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The terrestrialization of floodplains has become a concern to river managers and ecologists because it has degraded habitats for floodplain-dependent organisms. We examined the temporal distributions of the endangered deepbody bitterling (Acheilognathus longipinnis) throughout its life history, which is an autumn-spawning annual fish spending its egg and larval stages in unionid mussels and emerging in spring, to understand its population decline in the terrestrialized floodplains of the Kiso River, central Japan. We first validated our A. longipinnis environmental DNA (eDNA) sampling method and observed an 89.3% probability of consistency between the eDNA and the direct capture surveys of 56 floodplain waterbodies (FWBs). Subsequently, the temporal distributions with autumn dispersal (9 of 14 FWBs) were found using time-series eDNA samples collected from 14 FWBs on a floodplain with a length and width of 1.4 and 0.2 km, respectively. In the following spring, juveniles were only detected in the two FWBs connected to the river channel. Moreover, the direct capture data revealed that juveniles occurred in 52.9% (9/17) of the connected FWBs, but only in 5.1% (2/39) of the FWBs isolated from the river channel. Autumn dispersal of A. longipinnis would be disadvantageous for reproduction in terrestrialized floodplains with numerous isolated FWBs.

Treatment of L929 cells with tumour necrosis factor-α (TNF-α) plus actinomycin D induced DNA damage (indicated by the appearance of a sub-G1 peak due to extracellular leakage of low molecular weight DNA following DNA fragmentation) before significant cell lysis occurred. The DNA damage occurred in parallel with a decrease of the intracellular total glutathione content and an increase of intracellular reactive oxygen intermediates (ROI), as indicated by increased dihydrorhodamine 123 oxidation. Because the inhibition of mitochondrial respiration suppressed the increase of dihydrorhodamine 123 oxidation and DNA damage as well as the decrease in the total glutathione content, it was suggested that increased mitochondrial formation of ROI was responsible for DNA damage after TNF treatment. Deferoxamine (a ferric iron chelator) and dithiothreitol (a sulfhydryl reagent) both prevented DNA damage and cell killing, indicate that hydroxyl radicals generated from O2- and H2O2 produced by the mitochondria in a process catalysed by iron contributed to DNA damage and that this pathway may be involved in TNF-αinduced cytotoxicity. An inhibitor of poly(ADP)-ribose polymerase (3-aminobenzamide), worsened DNA damage, but was protective against cell lysis, suggesting that DNA repair subsequent to injury was more important than DNA damage per se in development of TNF-α cytotoxicity. [ABSTRACT FROM AUTHOR]

We previously established the selection-marker-free rice-based oral cholera vaccine (MucoRice-CTB) line 51A for human use by Agrobacterium -mediated co-transformation and conducted a double-blind, randomized, placebo-controlled phase I trial in Japan and the United States. Although MucoRice-CTB 51A was acceptably safe and well tolerated by healthy Japanese and U.S. subjects and induced CTB-specific antibodies neutralizing cholera toxin secreted by Vibrio cholerae , we were limited to a 6-g cohort in the U.S. trial because of insufficient production of MucoRice-CTB. Since MucoRice-CTB 51A did not grow in sunlight, we re-examined the previously established marker-free lines and selected MucoRice-CTB line 19A. Southern blot analysis of line 19A showed a single copy of the CTB gene. We resequenced the whole genome and detected the transgene in an intergenic region in chromosome 1. After establishing a master seed bank of MucoRice-CTB line 19A, we established a hydroponic production facility with LED lighting to reduce electricity consumption and to increase production capacity for clinical trials. Shotgun MS/MS proteomics analysis of MucoRice-CTB 19A showed low levels of α-amylase/trypsin inhibitor-like proteins (major rice allergens), which was consistent with the data for line 51A. We also demonstrated that MucoRice-CTB 19A had high oral immunogenicity and induced protective immunity against cholera toxin challenge in mice. These results indicate that MucoRice-CTB 19A is a suitable oral cholera vaccine candidate for Phase I and II clinical trials in humans, including a V. cholerae challenge study., Competing Interests: YY and HK-H are the co-founders and directors of HanaVax Inc., KK, SM, and TH are employed by Asahi Kogyosha Co. Ltd., and NT is employed by Nisseiken Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yuki, Kurokawa, Sugiura, Kashima, Maruyama, Yamanoue, Honma, Mejima, Takeyama, Kuroda, Kozuka-Hata, Oyama, Masumura, Nakahashi-Ouchida, Fujihashi, Hiraizumi, Goto and Kiyono.)

