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Purpose: We aimed to validate the performance of six available scoring models for predicting hospital mortality in children with suspected or confirmed infections., Methods: This single-center retrospective cohort study included pediatric patients admitted to the PICU for infection. The primary outcome was hospital mortality. The six scores included the age-adapted pSOFA score, SIRS score, PELOD2 score, Sepsis-2 score, qSOFA score, and PMODS., Results: Of the 5,356 children admitted to the PICU, 9.1% (488) died, and 25.1% (1,342) had basic disease with a mortality rate of 12.7% (171); 65.3% (3,499) of the patients were younger than 2 years, and 59.4% (3,183) were male. The discrimination abilities of the pSOFA and PELOD2 scores were superior to those of the other models. The calibration curves of the pSOFA and PELOD2 scores were consistent between the predictions and observations. Elevated lactate levels were a risk factor for mortality., Conclusion: The pSOFA and PELOD2 scores had superior predictive performance for mortality. Given the relative unavailability of items and clinical operability, the pSOFA score should be recommended as an optimal tool for acute organ dysfunction in pediatric sepsis patients. Elevated lactate levels are related to a greater risk of death from infection in children in the PICU., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Declaration of competing interest The authors declare no conflicts of interest relevant to this article.

Background/aims: Quick sequential organ failure assessment (qSOFA) is believed to identify patients at risk of poor outcomes in those with suspected infection. We aimed to evaluate the ability of modified qSOFA (m-qSOFA) to identify high-risk patients among those with acutely deteriorated chronic liver disease (CLD), especially those with acute-onchronic liver failure (ACLF)., Methods: We used data from both the Korean Acute-on-Chronic Liver Failure (KACLiF) and the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) cohorts. qSOFA was modified by replacing the Glasgow Coma Scale with hepatic encephalopathy, and an m-qSOFA ≥2 was considered high., Results: Patients with high m-qSOFA had a significantly lower 1-month transplant-free survival (TFS) in both cohorts and higher organ failure development in KACLiF than those with low m-qSOFA (Ps<0.05). Subgroup analysis by ACLF showed that patients with high m-qSOFA had lower TFS than those with low m-qSOFA. m-qSOFA was an independent prognostic factor (hazard ratios, HR=2.604, 95% confidence interval, CI 1.353-5.013, P=0.004 in KACLiF and HR=1.904, 95% CI 1.484- 2.442, P<0.001 in AARC). The patients with low m-qSOFA at baseline but high m-qSOFA on day 7 had a significantly lower 1-month TFS than those with high m-qSOFA at baseline but low m-qSOFA on day 7 (52.6% vs. 89.4%, P<0.001 in KACLiF and 26.9% vs. 61.5%, P<0.001 in AARC)., Conclusion: Baseline and dynamic changes in m-qSOFA may identify patients with a high risk of developing organ failure and short-term mortality among CLD patients with acute deterioration.

Objectives: While cytokine response patterns are pivotal in mediating immune responses, they are also often dysregulated in sepsis and critical illness. We hypothesized that these immunological deficits, quantifiable through ex vivo whole blood stimulation assays, may be indicative of subsequent organ dysfunction., Design: In a prospective observational study, adult septic patients and critically ill but nonseptic controls were identified within 48 hours of critical illness onset. Using a rapid, ex vivo assay based on responses to lipopolysaccharide (LPS), anti-CD3/anti-CD28 antibodies, and phorbol 12-myristate 13-acetate with ionomycin, cytokine responses to immune stimulants were quantified. The primary outcome was the relationship between early cytokine production and subsequent organ dysfunction, as measured by the Sequential Organ Failure Assessment score on day 3 of illness (SOFAd3)., Setting: Patients were recruited in an academic medical center and data processing and analysis were done in an academic laboratory setting., Patients: Ninety-six adult septic and critically ill nonseptic patients were enrolled., Interventions: None., Measurements and Main Results: Elevated levels of tumor necrosis factor and interleukin-6 post-endotoxin challenge were inversely correlated with SOFAd3. Interferon-gamma production per lymphocyte was inversely related to organ dysfunction at day 3 and differed between septic and nonseptic patients. Clustering analysis revealed two distinct immune phenotypes, represented by differential responses to 18 hours of LPS stimulation and 4 hours of anti-CD3/anti-CD28 stimulation., Conclusions: Our rapid immune profiling technique offers a promising tool for early prediction and management of organ dysfunction in critically ill patients. This information could be pivotal for early intervention and for preventing irreversible organ damage during the acute phase of critical illness., Competing Interests: Dr. Halstead is a speaker for Swedish Orphan Biovitrum pharmaceuticals and lectures specifically about the disease process and therapeutic strategies for hemophagocytic lymphohistiocytosis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Cytokine-mediated systemic inflammation after open thoracoabdominal aortic aneurysm (TAAA) repairs plays a pivotal role in disrupting circulatory homeostasis, potentially leading to organ dysfunction. The bioactive form of adrenomedullin (bio-ADM) is a peptide hormone with immunomodulatory and vasomotor effects, making it a potential diagnostic agent in these cases. This retrospective, bicentric study, conducted between January 2019 and December 2022, recruited 36 elective open TAAA repair patients in two German centres. Serum and plasma samples were collected at multiple time points to measure bio-ADM levels. The primary objective was to evaluate the association of bio-ADM levels with the onset of acute respiratory distress syndrome (ARDS), with secondary endpoints focusing on mortality and SIRS-related morbidity. Results showed a significant association between postoperative bio-ADM levels (12-48 h after surgery) and the onset of ARDS (p < .001), prolonged ventilation (p = .015 at 12h after surgery), atrial fibrillation (p < .001), and mortality (p = .05 at 24h). The biomarker was also strongly associated with sepsis (p = .01 at 12 h) and multi-organ dysfunction syndrome (MODS) (p = .02 at 24 h after surgery). The study underscores the potential utility of bio-ADM as a diagnostic tool for identifying patients at risk of postoperative complications following open TAAA repairs., (© 2024. The Author(s).)

A 51-year-old Thai woman diagnosed with β-thalassemia underwent regular blood transfusion and iron-chelating therapy. However, after voluntarily discontinuing treatment, the patient developed progressive dyspnea and was diagnosed with pulmonary hypertension following right heart catheterization. Despite resuming blood transfusions, her condition did not improve. Because the patient had a history of multiple organ failure, curative treatment for β-thalassemia was not feasible, and macitentan was administered. Despite experiencing hypotension as an adverse event, her condition remained stable during macitentan treatment. Thus, macitentan may be well tolerated in patients with pulmonary hypertension caused by β-thalassemia with multiple organ dysfunction.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is a natural focal disease transmitted mainly by tick bites, and the causative agent is SFTS virus (SFTSV). SFTS can rapidly progress to severe disease, with multiple-organ failure (MOF) manifestations such as shock, respiratory failure, disseminated intravascular coagulation (DIC) and death, but cases of SFTS patients with central nervous system (CNS) symptoms onset and marked persistent involuntary shaking of the perioral area and limbs have rarely been reported., Case Presentation: A 69-year-old woman with fever and persistent involuntary shaking of the perioral area and limbs was diagnosed with SFTS with CNS symptom onset after metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) and peripheral blood identified SFTSV. The patient developed a cytokine storm and MOF during the course of the disease, and after aggressive antiviral, glucocorticoid, and gamma globulin treatments, her clinical symptoms improved, her laboratory indices returned to normal, and she had a good prognosis., Conclusion: This case gives us great insight that when patients with CNS symptoms similar to those of viral encephalitis combined with thrombocytopenia and leukopenia are encountered in the clinic, it is necessary to consider the possibility of SFTS involving the CNS. Testing for SFTSV nucleic acid in CSF and blood (mNGS or polymerase chain reaction (PCR)) should be carried out, especially in critically ill patients, and treatment should be given accordingly., (© 2024. The Author(s).)

