Search

High precision is optimal in prehospital diagnostic algorithms for strokes and large vessel occlusions. We hypothesized that prehospital diagnostic algorithms for strokes and their subcategories using machine learning could have high predictive value. Consecutive adult patients with suspected stroke as per emergency medical service personnel were enrolled in a prospective multicenter observational study in 12 hospitals in Japan. Five diagnostic algorithms using machine learning, including logistic regression, random forest, support vector machine, and eXtreme Gradient Boosting, were evaluated for stroke and subcategories including acute ischemic stroke with/without large vessel occlusions, intracranial hemorrhage, and subarachnoid hemorrhage. Of the 1446 patients in the analysis, 1156 (80%) were randomly included in the training (derivation) cohort and cohorts, and 290 (20%) were included in the test (validation) cohort. In the diagnostic algorithms for strokes using eXtreme Gradient Boosting had the highest diagnostic value (test data, area under the receiver operating curve 0.980). In the diagnostic algorithms for the subcategories using eXtreme Gradient Boosting had a high predictive value (test data, area under the receiver operating curve, acute ischemic stroke with/without large vessel occlusions 0.898/0.882, intracranial hemorrhage 0.866, subarachnoid hemorrhage 0.926). Prehospital diagnostic algorithms using machine learning had high predictive value for strokes and their subcategories.

The blood lactate level is used to guide the management of trauma patients with circulatory disturbance. We hypothesized that blood lactate levels at the scene (Lac scene) could improve the prediction for immediate interventions for hemorrhage. We prospectively measured blood lactate levels and assessed retrospectively in 435 trauma patients both at the scene and on arrival at the emergency room (ER) of a level I trauma center. Primary outcome was immediate intervention for hemorrhage defined as surgical/radiological intervention and/or blood transfusion within 24 h. Physiological variables plus Lac scene significantly increased the predictive value for immediate intervention (area under the curve [AUC] 0.882, 95% confidence interval [CI] 0.839–0.925) compared to that using physiological variables only (AUC 0.837, 95% CI 0.787–0.887, P = 0.0073), replicated in the validation cohort (n = 85). There was no significant improvement in predicting value of physiological variables plus Lac scene for massive transfusion compared to physiological variables (AUC 0.903 vs 0.895, P = 0.32). The increased blood lactate level per minute from scene to ER was associated with increased probability for immediate intervention (P scene to physiological variables and the temporal elevation of blood lactate levels from scene to ER could improve the prediction of the immediate intervention.

Genetic variants are associated with altered clinical outcome of patients with sepsis and cardiovascular diseases. Common gene signaling pathways may be involved in the pathophysiology of these diseases. A better understanding of genetic commonality among these diseases may enable the discovery of important genes, signaling pathways, and therapeutic targets for these diseases. We investigated the common genetic factors by a systematic search of the literature. Twenty-four genes (ADRB2, CD14, FGB, FV, HMOX1, IL1B, IL1RN, IL6, IL10, IL17A, IRAK1, MASP2, MBL, MIR608, MIF, NOD2, PCSK9, PPARG, PROC, SERPINE1, SOD2, SVEP1, TF, TIRAP, TLR1) were extracted as reported genetic variations associated with altered outcome of both sepsis and cardiovascular diseases. Of these genes, the adverse allele (or combinations) was same in nine (ADRB2, FV, HMOX1, IL6, MBL, MIF, NOD2, PCSK9, SERPINE1), and the effect appears to be in the same direction in both sepsis and cardiovascular disease. Shared gene signaling pathways suggest that these are true biological results and could point to overlapping drug targets in sepsis and cardiovascular disease.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Acute mesenteric ischemia (AMI) is challenging to diagnose in the early phase. We tested the hypothesis that blood levels of cell-free DNA would increase early after AMI. In addition, proteome analysis was conducted as an exploratory analysis to identify other potential diagnostic biomarkers.Mesenteric ischemia, abdominal sepsis, and sham model were compared in Sprague-Dawley rats. The abdominal sepsis model was induced by cecum puncture and mesenteric ischemia model by ligation of the superior mesenteric artery. Blood levels of cell-free DNA were measured 2 h and 6 h after wound closure. Shotgun proteome analysis was performed using plasma samples obtained at the 2 h timepoint; quantitative analysis was conducted for proteins detected exclusively in the AMI models.Blood cell-free DNA levels at 2 h after wound closure were significantly higher in the AMI model than in the sham and the abdominal sepsis models (P0.05). Cell-free DNA was positively correlated with the pathologic ischemia severity score (correlation coefficient 0.793-0.834, P0.001). Derivative proteome analysis in blood at 2-h time point revealed higher intensity of paraoxonase-1 in the AMI models than in the abdominal sepsis models; the significantly high blood paraoxonase-1 levels in the AMI models were confirmed in a separate quantitative analysis (P = 0.015).Cell-free DNA was demonstrated to be a promising biomarker for the early diagnosis of mesenteric ischemia in a rat model of AMI. Paraoxonase-1 may also play a role in the differential diagnosis of mesenteric ischemia from abdominal sepsis. The current results warrant further investigation in human studies.

