and primary prevention should be a priority. Lifestyle factors are of particular interest since they represent a modifiable target. Methods: We conducted a prospective cohort study among participants in the population-based Norwegian HUNT2 Survey, where 64 027 participants were followed from 1995–97 through 2011 by linkage to prospectively recorded information on BSI at local and regional hospitals. The exposures were: baseline body mass index (BMI) measurements; and self-reported smoking habits, leisure time physical activity and alcohol intake. The outcomes were hazard ratios (HR) of BSI and BSI mortality. Results: During 810 453 person-years and median follow-up of 14.8 years, 1844 (2.9%) participants experienced at least one BSI and 396 (0.62%) died from BSI. Compared with normal weight participants (BMI 18.5–24.9 kg/m2), the age- and sex-adjusted risk of a first-time BSI was 31% [95% confidence interval (CI) 14–51%] higher at BMI 30.0–34.9 kg/m2, 87% (95% CI 50–135%) higher at BMI 35.0–39.9 kg/m2 and 210% (95% CI 117–341%) higher at BMI ≥ 40.0 kg/m2. The risk of BSI mortality was similarly increased. Compared with never-smokers, current smokers had 51% (95% CI 34–70%) and 75% (95% CI 34–129%) higher risks of BSI and BSI mortality, respectively. Physically inactive participants had 71% (95% CI 42–107%) and 108% (95% CI 37–216%) higher risks of BSI and BSI mortality, respectively, compared with the most physically active. © The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association. This is the authors' accepted and refereed manuscript to the article. Locked until 15 June 2018 due to copyright restrictions

Background The occurrence of bloodstream infection (BSI) and antimicrobial resistance have been increasing in many countries. We studied trends in antimicrobial resistance and empiric antibiotic therapy at a medium-sized general hospital in Mid-Norway. Methods Between 2002 and 2013, 1995 prospectively recorded episodes of BSI in 1719 patients aged 16–99 years were included. We analyzed the antimicrobial non-susceptibility according to place of acquisition, site of infection, microbe group, and time period. Results There were 934 community-acquired (CA), 787 health care-associated (HCA) and 274 hospital-acquired (HA) BSIs. The urinary tract was the most common site of infection. Escherichia coli was the most frequently isolated infective agent in all three places of acquisition. Second in frequency was Streptococcus pneumoniae in CA and Staphylococcus aureus in both HCA and HA. Of the BSI microbes, 3.5% were non-susceptible to the antimicrobial regimen recommended by the National Professional Guidelines for Use of Antibiotics in Hospitals, consisting of penicillin, gentamicin, and metronidazole (PGM). In contrast, 17.8% of the BSI microbes were non-susceptible to cefotaxime and 27.8% were non-susceptible to ceftazidime. Antimicrobial non-susceptibility differed by place of acquisition. For the PGM regimen, the proportions of non-susceptibility were 1.4% in CA, 4.8% in HCA, and 6.9% in HA-BSI (p

