Sepsis mortality due to drug-resistant organisms remains high. However, the effectiveness of empiric combination therapy for sepsis caused by potential drug-resistant gram‑negative bacilli remains debated. This was a nested case-control study using Japanese nationwide data from a medical reimbursement system between 2010 and 2017. The eligibility criteria were adult patients who were admitted to the intensive care unit, with new-onset sepsis at or after admission. We enrolled patients with combination therapy and monotherapy by propensity score matching using their baseline characteristics. We developed a logistic regression model including combination therapy, severity of organ dysfunction, and interaction terms as the adjusting variables. Overall, 7084 patients were included in this study, 3542 and 3542 of whom were enrolled in the combination therapy and monotherapy groups, respectively. The logistic regression model revealed combination therapy and moderate and severe organ dysfunction were significantly associated with in-hospital mortality (odds ratio [OR] 95% confidence interval [CI]: 1.52 [1.20-1.91], OR [95% CI]: 1.78 [1.43-2.23], and OR [95% CI]: 4.22 [2.61-6.81], respectively). Interaction between combination therapy and severe organ dysfunction was statistically significant (OR [95% CI]: 0.41 [0.21-0.80], P for interaction = .009). However, adjusted in-hospital mortality based on the model was not significantly different between the combination therapy and monotherapy groups among patients with severe organ dysfunction (44% [95% CI: 38-51] vs 47% [95% CI: 41-54]). Our results did not reveal any specific effectiveness of combination therapy; however, the significant interaction between combination therapy and severe organ dysfunction may indicate the possible survival benefit of combination therapy for severe sepsis subset.

BackgroundSevere trauma remains a leading cause of admission to the intensive care unit. The Trauma and Injury Severity Score (TRISS) is an established standard for predicting outcomes and benchmarking the quality of trauma care globally. However, the TRISS model has some limitations when used for benchmarking trauma care. ObjectiveThis study aimed to determine whether machine learning–derived trauma phenotypes can complement the TRISS via multivariable modeling to improve in-hospital death prediction. We also introduce “Trauma-Vis,” a freely accessible web-based platform, to facilitate the availability of this integrated assessment approach to clinicians. MethodsIn this retrospective cohort study using the nationwide Japan Trauma Data Bank (JTDB), which encompasses data from 303 hospitals in Japan, we divided the data chronologically into a derivation cohort (JTDB 2015-2018) and a temporal validation cohort (JTDB 2019-2022). An integrated model was developed using multivariable logistic regression, incorporating the logit-transformed TRISS-predicted mortality and the assigned trauma phenotypes. After applying the exclusion criteria, 87,882 patients with blunt trauma were analyzed in the derivation cohort and 80,964 in the validation cohort. Predictive performance was evaluated using the area under the receiver operating characteristic curve, Brier score, logarithmic loss, net reclassification improvement, integrated discrimination improvement, and decision curve analysis. ResultsIn the derivation cohort, multivariable modeling demonstrated that trauma phenotype classification significantly recalibrated mortality risk; multiple phenotypes exhibited significant independent associations with in-hospital death after adjusting for baseline TRISS predictions (eg, for phenotype 8: odds ratio 2.38, 95% CI 2.11-2.68; P<.001). In the temporal validation cohort, the integrated multivariable model yielded higher performance metrics than the baseline TRISS model: the area under the receiver operating characteristic curve increased from 0.889 to 0.897 (DeLong test, P<.001), Brier score improved from 0.0454 to 0.0394, and logarithmic loss decreased from 0.1670 to 0.1458. The integrated model demonstrated a calibration intercept of –0.152 and a slope of 0.965 and provided a higher net benefit in the decision curve analysis across evaluated threshold probabilities. ConclusionsIntegrating machine learning–derived trauma phenotypes with the TRISS via multivariable modeling improved the accuracy and utility of in-hospital death prediction. The developed “Trauma-Vis” platform demonstrates the technical feasibility of providing real-time risk stratification at the bedside.