Neutrophils are the principal trouper of the innate immune system. Activated neutrophils undergo a noble cell death termed NETosis and release a mesh-like structure called neutrophil extracellular traps (NETs) as a part of their defensive strategy against microbial pathogen attack. This web-like architecture includes a DNA backbone embedded with antimicrobial proteins like myeloperoxidase (MPO), neutrophil elastase (NE), histones and deploys in the entrapment and clearance of encountered pathogens. Thus NETs play an inevitable beneficial role in the host's protection. However, recent accumulated evidence shows that dysregulated and enhanced NET formation has various pathological aspects including the promotion of sepsis, pulmonary, cardiovascular, hepatic, nephrological, thrombotic, autoimmune, pregnancy, and cancer diseases, and the list is increasing gradually. In this review, we summarize the NET-mediated pathophysiology of different diseases and focus on some updated potential therapeutic approaches against NETs.

Purpose: To evaluate the computed tomography findings of intersigmoid hernias., Material and Methods: Between April 2010 and March 2018, 7 patients who were surgically diagnosed with intersigmoid hernia in 3 institutions were enrolled in this study. Two radiologists evaluated imaging findings for the herniated small bowel, the distance between the occlusion point and bifurcation of the left common iliac artery, and the anatomic relationship with adjacent organs., Results: All patients were male, and their mean age (standard deviation, range) was 61.0 (13.5, 36-85) years. The mean size of the bowel loops was 5.2 (1.3, 4.0-8.3) cm in the caudal direction, 3.6 (0.8, 2.5-5.1) cm in the lateral, and 3.4 (0.6, 2.5-4.7) cm in the anterior-posterior direction. The volume was 37.9 (27.8, 15.6-103.0) cm 3 approximated by an ellipse, and 24.0 (17.7, 9.9-65.6) cm 3 approximated by a truncated cone. The obstruction point was located 3.6 (0.6, 2.8-4.7) cm inferior to the bifurcation of the left common iliac artery. In all cases, the small bowel ran under the point at which the inferior mesenteric vessels bifurcated to the superior rectal vessels and the sigmoid vessels and formed a sac-like appearance between the left psoas muscle and the sigmoid colon. The ureter ran dorsal to the point of the bowel stenosis, and the left gonadal vein ran outside the small bowel loops., Conclusions: All cases showed common imaging findings, which may be characteristic of men's intersigmoid hernia. In addition, the fossa's position was lower, and the size was larger than in the previous study, which may be a risk factor., Competing Interests: The authors report no conflict of interest., (© Pol J Radiol 2023.)

Introduction: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used as an intra-aortic balloon occlusion in Japan; however, protocols for its effective use in different conditions have not been established. This study aimed to summarize the strategies of REBOA use in severe torso trauma., Methods: Twenty-nine cases of REBOA for torso trauma treated at our hospital over 5 years were divided into hemodynamically unstable (HU) ( n  = 12), cardiac arrest (CA) ( n  = 13), and hemodynamically stable (HS) ( n  = 4) groups. We retrospectively examined patient characteristics, trauma mechanism, injury site, severity score, intervention type, and survival rates at 24 h in each group., Results: In the HU group, 9 and 3 patients survived and died within 24 h, respectively; time to intervention (56.6 versus 130.7 min, P  = 0.346) tended to be shorter and total occlusion time (40.2 versus 337.7 min, P  = 0.009) was significantly shorter in survivors than in nonsurvivors. In the CA group, 10 patients were converted from resuscitative thoracotomy with aortic cross-clamp (RTACC); one patient survived. All four patients in the HS group survived, having received prophylactic REBOA., Conclusion: The efficacy of REBOA for severe torso trauma depends on the patient's condition. If the patients are hemodynamically unstable, time to intervention and total occlusion time could correlate with survival. The combined use of REBOA with definitive hemostasis could improve outcomes. Conversion from RTACC in the cardiac arrest patients and prophylactic use in the hemodynamically stable patients can be one of the potentially effective options, although further studies are needed., (© 2022 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Tranexamic acid (TXA) reduces the risk of bleeding trauma death without altering the need for blood transfusion. We examined the effects of TXA on coagulation and fibrinolysis dynamics and the volume of transfusion during the early stage of trauma. This subanalysis of a prospective multicenter study of severe trauma included 276 patients divided into propensity score-matched groups with and without TXA administration. The effects of TXA on coagulation and fibrinolysis markers immediately at (time point 0) and 3 hours after (time point 3) arrival at the emergency department were investigated. The transfusion volume was determined at 24 hours after admission. TXA was administered to the patients within 3 hours (median, 64 minutes) after injury. Significant reductions in fibrin/fibrinogen degradation products and D-dimer levels from time points 0 to 3 in the TXA group compared with the non-TXA group were confirmed, with no marked differences noted in the 24-hour transfusion volumes between the 2 groups. Continuously increased levels of soluble fibrin, a marker of thrombin generation, from time points 0 to 3 and high levels of plasminogen activator inhibitor-1, a marker of inhibition of fibrinolysis, at time point 3 were observed in both groups. TXA inhibited fibrin(ogen)olysis during the early stage of severe trauma, although this was not associated with a reduction in the transfusion volume. Other confounders affecting the dynamics of fibrinolysis and transfusion requirement need to be clarified., Competing Interests: S.G. has received honoraria from Grifols, and A.S. has received lecture fee from CSL Behring outside of this work. T.-a.N. has received a grant from and has stock in Smart 119 Inc outside of this work. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2022. The Author(s).)

