Chronic kidney disease and risk of bloodstream infections and sepsis: a 17-year follow-up of the population-based Trøndelag Health Study in Norway.

PURPOSE: Bloodstream infections (BSI) and sepsis are important causes of hospitalization, loss of health, and death globally. Targetable risk factors need to be identified to improve prevention and treatment. In this study, we aimed to evaluate the association of chronic kidney disease (CKD) and risk of and mortality from BSI and sepsis in the general population during a 22-year period. METHODS: We conducted a prospective cohort study among participants in the population-based Norwegian HUNT Study, where 68,438 participated. The median follow-up time was 17.4 years. The exposures were estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in urine. The outcomes were hazard ratios (HR) of hospital admission or death due to BSI or sepsis. The associations were adjusted for age, sex, diabetes, obesity, systolic blood pressure, smoking status, and cardiovascular disease. RESULTS: Participants with eGFR < 30 ml/min/1.732 had HR 3.35 for BSI (95% confidence intervals (CI) 2.12-5.3) and HR 2.94 for sepsis (95% CI 1.82-4.8) compared to normal eGFR (≥ 90 ml/min/1.732). HRs of death from BSI and sepsis were 4.2 (95% CI 1.71-10.4) and 4.1 (95% CI 1.88-8.9), respectively. Participants with severely increased albuminuria (ACR > 30 mg/mmol) had HR 3.60 for BSI (95% CI 2.30-5.6) and 3.14 for sepsis (95% CI 1.94-5.1) compared to normal albumin excretion (ACR < 3 mg/mmol). HRs of death were 2.67 (95% CI 0.82-8.7) and 2.16 (95% CI 0.78-6.0), respectively. CONCLUSION: In this large population-based cohort study, CKD was clearly associated with an increased risk of BSI and sepsis and related death.

Incidence of invasive infections with Group B streptococcus in adults in Norway 1996-2019: a nationwide registry-based case-control study.

PURPOSE: Group B streptococcus (GBS) colonizes the gastrointestinal and vaginal mucosa in healthy adults, but has also become an increasing cause of invasive infection. The aims of this study were to describe the incidence and factors associated with the occurrence of invasive GBS disease in adults in Norway. METHODS: We performed a nationwide retrospective case-control study of invasive GBS infections during 1996-2019, with two control groups; invasive Group A streptococcal disease (GAS) to control for changes in surveillance and diagnostics, and a second representing the general population. RESULTS: A total of 3710 GBS episodes were identified. The age-standardized incidence rate increased steadily from 1.10 (95% CI 0.80-1.50) in 1996 to 6.70 (95% CI 5.90-7.50) per 100,000 person-years in 2019. The incidence rate had an average annual increase of 6.44% (95% CI 5.12-7.78). Incidence rates of GAS varied considerably, and there was no evidence of a consistent change over the study period. GBS incidence was highest among adults > 60 years of age. Cardiovascular disease, cancer, and diabetes were the most common comorbid conditions. There was a shift in the distribution of capsular serotypes from three dominant types to more equal distribution among the six most common serotypes. CONCLUSIONS: The incidence of invasive GBS disease in adults increased significantly from 1996 to 2019. The increasing age of the population with accompanying underlying comorbid conditions might contribute to the increasing burden of invasive GBS disease. Interestingly, type 1 diabetes was also associated with the occurrence of invasive GBS disease.

Coding practice for sepsis 2008-21. / Kodepraksis ved sepsis 2008­21.

Background: Sepsis has a high incidence and mortality rate. Accurate data are needed for health service planning and for research, and there is a need to identify coding practices in Norway. Material and method: All patients over 17 years of age who had been admitted to Norwegian hospitals with sepsis in the period 2008-21 were identified using diagnostic codes for infection plus organ failure, and specific codes for sepsis, from the Norwegian Patient Registry. Results: There were 317 705 admissions with diagnostic codes for sepsis, of which 210 391 (66.2 %) were sepsis with a known focus, 77 627 (24.4 %) were of unknown focus and 29 687 (9.3 %) were codes for both a known and unknown focus. The percentage of sepsis episodes coded with a known focus varied between the health regions. The highest percentage was in the Western Norway Regional Health Authority (72.1 %, 95 % confidence interval (CI): 71.8 to 72.5), and the lowest was in the Central Norway Regional Health Authority (59.2 %, 95 %, CI 58.7 to 59.7). The use of codes with a known focus increased each year on average by 3.2 % (95 % CI 2.7 to 3.6, from 47.5 % in 2008 to 82.3 % in 2021), while the use of codes with an unknown focus decreased by 2.3 % (95 % CI -2.7 to -1.9) from 37.8 % in 2008 to 13.0 % in 2021. Known and unknown focus combined also decreased by 0.9 % per year on average (95 % CI -1.0 to -0.8) from 14.3 % in 2008 to 4.1 % in 2021. Interpretation: The coding of sepsis in Norwegian hospitals has become more uniform.