Traumatic brain injury (TBI) can alter various immune functions, including immunosuppression, and constitutes a risk factor for nosocomial infections and organ dysfunction. Although TBI can induce a decline in immune cell function, the detailed mechanisms remains to be elucidated. We aim to explore transcriptional signatures associated with post-TBI immune alterations in a pilot cohort using a comprehensive transcriptome analysis of immune cells. Three patients with traumatic brain injury and acute subdural hematoma were admitted to our hospital. We focused on three major subsets of immune cells responsible for the immune response: CD4 + T cells, CD8 + T cells, and monocytes. We evaluated the changes in immune function after injury using comprehensive transcriptome analysis. Blood samples were collected immediately after admission and one week later, and the data were compared with those of healthy volunteers. CD4 + , CD8 + T cells, and monocytes, the expression of pathways involved in cellular metabolism-including oxidative phosphorylation, mTORC1 signaling, MYC targets V1 and V2, and the unfolded protein response-was downregulated on day 7 compared with day 1. These findings suggest a transition from marked immune activation and metabolic upregulation on day 1 to an attenuated immune response by day 7. In CD4 + T cells, pathways associated with tissue remodeling and repair, such as hedgehog signaling and epithelial-mesenchymal transition, were upregulated from days 1 to 7, indicating a shift from inflammatory responses toward inflammation resolution and tissue repair. In this pilot study, comprehensive transcriptome profiling suggests time-dependent transcriptional shifts in CD4⁺ T cells, CD8⁺ T cells, and monocytes after TBI. These findings should be interpreted as hypothesis-generating and provide a framework for larger, confirmatory studies.

Traumatic brain injury (TBI) causes long-term cognitive and motor deficits driven partly by chronic neuroinflammation and oxidative stress. We evaluated whether an orally administered silicon (Si)-based antioxidant generating hydrogen in the intestine improves functional recovery after TBI. Male C57BL/6J mice were fed a 2.5% Si-based diet or control diet starting 1 week prior to controlled cortical impact (CCI) and subjected to CCI. The assigned diets were continuously administered for 1 week or 6 weeks after CCI. Behavioral outcomes were assessed using the Y-maze and open field tests at 1 and 6 weeks post-CCI. Histology, SV2A-PET imaging, systemic oxidative stress assays (d-ROMs and BAP), and brain qPCR for antioxidant-related genes were performed. At 1 week post-CCI, the Si group showed improved short-term memory in the Y-maze compared with controls. At 6 weeks post-CCI, locomotor activity was significantly higher in the Si group in the open field test. Microglial activation and SV2A-PET–derived synaptic density did not differ between groups. Systemic oxidative stress indices were similar; however, cortical and thalamic expression of Nrf2 pathway–related genes tended to be higher in the Si group at 6 weeks. In conclusion, oral administration of a Si-based agent improved short-term memory and locomotor function after CCI, potentially via localized antioxidant effects within the brain that support recovery of corticothalamic networks.

Circular RNAs (circRNA) lack 5' or 3' ends; their unique covalently closed structures prevent RNA degradation by exonucleases. These characteristics provide circRNAs with high pharmaceutical stability and biostability relative to current standard-of-care linear mRNAs. CircRNA levels are reportedly associated with certain human diseases, making them novel disease biomarkers and a noncanonical class of therapeutic targets. In this study, the endogenous circRNAs underlying the response to BNT162b2 mRNA vaccination were evaluated. To this end, peripheral blood samples were subjected to full-length sequencing of circRNAs via nanopore sequencing and transcriptome sequencing. Fifteen samples, comprising pre-, first, and second vaccination cohorts, were obtained from five healthcare workers with no history of SARS-CoV-2 infection or previous vaccination. A total of 4706 circRNAs were detected; following full-length sequencing, 4217 novel circRNAs were identified as being specifically expressed during vaccination. These circRNAs were enriched in the binding motifs of stress granule assemblies and SARS-CoV-2 RNA binding proteins, namely poly(A) binding protein cytoplasmic 1 (PABPC1), pumilio RNA binding family member 1 (PUM1), and Y box binding protein 1 (YBX1). Moreover, 489 circRNAs were identified as previously reported miRNA sponges. The differentially expressed circRNAs putatively originated from plasma B cells compared to circRNAs reported in human blood single-cell RNA sequencing datasets. The pre- and post-vaccination differences observed in the circRNA expression landscape in response to the SARS-CoV-2 BNT162b2 mRNA vaccine.

