Published papers

Objective: Ischaemia–reperfusion (I/R) injury is a severe post-operative complication that triggers an inflammatory response and causes severe damage. Hydrogen gas has anti-oxidant and anti-apoptotic properties and has been shown to be safe in humans. The study aimed to investigate whether hydrogen gas protects against skeletal muscle I/R injury. Methods: Experimental basic research using mice. A total of 160 eight to 10 week old albino laboratory bred strain of house mice (25.8 ± 0.68 g) were used in this study. The mice were cable tied to the hindlimb under anaesthesia and then placed in an anaesthesia box filled with air and 2% isoflurane (control group); 80 mice were additionally subjected to 1.3% hydrogen gas in this mix (hydrogen group). After two hours, the cable ties were removed to initiate reperfusion, and hydrogen inhalation lasted for six hours in the hydrogen group. After six hours, the mice were taken out of the box and kept in cages under standard conditions until time for observation at 16 different time points after reperfusion: zero, two, four, six, eight, and 10 hours and one, two, three, four, five, six, seven, 14, 21, and 28 days. Five mice were sacrificed using excess anaesthesia at each time point, and the bilateral hindlimb tissues were harvested. The inflammatory effects of the I/R injury were assessed by evaluating serum interleukin-6 concentrations using enzyme linked immunosorbent assay, as well as histological and immunohistochemical analyses. Untreated mice with I/R injury were used as controls. Results: Hydrogen gas showed protective effects associated with a reduction in inflammatory cell infiltration (neutrophils, macrophages, and lymphocytes), a reduced area of damaged muscle, maintenance of normal muscle cells, and replacement of damaged muscle cells with neoplastic myocytes. Conclusion: Inhalation of hydrogen gas had a protective effect against hindlimb I/R injury in mice, in part by reducing inflammatory cell infiltration and in part by preserving normal muscle cells.

This study aimed to assess the value of quick sequential organ failure assessment (qSOFA) combined with other risk factors in predicting in-hospital mortality in patients presenting to the emergency department with suspected infection. This post-hoc analysis of a prospective multicenter study dataset included 34 emergency departments across Japan (December 2017 to February 2018). We included adult patients (age ≥16 years) who presented to the emergency department with suspected infection. qSOFA was calculated and recorded by senior emergency physicians when they suspected an infection. Different types of sepsisrelated risk factors (demographic, functional, and laboratory values) were chosen from prior studies. A logistic regression model was used to assess the predictive value of qSOFA for in-hospital mortality in models based on the following combination of predictors: 1) qSOFAOnly; 2) qSOFA+Age; 3) qSOFA+Clinical Frailty Scale (CFS); 4) qSOFA+Charlson Comorbidity Index (CCI); 5) qSOFA+lactate levels; 6) qSOFA+Age+CCI+CFS+lactate levels. We calculated the area under the receiver operating characteristic curve (AUC) and other key clinical statistics at Youden's index, where the sum of sensitivity and specificity is maximized. Following prior literature, an AUC >0.9 was deemed to indicate high accuracy; 0.7- 0.9, moderate accuracy; 0.5-0.7, low accuracy; and 0.5, a chance result. Of the 951 patients included in the analysis, 151 (15.9%) died during hospitalization. The AUC for predicting inhospital mortality was 0.627 (95% confidence interval [CI]: 0.580-0.673) for the qSOFAOnly model. Addition of other variables only marginally improved the model's AUC; the model that included all potentially relevant variables yielded an AUC of only 0.730 (95% CI: 0.687-0.774). Other key statistic values were similar among all models, with sensitivity and specificity of 0.55-0.65 and 0.60-0.75, respectively. In this post-hoc data analysis from a prospective multicenter study based in Japan, combining qSOFA with other sepsis-related risk factors only marginally improved the model's predictive value.

