Search

Abstract Objectives This study aimed to comprehensively compare host responses of patients with bacterial sepsis and those with viral (COVID-19) sepsis by analyzing messenger RNA (mRNA) and microRNA (miRNA) profiles to shed light on their distinct pathophysiological mechanisms. Design Prospective observational study. Setting Whole blood RNA sequencing was used to analyze mRNA and miRNA profiles of patients diagnosed as having bacterial sepsis or viral (COVID-19) sepsis at the Department of Trauma and Emergency Medicine, Osaka University Graduate School of Medicine. Patients Twenty-two bacterial sepsis patients, 35 viral (COVID-19) sepsis patients, and 15 healthy subjects admitted to the department were included. We diagnosed bacterial sepsis patients according to the sepsis-3 criterion that the Sequential Organ Failure Assessment score must increase to 2 points or more among patients with suspected infections. Viral (COVID-19) sepsis patients were diagnosed using SARS-CoV-2 RT-PCR testing, and presence of pneumonia was assessed through chest computed tomography scans. Interventions None. Measurements and main results For RNA sequencing, 14,500 mRNAs, 1121 miRNAs, and 2556 miRNA-targeted mRNAs were available for analysis in the bacterial sepsis patients. Numbers of genes showing upregulated: downregulated gene expression (false discovery rate 1.5) were 256:2887 for mRNA, 53:5 for miRNA, and 49:2507 for miRNA-targeted mRNA. Similarly, in viral (COVID-19) sepsis patients, 14,500 mRNAs, 1121 miRNAs, and 327 miRNA-targeted mRNAs were analyzed, with numbers of genes exhibiting upregulated: downregulated gene expression of 672:1147 for mRNA, 3:4 for miRNA, and 165:162 for miRNA-targeted mRNA. This analysis revealed significant differences in the numbers of upregulated and downregulated genes expressed and pathways between the bacterial sepsis and viral (COVID-19) sepsis patients. Bacterial sepsis patients showed activation of the PD-1 and PD-L1 cancer immunotherapy signaling pathway and concurrent suppression of Th1 signaling. Conclusion Our study illuminated distinct molecular variances between bacterial sepsis and viral (COVID-19) sepsis. Bacterial sepsis patients had a greater number of upregulated and downregulated genes and pathways compared to viral (COVID-19) sepsis patients. Especially, bacterial sepsis caused more dramatic pathogenetic changes in the Th1 pathway than did viral (COVID-19) sepsis.

Abstract Resting memory B cells can be divided into classical or atypical groups, but the heterogenous marker expression on activated memory B cells makes similar classification difficult. Here, by longitudinal analysis of mass cytometry and CITE-seq data from cohorts with COVID-19, bacterial sepsis, or BNT162b2 mRNA vaccine, we observe that resting B cell memory consist of classical CD45RB+ memory and CD45RBlo memory, of which the latter contains of two distinct groups of CD11c+ atypical and CD23+ non-classical memory cells. CD45RB levels remain stable in these cells after activation, thereby enabling the tracking of activated B cells and plasmablasts derived from either CD45RB+ or CD45RBlo memory B cells. Moreover, in both COVID-19 patients and mRNA vaccination, CD45RBlo B cells formed the majority of SARS-CoV2 specific memory B cells and correlated with serum antibodies, while CD45RB+ memory are activated by bacterial sepsis. Our results thus identify that stably expressed CD45RB levels can be exploited to trace resting memory B cells and their activated progeny, and suggest that atypical and non-classical CD45RBlo memory B cells contribute to SARS-CoV-2 infection and vaccination.

Therapeutic hypothermia inhibits organ damage by suppressing metabolism, which makes it a therapy of choice for treating various diseases. Specifically, it is often used to treat conditions involving central nervous system disorders where it is expected to positively impact functional prognosis. Although keeping the body temperature at a hypothermic level has been conventionally used, how to manage the body temperature correctly remains a topic of debate. Recently, the concept of temperature management has been proposed to improve the quality of body temperature control and avoid hyperthermia. This review focuses on the effect of temperature on the central nervous system in conditions involving central nervous system disorders and the practice of temperature management in clinical situations.

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

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

Introduction: Burns from hot asphalt, although rare, typically occur in workers in the paving industry. Removal of asphalt, while not mandatory, improves patient comfort and allows early assessment of underlying tissue damage. Previous reports have emphasized the use of surface-active agents or butters to remove tar or asphalt from the affected area without causing further damage to the skin. Case presentation: A 69-year-old man was working as a driver of an asphalt tanker. While working on the side of the tanker, hot asphalt splashed off the roof of the tanker's hood. He sustained burns to his left face, neck, upper and lower extremities, and hands from the hot asphalt. Melted butter was soaked into gauze and applied to asphalt-covered areas of the face, neck, body, upper and lower extremities, and hands. The butter soaked into the gauze emulsified the asphalt, and the asphalt soaked into the gauze was painlessly removed. To remove the asphalt from the fingertips, melted butter was placed in plastic gloves and the hands were dipped into the gloves so that all fingers efficiently touched the melted butter. By doing so, the asphalt on the fingertips was easily emulsified by the butter in the gloves. Conclusion: The method of removing asphalt stuck to the hands by placing melted butter in gloves and applying the gloves to the hands should be considered as an option.

BackgroundAcute respiratory distress syndrome (ARDS) is respiratory failure that commonly occurs in critically ill patients, and the molecular mechanisms underlying its pathogenesis and severity are poorly understood. We evaluated mRNA and miRNA in patients with ARDS and elucidated the pathogenesis of ARDS after performing mRNA and miRNA integration analysis.MethodsIn this single-center, prospective, observational clinical study of patients with ARDS, peripheral blood of each patient was collected within 24 hours of admission. Sequencing of mRNA and miRNA was performed using whole blood from the ARDS patients and healthy donors.ResultsThirty-four ARDS patients were compared with 15 healthy donors. Compared with the healthy donors, 1233 mRNAs and 6 miRNAs were upregulated and 1580 mRNAs and 13 miRNAs were downregulated in the ARDS patients. For both mRNA and miRNA-targeted mRNA, canonical pathway analysis showed that programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) cancer immunotherapy pathway was most activated and the Th2 pathway was most suppressed. For mRNA, the Th1 pathway was most suppressed. miR-149-3p and several miRNAs were identified as upstream regulators.ConclusionmiRNAs regulated the PD-1 and PD-L1 cancer immunotherapy pathway and Th2 pathway through miRNA interference action of mRNA. Integrated analysis of mRNAs and miRNAs showed that T cells were dysfunctional in ARDS patients.