Leptospirosis is an uncommon infectious illness - a spirochetal zoonosis - caused by Leptospira species and the primary cause of human leptospirosis is exposure to the urine of infected rodents. Clinical manifestations of human leptospirosis are diverse, ranging from asymptomatic infection to severe life-threatening with multiorgan dysfunction. The severe condition is known as Weil's disease, which is characterized by feverish illness with jaundice, acute kidney damage, and bleeding. The aim of this case report was to present a Weil's disease which occurred simultaneously with a community-acquired pneumonia (CAP) resulting in serious complications. A 41-year-old man with Weil's disease, as well as CAP caused by Streptococcus pneumoniae , and septic shock was presented. The patient was treated accordingly after establishing the diagnosis through history taking, physical examination, and laboratory tests. In this instance, the score for diagnosing leptospirosis based on Modified Faine's Criteria was calculated resulting possible diagnoses; and therefore, therapeutic management was initiated. Despite presenting with severe symptoms, the patient recovered completely after receiving antibiotics and supportive care. This study highlights that when a patient has Weil's disease and a CAP infection, which could cause unfavorable consequence, a prompt diagnosis and proper treatment could result satisfied patient recovery., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 by the authors.)

We are interested in detecting a departure from the baseline in a longitudinal analysis in the context of multiple organ dysfunction syndrome (MODS). In particular, we are given gene expression reads at two time points for a fixed number of genes and individuals. The individuals can be subdivided into two groups, denoted as groups A and B . Using the two time points, we compute a contrast of gene expression reads per individual and gene. The age of each individual is known and it is used to compute, for each gene separately, a linear regression of the gene expression contrasts on the individual's age. Looking at the intercept of the linear regression to detect a departure from the baseline, we aim to reliably single out those genes for which there is a difference in the intercept among those individuals in group A and not in group B . In this work, we develop testing methodology for this setting based on two hypothesis tests-one under the null and one under an appropriately formulated alternative. We demonstrate the validity of our approach using a dataset created by bootstrapping from a real data application in the context of multiple organ dysfunction syndrome (MODS).

Background: Multisystem organ failure (MSOF) is the most important determinant of mortality in acute pancreatitis (AP). Obesity and alcoholic etiology have been examined as potential risk factors for MSOF, but prior studies have not adequately elucidated their independent effects on the risk of MSOF., Objective: We aimed to determine the adjusted effects of body mass index (BMI) and alcoholic etiology on the risk of MSOF in subjects with AP., Methods: A prospective observational study of 22 centers from 10 countries was conducted. Patients admitted to an APPRENTICE consortium center with AP between August 2015 and January 2018 were enrolled. Multivariable logistic regression was used to estimate the adjusted effects of BMI, etiology, and other relevant covariates on the risk of MSOF. Models were stratified by sex., Results: Among 1544 AP subjects, there was a sex-dependent association between BMI and the risk of MSOF. Increasing BMI was associated with increased odds of MSOF in males (OR 1.10, 95% confidence interval [CI] 1.04-1.15) but not in females (OR 0.98, 95% CI 0.90-1.1). Male subjects with AP, whose BMIs were 30-34 and >35 kg/m 2 , had odds ratios of 3.78 (95% CI 1.62-8.83) and 3.44 (95% CI 1.08-9.99), respectively. In females, neither higher grades of obesity nor increasing age increased the risk of MSOF. Alcoholic etiology was independently associated with increased odds of MSOF compared with non-alcohol etiologies (OR 4.17, 95% CI 2.16-8.05)., Conclusion: Patients with alcoholic etiology and obese men (but not women) are at substantially increased risk of MSOF in AP., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice., (© 2023. The Author(s).)

Anemia was a risk factor for a worse prognosis of many diseases. This study aims to investigate the relationship between anemia and the severity and prognosis of acute pancreatitis (AP). Inpatients hospitalized at the First Affiliated Hospital of Guangdong Pharmaceutical University with a primary diagnosis of AP between 1st July 2016 to 31st December 2020 were enrolled. Subsequently, disease severity, the incidence of complications, and the prognosis of patients with AP were compared between the anemic group and the non-anemic group. A total of 282 patients with acute pancreatitis were enrolled; 68.43% of them were also diagnosed with anemia. Notably, these patients had more severe disease (higher RANSON, acute physiologic assessment and chronic health evaluation-II, bedside index for severity in acute pancreatitis, and multiple organ dysfunction syndrome scores); higher incidence of organ failure (acute kidney injury [AKI] and acute heart failure); worse prognosis (higher incidence of vasoactive and diuretic agent use, longer hospital stays, and higher hospital costs) compared to that of patients without anemia (all P < .05). After adjusting for potential confounders, acute physiologic assessment and chronic health evaluation-II, bedside index for severity in acute pancreatitis, multiple organ dysfunction syndrome scores, hospital stay, and hospital costs in anemic patients were higher than those in non-anemic patients; besides, the incidence of AKI and using a diuretic agent in anemic patients was 6.645 and 4.053 times that of non-anemic patients in AP, respectively (all P < .05). Acute pancreatitis patients with anemia have more disease severity, higher incidence of AKI, and worse prognosis compared to those without anemia., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Systemic inflammatory response syndrome (SIRS), sepsis and associated organ dysfunctions are life-threating conditions occurring at paediatric intensive care units (PICUs). Early recognition and treatment within the first hours of onset are critical. However, time pressure, lack of personnel resources, and the need for complex age-dependent diagnoses impede an accurate and timely diagnosis by PICU physicians. Data-driven prediction models integrated in clinical decision support systems (CDSS) could facilitate early recognition of disease onset., Objectives: To estimate the sensitivity and specificity of previously developed prediction models (index tests) for the detection of SIRS, sepsis and associated organ dysfunctions in critically ill children up to 12 hours before reference standard diagnosis is possible., Methods and Analysis: We conduct a monocentre, prospective diagnostic test accuracy study. Clinicians in the PICU of the tertiary care centre Hannover Medical School, Germany, continuously screen and recruit patients until the adaptive sample size (originally intended sample size of 500 patients) is enrolled. Eligible are children (0-17 years, all sexes) who stay in the PICU for ≥12 hours and for whom an informed consent is given. All eligible patients are independently assessed for SIRS, sepsis and organ dysfunctions using corresponding predictive and knowledge-based CDSS models. The knowledge-based CDSS models serve as imperfect reference standards. The assessments are used to estimate the sensitivities and specificities of each predictive model using a clustered nonparametric approach (main analysis). Subgroup analyses ('age groups', 'sex' and 'age groups by sex') are predefined., Ethics and Dissemination: This study obtained ethics approval from the Hannover Medical School Ethics Committee (No. 10188&#95;BO&#95;SK&#95;2022). Results will be disseminated as peer-reviewed publications, at scientific conferences, and to patients in an appropriate dissemination approach., Trial Registration Number: This study was registered with the German Clinical Trial Register (DRKS00029071) on 2022-05-23., Protocol Version: 10188&#95;BO&#95;SK&#95;2022&#95;V.2.0-20220330&#95;4&#95;Studienprotokoll., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Motivation: Sepsis is a leading cause of death and disability in children globally, accounting for ∼3 million childhood deaths per year. In pediatric sepsis patients, the multiple organ dysfunction syndrome (MODS) is considered a significant risk factor for adverse clinical outcomes characterized by high mortality and morbidity in the pediatric intensive care unit. The recent rapidly growing availability of electronic health records (EHRs) has allowed researchers to vastly develop data-driven approaches like machine learning in healthcare and achieved great successes. However, effective machine learning models which could make the accurate early prediction of the recovery in pediatric sepsis patients from MODS to a mild state and thus assist the clinicians in the decision-making process is still lacking., Results: This study develops a machine learning-based approach to predict the recovery from MODS to zero or single organ dysfunction by 1 week in advance in the Swiss Pediatric Sepsis Study cohort of children with blood-culture confirmed bacteremia. Our model achieves internal validation performance on the SPSS cohort with an area under the receiver operating characteristic (AUROC) of 79.1% and area under the precision-recall curve (AUPRC) of 73.6%, and it was also externally validated on another pediatric sepsis patients cohort collected in the USA, yielding an AUROC of 76.4% and AUPRC of 72.4%. These results indicate that our model has the potential to be included into the EHRs system and contribute to patient assessment and triage in pediatric sepsis patient care., Availability and Implementation: Code available at https://github.com/BorgwardtLab/MODS-recovery. The data underlying this article is not publicly available for the privacy of individuals that participated in the study., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Critical trauma patients are particularly prone to increased mortality risk; hence, an accurate prediction of their conditions enables early identification of patients' mortality status. Thus, we aimed to develop and validate a real-time prediction model for physiological changes, organ dysfunctions and mortality risk in critical trauma patients., Methods: We used Dynamic Bayesian Networks (DBNs) to model complicated relationships of physiological variables across time slices, accessing data of trauma patients from the Medical Information Mart for Intensive Care database (MIMIC-III) (n = 2915) and validated with patients' data from ICU admissions at the Changhai Hospital (ICU-CH) (n = 1909). The DBN model's evaluation included the predictive ability of physiological changes, organ dysfunctions and mortality risk., Results: Our DBN model included two static variables (age and sex) and 18 dynamic physiological variables. The differences in ratios between the real values and the 24- and 48-h predicted values of most physiological variables were within 5% in the two datasets. The accuracy of our DBN model for predicting renal, hepatic, cardiovascular and hematologic dysfunctions was more than 0.8.The calculated area under the curve (AUC) from receiver operating characteristic curves and 95% confidence interval for predicting the 24- and 48-h mortality risk were 0.977 (0.967-0.988) and 0.958 (0.945-0.971) in the MIMIC-III and 0.967 (0.947-0.987) and 0.946 (0.925-0.967) in ICU-CH., Conclusions: A DBN is a promising method for predicting medical temporal data such as trauma patients' mortality risk, demonstrated by high AUC scores and validation by a real-life ICU scenario; thus, our DBN prediction model can be used as a real-time tool to predict physiological changes, organ dysfunctions and mortality risk during ICU admissions., (© 2022. The Author(s).)