Previous studies have shown inconsistent prognostic accuracy for mortality with both quick sequential organ failure assessment (qSOFA) and the systemic inflammatory response syndrome (SIRS) criteria. We aimed to validate the accuracy of qSOFA and the SIRS criteria for predicting in-hospital mortality in patients with suspected infection in the emergency department. A prospective study was conducted including participants with suspected infection who were hospitalised or died in 34 emergency departments in Japan. Prognostic accuracy of qSOFA and SIRS criteria for in-hospital mortality was assessed by the area under the receiver operating characteristic (AUROC) curve. Of the 1060 participants, 402 (37.9%) and 915 (86.3%) had qSOFA ≥ 2 and SIRS criteria ≥ 2 (given thresholds), respectively, and there were 157 (14.8%) in-hospital deaths. Greater accuracy for in-hospital mortality was shown with qSOFA than with the SIRS criteria (AUROC: 0.64 versus 0.52, difference + 0.13, 95% CI [+ 0.07, + 0.18]). Sensitivity and specificity for predicting in-hospital mortality at the given thresholds were 0.55 and 0.65 based on qSOFA and 0.88 and 0.14 based on SIRS criteria, respectively. To predict in-hospital mortality in patients visiting to the emergency department with suspected infection, qSOFA was demonstrated to be modestly more accurate than the SIRS criteria albeit insufficiently sensitive. Clinical Trial Registration: The study was pre-registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000027258).

OBJECTIVES: While potential risks for limb ischemia have been explored in studies of venoarterial extracorporeal membrane oxygenation (ECMO), they remain inadequately defined for patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR). We identified risk factors for the development of lower limb ischemia during ECPR using a large nationwide ECPR cohort. DESIGN: A post hoc analysis was conducted using a nationwide, multicenter, retrospective study (Study of Advanced Cardiac Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan II [SAVE-J II]). SETTING: Thirty-six institutions from 2013 to 2018. PATIENTS: Adult patients who underwent ECPR for out-of-hospital cardiac arrest.None. MEASUREMENTS AND MAIN RESULTS: Lower limb ischemia was defined as the requirement for a therapeutic distal perfusion catheter (DPC), fasciotomy, or amputation. Risk factors for lower limb ischemia were assessed using multivariate logistic regression models that included patient characteristics, ECPR-related information, and resuscitation content as potential confounders. Of the 969 patients, 72 (7.4%) developed lower limb ischemia. No significant differences were observed regarding background characteristics, cannulation location, puncture method, or venoarterial ECMO catheter size between patients with and without limb ischemia. However, a prophylactic DPC was less frequently employed in patients with lower limb ischemia than in those without (4 [5.6%] vs. 219 [24.4%]; p < 0.001). Higher incidences of cannulation-related bleeding and cannula malposition were observed in patients with limb ischemia than in those in patients without limb ischemia (22 [30.6%] vs. 162 [18.1%]; p = 0.009 and 9 [12.5%] vs. 29 [3.2%]; p < 0.001, respectively). Multivariable analyses revealed that prophylactic DPC placement was associated with a lower risk of limb ischemia (0.20 [0.07-0.55]; p = 0.002), whereas cannulation-related bleeding and cannula malposition were linked to an increased risk of lower limb ischemia (1.83 [1.06-3.14]; p = 0.030 and 3.81 [1.68-8.64]; p = 0.001, respectively). CONCLUSIONS: Lower limb ischemia during ECPR would be anticipated in patients with cannulation-related complications, and prophylactic DPC placement may be considered to mitigate the risk of lower limb ischemia.

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.

Background: The development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of “high disease severity” in addition to “sepsis with DIC” has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize “severe” sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy. Methods: This retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination. Results: In total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of < 1.5 and that this trend was more pronounced with higher DIC scores. Three-way interaction analysis demonstrated that anticoagulant therapy was associated with better survival outcome in patients with a high DIC score and high PT-INR. Furthermore, we identified a DIC score ≥ 5 and PT-INR ≥ 1.5 as the clinical threshold for identification of optimal targets for anticoagulant therapy. Conclusions: The combined use of the DIC score and PT-INR helps in selecting the optimal patient population for anticoagulant therapy in sepsis-induced DIC. The results obtained from this study will provide valuable information regarding the study design of randomized controlled trials examining the effects of anticoagulant therapy for sepsis. Trial registration: UMIN-CTR, UMIN000019742. Registered on November 16, 2015.