Acute respiratory distress syndrome (ARDS) remains a significant clinical challenge, and its pathogenesis is not fully understood. Proteomic analyses of plasma and bronchoalveolar lavage fluid (BALF) in patients with ARDS have been performed to uncover diagnostic and prognostic markers, although previous studies have not adequately focused on longitudinal comparison of biomarkers. This study aimed to elucidate the proteomic profiles of patients with ARDS in the acute and subacute phases to better understand the pathophysiological progression of ARDS. This was a single-center, prospective, observational study of adult patients with ARDS in whom plasma and BALF samples were collected in the acute and subacute phases of ARDS and comprehensive proteins were identified and analyzed by mass spectrometry. Plasma and BALF were collected from 21 ARDS patients and plasma from 24 healthy donors, from which 694 plasma proteins and 2017 BALF proteins were analyzed. Processes related to coagulation and complement commonly activated in plasma and BALF were more pronounced in the acute phase than in the subacute phase. In BALF in the acute phase, pathways related to humoral and immune responses were activated, whereas processes related to chaperones and protein folding were suppressed. IPA analysis showed that B cell receptor signaling was most activated, whereas heat shock protein 90 (HSP90) chaperone cycle, protein folding, and other pathways associated with cellular stress responses and proper protein processing were suppressed. The most activated upstream regulator was interferon gamma (IFN-γ) and the most suppressed was notch receptor 1 (NOTCH1). The proteomics of plasma and BALF from patients with ARDS were compared in both the acute and subacute phases. In BALF in the acute phase, humoral immunity, mainly B-cell receptor signaling, was activated, whereas the HSP90 cycle and protein folding mechanisms were inactivated.

Human NK cells exhibit functional heterogeneity, yet the clinical conditions and cellular processes driving this diversity remain insufficiently understood. Here, we report that NK cell diversity emerges during peripheral development, influenced by the divergence of adaptive NK cells from various stages of canonical NK cell maturation during the resolution phase of severe COVID-19. Using scRNA-seq, we analyzed blood NK cells from patients with severe COVID-19 (acute phase and post-intensive care), individuals vaccinated with the SARS-CoV-2 mRNA vaccine (BNT162b2), and healthy donors. The frequencies of immature CD56bright and proliferating NK cells increased following BNT162b2 vaccination. In contrast, the frequency of adaptive CD56dim cells was markedly elevated in patients recovering from severe COVID-19, alongside clonal expansion and enhanced mitochondrial oxidative phosphorylation. Trajectory analysis revealed a bifurcation in peripheral NK cell development, with CD56bright cells diverging into canonical and adaptive CD56dim subsets during the course of severe COVID-19. Notably, adaptive NK differentiation exhibited transcriptional and signaling profiles analogous to those of T-cell activation. Thus, NK cell diversity is shaped by the induction of an intrinsic adaptive program. These findings uncover the mechanisms underlying NK cell heterogeneity and have implications for medical applications, including the development of immunotherapies that leverage adaptive NK cell functions.

The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG) 2020 aimed to standardize sepsis care in Japan. However, the extent of their impact on clinical practice remains uncertain. We conducted a nationwide retrospective cohort study using the Japanese Diagnosis Procedure Combination database between April 2018 and December 2021. Of the 118 clinical questions (CQs) in the J-SSCG 2020, we identified 26 recommendations to which adherence could be evaluated using patient-level data. We evaluated adherence trends before and after the guideline’s publication using interrupted time series analysis and quantified hospital-level variation using intraclass correlation coefficients. A total of 213,099 patients with sepsis from 791 hospitals were included. Adherence rates varied widely across CQs (range: 0.5–98.7