Study Design: This is a retrospective, observational study., Objectives: To evaluate organ dysfunction in patients with an acute traumatic spinal cord injury (ATSCI) above T6 using the Sequential Organ Failure Assessment (SOFA) score to determine its association with mortality., Setting: The study was performed at the intensive care unit (ICU) of a tertiary hospital in the northwest of Spain., Methods: The study included 241 patients with an ATSCI above T6 who had been admitted to the ICU between 1998 and 2017. A descriptive analysis of all variables collected was performed to compare the survivors with the non-survivors. In addition, a logistic regression model was used in the multivariate analysis to identify variables that were independently associated with mortality., Results: The results revealed significant differences between the survivors and non-survivors in terms of their age, Charlson Comorbidity Index, Glasgow Coma Scale score on admission, APACHE II score, SOFA score on day 0 and day 4, and delta SOFA 4-0 (ΔSOFA 4-0). The results of this multivariate analysis identified the following variables as independent predictors of intra-ICU mortality: age (OR = 1.05; 95% CI: 1. 01-1.08), SOFA score on day 0 (OR = 1.42; 95% CI: 1.13-1.78), ΔSOFA 4-0 (OR = 1.53; 95% CI: 1.25-1.87), and fluid balance on day 4 (OR = 1.16; 95% CI: 1.00-1.35)., Conclusions: The SOFA score is useful for evaluating organ dysfunction in patients with an ATSCI above T6. After adjusting the analysis for conventional variables, organ dysfunction on admission, changes in organ function between day 4 and day 0 (ΔSOFA 4-0), and fluid balance on day 4 were seen to be independently associated with mortality in our study., (© 2021. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Macrophage activation syndrome (MAS) is a severe and under-recognized complication of rheumatologic diseases. We describe a patient who presented with rapidly progressive, refractory MAS found to have anti-MDA5 antibody Juvenile Dermatomyositis (JDM) as her underlying rheumatologic diagnosis., Case Presentation: We describe a 14-year-old female who at the time of admission had a history of daily fevers for 6 weeks and an unintentional sixteen-pound weight loss. Review of systems was significant for cough, shortness of breath, chest pain, headaches, sore throat, muscle aches, rash, nausea, and loss of appetite. An extensive initial workup revealed findings consistent with an autoimmune process. While awaiting results of her workup she had clinical decompensation with multi-organ system involvement including pancytopenias, interstitial lung disease, hepatitis, cardiac involvement, gastrointestinal distension and pain, feeding intolerance, extensive mucocutaneous candidiasis, and neuropsychiatric decline. Due to her decompensation, significant interstitial lung disease, and likely underlying rheumatologic condition she was started on high dose pulse steroids and mycophenolate. An MRI was performed due to her transaminitis and shoulder pain revealing significant myositis. Intravenous immunoglobulin was then initiated. The myositis antibody panel sent early in her workup was significant for anti-MDA5 and anti-SSA-52 antibodies. Despite high dose pulse steroids, mycophenolate, and IVIG, her disease progressed requiring escalating therapies. Ultimately, she responded with resolution of her MAS as well as significant and steady improvement in her feeding intolerance, interstitial lung disease, cardiac dysfunction, myositis, arthritis, and cutaneous findings., Conclusions: JDM in the pediatric patient is rare, as is MAS. In patients with complex rheumatologic conditions and lack of response to treatment, it is important to continually assess the patient's clinical status with MAS in mind, as this may change the treatment approach. Without proper recognition of this complication, patients can have a significant delay in diagnosis leading to life-threatening consequences., (© 2022. The Author(s).)

Sepsis is a systemic inflammatory response syndrome caused by viral infection. The circulatory dysfunction caused by sepsis is also called septic shock or septic shock. The main characteristics are rapid onset, rapid changes, and involvement. Multiple organs in the body make diagnosis difficult, which seriously threatens the survival of patients. As many as one million people worldwide die every year because of SIRS, it is also the leading cause of death among children in hospital ICUs. This article is aimed at studying the clinical characteristics of severe sepsis in children and the risk factors for death. Based on the analysis of the pathogenesis of sepsis and the treatment of septic shock, 65 cases of children with PICU sepsis admitted to a hospital were selected. Data, to study its clinical characteristics and risk factors for death. The results of the study showed that despite the interaction among the removal factors of the three indexes of serum lactic acid value, PCIS level, and the number of organs involved in MODS, they are still related to the mortality of children with severe sepsis., Competing Interests: There is no potential conflict of interest in our paper., (Copyright © 2022 Ying Zhang et al.)

