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Background Serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) have been associated with anxiety and depression in cross-sectional and Mendelian randomisation studies, but results regarding the effect size and direction have been mixed. A recent Mendelian Randomisation (MR) study suggested that CRP may decrease and IL-6 may increase anxiety and depression symptoms. Methods Among 68 769 participants of the population-based Trøndelag Health Study (HUNT), we performed cross-sectional observational and one-sample MR analyses of serum CRP and two-sample MR analysis of serum IL-6. The main outcomes were symptoms of anxiety and depression assessed using the Hospital Anxiety and Depression Scale (HADS) and life satisfaction assessed using a seven-level ordinal questionnaire where higher scores indicate lower life satisfaction. Results In cross-sectional observational analyses, a doubling in serum CRP level was associated with 0.27% (95% CI −0.20 to 0.75) difference in HADS depression score (HADS-D), −0.77% (95% CI −1.24 to −0.29) difference in HADS anxiety score (HADS-A) and −0.10% (95% CI −0.41 to 0.21) difference in life satisfaction score. In one-sample MR analyses, a doubling in serum CRP was associated with 2.43% (95% CI −0.11 to 5.03) higher HADS-D, 1.94% (95% CI −0.58 to 4.52) higher HADS-A, and 2.00% (95% CI 0.45 to 3.59) higher life satisfaction score. For IL-6, causal point estimates were in the opposite direction, but imprecise and far from conventional criteria for statistical significance. Conclusions Our results do not support a major causal role of serum CRP on anxiety and depression symptoms and life satisfaction, but provides weak evidence that serum CRP may modestly increase anxiety and depression symptoms and reduce life satisfaction. Our findings do not support the recent suggestion that serum CRP may lower anxiety and depression symptoms.

ImportanceSepsis is one of the leading causes of morbidity and mortality. The majority of sepsis cases is attributed to bacterial infections, but virus infections can also induce sepsis. Conflicting results in incidence rates and case fatality trends of sepsis is reported, and how the COVID-19 pandemic influenced these trends are unknown.ObjectiveTo estimate temporal trends in incidence rate and case fatality during a 14-year period from 2008 through 2021, and to assess possible shifts in these trends during the COVID-19 pandemic.DesignA nationwide longitudinal registry study using ICD-10 discharge codes to identify sepsis.SettingAll Norwegian hospitals from 2008 through 2021.ParticipantsAll sepsis cases included 317.705 patients and of these, 222.832 had a first sepsis episode.Main outcomes and measuresAnnual age-standardized incidence rates with 95% confidence intervals (CI). Poisson regression was used to estimate changes in incidence rates across time, and logistic regression was used to estimate odds ratios for in-hospital death.ResultsAmong 12.619.803 adult hospitalizations, 317.705 (2.5%) patients met the sepsis criteria and 222.832 (70.0%) had a first sepsis episode. In the period 2009-2019, the annual incidence rate for a first sepsis episode was stable (incidence rate ratio per year, 0.999; 95% CI, 0.994-1.004), whereas for all sepsis the incidence rate increased by 15.5% during the period (annual incidence rate ratio, 1.013; 95% CI 1.007-1.019). During the COVID-19 pandemic, the incidence rate ratio for a first sepsis was 0.877 (95% CI, 0.829-0.927) in 2020 and 0.929 (95% CI, 0.870-0.992) in 2021, and for all sepsis it was 0.870 (95% CI, 0.810-0.935) in 2020 and 0.908 (95% CI, 0.840-0.980) in 2021, compared to the previous 11-year period. In-hospital deaths declined in the period 2009-2019 (odds ratio per year, 0.954 [95% CI,0.950-0.958]), whereas deaths increased during the COVID-19 pandemic in 2020 (odds ratios, 1.061 [95% CI 1.001-1.124] and in 2021 odds ratio (1.164 [95% CI, 1.098-1.233]).Conclusion and relevanceWe found a stable incidence rate of a first sepsis episode during the years 2009-2019. However, the increasing burden of all sepsis admissions indicates that sepsis awareness with updated guidelines and education must continue.Key PointsQuestionHas there been a change in incidence rate and case fatality of sepsis over the past decade, and how did the COVID-19 pandemic influence sepsis incidence rates and in-hospital mortality?FindingsIn this nationwide longitudinal registry study the incidence rate of all sepsis episodes increased and the incidence rate of a first sepsis episode was stable during the period 2009-2019, whereas in 2020 and 2021, the incidence rate of a first and all sepsis episodes was lower than in the preceding 11-year period. Case fatality risk declined from 2009 to 2019, but increased somewhat in 2020 and 2021, when 9.7% of first sepsis cases were identified as COVID-19 related sepsis.MeaningDespite a stable incidence rate of first-time sepsis admissions over time, the burden of sepsis is rising due to an increased rate of patients admitted multiple times with sepsis. The COVID-19 pandemic have had an impact on sepsis incidence rate and hospital mortality and needs further evaluation.