Aim:Community-acquired pneumonia is an acute lung infection in patients without recent healthcare exposure that can progress to severe sepsis. Despite the well-established influence of miRNAs on inflammation, their specific roles in pneumonia-associated sepsis remain underexplored. In this pilot study, we aimed to provide insights into the pathogenesis of community-acquired pneumonia-associated sepsis by performing an integrative mRNA-miRNA analysis to identify key cellular signaling pathways and potential molecular targets for future research and treatment development. Methods:We conducted a prospective, observational, single-center study including 14 critically ill patients with community-acquired pneumonia-associated sepsis and 15 healthy controls (median age: 78 [interquartile range 67.3-83.5] and 55 [interquartile range 40.5-59.0] years, respectively). Results:Eleven patients required ventilatory support, and six met the diagnostic criteria for septic shock. All patients survived. RNA sequencing revealed 1209 upregulated and 1461 downregulated differentially expressed genes for mRNAs (false discovery rate < 0.05, |log2 fold change| >1.2), 51 upregulated and 21 downregulated genes for miRNAs, and 646 upregulated and 1274 downregulated for mRNA related to miRNAs. Canonical pathway analysis revealed activation of the programmed death-1/programmed death-ligand-1 cancer immunotherapy pathway and suppression of the Th1 pathway, indicating T-cell exhaustion in the acute phase of community-acquired pneumonia-associated sepsis. Conclusion:This study provides valuable insights into the molecular mechanisms underlying CAP-associated sepsis, confirming the occurrence of immune dysregulation, particularly T-cell exhaustion. Our findings suggest that specific miRNAs and signaling pathways identified here may serve as potential therapeutic targets or biomarkers.

PURPOSE:The aim of this study was to investigate the association between empiric MDR coverage and in-hospital mortality among adults with sepsis who received empiric anti-MRSA therapy. MATERIALS AND METHODS:This was a nested case‒control study using Japanese nationwide data from a medical reimbursement system between 2010 and 2017. Patients with sepsis and using empiric antimicrobials with MRSA coverage were extracted. Among them, we enrolled patients with MDR coverage and those without MDR coverage via propensity score matching on the basis of their baseline characteristics. RESULTS:Both the MDR coverage cohort and the non-MDR coverage cohort each comprised 6,068 patients. The MDR coverage group had more acute organ dysfunction than the non-MDR coverage group did (moderate: 34.0 % vs. 24.3 %; severe: 5.0 % vs. 2.7 %, p < 0.001). The MDR coverage group had significantly higher crude in-hospital mortality than the non-MDR coverage group did (22.9 % vs. 16.7 %, p < 0.001). The conditional logistic regression model revealed that MDR coverage and acute organ dysfunction were significantly associated with in-hospital mortality. The interaction between MDR coverage and severe acute organ dysfunction was statistically significant (p for interaction = 0.02). Stratified by severity, in-hospital mortality rates were reversed between moderate and severe (in-hospital mortality rates: mild 16.4 % vs. 12.3 %; moderate 31.6 % vs. 26.7 %; and severe 42.3 % vs. 44.8 %). CONCLUSIONS:Our study revealed that empiric concomitant MDR coverage might be considered for adults with sepsis who received empiric anti-MRSA therapy if they have multiple acute organ dysfunctions, although their population is small.

BackgroundSevere heat stroke can cause multi-organ dysfunction and can be fatal, yet its underlying pathophysiology remains poorly understood. While RNA alterations are known to occur in critical illness, their specific role in severe heat stroke has not been comprehensively studied. Understanding these molecular changes may improve diagnostic and therapeutic strategies. This study aimed to investigate the pathogenesis of severe heat stroke by analyzing RNA expression profiles in Japanese patients in comparison to healthy controls.ResultsThis single-center, prospective, observational study included seven patients (median age: 69 ± 21.5 years; 57.1% male) with severe heat stroke admitted to Osaka University Hospital Emergency Center between August 2020 and July 2021, along with five healthy controls. All patients exhibited central nervous system symptoms and renal dysfunction; 28.6% had hepatic dysfunction or coagulopathy, and one patient (14.3%) died. RNA sequencing of leukocyte total RNA identified 15,876 RNAs, among which 1,106 were upregulated and 1,000 were downregulated in patients relative to controls (|log2 fold change| > 1, false discovery rate < 0.1). Pathway analysis revealed significant activation of the endoplasmic reticulum stress response, particularly the unfolded protein response, which is involved in cellular stress adaptation and survival mechanisms.ConclusionSevere heat stroke in Japanese patients was associated with widespread changes in RNA expression, highlighting activation of the endoplasmic reticulum stress response. These findings provide new insights into the pathophysiology of heat stroke and suggest that targeting cellular stress pathways may be a potential therapeutic approach. Further research is needed to validate these results in larger cohorts and assess their clinical implications.