Rationale: Use of severity of illness scores to classify patients for clinical care and research is common outside of the neonatal ICU. Extremely premature (<29 weeks' gestation) infants with extremely low birth weight (<1,000 g) experience significant mortality and develop severe pathology during the protracted birth hospitalization. Objectives: To measure at high resolution the changes in organ dysfunction that occur from birth to death or discharge home by gestational age and time, and among extremely preterm infants with and without clinically meaningful outcomes using the neonatal sequential organ failure assessment score. Methods: A single-center, retrospective, observational cohort study of inborn, extremely preterm infants with extremely low birth weight admitted between January 2012 and January 2020. Neonatal sequential organ failure assessment scores were calculated every hour for every patient from admission until death or discharge. Measurements and Main Results: Longitudinal, granular scores from 436 infants demonstrated early and sustained discrimination of those who died versus those who survived to discharge. The discrimination for mortality by the maximum score was excellent (area under curve, 0.91; 95% confidence intervals, 0.88-0.94). Among survivors with and without adverse outcomes, most score variation occurred at the patient level. The weekly average score over the first 28 days was associated with the sum of adverse outcomes at discharge. Conclusions: The neonatal sequential organ failure assessment score discriminates between survival and nonsurvival on the first day of life. The major contributor to score variation occurred at the patient level. There was a direct association between scores and major adverse outcomes, including death.

Objective: To explore association between serum ferritin and severity of sepsis among children, and relate levels to the final outcome., Methods: This observational study was conducted in a tertiary care hospital between I February and 30 July, 2019. Serum ferritin level was estimated in children (age 6 months to 12 years) suffering from sepsis, irrespective of the probable etiology. Children with hemoglobinopathies, autoimmune diseases, previous blood transfusion, severe acute malnutrition, hemophagocytic lymphohistiocytosis and chronic hepatitis were excluded. The ferritin level was measured sequentially at pre-defined stages of illness viz., sepsis, severe sepsis, septic shock and multiorgan dysfunction syndrome (MODS). Association between serum ferritin and severity of sepsis was analyzed, and ferritin level was related to the final outcome of death or recovery by receiver operating characteristic (ROC) curve analysis., Results: The study group included 47 children with sepsis who progressed to a state of MODS; 32 recovered from MODS. Significant differences in serum ferritin level were observed with severity of sepsis. There was clear demarcation of ferritin levels between sepsis severity stages. The proportion of death among the 47 MODS cases was 31.9% (95% CI 18.6 - 45.2%). ROC analysis in the MODS group indicated that serum ferritin >1994.3 ng/mL predicts mortality (AUC 0.73 [95% CI 0.58-0.85]) with sensitivity 66.7% [95% CI 38.4-88%] and specificity 100.0% [95% CI 89.1-100%]., Conclusions: There is clear demarcation of serum ferritin levels that can help differentiation of sepsis severity stages in children with sepsis. There is no such demarcation between survivors and non-survivors in MODS cases.

Introduction: Little is known about the relationship between arterial stiffness and cardiovascular target organ damage (TOD) in the general population. The aim was to analyse the relationship between different measurements of arterial stiffness and TOD, in a general Spanish population without a history of cardiovascular event., Materials and Methods: Transversal descriptive study. Through stratified random sampling, a total of 501 individuals were included. Carotid-femoral pulse wave velocity (cf-PWV) was measured using a SphygmoCor System ® , the cardio-ankle vascular index (CAVI) was determined with aVasera VS-1500 ® and brachial-ankle pulse wave velocity (ba-PWV)was calculated through a validated equation., Results: The average age was 55.84 ± 14.26.The percentage of vascular TOD, left ventricular hypertrophy (LVH) and renal TOD was higher in men ( p  < .001). A positive correlation was obtained between carotid intima-media thickness (c-IMT) and the measurements of vascular function. In the model 1 of the logistic regression analysis, cf-PWV was associated with vascular TOD (OR = 1.15, p  = .040), ba-PWV was associated with vascular TOD (OR = 1.20, p  = .010) and LVH (OR = 1.12, p  = .047)., Conclusions: The different measurements of arterial stiffness are highly associated with each other. Moreover, cf-PWV and ba-PWV were associated with vascular TOD, and ba-PWV with LVH, although they disappear when adjusting for cardiovascular risk factors. Key Messages There is a strong correlation between the different measurements of vascular structure and function. Carotid-femoral and brachial-ankle pulse wave velocity were positively associated with vascular target organ damage, the latter was also positively associated with left ventricular hypertrophy. This associations disappear when adjusting for cardiovascular risk factors.

Background: Shock and organ damage occur in critically ill patients in the emergency department because of biological responses to invasion, and cytokines play an important role in their development. It is important to predict early multiple organ dysfunction (MOD) because it is useful in predicting patient outcomes and selecting treatment strategies. This study examined the accuracy of biomarkers, including interleukin (IL)-6, in predicting early MOD in critically ill patients compared with that of quick sequential organ failure assessment (qSOFA)., Methods: This was a multicenter observational sub-study. Five universities from 2016 to 2018. Data of adult patients with systemic inflammatory response syndrome who presented to the emergency department or were admitted to the intensive care unit were prospectively evaluated. qSOFA score and each biomarker (IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein, and procalcitonin [PCT]) level were assessed on Days 0, 1, and 2. The primary outcome was set as MOD on Day 2, and the area under the curve (AUC) was analyzed to evaluate qSOFA scores and biomarker levels., Results: Of 199 patients, 38 were excluded and 161 were included. Patients with MOD on Day 2 had significantly higher qSOFA, SOFA, and Acute Physiology and Chronic Health Evaluation II scores and a trend toward worse prognosis, including mortality. The AUC for qSOFA score (Day 0) that predicted MOD (Day 2) was 0.728 (95% confidence interval [CI]: 0.651-0.794). IL-6 (Day 1) showed the highest AUC among all biomarkers (0.790 [95% CI: 0.711-852]). The combination of qSOFA (Day 0) and IL-6 (Day 1) showed improved prediction accuracy (0.842 [95% CI: 0.771-0.893]). The combination model using qSOFA (Day 1) and IL-6 (Day 1) also showed a higher AUC (0.868 [95% CI: 0.799-0.915]). The combination model of IL-8 and PCT also showed a significant improvement in AUC., Conclusions: The addition of IL-6, IL-8 and PCT to qSOFA scores improved the accuracy of early MOD prediction., (© 2021. The Author(s).)