Predicting In-Hospital Death from Derived EHR Trajectory Features.

Medical histories of patients can predict a patient's immediate future. While most studies propose to predict survival from vital signs and hospital tests within one episode of care, we carried out selective feature engineering from longitudinal medical records in this study to develop a dataset with derived features. We thereafter trained multiple machine learning models for the binary prediction of whether an episode of care will culminate in death among patients suspected of bloodstream infections. The machine learning classifier performance is evaluated and compared and the feature importance impacting the model output is explored. The extreme gradient boosting model achieved the best performance for predicting death in the next hospital episode with an accuracy of 92%. Age at the time of the first visit, length of history, and information related to recent episodes were the most critical features.

Return to work after hospitalization for sepsis: a nationwide, registry-based cohort study.

BACKGROUND: Sepsis survivors commonly experience functional impairment, which may limit return to work. We investigated return to work (RTW) of patients hospitalized with sepsis and the associations with patient and clinical characteristics. METHODS: Working-age patients (18-60 years) admitted to a Norwegian hospital with sepsis between 2010 and 2021 were identified using the Norwegian Patient Registry and linked to sick-leave data from the Norwegian National Social Security System Registry. The main outcome was proportion of RTW in patients hospitalized with sepsis at 6 months, 1 year, and 2 years after discharge. Secondary outcomes were time trends in age-standardized proportions of RTW and probability of sustainable RTW (31 days of consecutive work). The time trends were calculated for each admission year, reported as percentage change with 95% confidence interval (CI). Time-to-event analysis, including crude and adjusted hazard risk (HRs), was used to explore the association between sustainable RTW, characteristics and subgroups of sepsis patients (intensive care unit (ICU) vs. non-ICU and COVID-19 vs. non-COVID-19). RESULTS: Among 35.839 hospitalizations for sepsis among patients aged 18-60 years, 12.260 (34.2%) were working prior to hospitalization and included in this study. The mean age was 43.7 years. At 6 months, 1 year, and 2 years post-discharge, overall estimates showed that 58.6%, 67.5%, and 63.4%, respectively, were working. The time trends in age-standardized RTW for ICU and non-ICU sepsis patients remained stable over the study period, except the 2-year age-standardized RTW for non-ICU patients that declined by 1.51% (95% CI - 2.22 to - 0.79) per year, from 70.01% (95% CI 67.21 to 74.80) in 2010 to 57.04% (95% CI 53.81-60.28) in 2019. Characteristics associated with sustainable RTW were younger age, fewer comorbidities, and fewer acute organ dysfunctions. The probability of sustainable RTW was lower in ICU patients compared to non-ICU patients (HR 0.56; 95% CI 0.52-0.61) and higher in patients with COVID-19-related sepsis than in sepsis patients (HR 1.31; 95% CI 1.15-1.49). CONCLUSION: Absence of improvement in RTW proportions over time and the low probability of sustainable RTW in sepsis patients need attention, and further research to enhance outcomes for sepsis patients is required.

Long-term temporal trends in incidence rate and case fatality of sepsis and COVID-19-related sepsis in Norwegian hospitals, 2008-2021: a nationwide registry study.