Current research regarding the association between body mass index (BMI) and altered clinical outcomes of sepsis in Asian populations is insufficient. We investigated the association between BMI and clinical outcomes using two Japanese cohorts of severe sepsis (derivation cohort, Chiba University Hospital, n = 614; validation cohort, multicenter cohort, n = 1561). Participants were categorized into the underweight (BMI p = 0.060). In the primary analysis, multivariate analysis adjusted for baseline imbalance revealed that patients in the underweight group had a significantly increased 28-day mortality compared to those in the non-underweight group (p = 0.031, adjusted odds ratio [OR] 1.91, 95% confidence interval [CI] 1.06–3.46). In a repeated analysis using a multicenter validation cohort (underweight n = 343, non-underweight n = 1218), patients in the underweight group had a significantly increased 28-day mortality compared to those in the non-underweight group (p = 0.045, OR 1.40, 95% CI 1.00–1.97). In conclusion, patients with a BMI

The toxicity caused by different organisms in septic shock is substantially complex and characterized by an intricate pathogenicity that involves several systems and pathways. Immune cells’ pattern recognition receptors initiate the host response to pathogens after the recognition of pathogen-associated molecular patterns. In essence, the subsequent activation of downstream pathways may progress to infection resolution or to a dysregulated host response that represents the hallmark of organ injury in septic shock. Likewise, the management of organism toxicity in septic shock is complicated and comprises a multiplicity of suitable targets. In this review, the classic immune responses to pathogens are discussed as well as other factors that are relevant in the pathogenicity of septic shock, including sepsis-induced immune suppression, inflammasome activation, intestinal permeability, and the role of lipids and proprotein convertase subtilisin/kexin type 9. Current therapies aiming to eliminate the organisms causing septic shock, recent and ongoing trials in septic shock treatment, and potential new therapeutic strategies are also explored.

Background: The IL10 family of genes includes crucial immune regulators. We tested the hypothesis that single nucleotide polymorphisms (SNPs) in IL10, IL19, IL20, and IL24 of the IL10 family gene cluster alter the clinical outcome of septic shock. Methods: Patients with septic shock (n = 1,193) were genotyped for 13 tag SNPs of IL10, IL19, IL20, and IL24. IL20 gene expression was measured in genotyped lymphoblastoid cells in vitro. Cardiac surgical ICU patients (n = 981) were genotyped for IL20 rs2981573 A/G. The primary outcome variable was 28-day mortality. Results: Patients with the G allele of IL20 rs2981573 had a significantly increased hazard of death over the 28-day period compared to patients with the A allele in the septic shock cohort (adjusted hazard ratio 1.27; 95% confidence interval 1.10-1.47; p = 8.0 × 10-4). Patients with the GG genotype had more organ dysfunction (p < 0.05). The GG genotype was associated with increased IL20 gene expression in stimulated lymphoblastoid cells in vitro (p < 0.05). The cardiac surgical ICU patients with the GG genotype had an increased length of ICU stay (p = 0.032). Conclusions: The GG genotype of IL20 rs2981573 SNP was associated with increased IL20 gene expression and increased adverse outcomes in patients with septic shock and following cardiac surgery.