Background: To provide multivariable prognostic models for severe complications prediction after heart valve surgery, including low cardiac output syndrome (LCOS), acute kidney injury requiring hemodialysis (AKI-rH) and multiple organ dysfunction syndrome (MODS)., Methods: We developed multivariate logistic regression models to predict severe complications after heart valve surgery using 930 patients collected retrospectively from the first affiliated hospital of Sun Yat-Sen University from January 2014 to December 2015. The validation was conducted using a retrospective dataset of 713 patients from the same hospital from January 2016 to March 2017. We considered two kinds of prognostic models: the PRF models which were built by using the preoperative risk factors only, and the PIRF models which were built by using both of the preoperative and intraoperative risk factors. The least absolute shrinkage selector operator was used for developing the models. We assessed and compared the discriminative abilities for both of the PRF and PIRF models via the receiver operating characteristic (ROC) curve., Results: Compared with the PRF models, the PIRF modes selected additional intraoperative factors, such as auxiliary cardiopulmonary bypass time and combined tricuspid valve replacement. Area under the ROC curves (AUCs) of PRF models for predicting LCOS, AKI-rH and MODS are 0.565 (0.466, 0.664), 0.688 (0.62, 0.757) and 0.657 (0.563, 0.751), respectively. As a comparison, the AUCs of the PIRF models for predicting LOCS, AKI-rH and MODS are 0.821 (0.747, 0.896), 0.78 (0.717, 0.843) and 0.774 (0.7, 0.847), respectively., Conclusions: Adding the intraoperative factors can increase the predictive power of the prognostic models for severe complications prediction after heart valve surgery., (© 2021. The Author(s).)

The Coronavirus disease 19 (Covid-19) pandemic is devastating the public health: it is urgent to find a viable therapy to reduce the multiorgan damage of the disease. A validated therapeutic protocol is still missing. The most severe forms of the disease are related to an exaggerated inflammatory response. The pivotal role of reactive oxygen species (ROS) in the amplification of inflammation makes the antioxidants a potential therapy, but clinical trials are needed. The lecitinized superoxide dismutase (PC-SOD) could represent a possibility because of bioaviability, safety, and its modulatory effect on the innate immune response in reducing the harmful consequences of oxidative stress. In this review we summarize the evidence on lecitinized superoxide dismutase in animal and human studies, to highlight the rationale for using the PC-SOD to treat COVID-19., (Copyright © 2021. Published by Elsevier Masson SAS.)

COVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology. Sequential Organ Failure Assessment (SOFA) score is an objective and comprehensive measurement that measures dysfunction severity of six organ systems, i.e., cardiovascular, central nervous system, coagulation, liver, renal, and respiration. Our aim was to identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of SOFA score. Intubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Distinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p = 0.033; intermediate stratum, 29.3% vs. 8.0%, p = 0.002; severe stratum, 53.7% vs. 22.2%, p < 0.001). Pathophysiologic biomarkers associated with progression were distinct at each stratum, including findings suggestive of inflammation in low baseline severity of illness versus hemophagocytic lymphohistiocytosis in higher baseline severity of illness. The findings suggest that there are clear worsening and recovering subphenotypes of COVID-19 respiratory failure after intubation, which are more predictive of outcomes than baseline severity of illness. Distinct progression biomarkers at differential baseline severity of illness suggests a heterogeneous pathobiology in the progression of COVID-19 respiratory failure., (© 2021. The Author(s).)

Background: Although both leukocytosis and leukopenia have been considered Systemic Inflammatory Response Syndrome criteria, leukopenia is not generally considered a normal response to infection. We sought to evaluate the prognostic validity of leukopenia as a sign of sepsis-defining hematological organ dysfunction within the Sepsis-3 framework. We hypothesized that leukopenia is associated with higher risk of mortality than leukocytosis among patients with suspected infection., Methods: We performed a retrospective cohort study using the Medical Information Mart v1.4 in Intensive Care-III database. Multivariable regression models were used to evaluate the association between leukopenia and mortality in patients with suspected infection defined by Sepsis-3., Results: We identified 5,909 ICU patients with suspected infection; 250 (4.2%) had leukopenia. Leukopenia was associated with increased in-hospital mortality compared with leukocytosis (OR, 1.5; 95% CI 1.1-1.9). After adjusting for demographics and comorbidities in the Sepsis-3 consensus model, leukopenia remained associated with increased risk of mortality compared with leukocytosis (OR 1.6, 95% CI 1.2-2.2). Further adjustment for the platelet component of the SOFA attenuated the association between leukopenia and mortality (OR decreased from 1.5 to 1.1). However, 83 (1.4%) of patients had leukopenia without thrombocytopenia and 14 had leukopenia prior to thrombocytopenia., Conclusions: Among ICU patients with suspected infection, leukopenia was associated with increased risk of death compared with leukocytosis. Due to correlation with thrombocytopenia, leukopenia did not independently improve the prognostic validity of SOFA; however, leukopenia may present as a sign of sepsis prior to thrombocytopenia in a small subset of patients., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Existing laboratory markers and clinical scoring systems have shown suboptimal accuracies for early prediction of persistent organ failure (POF) in acute pancreatitis (AP). We used information theory and machine learning to select the best-performing panel of circulating cytokines for predicting POF early in the disease course and performed verification of the cytokine panel's prognostic accuracy in an independent AP cohort., Methods: The derivation cohort included 60 subjects with AP with early serum samples collected between 2007 and 2010. Twenty-five cytokines associated with an acute inflammatory response were ranked by computing the mutual information between their levels and the outcome of POF; 5 high-ranking cytokines were selected. These cytokines were subsequently measured in early serum samples of an independent prospective verification cohort of 133 patients (2012-2016), and the results were trained in a Random Forest classifier. Cross-validated performance metrics were compared with the predictive accuracies of conventional laboratory tests and clinical scores., Results: Angiopoietin 2, hepatocyte growth factor, interleukin 8, resistin, and soluble tumor necrosis factor receptor 1A were the highest-ranking cytokines in the derivation cohort; each reflects a pathologic process relevant to POF. A Random Forest classifier trained the cytokine panel in the verification cohort and achieved a 10-fold cross-validated accuracy of 0.89 (area under the curve 0.91, positive predictive value 0.89, and negative predictive value 0.90), which outperformed individual cytokines, laboratory tests, and clinical scores (all P ≤ 0.006)., Discussion: We developed a 5-cytokine panel, which accurately predicts POF early in the disease process and significantly outperforms the prognostic accuracy of existing laboratory tests and clinical scores., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objective: To investigate clinical immunological characteristics and imaging findings of multiple organ damage of systemic lupus erythematosus (SLE) patients with hematologic involvement. Methods: SLE patients diagnosed in the Second Affiliated Hospital of Nanchang University from June 2015 to March 2019 were selected, including 93 SLE patients with hematologic involvement and 68 SLE patients without hematologic involvement. Immunological indicators such as autoantibodies, immunoglobulin G (IgG), complement 4 (C4) and imaging data of several organs were measured respectively. The results were statistically analyzed. Results: SLE patients with hematologic involvement were more likely to have autoimmune hemolytic anemia (AIHA) (20.43%, P <0.05). The erythrocyte sedimentation rate (ESR) of SLE patients with hematologic involvement was 75.82 (±35.33) mm/h, IgG was 28.84 (±6.00) g/L and C4 was 0.073 (±0.031) g/L ( P < 0.05). The area under the curve (AUC) of IgG was the highest among the above indicators ( P <0.01). The positive anti-RO-52 antibody (OR=15.926, P <0.05) was an independent risk factor for pulmonary inflammatory lesions in SLE patients with hematologic involvement. Conclusion: Compared with the control group, abnormal immunological indicators and multiple organs damage are more obvious. Positive anti-RO-52 antibody may play an important role in the pathogenesis of pulmonary inflammation in SLE patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Multiple organ dysfunction syndrome (MODS) and the consecutive multiple organ failure (MOF) are severe and dreaded complications with a high mortality in multiple trauma patients. The aim of this study was to investigate the potential of the adipokines leptin, resistin, interleukin-17A and interleukin-33 as possible biomarkers in the early posttraumatic inflammatory response and for identifying severely traumatized patients at risk of developing MODS., Methods: In total, 14 multiple trauma patients with an injury severity score (ISS) ≥ 16 as well as a control group of 14 non-multiple trauma patients were included in this study and blood samples were taken at the time points 0, 6, 24, 48 and 72 h after admission. For the trauma patients, the SIRS and Denver MOF score were determined daily. The quantitative measurement of the plasma concentrations of the adipokines was performed using ELISA., Results: In the statistical analysis, the multiple trauma patients showed statistically significant higher plasma concentrations of leptin, resistin, IL-17A and IL-33 compared to the control group. In addition, there was a statistically significant positive correlation between the concentrations of resistin, IL-17A and IL-33 and the corresponding SIRS scores and between the concentrations of resistin, IL-17A and IL-33 and the corresponding Denver MOF scores. Finally, ROC curve analysis revealed that the adipokines leptin and IL-17A are suitable diagnostic markers for the discrimination between multiple trauma patients with and without MOF., Conclusions: Leptin and IL-17A could be suitable diagnostic markers to identify severely injured patients with a developing SIRS and MOF earlier, to adjust surgical therapy planning and intensive care.