Introduction: Early appropriate care (EAC) is widely accepted as a safe strategy to perform early definitive fracture fixation, and good clinical outcomes have been reported in selected, multiply injured patients, although the optimal candidate for early definitive fixation (EDF) has not been validated. The aim of this study was to identify simple clinical parameters to help select patients who could undergo EDF. Methods: Patients with extremity injuries who underwent open reduction and internal fixation were retrospectively identified, using data from the Japan Trauma Data Bank (JTDB). Age, vital signs on hospital presentation, and the injury severity score (ISS) were examined by transforming these variables to binary categories. Patients were divided into categories based on these variables, and in-hospital mortality was compared between patients treated with EDF (EDF group) and those treated without EDF (non-EDF group) in each category. Results: Of the 12,735 patients who were eligible for the analyses, 3706 (29.1 %) were managed with EDF. In-hospital mortality was significantly higher in the EDF group than in the non-EDF group among patients with a low Glasgow Coma Scale (GCS) score (<13), low systolic blood pressure (sBP) (<90 mmHg), and ISS≥15, whereas in-hospital mortality was comparable between the EDF and non-EDF groups among patients with GCS scores ≥13, sBP ≥90 mmHg, and ISS <15. Discussion: In this large nationwide database of trauma patients, EDF was performed without affecting mortality in patients with GCS scores ≥13 and sBP ≥90 mmHg on hospital presentation, as well as ISS <15. These parameters might be useful as screening tools to select the candidates who could be treated with EDF safely.

Background: Perforated peptic ulcer (PPU) causes peritonitis and requires surgery based on disease severity. This study aimed to develop and validate a severity scale for PPU with generalized peritonitis. Materials and methods: This retrospective cohort study used a nationwide multicenter surgical database (2013-2020). Patients aged >15 years who underwent surgery for PPU with generalized peritonitis were included and categorized into the derivation (2013-2018) and two validation (2019 and 2020) cohorts. Possible severity predictors were selected via a literature review, and Lasso models were developed to predict severe postoperative adverse events with 2000 bootstrapping. Final variables for the scoring system were determined based on inclusion frequency (≥90%) in the Lasso models. Discrimination and accuracy were evaluated using C-statistics and calibration plots. Cutoff values for minimal postoperative adverse events were examined using negative predictive values. Results: Among 12 513 patients included (1202 underwent laparoscopic surgery), 533 (5.9%), 138 (7.6%), and 117 (6.9%) in the derivation and two validation cohorts experienced postoperative adverse events. Age, dyspnea at rest, preoperative sepsis, III/IV/V of American Society of Anesthesiologists physical status, and albumin and creatinine were selected for the final model. A 0-11 scoring system was developed with C-statistics of 0.812-0.819. Cutoff value was determined as 5, which predicted <3% probability of postoperative adverse events regardless of type of surgery. Conclusions: A score of <5 predicts minimal risks for postoperative adverse events and, therefore, would be clinically useful to determine the type of surgery. Further studies are needed to validate the score.

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

Introduction: The optimal distribution of burn centers remains unclear. We aimed to determine the appropriate number of burn centers per population (density) and examined a nationwide registry with the hypothesis that low-density burn centers would be associated with unfavorable outcomes. Patients and methods: A retrospective study was conducted using the Japanese Society of Burn Injury registry (2011–2021). Burn center density was defined as the number of burn centers per one million population in each prefecture, and centers were trisected on the basis of density. Hospital-free days until day 30 were compared between patients at high-, middle-, and low-density centers. Inverse probability weighting was conducted to adjust baseline characteristics, including age, burn mechanism, and burn severity. Results: We included 6764, 6209, and 2200 patients at high-, middle-, and low-density burn centers, respectively. After adjusting for patient demographics and burn severity, patients at high- and middle-density centers (≥0.4 centers per one million population) had longer hospital-free days compared with those at low-density centers (11 [0–23] vs 11 [0–23] vs 8 [0–22] days; p < 0.001). Conclusions: Low burn center density (<0.4 centers per one million population) was associated with longer hospital stay, whereas no higher limit was determined.

