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Early outcome prediction for out-of-hospital cardiac arrest with initial shockable rhythm is useful in selecting the choice of resuscitative treatment by clinicians. This study aimed to develop and validate a machine learning-based outcome prediction model for out-of-hospital cardiac arrest with initial shockable rhythm, which can be used on patient's arrival at the hospital.Data were obtained from a nationwide out-of-hospital cardiac arrest registry in Japan. Of 43,350 out-of-hospital cardiac arrest patients with initial shockable rhythm registered between 2013 and 2017, patients aged18 years and those with cardiac arrest caused by external factors were excluded. Subjects were classified into training (n = 23,668, 2013-2016 data) and test (n = 6381, data from 2017) sets for validation. Only 19 prehospital variables were used for the outcome prediction. The primary outcome was death at 1 month or survival with poor neurological function (cerebral performance category 3-5; "poor" outcome). Several machine learning models, including those based on logistic regression, support vector machine, random forest, and multilayer perceptron classifiers were compared.In validation analyses, all machine learning models performed satisfactorily with area under the receiver operating characteristic curve values of 0.882 [95% confidence interval [CI]: 0.869-0.894] for logistic regression, 0.866 [95% CI: 0.853-0.879] for support vector machine, 0.877 [95% CI: 0.865-0.890] for random forest, and 0.888 [95% CI: 0.876-0.900] for multilayer perceptron classifiers.A favourable machine learning-based prognostic model available to use on patient arrival at the hospital was developed for out-of-hospital cardiac arrest with initial shockable rhythm.

Background The European Society of Cardiology (ESC) recommends a 0-h/1-h (0/1-h) algorithm to classify patients with suspected non-ST-segment elevation myocardial infarction (NSTEMI). However, reliable evidence about patients who present early after the onset of symptoms is limited, likely because high-sensitivity cardiac troponin (hs-cTn) values cannot increase sufficiently within that time. This study aimed to evaluate the outcomes in real-world situations that utilized the 0/1-h algorithm. Methods In a prospective, international, multicenter cohort study that enrolled 1638 patients presenting with acute chest pain to the emergency department, we assessed the performance of the 0/1-h algorithm using hs-cTnT and the associated 30-day rates of major adverse cardiac events: death and acute myocardial infarction (AMI). Results Among 1074 patients, the prevalence of AMI was 16.0%. An approximately 60.1% (n = 645) of patients visited the hospital within 3 h after onset of chest pain (less than 1 h; 18.2% [n = 196], less than 2 h; 27.5% [n = 295], and less than 3 h; 14.3% [n = 154]). Moreover, the prevalence rates of AMI were similar at all times (1 h, 16.8%; 1–2 h, 20.7%; 2–3 h, 18.2%; p = .5). According to the ESC 0/1-h algorithm, the distribution patterns of rule-out, observe, and rule-in groups were similar; however, none of the patients was diagnosed with AMI or cardiac death in the rule-out group. Conclusion This study revealed the applicability of the 0/1-h algorithm for the management of early presenters.

Background: Mechanically ventilated patients are susceptible to nosocomial infections such as ventilator-associated pneumonia. To treat ventilated patients with suspected infection, clinicians select appropriate antibiotics. However, decision-making regarding the use of antibiotics for methicillin-resistant Staphylococcus aureus (MRSA) is challenging, because of the lack of evidence-supported criteria. This study aims to derive a machine learning model to predict MRSA as a possible pathogen responsible for infection in mechanically ventilated patients.Methods: Data were collected from the Medical Information Mart for Intensive Care (MIMIC)-IV database (an openly available database of patients treated at the Beth Israel Deaconess Medical Center in the period 2008–2019). Of 26,409 mechanically ventilated patients, 809 were screened for MRSA during the mechanical ventilation period and included in the study. The outcome was positivity to MRSA on screening, which was highly imbalanced in the dataset, with 93.9% positive outcomes. Therefore, after dividing the dataset into a training set (n = 566) and a test set (n = 243) for validation by stratified random sampling with a 7:3 allocation ratio, synthetic datasets with 50% positive outcomes were created by synthetic minority over-sampling for both sets individually (synthetic training set: n = 1,064; synthetic test set: n = 456). Using these synthetic datasets, we trained and validated an XGBoost machine learning model using 28 predictor variables for outcome prediction. Model performance was evaluated by area under the receiver operating characteristic (AUROC), sensitivity, specificity, and other statistical measurements. Feature importance was computed by the Gini method.Results: In validation, the XGBoost model demonstrated reliable outcome prediction with an AUROC value of 0.89 [95% confidence interval (CI): 0.83–0.95]. The model showed a high sensitivity of 0.98 [CI: 0.95–0.99], but a low specificity of 0.47 [CI: 0.41–0.54] and a positive predictive value of 0.65 [CI: 0.62–0.68]. Important predictor variables included admission from the emergency department, insertion of arterial lines, prior quinolone use, hemodialysis, and admission to a surgical intensive care unit.Conclusions: We were able to develop an effective machine learning model to predict positive MRSA screening during mechanical ventilation using synthetic datasets, thus encouraging further research to develop a clinically relevant machine learning model for antibiotics stewardship.