Aortic surgery results in ischemia–reperfusion injury that induces an inflammatory response and frequent complications. The magnitude of the inflammatory response in blood and bronchi may be associated with the risk of immediate complications. The purpose of the study was to evaluate bronchial microdialysis as a continuous monitoring of cytokines in bronchial epithelial lining fluid (ELF) and to determine whether bronchial ELF cytokine levels reflect the ischemia–reperfusion injury and risk for complications during open abdominal aortic aneurysm (AAA) repair. We measured cytokines in venous blood using microdialysis and in serum for comparison. Sixteen patients scheduled for elective open AAA repair were included in a prospective observational study. Microdialysis catheters were introduced into a bronchi and a cubital vein. Eighteen cytokines were measured using a Bio‐Plex Magnetic Human Cytokine Panel. Samples were collected before and during cross‐clamping of the aorta as well as from 0 to 60 min and from 60 to 120 min of reperfusion. The ELF levels of several cytokines changed significantly during reperfusion. In particular, IL‐6 increased more than 10‐fold and IL‐13 more than 5‐fold during ischemia and reperfusion. Also, the venous levels of several inflammatory and anti‐inflammatory cytokines increased and exhibited their highest concentration during reperfusion. Both bronchial and venous cytokine levels correlated with duration of the procedure, intensive care days, and preoperative kidney disease. Three patients suffered organ failure as a direct consequence of the procedure, and in these patients the bronchial ELF concentrations of 17 of 18 cytokines differed significantly from patients without such complications. Bronchial microdialysis is suited for continuous monitoring of inflammation during open AAA repair. The bronchial ELF cytokine levels may be useful in predicting immediate complications such as organ failure in patients undergoing vascular surgery. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Accepted manuscript version. Published version available at https://doi.org/10.1016/j.ijcard.2017.05.106. Accepted manuscript version, licensed CC BY-NC-ND 4.0. Background: We hypothesized that circulating markers reflecting monocyte/macrophage and T cell activation are associated with increased risk of myocardial infarction (MI) in apparently healthy individuals. Methods: Serum monocyte/macrophage and T cell activation markers soluble (s) CD163, sCD14, Gal3BP, sCD25 and sCD166 were analyzed by enzyme-immunoassay in a case-control study nested within the population-based HUNT2 cohort in Norway. Among 58,761 apparently healthy men and women followed a median 11.3 years, 1587 incident MI cases were registered, and compared to 3959 age- and sex-matched controls. Results: Higher serum sCD163 (Q4 vs. Q1 OR: 1.27, P-trend 0.002), sCD14 (Q4 vs. Q1 OR: 1.38, P-trend < 0.001), and especially sCD25 (Q4 vs. Q1 OR: 1.45, P-trend < 0.001), were associated with increased MI risk in the age-and sex adjusted models. However, after additional adjustment for cardiovascular risk factors these associations were strongly attenuated (Q4 vs Q1 ORs between 1.02 and 1.12, P-trends between 0.30 and 0.58). Conclusions: sCD163, sCD14 and sCD25 may reflect leukocyte activation and inflammatory mechanisms related to atherogenesis, but do not predict MI risk above and beyond conventional cardiovascular risk factors.

Background Studies from several countries indicate that the incidence and mortality of bloodstream infection (BSI) have been increasing over time. Methods We studied the burden of disease and death related to BSI in a defined geographical area of Mid-Norway, where BSI episodes were prospectively recorded by the same microbiological department during 12 consecutive years. Death from BSI was defined as death within 30 days of BSI detection. Age and sex standardized incidence and mortality rates and case fatality rates were calculated. Results Between 2002 and 2013, 1995 episodes of BSI in 1719 patients aged 16 to 99 years were included. The overall incidence of BSI was 215 per 100,000 person-years. The incidence increased exponentially with age, particularly in males. The incidence increased from 205 to 223 per 100,000 person-years from 2002–07 to 2008–13. Escherichia coli was the most frequently isolated infective agent, followed by Streptococcus pneumoniae and Staphylococcus aureus. The rate of S. pneumoniae BSI decreased over time in males (on average by 9.2% annually), but not in females. The total rate of BSI microbes with acquired resistance increased slightly over time, but did not exceed 2 episodes per 100,000 person-years. The mortality of BSI was 32 per 100,000 person-years, higher in males than in females (36 vs. 28 per 100,000 person-years) and was significantly higher in old age, particularly in males. The total BSI mortality was similar in the first and second halves of the study period, but the mortality of S. pneumoniae BSI decreased in males (15.0% annually). The crude case fatality decreased from the first to the second half of the study period (17.2% to 13.1%; p = 0.014). The rate of blood culture sampling increased more than twofold during the study period. Conclusions The mortality of BSI remained stable during 2002–2013. At the same time, BSI incidence increased and case fatality rate decreased, perhaps because an increased rate of blood culture sampling may have led to improved detection of milder BSI episodes. Very low, yet slightly increasing rates of microbes with acquired resistance were observed. © The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Background: Invasive pneumococcal disease (IPD) is responsible for significant mortality and morbidity worldwide. There are however few longitudinal studies on the changes in case fatality rate of IPD in recent years. We carried out a prospective observational study of patients with IPD in Nord Trøndelag county in Norway from 1993 to 2011 to study the clinical variables and disease outcome. The main outcome was all-cause mortality after 30 and 90 days. Methods: Patients with positive blood cultures were registered prospectively by the microbiology laboratory and clinical variables were registered retrospectively from patients’ hospital records. The severity of sepsis was assigned according to the 2001 International Sepsis Definition Conference criteria. The association between mortality and predictive factors was studied using a logistic regression model. Results: The total number of patients was 414 with mean age of 67 years and 53 % were male. Comorbidity was assessed by the Charlson Comorbidity Index (CCI). A CCI-score of 0 was registered in 144 patients (34.8 %), whereas 190 had a score of 1–2 (45.9 %) and 80 (19.3 %) had a score ≥3. 68.8 % of the patients received appropriate antibiotics within the first 6 h. The 30-day mortality risk increased by age and was 3-fold higher for patients aged ≥80 years (24.9, 95 % CI 16.4–33.4 %) compared to patients aged