In settings where traditional medicine is a crucial part of the healthcare system, providing culturally competent healthcare services is vital to improving patient satisfaction and health outcomes. Therefore, this study sought to gain insight into how cultural beliefs influence health-seeking behaviors (HSBs) among Mozambicans. Participant observation and in-depth interviews (IDIs) were undertaken using the ethnonursing method to investigate beliefs and views that Mozambicans (living in Pemba City) often take into account to meet their health needs. Data were analyzed in accordance with Leininger's ethnonursing guidelines. Twenty-seven IDIs were carried out with 12 informants from the Makonde and Makuwa tribes. The choice of health service was influenced by perceptions of health and illness through a spiritual lens, belief in supernatural forces, dissatisfaction with and dislike of the public medical system on grounds of having received poor-quality treatment, perceived poor communication skills of health professionals, and trust in the indigenous medical system. This study confirmed the need for health professionals to carefully take cultural influences into consideration when providing care for their patients. We recommend an educational intervention that emphasizes communication skills training for healthcare workers to ensure successful physician/nurse-patient relationships.

Background: The updated Surviving Sepsis Campaign guidelines recommend a 1-hour window for completion of a sepsis care bundle; however, the effectiveness of the hour-1 bundle has not been fully evaluated. The present study aimed to evaluate the impact of hour-1 bundle completion on clinical outcomes in sepsis patients., Methods: This was a multicenter, prospective, observational study conducted in 17 intensive care units in tertiary hospitals in Japan. We included all adult patients who were diagnosed as having sepsis by Sepsis-3 and admitted to intensive care units from July 2019 to August 2020. Impacts of hour-1 bundle adherence and delay of adherence on risk-adjusted in-hospital mortality were estimated by multivariable logistic regression analyses., Results: The final study cohort included 178 patients with sepsis. Among them, 89 received bundle-adherent care. Completion rates of each component (measure lactate level, obtain blood cultures, administer broad-spectrum antibiotics, administer crystalloid, apply vasopressors) within 1 hour were 98.9%, 86.2%, 51.1%, 94.9%, and 69.1%, respectively. Completion rate of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the patients with and 30.3% in the patients without bundle-adherent care (p = 0.054). The adjusted odds ratio of non-bundle-adherent versus bundle-adherent care for in-hospital mortality was 2.32 (95% CI 1.09-4.95) using propensity scoring. Non-adherence to obtaining blood cultures and administering broad-spectrum antibiotics within 1 hour was related to in-hospital mortality (2.65 [95% CI 1.25-5.62] and 4.81 [95% CI 1.38-16.72], respectively). The adjusted odds ratio for 1-hour delay in achieving hour-1 bundle components for in-hospital mortality was 1.28 (95% CI 1.04-1.57) by logistic regression analysis., Conclusion: Completion of the hour-1 bundle was associated with lower in-hospital mortality. Obtaining blood cultures and administering antibiotics within 1 hour may have been the components most contributing to decreased in-hospital mortality., Competing Interests: The authors have declared that no competing interests exist.

Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Umetsu, Tanaka, Nakayama, Kato, Ueda, Nishibata, Hasegawa, Matsumoto, Takeyama, Iguchi, Tanaka, Hinoi, Inagaki, Inden, Muto and Nakamura.)

Background: Traumatic brain injury (TBI)-associated coagulopathy is a widely recognized risk factor for secondary brain damage and contributes to poor clinical outcomes. Various theories, including disseminated intravascular coagulation (DIC), have been proposed regarding its pathomechanisms; no consensus has been reached thus far. This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing coagulofibrinolytic changes in isolated TBI (iTBI) to those in non-TBI, to determine the associated factors, and identify the clinical significance of DIC diagnosis in patients with iTBI. Methods: This secondary multicenter, prospective study assessed patients with severe trauma. iTBI was defined as Abbreviated Injury Scale (AIS) scores ≥4 in the head and neck, and ≤2 in other body parts. Non-TBI was defined as AIS scores ≥4 in single body parts other than the head and neck, and the absence of AIS scores ≥3 in any other trauma-affected parts. Specific biomarkers for thrombin and plasmin generation, anticoagulation, and fibrinolysis inhibition were measured at the presentation to the emergency department (0 h) and 3 h after arrival. Results: We analyzed 34 iTBI and 40 non-TBI patients. Baseline characteristics, transfusion requirements and in-hospital mortality did not significantly differ between groups. The changes in coagulation/fibrinolysis-related biomarkers were similar. Lactate levels in the iTBI group positively correlated with DIC scores (rho = -0.441, p = 0.017), but not with blood pressure (rho = -0.098, p = 0.614). Multiple logistic regression analyses revealed that the injury severity score was an independent predictor of DIC development in patients with iTBI (odds ratio = 1.237, p = 0.018). Patients with iTBI were further subdivided into two groups: DIC ( n = 15) and non-DIC ( n = 19) groups. Marked thrombin and plasmin generation were observed in all patients with iTBI, especially those with DIC. Patients with iTBI and DIC had higher requirements for massive transfusion and emergency surgery, and higher in-hospital mortality than those without DIC. Furthermore, DIC development significantly correlated with poor hospital survival; DIC scores at 0 h were predictive of in-hospital mortality. Conclusions: Coagulofibrinolytic changes in iTBI and non-TBI patients were identical, and consistent with the pathophysiology of DIC. DIC diagnosis in the early phase of TBI is key in predicting the outcomes of severe TBI., Competing Interests: AS reported receiving personal fees from CSL Behring outside of the submitted work. SG reported receiving personal fees from Asahi Kasei Pharma America Inc. and Asahi Kasei Pharma Japan Inc. outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wada, Shiraishi, Gando, Yamakawa, Fujishima, Saitoh, Kushimoto, Ogura, Abe, Mayumi, Sasaki, Kotani, Takeyama, Tsuruta, Takuma, Shiraishi, Shiino, Nakada, Okamoto, Sakamoto, Hagiwara, Fujimi, Umemura and Otomo.)