Introduction Patients with combined burn and trauma are common in the United States and combined trauma in the burn increase the mortality. On contrast, their characteristics and outcomes remain unknown in Japan. The aim of present study was to elucidate the characteristics of trauma combined burn in Japan. Methods A multicenter retrospective study was performed between 2004 and 2017 using data from the Japan Trauma Data Bank (JTDB). We evaluated characteristics in burn patients (n=5,783) by segregating them into two groups cohorts: burn only (n=5,537) and combined burn and trauma(n=246). Clinical characteristics such as patient background, severity of burn and trauma, mechanism of injuries, total body surface area (TBSA), injury lesion, treatment and outcome were examined. Results The results showed significant differences in age between the burn only group and combined burn and trauma group (median [IQR]: 61 [43–76] for burn only group vs 51 [39–66] for combined burn and trauma group, p < 0.001). Most patients were injured due to flame (burn only group, 65.7%; combined burn and trauma group, 54.9%). Furthermore, 40-89% TBSA was higher in burn only group (19.3%) than in the combined burn and trauma group (9.3%). In-hospital mortality in burn only group (18.2%) was higher than that in the combined burn and trauma group (6.9%). Conclusions We demonstrated that the characteristics of burn only and combined burn and trauma patients in Japan. Flame was main cause of burn and in-hospital mortality was higher in burn only group because of higher burn area.

In this study, we aimed to develop and validate a machine learning-based mortality prediction model for hospitalized heat-related illness patients. After 2393 hospitalized patients were extracted from a multicentered heat-related illness registry in Japan, subjects were divided into the training set for development (n = 1516, data from 2014, 2017–2019) and the test set (n = 877, data from 2020) for validation. Twenty-four variables including characteristics of patients, vital signs, and laboratory test data at hospital arrival were trained as predictor features for machine learning. The outcome was death during hospital stay. In validation, the developed machine learning models (logistic regression, support vector machine, random forest, XGBoost) demonstrated favorable performance for outcome prediction with significantly increased values of the area under the precision-recall curve (AUPR) of 0.415 [95% confidence interval (CI) 0.336–0.494], 0.395 [CI 0.318–0.472], 0.426 [CI 0.346–0.506], and 0.528 [CI 0.442–0.614], respectively, compared to that of the conventional acute physiology and chronic health evaluation (APACHE)-II score of 0.287 [CI 0.222–0.351] as a reference standard. The area under the receiver operating characteristic curve (AUROC) values were also high over 0.92 in all models, although there were no statistical differences compared to APACHE-II. This is the first demonstration of the potential of machine learning-based mortality prediction models for heat-related illnesses.

Aim The objective of this study is to identify the risk factors for cancellation after dispatch of rapid response cars (RRC) for prehospital emergency care. Methods We retrospectively extracted data from all RRC cases dispatched from our hospital between April 2017 and March 2019. A total of 1,440 cases were included in our study and divided into either the “cancelled” group (n = 723) or the “treated” group (n = 717), based on the occurrence of cancellation. The variables obtained from the request calls for RRC included patient characteristics, distance from the hospital to the scene, and reasons for RRC request. The variables were compared between the two groups and logistic regression analysis was carried out to identify the risk factors for RRC cancellation. Results Multivariable analysis showed that distance from the hospital to the scene (odds ratio [OR] 1.25; 95% confidence interval (CI), 1.21–1.28), suspicion of cardiopulmonary arrest with no witness information (OR 7.61; 95% CI, 4.13–14.00), dyspnea (OR 2.22; 95% CI, 1.19–4.11), and suicide by hanging (OR 3.49; 95% CI, 1.37–8.89) were independent risk factors for cancellation. Conclusions In our study, a greater distance from the hospital to the scene, suspicion of cardiopulmonary arrest with no witness information, dyspnea, and suicide by hanging were identified as independent risk factors for cancellation after dispatch of RRC. Evaluating the risk factors for cancellation at individual facilities could help hospitals adjust their dispatch criteria to allocate limited medical resources more effectively., Our study suggests that the greater distance from the hospital to the scene, suspicion of cardiopulmonary arrest with no witness information, dyspnea, and suicide by hanging are the independent risk factors for cancellation after dispatch of rapid response cars.

