Coccomyxa sp.KJ extract affects the fate of T cells stimulated by toxic shock syndrome toxin-1, a superantigen secreted by Staphylococcus aureus.

T cell stimulation by bacterial superantigens induces a cytokine storm. After T cell activation and inflammatory cytokine secretion, regulatory T cells (Treg) are produced to suppress the immune response. Coccomyxa sp.KJ (IPOD FERM BP-22254), a green alga, is reported to regulate immune reactions. Therefore, we examined the effects of Coccomyxa sp.KJ extract (CE) on the superantigen-induced immune response. When human peripheral blood mononuclear cells (PBMCs) were stimulated with toxic shock syndrome-1 (TSST-1) in the presence of CE, the number of activated T cells decreased moderately. Purified T cells stimulated in the presence of CE comprised more non-proliferating cells than those stimulated in the absence of CE, whereas some T cells proliferated more quickly. The levels of activation markers on the stimulated T cells increased in the presence of CE. Most of the inflammatory cytokines did not change but IL-1ß, IL-17, IL-4, and IL-13 secretion increased, whereas that of IL-2, TNF-α, and IL-18 decreased. IL-10 secretion was also decreased by CE treatment, suggesting that the immune response was not suppressed by Treg cells. CE enhanced the expression of stem cell-like memory cell markers in T cells. These results suggest that CE can regulate the fate of T cells and can help to ameliorate superantigen-induced T cell hyperactivation and immune suppression.

Termination-of-resuscitation rule in the emergency department for patients with refractory out-of-hospital cardiac arrest: a nationwide, population-based observational study.

BACKGROUND: In Japan, emergency medical service (EMS) providers are prohibited from field termination-of-resuscitation (TOR) in out-of-hospital cardiac arrest (OHCA) patients. In 2013, we developed a TOR rule for emergency department physicians (Goto's TOR rule) immediately after hospital arrival. However, this rule is subject to flaws, and there is a need for revision owing to its relatively low specificity for predicting mortality compared with other TOR rules in the emergency department. Therefore, this study aimed to develop and validate a modified Goto's TOR rule by considering prehospital EMS cardiopulmonary resuscitation (CPR) duration. METHODS: We analysed the records of 465,657 adult patients with OHCA from the All-Japan Utstein registry from 2016 to 2019 and divided them into two groups: development (n = 231,363) and validation (n = 234,294). The primary outcome measures were specificity, false-positive rate (FPR), and positive predictive value (PPV) of the revised TOR rule in the emergency department for predicting 1-month mortality. RESULTS: Recursive partitioning analysis for the development group in predicting 1-month mortality revealed that a modified Goto's TOR rule could be defined if patients with OHCA met the following four criteria: (1) initial asystole, (2) unwitnessed arrest by any laypersons, (3) EMS-CPR duration > 20 min, and (4) no prehospital return of spontaneous circulation (ROSC). The specificity, FPR, and PPV of the rule for predicting 1-month mortality were 99.2% (95% confidence interval [CI], 99.0-99.4%), 0.8% (0.6-1.0%), and 99.8% (99.8-99.9%), respectively. The proportion of patients who fulfilled the rule and the area under the receiver operating curve (AUC) was 27.5% (95% CI 27.3-27.7%) and 0.904 (0.902-0.905), respectively. In the validation group, the specificity, FPR, PPV, proportion of patients who met the rule, and AUC were 99.1% (95% CI 98.9-99.2%), 0.9% (0.8-1.1%), 99.8% (99.8-99.8%), 27.8% (27.6-28.0%), and 0.889 (0.887-0.891), respectively. CONCLUSION: The modified Goto's TOR rule (which includes the following four criteria: initial asystole, unwitnessed arrest, EMS-CPR duration > 20 min, and no prehospital ROSC) with a > 99% predictor of 1-month mortality is a reliable tool for physicians treating refractory OHCAs immediately after hospital arrival.

Dispatcher instructions for bystander cardiopulmonary resuscitation and neurologically intact survival after bystander-witnessed out-of-hospital cardiac arrests: a nationwide, population-based observational study.