Obese patients have lower sepsis mortality termed the "obesity paradox." We hypothesized that lipopolysaccharide, known to be carried within lipoproteins such as very low density lipoprotein, could be sequestered in adipose tissue during sepsis; potentially contributing a survival benefit.Retrospective analysis.University research laboratory.Vldlr knockout mice to decrease very low density lipoprotein receptors, Pcsk9 knockout mice to increase very low density lipoprotein receptor, and Ldlr knockout mice to decrease low density lipoprotein receptors. Differentiated 3T3-L1 adipocytes. Caucasian septic shock patients.We measured lipopolysaccharide uptake into adipose tissue 6 hours after injection of fluorescent lipopolysaccharide into mice. Lipopolysaccharide uptake and very low density lipoprotein receptor protein expression were measured in adipocytes. To determine relevance to humans, we genotyped the VLDLR rs7852409 G/C single-nucleotide polymorphism in 519 patients and examined the association of 28-day survival with genotype.Lipopolysaccharide injected into mice was found in adipose tissue within 6 hours and was dependent on very low density lipoprotein receptor but not low density lipoprotein receptors. In an adipocyte cell line decreased very low density lipoprotein receptor expression resulted in decreased lipopolysaccharide uptake. In septic shock patients, the minor C allele of VLDLR rs7852409 was associated with increased survival (p = 0.010). Previously published data indicate that the C allele is a gain-of-function variant of VLDLR which may increase sequestration of very low density lipoprotein (and lipopolysaccharide within very low density lipoprotein) into adipose tissue. When body mass index less than 25 this survival effect was accentuated and when body mass index greater than or equal to 25 this effect was diminished suggesting that the effect of variation in very low density lipoprotein receptor function is overwhelmed when copious adipose tissue is present.Lipopolysaccharide may be sequestered in adipose tissue via the very low density lipoprotein receptor and this sequestration may contribute to improved sepsis survival.

Previous studies have shown lipopolysaccharide from Gram-negative bacteria is cleared from the circulation via LDL receptors on hepatocytes, which are downregulated by PCSK9. Whether clearance of Gram positive bacterial lipoteichoic acid (LTA) shows similar dependence on PCSK9, and whether this is clinically relevant in Gram positive human sepsis, is unknown. We examined survival data from three cohorts of patients who had Gram positive septic shock (n = 170, n = 130, and n = 59) and found that patients who carried a PCSK9 loss-of-function (LOF) allele had significantly higher 28-day survival (73.8%) than those with no LOF alleles (52.8%) (p = 0.000038). Plasma clearance of LTA was also found to be increased in PCSK9 knockout mice compared to wildtype control mice (p = 0.002). In addition, hepatocytes pre-treated with recombinant wildtype PCSK9 showed a dose-dependent decrease in uptake of fluorescently-labeled LTA (p

Background The prognosis of non-shockable out-of-hospital cardiac arrest is worse than that of shockable out-of-hospital cardiac arrest. We investigated the associations between the etiology and prognosis of non-shockable out-of-hospital cardiac arrest patients who experienced the return of spontaneous circulation after arriving at hospital. Methods and Results All subjects were extracted from the SOS-KANTO 2012 study population. The subjects were 3,031 adults: (i) who had suffered out-of-hospital cardiac arrest, (ii) for whom there were no pre-hospital data on ventricular fibrillation/pulseless ventricular tachycardia until arrival at hospital, (iii) who experienced the return of spontaneous circulation after arriving at hospital. We compared the patients' prognosis after 1 and 3 months between various etiological and presumed cardiac factors. The proportion of the favorable brain function patients that developed pulmonary embolism or incidental hypothermia was significantly higher than that of the patients with presumed cardiac factors (1 month, P

