Blood transfusions have been the cornerstone of life support since the introduction of the ABO classification in the 20th century. The physiologic goal is to restore adequate tissue oxygenation when the demand exceeds the offer. Although it can be a life-saving therapy, blood transfusions can lead to serious adverse effects, and it is essential that physicians remain up to date with the current literature and are aware of the pathophysiology, initial management and risks of each type of transfusion reaction. We aim to provide a structured overview of the pathophysiology, clinical presentation, diagnostic approach and management of acute transfusion reactions based on the literature available in 2022. The numbers of blood transfusions, transfusion reactions and the reporting rate of transfusion reactions differ between countries in Europe. The most frequent transfusion reactions in 2020 were alloimmunizations, febrile non-hemolytic transfusion reactions and allergic transfusion reactions. Transfusion-related acute lung injury, transfusion-associated circulatory overload and septic transfusion reactions were less frequent. Furthermore, the COVID-19 pandemic has challenged the healthcare system with decreasing blood donations and blood supplies, as well as rising concerns within the medical community but also in patients about blood safety and transfusion reactions in COVID-19 patients. The best way to prevent transfusion reactions is to avoid unnecessary blood transfusions and maintain a transfusion-restrictive strategy. Any symptom occurring within 24 h of a blood transfusion should be considered a transfusion reaction and referred to the hemovigilance reporting system. The initial management of blood transfusion reactions requires early identification, immediate interruption of the transfusion, early consultation of the hematologic and ICU departments and fluid resuscitation.

IL-23 (interleukin 23) regulates immune responses against pathogens and plays a major role in the differentiation and maintenance of T_H17 cells and the development of autoimmune diseases and cancer. The IL-23 receptor (IL-23R) complex consists of the unique IL-23R and the common IL-12 receptor β1 (IL-12Rβ1). Differential splicing generates antagonistic soluble IL-23R (sIL-23R) variants, which might limit IL-23-mediated immune responses. Here, ectodomain shedding of human and murine IL-23R was identified as an alternative pathway for the generation of sIL-23R. Importantly, proteolytically released sIL-23R has IL-23 binding activity. Shedding of IL-23R was induced by stimulation with the phorbol ester phorbol 12-myristate 13-acetate (PMA), but not by ionomycin. PMA-induced shedding was abrogated by an ADAM (A disintegrin and metalloprotease) 10 and 17 selective inhibitor, but not by an ADAM10 selective inhibitor. ADAM17-deficient but not ADAM10-deficient HEK293 cells failed to shed IL-23R after PMA stimulation, demonstrating that ADAM17 but not ADAM10 cleaves the IL-23R. Constitutive shedding was, however, inhibited by an ADAM10 selective inhibitor. Using deletions and specific amino acid residue exchanges, we identified critical determinants of ectodomain shedding within the stalk region of the IL-23R. Finally, interaction studies identified domains 1 and 3 of the IL-23R as the main ADAM17 binding sites. In summary, we describe human and murine IL-23R as novel targets for protein ectodomain shedding by ADAM10 and ADAM17.

Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)–IL-12 receptor β1 (IL-12Rβ1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellular-membrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligand-independent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand-independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12Rβ1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an as-yet-undescribed receptor complex of the IL-6/IL-12 cytokine family.

Phaeochromocytomas are rare catecholamine-secreting tumours, usually benign, originating from chromaffin cells of the adrenal glands. Their typical presentation includes the triad of headaches, sweating and tachycardia due to excessive catecholamine release. However, many patients do not exhibit all three symptoms, making diagnosis challenging. A significant proportion of cases (around 40%) are linked to genetic disorders. Cardiac complications, including life-threatening events, are common. This report details the case of a 43-year-old woman presenting with chest pain, headaches and diaphoresis. Initial ECG showed an anterolateral ST-elevation myocardial infarction pattern, but coronary angiography revealed no arterial disease. The left ventricular angiogram indicated apical ballooning. Elevated blood pressure prompted suspicion of phaeochromocytoma, which was confirmed through positive metanephrine tests. The tumour, located in the right adrenal gland, was successfully removed laparoscopically, and pathological examination confirmed the diagnosis. Phaeochromocytoma should be suspected in patients with unexplained myocardial infarction, labile hypertension and normal coronary arteries, as beta-blockers can be harmful if used in untreated cases.

Background/Objective: Diagnostic safety is a major challenge in emergency departments (ED), where clinicians frequently make decisions under time pressure and with incomplete information. Prospective data on diagnostic discrepancies in Swiss EDs remain limited. To determine the frequency of diagnostic discrepancies between the initial ED diagnosis and the final Internal Medicine (IM) discharge diagnosis, identify associated patient-, physician-, and context-related factors, and evaluate clinical outcomes associated with diagnostic discrepancy. Methods: We conducted a prospective observational study including 515 patients admitted from the ED to an IM ward and managed by 44 physicians at a Swiss tertiary non-university hospital. The initial ED diagnosis was compared with the IM discharge diagnosis (or diagnosis on day 28 if the patient remained hospitalized). Diagnostic discrepancies were classified using a predefined algorithm with independent expert opinion where required. Generalized linear mixed-effects models were used to assess associations between diagnostic discrepancy and mortality, in-hospital transfers and length of stay; a multivariable logistic regression model was used to identify factors associated with diagnostic discrepancy. Results: Diagnostic discrepancies were identified in 10.1% of patients (n = 52). These patients had longer hospital stays (9.3 ± 9.2 vs. 6.9 ± 5.8 days; p = 0.069) and were more frequently transferred within the hospital (17% vs. 5.8%; p = 0.006). After adjustment, diagnostic discrepancies were associated with higher odds of in-hospital transfer (OR 3.35; 95% CI 1.47–7.66; p = 0.004) and a 20% longer stay (exp β = 1.20; 95% CI 1.00–1.45; p = 0.049), although the latter was attenuated after adjustment for comorbidity. Specialist involvement in the ED was independently associated with lower odds of diagnostic discrepancy (OR 0.30; 95% CI 0.10–0.72; p = 0.015), whereas each one-point increase in physician-perceived diagnostic difficulty was associated with higher odds (OR 1.42; 95% CI 1.07–1.90; p = 0.016). Conclusions: Diagnostic discrepancies occurred in approximately one in ten patients admitted from the ED to IM and were associated with increased in-hospital transfer and, less robustly, with prolonged hospitalization. Prospective multicenter studies should evaluate strategies to reduce diagnostic discrepancies and improve diagnostic safety.