The human gastrointestinal tract is home to a complex microbial community that plays an important role in the general well-being of the entire organism. The gut microbiota generates a variety of metabolites and thereby regulates many biological processes, such as the regulation of the immune system. In the gut, bacteria are in direct contact with the host. The major challenge here is to prevent unwanted inflammatory reactions on one hand and on the other hand to ensure that the immune system can be activated when pathogens invade. Here the REDOX equilibrium is of utmost importance. This REDOX equilibrium is controlled by the microbiota either directly or indirectly via bacterial-derived metabolites. A balanced microbiome sorts for a stable REDOX balance, whereas dysbiosis destabilizes this equilibrium. An imbalanced REDOX status directly affects the immune system by disrupting intracellular signaling and promoting inflammatory responses. Here we (i) focus on the most common reactive oxygen species (ROS) and (ii) define the transition from a balanced REDOX state to oxidative stress. Further, we (iii) describe the role of ROS in regulating the immune system and inflammatory responses. Thereafter, we (iv) examine the influence of microbiota on REDOX homeostasis and how shifts in pro- and anti-oxidative cellular conditions can suppress or promote immune responses or inflammation.

Cells constantly face the challenge of managing oxidants. In aerobic organisms, oxygen (O₂) is used for energy production, generating reactive oxygen species (ROS) as byproducts of enzymatic reactions. To protect against oxidative damage, cells possess an intricate system of redox scavengers and antioxidant enzymes, collectively forming the antioxidant defense system. This system maintains the redox equilibrium and enables the generation of localized oxidative signals that regulate essential cellular functions. One key component of this defense is the thioredoxin (Trx) system, which includes Trx, thioredoxin reductase (TrxR), and NADPH. The Trx system reverses oxidation of macromolecules and indirectly neutralizes ROS via peroxiredoxin (Prx). This dual function protects cells from damage accumulation and supports physiological cell signaling. However, the Trx system also shields tumors from oxidative damage, aiding their survival. Due to elevated ROS levels from their metabolism, tumors often rely on the Trx system. In addition, the Trx system regulates critical pathways such as proliferation and neoangiogenesis, which tumors exploit to enhance growth and optimize nutrient and oxygen supply. Consequently, the Trx system is a potential target for cancer therapy. The challenge lies in selectively targeting malignant cells without disrupting the redox equilibrium in healthy cells. The aim of this review article is threefold: first, to elucidate the function of the Trx system; second, to discuss the Trx system as a potential target for cancer therapies; and third, to present the possibilities for inhibiting key components of the Trx system, along with an overview of the latest clinical studies on these inhibitors.

Reactive oxygen species (ROS) are central to inter- and intracellular signaling. Their localized and transient effects are due to their short half-life, especially when generated in controlled amounts. Upon T cell receptor (TCR) activation, regulated ROS signaling is primarily initiated by complexes I and III of the electron transport chain (ETC). Subsequent ROS production triggers the activation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2), prolonging the oxidative signal. This signal then engages kinase signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and increases the activity of REDOX-sensitive transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). To limit ROS overproduction and prevent oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant proteins such as superoxide dismutases (SODs) finely regulate signal intensity and are capable of terminating the oxidative signal when needed. Thus, oxidative signals, such as T cell activation, are well-controlled and critical for cellular communication.

(1) Background: Antibiotic resistance is a worldwide health threat. The WHO published a global strategic plan in 2001 to contain antimicrobial resistance. In the following year, a workshop identified crucial barriers to the implementation of the strategy, e.g., underdeveloped health infrastructures and the scarcity of valid data as well as a lack of implementation of antibiotic stewardship (ABS) programs in medical curricula. Here, we show that interprofessional learning and education can contribute to the optimization of antibiotic use and preserving antibiotic effectiveness. We have initiated interprofessional rounds on a medical intensive care unit (MICU) with a focus on gastroenterology, hepatology, infectious diseases, endocrinology, and liver transplantation. We integrated ICU physicians, hospital pharmacists, nursing staff, and medical students as well as students of pharmacy to broaden the rather technical concept of ABS with an interprofessional approach to conceptualize awareness and behavioral change in antibiotic prescription and use. Methods: Clinical performance data and consumption figures for antibiotics were analyzed over a 10-year period from 2012 to 2021. The control period covered the years 2012–2014. The intervention period comprised the years 2015–2021, following the implementation of an interprofessional approach to ABS at a MICU of a German university hospital. Data from the hospital pharmacy, hospital administration, and hospital information system were included in the analyses. A specific electronic platform was developed for the optimization of documentation, interprofessional learning, education, and sustainability. The years 2020 and 2021 were analyzed independently due to the SARS-CoV-2 pandemic and the care of numerous COVID-19 patients at the MICU. Results: Implementation of an interprofessional ABS program resulted in the optimization of antibiotic management at the MICU. The suggestions of the hospital pharmacist for optimization can be divided into the following categories (i) indication for and selection of therapy (43.6%), (ii) optimization of dosing (27.6%), (iii) drug interactions (9.4%), (iv) side effects (4.1%), and (v) other pharmacokinetic, pharmacodynamic, and pharmacoeconomic topics (15.3%). These suggestions were discussed among the interprofessional team at the MICU; 86.1% were consequently implemented and the prescription of antibiotics was changed. In addition, further analysis of the intensive care German Diagnosis Related Groups (G-DRGs) showed that the case mix points increased significantly by 31.6% during the period under review. Accordingly, the severity of illness of the patients treated at the ICU as measured by the Simplified Acute Physiology Score (SAPS) II increased by 21.4% and the proportion of mechanically ventilated patients exceeded 50%. Antibiotic spending per case mix point was calculated. While spending was EUR 60.22 per case mix point in 2015, this was reduced by 42.9% to EUR 34.37 per case mix point by 2019, following the implementation of the interprofessional ABS program on the MICU. Through close interprofessional collaboration between physicians, hospital pharmacists, and staff nurses, the consumption of broad-spectrum antibiotics, e.g., carbapenems, was significantly reduced, thus improving patient care. In parallel, the case mix and case mix index increased. Thus, the responsible use of resources and high-performance medicine are not contradictory. In our view, close interprofessional and interdisciplinary collaboration between physicians, pharmacists, and nursing staff will be of outstanding importance in the future to prepare health care professionals for global health care to ensure that the effectiveness of our antibiotics is preserved.