Background The effect of corticosteroid treatment on survival outcome in early acute respiratory distress syndrome (ARDS) is still debated. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy of prolonged corticosteroid therapy in early ARDS. Methods We assessed the MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science databases from inception to August 1, 2020. We included RCTs that compared prolonged corticosteroid therapy with control treatment wherein the intervention was started within 72 h of ARDS diagnosis. Two investigators independently screened the citations and conducted the data extraction. The primary outcomes were all-cause 28- or 30-day mortality and 60-day mortality. Several endpoints such as ventilator-free days and adverse events were set as the secondary outcomes. DerSimonian-Laird random-effects models were used to report pooled odds ratios (ORs). Results Among the 4 RCTs included, all referred to the all-cause 28- or 30-day mortality. In the corticosteroid group, 108 of 385 patients (28.1%) died, while 139 of 357 (38.9%) died in the control group (pooled OR, 0.61; 95% confidence interval [CI], 0.44–0.85). Three RCTs mentioned the all-cause 60-day mortality. In the corticosteroid group, 78 of 300 patients (26.0%) died, while 101 of 265 (38.1%) died in the control group (pooled OR, 0.57; 95% CI, 0.40–0.83). For secondary outcomes, corticosteroid treatment versus control significantly prolonged the ventilator-free days (4 RCTs: mean difference, 3.74; 95% CI, 1.53–5.95) but caused hyperglycemia (3 RCTs: pooled OR, 1.52; 95% CI, 1.04–2.21). Conclusions Prolonged corticosteroid treatment in early ARDS improved the survival outcomes. Trial registration PROSPERO, CRD42020195969

Geriatric trauma is a major socio-economic problem, especially among the aging Japanese society. Geriatric people are more vulnerable to trauma than younger people; thus, their outcomes are often severe. This study evaluates the characteristics of geriatric trauma divided by age in the Japanese population. We evaluated trauma characteristics in patients (n = 131,088) aged ≥ 65 years by segregating them into 2 age-based cohorts: age 65–79 years (65–79 age group; n = 70,707) and age ≥ 80 years (≥ 80 age group; n = 60,381). Clinical characteristics such as patient background, injury mechanism, injury site and severity, treatment, and outcome were examined. Injuries among men were more frequent in the 65–79 age group (58.6%) than in the ≥ 80 age group (36.3%). Falls were the leading cause of trauma among the 65–79 age group (56.7%) and the ≥ 80 age group (78.9%). In-hospital mortality was 7.7% in the 65–79 age group and 6.6% in the ≥ 80 age group. High fall in the ≥ 80 age group showed 30.5% mortality. The overall in-hospital mortality was 11.8% (the 65–79 age group, 12.3%; the ≥ 80 age group, 11.2%). Most hospitalized patients were transferred to another hospital (the 65–79 age group, 52.5%; the ≥ 80 age group, 66.2%). We demonstrated the epidemiological characteristics of Japanese geriatric trauma patients. The overall in-hospital mortality was 11.8%, and fall injury in the ≥ 80 age group required caution of trauma care.

Background/Introduction; A rapid rule-out or rule-in protocol based on the 0-h/1-hour algorithm using high-sensitivity cardiac troponin T (hs-cTnT) is recommended by the European Society of Cardiology (ESC). Around 40–50% were stratified into “rule-out” group, and their 30-days prognosis was excellent. However, the one-year prognosis is uncertain. We aimed to better characterize these patients. Methods This study was a prospective, multi-center, observational study of patients with suspected non-ST elevation acute coronary syndrome (NSTE-ACS) admitted to 5 hospitals in Japan and Taiwan from 2014 November to 2018 December, respectively. All patients underwent a clinical assessment the included medical history, physical examination, 12-lead ECG, standard blood test, chest radiography. Exclusion criteria were ST elevated myocardial infarction, chronic kidney disease (serum creatinine more than 3 mg/dL) and congestive heart failure, arrhythmia, or infection disease. The patients were divided into three groups according to the algorithm; “rule-out”, “observe” and “rule-in”. The final diagnosis was then adjudicated by 2 independent cardiologists using all available information, including coronary angiography, coronary computed tomography, stress electrocardiography and follow-up data. The presence of acute myocardial infarction (AMI) was defined according to the Fourth Universal Definition of Myocardial Infarction. After hospital discharge patients were follow after one-year b telephone or in written form. Major adverse cardiovascular events (including death myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention (PCI)) were recorded by establishing contact with the patient and the family physicians. The primary prognosis end point was all-cause mortality. Results Of the 1,187 patients were analyzed after exclusion. The prevalence rate of AMI was 16.1%. According to the algorithm, 42% (n=493) of patients were assigned to “rule-out” group and had no AMI nor death. The most common final adjudicated diagnoses were atypical chest pain (80%), gallstone attack (3%) and vasospastic angina pectoris (2%). All patients with unstable angina (4.7%) underwent PCI. Conclusion(s) Our findings suggest that the “rule-out” group patients according to ESC 0-h/1-hour algorithm provides very high safety and efficacy for the triage toward AMI. Funding Acknowledgement Type of funding source: None

Electrical injuries induce ventricular arrhythmias, which are lethal. Therefore, it is important to evaluate the risk of arrhythmias at initial presentation to the emergency department in cases of electrical injuries. Here, we report two cases with electrical injuries, where current flowed between the upper limbs, requiring 24-h hospitalization for arrhythmia monitoring. The patients were 57- and 30-year-old men, who sustained separate electrical injuries (6600 V, line voltage), with current flow from one hand to the other. They did not develop any ventricular arrhythmias during hospitalization and were discharged. The risk for ventricular arrhythmias is lower for electrical injuries occurring between the upper limbs than for those occurring between the upper and lower limbs. We conclude that 24-h hospitalization for monitoring of patients with electrical injuries of the upper limbs may be sufficient.