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)

IntroductionObservational studies have indicated an association between iron status and risk of sepsis and severe COVID-19. However, these findings may be affected by residual confounding, reverse causation.MethodsIn a two-sample Mendelian randomization study using inverse variance weighted method, we estimated the effect of genetically-predicted iron biomarkers (serum iron, transferrin saturation (TSAT), total iron binding capacity (TIBC) and ferritin) on risk of sepsis and risk of being hospitalized with COVID-19. For the COVID-19 outcomes we additionally conducted sex-stratified analyses. Weighted median, Weighted mode and MR Egger were used as sensitivity analyses.ResultsFor risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01 to 1.29, P=0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97–1.72, P=0.08), where sex stratified analyses showed OR 1.63 (CI 0.94–2.86, P=0.09) for women and OR 1.21 (CI 0.92–1.62, P=0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy.ConclusionsOur findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.

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.

Context Inflammation is proposed to influence tumor response in radiotherapy (RT). Clinical studies to investigate the relationship between inflammatory markers and RT response is warranted to understand the variable RT efficacy in patients with painful bone metastases. Objectives To evaluate the association between inflammatory markers and analgesic response to RT in patients with painful bone metastases. Methods Adult patients from 7 European study sites undergoing RT for painful bone metastases were included in this prospective and longitudinal analysis. The association between RT response and 17 inflammatory markers at baseline, as well as the association between RT response and the changes observed in inflammatory markers between baseline and three and eight weeks after RT, was analyzed with univariate regression analyses. Baseline analyses were adjusted for potential clinical predictors of RT response. Results None of the inflammatory markers were significantly associated with an upcoming RT response in the analysis of 448 patients with complete baseline data. In patients available for follow-up, the three-week change in TNF (P 0.017), IL-8 (P 0.028), IP-10 (P 0.032), eotaxin (P 0.043), G-CSF (P 0.033) and MCP-1 (P 0.002) were positively associated with RT response, while the three-week change in CRP (P 0.006) was negatively associated. Conclusion Results from this study show an association between RT response and change in pro-inflammatory mediators and indicate that inflammation may be important to achieve an analgesic RT response in patients with painful bone metastases. None of the investigated inflammatory markers were found to be pre-treatment predictors of RT response.

To characterise all bloodstream infections (BSIs) in a low antimicrobial resistance (AMR) prevalence setting with regard to the appropriateness of empirical antimicrobial therapy, compliance with the national clinical practice guideline, de-escalation practice and outcome. A retrospective observational study including patients aged ≥ 18 years admitted to a university hospital in central Norway with positive blood culture in 2019. We included 756 BSI episodes in our analysis. Empirical antimicrobial therapy was in accordance with the national guideline in 534 (70.6%), and not in accordance in 190 (25.1%) of the BSI episodes. There was a statistically significant association between compliance with the national guideline and concordant empirical antimicrobial therapy (p = .001). De-escalation of antimicrobial therapy was possible but not done in 217 (31.1%) of the BSI episodes. Variables identified as independent predictors of discordant empirical antimicrobial therapy included hospital department, type of empirical antimicrobial regimen, bacterial species, and AMR. Independent predictors of intra-hospital case fatality rate were coverage of empirical antimicrobial therapy, CCI-score, SAPS-II score, site of infection, and type of empirical antimicrobial regimen. Furthermore, the intra-hospital and long-term unadjusted all-cause case fatality rates were increased (p < .001, log-rank test for overall difference in survival) for the patients who received discordant empirical antimicrobial therapy. Our study shows that empirical antimicrobial therapy initiated in accordance with national guideline recommendations increases the likelihood of receiving concordant therapy. Discordant empirical antimicrobial therapy was associated with poorer outcomes, even in a setting with low AMR prevalence.