BackgroundAlthough an increase in neutrophil count has been observed in patients with coronavirus disease 2019 (COVID-19), the relationship between the systemic neutrophil transcriptome and clinical course of COVID-19 remains unclear. Hence, we examined the relationship between the clinical course and RNA sequencing analysis results in COVID-19 patients.MethodsPeripheral blood samples were obtained from 28 patients with COVID-19-associated ARDS and 16 healthy controls. Bulk RNA sequencing was performed, and clustering analysis was used to explore relationships between gene expression and clinical characteristics. In a separate cohort, neutrophils were isolated from the peripheral blood of five COVID-19 patients with ARDS for single-cell RNA sequencing to further characterize the neutrophil subpopulations.ResultsIn bulk RNA sequencing analysis, COVID-19 patients with ARDS had elevated gene expression associated with neutrophils compared with healthy controls.Clustering analysis revealed no differences in the clinical characteristics of COVID-19 patients with ARDS. In the single-cell RNA sequencing analysis, clustering analysis showed that the patients were divided into two groups: those who could be weaned from the ventilator within 28 days and those who could not be weaned.ConclusionThese findings indicate that differences in neutrophil gene expression may have important clinical implications. This study may support the exploratory identification of genomic factors, such as neutrophil gene expression, that are relevant to clinical parameters.

Diversity of the microbiota, which is essential for lower airway homeostasis, is greatly altered in acute respiratory distress syndrome (ARDS). Extracorporeal membrane oxygenation (ECMO) is the ultimate protective treatment for the lungs of patients with severe ARDS, but little is known about its effect on the lung microbiota of these patients. To evaluate the effect of ECMO on the lung microbiota of ARDS patients, we performed 16S rRNA and fungal ITS1 profiling and shotgun sequencing on bronchoalveolar lavage fluid (BALF) collected from ARDS patients due to COVID-19. BALF was collected from 13 patients, five of whom underwent ECMO. In all patients, Pseudomonas was the most abundant of the bacteria. The patients with ECMO had more Pseudomonas and more Klebsiella than those without ECMO. The most abundant fungi were unspecified fungi in the patients with ECMO and Emmia lacerata in the patients without ECMO. Alpha diversity of bacteria and fungi did not differ significantly between the two groups. Human betaherpesvirus 5 and human alphaherpesvirus 1 were predominant in all patients, with human betaherpesvirus 5 decreasing over time in the ECMO patients. The patients with ARDS due to COVID-19 receiving ECMO had a different lung microbiota than those not receiving ECMO.

AbstractAimThis study investigated whether contrast extravasation on computed tomography (CT) angiography in patients with traumatic brain injury (TBI) is associated with death or surgical procedures.MethodsPatients over 18 years old, directly brought in by ambulance with an isolated head injury and confirmed to have acute intracranial hemorrhage on a CT scan upon admission between 2010 and 2020, were included. The primary outcome was mortality, and the secondary outcome was neurosurgical procedures performed from admission to discharge from the intensive care unit. Multivariable logistic regression analyses were performed to evaluate the association between these outcomes and contrast extravasation.ResultsThe analysis included 188 patients with a median age of 65 years, 123 men (65.4%), 34 deaths (18.1%), and 91 surgeries (48.4%). Among the 66 patients with contrast extravasation, 22 (33.3%) died and 47 (71.2%) required surgery. Among the 122 patients with no contrast extravasation, 12 (9.8%) died, and 44 (36.1%) required surgery. The presence or absence of extravascular leakage was associated with death (odds ratio, 3.6 [95% CI: 1.2–12.2]) and surgery (odds ratio, 7.6 [95% CI: 2.5–22.7]).ConclusionContrast extravasation was associated with mortality and performance of surgery in patients with an isolated head injury.