The long-term outcomes of patients with disorders of consciousness after traumatic brain injury (TBI) is unclear. We investigated the long-term outcomes over 20 years in patients who were in a persistent vegetative state (VS). We conducted a retrospective cohort study using a review of medical records and collected data by telephone and written interviews with patients and their families. We included patients who were treated for TBI at our hospital, between October 1996 and January 2003 and who were in a persistent VS, defined as a Disability Rating Scale (DRS) score of ?22 at 1 month after TBI. The DRS was administered at 1 month, 6 months, 1 year, and then annually out to 20 years. We evaluated their clinical course until July 2021 with the DRS. We analyzed 35 patients in a persistent VS attributable to TBI. We were able to confirm the 20-year outcomes for 26 of the 35 patients (74%); at 20 years post-TBI, 19 (54%) patients were found to be deceased and 7 (20%) were alive. Over the 20-year study period, 23 of the 35 patients (65.7%) emerged from a persistent VS. Among the 35 patients in a persistent VS at 1 month post-TBI, 20 (57%) emerged from a persistent VS within 1 year, and 3 patients (8.6%) emerged from a persistent VS after more than a year after injury. DRS scores improved up to 9 years post-injury, whereas the change in DRS scores from 10 to 20 years post-injury was within ?1 point in all patients. We found that patients with persistent VS attributable to TBI may show improvement in functional disability up to 10 years post-injury. On the other hand, no substantial improvement in functional disability was observed after the 10th year.

Abstract Introduction Methemoglobinemia is a condition in which methemoglobin is increased and the oxygen carrying capacity of tissues is decreased, causing a lack of oxygen to the whole body. RNA (ribonucleic acid) sequencing technologies have made it possible to systematically examine how the human transcriptome responds to invasive pathologies. To our knowledge, no previous studies have reported the results of RNA sequencing in a patient with methemoglobinemia. We describe the analysis of RNAs from the whole blood of a patient with methemoglobinemia. Case presentation A 31-year-old Japanese man was brought to our hospital with symptoms of dyspnea due to inhalation of gas from an acetic acid phosphonitrate storage tank at a factory. The nitrogen oxide concentration measured around the storage tank was over 2500 ppm, and he witnessed orange–brown smoke at that time. After entering the area and taking a few breaths, he suddenly became unwell, with dyspnea and numbness in his extremities. He was evacuated from the area within a few minutes, at which time he was suffering from whole-body cyanosis and was still aware of the above symptoms. On arrival at the hospital, his respiration rate was 18 breaths/minute, and his SpO2 ranged from 80% to 85% on 15 L/minute of oxygen by mask (2.5 hours postexposure). Arterial blood gas testing revealed a methemoglobin level of 23.1%. After the administration of methylene blue, the patient’s methemoglobin level normalized and his symptoms improved. Chest X-ray and chest computed tomography showed no evidence of pulmonary edema or interstitial pneumonia, and no other abnormal findings were observed. RNA sequencing was performed on the blood samples obtained at the time of the visit, with the blood sample collected on day 5 used as a control. To our knowledge, the present study is the first to describe the analysis of RNAs from the whole blood of a patient with methemoglobinemia. The RNA sequencing analysis showed that an activated “hydrogen peroxide catabolic process” may be associated with the pathogenesis of methemoglobinemia. Conclusion The results reported in the present study may explain the pathogenesis of methemoglobinemia.

Background: The effect of hospital spending on the mortality rate of patients with sepsis has not yet been fully elucidated. We hypothesized that hospitals that consume more medical resources would have lower mortality rates among patients with sepsis. Methods: This retrospective study used administrative data from 2010 to 2017. The enrolled hospitals were divided into quartiles based on average daily medical cost per sepsis case. The primary and secondary outcomes were the average in-hospital mortality rate of patients with sepsis and the effective cost per survivor among the enrolled hospitals, respectively. A multiple regression model was used to determine the significance of the differences among hospital categories to adjust for baseline imbalances. Results: Among 997 hospitals enrolled in this study, the crude in-hospital mortality rates were 15.7% and 13.2% in the lowest and highest quartiles of hospital spending, respectively. After adjusting for confounding factors, the highest hospital spending group demonstrated a significantly lower in-hospital mortality rate than the lowest hospital spending group (coefficient = −0.025, 95% confidence interval [CI] −0.034 to −0.015; p

BackgroundResearch has described differences in the provision of prehospital treatment for women who experience out-of-hospital cardiac arrest. However, studies have reported conflicting results regarding survival outcomes or in-hospital interventions between sexes. Thus, this study aimed to investigate the association of sex with survival outcomes and in-hospital treatments in Japan.MethodsWe retrospectively analyzed data from the Japanese Association for Acute Medicine–Out-of-Hospital Cardiac Arrest Registry. Patients aged ≥18 years who presented with a shockable rhythm at the scene between June 2014 and December 2020 were included in our analysis. Outcome measures were 30-day survival and in-hospital interventions. We compared the outcomes between the sexes using multivariable logistic regression.ResultsIn total, 5,926 patients (4,270 men; 1,026 women) with out-of-hospital cardiac arrest were eligible for our analysis. The proportions of patients with 30-day survival outcomes were 39.5% (1685/4,270) and 37.4% (384/1,026) in the male and female groups, respectively (crude odds ratio, 0.92; 95% confidence interval, 0.80–1.06). Although there were no significant differences, survival outcomes tended to be better in women than in men in the multiple regression analysis (adjusted odds ratio: 1.38; 95% confidence interval: 0.82–2.33). Furthermore, there was no significant difference between the sexes in terms of patients who received extracorporeal cardiopulmonary resuscitation (adjusted odds ratio: 0.81; 95% confidence interval: 0.49–1.33) or targeted temperature management (adjusted odds ratio: 0.99; 95% confidence interval: 0.68–1.46).ConclusionsAfter adjusting for prognostic factors, there were no differences in survival rates and in-hospital interventions between men and women.