Background New drugs for rheumatoid arthritis (RA) have resulted in an improvement in patients' functioning and morbidity, but are linked with increased risk of infections. Traditional immunosuppressant drugs are often used in combination with anti-tumour necrosis factor-alpha (TNF-α) inhibitors or anti-CD20 (rituximab). Method The review is based on a search in PubMed and on the authors' own experience of treating infections in patients who receive immunosuppressant treatment. Results Traditional immunomodulating treatment results in an increased risk of infection. The disease RA in itself increases the risk of infections. There is evidence of an increased incidence of infections with both extracellular bacteria and intracellular microorganisms such as mycobacteria, including Mycobacterium tuberculosis, and viruses in patients who are treated with TNF-α inhibitors. Patients who are about to start taking TNF-α inhibitors must therefore undergo a tuberculosis-risk assessment. Rituximab may increase the incidence of infection, but long-term observations are limited. Combination therapy involving different drugs that selectively modulate immune response is normally contraindicated because of the increased risk of infection. Interpretation The benefit of TNF-α inhibitors and rituximab treatment for RA must be weighed up against the increased risk of infections. Symptoms, findings and laboratory test results pertaining to serious infections may be influenced by immunomodulation therapy and thereby make clinical assessment difficult.

Objective. The hypothesis was that the levels of circulating inflammatory mediators are related to the degree of volume and pressure stress on the pulmonary vasculature in children with congenital systemic to pulmonary shunts. Design. Prospective, cross-sectional study. Setting. Tertiary center covering all pediatric heart surgery and interventions in Norway. Patients. Seventy-four children, aged 0–12 years, admitted for surgical or interventional treatment of congenital systemic to pulmonary shunts. Outcome Measures. Plasma levels of eight mediators of vascular inflammation and endothelial activation, sampled from different vascular compartments. Results. Patients with the most pronounced pulmonary flow and pressure stress demonstrated no elevation of inflammatory mediator levels when compared with healthy controls. No pulmonary production or uptake of the measured markers was found. Hemodynamic explanatory factors showed weak correlations to the inflammatory marker levels by univariate analysis. Age was the only factor that significantly explained inflammatory response in the multivariate model. The presence of Down syndrome, irrespective of hemodynamic category, was associated with elevated plasma levels of soluble tumor necrosis factor receptor I, when controlling for age. Conclusions. Inflammatory mediators show no significant relationship to pulmonary hemodynamics in children with systemic to pulmonary shunts. Children with Down syndrome may have an increased inflammatory response.

Background Neutrophil gelatinase-associated lipocalin (NGAL) is an antimicrobial peptide that could be involved in the pathogenesis of COPD. This study aimed to measure the plasma levels of NGAL in a large cohort of patients with COPD and control subjects and examine the levels of NGAL by COPD characteristics. Methods The study included 402 patients with COPD and 229 control subjects aged 40 to 76 years from the Bergen COPD Cohort Study. All patients with COPD had an FEV1/FVC ratio of Results Mean ± SD plasma concentrations of NGAL were 75.1 ± 31.8 ng/mL in patients with COPD and 56.5 ± 22.0 ng/mL in control subjects (P Conclusions Plasma levels of NGAL were significantly higher in patients with COPD compared with control subjects. NGAL was related to important COPD characteristics.