Abstract: Glycemic control strategies for sepsis have changed significantly over the last decade, but their impact on dysglycemia and its associated outcomes has been poorly understood. In addition, there is controversy regarding the detrimental effects of hyperglycemia in sepsis. To evaluate the incidence and risks of dysglycemia under current strategy, we conducted a preplanned subanalysis of the sepsis cohort in a prospective, multicenter FORECAST study. A total of 1,140 patients with severe sepsis, including 259 patients with pre-existing diabetes, were included. Median blood glucose levels were approximately 140 mg/dL at 0 and 72 h indicating that blood glucose was moderately controlled. The rate of initial and late hyperglycemia was 27.3% and 21.7%, respectively. The rate of early hypoglycemic episodes during the initial 24 h was 13.2%. Glycemic control was accompanied by a higher percentage of initial and late hyperglycemia but not with early hypoglycemic episodes, suggesting that glycemic control was targeted at excess hyperglycemia. In nondiabetic patients, late hyperglycemia (hazard ratio, 95% confidence interval; P value: 1.816, 1.116-2.955, 0.016) and early hypoglycemic episodes (1.936, 1.180-3.175, 0.009) were positively associated with in-hospital mortality. Further subgroup analysis suggested that late hyperglycemia and early hypoglycemic episodes independently, and probably synergistically, affect the outcomes. In diabetic patients, however, these correlations were not observed. In conclusion, a significantly high incidence of dysglycemia was observed in our sepsis cohort under moderate glycemic control. Late hyperglycemia in addition to early hypoglycemia was associated with poor outcomes at least in nondiabetic patients. More sophisticated approaches are necessary to reduce the incidence of these serious complications., Competing Interests: The other authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Objective: To investigate the efficacy and feasibility of a self-management programme incorporating a sleep intervention for improving diabetes outcomes., Design: A single-arm pre-test and post-test study was conducted within a community setting in Hiroshima, Japan., Participants: Participants were aged 52-74 years and diagnosed with type 2 diabetic nephropathy stages 1-3., Interventions: Participants received self-management education from nurses for 6 months. First, the nurses assessed their sleep conditions using insomnia scales and a sleep metre. Then, the participants learnt self-management to increase their physical activity and improve their sleep condition. They also implemented diet therapy and medication adherence., Outcome Measures: Physiological indicators, subjective and objective indicators of sleep quality, self-management indicators, quality of life (QOL) and feasibility were evaluated. To confirm the efficacy of intervention, Freidman tests, analysis of variance, Wilcoxon signed-rank test and t-test were performed. Pearson's correlations were analysed between activities and sleep condition., Results: Of the 26 enrolled participants, 24 completed the programme and were analysed. Among them, 15 participants (62.5%) had sleep disorders caused by multiple factors, such as an inappropriate lifestyle and physical factors that interfere with good sleep. Although insomnia scales did not change for the sleep disorders, their subjective health status improved. Regarding indicators related to diabetes management, lifestyles improved significantly. Haemoglobin A1c, body mass index, systolic blood pressure, non-high-density lipoprotein-cholesterol and QOL also improved. All participants except one were satisfied with the programme. However, use of the sleep metre and nurses' consultation about sleep disturbance were not well evaluated., Conclusions: This programme was effective in improving diabetes status, lifestyle and behaviour changes. However, its effect on sleep condition was limited because of its complexity. A simple and novel approach is needed to strengthen the motivation for sleep behaviour change and to increase programme efficacy and feasibility., Trial Registration Number: UMIN000025906., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 < 0.001), higher frequency of massive transfusion and MODS and a higher mortality rate than no such diagnosis. The DIC scores at 0 and 3 h significantly predicted massive transfusion, MODS, and hospital death. Markers of thrombin and plasmin generation and fibrinolysis inhibition also showed a good predictive ability for these three items. In conclusion, a DIC diagnosis on admission was associated with a low survival probability. DIC scores obtained immediately after trauma predicted a poor prognosis of severely injured trauma patients.