OBJECTIVES: To estimate temporal trends in incidence rate (IR) and case fatality during a 14-year period from 2008 to 2021, and to assess possible shifts in these trends during the COVID-19 pandemic. SETTING: All Norwegian hospitals 2008-2021. PARTICIPANTS: 317 705 patients ≥18 year with a sepsis International Classification of Diseases 10th revision code retrieved from The Norwegian Patient Registry. PRIMARY AND SECONDARY MEASURES: Annual age-standardised IRs with 95% CIs. Poisson regression was used to estimate changes in IRs across time, and logistic regression was used to estimate ORs for in-hospital death. RESULTS: Among 12 619 803 adult hospitalisations, a total of 317 705 (2.5%) hospitalisations in 222 832 (70.0%) unique patients met the sepsis criteria. The overall age-standardised IR of a first sepsis admission was 246/100 000 (95% CI 245 to 247), whereas the age-standardised IR of all sepsis admissions was 352/100 000 (95% CI 351 to 354). In the period 2009-2019, the annual IR for a first sepsis episode was stable (IR ratio (IRR) per year, 0.999; 95% CI 0.994 to 1.004), whereas for recurrent sepsis the IR increased (annual IRR, 1.048; 95% CI 1.037 to 1.059). During the COVID-19 pandemic, the IRR for a first sepsis was 0.877 (95% CI 0.829 to 0.927) in 2020 and 0.929 (95% CI 0.870 to 0.992) in 2021, and for all sepsis it was 0.870 (95% CI 0.810 to 0.935) in 2020 and 0.908 (95% CI 0.840 to 0.980) in 2021, compared with the previous 11-year period. Case fatality among first sepsis admissions declined in the period 2009-2019 (annual OR 0.954 (95% CI 0.950 to 0.958)), whereas case fatality increased during the COVID-19 pandemic in 2020 (OR 1.061 (95% CI 1.001 to 1.124) and in 2021 (OR 1.164 (95% CI 1.098 to 1.233)). CONCLUSION: The overall IR of sepsis increased from 2009 to 2019, due to an increasing IR of recurrent sepsis, and indicates that sepsis awareness with updated guidelines and education must continue.

Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab.

BACKGROUND: Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. METHODS: STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. RESULTS: Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively). CONCLUSIONS: Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients. TRIAL REGISTRATION NUMBER: NCT03004703.

Trends in mortality after a sepsis hospitalization: a nationwide prospective registry study from 2008 to 2021.

BACKGROUND: Few studies have reported on mortality beyond one year after sepsis. We aim to describe trends in short- and long-term mortality among patients admitted with sepsis, and to describe the association between clinical characteristics and mortality for improved monitoring, treatment and prognosis. METHODS: Patients ≥ 18 years admitted to all Norwegian hospitals (2008-2021) with a first sepsis episode were identified using Norwegian Patient Registry and International Classification of Diseases 10th Revision codes. Sepsis was classified as implicit (known infection site plus organ dysfunction), explicit (unknown infection site), or COVID-19-related sepsis. The outcome was all-cause mortality. We describe age-standardized 30-day, 90-day, 1-, 5- and 10-year mortality for each admission year and estimated the annual percentage change with 95% confidence interval (CI). The association between clinical characteristics and all-cause mortality is reported as hazard ratios (HRs) adjusted for age, sex and calendar year in Cox regression. RESULTS: The study included 222,832 patients, of whom 127,059 (57.1%) had implicit, 92,928 (41.7%) had explicit, and 2,845 (1.3%) had COVID-19-related sepsis (data from 2020 and 2021). Trends in overall age-standardized 30-day, 90-day, 1- and 5-year mortality decreased by 0.29 (95% CI - 0.39 to - 0.19), 0.43 (95% CI - 0.56 to - 0.29), 0.61 (95% CI - 0.73 to - 0.49) and 0.66 (95% CI - 0.84 to - 0.48) percent per year, respectively. The decrease was observed for all infections sites but was largest among patients with respiratory tract infections. Implicit, explicit and COVID-19-related sepsis had largely similar overall mortality, with explicit sepsis having an adjusted HR of 0.980 (95% CI 0.969 to 0.991) and COVID-19-related sepsis an adjusted HR of 0.916 (95% CI 0.836 to 1.003) compared to implicit sepsis. Patients with respiratory tract infections have somewhat higher mortality than those with other infection sites. Number of comorbidities was positively associated with mortality, but mortality varied considerably between different comorbidities. Similarly, number of acute organ dysfunctions was strongly associated with mortality, whereas the risk varied for each type of organ dysfunction. CONCLUSION: Overall mortality has declined over the past 14 years among patients with a first sepsis admission. Comorbidity, site of infection, and acute organ dysfunction are patient characteristics that are associated with mortality. This could inform health care workers and raise the awareness toward subgroups of patients that needs particular attention to improve long-term mortality.

