Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.

Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysaccharide‐ (LPS‐) treated mice in which ADAM8 expression was markedly upregulated compared to control mice. In vitro, stimulation with LPS enhanced ADAM8 expression in murine and human endothelial and hepatoma cell lines as well as in primary murine hepatocytes. The enhanced ADAM8 expression was associated with an upregulation of TNF‐α and IL‐6 expression and release. Inhibition studies indicate that the cytokine response of hepatoma cells to LPS depends on the activity of ADAM8 and that signalling by TNF‐α can contribute to these ADAM8‐dependent effects. The role of ADAM8 was further confirmed with primary hepatocytes from ADAM8 knockout mice in which TNF‐α and IL‐6 induction and release were considerably attenuated. As a model of chronic liver injury, we studied liver tissue from mice undergoing high‐fat diet‐induced steatohepatitis and again observed upregulation of ADAM8 mRNA expression compared to healthy controls. In vitro, ADAM8 expression was upregulated in hepatoma, endothelial, and stellate cell lines by various mediators of steatohepatitis including fatty acid (linoleic‐oleic acid), IL‐1β, TNF‐α, IFN‐γ, and TGF‐β. Upregulation of ADAM8 was associated with the induction and release of proinflammatory cytokines (TNF‐α and IL‐6) and chemokines (CX3CL1). Finally, knockdown of ADAM8 expression in all tested cell types attenuated the release of these mediators. Thus, ADAM8 is upregulated in acute and chronic liver inflammation and is able to promote inflammation by enhancing expression and release of inflammatory mediators.

Background: The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug–drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate properties of drugs for certain polymorphic CYP2 enzymes. Methods: A standardized manual method and an automatic method were developed and compared to assess the substrate properties for the metabolism of drugs by CYP2D6, 2C9, and 2C19. The automatic method used a matching approach to three freely available resources. We applied the manual and automatic methods to a large real-world dataset deriving from a prospective multicenter study collecting adverse drug reactions in emergency departments in Germany (ADRED). Results: In total, 23,878 medication entries relating to 895 different drugs were analyzed in the real-world dataset. The manual method was able to assess 12.2% (n = 109) of drugs, and the automatic method between 12.1% (n = 109) and 88.9% (n = 796), depending on the resource used. The CYP substrate classifications demonstrated moderate to almost perfect agreements for CYP2D6 and CYP2C19 (Cohen’s Kappa (κ) 0.48–0.90) and fair to moderate agreements for CYP2C9 (κ 0.20–0.48). Conclusion: A closer look at different classifications between methods revealed that both methods are prone to error in different ways. While the automated method excels in time efficiency, completeness, and actuality, the manual method might be better able to identify CYP2 substrates with clinical relevance.

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, incomplete information on phenotypic groups, and heterogeneity of study design. Data on psychotropic drugs metabolized by the cytochrome P450 enzyme CYP2C19 were used as a case study. CYP2C19 activity scores were estimated, while statistically assessing the influence of methodological differences between studies, and used to estimate dose adjustments in genotypic groups. Modeling effects of activity scores in each substance as a population led to prudential predictions of adjustments when few data were available (‘shrinkage’). The best results were obtained with the regularized horseshoe, an innovative Bayesian approach to estimate coefficients viewed as a sample from two populations. This approach was compared to modeling the population of substance as normally distributed, to a more traditional “fixed effects” approach, and to dose adjustments based on weighted means, as in current practice. Modeling strategies were able to assess the influence of study parameters and deliver adjustment levels when necessary, extrapolated to all phenotype groups, as well as their level of uncertainty. In addition, the horseshoe reacted sensitively to small study sizes, and provided conservative estimates of required adjustments.

Background: Medication errors (MEs) are an important cause of preventable harm but remain insufficiently quantified in emergency care. This study assessed the frequency, characteristics, and clinical impact of MEs among adverse drug reaction (ADR)–related emergency department (ED) admissions in Germany. Methods: We conducted a prospective multicenter study across six EDs between 2015 and 2021 (n = 7967). ADRs and MEs were classified using standard causality (World Health Organization-Uppsala Monitoring Centre (WHO-UMC)) and preventability criteria (Schumock). Patient, medicine, symptom, and outcome characteristics were compared between ADRs caused by MEs and ADRs without documented MEs. Regression models assessed factors associated with ME involvement among ADR cases and length of hospital stay. Results: 20.1% of ADR-related cases involved an ME. Clinical presentation, symptom burden, triage severity, and discharge outcomes were similar between groups. MEs clustered around commonly used chronic medications, including pantoprazole, torasemide, metoprolol, ramipril, phenprocoumon, and ibuprofen. Schumock analysis showed preventability as primarily linked to dosing errors (30%), non-adherence (28%), contraindications (26%), and monitoring (20%). Medicine-specific symptom clusters mirrored expected pharmacological effects but were not specific to ME involvement. Multimorbidity was associated with slightly lower odds of ME attribution, although the estimate was borderline (OR 0.84, 95% CI 0.71–1.00); no robust associations were identified for the other patient-level characteristics examined. Adjusted length of hospital stay was slightly longer in cases involving MEs (+4.8%; p = 0.025), corresponding to an adjusted difference of 0.33 days. Conclusions: MEs were identified in a substantial proportion of ADR-related ED admissions. Most MEs arose from routine prescribing and monitoring processes involving commonly used medicines, suggesting that preventive efforts should focus on upstream safeguards, including medication reviews, electronic prescribing support, pharmacist involvement, and adherence support, rather than detection at emergency presentation.

Background: Medication errors (MEs) are a frequent cause of preventable harm but remain insufficiently quantified in emergency care. This study assessed the frequency, characteristics, and clinical impact of MEs among adverse drug reaction (ADR)–related emergency department (ED) admissions in Germany. Methods: We conducted a prospective multicenter study across six EDs over six years (n=7,967). ADRs and MEs were classified using standard causality (World Health Organization-Uppsala Monitoring Centre (WHO-UMC)) and preventability criteria (Schumock). Patient, drug, symptom, and outcome characteristics were compared between ADRs with and without MEs. Regression models assessed predictors of MEs and length of stay in hospital. Results: 20.1% of ADR-related cases, involved a preventable ME. Clinical presentation between groups; symptom burden, triage severity, and discharge outcomes, were similar. MEs clustered around chronic medications (pantoprazole, torasemide, metoprolol, ramipril, phenprocoumon, ibuprofen). Schumock analysis showed preventability as primarily linked to dosing errors (30%), non-adherence (28%), contraindications (26%), and monitoring (20%). Drug-specific symptom clusters mirrored expected pharmacology but were not error-specific. Multimorbidity was modestly protective (OR 0.84, 95%CI 0.71–1.00), while age, sex, polypharmacy, and number of diagnoses were not. Length of hospital stay was slightly longer in ME cases (+0.37 days; p = 0.037). Conclusion: MEs were identified in a substantial proportion of ADR-related ED admissions. Most MEs arose from routine prescribing and monitoring processes involving commonly used drugs suggesting that preventive efforts should focus on upstream safeguards, including medication reviews, electronic prescribing support, pharmacist involvement, and adherence monitoring, rather than detection at emergency presentation.