We report a case of COVID‐19‐induced extracorporeal membrane oxygenation treated by late i.v. steroid administration. Our case suggests the value of prospective clinical trials for the evaluation of steroid use in severe COVID‐19‐induced extracorporeal membrane oxygenation., Background The efficacy of steroid treatment for coronavirus disease (COVID‐19) is unknown. Case presentation A 67‐year‐old man was transported to our hospital due to impaired consciousness and respiratory failure. After admission, tracheal aspirate of the patient was harvested, and it tested positive for severe acute respiratory syndrome coronavirus 2 nucleic acid. He required veno‐venous extracorporeal membrane oxygenation to sustain his oxygenation. However, his respiratory failure did not improve for 20 days. On day 20 of admission, we started to use i.v. steroid therapy. On day 23, lung opacity on the chest X‐ray cleared and the patient’s oxygen saturation improved significantly. We successfully removed extracorporeal membrane oxygenation on day 27. Conclusion Our case report encourages more future trials to evaluate the therapeutic use of i.v. steroid in severe COVID‐19‐induced acute respiratory distress syndrome.

Sepsis is a severe inflammatory condition associated with high mortality. Transmigration of neutrophils into tissues increases their lifespan to promote deleterious function. Junctional adhesion molecule-C (JAM-C) plays a pivotal role in neutrophil transmigration into tissues. We aim to study the role of JAM-C on the aging of neutrophils to cause sepsis-induced acute lung injury (ALI). Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP) and JAM-C expression in serum was assessed. Bone marrow-derived neutrophils (BMDN) were treated with recombinant mouse JAM-C (rmJAM-C) ex vivo and their viability was assessed. CLP-operated animals were administrated with either isotype IgG or anti-JAM-C Ab at a concentration of 3 mg/kg and after 20 h, aged neutrophils (CXCR4+) were assessed in blood and lungs and correlated with systemic injury and inflammatory markers. Soluble JAM-C level in serum was up-regulated during sepsis. Treatment with rmJAM-C inhibited BMDN apoptosis, thereby increasing their lifespan. CLP increased the frequencies of CXCR4+ neutrophils in blood and lungs, while treatment with anti-JAM-C Ab significantly reduced the frequencies of CXCR4+ aged neutrophils. Treatment with anti-JAM-C Ab significantly reduced systemic injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as systemic and lung inflammatory cytokines (IL-6 and IL-1β) and chemokine (macrophage inflammatory protein-2). The blockade of JAM-C improved lung histology and reduced neutrophil contents in lungs of septic mice. Thus, reduction of the pro-inflammatory aged neutrophils by blockade of JAM-C has a novel therapeutic potential in sepsis-induced ALI. Blood JAM-C levels are increased during sepsis, causing neutrophil aging by up-regulating surface CXCR4 expression. Blocking JAM-C ameliorates sepsis-induced acute lung injury in mice.

Background We assessed the effect of liberal versus restrictive red blood cell transfusion strategy on survival outcome in sepsis or septic shock by systematically reviewing the literature and synthesizing evidence from randomized controlled trials (RCTs). Methods We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science databases. We included RCTs that compared mortality between a liberal transfusion strategy with a hemoglobin threshold of 9 or 10 g/dL and a restrictive transfusion strategy with a hemoglobin threshold of 7 g/dL in adults with sepsis or septic shock. Two investigators independently screened citations and conducted data extraction. The primary outcome was 28- or 30-day mortality. Secondary outcomes were 60- and 90-day mortality, use of life support at 28 days of admission, and number of patients transfused during their intensive care unit stay. DerSimonian-Laird random-effects models were used to report pooled odds ratios (ORs). Results A total of 1516 patients from three RCTs were included; 749 were randomly assigned to the liberal transfusion group and 767 to the restrictive strategy group. Within 28–30 days, 273 patients (36.4%) died in the liberal transfusion group, while 278 (36.2%) died in the restrictive transfusion group (pooled OR, 0.99; 95% confidence interval [CI], 0.67–1.46). For the primary outcome, heterogeneity was observed among the studies (I2 = 61.0%, χ2 = 5.13, p = 0.08). For secondary outcomes, only two RCTs were included. There were no significant differences in secondary outcomes between the two groups. Conclusions We could not show any difference in 28- or 30-day mortality between the liberal and restrictive transfusion strategies in sepsis or septic shock patients by meta-analysis of RCTs. Our results should be interpreted with caution due to the existence of heterogeneity. As sepsis complicates a potentially wide range of underlying diseases, further trials in carefully selected populations are anticipated. Trial registration This present study was registered in the PROSPERO database (CRD42018108578). Electronic supplementary material The online version of this article (10.1186/s13054-019-2543-1) contains supplementary material, which is available to authorized users.