Purpose: This survey of bile replacement (BR) was conducted on patients with external biliary drainage to assess the current status of indication and implementation protocol of BR with special reference to infection control. Methods: A 12-item questionnaire regarding the performance of perioperative BR was sent to 124 institutions in Japan. Results: BR was performed in 29 institutions, and the indication protocol was introduced in 19. BR was performed preoperatively in 11 institutions, pre- and postoperatively in 12, and postoperatively in 6. The methods used for BR administration included oral intake (n = 10), nasogastric tube (n = 1), enteral nutrition tube (n = 3), oral intake and enteral nutrition tube (n = 6), oral intake or nasogastric tube (n = 2), nasogastric tube and enteral nutrition tube (n = 2), and oral intake or nasogastric tube and enteral nutrition tube (n = 5). In 10 of 29 institutions, isolation of multidrug-resistant organisms and a high bacterial load were considered contraindications for the use of BR. Seven institutions experienced environmental contamination. Conclusions: Given the different implementation of BR among institutions, the appropriate indication and protocols for BR should be established for infection control.

Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability following cardiac arrest (CA). Nicotinamide adenine dinucleotide (NAD+) depletion after CA contributes to neuronal injury, while nicotinamide mononucleotide (NMN) replenishes NAD+ and may provide neuroprotection via sirtuin activation. This study aimed to investigate the effects of systemic NMN administration on neurological function, survival, and sirtuin-3 (SIRT3) levels in the brain post-CA. In adult male mice (C57BL/6NCrSlc, 10–15 weeks old), 10-min CA was induced by intravenous potassium chloride injection followed by cardiopulmonary resuscitation. NMN (60 mg/ kg body weight) or normal saline (control) was randomly administered by intraperitoneal injection immediately after the return of spontaneous circulation (ROSC) and 24 and 48 h post-CA. Brain NAD+ and adenosine triphosphate (ATP) levels, neurological function score (NFS), survival, histological neuronal injury, and brain gene expression and protein levels were measured. Brain NAD+ levels decreased at 2 h post-ROSC and NMN significantly increased brain NAD+ and ATP levels. At 48 h post-CA, surviving mice in the NMN group exhibited significantly higher NFS (control: 8 [IQR: 4–12] vs. NMN: 12 [IQR: 9–12], p = 0.03) and less severe hippocampal neuronal injury compared with controls. Moreover, the NMN group showed significantly higher 7-day survival rate (control: 22.2% [4/18] vs. NMN: 61.1% [11/18], p = 0.03) and brain SIRT3 levels (control: 17.7 ± 3.6 vs. NMN: 34.5 ± 4.4 pg/mg protein, p = 0.01). In conclusion, systemic NMN administration after ROSC attenuates PCABI. The increased brain ATP levels and SIRT3 upregulation may suggest the usefulness of NMN for improving mitochondrial function and contributing to neuroprotection. NAD+ supplementation with NMN is a promising therapeutic approach against PCABI.

Background: At lower ambient temperature, patients with out-of-hospital cardiac arrest (OHCA) easily experience hypothermia. Hypothermia has shown to improve the rate of successful return of spontaneous circulation (ROSC) in animal models. We hypothesized that lower temperature affects the impact of bystander cardiopulmonary resuscitation (CPR) on the increased odds of a favorable neurological outcome post-OHCA. Methods: This study used information collected by the prospective, nationwide, Utstein registry to examine data from 352,689 adult patients who experienced OHCA from 2012 to 2016 in Japan. The primary outcome was a 1-month favorable neurological outcomes. Multivariable logistic regression analyses were conducted to test the impact of bystander CPR according to the temperature on the favorable outcome. Results: A total of 201,111 patients with OHCA were included in the complete case analysis. The lower temperature group had lower proportions of receiving bystander CPR (46.5 vs. 47.9%) and having favorable outcome (2.1 vs 2.8%) than those in the higher group. Multivariable analysis revealed that bystander CPR at lower temperatures was significantly associated with favorable outcomes (adjusted odds ratio, 1.22; 95% CI, 1.09–1.37), whereas bystander CPR at higher temperatures was not associated with favorable outcomes (1.02; 0.92–1.13). The nonlinear relationship using a spline curve in the multivariable model revealed that odds ratio of favorable neurological outcomes associated with bystander CPR increased as the temperature decreased. Conclusion: Bystander CPR was associated with favorable neurological outcomes at lower temperatures. The odds of a favorable outcome associated with bystander CPR increased as the temperature decreased.

