Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI.

BACKGROUND: Tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size. METHODS: This is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1-2, 3-7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months. RESULTS: Tocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly. CONCLUSION: This study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines.

In-hospital mortality, readmission, and prolonged length of stay risk prediction leveraging historical electronic patient records.

Objective: This study aimed to investigate the predictive capabilities of historical patient records to predict patient adverse outcomes such as mortality, readmission, and prolonged length of stay (PLOS). Methods: Leveraging a de-identified dataset from a tertiary care university hospital, we developed an eXplainable Artificial Intelligence (XAI) framework combining tree-based and traditional machine learning (ML) models with interpretations and statistical analysis of predictors of mortality, readmission, and PLOS. Results: Our framework demonstrated exceptional predictive performance with a notable area under the receiver operating characteristic (AUROC) of 0.9625 and an area under the precision-recall curve (AUPRC) of 0.8575 for 30-day mortality at discharge and an AUROC of 0.9545 and AUPRC of 0.8419 at admission. For the readmission and PLOS risk, the highest AUROC achieved were 0.8198 and 0.9797, respectively. The tree-based models consistently outperformed the traditional ML models in all 4 prediction tasks. The key predictors were age, derived temporal features, routine laboratory tests, and diagnostic and procedural codes. Conclusion: The study underscores the potential of leveraging medical history for enhanced hospital predictive analytics. We present an accurate and intuitive framework for early warning models that can be easily implemented in the current and developing digital health platforms to predict adverse outcomes accurately.

Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated With Infarct Size.

Background: Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect. Objectives: The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI. Methods: In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI). Results: All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P = 0.001 [dsDNA] and 0.02, P = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (10.9 [95% CI: 4.0-15.0] [dsDNA] and 8.9 [95% CI: 2.0-15.9] [H3Cit], both P = 0.01). Conclusions: NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]; NCT03004703).

Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1ß Release.

Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1ß, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

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.

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.

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.

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.

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.