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., other authors: Satoru Hashimoto,Daisuke Hasegawa,Junji Hatakeyama,Naoki Hara,Naoki Higashibeppu,Nana Furushima,Hirotaka Furusono,Yujiro Matsuishi,Tasuku Matsuyama,Yusuke Minematsu,Ryoichi Miyashita,Yuji Miyatake,Megumi Moriyasu,Toru Yamada,Hiroyuki Yamada,Ryo Yamamoto,Takeshi Yoshida,Yuhei Yoshida,Jumpei Yoshimura,Ryuichi Yotsumoto,Hiroshi Yonekura,Takeshi Wada,Eizo Watanabe,Makoto Aoki,Hideki Asai,Takakuni Abe,Yutaka Igarashi,Naoya Iguchi,Masami Ishikawa,Go Ishimaru,Shutaro Isokawa,Ryuta Itakura,Hisashi Imahase,Haruki Imura,Takashi Irinoda,Kenji Uehara,Noritaka Ushio,Takeshi Umegaki,Yuko Egawa,Yuki Enomoto,Kohei Ota,Yoshifumi Ohchi,Takanori Ohno,Hiroyuki Ohbe,Kazuyuki Oka,Nobunaga Okada,Yohei Okada,Hiromu Okano,Jun Okamoto,Hiroshi Okuda,Takayuki Ogura,Yu Onodera,Yuhta Oyama,Motoshi Kainuma,Eisuke Kako,Masahiro Kashiura,Hiromi Kato,Akihiro Kanaya,Tadashi Kaneko,Keita Kanehata,Ken-ichi Kano,Hiroyuki Kawano,Kazuya Kikutani,Hitoshi Kikuchi,Takahiro Kido,Sho Kimura,Hiroyuki Koami,Daisuke Kobashi,Iwao Saiki,Masahito Sakai,Ayaka Sakamoto,Tetsuya Sato,Yasuhiro Shiga,Manabu Shimoto,Shinya Shimoyama,Tomohisa Shoko,Yoh Sugawara,Atsunori Sugita,Satoshi Suzuki,Yuji Suzuki,Tomohiro Suhara,Kenji Sonota,Shuhei Takauji,Kohei Takashima,Sho Takahashi,Yoko Takahashi,Jun Takeshita,Yuuki Tanaka,Akihito Tampo,Taichiro Tsunoyama,Kenichi Tetsuhara,Kentaro Tokunaga,Yoshihiro Tomioka,Kentaro Tomita,Naoki Tominaga,Mitsunobu Toyosaki,Yukitoshi Toyoda,Hiromichi Naito,Isao Nagata,Tadashi Nagato,Yoshimi Nakamura,Yuki Nakamori,Isao Nahara,Hiromu Naraba,Chihiro Narita,Norihiro Nishioka,Tomoya Nishimura,Kei Nishiyama,Tomohisa Nomura,Taiki Haga,Yoshihiro Hagiwara,Katsuhiko Hashimoto,Takeshi Hatachi,Toshiaki Hamasaki,Takuya Hayashi,Minoru Hayashi,Atsuki Hayamizu,Go Haraguchi,Yohei Hirano,Ryo Fujii,Motoki Fujita,Naoyuki Fujimura,Hiraku Funakoshi,Masahito Horiguchi,Jun Maki,Naohisa Masunaga,Yosuke Matsumura,Takuya Mayumi,Keisuke Minami,Yuya Miyazaki,Kazuyuki Miyamoto,Teppei Murata,Machi Yanai,Takao Yano,Kohei Yamada,Naoki Yamada,Tomonori Yamamoto,Shodai Yoshihiro,Hiroshi Tanaka,Osamu Nishida, Guidelines

Transmigration of neutrophils through vascular endothelial walls into the inflamed tissues is a critical defense mechanism of innate immune system against infection and injury caused by sepsis, trauma, ischemia-reperfusion, and other acute or chronic inflammatory diseases. However, their excessive infiltration and uncontrolled activation may lead to the destruction of normal tissue architecture and unrestrained inflammation. Transendothelial migration (TEM) in a luminal-to-abluminal direction is widely known as the final step of neutrophil migration cascade into the inflamed tissues. Recent studies have shown that neutrophils not necessarily move from the vascular lumen to the extravascular tissues in a one way direction; they also proceed in an opposite direction, known as reverse transendothelial migration (rTEM) to get back into the vascular lumen again. This novel paradigm of neutrophil round trip is currently on the spotlight due to its possible interaction with immune system. Current review highlighting the growing demand of this newly identified neutrophil migratory event will not only rewrite the disease pathophysiology, but also help scientists design novel therapeutic strategy leading to the remission of inflammatory diseases in which controlling exaggerated neutrophil infiltration is a major challenge.