Critical care medicine has been a field for Bayesian networks (BNs) application for investigating relationships among failing organs. Criticisms have been raised on using mortality as the only outcome to determine the treatment efficacy. We aimed to develop a dynamic BN model for detecting interrelationships among failing organs and their progression, not predefining outcomes and omitting hierarchization of organ interactions. We collected data from 850 critically ill patients from the national database used in many intensive care units. We considered as nodes the organ failure assessed by a score as recorded daily. We tested several possible DBNs and used the best bootstrapping results for calculating the strength of arcs and directions. The network structure was learned using a hill climbing method. The parameters of the local distributions were fitted with a maximum of the likelihood algorithm. The network that best satisfied the accuracy requirements included 15 nodes, corresponding to 5 variables measured at three times: ICU admission, second and seventh day of ICU stay. From our findings some organ associations had probabilities higher than 50% to arise at ICU admittance or in the following days persisting over time. Our study provided a network model predicting organ failure associations and their evolution over time. This approach has the potential advantage of detecting and comparing the effects of treatments on organ function., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Acutefatty liver of pregnancy (AFLP) is a potentially fatal obstetric emergency characterized by acute hepatic failure secondary to fatty infiltration. The resultant effects include coagulopathy, electrolyte abnormalities, and multisystem organ dysfunction. Pancreatitis typically develops after the onset of renal and hepatic dysfunction. Pancreatitis has been suggested as a poor prognostic indicator because it is associated with more adverse outcomes., Patient Concerns: A 29-year-old Chinese woman at 34.7 weeks pregnancy was admitted to hospital due to paroxysmal hypogastric pain and massive colporrhagia for 1 day., Diagnosis: Laboratory tests revealed hepatic and renal impairment, coagulopathy. Thoracoabdominal computed tomography (CT) scanning showed pleural and peritoneal effusion, fatty liver, and pancreatitis. She was diagnosed with AFLP, severe acute pancreatitis (SAP), multiple organ dysfunction syndrome (MODS), and intrauterine fetal death., Interventions: The patient was treated with blood component transfusions, plasma exchange combined with renal replacement therapy, antibiotic de-escalation, gastric and pancreatic secretion inhibitor, and enteral nutrition., Outcomes: After successful management, the patient was discharged without any complications on day 35 of admission. At 10 months follow-up, thoracoabdominal enhanced CT revealed was normal and laboratory tests revealed normal liver and kidney function., Lessons: Once AFLP is highly suspected or confirmed, the pregnancy should be terminated in time and active symptomatic management should be given., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Fibrinolysis shutdown associated with severe thrombotic complications is a recently recognized syndrome that was previously seldom investigated in patients with severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It presents a unique therapeutic dilemma, as anticoagulation with heparin alone is insufficient to address the imbalance in fibrinolysis. And while the use of fibrinolytic agents could limit the disease severity, it is often associated with bleeding complications. There is a need for biomarkers that will guide the timely stratification of patients into those who may benefit from both anticoagulant and fibrinolytic therapies., Patient Concerns: All 3 patients presented with shortness of breath along with comorbidities predisposing them to severe SARS-CoV-2 infection. One patient (Patient 3) also suffered from bilateral deep venous thrombosis., Diagnoses: All 3 patients tested positive for SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) and were eventually diagnosed with respiratory failure necessitating intubation., Interventions: All 3 patients required mechanical ventilation support, 2 of which also required renal replacement therapy. All 3 patients were also placed on anticoagulation therapy., Outcomes: In Patients 1 and 2, the initial D-dimer levels of 0.97 μg/ml fibrinogen equivalent units (FEU) and 0.83 μg/ml FEU were only slightly elevated (normal <0.50 μg/ml FEU). They developed rising D-dimer levels to a peak of 13.21 μg/ml FEU and >20.0 μg/ml FEU, respectively, which dropped to 1.34 μg/ml FEU 8 days later in Patient 1 and to 2.94 μg/ml on hospital day 13 in Patient 2. In Patient 3, the D-dimer level on admission was found to be elevated to >20.00 μg/ml FEU together with imaging evidence of thrombosis. And although he received therapeutic heparin infusion, he still developed pulmonary embolism (PE) and his D-dimer level declined to 5.91 μg/ml FEU. Despite "improvement" in their D-dimer levels, all 3 patients succumbed to multi-system organ failure. On postmortem examination, numerous arterial and venous thromboses of varying ages, many consisting primarily of fibrin, were identified in the lungs of all patients., Lessons: High D-dimer levels, with subsequent downtrend correlating with clinical deterioration, seems to be an indicator of fibrinolysis suppression. These findings can help form a hypothesis, as larger cohorts are necessary to demonstrate their reproducibility., Competing Interests: Oksana Volod, MD, is a consultant for Stago Diagnostica and Haemonetics. No conflict of interest is declared for the remaining authors., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Since the emergence of SARS-CoV-2, clinicians have been challenged with a wide spectrum of disease severity. One of the serious complications associated with the virus is multisystem inflammatory syndrome in children (MIS-C). It is characterised by inflammation leading to organ damage, in the setting of positive SARS-CoV-2 infection. MIS-C is thought to be a postviral reaction where most children are negative on PCR testing but are positive for SARS-CoV-2 antibodies. The Centers for Disease Control and Prevention recently defined the same phenomenon occurring in adults as multisystem inflammatory syndrome in adults (MIS-A) and emphasised on the use of antibody testing in this population. Here we describe an adult woman with an exposure to SARS-CoV-2 who presented with unexplained organ failure and shock. Positive antibody testing was the only clue to the diagnosis of MIS-A. We stress the importance of SARS-CoV-2 antibody detection in order to identify these cases., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome are two uncommon disorders that mimic each other clinically, but are distinct pathophysiologically. This study aimed to compare maternal and neonatal outcomes between AFLP and HELLP syndrome., Methods: This retrospective cohort study was performed at a tertiary referral center in Taiwan between June 2004 and April 2020. We used the Swansea Criteria to diagnose AFLP, and the Tennessee Classification System to diagnose HELLP syndrome. Maternal characteristics, laboratory data, complications, and neonatal outcomes were compared. We analyzed the categorical variables with Chi-square test or Fisher's exact test and continuous variables with Student's t test or Mann-Whitney U test. Subsequent logistic regression analyses adjusting by potential confounding factors with significant difference were analyzed., Results: During the study period, 21 women had AFLP and 80 women had HELLP syndrome. There was a higher rate of preeclampsia (95.0 % versus 23.8 %) in the HELLP syndrome group compared to the AFLP group. However, the AFLP group had more other maternal complications including jaundice (85.7 % versus 13.8 %), acute kidney injury (61.9 % versus 15.0 %), disseminated intravascular coagulopathy (66.7 % versus 8.8 %), and sepsis (47.6 % versus 10.0 %) compared to the HELLP syndrome group. Nevertheless, higher rates of small for gestational age neonates (57.1 % versus 33.3 %), neonatal respiratory distress syndrome (39.2 % versus 8.3 %) and neonatal sepsis (34.2 % versus 12.5 %) were noted in the HELLP syndrome group., Conclusions: AFLP is associated with a higher rate of multiple organ dysfunction in mothers, whereas HELLP syndrome is associated with a higher rate of neonatal morbidity.