Objectives. Patients with inflammatory rheumatic diseases (IRDs) have a higher morbidity and mortality from accelerated atherosclerosis than the general population. We hypothesized that patients with the combination of IRD and coronary artery disease (CAD) would have a certain inflammatory phenotype compared with CAD patients without this comorbidity. Methods. Four groups of patients were included: patients with IRD, referred to coronary artery bypass grafting (CABG) (CAD–IRD, n = 67), patients without IRD, referred to CABG (CAD, n = 52), patients with IRD without CAD (IRD, n = 32) and healthy controls (n = 30). Plasma levels of several inflammatory markers were analysed by enzyme immunoassays. Results. (i) Plasma levels of markers of endothelial cell activation [i.e. vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor] and osteoprotegerin (OPG) were significantly increased and plasma levels of CCL21 significantly decreased in CAD–IRD patients as compared with CAD patients without IRD. (ii) Within the CAD–IRD group, acute coronary syndrome was a significant predictor of OPG, suggesting an enhanced inflammatory response during plaque destabilization in CAD–IRD patients. (iii) Plasma levels of VCAM-1, OPG and CCL21, but not lipid parameters, IRD characteristics and several other inflammatory markers (e.g. CRP), were significant predictors of CAD–IRD as opposed to CAD in two logistic regression models. Conclusion. Our findings further support a role for inflammation in the accelerated form of atherosclerosis in IRD patients, and suggest that certain inflammatory pathways, such as the enhanced endothelial cell activation and the RANK ligand/RANK/OPG system, may be of particular importance.

Aims Several studies suggest a pro-atherogenic role for the CC chemokine receptor 2 (CCR2), thought to reflect interaction with monocyte chemoattractant protein (MCP)-1. Based on its ability to attract leucocytes into inflamed tissue, we hypothesized a pro-atherogenic role for MCP-4, another CCR2 ligand. Methods and results Our main findings were: (i) patients with symptomatic carotid stenosis ( n = 29), but not those with asymptomatic plaques ( n = 31), had significantly raised plasma levels of MCP-4 compared with healthy controls ( n = 20); (ii) in vitro , releasate from activated platelets markedly increased the expression of MCP-4 and CCR2 in THP-1 monocytes, and enhanced the MCP-4-mediated effect on interleukin-8 secretion in these cells, involving the platelet-derived chemokine RANTES; (iii) while MCP-1 had no effect on the release of RANTES and interferon-inducible protein of 10 kDa in tumour necrosis factor α-pre-activated THP-1 monocytes, MCP-4 profoundly enhanced the release of these pro-atherogenic chemokines; and (iv) the data indicate an inflammatory interaction between RANTES and MCP-4, involving CCR2, and mRNA levels of these mediators were markedly up-regulated within symptomatic atherosclerotic carotid plaque ( n = 81). Conclusion Our findings suggest that the pro-atherogenic effects of CCR2 may not be restricted to interaction with MCP-1, but could also involve activation by MCP-4, being an inflammatory link between platelet and monocyte activation.

ObjectivesThiazolidinediones (TZDs) reduce insulin resistance, but also have pleiotropic properties including effects on inflammation. The balance between protective and proatherogenic effects may differ in various patient populations. We studied the effect of rosiglitazone on inflammatory markers in patients with metabolic syndrome (MetSyn).MethodsIn a cross-over randomized controlled trial, 23 subjects with MetSyn were assigned to treatment with rosiglitazone that was uptitrated from 4 mg/day for 6 weeks followed by 8 mg/day for 6 weeks or matching placebo for 12 weeks, and then to the opposite treatment for 12 weeks. Plasma levels of inflammatory and metabolic markers were measured during follow-up.ResultsOur main findings were i) compared to placebo, rosiglitazone significantly decreased the plasma levels of the naturally occurring interleukin (IL)1 inhibitor, IL1 receptor antagonist (IL1Ra; P=0.001), potentially reflecting inflammatory effects on the IL1 system; ii) parallel to this, rosiglitazone decreased plasma levels of IL10 (P=0.029) further suggesting inflammatory effects; iii) rosiglitazone decreased uric acid levels (P=0.001), and monocyte chemoattractant protein-1 (P=0.05) and C-reactive protein (P=0.06) tended to be lower after rosiglitazone than placebo, suggesting potential pro- and anti-inflammatory effects simultaneously and iv) in vitro, rosiglitazone enhanced IL1Ra and decreased IL1β in THP-1 monocytes, illustrating the complex effects of these medications, potentially exhibiting anti-inflammatory effects on the IL1 system in certain tissues or cells at least at certain concentrations.ConclusionOur findings suggest inflammatory effects on the IL1 system during rosiglitazone therapy in MetSyn. However, anti-inflammatory effects were also observed, and the net effect of TZDs in MetSyn should be further investigated.