Background: Disseminated intravascular coagulation (DIC) is a severe complication of sepsis. Recently, the Japanese Association for Acute Medicine (JAAM) DIC criteria were modified into the JAAM-2-DIC criteria. This study aimed to assess the utility of the JAAM-2 DIC criteria as an indicator for initiating treatment for DIC using a large-scale database. Methods: We analyzed data from the Japanese Administrative Claims Database, which covers approximately 18 million patients from 600 hospitals. Adult patients with sepsis, defined by the Sepsis-3 criteria, were included. The relationship between DIC treatment (recombinant thrombomodulin and antithrombin) and survival, and bleeding complications, including the timing of initiation, was evaluated according to the JAAM-2-DIC, ISTH-overt DIC, and sepsis-induced coagulopathy (SIC) criteria. Results: Among 1903 patients, 415 (22 %) received DIC treatment. At sepsis diagnosis, 673 (35 %), 174 (9 %), and 699 (37 %) patients met the JAAM-2 DIC, ISTH-overt DIC, and SIC criteria, respectively. DIC treatment was associated with improved survival in patients diagnosed with DIC by any criteria but not in those without DIC. In patients without DIC, DIC treatment increased bleeding complications requiring transfusion, whereas this risk was not elevated in patients with DIC. Only the JAAM-2-DIC criteria showed significant effect modification for both efficacy and safety. Initiating DIC treatment based on JAAM-2-DIC criteria most effectively identified patients with a survival benefit. Conclusion: The JAAM-2-DIC criteria effectively identify patients with better survival outcomes and a low risk of bleeding among those receiving DIC treatment. These criteria may serve as a useful indicator for starting DIC treatment in this population.

The clinical course of coronavirus disease 2019 (COVID-19) varies from mild to critical. We retrospectively examined whether clinical and laboratory findings on admission could predict COVID-19 prognosis. Among various factors associated with COVID-19 severity, our results indicated that the real-time reverse transcription-polymerase chain reaction (RT-PCR) threshold cycle (Ct) values for severe acute respiratory syndrome coronavirus 2 were the most useful predictor of COVID-19 prognosis.

Background: Abdominal sepsis frequently leads to disseminated intravascular coagulation (DIC), exacerbating organ dysfunction and bleeding complications. Although anticoagulant therapy is a potential treatment for DIC, its use in this context raises concerns about bleeding risks. Objectives: The purpose of this study is to investigate the risks and benefits of DIC-targeted anticoagulant therapy in patients with abdominal sepsis. Methods: Data were analyzed from a dataset from a multicenter nationwide retrospective cohort study (J-Septic DIC registry) in Japan between 2011 and 2013. The study included 987 patients with abdominal sepsis-induced DIC, diagnosed within three days of ICU admission. Patients were divided into DIC-targeted anticoagulant therapy (recombinant thrombomodulin or antithrombin) and non-use groups. Propensity score matching was used to adjust for confounding factors. The primary outcome was all-cause 90-day mortality, with bleeding complications requiring blood transfusion as the primary safety outcome. Results: The results indicated that anticoagulant therapy was associated with improved survival (hazard ratio: 0.662, 95 % confidential interval: 0.472–0.929), but a higher risk of bleeding complications (OR: 2.451, 95 % confidential interval:1.372–4.379). Dual combination of anticoagulant therapy did not provide additional survival benefits and increased bleeding risks. The efficacy of DIC-targeted anticoagulant therapy correlated with disease severity, while bleeding risk was inversely correlated with severity. Conclusion: DIC-targeted anticoagulant therapy in patients with abdominal sepsis was related with improved prognosis but increased bleeding risks. The risk-benefit profile varies with disease severity, suggesting a need for cautious and personalized treatment strategies.