Aim Sivelestat sodium, a selective neutrophil elastase inhibitor, is the only commercially available, specific therapy for acute respiratory distress syndrome (ARDS); however, its clinical efficacy is controversial. We aimed to evaluate appropriate indications for its use in ARDS. Methods We studied 66 patients with ARDS who were treated with sivelestat sodium. They were divided into survivors (n = 37) or non‐survivors (n = 29) at 60 days, and clinical characteristics were analyzed. Results Patients’ backgrounds evaluated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the sequential organ failure assessment (SOFA) score were significantly different between both groups (survivors versus non‐survivors: APACHE II score, 14.7 ± 6.7 versus 20.5 ± 4.7, P 198 at 3 days after the use of sivelestat sodium predicted a good outcome., There is no specific therapeutic method available to ameliorate lung damage in patients with acute respiratory distress syndrome. We found that sivelestat sodium, if given early in patients with less severe acute respiratory distress syndrome, could improve clinical outcomes, including mortality.

Purpose The beneficial effect of the presence of an emergency physician in prehospital major trauma care is controversial. The aim in this study is to assess whether an emergency physician on scene can improve survival outcome of critical trauma patients. Methods This retrospective cohort study was conducted by using nationwide trauma registry data between 2004 and 2013 in Japan. Severe trauma patients (injury severity score (ISS) ≥ 16) who were transported directly to the hospital from the injury site were included in our analysis. Patients who were predicted to be untreatable (abbreviated injury score (AIS) = 6 and/or cardiopulmonary arrest at least one time before hospital arrival) were excluded. Participants were divided into either a physician or paramedics group based on the prehospital practitioner. The primary outcome was survival rate at discharge. Multivariable logistic regression analysis was performed to compare the outcome with adjustment for age, gender, ISS, cause of injury, and pre-hospital vital signs. Results A total of 30,283 patients were eligible for the selection criteria (physician: 1222, paramedics: 29,061). Overall, 172 patients (14.1%) died in the physician group compared to 3508 patients (12.1%) in the paramedics group. Patients in the physician group had higher ISSs than those in the paramedics group. In multivariable logistic regression, the physician group had an odds ratio (OR) of 1.16 (95% confidence interval (CI) = 0.97 to 1.40, p = 0.11) for in-hospital survival. Conclusions Our results failed to show a difference in survival at discharge between non-physician-staffed ambulances and physician-staffed ambulances.

Sepsis is a severe inflammatory condition causing high mortality. Transmigration of neutrophils into tissues increases their lifespan to promote deleterious function. Junctional adhesion molecule-C (JAM-C) plays a pivotal role in neutrophil transmigration into tissues. We aim to study the role of JAM-C on the aging of neutrophils to cause sepsis-induced acute lung injury (ALI). Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP) and JAM-C expression in serum was assessed. Bone marrow-derived neutrophils (BMDN) were treated with recombinant mouse JAM-C (rmJAM-C) ex vivo and their viability was assessed. CLP-operated animals were administrated with either isotype IgG or anti-JAM-C Ab at a concentration of 3 mg/kg and after 20 h, aged neutrophils (CXCR4(+)) were assessed in blood and lungs and correlated with systemic injury and inflammatory markers. Soluble JAM-C level in serum was upregulated during sepsis. Treatment with rmJAM-C inhibited BMDN apoptosis, thereby increasing their lifespan. CLP increased the frequencies of CXCR4(+) neutrophils in blood and lungs, while treatment with anti-JAM-C Ab significantly reduced the frequencies of CXCR4(+) aged neutrophils. Treatment with anti-JAM-C Ab significantly reduced systemic injury markers (ALT, AST and LDH) as well as systemic and lung inflammatory cytokines (IL-6 and IL-1β) and chemokine (MIP-2). The blockade of JAM-C improved lung histology and reduced neutrophil contents in lungs of septic mice. Thus, reduction of the pro-inflammatory aged neutrophils by blockade of JAM-C has a novel therapeutic potential in sepsis-induced ALI.

IntroductionThe catastrophic Great East Japan Earthquake in 2011 created a crisis in a university-affiliated hospital by disrupting the water supply for 10 days. In response, this study was conducted to analyze water use and prioritize water consumption in each department of the hospital by applying a business impact analysis (BIA). Identifying the minimum amount of water necessary for continuing operations during a disaster was an additional goal.ProblemWater is essential for many hospital operations and disaster-ready policies must be in place for the safety and continued care of patients.MethodsA team of doctors, nurses, and office workers in the hospital devised a BIA questionnaire to examine all operations using water. The questionnaire included department name, operation name, suggested substitutes for water, and the estimated daily amount of water consumption. Operations were placed in one of three ranks (S, A, or B) depending on the impact on patients and the need for operational continuity. Recovery time objective (RTO), which is equivalent to the maximum tolerable period of disruption, was determined. Furthermore, the actual use of water and the efficiency of substitute methods, practiced during the water-disrupted periods, were verified in each operation.ResultsThere were 24 activities using water in eight departments, and the estimated water consumption in the hospital was 326 (SD = 17) m3per day: 64 (SD = 3) m3for S (20%), 167 (SD = 8) m3for A (51%), and 95 (SD = 5) m3for B operations (29%). During the disruption, the hospital had about 520 m3of available water. When the RTO was set to four days, the amount of water available would have been 130 m3per day. During the crisis, 81% of the substitute methods were used for the S and A operations.ConclusionThis is the first study to identify and prioritize hospital operations necessary for the efficient continuation of medical treatment during suspension of the water supply by applying a BIA. Understanding the priority of operations and the minimum daily water requirement for each operation is important for a hospital in the event of an unexpected adverse situation, such as a major disaster.SuginakaH,OkamotoK,HiranoY,FukumotoY,MorikawaM,OodeY,SumiY,InoueY,MatsudaS,TanakaH.Hospital disaster response using business impact analysis.Prehosp Disaster Med.2014;29(5):1-8.

Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) plays an immunomodulatory role in inflammatory diseases. MFG-E8-derived short peptide (MSP68) greatly reduces neutrophil infiltration and injury in the lung during sepsis. In this study, we examined the effect of MSP68 on chemotaxis of various immune cells and its regulatory mechanism. Bone marrow-derived neutrophils (BMDNs) from C57BL/6 mice, human monocyte THP-1 cell line, and human T lymphocyte Jurkat cell line were used for adhesion and migration assays using a Transwell method in the presence of MSP68. Treatment with MSP68 significantly inhibited the BMDN and THP-1 cell but not Jurkat cell adhesion on the TNF-α-stimulated pulmonary artery endothelial cell (PAEC) monolayer dose-dependently. MSP68 also significantly reduced BMDN adhesion on VCAM-1-coated wells dose dependently. Surface plasmon resonance (SPR) analysis revealed that MSP68 efficiently recognized integrin α4β1 (receptor for VCAM-1) at the dissociation constant (KD) of 1.53 × 10−7 M. These findings implicate that MSP68 prevents neutrophil adhesion to the activated endothelial cells by interfering with the binding between integrin α4β1 on neutrophils and VCAM-1 on endothelial cells. Moreover, MSP68 significantly attenuated the migration of BMDN and THP-1 cells but not Jurkat cells to their chemoattractants. Pretreatment with MSP68 inhibited the transmigration of BMDNs across the PAECs toward chemoattractants, fMLP, MIP-2, and complement fragment 5a (C5a) dose-dependently. Finally, we identified that the activation of p38 MAPK in BMDNs by fMLP was inhibited by MSP68. Thus, MSP68 attenuates extravasation of immune cells through the endothelial cell lining into inflamed tissue, implicating MSP68 to be a novel, therapeutic agent for inflammatory diseases caused by excessive immune cell infiltration.

Intestinal ischemia-reperfusion (I/R) is associated with acute respiratory distress syndrome (ARDS). Osteopontin (OPN), a glycoprotein secreted from immune-reactive cells, plays a deleterious role in various inflammatory diseases. Considering OPN as a pro-inflammatory molecule, we hypothesize that the treatment with its neutralizing antibody (anti-OPN Ab) protects mice against intestinal I/R-induced acute lung injury (ALI). Intestinal I/R was induced in mice by superior mesenteric artery (SMA) occlusion with a vascular clip. After 45 minutes of occlusion, the clip was removed and anti-OPN Ab (25 µg/mouse) or normal IgG isotype control (25 µg/mouse) was immediately administrated intravenously. Blood, small intestine, and lung tissues were collected at 4 hours after reperfusion for various analyses. After intestinal I/R, mRNA and protein levels of OPN were significantly induced in the small intestine, lungs, and blood relative to sham-operated animals. Compared with the IgG control group, treatment of anti-OPN Ab significantly reduced plasma levels of pro-inflammatory cytokine and chemokine (IL-6 and MIP-2) and organ injury markers (AST, ALT, and LDH). The histological architecture of the gut and lung tissues in anti-OPN Ab-treated intestinal I/R-induced mice showed significant improvement versus the IgG control mice. The lung inflammation measured by the levels of IL-6, IL-1β, and MIP-2 was also significantly downregulated in the anti-OPN Ab-treated mice as compared with the IgG control mice. Besides, the lung MPO and neutrophil infiltration in anti-OPN Ab-treated mice showed significant reduction as compared with the IgG control animals. In conclusion, we have demonstrated beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic potential in intestinal I/R.

A 40-year-old male tried to clean a urinal at his home storing 900 mL of a toilet cleaner containing 9.8% nitric acid to remove calcium deposit, and clean the toilet floor for twenty minutes. Immediately after using the cleaner, he experienced eye irritation. He washed out the toilet cleaner. However, he thereafter experienced dyspnea, a compressive sensation in his chest, and chest and back pain about 40 minutes after the cleaning the toilet. He monitored his symptoms overnight and found them to gradually improve. However, the symptoms still remained the next morning and therefore he came to our department on foot. He had no particular past or family history. On arrival, his physiological findings and chest computed tomography scan were negative for any abnormalities. His arterial blood gas analysis revealed a mild abnormality of oxygenation. Observation without any drugs revealed that a complete remission of his symptoms occurred after approximately 4 weeks. Based on the results of the experiments, contact with the mucosal membrane and nitric acid gas produced by any accidentally coexisting metals or contact with moisture, including nitric acid produced by a reaction between CaCO3 and cleaner, may have been the mechanism of occurrence for the symptoms observed in this case. This is the first reported case of nitric acid poisoning due to the use of a toilet cleanser intended for household use.