Role of fungal burden in risk stratification of HIV-negative patients with Pneumocystis pneumonia: A 12-year, retrospective, observational, multicenter cohort.

OBJECTIVES: This study aimed to explore the role of fungal burden in risk stratification of patients without HIV-negative patients with Pneumocystis pneumonia (PCP). METHODS: This was a retrospective analysis of the characteristics associated with 30-day mortality in patients who were positive for P. jirovecii using polymerase chain reaction in bronchoalveolar lavage fluid between 2006 and 2017 in a multicenter cohort from Central Norway. The fungal burden was indicated by the cycle threshold (CT) values from semiquantitative real-time polymerase chain reaction targeting the ß-tubulin gene. RESULTS: We included 170 patients with proven or probable PCP. The all-cause 30-day mortality was 18.2%. After adjusting for host characteristics and premorbid corticosteroid use, a higher fungal burden was associated with a higher risk of dying: adjusted odds ratio 1.42 (95% confidence interval 0.48-4.25) for a CT value 31-36, increasing to odds ratio 5.43 (95% confidence interval 1.48-19.9) for a CT value ≤30 compared with patients with a CT value ≥37. The Charlson comorbidity index (CCI) improved the risk stratification: patients with a CT value ≥37 and CCI ≤2 had a 9% mortality risk compared with 70% among those with a CT value ≤30 and CCI ≥6. Comorbid cardiovascular disease, solid tumors, immunological disorders, premorbid corticosteroids, hypoxemia, abnormal leukocyte counts, low serum albumin, and C-reactive protein ≥100 were also independently associated with 30-day mortality. The sensitivity analyses did not suggest selection bias. CONCLUSION: Fungal burden may improve the risk stratification of patients without HIV-negative patients with PCP.

The causal role of C-reactive protein and interleukin-6 on anxiety and depression symptoms and life satisfaction: Mendelian randomisation analyses in the HUNT study.

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.

Direct and indirect effects of socioeconomic status on sepsis risk and mortality: a mediation analysis of the HUNT Study.

BACKGROUND: Socioeconomic status (SES) may influence risk of sepsis and sepsis-related mortality, but to what extent lifestyle and health-related factors mediate this effect is not known. METHODS: The study included 65 227 participants of the population-based HUNT Study in Norway linked with hospital records to identify incident sepsis and sepsis-related deaths. Cox regression estimated HRs of sepsis risk and mortality associated with different indicators of SES, whereas mediation analyses were based on an inverse odds weighting approach. RESULTS: During ~23 years of follow-up (1.3 million person-years), 4200 sepsis cases and 1277 sepsis-related deaths occurred. Overall, participants with low SES had a consistently increased sepsis risk and sepsis-related mortality using education, occupational class and financial difficulties as indicators of SES. Smoking and alcohol consumption explained 57% of the sepsis risk related to low education, whereas adding risk factors of cardiovascular disease and chronic diseases to the model increased the explained proportion to 78% and 82%, respectively. CONCLUSION: This study shows that SES is inversely associated with sepsis risk and mortality. Approximately 80% of the effect of education on sepsis risk was explained by modifiable lifestyle and health-related factors that could be targets for prevention.

The Effects of Shift Work on the Immune System: A Narrative Review.

Working a shift work schedule has been hypothesized to have negative effects on health. One such described consequence is altered immune response and increased risk of infections. Former reviews have concluded that more knowledge is needed to determine how shift work affects the immune system. Since the last review focusing on this subject was published in 2016, new insight has emerged. We performed a search of the topic in PubMed, Scopus and Embase, identifying papers published after 2016, finding a total of 13 new studies. The articles identified showed inconsistent effect on immune cells, cytokines, circadian rhythms, self-reported infections, and vaccine response as a result of working a shift schedule. Current evidence suggests working shifts influence the immune system, however the clinical relevance and the mechanism behind this potential association remains elusive. Further studies need to include longitudinal design and objective measures of shift work and immune response.