ABSTRACT Although the development of vaccines has considerably reduced the severity of COVID-19, its incidence is still high. Hence, a targeted approach based on RNA endotypes of a population should be developed to help design biomarker-based therapies for COVID-19. We evaluated the major RNAs transcribed in blood cells during COVID-19 using PCR to further elucidate its pathogenesis and determine predictive phenotypes in COVID-19 patients. In a discovery cohort of 40 patients with COVID-19, 26,354 RNAs were measured on day 1 and day 7. Five RNAs associated with disease severity and prognosis were derived. In a validation cohort of 153 patients with COVID-19 treated in the intensive care unit, we focused on prolactin (PRL) and toll-like receptor 3 (TLR3), among RNAs that have a strong association with prognosis, and evaluated the accuracy for predicting survival of PRL-to-TL3 ratios (PRL/TLR3) with the areas under the receiver operator characteristic (ROC) curves (AUC). The validation cohort was divided into two groups based on the cut-off value in the ROC curve with the maximum AUC. The two groups were defined by high PRL/TLR3 (n = 47) and low PRL/TLR3 (n = 106), and the clinical outcomes were compared. In the validation cohort, the AUC for PRL/TLR3 was 0.79, showing superior prognostic ability compared to severity scores such as Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment. The high PRL/TLR3 group had a significantly higher 28-day mortality than the low PRL/TLR3 group (17.0% vs 0.9%, P < 0.01). A new RNA endotype classified using high PRL/TLR3 was associated with mortality in COVID-19 patients. IMPORTANCE In this study, whole-blood RNAs (prolactin and toll-like receptor 3) involved in the prognosis of patients with COVID-19 were identified. The RNA endotypes classified by these important RNAs highlight the possibility of stratifying the COVID-19 patient population and the need for targeted therapy based on these phenotypes.

Abstract Background Acute mountain sickness (AMS) affects around 30% of people climbing Mt. Fuji, but its pathogenesis is incompletely understood. The influence of a rapid ascent to high altitude by climbing and summiting Mt. Fuji on cardiac function in the general population is unknown, and its association with altitude sickness has not been clarified. Methods Subjects climbing Mt. Fuji were included. Heart rate, oxygen saturation, systolic blood pressure, cardiac index (CI) and stroke volume index were measured multiple times at 120 m as baseline values and at Mt. Fuji Research Station (MFRS) at 3,775 m. Each value and its difference from the baseline value (Δ) of subjects with AMS (defined as Lake Louise Score [LLS] ≥ 3 with headache after sleeping at 3,775 m) were compared with those of non-AMS subjects. Results Eleven volunteers who climbed from 2,380 m to MFRS within 8 h and stayed overnight at MFRS were included. Four suffered AMS. Compared with the non-AMS subjects, CI in the AMS subjects was significantly higher than that before sleeping (median [interquartile range]: 4.9 [4.5, 5.0] vs. 3.8 [3.4, 3.9] mL/min/m2; p = 0.04), and their ΔCI was significantly higher before sleeping (1.6 [1.4, 2.1] vs. 0.2 [0.0, 0.7] mL/min/m2; p

Abstract 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

Background Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with severe infection.Methods A post-hoc analysis of a nationwide multicentre prospective observational study on sepsis (SPICE Study) was conducted, including adult patients admitted to the intensive care unit with available arterial partial pressure of oxygen (PaO2) at the treatment initiation for severe infection. Hyperoxia was defined as a PaO2 level of ≥300 mm Hg and in-hospital mortality was compared between patients with and without hyperoxia.Results Of the 563 patients eligible for the study, 49 had hyperoxia at treatment initiation for severe infection. The in-hospital all-cause mortality rates of patients with and without hyperoxia were 14 (29.2%) and 90 (17.6%), respectively. Inverse probability weighting analyses with propensity scores revealed the association between hyperoxia and increased in-hospital mortality rate (28.8% vs 18.8%; adjusted OR 1.75 (1.03 to 2.97); p=0.038), adjusting for patient demographics, comorbidities, site of infection, severity of infection, haemodynamic and respiratory status, laboratory data and location of patient at infection development. Acute lung injury developed more frequently in patients with hyperoxia on the following days after infection treatment, whereas sepsis-related mortality was comparable regardless of hyperoxia exposure.Conclusion Hyperoxia with PaO2 ≥300 mm Hg at treatment initiation of severe infection was associated with an increased in-hospital mortality rate in patients requiring intensive care. The amount of oxygen to administer to patients with severe infection should be carefully determined.Trial registration number University Hospital Medical Information Network Clinical Trial Registry (UMIN000027452).

Extravascular leakage on computed tomography (CT) angiography in patients with traumatic brain injury (TBI) is associated with hematoma expansion, functional prognosis, subsequent surgery, and death. Fresh frozen plasma (FFP) administration is often necessary to treat coagulation disorders associated with TBI. This study aimed to determine the relationship between the presence of extravascular leakage on contrast-enhanced head CT, fibrinogen level at admission, and FFP administration in patients with TBI. The medical records of patients with TBI ?18 years of age referred to our hospital between January 2010 and December 2020 were examined retrospectively. Patients who underwent contrast-enhanced CT immediately after admission were selected, and the presence or absence of extravascular leakage, fibrinogen level at admission, and percentage of patients who required FFP administration within 24?h of admission were examined; 172 patients were included. Multi-variable linear regression analysis was performed to determine the effects of contrast extravasation on fibrinogen levels at admission and was adjusted for age, sex, systolic blood pressure, time from injury to admission, Marshall CT score, Glasgow Coma Scale score at admission, Injury Severity Score, and need for emergency surgery; the regression coefficient was ?19.8. The effect of extravasation on FFP administration within 24?h of admission was analyzed using logistic regression while adjusting for age, systolic blood pressure, Marshall CT score, need for emergency surgery, and fibrinogen level at admission. The odds ratio of contrast extravasation was 7.08 after adjustment. Extravascular leakage is associated with fibrinogen levels at admission and FFP administration within 24?h of admission.

Abstract Background A substantial number of sepsis patients require specialized care, including multidisciplinary care, close monitoring, and artificial organ support in the intensive care unit (ICU). However, the efficacy of ICU management on clinical outcomes remains insufficiently researched. Therefore, we tested the hypothesis that ICU admission would increase the survival rate among sepsis patients. Methods We conducted a retrospective study using the nationwide medical claims database of sepsis patients in Japan from 2010 to 2017 with propensity score matching to adjust for baseline imbalances. Patients aged over 20 years, with a combined diagnosis of presumed serious infection and organ failure, were included in this study. The primary outcome studied was the in-hospital mortality among non-ICU and ICU patients. In addition to propensity score matching, we performed a multivariable logistic regression analysis for the primary outcome. As the treatment policy was not extracted from the database, we performed sensitivity analyses to determine mortality differences in adults (20 ≤ age ≤ 64), independent patients, patients without malignant tumors, based on the assumption that treatment intensity is likely to increase in those population. Results Among 1,167,901 sepsis patients (974,289 in non-ICU and 193,612 in ICU settings), the unadjusted in-hospital mortality was 22.5% among non-ICU patients and 26.2% among ICU patients (3.7% [95% CI 3.5–3.9]). After propensity score matching, the in-hospital mortality was 29.2% among non-ICU patients and 25.8% among ICU patients ( $$-$$ - 3.4% [95% CI $$-$$ - 3.7 to $$-$$ - 3.1]). In-hospital mortality with a multivariable regression analysis ( $$-$$ - 5.0% [95% CI $$-$$ - 5.2 to $$-$$ - 4.8]) was comparable with the results of the propensity score matching analysis. In the sensitivity analyses, the mortality differences between non-ICU and ICU in adults, independent patients, and patients without malignant tumors were $$-$$ - 2.7% [95% CI $$-$$ - 3.3 to $$-$$ - 2.2], $$-$$ - 5.8% [95% CI $$-$$ - 6.4 to $$-$$ - 5.2], and $$-$$ - 1.3% [95% CI $$-$$ - 1.7 to $$-$$ - 1.0], respectively. Conclusions Herein, using the nationwide medical claims database, we demonstrated that ICU admission was potentially associated with decreasing in-hospital mortality among sepsis patients. Further investigations are warranted to validate these results and elucidate the mechanisms favoring ICU management on clinical outcomes.