BACKGROUND: The International Liaison Committee on Resuscitation recommends that dispatchers provide instructions to perform compression-only cardiopulmonary resuscitation (CPR) to callers responding to adults with out-of-hospital cardiac arrest (OHCA). This study aimed to determine the optimal dispatcher-assisted CPR (DA-CPR) instructions for OHCA. METHODS: We analysed the records of 24,947 adult patients (aged ≥ 18 years) who received bystander DA-CPR after bystander-witnessed OHCA. Data were obtained from a prospectively recorded Japanese nationwide Utstein-style database for a 2-year period (2016-2017). Patients were divided into compression-only DA-CPR (n = 22,778) and conventional DA-CPR (with a compression-to-ventilation ratio of 30:2, n = 2169) groups. The primary outcome measure was 1-month neurological intact survival, defined as a cerebral performance category score of 1-2 (CPC 1-2). RESULTS: The 1-month CPC 1-2 rate was significantly higher in the conventional DA-CPR group than in the compression-only DA-CPR group (before propensity score (PS) matching, 7.5% [162/2169] versus 5.8% [1309/22778], p < 0.01; after PS matching, 7.5% (162/2169) versus 5.7% (123/2169), p < 0.05). Compared with compression-only DA-CPR, conventional DA-CPR was associated with increased odds of 1-month CPC 1-2 (before PS matching, adjusted odds ratio 1.39, 95% confidence interval [CI] 1.14-1.70, p < 0.01; after PS matching, adjusted odds ratio 1.34, 95% CI 1.00-1.79, p < 0.05). CONCLUSION: Within the limitations of this retrospective observational study, conventional DA-CPR with a compression-to-ventilation ratio of 30:2 was preferable to compression-only DA-CPR as an optimal DA-CPR instruction for coaching callers to perform bystander CPR for adult patients with bystander-witnessed OHCAs.

Sex-specific differences in survival after out-of-hospital cardiac arrest: a nationwide, population-based observational study.

BACKGROUND: It remains unclear whether men have more favorable survival outcomes after out-of-hospital cardiac arrest (OHCA) than women. METHODS: We reviewed a total of 386,535 patients aged ≥ 18 years with OHCA who were included in the Japanese registry from 2013 to 2016. The study endpoints were the rates of 1-month survival and neurologically intact survival (Cerebral Performance Category Scale score = 1 or 2). Based on age, the reviewed patients were categorized into the following eight groups: < 30, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89, and ≥ 90 years. The survival outcomes in men and women were compared using hierarchical propensity score matching. RESULTS: The crude survival rate was significantly higher in men than in women in five groups: 30-39, 40-49, 50-59, 60-69, and 70-79 years (all P < 0.001). Similarly, the crude neurologically intact survival rate was significantly higher in men than in women in seven groups: < 30, 30-39, 40-49, 50-59, 60-69, 70-79, and 80-89 years (all P < 0.005). However, multivariate logistic regression analysis of each group revealed no significant sex-specific differences in 1-month survival outcomes (all P > 0.02). Moreover, after hierarchical propensity score matching, the survival outcomes did not significantly differ between both sexes (all P > 0.05). CONCLUSIONS: No significant sex-specific differences were found in the rates of 1-month survival and neurologically intact survival after OHCA.

Duration of Prehospital Cardiopulmonary Resuscitation and Favorable Neurological Outcomes for Pediatric Out-of-Hospital Cardiac Arrests: A Nationwide, Population-Based Cohort Study.

BACKGROUND: The appropriate duration of cardiopulmonary resuscitation (CPR) for pediatric out-of-hospital cardiac arrests (OHCAs) remains unclear and may differ based on initial rhythm. We aimed to determine the relationship between the duration of prehospital CPR by emergency medical services (EMS) personnel and post-OHCA outcomes. METHODS: We analyzed the records of 12 877 pediatric patients who experienced OHCAs (<18 years of age). Data were recorded in a nationwide Japanese database between 2005 and 2012. Study end points were 30-day survival and 30-day survival with favorable neurological outcomes (Cerebral Performance Category [CPC] scale 1-2). Prehospital EMS-initiated CPR duration was defined as the time from CPR initiation by EMS personnel to prehospital return of spontaneous circulation (ROSC) or to hospital arrival when prehospital ROSC was not achieved during prehospital CPR efforts. RESULTS: The rates of 30-day survival and 30-day CPC 1 to 2 were 9.1% (n=1167) and 2.5% (n=325), respectively. Prehospital EMS-initiated CPR duration was significantly and inversely associated with 30-day outcomes (adjusted odds ratio for 1-minute increments: 0.94, 95% confidence interval: 0.93-0.95 for survival; adjusted odds ratio: 0.90, 95% confidence interval: 0.88-0.92 for CPC 1-2). The duration of prehospital EMS-initiated CPR, beyond which the chance for favorable outcomes diminished to <1%, was 42 minutes for each key outcome, 30-day survival, and 30-day survival with CPC 1 to 2. When categorized by initial rhythm, the prehospital EMS-initiated CPR durations beyond which the chance for 30-day survival with CPC 1 to 2 diminished to <1% were 39 minutes for shockable rhythms, 42 minutes for pulseless electric activity, and 46 minutes for asystole, respectively. In patients with bystander-initiated CPR, the prehospital CPR duration, beyond which the chance for favorable outcome diminished to <1%, was 46 minutes from call receipt. CONCLUSIONS: Prehospital EMS-initiated CPR duration for pediatric OHCAs was independently and inversely associated with 30-day favorable outcomes. The duration of prehospital EMS-initiated CPR, beyond which the chance for 30-day favorable outcomes diminished to <1%, was 42 minutes. However, the CPR duration to achieve this proportion of outcomes differed based on initial rhythm. Further research is required to elucidate appropriate CPR duration for pediatric OHCAs, including in-hospital CPR time. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02432196.