Background: Disseminated intravascular coagulation (DIC) is a severe complication in septic patients. The Japanese Ministry of Health and Welfare (JMHW)-DIC criteria, the first DIC criteria, were established in 1983, and several other criteria have been proposed since then, including the International Society on Thrombosis and Haemostasis (ISTH)-overt DIC criteria and the Japanese Association for Acute Medicine (JAAM) DIC criteria. This study aimed to look into the transition of DIC criteria used in randomized controlled trials (RCTs) for sepsis-induced DIC. Methods: We searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials for English-language studies published through September 30, 2023. Two reviewers looked through citations that assessed the DIC criteria used in RCTs and their secondary analyses. Data on DIC diagnostic criteria, patient characteristics, interventions, and results were gathered. Results: Twenty-one studies (thirteen RCTs: JMHW-DIC in 5, JAAM-DIC in 4, the sepsis-induced coagulopathy (SIC) in 2; and eight secondary analyses: ISTH-overt DIC in 3, single parameter in 5) were eligible for inclusion. Most RCTs were conducted in Japan, using the criteria of JMHW-DIC, which were followed by JAAM-DIC. Recently, SIC has been used in international RCTs. Meanwhile, other countries tended to conduct RCTs that focused on sepsis, with secondary analyses for DIC using the ISTH-overt DIC criteria. Conclusions: The criteria used in RCTs have changed over decades, from the JMHW-DIC to the JAAM-DIC criteria, and the ISTH-overt DIC criteria were retained in the secondary analysis. Based on these findings, additional research is needed to determine the best criterion for diagnosing septic patients.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

Background Rapid deterioration of oxygenation occurs in novel coronavirus disease 2019 (COVID-19), and prediction of mechanical ventilation (MV) is needed for allocation of patients to intensive care unit. Since intubation is usually decided based on varying clinical conditions, such as required oxygen changes, we aimed to elucidate thresholds of increase in oxygen demand to predict MV use within 12 h. Methods A single-center retrospective cohort study using data between January 2020 and January 2021was conducted. Data were retrieved from the hospital data warehouse. Adult patients diagnosed with COVID-19 with a positive polymerase chain reaction (PCR) who needed oxygen during admission were included. Hourly increments in oxygen demand were calculated using two consecutive oxygen values. Covariates were selected from measurements at the closest time points of oxygen data. Prediction of MV use within 12 h by required oxygen changes was evaluated with the area under the receiver operating curves (AUCs). A threshold for increased MV use risk was obtained from restricted cubic spline curves. Results Among 66 eligible patients, 1835 oxygen data were analyzed. The AUC was 0.756 for predicting MV by oxygen demand changes, 0.888 by both amounts and changes in oxygen, and 0.933 by the model adjusted with respiratory rate, PCR quantification cycle (Ct), and days from PCR. The threshold of increments of required oxygen was identified as 0.44 L/ min/h and the probability of MV use linearly increased afterward. In subgroup analyses, the threshold was lower (0.25 L/min/h) when tachypnea or frequent respiratory distress existed, whereas it was higher (1.00 L/min/h) when viral load is low (Ct ≥20 or days from PCR >7 days). Conclusions Hourly changes in oxygen demand predicted MV use within 12 h, with a threshold of 0.44 L/ min/h. This threshold was lower with an unstable respiratory condition and higher with a low viral load.

Purpose: This research aimed to establish a scoring system for selecting candidates for urgent angioembolization (AE). Methods: Patients with blunt trauma were retrospectively identified in a nationwide trauma registry. Patients aged ≥ 15 years with a systolic blood pressure of ≥90 mmHg were included. These individuals were then categorized into development and validation cohorts based on the date of admission. Next, an eight-point scaled system was developed using odds ratios obtained from the multivariate analysis of patients’ clinical factors on their arrival at the hospital, with the implementation of urgent AE as a dependent variable. Results: The development cohort and validation cohort included 158,192 and 116,941 patients, respectively, and 3296 (2.1%) patients in the development cohort and 2,550 (2.2%) patients in the validation cohort underwent urgent AE. The frequency of transfusion within 24 h after arrival and the Injury Severity Score were similar between the two cohorts (16,867 [10.7%] vs. 11,222 [9.6%] and 10 [9–18] vs. 10 [9–17], respectively). The number of patients who were discharged and hospital-free days were comparable between the two cohorts (139,436 [94.4%] vs. 106,107 [95.6%] and 72 [53–84] vs. 73 [57–84] days, respectively). The probabilities and the observed rates of urgent AE increased proportionally from 2% at a score of ≤ 3 to almost 15% at a score of ≥ 7. In terms of predictive factors, no significant interaction was noted. Conclusion: The Trauma-Angio scoring system can be used as a trigger to suggest the possibility of urgent AE. Trial Registration: 20090087, 31st July 2009.