Background We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. Methods In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). Findings (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. Interpretation Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. Funding South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

Previous studies indicate sex differences in incidence and severity of bloodstream infections (BSI). We examined the effect of sex on risk of BSI, BSI mortality, and BSI caused by the most common infecting bacteria. Using causal mediation analyses, we assessed if this effect is mediated by health behaviours (smoking, alcohol consumption), education, cardiovascular risk factors (systolic blood pressure, non-HDL cholesterol, body mass index) and selected comorbidities (cardiovascular disease, chronic kidney disease, diabetes, cancer history and chronic lung disease). This prospective study included 64,040 participants (46.8% men) in the population-based HUNT2 Survey (1995−97) linked with hospital records in incident BSI. During median follow-up of 14.8 years, 1840 (2.9%) participants (51.3% men) experienced a BSI and 396 (0.6%) died (56.6% men). Men had 41% higher risk of first-time BSI (95% confidence interval (CI), 28−54%) than women. Together, health behaviours, education, cardiovascular risk factors and the selected comorbidities mediated 34% of the excess risk of BSI observed in men. The HR of BSI mortality was 1.87 (95%CI, 1.53−2.28), for BSI due to S. aureus 2.09 (1.28−2.54), S. pneumoniae 1.36 (1.05−1.76), and E. coli 0.97 (0.84−1.13) in men vs women. This population-based study shows that men have higher risk of BSI and BSI mortality than women. One-third of this effect was mediated by potential modifiable risk factors for incident BSI. Explaining sex differences in risk of bloodstream infections using mediation analysis in the population-based HUNT study in Norway

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.

Background Inflammatory aneurysms and mycotic aneurysms make up a minority of abdominal aortic aneurysms. Mainly autoimmune mechanisms are proposed in the pathogenesis of inflammatory aneurysms, and it is not routine to check for infectious agents as disease culprits. Case presentation A 58-year-old European male with complaints of abdominal and back pain for 8 weeks was admitted after a semi-urgent computed tomography scan revealed an 85 mm inflammatory abdominal aortic aneurysm. The patient had normal vital signs, slightly elevated inflammatory markers, and mild anemia on admission. Clinical examination revealed a tender pulsating mass in his abdomen. His clinical condition was interpreted as impending rupture and urgent repair of the aneurysm was deemed necessary. Due to the patient’s relatively young age and aneurysm neck morphology, open aortic repair was preferred. Preoperatively, the aneurysm appeared inflamed, with fibrous wall thickening and perianeurysmal adhesions. Aneurysm wall biopsies were sent to histopathological and microbiological diagnostics. Routine cultures were negative, but 16S rRNA gene real-time polymerase chain reaction was positive and Borrelia afzelii was identified by DNA sequencing of the polymerase chain reaction product. B. afzelii was also identified by sequencing the polymerase chain reaction product of a Borrelia-specific groEL target. Immunoglobulin G and M anti-Borrelia antibodies were present on serological analysis. Histopathological analysis displayed loss of normal aortic wall structure and diffuse infiltration of lymphocytes and plasma cells. The patient had an uneventful recovery and was discharged after 1 week to a regional rehabilitation facility. Though the patient fares clinically well and inflammatory markers had normalized, antimicrobial treatment with doxycycline continues at 3 months follow-up due to remaining radiologic signs of inflammation. Conclusions Borrelia infection in the setting of acute aortic pathology is a rare entity. To our knowledge, this is the first case report to demonstrate a mycotic abdominal aortic aneurysm as a rare manifestation of Lyme disease. Aortic wall biopsies and real-time polymerase chain reaction analysis of the specimen were essential for accurate diagnosis. This finding may contribute to the understanding of the etiology of inflammatory aneurysmal disease and abdominal aneurysms in general.

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.

