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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. [ABSTRACT FROM AUTHOR]

The correction is presented to the article "Trends in mortality after a sepsis hospitalization: a nationwide prospective registry study from 2008 to 2021," published in the Infection journal (2023), including subgroups and comorbidities.

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. [ABSTRACT FROM AUTHOR]

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. This prospective study included 64,040 participants (46.8% men) in the population-based HUNT2 Survey (1995–1997) linked with hospital records in incident BSI. During median follow-up of 15.2 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 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), E. coli 0.97 (0.84–1.13) in men vs women. This 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: As iron is essential for both immune function and microbial growth, alterations in iron status could influence the risk of infections. We assessed the associations of iron status with risk of bloodstream infections (BSIs) and BSI mortality.Methods: We measured serum iron, transferrin saturation (Tsat) and total iron-binding capacity (TIBC) in 61,852 participants in the population-based HUNT2 study (1995-97). Incident BSIs (1995-2011) were identified through linkage with the Mid-Norway Sepsis Register, which includes prospectively registered information on BSI from local and regional hospitals. We assessed the risk of a first-time BSI and BSI mortality with the iron indices using Cox proportional hazards regression analysis.Results: During a median follow-up of 14.8 years, 1738 individuals experienced at least one episode of BSI, and 370 died within 30 days after a BSI. In age- and sex-adjusted analyses, BSI risk was increased among participants with indices of iron deficiency, serum iron ≤ 2.5th percentile (HR 1.72, 95% CI 1.34-2.21), Tsat ≤ 2.5th percentile (HR 1.48, 95% CI 1.12-1.96) or TIBC ≥ 97.5th percentile (HR 1.46, 95% CI 1.06-2.01). The associations remained similar after adjusting for comorbidities and exclusion of BSI related to cancer, rheumatic illnesses and inflammatory bowel disease. BSI mortality showed similar associations.Conclusion: Indices of severe iron deficiency are associated with an increased risk of a future BSI. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD).METHODS:Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes.RESULTS:Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A–follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-β1, promoted matrix metalloproteinase activity, induced mitochondrial β-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs.CONCLUSIONS:Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation. [ABSTRACT FROM AUTHOR]

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFα in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF. [ABSTRACT FROM AUTHOR]