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Background We aimed to evaluate the clinical usefulness of qSOFA as a risk stratification tool for patients admitted with infection compared to traditional SIRS criteria or our triage system; the Rapid Emergency Triage and Treatment System (RETTS). Methods The study was an observational cohort study performed at one Emergency Department (ED) in an urban university teaching hospital in Norway, with approximately 20,000 visits per year. All patients >16 years presenting with symptoms or clinical signs suggesting an infection ( n  = 1535) were prospectively included in the study from January 1 to December 31, 2012. At arrival in the ED, vital signs were recorded and all patients were triaged according to RETTS vital signs, presenting infection, and sepsis symptoms. These admission data were also used to calculate qSOFA and SIRS. Treatment outcome was later retrieved from the patients’ electronic records (EPR) and mortality data from the Norwegian population registry. Results Of the 1535 admitted patients, 108 (7.0%) fulfilled the Sepsis2 criteria for severe sepsis. The qSOFA score ≥2 identified only 33 (sensitivity 0.32, specificity 0.98) of the patients with severe sepsis, whilst the RETTS-alert ≥ orange identified 92 patients (sensitivity 0.85, specificity 0.55). Twenty-six patients died within 7 days of admission; four (15.4%) of them had a qSOFA ≥2, and 16 (61.5%) had RETTS ≥ orange alert. Of the 68 patients that died within 30 days, only eight (11.9%) scored ≥2 on the qSOFA, and 45 (66.1%) had a RETTS ≥ orange alert. Discussion In order to achieve timely treatment for sepsis, a sensitive screening tool is more important than a specific one. Our study is the fourth study were qSOFA finds few of the sepsis cases in prehospital or at arrival to the ED. We add information on the RETTS triage system, the two highest acuity levels together had a high sensitivity (85%) for identifying sepsis at arrival to the ED - and thus, RETTS should not be replaced by qSOFA as a screening and trigger tool for sepsis at arrival. Conclusion In this observational cohort study, qSOFA failed to identify two thirds of the patients admitted to an ED with severe sepsis. Further, qSOFA failed to be a risk stratification tool as the sensitivity to predict 7-day and 30-day mortality was low. The sensitivity was poorer than the other warning scores already in use at the study site, RETTS-triage and the SIRS criteria.

The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT ), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.

The most severe forms of COVID-19 share many features with bacterial sepsis and have thus been considered to be a viral sepsis. Innate immunity and inflammation are closely linked. While the immune response aims to get rid of the infectious agent, the pro-inflammatory host response can result in organ injury including acute respiratory distress syndrome. On its side, a compensatory anti-inflammatory response, aimed to dampen the inflammatory reaction, can lead to immunosuppression. Whether these two key events of the host inflammatory response are consecutive or concomitant has been regularly depicted in schemes. Initially proposed from 2001 to 2013 to be two consecutive steps, the concomitant occurrence has been supported since 2013, although it was proposed for the first time in 2001. Despite a consensus was reached, the two consecutive steps were still recently proposed for COVID-19. We discuss why the concomitance view could have been initiated as early as 1995.

Background Nucleated red blood cells (nRBCs) are increased by disease processes and hematopoietic stress. Objectives To evaluate the utility of nRBCs as a marker of disease severity and prognosis in dogs with systemic inflammatory response syndrome (SIRS). Animals Sixty‐two client‐owned dogs met the criteria of SIRS without anemia. Methods nRBC‐positive (nRBCs: ≥5/500, n = 32) and nRBC‐negative (nRBCs: <5/500, n = 30) dogs were classified, and clinicopathological data, Acute Patient Physiologic and Laboratory Evaluation (APPLEfast) scores, cytokines, 2‐ and 4‐weeks survival were compared. Results The median WBC (17.63, interquartile range [IQR]: 11.72‐20.24 × 109/L), neutrophils (12.28, IQR: 7.17‐16.88 × 109/L), band neutrophils (1288.5, IQR: 252.5‐2575 cells/μL), serum IL‐6 (731.80, IQR: 299.79‐5522.05 pg/mL), and plasma C‐reactive protein (4.10, IQR: 1.00‐8.58 mg/L) were significantly higher in nRBC‐positive dogs than negative dogs (11.27, IQR: 7.63‐15.13 × 109/L; 7.57, IQR: 4.96‐11.71 × 109/L; 62.5, IQR: 0‐350.25 cells/μL; 232.30, IQR: 99.33‐447.01 pg/mL; 0.40, IQR: 0.10‐3.00 mg/L, respectively; P < .05). The median reticulocyte count (87.95, IQR: 52.45‐130.55 × 103/μL) and serum IL‐3 (40.94, IQR: 29.85‐53.52 ng/L) were also significantly greater in nRBC‐positive dogs than nRBC‐negative dogs (46.00, IQR: 26.43‐68.15 × 103/μL; 25.24, IQR: 21.65‐37.40 ng/L, respectively; P < .01). The presence of circulating nRBCs, but not the reticulocyte count, at admission was predictive of death in dogs with SIRS at 2 weeks (P = .01, AUC: 0.729) and 4 weeks (P = .002, AUC: 0.731). The overall survival time was shorter in nRBC‐positive dogs (95% CI, 47.35‐113.90) than nRBC‐negative dogs (95% CI, 90.92‐135.55; P = .03). Conclusions and Clinical Importance Measuring peripheral nRBCs in dogs with SIRS is rapid and clinically applicable, reflecting disease severity and associated prognosis.