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 PaO 2 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.

Background: The purpose of this study is to investigate the time course of syndecan-1 (Syn-1) plasma levels, the correlation between Syn-1 and organ damage development, and the associations of Syn-1 level with cumulative fluid balance and ventilator-free days (VFD) in patients with septic shock., Methods: We collected blood samples from 38 patients with septic shock upon their admission to ICU and for the first 7 days of their stay. Syn-1 plasma level, acute respiratory distress syndrome (ARDS), other organ damage, VFD, and cumulative fluid balance were assessed daily., Results: Over the course of 7 days, Syn-1 plasma levels increased significantly more in patients with ARDS than in those without ARDS. Patients with high levels of Syn-1 in the 72 h after ICU admission had significantly higher cumulative fluid balance, lower PaO 2 /FiO 2 , and fewer VFD than patients with low levels of Syn-1. Syn-1 levels did not correlate with sequential organ failure assessment score or with APACHE II score., Conclusions: In our cohort of patients with septic shock, higher circulating level of Syn-1 of cardinal glycocalyx component is associated with more ARDS, cumulative positive fluid balance, and fewer VFD. Measurement of Syn-1 levels in patients with septic shock might be useful for predicting patients at high risk of ARDS.

Abstract: This study aimed to identify prognostic factors for severe sepsis-related in-hospital mortality using the structural equation model (SEM) analysis with statistical causality. Sepsis data from the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma study (FORECAST), a multicenter cohort study, was used. Forty seven observed variables from the database were used to construct 4 latent variables. SEM analysis was performed on these latent variables to analyze the statistical causality among these data. This study evaluated whether the variables had an effect on in-hospital mortality. Overall, 1148 patients were enrolled. The SEM analysis showed that the 72-hour physical condition was the strongest latent variable affecting mortality, followed by physical condition before treatment. Furthermore, the 72-hour physical condition and the physical condition before treatment strongly influenced the Sequential Organ Failure Assessment (SOFA) score with path coefficients of 0.954 and 0.845, respectively. The SOFA score was the strongest variable that affected mortality after the onset of severe sepsis. The score remains the most robust prognostic factor and can facilitate appropriate policy development on care., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 < 18.5) and non-underweight (BMI ≥ 18.5) groups. The primary outcome was 28-day mortality. Univariate analysis of the derivation cohort indicated increased 28-day mortality trend in the underweight group compared to the non-underweight group (underweight 24.4% [20/82 cases] vs. non-underweight 16.0% [85/532 cases]; p = 0.060). In the primary analysis, multivariate analysis adjusted for baseline imbalance revealed that patients in the underweight group had a significantly increased 28-day mortality compared to those in the non-underweight group (p = 0.031, adjusted odds ratio [OR] 1.91, 95% confidence interval [CI] 1.06-3.46). In a repeated analysis using a multicenter validation cohort (underweight n = 343, non-underweight n = 1218), patients in the underweight group had a significantly increased 28-day mortality compared to those in the non-underweight group (p = 0.045, OR 1.40, 95% CI 1.00-1.97). In conclusion, patients with a BMI < 18.5 had a significantly increased 28-day mortality compared to those with a BMI ≥ 18.5 in Japanese cohorts with severe sepsis.

Background: Frailty is associated with morbidity and mortality in patients admitted to intensive care units (ICUs). However, the characteristics of frail patients with suspected infection remain unclear. We aimed to investigate the characteristics and outcomes of frail patients with suspected infection in ICUs., Methods: This is a secondary analysis of a multicenter cohort study, including 22 ICUs in Japan. Adult patients (aged ≥16 years) with newly suspected infection from December 2017 to May 2018 were included. We compared baseline patient characteristics and outcomes among three frailty groups based on the Clinical Frailty Scale (CFS) score: fit (score, 1-3), vulnerable (score, 4), and frail (score, 5-9). We conducted subgroup analysis of patients with sepsis defined as per Sepsis-3 criteria. We also produced Kaplan-Meier survival curves for 90-day survival., Results: We enrolled 650 patients with suspected infection, including 599 (92.2%) patients with sepsis. Patients with a median CFS score of 3 (interquartile range [IQR] 3-5) were included: 337 (51.8%) were fit, 109 (16.8%) were vulnerable, and 204 (31.4%) were frail. The median patient age was 72 years (IQR 60-81). The Sequential Organ Failure Assessment scores for fit, vulnerable, and frail patients were 7 (IQR 4-10), 8 (IQR 5-11), and 7 (IQR 5-10), respectively (p = 0.59). The median body temperatures of fit, vulnerable, and frail patients were 37.5 °C (IQR 36.5 °C-38.5 °C), 37.5 °C (IQR 36.4 °C-38.6 °C), and 37.0 °C (IQR 36.3 °C-38.1 °C), respectively (p < 0.01). The median C-reactive protein levels of fit, vulnerable, and frail patients were 13.6 (IQR 4.6-24.5), 12.1 (IQR 3.9-24.9), 10.5 (IQR 3.0-21.0) mg/dL, respectively (p < 0.01). In-hospital mortality did not statistically differ among the patients according to frailty (p = 0.19). Kaplan-Meier survival curves showed little difference in the mortality rate during short-term follow-up. However, more vulnerable and frail patients died after 30-day than fit patients; this difference was not statistically significant (p = 0.25). Compared with the fit and vulnerable groups, the rate of home discharge was lower in the frail group., Conclusion: Frail and vulnerable patients with suspected infection tend to have poor disease outcomes. However, they did not show a statistically significant increase in the 90-day mortality risk.