Record-breaking heat waves over the past 20 years have led to a global increase in heat-related deaths, including heatstroke. Heat-related illnesses occur when the body cannot adapt to the elevated temperatures in the environment, leading to various symptoms. In severe situations, such as heatstroke, the body temperature can rise above 40°C, leading to significant injury to body systems, with particular susceptibility of the central nervous system (CNS). Neuroimaging studies conducted months or years after a heatstroke have revealed cellular damage in the cerebellum and other brain regions, including the hippocampus, midbrain, and thalamus, with the potential for long-term neurological complications in survivors of a heatstroke. This mini review aimed to describe the mechanisms and pathways underlying the development of brain injury induced by heatstroke and identify diagnostic imaging tools and biomarkers for injury to the CNS due to a heatstroke.

BACKGROUND:Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES:To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS:We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS:Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION:JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

Background: Recent studies suggested an expected survival benefit associated with anticoagulant therapies for sepsis in patients with disseminated intravascular coagulation (DIC). However, anticoagulant therapies for overt DIC are no longer assumed to regulate pathologic progression as overt DIC is a late-phase coagulation disorder. Therefore, methods for early prediction of sepsis-induced DIC before its progression to an overt stage are strongly required. Objectives: We aimed to develop a prediction model for overt DIC using machine learning. Methods: This retrospective, observational study included adult septic patients without overt DIC. The objective variable was binary classification of whether patients developed overt DIC based on International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. Explanatory variables were the baseline and time series data within 7 days from sepsis diagnosis. Light Gradient Boosted Machine method was used to construct the prediction model. For controls, we assessed sensitivity and specificity of Japanese Association for Acute Medicine DIC criteria and ISTH sepsis-induced coagulopathy criteria for subsequent onset of overt DIC. Results: Among 912 patients with sepsis, 139 patients developed overt DIC within 7 days from diagnosis of sepsis. Sensitivity, specificity, and area under the receiver operating characteristic curve for predicting onset of overt DIC within 7 days were 84.4%, 87.5%, and 0.867 in the test cohort and 95.0%, 75.9%, and 0.851 in the validation cohort, respectively. Sensitivity and specificity by the diagnostic thresholds were 54.7% and 74.9% for Japanese Association for Acute Medicine DIC criteria and 63.3% and 71.9% for ISTH sepsis-induced coagulopathy criteria, respectively. Conclusion: Compared with conventional DIC scoring systems, a machine learning model might exhibit higher prediction accuracy.

Background: Although coagulopathy is often observed in acute respiratory distress syndrome (ARDS), its clinical impact remains poorly understood. Objectives: This study aimed to clarify the coagulopathy parameters that are clinically applicable for prognostication and to determine anticoagulant indications in sepsis-induced ARDS. Method: This study enrolled patients with sepsis-derived ARDS from two nationwide multicenter, prospective observational studies. We explored coagulopathy parameters that could predict outcomes in the Focused Outcome Research on Emergency Care for Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) cohort, and the defined coagulopathy criteria were validated in the Sepsis Prognostication in Intensive Care Unit and Emergency Room-Intensive Care Unit (SPICE-ICU) cohort. The correlation between anticoagulant use and outcomes was also evaluated. Results: A total of 181 patients with sepsis-derived ARDS in the FORECAST study and 61 patients in the SPICE-ICU study were included. In a preliminary study, we found the set of prothrombin time-international normalized ratio >= 1.4 and platelet count <= 12 x 104/mu L, and thrombocytopenia and elongated prothrombin time (TEP) coagulopathy as the best coagulopathy parameters and used it for further analysis; the odds ratio (OR) of TEP coagulopathy for in-hospital mortality adjusted for confounding was 3.84 (95% confidence interval [CI], 1.66-8.87; P = 0.005). In the validation cohort, the adjusted OR for in-hospital mortality was 32.99 (95% CI, 2.60-418.72; P = 0.002). Although patients without TEP coagulopathy showed significant improvements in oxygenation over the first 4 days, patients with TEP coagulopathy showed no significant improvement (Delta PaO2/FiO2 ratio, 24 +/- 20 vs. 90 +/- 9; P = 0.026). Furthermore, anticoagulant use was significantly correlated with mortality and oxygenation recovery in patients with TEP coagulopathy but not in patients without TEP coagulopathy. Conclusion: Thrombocytopenia and elongated prothrombin time coagulopathy is closely associated with better outcomes and responses to anticoagulant therapy in sepsis-induced ARDS, and our coagulopathy criteria may be clinically useful.