Neurological outcomes in children dead on hospital arrival.

INTRODUCTION: Obtaining favorable neurological outcomes is extremely difficult in children transported to a hospital without a prehospital return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). However, the crucial prehospital factors affecting outcomes in this cohort remain unclear. We aimed to determine the prehospital factors for survival with favorable neurological outcomes (Cerebral Performance Category 1 or 2 (CPC 1-2)) in children without a prehospital ROSC after OHCA. METHODS: Of 9093 OHCA children, 7332 children (age <18 years) without a prehospital ROSC after attempting resuscitation were eligible for enrollment. Data were obtained from a prospectively recorded Japanese national Utstein-style database from 2008 to 2012. The primary endpoint was 1-month CPC 1-2 after OHCA. RESULTS: The 1-month survival and 1-month CPC 1-2 rates were 6.92 % (n = 508) and 0.99 % (n = 73), respectively. The proportions of the following prehospital variables were significantly higher in the 1-month CPC 1-2 cohort than in the 1-month CPC 3-5 cohort: age (median, 3 years (interquartile range (IQR), 0-14) versus 1 year (IQR, 0-11), p <0.05), bystander-witnessed arrest (52/73 (71.2 %) versus 1830/7259 (25.2 %), p <0.001), initial ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) rhythm (28/73 (38.3 %) versus 241/7259 (3.3 %), p <0.001), presumed cardiac causes (42/73 (57.5 %) versus 2385/7259 (32.8 %), p <0.001), and actual shock delivery (25/73 (34.2 %) versus 314/7259 (4.3 %), p <0.0001). Multivariate logistic regression analysis indicated that 2 prehospital factors were associated with 1-month CPC 1-2: initial non-asystole rhythm (VF/pulseless VT: adjusted odds ratio ( aOR), 16.0; 95 % confidence interval (CI), 8.05-32.0; pulseless electrical activity (PEA): aOR, 5.19; 95 % CI, 2.77-9.82) and bystander-witnessed arrest (aOR, 3.22; 95 % CI, 1.84-5.79). The rate of 1-month CPC 1-2 in witnessed-arrest children with an initial VF/pulseless VT was significantly higher than that in those with other initial cardiac rhythms (15.6 % versus 2.3 % for PEA and 1.2 % for asystole, p for trend <0.001). CONCLUSIONS: The crucial prehospital factors for 1-month survival with favorable neurological outcomes after OHCA were initial non-asystole rhythm and bystander-witnessed arrest in children transported to hospitals without a prehospital ROSC.

Nitrogen removal using an anammox membrane bioreactor at low temperature.

Membrane bioreactors (MBRs) have the ability to completely retain biomass and are thus suitable for slowly growing anammox bacteria. In the present study, an anammox MBR was operated to investigate whether the anammox activity would remain stable at low temperature, without anammox biomass washout. The maximum nitrogen removal rates were 6.7 and 1.1 g-N L⁻¹ day⁻¹ at 35 °C and 15 °C, respectively. Fluorescence in situ hybridization and 16S rRNA-based phylogenetic analysis revealed no change in the predominant anammox species with temperature because of the complete retention of anammox biomass in the MBR. These results indicate that the predominant anammox bacteria in the MBR cannot adapt to a low temperature during short-term operation. Conversely, anammox activity recovered rapidly after restoring the temperature from the lower value to the optimal temperature (35 °C). The rapid recovery of anammox activity is a distinct advantage of using an MBR anammox reactor.

Prognostic implications of conversion from nonshockable to shockable rhythms in out-of-hospital cardiac arrest.