Abstract Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has led to major public health crises worldwide. Several studies have reported the comprehensive mRNA expression analysis of immune-related genes in patients with COVID-19, using blood samples, to understand its pathogenesis; however, the characteristics of RNA expression in COVID-19 and bacterial sepsis have not been compared. The current study aimed to address this gap. Methods RNA-sequencing and bioinformatics analyses were used to compare the transcriptome expression of whole blood samples from patients with COVID-19 and patients with sepsis who were admitted to the intensive care unit of Osaka University Graduate School of Medicine. Results The COVID-19 and sepsis cohorts showed upregulation of mitochondrial- and neutrophil-related transcripts, respectively. Compared with that in the control cohort, neutrophil-related transcripts were upregulated in both the COVID-19 and sepsis cohorts. In contrast, mitochondrial-related transcripts were upregulated in the COVID-19 cohort and downregulated in the sepsis cohort, compared to those in the control cohort. Moreover, transcript levels of the pro-apoptotic genes BAK1, CYCS, BBC3, CASP7, and CASP8 were upregulated in the COVID-19 cohort, whereas those of anti-apoptotic genes, such as BCL2L11 and BCL2L1, were upregulated in the sepsis cohort. Conclusions This study clarified the differential expression of transcripts related to neutrophils and mitochondria in sepsis and COVID-19 conditions. Mitochondrial-related transcripts were downregulated in sepsis than in COVID-19 conditions, and our results indicated suboptimal intrinsic apoptotic features in sepsis samples compared with that in COVID-19 samples. This study is expected to contribute to the development of specific treatments for COVID-19.

Abstract Background The appropriate duration of antibiotic treatment in patients with bacterial sepsis remains unclear. The purpose of this study was to evaluate the association of a shorter course of antibiotics on 28-day mortality in comparison with a longer course using a national database in Japan. Methods We conducted a post hoc analysis from the retrospective observational study of patients with sepsis using a Japanese claims database from 2010 to 2017. The patient dataset was divided into short-course (≤ 7 days) and long-course (≥ 8 days) groups according to the duration of initial antibiotic administration. Subsequently, propensity score matching was performed to adjust the baseline imbalance between the two groups. The primary outcome was 28-day mortality. The secondary outcomes were re-initiated antibiotics at 3 and 7 days, during hospitalization, administration period, antibiotic-free days, and medical cost. Results After propensity score matching, 448,146 pairs were analyzed. The 28-day mortality was significantly lower in the short-course group (hazard ratio, 0.94; 95% CI, 0.92–0.95; P

We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-β, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6–8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-β plasma level was elevated in line with increased severity compared with HCs, as were IFN-β downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-β (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression.

Summary: Recent advancements in proteomics allow for the concurrent identification and quantification of multiple proteins. This study aimed to identify proteins associated with severe burn pathology and establish a clinically useful molecular pathology classification. In a retrospective observational study, blood samples were collected from severe burn patients. Proteins were measured using mass spectrometry, and prognosis-related proteins were extracted by comparing survivors and non-survivors. Enrichment and ROC analyses evaluated the extracted proteins, followed by latent class analysis. Measurements were performed on 83 burn patients. In the non-survivor group, ten proteins significantly changing on the day of injury were associated with metabolic processes and toxin responses. ROC analysis identified HBA1, TTR, and SERPINF2 with AUCs > 0.8 as predictors of 28-day mortality. Latent class analysis classified three molecular pathotypes, and plasma mass spectrometry revealed ten proteins associated with severe burn prognosis. Molecular pathotypes based on HBA1, TTR, and SERPINF2 significantly correlated with outcomes.

Septic encephalopathy (SE) is characterized by symptoms such as coma, delirium, and cognitive dysfunction, and effective therapeutic interventions for SE remain elusive. In this study, we aimed to investigate the potential alleviating effects of vagal nerve stimulation (VNS) on SE-associated signs. To evaluate our hypothesis, we utilized a mouse model of SE induced by intraperitoneal injection of lipopolysaccharide (0.3 mg per mouse) and administered noninvasive, high-frequency ultrasound VNS. To assess the efficacy of ultrasound VNS, we measured inflammation-related molecules, including the α7 nicotinic acetylcholine receptor (α7nAChR) expression in peritoneal macrophages and plasma interleukin 1β (IL-1β) levels. Consistent with our hypothesis, SE mice exhibited reduced α7nAChR expression in macrophages and elevated IL-1β levels in the blood. Remarkably, VNS in SE mice restored α7nAChR expression and IL-1β levels to those observed in control mice. Furthermore, we evaluated the effects of VNS on survival rate, body temperature, and locomotor activity. SE mice subjected to VNS demonstrated a modest, yet significant, improvement in survival rate, recovery from hypothermia, and increased locomotor activity. To investigate the impact on the brain, we examined the hippocampus of SE mice. In control mice, VNS increased the expression of c-fos, a marker of neuronal electrical excitability, in the hippocampus. In SE mice, VNS led to the restoration of aberrant firing patterns in hippocampal neurons. Additionally, proteomic analysis of hippocampal tissue in SE mice revealed abnormal increases in two proteins, tissue factor (TF) and acyl-CoA dehydrogenase family member 9 (ACAD9), which returned to control levels following VNS. Collectively, our findings support the value of exploring the beneficial effects of ultrasound VNS on SE.