We investigated whether an Information and Communication Technology (ICT) application (app) motivated to increase adherence to lifestyle changes, and to improve indicators of metabolic disturbances among Japanese civil servants. A non-randomized, open-label, parallel-group study was conducted with 102 participants aged 20-65 years undergoing a health check during 2016-2017, having overweight and/or elevated glucose concentration. Among them, 63 participants chose Specific Health Guidance (SHG) and ongoing support incorporating the use of an app (ICT group) and 39 individuals chose only SHG (control group). Fifty from the ICT group and 38 from the control group completed the study. After completing the 6-month program, the control group showed a significant decrease in body mass index ( p = 0.008), male waist circumference ( p < 0.001), systolic blood pressure (BP) ( p = 0.005), diastolic BP ( p < 0.001), and glycated hemoglobin (HbA1c) ( p < 0.001), and increase in high-density lipoprotein (HDL) cholesterol ( p = 0.008). However, the ICT group showed a significant decrease in male waist circumference ( p < 0.001), diastolic BP ( p = 0.003), and HbA1c ( p < 0.001), and increase in HDL cholesterol ( p = 0.032). The magnitude of change for most indicators tended to be highest for ICT participants (used the app ≥5 times/month). Both groups reported raised awareness on BP and weight. The app use program did not have a major impact after the observation period. Proper action requires frequent use of the app to enhance best results.

Introduction: Polymyxin B hemoperfusion (PMX-HP) is an adjuvant therapy for sepsis or septic shock that removes circulating endotoxin. However, PMX-HP has seldom achieved expectations in randomized trials targeting nonspecific overall sepsis patients. If used in an optimal population, PMX-HP may be beneficial. This study aimed to identify the optimal population for PMX-HP in patients with septic shock., Methods: We used a prospective nationwide cohort targeting consecutive adult patients with severe sepsis (Sepsis-2) in 59 intensive care units in Japan. Associations between PMX-HP therapy and in-hospital mortality were assessed using multivariable Cox proportional hazard regression models. To identify best targets for PMX-HP, we developed a non-linear restricted cubic spline model including two-way interaction term (treatment × Acute Physiology and Chronic Health Evaluation [APACHE] II score/Sequential Organ Failure Assessment [SOFA] score) and three-way interaction term (treatment × age × each score)., Results: The final study cohort comprised 741 sepsis patients (92 received PMX-HP, 625 did not). Cox proportional hazards regression model adjusted for the covariates suggested no association between PMX-HP therapy and improved mortality overall. Effect modification of PMX-HP by APACHE II score was statistically significant (P for interaction = 0.189) but non-significant for SOFA score (P for interaction = 0.413). Three-way interaction analysis revealed suppressed risk hazard in the PMX-HP group versus control group only in septic shock patients with high age and in the most severe subset of both scores, whereas increased risk hazard was observed in those with high age but in the lower severity subset of both scores., Conclusions: Our results suggested that although PMX-HP did not reduce in-hospital mortality among overall septic shock patients, it may benefit a limited population with high age and higher disease severity.