INTRODUCTION: The prognostic significance of conversion from nonshockable to shockable rhythms in patients with initial nonshockable rhythms who experience out-of-hospital cardiac arrest (OHCA) remains unclear. We hypothesized that the neurological outcomes in those patients would improve with subsequent shock delivery following conversion to shockable rhythms and that the time from initiation of cardiopulmonary resuscitation by emergency medical services personnel to the first defibrillation (shock delivery time) would influence those outcomes. METHODS: We analyzed the data of 569,937 OHCA adults with initial nonshockable rhythms. The data were collected in a nationwide Utstein-style Japanese database between 2005 and 2010. Patients were divided into subsequently shocked (n =21,944) and subsequently not-shocked (n =547,993) cohorts. The primary study endpoint was 1-month favorable neurological outcome (Cerebral Performance Categories scale, category 1 or 2). RESULTS: In the subsequently shocked cohort, the ratio of 1-month favorable neurological outcome was significantly higher than that in the subsequently not-shocked cohort (1.79% versus 0.60%, P <0.001). Multivariate logistic regression analysis for 11 prehospital variables revealed that when the shock delivery time was less than 20 minutes, subsequent shock delivery was significantly associated with increased odds of 1-month favorable neurological outcomes (adjusted odds ratios (95% confidence interval), 6.55 (5.21 to 8.22) and 2.97 (2.58 to 3.43) for shock delivery times less than 10 minutes and from 10 to 19 minutes, respectively). However, when the shock delivery time was more than or equal to 20 minutes, subsequent shock delivery was not associated with increased odds of 1-month favorable neurological outcomes. CONCLUSIONS: In patients with an initial nonshockable rhythm after OHCA, subsequent conversion to shockable rhythms during emergency medical services resuscitation efforts was associated with increased odds of 1-month favorable neurological outcomes when the shock delivery time was less than 20 minutes.

Decision tree model for predicting long-term outcomes in children with out-of-hospital cardiac arrest: a nationwide, population-based observational study.

INTRODUCTION: At hospital arrival, early prognostication for children after out-of-hospital cardiac arrest (OHCA) might help clinicians formulate strategies, particularly in the emergency department. In this study, we aimed to develop a simple and generally applicable bedside tool for predicting outcomes in children after cardiac arrest. METHODS: We analyzed data of 5,379 children who had undergone OHCA. The data were extracted from a prospectively recorded, nationwide, Utstein-style Japanese database. The primary endpoint was survival with favorable neurological outcome (Cerebral Performance Category (CPC) scale categories 1 and 2) at 1 month after OHCA. We developed a decision tree prediction model by using data from a 2-year period (2008 to 2009, n = 3,693), and the data were validated using external data from 2010 (n = 1,686). RESULTS: Recursive partitioning analysis for 11 predictors in the development cohort indicated that the best single predictor for CPC 1 and 2 at 1 month was the prehospital return of spontaneous circulation (ROSC). The next predictor for children with prehospital ROSC was an initial shockable rhythm. For children without prehospital ROSC, the next best predictor was a witnessed arrest. Use of a simple decision tree prediction model permitted stratification into four outcome prediction groups: good (prehospital ROSC and initial shockable rhythm), moderately good (prehospital ROSC and initial nonshockable rhythm), poor (prehospital non-ROSC and witnessed arrest) and very poor (prehospital non-ROSC and unwitnessed arrest). By using this model, we identified patient groups ranging from 0.2% to 66.2% for 1-month CPC 1 and 2 probabilities. The validated decision tree prediction model demonstrated a sensitivity of 69.7% (95% confidence interval (CI) = 58.7% to 78.9%), a specificity of 95.2% (95% CI = 94.1% to 96.2%) and an area under the receiver operating characteristic curve of 0.88 (95% CI = 0.87 to 0.90) for predicting 1-month CPC 1 and 2. CONCLUSIONS: With our decision tree prediction model using three prehospital variables (prehospital ROSC, initial shockable rhythm and witnessed arrest), children can be readily stratified into four groups after OHCA. This simple prediction model for evaluating children after OHCA may provide clinicians with a practical bedside tool for counseling families and making management decisions soon after patient arrival at the hospital.

Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation.

Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions acidic (AS), basic (BS), and neutral (NS). These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods.

Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: an observational cohort study.