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Purpose Severe bacterial infections are important causes of hospitalization and loss of health worldwide. In this study we aim to characterize the total burden, recurrence and severity of bacterial infections in the general population during a 22-year period. Methods We investigated hospitalizations due to bacterial infection from eight different foci in the prospective population-based Trøndelag Health Study (the HUNT Study), where all inhabitants aged ≥ 20 in a Norwegian county were invited to participate. Enrollment was between 1995 and 1997, and between 2006 and 2008, and follow-up ended in February 2017. All hospitalizations, positive blood cultures, emigrations and deaths in the follow-up period were captured through registry linkage. Results A total of 79,393 (69.5% and 54.1% of the invited population) people were included, of which 42,237 (53%) were women and mean age was 48.5 years. There were 37,298 hospitalizations due to infection, affecting 15,496 (22% of all included) individuals. The median time of follow-up was 20 years (25th percentile 9.5–75th percentile 20.8). Pneumonia and urinary tract infections were the two dominating foci with incidence rates of 639 and 550 per 100,000 per year, respectively, and with increasing incidence with age. The proportion of recurring admissions ranged from 10.0% (central nervous system) to 30.0% (pneumonia), whilst the proportion with a positive blood culture ranged from 4.7% (skin- and soft tissue infection) to 40.9% (central nervous system). The 30-day mortality varied between 3.2% (skin- and soft tissue infection) and 20.8% (endocarditis). Conclusions In this population-based cohort, we observed a great variation in the incidence, positive blood culture rate, recurrence and mortality between common infectious diseases. These results may help guide policy to reduce the infectious disease burden in the population.

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

Microbial invasion of the skin and underlying soft tissues, known as skin and soft tissue infections (SSTIs), contribute to considerable burden of disease worldwide (Kaye et al. 2019; Lozano et al. 2012). Knowledge about host factors contributing to SSTI risk is important to prevent the SSTIs. The genetics of SSTI susceptibility remain largely unknown, and the only previously published genome-wide study on SSTIs is a small family-based linkage study that did not identify significant linkage to any genes for erysipelas or cellulitis susceptibility (Hannula-Jouppi et al. 2013).

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.

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.

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.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.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.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.

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.

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.

During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development., Manipulation of Toll-like receptors (TLRs) affects HIV-1 infection and latency reversal. Here, the authors show that HIV-1 is endocytosed and recognized by TLR8 in human primary CD4+T cells and that TLR8 stimulation induces an inflammatory response that promotes HIV-1 replication and reversal of latency.

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 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 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 Carnitine plays an essential role in fatty acid metabolism, exerts substantial antioxidant action and regulates immune functions. We hypothesized that a disturbed carnitine metabolism could be involved in progression of HIV infection. MATERIALS AND METHODS Plasma levels of L-carnitine, its precursors, and short-, medium- and long-chain acylcarnitines were analysed with HPLC/mass spectrometry in HIV-infected patients with various disease severities including patients who acquired Mycobacterium avium complex (MAC) infection. In vitro, we examined the MAC-purified protein derivate (PPD)-induced release of TNF-α and IFN-γ in peripheral blood mononuclear cells (PBMCs) from patients with either high or low plasma levels of acylcarnitines. RESULTS Plasma levels of the short-chain (e.g. propionyl-carnitine) and medium-chain (e.g. octanoyl-carnitine) acylcarnitines were reduced in patients with advanced HIV infection. These acylcarnitines gradually decreased in rapid progressors, while minimal changes were observed in the nonprogressors. Plasma levels of propionyl-carnitine and octanoyl-carnitine significantly increased during antiretroviral therapy (ART). However, ART did not restore levels to those observed in healthy controls. Depletion of propionyl-carnitine and octanoyl-carnitine was observed prior to MAC infection, and the release of TNF-α and IFN-γ from PBMC was decreased after stimulation with MAC-PPD in samples from HIV-infected patients with low levels of propionyl-carnitine or octanoyl-carnitine. CONCLUSIONS Our findings suggest an association between disturbed acylcarnitine metabolism, immune dysregulation and disease progression in HIV-infected patients. Low levels of propionyl-carnitine and octanoyl-carnitine were associated with increased susceptibility to MAC infection in HIV patients with advanced disease.

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.

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.

Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk. In this study, we sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. rHDL bound to CC and inhibited the CC-induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. rHDL attenuated the amount of CC-induced complement receptor 3 (CD11b/CD18) expression on monocytes and granulocytes, as well as reactive oxygen species generation. Moreover, addition of CC to whole blood resulted in release of proinflammatory cytokines that were inhibited by rHDL. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC-induced inflammatory responses by inhibiting complement deposition on the crystals.