Abstract Background Trauma is a heterogeneous condition, and specific clinical phenotypes may identify target populations that could benefit from certain treatment strategies. In this retrospective study, we determined clinical phenotypes and identified new target populations of trauma patients and their treatment strategies. Methods We retrospectively analyzed datasets from the Japan Trauma Data Bank and determined trauma death clinical phenotypes using statistical machine learning techniques and evaluation of biological profiles. Results The analysis included 71,038 blunt trauma patients [median age, 63 (interquartile range [IQR], 40–78) years; 45,479 (64.0%) males; median Injury Severity Score, 13 (IQR, 9–20)], and the derivation and validation cohorts included 42,780 (60.2%) and 28,258 (39.8%) patients, respectively. Of eight derived phenotypes (D-1–D-8), D-8 (n = 2178) had the highest mortality (48.6%) with characteristic severely disturbed consciousness and was further divided into four phenotypes: D-8α, multiple trauma in the young (n = 464); D-8β, head trauma with lower body temperature (n = 178); D-8γ, severe head injury in the elderly (n = 957); and D-8δ, multiple trauma, with higher predicted mortality than actual mortality (n = 579). Phenotype distributions were comparable in the validation cohort. Biological profile analysis of 90 trauma patients revealed that D-8 exhibited excessive inflammation, including enhanced acute inflammatory response, dysregulated complement activation pathways, and impaired coagulation, including downregulated coagulation and platelet degranulation pathways, compared with other phenotypes. Conclusions We identified clinical phenotypes with high mortality, and the evaluation of the molecular pathogenesis underlying these clinical phenotypes suggests that lethal trauma may involve excessive inflammation and coagulation disorders.

Abstract Background Sepsis is the leading cause of death worldwide. Although the mortality of sepsis patients has been decreasing over the past decade, the trend of medical costs and cost-effectiveness for sepsis treatment remains insufficiently determined. Methods We conducted a retrospective study using the nationwide medical claims database of sepsis patients in Japan between 2010 and 2017. After selecting sepsis patients with a combined diagnosis of presumed serious infection and organ failure, patients over the age of 20 were included in this study. We investigated the annual trend of medical costs during the study period. The primary outcome was the annual trend of the effective cost per survivor, calculated from the gross medical cost and number of survivors per year. Subsequently, we performed subgroup and multiple regression analyses to evaluate the association between the annual trend and medical costs. Results Among 50,490,128 adult patients with claims, a total of 1,276,678 patients with sepsis were selected from the database. Yearly gross medical costs to treat sepsis gradually increased over the decade from $3.04 billion in 2010 to $4.38 billion in 2017, whereas the total medical cost per hospitalization declined (rate = − $1075/year, p

Abstract Background Tracheal intubation in the emergency department (ED) can cause serious complications. Available evidence on the use of a high-flow nasal cannula (HFNC) during intubation in the ED is limited. This study evaluated the effect of oxygen therapy by HFNC on oxygen desaturation during tracheal intubation in the ED. Methods This was a single-center before-and-after study designed to compare two groups that received oxygen therapy during intubation: one received conventional oxygen, and the other received oxygen therapy using HFNC. We included non-trauma patients who required tracheal intubation in the ED. Linear regression analysis was performed to evaluate the relationship between oxygen therapy using HFNC and the lowest peripheral oxygen saturation (SpO2) during intubation in the conventional and HFNC groups. Results The study population included 87 patients (conventional group, n = 67; HFNC group, n = 20). The median lowest SpO2 in the HFNC group was significantly higher than that in the conventional group (94% [84–99%] vs. 85% [76–91%], p = 0.006). The percentage of cases with oxygen desaturation to

Abstract Disseminated intravascular coagulation (DIC) is one of the major organ dysfunctions associated with sepsis. This retrospective secondary analysis comprised data from a prospective multicenter study to investigate the age-related differences in the survival benefit of anticoagulant therapy in sepsis according to the DIC diagnostic criteria. Adult patients with severe sepsis based on the Sepsis-2 criteria were enrolled and divided into the following groups: (1) anticoagulant group (patients who received anticoagulant therapy) and (2) non-anticoagulant group (patients who did not receive anticoagulant therapy). Patients in the former group were administered antithrombin, recombinant human thrombomodulin, or their combination. The increases in the risk of hospital mortality were suppressed in the high-DIC-score patients aged 60–70 years receiving anticoagulant therapy. No favorable association of anti-coagulant therapy with hospital mortality was observed in patients aged 50 years and 80 years. Furthermore, anticoagulant therapy in the lower-DIC-score range increased the risk of hospital mortality in patients aged 50–60 years. In conclusion, anticoagulant therapy was associated with decreased hospital mortality according to a higher DIC score in septic patients aged 60–70 years. Anticoagulant therapy, however, was not associated with a better outcome in relatively younger and older patients with sepsis.

Abstract Recently, revisions of two sepsis guidelines, namely, the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 and the Surviving Sepsis Campaign Guidelines 2021, were published. Although both guidelines were created in accordance with the Grading of Recommendations, Assessment, Development and Evaluation approach, the evidence-to-decision tables differed between them. In addition, certain recommendations may differ between these guidelines for similar clinical questions because of differences in the “PICO” criteria. Other differences in recommendations between the two guidelines are due to unclear evidence, and these ambiguities may provide the basis for further sepsis research. We hope that these two guidelines will contribute to the creation of new clinical evidence in addition to supporting treatment of patients with sepsis.

Abstract Background Traumatic brain injury (TBI), both isolated and in combination with extracranial lesions, is a global health problem associated with high mortality. Among various risk factors for poor clinical outcomes, age is the most important independent predictor of mortality in patients with TBI. TBI-related mortality is expected to increase as the society ages. However, in a super-aged society such as Japan, little is known about the trend of TBI-related mortality among older adults. Herein, we assessed the nationwide trend of the incidence and clinical outcomes of geriatric patients with TBI in Japan using the national Japanese Trauma Data Bank (JTDB) registry. Methods In this retrospective cohort study, cases of TBI (aged ≥65 years) in hospitals registered with the JTDB database between January 2004 and December 2018 were included. In-hospital mortality was the primary outcome, and mortality in the emergency department was the secondary outcome. The odds ratios (ORs) and 95% confidence intervals (CIs) for in-hospital deaths with respect to 3-year periods were assessed using multivariable analysis after adjusting for potential confounders. Results The main cause of TBI in older individuals was falls. The proportion of patients who died after hospitalization during the study period decreased markedly from 29.5% (194/657) during 2004–2006 to 14.2% (1309/9240) during 2016–2018 in the isolated TBI group (adjusted OR = 0.42, 95% CI: 0.33–0.53) and from 48.0% (119/248) during 2004–2006 to 21.7% (689/3172) during 2016–2018 in the multiple trauma group (adjusted OR = 0.32, 95% CI: 0.23–0.45). The adjusted ORs for the 3-year increment were 0.84 (95% CI: 0.81–0.88) and 0.78 (95% CI: 0.75–0.83) for the isolated TBI and multiple trauma groups, respectively. Conclusions Using the national JTDB registry, we demonstrated a nationwide reduction in TBI-related mortality. Our findings in the super-aged society of Japan may provide insight for the treatment of geriatric patients with TBI worldwide.