INTRODUCTION: Few clinical trials have provided evidence that epinephrine administration after out-of-hospital cardiac arrest (OHCA) improves long-term survival. Here we determined whether prehospital epinephrine administration would improve 1-month survival in OHCA patients. METHODS: We analyzed the data of 209,577 OHCA patients; the data were prospectively collected in a nationwide Utstein-style Japanese database between 2009 and 2010. Patients were divided into the initial shockable rhythm (n = 15,492) and initial non-shockable rhythm (n = 194,085) cohorts. The endpoints were prehospital return of spontaneous circulation (ROSC), 1-month survival, and 1-month favorable neurological outcomes (cerebral performance category scale, category 1 or 2) after OHCA. We defined epinephrine administration time as the time from the start of cardiopulmonary resuscitation (CPR) by emergency medical services personnel to the first epinephrine administration. RESULTS: In the initial shockable rhythm cohort, the ratios of prehospital ROSC, 1-month survival, and 1-month favorable neurological outcomes in the non-epinephrine group were significantly higher than those in the epinephrine group (27.7% vs. 22.8%, 27.0% vs. 15.4%, and 18.6% vs. 7.0%, respectively; all P < 0.001). However, in the initial non-shockable rhythm cohort, the ratios of prehospital ROSC and 1-month survival in the epinephrine group were significantly higher than those in the non-epinephrine group (18.7% vs. 3.0% and 3.9% vs. 2.2%, respectively; all P < 0.001) and there was no significant difference between the epinephrine and non-epinephrine groups for 1-month favorable neurological outcomes (P = 0.62). Prehospital epinephrine administration for OHCA patients with initial non-shockable rhythms was independently associated with prehospital ROSC (adjusted odds ratio [aOR], 8.83, 6.18, 4.32; 95% confidence interval [CI], 8.01-9.73, 5.82-6.56, 3.98-4.69; for epinephrine administration times ≤9 min, 10-19 min, and ≥20 min, respectively), with improved 1-month survival when epinephrine administration time was <20 min (aOR, 1.78, 1.29; 95% CI, 1.50-2.10, 1.17-1.43; for epinephrine administration times ≤9 min and 10-19 min, respectively), and with deteriorated 1-month favorable neurological outcomes (aOR, 0.63, 0.49; 95% CI, 0.48-0.80, 0.32-0.71; for epinephrine administration times 10-19 min and ≥20 min, respectively). CONCLUSIONS: Prehospital epinephrine administration for OHCA patients with initial nonshockable rhythms was independently associated with achievement of prehospital ROSC and had association with improved 1-month survival when epinephrine administration time was <20 min.

Decision-tree model for predicting outcomes after out-of-hospital cardiac arrest in the emergency department.

INTRODUCTION: Estimation of outcomes in patients after out-of-hospital cardiac arrest (OHCA) soon after arrival at the hospital may help clinicians guide in-hospital strategies, particularly in the emergency department. This study aimed to develop a simple and generally applicable bedside model for predicting outcomes after cardiac arrest. METHODS: We analyzed data for 390,226 adult patients who had undergone OHCA, from a prospectively recorded nationwide Utstein-style Japanese database for 2005 through 2009. The primary end point was survival with favorable neurologic outcome (cerebral performance category (CPC) scale, categories 1 to 2 [CPC 1 to 2]) at 1 month. The secondary end point was survival at 1 month. We developed a decision-tree prediction model by using data from a 4-year period (2005 through 2008, n = 307,896), with validation by using external data from 2009 (n = 82,330). RESULTS: Recursive partitioning analysis of the development cohort for 10 predictors indicated that the best single predictor for survival and CPC 1 to 2 was shockable initial rhythm. The next predictors for patients with shockable initial rhythm were age (<70 years) followed by witnessed arrest and age (>70 years) followed by arrest witnessed by emergency medical services (EMS) personnel. For patients with unshockable initial rhythm, the next best predictor was witnessed arrest. A simple decision-tree prediction mode permitted stratification into four prediction groups: good, moderately good, poor, and absolutely poor. This model identified patient groups with a range from 1.2% to 30.2% for survival and from 0.3% to 23.2% for CPC 1 to 2 probabilities. Similar results were observed when this model was applied to the validation cohort. CONCLUSIONS: On the basis of a decision-tree prediction model using four prehospital variables (shockable initial rhythm, age, witnessed arrest, and witnessed by EMS personnel), OHCA patients can be readily stratified into the four groups (good, moderately good, poor, and absolutely poor) that help predict both survival at 1 month and survival with favorable neurologic outcome at 1 month. This simple prediction model may provide clinicians with a practical bedside tool for the OHCA patient's stratification in the emergency department.

Termination-of-resuscitation rule for emergency department physicians treating out-of-hospital cardiac arrest patients: an observational cohort study.