Background: Delirium prevalence is high in critical care settings. We examined the incidence, risk factors, and outcome of delirium in a medical intensive care unit (MICU) with a particular focus on liver diseases. We analyzed this patient population in terms of delirium risk prediction and differentiation between delirium and hepatic encephalopathy. Methods: We conducted an observational study and included 164 consecutive patients admitted to an MICU of a university hospital. Patients were assessed for delirium using the Confusion Assessment Method for ICUs and the Richmond Agitation-Sedation Scale (RASS). On admission and at the onset of delirium Sequential Organ Failure Assessment (SOFA) score was determined. A population of patients with liver disease was compared to a population with gastrointestinal diseases. In the population with liver diseases, hepatic encephalopathy was graded according to the West Haven classification. We analyzed the incidence, subtype, predisposing, precipitating, and health-care setting-related factors, treatment, outcome of delirium and the association between delirium and hepatic encephalopathy in patients with liver diseases. Results: The incidence of delirium was 32.5% (n = 53). Univariable binary regression analyses adjusted by the Holm-Bonferroni method showed that the development of delirium was significantly determined by 10 risk factors: Alcohol abuse (p = 0.016), severity of disease (Simplified Acute Physiology Score (SAPS) II, p = 0.016), liver diseases (p = 0.030) and sepsis (p = 0.016) compared to the control group (gastrointestinal (GI) diseases and others), increased sodium (p = 0.016), creatinine (p = 0.030), urea (p = 0.032) or bilirubin (p = 0.042), decreased hemoglobin (p = 0.016), and mechanical ventilation (p = 0.016). Of note, we identified liver diseases as a novel and relevant risk factor for delirium. Hepatic encephalopathy was not a risk factor for delirium. Delirium and hepatic encephalopathy are both life-threatening but clearly distinct conditions. The median SOFA score for patients with delirium at delirium onset was significantly higher than the SOFA score of all patients at admission (p = 0.008). Patients with delirium had five times longer ICU stays (p = 0.004) and three times higher in-hospital mortality (p = 0.036). Patients with delirium were five times more likely to be transferred to an intensive medical rehabilitation unit for post-intensive care (p = 0.020). Treatment costs per case were more than five times higher in patients with delirium than in patients without delirium (p = 0.004). Conclusions: The 10 risk factors identified in this study should be assessed upon admission to ICU for effective detection, prevention, and treatment of delirium. Liver diseases are a novel risk factor for delirium with a level of significance comparable to sepsis as an established risk factor. Of note, in patients with liver diseases delirium and hepatic encephalopathy should be recognized as distinct entities to initiate appropriate treatment. Therefore, we propose a new algorithm for efficient diagnosis, characterization, and treatment of altered mental status in the ICU. This algorithm integrates the 10 risk factor prediction-model for delirium and prompts grading of the severity of hepatic encephalopathy using the West Haven classification if liver disease is present or newly diagnosed.

Background: Out-of-hospital cardiac arrest (OHCA) is a critical health issue with survival influenced by multiple factors. This study analyzed resuscitation outcomes at the County Clinical Emergency Hospital of Sibiu, Romania, during pre-COVID-19 and pandemic periods. Methods: A retrospective analysis of 508 OHCA patients (2017–2020) assessed the return of spontaneous circulation (ROSC) as the primary endpoint. Statistical methods included decision tree analysis, logistic regression and ROC curve analysis to evaluate the predictive value of adrenaline dose and patient factors. Results: The mortality rate was 68.7%, with non-shockable rhythms predominant among fatalities. Rural patients, though younger, had lower ROSC rates than urban counterparts. Logistic regression showed that lower adrenaline doses (≤4 mg, OR 11.835 [95% CI: 6.726–20.27]; 4–6 mg, OR 2.990 [95% CI: 1.773–5.042]) were associated with better ROSC outcomes. Conclusions: A multivariable model (AUC = 0.773) incorporating demographics and pandemic status outperformed adrenaline dose alone (AUC = 0.711).