Differentiation between culture-negative sepsis and noninfectious systemic inflammatory response syndrome (SIRS) remains a diagnostic challenge for clinicians, both conditions having similar clinical presentations. Therefore, a swift accurate diagnostic tool, which helps differentiate these 2 conditions would immensely aid appropriate therapeutic continuum. This prospective study was conducted to evaluate the potential diagnostic role of biomarkers, procalcitonin (PCT) and interleukin 6 (IL-6), in culture-negative sepsis patients. Enrolled patients (208) included 46 noninfectious SIRS, 90 culture-negative sepsis, and 72 culture-positive sepsis. Culture, PCT, and IL-6 estimations were performed on day 1 of intensive care unit admission. Procalcitonin and IL-6 levels were significantly higher (P < .001) in both culture-negative and culture-positive groups as compared with SIRS group. Procalcitonin was a better predictor of sepsis in both culture-negative (area under curves 0.892 vs 0.636) and culture-positive (area under curves 0.959 vs 0.784) groups as compared with IL-6. In culture-negative group, the best cutoff point for PCT was at 1.43 ng/mL (92% sensitivity; 83% negative predictive value), best cutoff point for IL-6 was at 219.85 pg/mL (47% sensitivity and 42% negative predictive value). Procalcitonin can accurately differentiate culture-negative sepsis from noninfectious SIRS and thereby contribute to early diagnosis and effective management of these conditions.

Background This qualitative study of the opinions of legal guardians of minors with Systemic Inflammatory Response Syndrome (SIRS) in Turkey identifies and analyses the ethical challenges accompanying the management of paediatric SIRS patients and the collection of genetic data as part of a large multiomics dataset for the development of an AI-based tool for diagnostics and management of SIRS. Methods Between January and June 2024, 14 problem-centred, semi-structured exploratory interviews with legal guardians of children with SIRS were conducted in Istanbul, Turkey. The interview consisted of 19 open-ended questions. The interviews were digitally recorded, translated into English, and two independent researchers analysed the content of the information. Qualitative content and thematic analysis were performed to identify major ethical issues. Results The analysis identified five major topics: solidarity, autonomy, informed consent, protection of privacy, and AI-driven ethical issues. Solidarity was the most prominent topic and encompassed the aspects of motivation for participation, raising awareness, supporting communication, and loosening data protection. Parents expressed high respect for children’s autonomy. In the vein of the triadic relationship model, the necessity of children with SIRS participating in decision-making was supported by the interviewees as well as the reconfirmation of informed consent in case of future use of collected genetic data. Regarding the development of AI-tool for SIRS, five principles were identified: wide representation, confidentiality, trustworthiness, human control, and orientation. Conclusion Our study contributes to the understanding of the ethical challenges accompanying the study of diagnostics using multi-omics data and derived treatment strategies of SIRS in children and adolescents. Different functions of solidarity linked it to the other major topics, thus composing a coherent picture of the ethical aspects of paediatric SIRS research. The identified principles of AI-development correspond to those in the Assessment List for Trustworthy Artificial Intelligence (ALTAI); thus, our research confirmed their real-life relevance and usefulness.