Abstract In previous studies, we have treated real written texts as time series data and have tried to investigate dynamic correlations of word occurrences by utilizing autocorrelation functions (ACFs) and also by simulation of pseudo-text synthesis. The results showed that words that appear in written texts can be classified into two groups: a group of words showing dynamic correlations (Type-I words), and a group of words showing no dynamic correlations (Type-II words). In this study, we investigate the characteristics of these two types of words in terms of their waiting time distributions (WTDs) of word occurrences. The results for Type-II words show that the stochastic processes that govern generating Type-II words are superpositions of Poisson point processes with various rate constants. We further propose a model of WTDs for Type-I words in which the hierarchical structure of written texts is considered. The WTDs of Type-I words in real written texts agree well with the predictions of the proposed model, indicating that the hierarchical structure of written texts is important for generating long-range dynamic correlations of words.

Recently accumulating evidence has highlighted the rare occurrence of COVID-19 vaccination-induced inflammation in the central nervous system. However, the precise information on immune dysregulation related to the COVID-19 vaccination-associated autoimmunity remains elusive. Here we report a case of encephalitis temporally associated with COVID-19 vaccination, where single-cell RNA sequencing (scRNA-seq) analysis was applied to elucidate the distinct immune signature in the peripheral immune system. Peripheral blood mononuclear cells (PBMCs) were analyzed using scRNA-seq to clarify the cellular components of the patients in the acute and remission phases of the disease. The data obtained were compared to those acquired from a healthy cohort. The scRNA-seq analysis identified a distinct myeloid cell population in PBMCs during the acute phase of encephalitis. This specific myeloid population was detected neither in the remission phase of the disease nor in the healthy cohort. Our findings illustrate induction of a unique myeloid subset in encephalitis temporally associated with COVID-19 vaccination. Further research into the dysregulated immune signature of COVID-19 vaccination-associated autoimmunity including the cerebrospinal fluid (CSF) cells of central nervous system (CNS) is warranted to clarify the pathogenic role of the myeloid subset observed in our study.

Abstract The purpose of this study was to describe the characteristics of published international literature using the Japan Trauma Data Bank (JTDB). We undertook a scoping review of studies using data from JTDB. We carried out a systematic search of the following databases on November 21, 2022, using search terms that covers trauma registries in Japan: MEDLINE, Web of Science, CINAHL, and Cochrane Library. Two authors independently abstracted the data. We included all original articles written in English. We identified 166 studies from the 456 included articles. From 2010 to 2016, the annual number of published articles was less than 10. In 2017, there were 10 articles published (6.0%). This increased to 18 (10.8%) in 2018, 21 (12.7%) in 2019, 28 (16.9%) in 2020, 33 (19.9%) in 2021, and 37 (22.3%) in 2022. Most articles (n = 138, 83.1%) reported in‐hospital mortality as the primary outcome. There were more articles on the adult population (n = 86, 51.8%) than those on the pediatric population (n = 21, 12.7%). Twenty‐one articles (12.7%) specified a mechanism of injury for the study population, and three articles (1.8%) focused on burns. Most articles did not specify injury sites for the study population (n = 108, 65.1%) and the most common injury site described in publications was the head (n = 21, 12.7%), followed by the abdomen (n = 13, 7.8%). We observed an increase in international publications using the JTDB and highlighted the major topics and knowledge gaps. Our findings could encourage studies to explore less studied areas in research using the JTDB.

Abstract Disseminated intravascular coagulation (DIC) is a frequent but lethal complication in sepsis. Anticoagulant therapies, such as heparin, antithrombin, activated protein C, and recombinant human‐soluble thrombomodulin, were expected to regulate the progression of coagulopathy in sepsis. Although a number of randomized controlled trials (RCTs) have evaluated the survival effects of these therapies over the past few decades, there remains no consistent evidence showing a significant survival benefit of anticoagulant therapies. Currently, anticoagulant therapies are not conducted as a standard treatment against sepsis in many countries and regions. However, most of these RCTs were performed overall in patients with sepsis but not in those with sepsis‐induced DIC, who were theoretically the optimal target population of anticoagulants. Actually, multiple lines of evidence from observational studies and meta‐analyses of the RCTs have suggested that anticoagulant therapies might reduce mortality only when used in septic DIC. In addition, the severity of illness is another essential factor that maximally affects the efficacy of the therapy. Therefore, to provide evidence on the true effect of anticoagulant therapies, the next RCTs must be designed to enroll only patients with sepsis‐induced overt DIC and a high severity of illness. To prepare these future RCTs, a novel scientific infrastructure for accurate detection of patients who can receive maximal benefit from anticoagulant therapies also needs to be established.

Abstract The emergence of multidrug‐resistant organisms poses a significant threat to global public health, making the optimization of antimicrobial use crucial. Antimicrobial therapy is often initiated in emergency rooms (ERs) and intensive care units (ICUs), where patients are at high risk of infection. Prompt antimicrobial selection is essential in these facilities, and point‐of‐care testing can guide the appropriate initial antimicrobial therapy. Gram staining, a quick and inexpensive method, was previously used for point‐of‐care testing by physicians in the 1980s but was discontinued in 1988 in the United States. However, in Japan, the clinical practice of Gram stain‐based antimicrobial therapy by physicians has continued in a limited number of hospitals. Several studies undertaken in Japan have shown that Gram staining carried out by trained physicians can reduce the overuse of broad‐spectrum antimicrobial agents in ERs and ICUs without worsening patients' outcomes. Gram stain‐based antimicrobial therapy reduced unnecessary use of carbapenems in the ER. Furthermore, Gram staining has been shown to significantly reduce the overuse of broad‐spectrum antimicrobials without worsening clinical cure and mortality for patients with ventilator‐associated pneumonia in the ICU. The classic technique of Gram staining has regained its usefulness through persistent clinical practice in Japan. It is hoped that Japanese researchers in this field will demonstrate to the world the efficacy of the classic technique of Gram staining in addressing this critical problem. Gram staining carried out by trained physicians could serve as a valuable means of optimizing antimicrobial treatment in ERs and ICUs.

