Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers. We included studies published in English and searched on PubMed^® and Cochrane^®. After a detailed discussion on the actual knowledge of PAMPs/DAMPs, we analyzed their role in the different organs affected by sepsis, trying to elucidate the molecular basis of some of the most-used prognostic scores for sepsis. Furthermore, we described a chronological trend for the release of PAMPs/DAMPs that may be useful to identify different subsets of septic patients, who may benefit from targeted therapies. These findings are preliminary since these pathways seem to be strongly influenced by the peculiar characteristics of different pathogens and host features. Due to these reasons, while initial findings are promising, additional studies are necessary to clarify the potential involvement of these molecular patterns in the natural evolution of sepsis and to facilitate their transition into the clinical setting.

Intensive Care Unit-Acquired Weakness (ICU-AW) is a common and severe complication in critically ill patients, characterized by profound and often prolonged muscle weakness. The complexity of its diagnosis and management requires a multidimensional approach that integrates clinical, electrophysiological, and imaging tools. This review focuses on the challenges in diagnosing ICU-AW, emphasizing the limitations of traditional methods such as manual muscle testing and electrophysiological studies, and highlights the emerging role of neuromuscular ultrasound (NMUS) as a promising, non-invasive diagnostic aid. Despite its utility, no gold standard exists for NMUS, making it an evolving area of research. The pathophysiological basis of ICU-AW involves multiple mechanisms, including critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and muscle atrophy due to disuse. Understanding these underlying mechanisms is crucial for advancing diagnostic strategies and informing therapeutic interventions. Recent insights into the molecular and cellular pathways involved, such as the role of oxidative stress, mitochondrial dysfunction, and the ubiquitin-proteasome system, have opened new avenues for targeted therapies. Management of ICU-AW remains challenging as no specific treatment has been proven fully effective. Current strategies focus on early mobilization, minimizing sedation, and optimizing nutritional support. Emerging therapies targeting molecular pathways involved in muscle degradation are under investigation, highlighting the potential to translate pathophysiological understanding into therapeutic innovations. This review underscores the need for ongoing research to establish standardized diagnostic protocols and develop targeted treatments for ICU-AW.

Fibrosis, sustained by the transformation of intestinal epithelial cells into fibroblasts (epithelial-to-mesenchymal transition, EMT), has been extensively studied in recent decades, with the molecular basis well-documented in various diseases, including inflammatory bowel diseases (IBDs). However, the factors influencing these pathways remain unclear. In recent years, the role of the gut microbiota in health and disease has garnered significant attention. Evidence suggests that an imbalanced or dysregulated microbiota, along with environmental and genetic factors, may contribute to the development of IBDs. Notably, microbes produce various metabolites that interact with host receptors and associated signaling pathways, influencing physiological and pathological changes. This review aims to present recent evidence highlighting the emerging role of the most studied metabolites as potential modulators of molecular pathways implicated in intestinal fibrosis and EMT in IBDs. These studies provide a deeper understanding of intestinal inflammation and fibrosis, elucidating the molecular basis of the microbiota role in IBDs, paving the way for future treatments.

Intensive Care Unit-Acquired Weakness (ICU-AW) is a common and severe complication in critically ill patients, characterized by profound and often prolonged muscle weakness. The complexity of its diagnosis and management requires a multidimensional approach that integrates clinical, electrophysiological, and imaging tools. This review focuses on the challenges in diagnosing ICU-AW, emphasizing the limitations of traditional methods such as manual muscle testing and electrophysiological studies, and highlights the emerging role of neuromuscular ultrasound (NMUS) as a promising, non-invasive diagnostic aid. Despite its utility, no gold standard exists for NMUS, making it an evolving area of research. The pathophysiological basis of ICU-AW involves multiple mechanisms, including critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and muscle atrophy due to disuse. Understanding these underlying mechanisms is crucial for advancing diagnostic strategies and informing therapeutic interventions. Recent insights into the molecular and cellular pathways involved, such as the role of oxidative stress, mitochondrial dysfunction, and the ubiquitin-proteasome system, have opened new avenues for targeted therapies. Management of ICU-AW remains challenging, as no specific treatment has been proven fully effective. Current strategies focus on early mobilization, minimizing sedation, and optimizing nutritional support. Emerging therapies targeting molecular pathways involved in muscle degradation are under investigation, highlighting the potential to translate pathophysiological understanding into therapeutic innovations. This review underscores the need for ongoing research to establish standardized diagnostic protocols and develop targeted treatments for ICU-AW.

Background: Early recognition of sepsis-related coagulation derangements may support timely risk stratification in emergency department (ED) patients with suspected infection. Evidence comparing coagulation-oriented scores in unselected “suspected sepsis” populations remains limited, particularly for predicting progression to sepsis, overt thrombotic/hemorrhagic events, and mortality. Methods: We conducted a single-center retrospective cohort study including consecutive ED patients evaluated for sepsis, suspected sepsis, or infection (January 2016–December 2024). Patients with overt disseminated intravascular coagulation (DIC) at admission were excluded. The Sepsis-Induced Coagulopathy (SIC), Japanese Association for Acute Medicine DIC (JAAM-DIC), International Society on Thrombosis and Haemostasis (ISTH) score, and Endothelial Activation and Stress Index (EASIX; and log2-EASIX) were calculated at admission. Outcomes were progression to confirmed sepsis (Sepsis-3), symptomatic coagulopathy (thrombotic and/or hemorrhagic events), and in-hospital mortality. Discrimination was assessed by ROC analysis (AUC with 95% CI) and clinical utility by decision curve analysis (DCA). Results: Among 11.274 patients without overt DIC, all scores showed moderate discrimination for mortality and sepsis progression. SIC performed best for in-hospital mortality (AUC 0.701, 95% CI 0.692–0.710) and for progression to confirmed sepsis (AUC 0.672, 95% CI 0.663–0.681). Prediction of overt thrombotic/hemorrhagic complications was poor across scores; ISTH yielded the highest (yet modest) AUCs for thrombotic events (0.614, 95% CI 0.604–0.623), hemorrhagic events (0.545, 95% CI 0.535–0.554), and combined coagulopathy (0.605, 95% CI 0.596–0.614). DCA suggested net benefit at low-to-intermediate threshold probabilities, particularly for SIC (and JAAM2) in early decision ranges. In the confirmed sepsis subgroup, discrimination attenuated overall; for combined coagulopathy, SIC showed the highest AUC (0.558, 95% CI 0.518–0.597). Conclusions: In ED patients with suspected sepsis and no overt DIC at presentation, SIC provides the strongest performance for early prognostic stratification (mortality and sepsis progression), whereas none of the evaluated scores reliably predict clinically overt thrombotic or hemorrhagic complications.