INTRODUCTIONThe clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories.METHODSWe conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza.RESULTSWe found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist.CONCLUSIONcfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.FUNDINGIntramural Targeted Anti-COVID-19 grant, NIH.

Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups ( n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.

Objective: Our aim was to assess the accuracy of angiopoietin-2 (Ang-2) as a prognostic marker for acute pancreatitis (AP) with organ failure (OF)., Methods: We undertook a systematic search of the PubMed, Cochrane Library, Embase, Chinese Journals Full-text, Wanfang, China Biology Medicine disc, and Weipu databases to identify eligible cohort studies on the predictive value of Ang-2 for AP with OF. The main outcome measures were sensitivity and specificity. The effects were pooled using a bivariate mixed-effects model., Results: Six articles with seven case-control studies (n = 650) were included. Pooled sensitivity, specificity, and positive and negative likelihood ratios with 95% confidence intervals (CI) for AP with OF were 0.93 (95%CI: 0.75-0.99), 0.85 (95%CI: 0.75-0.92), 6.40 (95%CI: 3.36-12.19), and 0.08 (95%CI: 0.02-0.36), respectively. The area under the summary receiver operating characteristic curve was 0.95 (95%CI: 0.92-0.96), and the diagnostic odds ratio was 83.18 (95%CI: 11.50-623.17). Subgroup analysis showed that admission time of AP onset (< or ≥24 hours) was a source of overall heterogeneity. Sensitivity analysis supported this finding., Conclusion: Ang-2 had high diagnostic accuracy for AP with OF; the best prediction of Ang-2 may be 24 to 72 hours after onset of AP.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an acute infectious disease that spreads mainly via the respiratory route. Elderly patients or those with underlying diseases are more seriously affected. We report a case of COVID-19 infection in a geriatric patient with arteriovenous thrombosis of the right lower limb. Despite persistent anticoagulant therapy, the patient's arterial thrombosis continued to progress and presented with ischemic necrosis of the lower extremity. After amputation in this case, the levels of D-dimer and inflammatory cytokine increased progressively, and he presented with acute myocardial infarction, which progressed rapidly to multisystem organ failure. However, whether coronavirus can directly cause the damage of the cardiovascular system and thrombosis needs further investigation.

Background: Musculoskeletal injuries are common following trauma and variables that are associated with late femur fracture fixation are important to perioperative management. Furthermore, the association of late fracture fixation and multiple organ failure (MOF) is not well defined., Methods: We performed a retrospective cohort investigation from 2 academic trauma centers., Inclusion Criteria: age 18-89 years, injury severity score (ISS) >15, femoral shaft fracture requiring operative fixation, and admission to the intensive care unit >2 days. Admission physiology variables and abbreviated injury scale (AIS) scores were obtained. Lactate was collected as a marker of shock and was described as admission lactate (LacAdm) and as 24-hour time-weighted lactate (LacTW24h), which reflects an area under the curve and is considered a marker for the overall depth of shock. The primary aim was to evaluate clinical variables associated with late femur fracture fixation (defined as ≥24 hours after admission). A multivariable logistic regression model tested variables associated with late fixation and is reported by odds ratio (OR) with 95% confidence interval (CI). The secondary aim evaluated the association between late fixation and MOF, defined by the Denver MOF score. The summation of scores (on a scale from 0 to 3) from the cardiac, pulmonary, hepatic, and renal systems was calculated and MOF was confirmed if the total daily sum of the worst scores from each organ system was >3. We assessed the association between late fixation and MOF using a Cox proportional hazards model adjusted for confounding variables by inverse probability weighting (a propensity score method). A P value <.05 was considered statistically significant., Results: One hundred sixty of 279 (57.3%) patients received early fixation and 119 of 279 (42.7%) received late fixation. LacTW24h (OR = 1.66 per 1 mmol/L increase, 95% CI, 1.24-2.21; P < .001) and ISS (OR = 1.07 per 1-point increase, 95% CI, 1.03-1.10; P < .001) were associated with higher odds of late fixation. Late fixation was associated with a 3-fold increase in the odds of MOF (hazard ratio [HR] = 3.21, 95% CI, 1.48-7.00; P < .01)., Conclusions: In a cohort of multisystem trauma patients with femur fractures, greater injury severity and depth of shock, as measured by LacTW24h, were associated with late operative fixation. Late fixation was also associated with MOF. Strategies to reduce the burden of MOF in this population require further investigation.