Antimicrobial therapy of community-acquired pneumonia during stewardship efforts and a coronavirus pandemic: an observational study.

BACKGROUND: Community-acquired pneumonia (CAP) is the most frequent infection diagnosis in hospitals. Antimicrobial therapy for CAP is depicted in clinical practice guidelines, but adherence data and effect of antibiotic stewardship measures are lacking. METHODS: A dedicated antibiotic team pointed out CAP as a potential target for antimicrobial stewardship (AMS) measures at a 1.000-bed, tertiary care, teaching university hospital in Norway from March until May for the years 2016 throughout 2021. The aim of the AMS program was to increase diagnostic and antimicrobial therapy adherence to national clinical practice guideline recommendations through multiple and continuous AMS efforts. Descriptive statistics were retrospectively used to delineate antimicrobial therapy for CAP. The primary outcomes were proportions that received narrow-spectrum beta-lactams, and broad-spectrum antimicrobial therapy. RESULTS: 1.112 CAP episodes were identified. The annual proportion that received narrow-spectrum beta-lactams increased from 56.1 to 74.4% (p = 0.045). Correspondingly, the annual proportion that received broad-spectrum antimicrobial therapy decreased from 34.1 to 17.1% (p = 0.002). Trends were affected by the coronavirus pandemic. Mortality and 30-day readmission rates remained unchanged. De-escalation strategies were frequently unutilized, and overall therapy duration exceeded clinical practice guideline recommendations substantially. Microbiologically confirmed CAP episodes increased from 33.7 to 56.2% during the study period. CONCLUSION: CAP is a suitable model condition that is sensitive to AMS measures. A continuous focus on improved microbiological diagnostics and antimicrobial therapy initiation is efficient in increasing adherence to guideline recommendations. There is an unmet need for better antimicrobial de-escalation strategies.

Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study.

Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For 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] 1.01-1.29, 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), whereas 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. Our 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.

Empirical antimicrobial therapy for bloodstream infections not compliant with guideline was associated with discordant therapy, which predicted poorer outcome even in a low resistance environment.

OBJECTIVES: 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. METHODS: A retrospective observational study including patients aged ≥ 18 years admitted to a university hospital in central Norway with positive blood culture in 2019. RESULTS: 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. CONCLUSION: 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.

Inflammatory Markers and Radiotherapy Response in Patients With Painful Bone Metastases.

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.

Incidence, recurring admissions and mortality of severe bacterial infections and sepsis over a 22-year period in the population-based HUNT study.

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.

High levels of discordant antimicrobial therapy in hospital-acquired bloodstream infections is associated with increased mortality in an intensive care, low antimicrobial resistance setting.

BACKGROUND: Bloodstream infections (BSI) occur frequently and are associated with severe outcomes. In this study we aimed to investigate proportions of patients that received discordant empirical antimicrobial therapy and its association to mortality. METHODS: A retrospective cohort study model was undertaken to outline BSI in an intensive care, single centre, and low antimicrobial resistance prevalence setting. We used descriptive statistics to delineate proportions of patients that received discordant empirical antimicrobial therapy, and a correlation model and a logistic regression model to calculate the association with mortality and predictors of receiving discordant therapy, respectively. RESULTS: From 2014 to 2018 we included 270 BSI episodes, of which one third were hospital-acquired. Gram negative, Gram positive, and anaerobic pathogens were detected in 49.0%, 45.3% and 5.7% respectively. The proportion of isolates that conferred extended-spectrum beta-lactamase (ESBL) properties were 5.9% among enterobactereales, and no methicillin-resistant Staphylococcus aureus isolates were detected. Empirical antimicrobial therapy for community-acquired (CA) and hospital-acquired (HA) BSI were discordant at day 0 in 6.5% and 24.4%, respectively (p<.001). Discordant therapy was significantly associated with mortality at day 28 (p=.041). HA-onset BSI, enterococcal BSI and BSI of intraabdominal origin were statistically significant predictors of receiving discordant therapy. CONCLUSION: A significant proportion of HA-BSI did not receive effective antimicrobial therapy and this was significantly associated with mortality. The results underscore the need for more accurate diagnostic tools, improved communication between the microbiological laboratory and the clinicians, and antimicrobial stewardship measures.

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

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).