INTRODUCTION: The 2010 cardiopulmonary resuscitation guidelines recommend emergency medical services (EMS) personnel consider prehospital termination-of-resuscitation (TOR) rules for out-of-hospital cardiac arrest (OHCA) following basic life support and/or advanced life support efforts in the field. However, the rate of implementation of international TOR rules is still low. Here, we aimed to develop and validate a new TOR rule for emergency department physicians to replace the international TOR rules for EMS personnel in the field. This rule aims to guide physicians in deciding whether to withhold further resuscitation attempts or terminate on-going resuscitation immediately after patient arrival. METHODS: We analyzed data prospectively collected in a nationwide Utstein-style Japanese database between 2005 and 2009, from 495,607 adult patients with OHCA. Patients were divided into development (n = 390,577) and validation (n = 105,030) groups. The main outcome measures were specificity, positive predictive value (PPV), and area under the receiver operating characteristic (ROC) curve for the newly developed TOR rule. RESULTS: We developed a new TOR rule that includes 3 criteria based on the results of multivariate logistic regression analysis for predicting a 1-month death after OHCA: no prehospital return of spontaneous circulation (adjusted odds ratio [OR], 25.8; 95% confidence interval [CI], 24.7-26.9), unshockable initial rhythm (adjusted OR, 2.76; 95% CI, 2.54-3.01), and unwitnessed by bystanders (adjusted OR, 2.18; 95% CI, 2.09-2.28). The specificity, PPV, and area under the ROC curve for this new TOR rule for predicting 1-month death in the validation group were 0.903 (95% CI, 0.894-0.911), 0.993 (95% CI, 0.992-0.993), and 0.874 (95% CI, 0.872-0.876), respectively. CONCLUSIONS: We developed and validated a new TOR rule for emergency department physicians consisting of 3 prehospital variables (no prehospital ROSC, unshockable initial rhythm, and unwitnessed by bystanders) that is a >99% predictor of very poor outcome. However, the implementation of this new rule in other countries or EMS systems requires further validation studies.

Neurological outcomes in patients transported to hospital without a prehospital return of spontaneous circulation after cardiac arrest.

INTRODUCTION: As emergency medical services (EMS) personnel in Japan are not allowed to perform termination of resuscitation in the field, most patients experiencing an out-of-hospital cardiac arrest (OHCA) are transported to hospitals without a prehospital return of spontaneous circulation (ROSC). As the crucial prehospital factors for outcomes are not clear in patients who had an OHCA without a prehospital ROSC, we aimed to determine the prehospital factors associated with 1-month favorable neurological outcomes (Cerebral Performance Category scale 1 or 2 (CPC 1-2)). METHODS: We analyzed the data of 398,121 adult OHCA patients without a prehospital ROSC from a prospectively recorded nationwide Utstein-style Japanese database from 2007 to 2010. The primary endpoint was 1-month CPC 1-2. RESULTS: The rate of 1-month CPC 1-2 was 0.49%. Multivariate logistic regression analysis indicated that the independent variables associated with CPC 1-2 were the following nine prehospital factors: (1) initial non-asystole rhythm (ventricular fibrillation (VF): adjusted odds ratio (aOR), 9.37; 95% confidence interval (CI), 7.71 to 11.4; pulseless ventricular tachycardia (VT): aOR, 8.50; 95% CI, 5.36 to 12.9; pulseless electrical activity (PEA): aOR, 2.75; 95% CI, 2.40 to 3.15), (2) age <65 years (aOR, 3.90; 95% CI, 3.28 to 4.67), (3) arrest witnessed by EMS personnel (aOR, 2.82; 95% CI, 2.48 to 3.19), (4) call-to-hospital arrival time <24 minutes (aOR, 2.58; 95% CI, 2.22 to 3.01), (5) arrest witnessed by any layperson, (6) physician-staffed ambulance, (7) call-to-response time <5 minutes, (8) prehospital shock delivery, and (9) presumed cardiac cause. When four crucial key factors (with an aOR >2.0 in the regression model: initial non-asystole rhythm, age <65 years, EMS-witnessed arrest, and call-to-hospital arrival time <24 minutes) were present, the rates of 1-month CPC 1-2 and 1-month survival were 16.1% and 23.2% in initial VF, 8.3% and 16.7% in pulseless VT, and 3.8% and 9.4% in PEA, respectively. CONCLUSIONS: In OHCA patients transported to hospitals without a prehospital ROSC, nine prehospital factors were significantly associated with 1-month CPC 1-2. Of those, four are crucial key factors: initial non-asystole rhythm, age <65 years, EMS-witnessed arrest, and call-to-hospital arrival time <24 minutes.

Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone.