A 78-year-old woman with rheumatoid arthritis while being treated with tocilizumab and steroid treatment presented with pharyngeal pain and general malaise. She felt chills and vomited while waiting in the waiting room, in addition to urinary incontinence. An immediate evaluation of her condition indicated that she was in shock and a physical examination revealed moist rales in the right lung field. Her white cell count and C reactive protein level were within normal limits; however, a radiological study indicated pneumonia. Antibiotic treatment resulted in improvement of her condition. Blood culture later revealed bacteraemia due to Streptococcus pneumoniae. The anti-inflammatory effect of tocilizumab and steroid treatment may mask the typical symptoms and signs of infection, so physicians must be aware of the potential for hidden infection when such patients present with an unidentified complaint.

Purpose: To clarify the characteristics of AKA patients with visual disturbances. Material and methods: An Ichushi and Pubmed search was undertaken to identify articles that reported patients with visual disturbances due to AKA. The clinical data in the articles were reviewed. This study also performed a subanalysis by classifying the patients with visual disturbance due to AKA into two groups: an arrest group, which experienced cardiac arrest during hospitalization and a no-arrest group, which did not. Results: There were 12 case reports describing patients with visual disturbances due to AKA. There were 14 patients who showed a visual disturbance due to AKA. There were 11 males and 3 females. The range of age was from 44 to 68, with an average of 55 years old. Seven cases had loss of consciousness and the systolic blood pressure of in 12 cases was under 90 mmHg. All cases show arterial blood gas pH under 6.90 and severe metabolic acidosis. All but one of the visual disturbance cases improved after correction of acidemia by infusion of sodium bicarbonate or blood purification. Six cases experienced cardiac arrest during their hospitalization. Three cases finally died. The subanalysis showed the average pH on arrival in the arrest group was lower than that in the no-arrest group (6.63 vs. 6.75, respectively). And the survival ratio in the arrest group was smaller than that in the no-arrest group (50 vs. 100%, respectively). Conclusion: Severe AKA was associated with visual disturbances, which could be cured by correction of acidosis. In addition, patients with severe AKA with a pH on arterial gas analysis under 6.70 tended to experience cardiac arrest and the patients with arrest had a poor prognosis. Physicians should understand how to treat such patients.

A 79-year-old female with diabetes mellitus had general fatigue, a high fever and vomiting. A CT revealed acute emphysematous pyelonephritis (EPN). A nephrectomy was performed on the 2(nd) hospital day. The results of the blood culture showed the presence of Citrobacter freundii infection. The patient's post-operative course was uneventful. This case is the second reported case of EPN induced by Citrobacter freundii. Bacteremia induced by Citrobacter freundii infection typically results in a high mortality rate. In this case, the early diagnosis of the EPN using CT and immediate medical treatment, including urgent elective nephrectomy, were key to the favorable outcome.

Introduction Sepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis. Methods Sepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 μg/mouse, was intravenously injected at the time of CLP. After 20 hours, the expression of OPN and proinflammatory cytokines in tissues and plasma was examined by real-time PCR, Western blot, and ELISA. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) and the lung myeloperoxidase (MPO) levels were determined by colorimetric assays. Lung damage and neutrophil infiltrations were determined by histological H&E and Gr-1 staining, respectively. The effect of recombinant mouse OPN (rmOPN) on human neutrophil-like cell (HL-60) migration was performed by Boyden chamber assays and the involvement of intracellular signaling molecules in HL-60 cells was revealed by Western blot. Results After 20 hours of sepsis, mRNA and protein levels of OPN were significantly induced in lungs, spleen, and plasma. Treatment with an anti-OPN Ab in septic mice significantly reduced the plasma levels of ALT, AST, and LDH, and the proinflammatory cytokines IL-6, IL-1β and the chemokine MIP-2, compared with the vehicle group. Similarly, the lung mRNA and protein expressions of proinflammatory cytokines and chemokine were greatly reduced in anti-OPN Ab-treated animals. The lung histological architecture, MPO and neutrophil infiltration were significantly improved in anti-OPN Ab-treated mice compared with the vehicle animals. Treatment of rmOPN in HL-60 cells significantly increased their migration, in vitro. The neutrophils treated with rmOPN remarkably increased the levels of phospho focal adhesion kinase (pFAK), phospho extracellular signal-regulated kinase (pERK) and phospho p38. Conclusions Our findings clearly demonstrate the beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic strategy in sepsis.