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 The post cardiac arrest syndrome (PCAS) is responsible for the majority of in-hospital deaths following cardiac arrest (CA). The major elements of PCAS are anoxic brain injury and circulatory failure. OBJECTIVE This study aimed to investigate the clinical characteristics of circulatory failure and inflammatory responses after out-of-hospital cardiac arrest (OHCA) and to identify patterns of circulatory and inflammatory responses, which may predict circulatory deterioration in PCAS. METHODS This study is a single-center cohort study of 50 patients who receive intensive care after OHCA. The patients are followed for 5 days where detailed information from circulatory variables, including measurements by pulmonary artery catheters (PACs), is obtained in high resolution. Blood samples for inflammatory and endothelial biomarkers are taken at inclusion and thereafter daily. Every 10 min, the patients will be assessed and categorized in one of three circulatory categories. These categories are based on mean arterial pressure; heart rate; serum lactate concentrations; superior vena cava oxygen saturation; and need for fluid, vasoactive medications, and other interventions. We will analyze predictors of circulatory failure and their relation to inflammatory biomarkers. RESULTS Patient inclusion started in January 2016. CONCLUSIONS This study will obtain advanced hemodynamic data with high resolution during the acute phase of PCAS and will analyze the details in circulatory state transitions related to circulatory failure. We aim to identify early predictors of circulatory deterioration and favorable outcome after CA. CLINICALTRIAL ClinicalTrials.gov: NCT02648061; https://clinicaltrials.gov/ct2/show/NCT02648061 (Archived by WebCite at http://www.webcitation.org/6wVASuOla)

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.

Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown that BCD has an anti-inflammatory effect on CC via suppression of the inflammasome and liver X receptor activation. The putative effects of BCD on CC-induced complement activation remain unknown. In this study, we found that BCD bound to CC and reduced deposition of Igs, pattern recognition molecules, and complement factors on CC in human plasma. Furthermore, BCD decreased complement activation as measured by terminal complement complex and lowered the expression of complement receptors on monocytes in whole blood in response to CC exposure. In line with this, BCD also reduced reactive oxygen species formation caused by CC in whole blood. Furthermore, BCD attenuated the CC-induced proinflammatory cytokine responses (e.g., IL-1α, MIP-1α, TNF, IL-6, and IL-8) as well as regulated a range of CC-induced genes in human PBMC. BCD also regulated complement-related genes in human carotid plaques treated ex vivo. Formation of terminal complement complex on other complement-activating structures such as monosodium urate crystals and zymosan was not affected by BCD. These data demonstrate that BCD inhibits CC-induced inflammatory responses, which may be explained by BCD-mediated attenuation of complement activation. Thus, these findings support the potential for using BCD in treatment of atherosclerosis. This is a submitted manuscript of an article published by American Association of Immunologists in Journal of Immunology, October 15, 2017

Inflammation is associated with development of atherosclerosis, and cholesterol crystals (CC) have long been recognized as a hallmark of atherosclerotic lesions. CC appear early in the atheroma development and trigger inflammation by NLRP3 inflammasome activation. In this study we hypothesized whether CC employ the complement system to activate inflammasome/caspase-1, leading to release of mature IL-1β, and whether complement activation regulates CC-induced cytokine production. In this study we describe that CC activated both the classical and alternative complement pathways, and C1q was found to be crucial for the activation. CC employed C5a in the release of a number of cytokines in whole blood, including IL-1β and TNF. CC induced minimal amounts of cytokines in C5-deficient whole blood, until reconstituted with C5. Furthermore, C5a and TNF in combination acted as a potent primer for CC-induced IL-1β release by increasing IL-1β transcripts. CC-induced complement activation resulted in upregulation of complement receptor 3 (CD11b/CD18), leading to phagocytosis of CC. Also, CC mounted a complement-dependent production of reactive oxygen species and active caspase-1. We conclude that CC employ the complement system to induce cytokines and activate the inflammasome/caspase-1 by regulating several cellular responses in human monocytes. In light of this, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis.

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.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.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.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.

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.