High-density cholesterol (HDL-C) levels are influenced by genetic variation in several genes. Low levels of HDL-C have been associated with increased risk of acute kidney injury (AKI). We investigated whether genetic polymorphisms in ten genes known to regulate HDL-C levels are associated with both HDL-C levels and AKI development during sepsis. Two cohorts were retrospectively analyzed: Derivation Cohort (202 patients with sepsis enrolled at the Emergency Department from 2011 to 2014 in Vancouver, Canada); Validation Cohort (604 septic shock patients enrolled into the Vasopressin in Septic Shock Trial (VASST)). Associations between HDL-related genetic polymorphisms and both HDL-C levels, and risk for clinically significant sepsis-associated AKI (AKI KDIGO stages 2 and 3) were evaluated. In the Derivation Cohort, one genetic variant in the Cholesteryl Ester Transfer Protein (CETP) gene, rs1800777 (allele A), was strongly associated with lower HDL-C levels (17.4 mg/dL vs. 32.9 mg/dL, P = 0.002), greater CETP mass (3.43 µg/mL vs. 1.32 µg/mL, P = 0.034), and increased risk of clinically significant sepsis-associated AKI (OR: 8.28, p = 0.013). Moreover, the same allele was a predictor of sepsis-associated AKI in the Validation Cohort (OR: 2.38, p = 0.020). Our findings suggest that CETP modulates HDL-C levels in sepsis. CETP genotype may identify patients at high-risk of sepsis-associated AKI.

Background Mechanical cardiopulmonary resuscitation ( mCPR ) for patients with out‐of‐hospital cardiac arrest attending the emergency department has become more widespread in Japan. The objective of this study is to determine the association between the mCPR in the emergency department and clinical outcomes. Methods and Results In a prospective, multicenter, observational study, adult patients with out‐of‐hospital cardiac arrest with sustained circulatory arrest on hospital arrival were identified. The primary outcome was survival to hospital discharge. The secondary outcomes included a return of spontaneous circulation and successful hospital admission. Multivariate analyses adjusted for potential confounders and within‐institution clustering effects using a generalized estimation equation were used to analyze the association of the mCPR with outcomes. Between January 1, 2012 and March 31, 2013, 6537 patients with out‐of‐hospital cardiac arrest were eligible; this included 5619 patients (86.0%) in the manual CPR group and 918 patients (14.0%) in the mCPR group. Of those patients, 28.1% (1801/6419) showed return of spontaneous circulation in the emergency department, 20.4% (1175/5754) had hospital admission, 2.6% (168/6504) survived to hospital discharge, and 1.2% (75/6419) showed a favorable neurological outcome at 1 month after admission. Multivariate analyses revealed that mCPR was associated with a decreased likelihood of survival to hospital discharge (adjusted odds ratio, 0.40; 95% confidence interval, 0.20–0.78; P =0.005), return of spontaneous circulation (adjusted odds ratio, 0.71; 95% confidence interval, 0.53–0.94; P =0.018), and hospital admission (adjusted odds ratio, 0.57; 95% confidence interval, 0.40–0.80; P =0.001). Conclusions After accounting for potential confounders, the mCPR in the emergency department was associated with decreased likelihoods of good clinical outcomes after adult nontraumatic out‐of‐hospital cardiac arrest. Further studies are needed to clarify circumstances in which mCPR may benefit these patients.

Background The American Heart Association and European Resuscitation Council guidelines for cardiopulmonary resuscitation present rules for termination of resuscitation (TOR) in cases of out-of-hospital cardiac arrest (OHCA). In Japan, only doctors are legally allowed TOR in OHCA cases. Objective This study aimed to develop a new TOR rule that suits the actual situations of the Japanese emergency medical services system. Methods Five different combinations of the TOR rule criteria were compared regarding specificity and positive predictive value (PPV) for 1-month survival with unfavorable neurologic outcomes. The criteria were unwitnessed by emergency medical service personnel, unwitnessed by bystanders, initial unshockable rhythm in the field, initial asystole in the field, no shock delivered, no prehospital return of spontaneous circulation, unshockable rhythm at hospital arrival, and asystole at hospital arrival. Results A total of 13,291 cases were included. The following combination provided the highest specificity and PPV for predicting 1-month unfavorable neurologic outcomes and death: unwitnessed by bystanders, initial asystole in the field, and asystole at hospital arrival. The specificity and PPV for the combination of the three criteria for predicting 1-month unfavorable neurologic outcomes were 0.992 and 0.999, and for predicting death at 1 month after OHCA were 0.986 and 0.998, respectively. Conclusions OHCA patients fulfilling the criteria unwitnessed by bystanders and asystole in the field and at hospital arrival had universally poor outcomes. Termination of resuscitation after hospital arrival for these patients may decrease unwarranted treatments.