Components of neutrophil extracellular traps (NETs) are released into the circulation by neutrophils and contribute to microcirculatory disturbance in sepsis. Removing NET components (DNA, histones, and proteases) from the circulation could be a new strategy for counteracting NET-dependent tissue damage. We evaluated the effect of hemoperfusion with a polymyxin B (PMX) cartridge, which was originally developed for treating gram-negative infection, on circulating NET components in patients with septic shock, as well as the effect on phorbol myristate acetate (PMA)-stimulated neutrophils obtained from healthy volunteers. Ex vivo closed loop hemoperfusion was performed through PMX filters in a laboratory circuit. Whole blood from healthy volunteers (incubated with or without PMA) or from septic shock patients was perfused through the circuit. For in vivo experiment blood samples were collected before and immediately after hemoperfusion with PMX to measure the plasma levels of cell-free NETs. The level of cell-free NETs was assessed by measuring myeloperoxidase-associated DNA (MPO-DNA), neutrophil elastase-associated DNA (NE-DNA), and cell-free DNA (cf-DNA). Plasma levels of MPO-DNA, NE-DNA, and cf-DNA were significantly increased after 2 h of PMA stimulation. When the circuit was perfused with blood from septic shock patients or PMA-stimulated neutrophils from healthy volunteers, circulating levels of MPO-DNA, NE-DNA, and cf-DNA were significantly reduced after 1 and 2 h of perfusion with a PMX filter compared with perfusion without a PMX filter. In 10 patients with sepsis, direct hemoperfusion through filters with immobilized PMX significantly reduced plasma levels of MPO-DNA and NE-DNA. These ex vivo and in vivo findings demonstrated that hemoperfusion with PMX removes circulating NET components. Selective removal of circulating NET components from the blood could be effective for prevention/treatment of NET-related inappropriate inflammation and thrombogenesis in patients with sepsis.

Background: Elderly patients have a blunted host response, which may influence vital signs and clinical outcomes of sepsis. This study was aimed to investigate whether the associations between the vital signs and mortality are different in elderly and non-elderly patients with sepsis., Methods: This was a retrospective observational study. A Japanese multicenter sepsis cohort (FORECAST, n = 1148) was used for the discovery analyses. Significant discovery results were tested for replication using two validation cohorts of sepsis (JAAMSR, Japan, n = 624; SPH, Canada, n = 1004). Patients were categorized into elderly and non-elderly groups (age ≥ 75 or < 75 years). We tested for association between vital signs (body temperature [BT], heart rate, mean arterial pressure, systolic blood pressure, and respiratory rate) and 90-day in-hospital mortality (primary outcome)., Results: In the discovery cohort, non-elderly patients with BT < 36.0 °C had significantly increased 90-day mortality (P = 0.025, adjusted hazard ratio 1.70, 95% CI 1.07-2.71). In the validation cohorts, non-elderly patients with BT < 36.0 °C had significantly increased mortality (JAAMSR, P = 0.0024, adjusted hazard ratio 2.05, 95% CI 1.29-3.26; SPH, P = 0.029, adjusted hazard ratio 1.36, 95% CI 1.03-1.80). These differences were not observed in elderly patients in the three cohorts. Associations between the other four vital signs and mortality were not different in elderly and non-elderly patients. The interaction of age and hypothermia/fever was significant (P < 0.05)., Conclusions: In septic patients, we found mortality in non-elderly sepsis patients was increased with hypothermia and decreased with fever. However, mortality in elderly patients was not associated with BT. These results illuminate the difference in the inflammatory response of the elderly compared to non-elderly sepsis patients.

Background: Diagnosing sepsis remains difficult because it is not a single disease but a syndrome with various pathogen- and host factor-associated symptoms. Sepsis-3 was established to improve risk stratification among patients with infection based on organ failures, but it has been still controversial compared with previous definitions. Therefore, we aimed to describe characteristics of patients who met sepsis-2 (severe sepsis) and sepsis-3 definitions., Methods: This was a multicenter, prospective cohort study conducted by 22 intensive care units (ICUs) in Japan. Adult patients (≥ 16 years) with newly suspected infection from December 2017 to May 2018 were included. Those without infection at final diagnosis were excluded. Patient's characteristics and outcomes were described according to whether they met each definition or not., Results: In total, 618 patients with suspected infection were admitted to 22 ICUs during the study, of whom 530 (85.8%) met the sepsis-2 definition and 569 (92.1%) met the sepsis-3 definition. The two groups comprised different individuals, and 501 (81.1%) patients met both definitions. In-hospital mortality of study population was 19.1%. In-hospital mortality among patients with sepsis-2 and sepsis-3 patients was comparable (21.7% and 19.8%, respectively). Patients exclusively identified with sepsis-2 or sepsis-3 had a lower mortality (17.2% vs. 4.4%, respectively). No patients died if they did not meet any definitions. Patients who met sepsis-3 shock definition had higher in-hospital mortality than those who met sepsis-2 shock definition., Conclusions: Most patients with infection admitted to ICU meet sepsis-2 and sepsis-3 criteria. However, in-hospital mortality did not occur if patients did not meet any criteria. Better criteria might be developed by better selection and combination of elements in both definitions., Trial Registration: UMIN000027452., Competing Interests: Competing interestsAll authors declare that they have no competing interests., (© The Author(s) 2020.)