Immune checkpoint inhibitors highlight the importance of anticancer immunity. However, their clinical utility and safety are limited by the low response rates and adverse effects. We focused on progesterone (P4), a hormone produced by the placenta during pregnancy, because it has multiple biological activities related to anticancer and immune regulation effects. P4 has a reversible immune regulatory function distinct from that of the stress hormone cortisol, which may drive irreversible immune suppression that promotes T cell exhaustion and apoptosis in patients with cancer. Because the anticancer effect of P4 is induced at higher than physiological concentrations, we aimed to develop a new anticancer drug by encapsulating P4 in liposomes. In this study, we prepared liposome-encapsulated anti-programmed death ligand 1 (PD-L1) antibody-conjugated P4 (Lipo-anti-PD-L1-P4) and evaluated the effects on the growth of MDA-MB-231 cells, a PD-L1-expressing triple-negative breast cancer cell line, in vitro and in NOG-hIL-4-Tg mice transplanted with human peripheral blood mononuclear cells (humanized mice). Lipo-anti-PD-L1-P4 at physiological concentrations reduced T cell exhaustion and proliferation of MDA-MB-231 in vitro. Humanized mice bearing MDA-MB-231 cells expressing PD-L1 showed suppressed tumor growth and peripheral tissue inflammation. The proportion of B cells and CD4+ T cells decreased, whereas the proportion of CD8+ T cells increased in Lipo-anti-PD-L1-P4-administrated mice spleens and tumor-infiltrated lymphocytes. Our results suggested that Lipo-anti-PD-L1-P4 establishes a systemic anticancer immune environment with minimal toxicity. Thus, the use of P4 as an anticancer drug may represent a new strategy for cancer treatment.

Enhanced expression of sulfatide, a sulfated glycolipid, in well-differentiated endometrial adenocarcinoma.

OBJECTIVES: It is well known that a poorly differentiated endometrial adenocarcinoma shows more rapid progression and a worse response to therapy than a well-differentiated endometrial adenocarcinoma. Qualitative and quantitative changes of cell surface glycolipids occur during neoplastic transformation. Sulfatide is one of the sulfated glycolipids in the cell membrane that may have an important role in various functions such as cell adhesion. To examine the molecular background of the morphological and biological features of well-differentiated and poorly differentiated cancer, we measured the levels of lipids, especially glycolipids, in tumor tissues from patients with endometrial carcinoma. MATERIALS AND METHODS: We determined the composition of lipids and glycolipids in tumor tissues, investigated glycosyltransferase messenger RNA expression by the reverse transcription-polymerase chain reaction, and assessed the localization of galactosylceramide sulfotransferase (an enzyme involved in sulfatide biosynthesis) by immunohistochemical staining. RESULTS: No significant differences were observed between well-differentiated and poorly differentiated cancer with respect to the levels of cholesterol ester, cholesterol, phospholipids, cholesterol sulfate, ceramides, neutral glycolipids of the globo series, and GM3 ganglioside. However, the amount of sulfatides in well-differentiated tumors was significantly greater than that in poorly differentiated tumors, which was confirmed by thin-layer chromatography and immunostaining with a monoclonal antisulfatide antibody. Altered expression of sulfatide was found to be secondary to a change of galactosylceramide sulfotransferase messenger RNA expression. Immunohistochemical staining revealed that galactosylceramide sulfotransferase expression was characteristically observed in glandular areas but not in solid areas. CONCLUSION: These findings suggest that sulfatide contributes to the well-differentiated phenotype of endometrial adenocarcinoma and that it is being expressed in normal uterine endometrium at sites of gland formation during the luteal phase, as we have previously reported.

Association of dispatcher-assisted cardiopulmonary resuscitation with initial shockable rhythm and survival after out-of-hospital cardiac arrest.