Abstract Aim This study aimed to investigate the association of early vasopressor initiation with improved septic shock outcomes. Methods This multicenter observational study was conducted in 17 intensive care units in Japan and included adult patients with sepsis admitted to the intensive care unit from July 2019 to August 2020 and treated with vasopressor therapy. Patients were divided into the early vasopressor group (≤1 h from sepsis recognition) and the delayed vasopressor group (>1 h). The impact of early vasopressor administration on risk‐adjusted in‐hospital mortality was estimated using logistic regression analyses adjusted by an inverse probability of treatment weighting analysis with propensity scoring. Results Among the 97 patients, 67 received vasopressor therapy within 1 h from sepsis recognition and 30 received vasopressor after 1 h. In‐hospital mortality was 32.8% in the early vasopressor group and 26.7% in the delayed vasopressor group (p = 0.543). The adjusted odds ratio for in‐hospital mortality was 0.76 (95% confidence interval 0.17–3.29) when comparing patients in the early vasopressor with those in the delayed vasopressor group. The fit curve from the mixed‐effects model showed a relatively lower trend toward an infusion volume over time in the early vasopressor group than in the delayed vasopressor group. Conclusion Our study did not reach a definitive conclusion for early vasopressor administration. However, early vasopressor administration may help avoid volume overload in the long course of sepsis care.

IntroductionTrauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients.MethodsThis retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values.ConclusionDecreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

Abstract Background Trends in the incidence and outcomes of sepsis using a Japanese nationwide database were investigated. Methods This was a retrospective cohort study. Adult patients, who had both presumed serious infections and acute organ dysfunction, between 2010 and 2017 were extracted using a combined method of administrative and electronic health record data from the Japanese nationwide medical claim database, which covered 71.5% of all acute care hospitals in 2017. Presumed serious infection was defined using blood culture test records and antibiotic administration. Acute organ dysfunction was defined using records of diagnosis according to the international statistical classification of diseases and related health problems, 10th revision, and records of organ support. The primary outcomes were the annual incidence of sepsis and death in sepsis per 1000 inpatients. The secondary outcomes were in-hospital mortality rate and length of hospital stay in patients with sepsis. Results The analyzed dataset included 50,490,128 adult inpatients admitted between 2010 and 2017. Of these, 2,043,073 (4.0%) patients had sepsis. During the 8-year period, the annual proportion of patients with sepsis across inpatients significantly increased (slope = + 0.30%/year, P

Abstract The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Abstract Background Few reports have examined dental arch morphology (DAM) after dental implant placement in cleft patients and its actual state is unclear. Objective To analyze the presence of changes in DAM and influencing factors in cleft lip and/or palate (CLP) patients who receive implant treatment in the alveolar cleft region. Methods Subjects comprised 20 CLP patients in whom maxillary dental arch width (DAW) was evaluated before and after implant treatment based on computed tomography data. First, widths between the canines (W3), between the first premolars (W4), between the second premolars (W5), and between the first molars (W6) were measured before and after surgery. Changes in distance were analyzed using the Wilcoxon signed‐rank test, revealing a significant increase in W6. Analysis of Co‐Variance was performed with the difference in W6 after implant treatment as the response variable, and the following six items as explanatory variables: sex; cleft type; age at alveolar bone graft; time to implantation after bone grafting; number of implants; and time after completion of the observation period. Results The reduction in W6 was larger in the order of complete bilateral CLP, complete unilateral CLP, and unilateral cleft lip and alveolus, and the change decreased with an increasing number of implants. Conclusions Implant treatment of the alveolar cleft region may result in a slight reduction in width of the dental arch after treatment completion.

Abstract Background Among the many factors that may influence traumatic brain injury (TBI) progression, sex is one of the most controversial. The objective of this study was to investigate sex differences in TBI-associated morbidity and mortality using data from the largest trauma registry in Japan. Methods This retrospective, population-based observational study included patients with isolated TBI, who were registered in a nationwide database between 2004 and 2018. We excluded patients with extracranial injury (Abbreviated Injury Scale score ≥ 3) and removed potential confounding factors, such as non-neurological causes of mortality. Patients were stratified by age and mortality and post-injury complications were compared between males and females. Results A total of 51,726 patients with isolated TBI were included (16,901 females and 34,825 males). Mortality across all ages was documented in 12.01% (2030/16901) and 12.76% (4445/34825) of males and females, respectively. The adjusted odds ratio (OR) of TBI mortality for males compared to females was 1.32 (95% confidence interval [CI], 1.22–1.42]. Males aged 10–19 years and ≥ 60 years had a significantly higher mortality than females in the same age groups (10–19 years: adjusted OR, 1.97 [95% CI, 1.08–3.61]; 60–69 years: adjusted OR, 1.24 [95% CI, 1.02–1.50]; 70–79 years: adjusted OR, 1.20 [95% CI, 1.03–1.40]; 80–89 years: adjusted OR, 1.50 [95% CI, 1.31–1.73], and 90–99 years: adjusted OR, 1.72 [95% CI, 1.28–2.32]). In terms of the incidence of post-TBI neurologic and non-neurologic complications, the crude ORs were 1.29 (95% CI, 1.19–1.39) and 1.14 (95% CI, 1.07–1.22), respectively, for males versus females. This difference was especially evident among elderly patients (neurologic complications: OR, 1.27 [95% CI, 1.14–1.41]; non-neurologic complications: OR, 1.29 [95% CI, 1.19–1.39]). Conclusions In a nationwide sample of patients with TBI in Japan, males had a higher mortality than females. This disparity was particularly evident among younger and older generations. Furthermore, elderly males experienced more TBI complications than females of the same age.

Abstract Surgeons and medical staff attend academic meetings several times a year. However, there is insufficient evidence on the influence of the “meeting effect” on traumatic brain injury (TBI) treatments and outcomes. Using the Japan Trauma Data Bank, we analyzed the data of TBI patients admitted to the hospital from 2004 to 2018 during the national academic meeting days of the Japanese Association for Acute Medicine, the Japanese Society of Intensive Care Medicine, the Japanese Association for the surgery of trauma, the Japan Society of Neurotraumatology and the Japan Neurosurgical Society. The data of these patients were compared with those of TBI patients admitted 1 week before and after the meetings. The primary outcome was in-hospital death. We included 7320 patients in our analyses, with 5139 and 2181 patients admitted during the non-meeting and meeting days, respectively; their in-hospital mortality rates were 15.7% and 14.5%, respectively. No significant differences in in-hospital mortality were found (adjusted odds ratio, 0.93; 95% confidence interval, 0.78–1.11). In addition, there were no significant differences in in-hospital mortality during the meeting and non-meeting days by the type of national meeting. In Japan, it is acceptable for medical professionals involved in TBI treatments to attend national academic meetings without impacting the outcomes of TBI patients.

IntroductionResistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis.Materials and MethodsFirst, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis.ResultsIn the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules.ConclusionResistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

Abstract Trauma patients die from massive bleeding due to disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype in the early phase, which transforms to DIC with a thrombotic phenotype in the late phase of trauma, contributing to the development of multiple organ dysfunction syndrome (MODS) and a consequently poor outcome. This is a sub-analysis of a multicenter prospective descriptive cross-sectional study on DIC to evaluate the effect of a DIC diagnosis on the survival probability and predictive performance of DIC scores for massive transfusion, MODS, and hospital death in severely injured trauma patients. A DIC diagnosis on admission was associated with a lower survival probability (Log Rank P

Abstract Background Information on hyperoxemia among patients with trauma has been limited, other than traumatic brain injuries. This study aimed to elucidate whether hyperoxemia during resuscitation of patients with trauma was associated with unfavorable outcomes. Methods A post hoc analysis of a prospective observational study was carried out at 39 tertiary hospitals in 2016–2018 in adult patients with trauma and injury severity score (ISS) of > 15. Hyperoxemia during resuscitation was defined as PaO2 of ≥ 300 mmHg on hospital arrival and/or 3 h after arrival. Intensive care unit (ICU)-free days were compared between patients with and without hyperoxemia. An inverse probability of treatment weighting (IPW) analysis was conducted to adjust patient characteristics including age, injury mechanism, comorbidities, vital signs on presentation, chest injury severity, and ISS. Analyses were stratified with intubation status at the emergency department (ED). The association between biomarkers and ICU length of stay were then analyzed with multivariate models. Results Among 295 severely injured trauma patients registered, 240 were eligible for analysis. Patients in the hyperoxemia group (n = 58) had shorter ICU-free days than those in the non-hyperoxemia group [17 (10–21) vs 23 (16–26), p < 0.001]. IPW analysis revealed the association between hyperoxemia and prolonged ICU stay among patients not intubated at the ED [ICU-free days = 16 (12–22) vs 23 (19–26), p = 0.004], but not among those intubated at the ED [18 (9–20) vs 15 (8–23), p = 0.777]. In the hyperoxemia group, high inflammatory markers such as soluble RAGE and HMGB-1, as well as low lung-protective proteins such as surfactant protein D and Clara cell secretory protein, were associated with prolonged ICU stay. Conclusions Hyperoxemia until 3 h after hospital arrival was associated with prolonged ICU stay among severely injured trauma patients not intubated at the ED. Trial registration UMIN-CTR, UMIN000019588 . Registered on November 15, 2015.

Objectives: The spleen is a key organ of the immune system. Asplenia has been reported to increase the risk of sepsis from overwhelming post-splenectomy infection. However, there are few reports on the association between splenic volume and mortality in patients with no history of splenectomy. This study focused on splenic volume of patients with sepsis and evaluated the association between splenic volume and mortality. Methods: We retrospectively investigated 232 patients with sepsis. The splenic volume was calculated by using computed tomography scans obtained on admission. The patients were categorized into tertiles based on their splenic volume, and the relationship between splenic volume and mortality was evaluated. Odds ratio curves based on splenic volume were created to assess the continuous associations between splenic volume and outcome with a logistic regression model. Results: The patients with sepsis were divided into three groups according to the first (73.6 cm3) and second (128.7 cm3) tertile values of splenic volume. Kaplan–Meier estimation of the probability of the patients’ survival followed up to 28 days showed significant differences between the groups (p= 0.03). The hazard ratio for 28-day mortality in the first tertile group was 3.46 (95% CI 1.3–10.2; p = 0.01) as compared with patients in the third tertile group. Patients with smaller spleens had increased odds ratios for mortality in the logistic regression model. Conclusions: Splenic volume appeared to be an independent predictor of poor prognosis.

Abstract We comment on the study by Batra et al. on the efficacy of probiotics in the prevention of ventilator-associated pneumonia in critically ill ICU patients. They also reported that probiotics administration was not associated with a statistically significant reduction in the incidence of diarrhea (OR 0.59; CI 0.34, 1.03; P = 0.06; I 2 = 38%). However, their meta-analysis missed one RCT, and when we repeated the analysis including this RCT, we found that probiotics administration significantly reduced the incidence of diarrhea (OR 0.51; CI 0.28, 0.92; P = 0.02; I 2 = 45.6%). We thus believe that probiotics administration is effective in reducing the incidence of diarrhea in ventilated critically ill ICU patients.

Background: There is no one-size-fits-all empiric antimicrobial therapy for sepsis because the pathogens vary according to the site of infection and have changed over time. Therefore, updating knowledge on the spectrum of pathogens is necessary for the rapid administration of appropriate antimicrobials. Objective: The aim of this study was to elucidate the current spectrum of pathogens and its variation by site of infection in sepsis. Methods: This was a prospective nationwide cohort study of consecutive adult patients with sepsis in 59 intensive care units in Japan. The spectrum of pathogens was evaluated in all patients and in subgroups by site of infection. Regression analyses were conducted to evaluate the associations between the pathogens and mortality. Results: The study cohort comprised 1184 patients. The most common pathogen was Escherichia coli (21.5%), followed by Klebsiella pneumoniae (9.0%). However, the pattern varied widely by site of infection; for example, gram-positive bacteria were the dominant pathogen in bone/soft tissue infection (55.7%) and cardiovascular infection (52.6%), but were rarely identified in urinary tract infection (6.4%). In contrast, gram-negative bacteria were the predominant pathogens in abdominal infection (38.4%) and urinary tract infection (72.0%). The highest mortality of 47.5% was observed in patients infected with methicillin-resistant Staphylococcus aureus, which was significantly associated with an increased risk of death (odds ratio 1.88, 95% confidence interval 1.22–2.91). Conclusions: This study revealed the current spectrum of pathogens and its variation based on the site of infection, which is essential for empiric antimicrobial therapy against sepsis.

Abstract 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

For Pseudomonas aeruginosa (PA), infection control and appropriate antimicrobial treatment have become important issues. Diagnosis is critical in managing PA infection, but conventional methods are not highly accurate or rapid. We developed a new PA quantification system based on 23S rRNA-targeted reverse transcription quantitative PCR (RT-qPCR). We confirmed that RT-qPCR can quantify PA directly from clinical samples quickly (within 6 h) and with high sensitivity (blood, 1 cell/mL; stool, 100 cells/g) and without cross-reaction. Also, under antibiotic treatment, PA viable counts detected by this system correlated well with the inflammatory response of infected Caco-2 cells compared to other methods such as culturing and qPCR. Next, we utilized this system on fecal samples collected from 65 septic ICU patients and 44 healthy volunteers to identify ICU infection status. We confirmed that the PA detection ratio in ICU patients was significantly higher than that in healthy volunteers (49.2% vs. 13.6%, P