Background: Multiple organ dysfunction syndrome (MODS) occurs in the setting of a variety of pathologies including infection and trauma. Some patients decompensate and require Veno-Arterial extra corporeal membrane oxygenation (ECMO) as a palliating manoeuvre for recovery of cardiopulmonary function. The molecular mechanisms driving progression from MODS to cardiopulmonary collapse remain incompletely understood, and no biomarkers have been defined to identify those MODS patients at highest risk for progression to requiring ECMO support., Methods: Whole blood RNA-seq profiling was performed for 23 MODS patients at three time points during their ICU stay (at diagnosis of MODS, 72 hours after, and 8 days later), as well as four healthy controls undergoing routine sedation. Of the 23 MODS patients, six required ECMO support (ECMO patients). The predictive power of conventional demographic and clinical features was quantified for differentiating the MODS and ECMO patients. We then compared the performance of markers derived from transcriptomic profiling including [1] transcriptomically imputed leukocyte subtype distribution, [2] relevant published gene signatures and [3] a novel differential gene expression signature computed from our data set. The predictive power of our novel gene expression signature was then validated using independently published datasets., Finding: None of the five demographic characteristics and 14 clinical features, including The Paediatric Logistic Organ Dysfunction (PELOD) score, could predict deterioration of MODS to ECMO at baseline. From previously published sepsis signatures, only the signatures positively associated with patient's mortality could differentiate ECMO patients from MODS patients, when applied to our transcriptomic dataset (P-value ranges from 0.01 to 0.04, Student's test). Deconvolution of bulk RNA-Seq samples suggested that lower neutrophil counts were associated with increased risk of progression from MODS to ECMO (P-value = 0.03, logistic regression, OR=2.82 [95% CI 0.63 - 12.45]). A total of 30 genes were differentially expressed between ECMO and MODS patients at baseline (log2 fold change ≥ 1 or ≤ -1 with false discovery rate ≤ 0.01). These genes are involved in protein maintenance and epigenetic-related processes. Further univariate analysis of these 30 genes suggested a signature of seven DE genes associated with ECMO (OR > 3.0, P-value ≤ 0.05, logistic regression). Notably, this contains a set of histone marker genes, including H1F0, HIST2H3C, HIST1H2AI, HIST1H4, HIST1H2BL and HIST1H1B, that were highly expressed in ECMO. A risk score derived from expression of these genes differentiated ECMO and MODS patients in our dataset (AUC = 0.91, 95% CI 0.79-1.00, P-value = 7e-04, logistic regression) as well as validation dataset (AUC= 0.73, 95% CI 0.53-0.93, P-value = 2e-02, logistic regression)., Interpretation: This study demonstrates that transcriptomic features can serve as indicators of severity that could be superior to traditional methods of ascertaining acuity in MODS patients. Analysis of expression of signatures identified in this study could help clinicians in the diagnosis and prognostication of MODS patients after arrival to the Hospital., Competing Interests: Declaration of competing interest AB is president and cofounder of Hibiskus Biopharma, Inc, and declares that none of the work in this manuscript is related to the interests of the company. All other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Vitamin D deficiency is common in intensive care unit (ICU) patients (50 - 82%) and is associated with multi-organ dysfunction. Vitamin D deficiency alters pathways of glutamine metabolism in critical illness, but the impact of vitamin D status on glutamine levels is poorly characterised., Objectives: To assess the prevalence of vitamin D deficiency and its association with organ dysfunction and glutamine levels in a South African (SA) ICU., Methods: Records of 103 adult patients admitted to the Wits Donald Gordon Medical Centre ICU, Johannesburg, SA were retrospectively reviewed. 25-hydroxyvitamin D (25(OH)D) and glutamine levels were measured on admission. The association between admission vitamin D levels and glutamine levels, illness severity scores, organ support and outcomes was examined., Results: On ICU admission, 66% (68/103) of patients were vitamin D deficient (&lt;20 ng/mL) (95% confidence interval (CI) 56 - 75). Vitamin D deficiency was significantly associated with mechanical ventilation (40% v. 14%) (p=0.013) and a higher median sequential organ failure assessment (SOFA) score on admission (6 (interquartile range (IQR) 3 - 8) v. 4 (IQR 2 - 6)) (p=0.047) and on day 7 (5 (IQR 2 - 10) v. 2 (IQR 1 - 4)) (p=0.017). Median admission serum glutamine levels were 481 μmol/L, with 38% deficient (&lt;420 μmol/L) (95% CI 28 - 48). Vitamin D deficiency status on admission was not significantly associated with median admission glutamine levels (p=0.66)., Conclusions: Vitamin D deficiency is common in ICU patients in SA. Deficient patients were more severely ill and required more respiratory support. No significant relationship between deficiency and median glutamine levels was noted.

Importance: Multiple organ dysfunction syndrome (MODS) is a dynamic and heterogeneous process associated with high morbidity and mortality in critically ill children., Objective: To determine whether data-driven phenotypes of MODS based on the trajectories of 6 organ dysfunctions have prognostic and therapeutic relevance in critically ill children., Design, Setting, and Participants: This cohort study included 20 827 pediatric intensive care encounters among 14 285 children admitted to 2 large academic pediatric intensive care units (PICUs) between January 2010 and August 2016. Patients were excluded if they were older than 21 years or had undergone cardiac surgery. The 6 subscores of the pediatric Sequential Organ Failure Assessment (pSOFA) score were calculated for the first 3 days, including the subscores for respiratory, cardiovascular, coagulation, hepatic, neurologic, and renal dysfunctions. MODS was defined as a pSOFA subscore of at least 2 in at least 2 organs. Encounters were split in a 80:20 ratio for derivation and validation, respectively. The trajectories of the 6 subscores were used to derive a set of data-driven phenotypes of MODS using subgraph-augmented nonnegative matrix factorization in the derivation set. Data analysis was conducted from March to October 2019., Exposures: The primary exposure was phenotype membership. In the subset of patients with vasoactive-dependent shock, the interaction between hydrocortisone and phenotype membership and its association with outcomes were examined in a matched cohort., Main Outcomes and Measures: The primary outcome was in-hospital mortality. Secondary outcomes included persistent MODS on day 7, and vasoactive-free, ventilator-free, and hospital-free days. Regression analysis was used to adjust for age, severity of illness, immunocompromised status, and study site., Results: There were 14 285 patients with 20 827 encounters (median [interquartile range] age 5.2 years [1.5-12.7] years; 11 409 [54.8%; 95% CI, 54.1%-55.5%] male patients). Of these, 5297 encounters (25.4%; 95% CI, 24.8%-26.0%) were with patients who had MODS, of which 5054 (95.4%) met the subgraph count threshold and were included in the analysis. Subgraph augmented nonnegative matrix factorization uncovered 4 data-driven phenotypes of MODS, characterized by a combination of neurologic, respiratory, coagulation, and cardiovascular dysfunction, as follows: phenotype 1, severe, persistent encephalopathy (1019 patients [19.2%]); phenotype 2, moderate, resolving hypoxemia (1828 patients [34.5%]); phenotype 3, severe, persistent hypoxemia and shock (1012 patients [19.1%]); and phenotype 4, moderate, persistent thrombocytopenia and shock (1195 patients [22.6%]). These phenotypes were reproducible in a validation set of encounters, had distinct clinical characteristics, and were independently associated with outcomes. For example, using phenotype 2 as reference, the adjusted hazard ratios (aHRs) for death by 28 days were as follows: phenotype 1, aHR of 3.0 (IQR, 2.1-4.3); phenotype 3, aHR of 2.8 (IQR, 2.0-4.1); and phenotype 4, aHR of 1.8 (IQR, 1.2-2.6). Interaction analysis in a matched cohort of patients with vasoactive-dependent shock revealed that hydrocortisone had differential treatment association with vasoactive-free days across phenotypes. For example, patients in phenotype 3 who received hydrocortisone had more vasoactive-free days than those who did not (23 days vs 18 days; P for interaction < .001), whereas patients in other phenotypes who received hydrocortisone either had no difference or had less vasoactive-free days., Conclusions and Relevance: In this study, data-driven phenotyping in critically ill children with MODS uncovered 4 distinct and reproducible phenotypes with prognostic relevance and possible therapeutic relevance. Further validation and characterization of these phenotypes is warranted.

Outcomes variables for research on sepsis have centered on mortality and changes in the host immune response. However, a recent task force (Sepsis-3) revised the definition of sepsis to "life-threatening organ dysfunction caused by a dysregulated host response to infection." This new definition suggests that human studies should focus on organ dysfunction. The appropriate criteria for organ dysfunction in either human sepsis or animal models are, however, poorly delineated, limiting the potential for translation. Further, in many systems, the difference between "dysfunction" and "injury" may not be clear. In this review, we identify criteria for organ dysfunction and/or injury in human sepsis and in rodents subjected to cecal ligation and puncture (CLP), the most commonly used animal model of sepsis. We further examine instances where overlap between human sepsis and CLP is sufficient to identify translational endpoints. Additional verification may demonstrate that these endpoints are applicable to other animals and to other sepsis models, for example, pneumonia. We believe that the use of these proposed measures of organ dysfunction will facilitate mechanistic studies on the pathobiology of sepsis and enhance our ability to develop animal model platforms to evaluate therapeutic approaches to human sepsis.