Since February, 2023, the omicron variant has accounted for essentially all new coronavirus infections in Japan. If future infections involve mutant strains with the same level of infectivity and virulence as omicron, the government’s basic policy will be to prevent the spread of infection, without compromising socioeconomic activities. Objectives include protecting pregnant women and elderly persons, and focusing on citizens requiring hospitalization and those at risk of serious illness, without imposing new social restrictions. Although the government tries to raise public awareness through education, most people affected by COVID-19 stay at home, and by the time patients become aware of the seriousness of their disease, it has often reached moderate or higher severity. In this review, we discuss why this situation persists even though the disease seems to have become milder with the shift from the delta variant to omicron. We also propose a pathophysiological method to determine the risk of severe illness. This assessment can be made at home in the early stages of COVID-19 infection, using urine analysis. Applicability of this method to drug discovery and development is also discussed.

(1) Background: Sepsis is a life-threatening condition, and most patients with sepsis first present to the emergency department (ED) where early identification of sepsis is challenging due to the unavailability of an effective diagnostic model. (2) Methods: In this retrospective study, patients aged ≥20 years who presented to the ED of an academic hospital with systemic inflammatory response syndrome (SIRS) were included. The SIRS, sequential organ failure assessment (SOFA), and quick SOFA (qSOFA) scores were obtained for all patients. Routine complete blood cell testing in conjugation with the examination of new inflammatory biomarkers, namely monocyte distribution width (MDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), was performed at the ED. Propensity score matching was performed between patients with and without sepsis. Logistic regression was used for constructing models for early sepsis prediction. (3) Results: We included 296 patients with sepsis and 1184 without sepsis. A SIRS score of >2, a SOFA score of >2, and a qSOFA score of >1 showed low sensitivity, moderate specificity, and limited diagnostic accuracy for predicting early sepsis infection (c-statistics of 0.660, 0.576, and 0.536, respectively). MDW > 20, PLR > 9, and PLR > 210 showed higher sensitivity and moderate specificity. When we combined these biomarkers and scoring systems, we observed a significant improvement in diagnostic performance (c-statistics of 0.796 for a SIRS score of >2, 0.761 for a SOFA score of >2, and 0.757 for a qSOFA score of >1); (4) Conclusions: The new biomarkers MDW, NLR, and PLR can be used for the early detection of sepsis in the current sepsis scoring systems.

Colic is a common and potentially life-threatening condition in horses; in many cases, it remains challenging for clinicians to determine the cause, appropriate treatment, and prognosis. One approach that could improve patient care and outcomes is identification of novel diagnostic and prognostic biomarkers. Plasma cell-free DNA (cfDNA) is a biomarker that shows promise for characterizing disease severity and predicting survival in humans with acute abdominal pain or requiring emergency abdominal surgery. In horses, we recently determined that extracted plasma cfDNA concentrations are elevated in colic patients compared to healthy controls. For this current study, we hypothesized that extracted plasma cfDNA concentrations would be significantly higher in horses with strangulating or inflammatory colic lesions, in colic patients with systemic inflammatory response syndrome (SIRS), and in non-survivors. Cell-free DNA concentrations were measured in extracted plasma samples using a compact, portable Qubit fluorometer. Colic patients that met published criteria for equine SIRS had significantly higher median extracted plasma cfDNA compared to non-SIRS colic patients. There were no significant differences in extracted plasma cfDNA concentrations between other groups of interest. Our data offer early evidence that extracted plasma cfDNA concentration may provide information about systemic inflammation in colic patients, and additional research is warranted to expand on these findings.

Immune dysregulation presents a significant clinical challenge due to its rapid progression and complex interplay between hyperinflammatory and immunosuppressive responses. Different responses from the innate and adaptive immune systems can result in diseases such as immunoparalysis, cytokine storms, and secondary infections. Current diagnostic methods remain non-specific and time-consuming, delaying targeted interventions. A compartmentalized approach to immune monitoring, distinguishing innate and acquired immune response functional differentiation, is essential for distinguishing between hyperactivation and suppression. Key biomarkers, including cytokines, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), and CD4/CD8 counts, as well as Programmed Death Ligand-1 (PDL-1) and V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) regulators, can guide personalized treatment strategies. Although they need more clinical validation, novel therapeutic methods such as cytokine inhibitors, immunological stimulants, and immunomodulators have demonstrated promise. Early diagnosis and precision medicine developments could lead to better patient outcomes. Advances in non-coding RNAs have led to specific diagnostic panels based on microRNA (MiRNA) levels. A deeper understanding of immune imbalance in sepsis is critical for optimizing treatment and reducing mortality rates. This review highlights emerging diagnostic and therapeutic strategies to address the multifaceted nature of sepsis-related immune dysregulation.