Purpose: Acute respiratory distress syndrome (ARDS) remains a major cause of death. Epidemiology should be continually examined to refine therapeutic strategies for ARDS. We aimed to elucidate demographics, treatments, and outcomes of ARDS in Japan., Methods: This is a prospective cohort study for ARDS. We included adult patients admitted to intensive care units through emergency and critical care departments who satisfied the American-European Consensus Conference (AECC) acute lung injury (ALI) criteria. In addition, the fulfillment of the Berlin definition was assessed. Logistic regression analyses were used to examine the association of independent variables with outcomes., Results: Our study included 166 patients with AECC ALI from 34 hospitals in Japan; among them, 157 (94.6%) fulfilled the Berlin definition. The proportion of patients with PaO2/FIO2 ≤ 100, patients under invasive positive pressure ventilation (IPPV), and in-hospital mortality was 39.2%, 92.2%, and 38.0% for patients with AECC ALI and 38.9%, 96.8%, and 37.6% for patients with Berlin ARDS, respectively. The area of lung infiltration was independently associated with outcomes of ARDS. Low-mid-tidal volume ventilation was performed in 75% of patients under IPPV. Glucocorticoid use was observed in 54% patients, and it was positively associated with mortality., Conclusions: Our study included a greater percentage of patients with ARDS with high severity and found that the overall mortality was 38%. The management of ARDS in Japan was characterized by high the utilization rate of glucocorticoids, which was positively associated with mortality.

Halomonas hydrothermalis strain Slthf2 is a Gram-negative bacterium isolated from low-temperature hydrothermal fluids in South Pacific Ocean vent fields located at 2,580-m depth. Here, we report the complete genome sequence of this strain, which has a genome size of 4.12 Mb, with a GC content of 53.2%., (Copyright © 2020 Takeyama et al.)

Background: Dysglycemia is frequently observed in patients with sepsis. However, the relationship between dysglycemia and outcome is inconsistent. We evaluate the clinical characteristics, glycemic abnormalities, and the relationship between the initial glucose level and mortality in patients with sepsis., Methods: This is a retrospective sub-analysis of a multicenter, prospective cohort study. Adult patients with severe sepsis (Sepsis-2) were divided into groups based on blood glucose categories (<70 (hypoglycemia), 70-139, 140-179, and ≥180 mg/dL), according to the admission values. In-hospital mortality and the relationship between pre-existing diabetes and septic shock were evaluated., Results: Of 1158 patients, 69, 543, 233, and 313 patients were categorized as glucose levels <70, 70-139, 140-179, ≥180 mg/dL, respectively. Both the Acute Physiological and Chronic Health Evaluation II and Sequential Organ Failure Assessment (SOFA) scores on the day of enrollment were higher in the hypoglycemic patients than in those with 70-179 mg/dL. The hepatic SOFA scores were also higher in hypoglycemic patients. In-hospital mortality rates were higher in hypoglycemic patients than in those with 70-139 mg/dL (26/68, 38.2% vs 43/221, 19.5%). A significant relationship between mortality and hypoglycemia was demonstrated only in patients without known diabetes. Mortality in patients with both hypoglycemia and septic shock was 2.5-times higher than that in patients without hypoglycemia and septic shock., Conclusions: Hypoglycemia may be related to increased severity and high mortality in patients with severe sepsis. These relationships were evident only in patients without known diabetes. Patients with both hypoglycemia and septic shock had an associated increased mortality rate., Competing Interests: The authors have declared that no competing interests exist.

Clinical manifestations of sepsis differ between patients with and without diabetes mellitus (DM), and these differences could influence the clinical behaviors of medical staff. Therefore, we aimed to investigate whether pre-existing DM was associated with the time to antibiotics or sepsis care protocols.This was a retrospective cohort study.It conducted at 53 intensive care units (ICUs) in Japan.Consecutive adult patients with severe sepsis admitted directly to ICUs form emergency departments from January 2016 to March 2017 were included.The primary outcome was time to antibiotics.Of the 619 eligible patients, 142 had DM and 477 did not have DM. The median times (interquartile ranges) to antibiotics in patients with and without DM were 103 minutes (60-180 minutes) and 86 minutes (45-155 minutes), respectively (P = .05). There were no significant differences in the rates of compliance with sepsis protocols or with patient-centred outcomes such as in-hospital mortality. The mortality rates of patients with and without DM were 23.9% and 21.6%, respectively (P = .55). Comparing patients with and without DM, the gamma generalized linear model-adjusted relative difference indicated that patients with DM had a delay to starting antibiotics of 26.5% (95% confidence intervals (95%CI): 4.6-52.8, P = .02). The gamma generalized linear model-adjusted relative difference with multiple imputation for missing data of sequential organ failure assessment was 19.9% (95%CI: 1.0-42.3, P = .04). The linear regression model-adjusted beta coefficient indicated that patients with DM had a delay to starting antibiotics of 29.2 minutes (95%CI: 6.8-51.7, P = .01). Logistic regression modelling showed that pre-existing DM was not associated with in-hospital mortality (odds ratio, 1.26; 95%CI: 0.72-2.19, P = .42).Pre-existing DM was associated with delayed antibiotic administration among patients with severe sepsis or septic shock; however, patient-centred outcomes and compliance with sepsis care protocols were comparable.