Sepsis is a frequently fatal condition characterized by an uncontrolled and harmful host reaction to microbial infection. Despite the prevalence and severity of sepsis, we lack a fundamental grasp of its pathophysiology. Here we report that the cytokine interleukin (IL)-3 potentiates inflammation in sepsis. Using a mouse model of abdominal sepsis, we show that innate response activator (IRA) B cells produce IL-3, which induces myelopoiesis of Ly-6Chigh monocytes and neutrophils, and fuels a cytokine storm. IL-3 deficiency protects mice against sepsis. In humans with sepsis, high plasma IL-3 levels associate with high mortality even after adjusting for prognostic indicators. Altogether, this study deepens our understanding of immune activation, identifies IL-3 as an orchestrator of emergency myelopoiesis, and reveals a new therapeutic target for treating sepsis.

BackgroundAntidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain.MethodsSystematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis.ResultsOut of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects.ConclusionOur synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

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Objective: To assess polypharmacy and related medication aspects in Middle-European rheumatoid arthritis (RA) patients, and to discuss the results in view of a systematic literature review.Methods: In this retrospective cohort study, charts were reviewed from RA-patients consecutively recruited between September 27, 2017 and April 29, 2019. Drugs were assigned to the Anatomical Therapeutic Chemical (ATC) groups as proposed by the World Health Organization (WHO). Results were compared to those of a systematic literature review.Results: One hundred seventy-five consecutive RA-patients were included. The mean number of drugs was 6.6 ± 3.5, with 2.4 ± 1.2 drugs taken specifically for RA—compared to 2.6 in the literature. 33.7% of patients experienced polypharmacy defined by ≥5 drugs, compared to 61.6% in the literature–with women affected more frequently than men. After 7 years of follow-up, the number of drugs increased in all ATC-groups by an average of 12.7 %, correlating with age (Corrcoeff = 0.46) and comorbidities (Corrcoeff = 0.599). In the literature, polypharmacy is not always defined precisely, and has not been considered in management guidelines so far.Conclusion: Polypharmacy is a frequent issue in RA-management. With an increasing number of comorbidities during the course of the disease, polypharmacy becomes even more relevant.

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