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n = 123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF −308GA, IL1β −31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC–AUC = 0.68), use of APACHE II score and two genetic parameters (TNF −308 and IL1β −31) enabled more accurate prediction of ICU mortality (ROC–AUC = 0.80). Significant association of two genetic polymorphisms, TNF −308 and IL1β −31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients.

はじめに:重症敗血症に酷似した病態を呈したSweet症候群の1例を経験したので報告する。症例:患者は32歳の女性。ICU入室11日前に男児を出産。その際に会陰切開施行される。翌日より39℃の発熱,血液検査上炎症反応を認めた。創感染を疑い,抗菌薬投与開始。またICU入室5日前頃より注射施行部に有痛性隆起性紅斑を認めた。抗菌薬投与を継続するも血圧低下,両側肺浸潤影を伴う呼吸状態の悪化を認め,敗血症,敗血症性ショック,敗血症性ARDS (acute respiratory distress syndrome)の疑いで,ICU入室となった。第2 ICU病日に骨盤部CT検査施行。骨盤内膿瘍が疑われ,同日ドレナージ術施行。ドレナージ液も含め各種培養検査を施行するも結果は全て陰性であった。感染症以外の疾患の存在を疑い,注射施行部に認められた有痛性隆起性紅斑に関し皮膚科医にコンサルテーションしたところ,Sweet症候群と診断された。そしてこの重症敗血症様の病態もSweet症候群に関連するものと判断された。第4 ICU病日よりSweet症候群に対してステロイドパルス療法を施行。その後すみやかに呼吸状態改善,炎症反応低下。第8 ICU病日に退室となった。考察:Sweet症候群は発熱,白血球増多などの炎症所見を呈し,かつ皮膚に有痛性隆起性紅斑を認める比較的まれな原因不明の皮膚疾患である。文献的には本症例のように重症敗血症に酷似した病態を呈したSweet症候群報告例はいままでに2例のみであり,稀な症例であった。病因は不明であるが,病理所見上好中球の増多,活性化が特徴的であり,好中球の活性,遊走に関わるG-CSF (granulocyte colony-stimulating factor)などのcytokineの関与が考えられている。治療としては感染症様症状を呈するも抗菌薬に全く反応せず,ステロイドが著効を示す。そのため,早期の診断,早期のステロイド投与が肝要である。結語:重症敗血症に酷似した病態を呈したSweet症候群の1例を経験した。感染症が疑われるが,抗菌薬に不応で,培養検査が陰性の症例はSweet症候群である可能性がある。

Introduction Neurological prognostic factors after cardiopulmonary resuscitation (CPR) in patients with cardiac arrest (CA) as early and accurately as possible are urgently needed to determine therapeutic strategies after successful CPR. In particular, serum levels of protein neuron-specific enolase (NSE) and S-100B are considered promising candidates for neurological predictors, and many investigations on the clinical usefulness of these markers have been published. However, the design adopted varied from study to study, making a systematic literature review extremely difficult. The present review focuses on the following three respects for the study design: definitions of outcome, value of specificity and time points of blood sampling. Methods A Medline search of literature published before August 2008 was performed using the following search terms: "NSE vs CA or CPR", "S100 vs CA or CPR". Publications examining the clinical usefulness of NSE or S-100B as a prognostic predictor in two outcome groups were reviewed. All publications met with inclusion criteria were classified into three groups with respect to the definitions of outcome; "dead or alive", "regained consciousness or remained comatose", and "return to independent daily life or not". The significance of differences between two outcome groups, cutoff values and predictive accuracy on each time points of blood sampling were investigated. Results A total of 54 papers were retrieved by the initial text search, and 24 were finally selected. In the three classified groups, most of the studies showed the significance of differences and concluded these biomarkers were useful for neurological predictor. However, in view of blood sampling points, the significance was not always detected. Nevertheless, only five studies involved uniform application of a blood sampling schedule with sampling intervals specified based on a set starting point. Specificity was not always set to 100%, therefore it is difficult to indiscriminately assess the cut-off values and its predictive accuracy of these biomarkers in this meta analysis. Conclusions In such circumstances, the findings of the present study should aid future investigators in examining the clinical usefulness of these markers and determination of cut-off values.