BACKGROUND AND IMPORTANCE: Bystander cardiopulmonary resuscitation (CPR) and initial shockable rhythm are crucial predictors of survival after out-of-hospital cardiac arrest (OHCA). However, the relationship between dispatcher-assisted CPR (DA-CPR) and initial shockable rhythm is not completely elucidated. OBJECTIVE: To examine the association of DA-CPR with initial shockable rhythm and outcomes. DESIGN, SETTING AND PARTICIPANTS: This nationwide population-based observational study conducted in Japan included 59 688 patients with witnessed OHCA of cardiac origin after excluding those without bystander CPR. Patients were divided into DA-CPR (n = 42 709) and CPR without dispatcher assistance (unassisted CPR, n = 16 979) groups. OUTCOME MEASURES AND ANALYSIS: The primary outcome measure was initial shockable rhythm, and secondary outcome measures were 1-month survival and neurologically intact survival. A Cox proportional hazards model adjusted for collapse-to-first-rhythm-analysis time and multivariable logistic regression models were used after propensity score (PS) matching to compare the incidence of initial shockable rhythm and outcomes, respectively. MAIN RESULTS: Among all patients (mean age 76.7 years), the rates of initial shockable rhythm, 1-month survival and neurologically intact survival were 20.8, 10.7 and 7.0%, respectively. The incidence of initial shockable rhythm in the DA-CPR group (20.4%, 3462/16 979) was significantly higher than that in the unassisted CPR group (18.5%, 3133/16 979) after PS matching (P < 0.0001). However, no significant differences were found between the two groups with respect to the incidence of initial shockable rhythm in the Cox proportional hazards model [adjusted hazard ratio of DA-CPR for initial shockable rhythm compared with unassisted CPR, 0.99; 95% confidence interval (CI), 0.97-1.02, P = 0.56]. No significant differences were observed in the survival rates in the two groups after PS matching [10.8% (1833/16 979) vs. 10.3% (1752/16 979), P = 0.16] and neurologically intact survival rates [7.3% (1233/16 979) vs. 6.8% (1161/16 979), P = 0.13]. The multivariable logistic regression model showed no significant differences between the groups with regard to survival (adjusted odds ratio of DA-CPR compared with unassisted CPR: 1.00; 95% CI, 0.89-1.13, P = 0.97) and neurologically intact survival (adjusted odds ratio: 1.12; 95% CI, 0.98-1.29, P = 0.14). CONCLUSION: DA-CPR after OHCA had the same independent association with the likelihood of initial shockable rhythm and 1-month meaningful outcome as unassisted CPR.

Dispatcher-assisted conventional cardiopulmonary resuscitation and outcomes for paediatric out-of-hospital cardiac arrests.

AIM: As asphyxial cardiac arrest is more common than cardiac arrest from a primary cardiac event in paediatric cardiac arrest, effective ventilation is important during paediatric cardiopulmonary resuscitation (CPR). We aimed to determine optimal dispatcher-assisted CPR instructions for bystanders after paediatric out-of-hospital cardiac arrest (OHCA). METHODS: We analysed the records of 8172 children who received bystander dispatcher-assisted CPR. Data were obtained from an All-Japan Utstein-style registry from 2005 to 2017. Patients were divided into conventional CPR and compression-only CPR groups. The primary study endpoint was 1-month neurologically intact survival, defined as a Cerebral Performance Category score of 1 or 2 (CPC 1-2). RESULTS: The 1-month CPC 1-2 rate was significantly higher in the dispatcher-assisted conventional CPR group than in the dispatcher-assisted compression-only CPR group (before propensity score matching, 5.7% [175/3077] vs. 3.1% [160/5095], p < 0.0001, adjusted odds ratio 2.48, 95% confidence interval 1.19-3.22; after propensity score matching, 6.0% [156/2618] vs. 2.6% [69/2618], p < 0.0001, adjusted odds ratio 2.42, 95% confidence interval 1.76-3.32). In most subgroup analyses after matching, dispatcher-assisted conventional CPR had a higher CPC 1-2 rate than dispatcher-assisted compression-only CPR; however, CPC 1-2 rates were similar between the two groups for patients with an initial shockable rhythm, those with total prehospital CPR time ≥ 20 min, those receiving public access defibrillation, advanced airway management, or adrenaline administration. CONCLUSION: Within the limitations of this retrospective observational study, dispatcher-assisted conventional CPR was preferable to dispatcher-assisted compression-only CPR as optimal CPR instructions for coaching callers to perform bystander CPR.

High-progesterone environment preserves T cell competency by evading glucocorticoid effects on immune regulation.

Progesterone (P4) and glucocorticoid (GC) play crucial roles in the immunoregulation of a mother to accept and maintain a semi-allogenic fetus. P4 concentration increases during pregnancy and becomes much higher in the placenta than in the other peripheral tissues, wherein the concentration of cortisol (COR), the most abundant GC and a strong immunosuppressor, remains uniform throughout the rest of the body. Here, we evaluated the effect of a high-P4 environment on pregnant immunity by comparing it with COR. Naïve T cell proportion increased transiently in peripheral blood of pregnant women just after delivery and decreased after one month. T cells stimulated with superantigen toxic-shock-syndrome-1 (TSST-1) in the presence of P4 stayed in the naïve state and did not increase, irrespective of the presence of COR, and reactive T cells could not survive. Treatment of T cells with P4 without T cell receptor (TCR) stimulation transiently suppressed T cell activation and proliferation, whereas the levels remain unaltered if P4 was not given before stimulation. Comparison of the engraftment and response against specific antigens using hu-PBL-NOG-hIL-4-Tg mice showed that P4-pretreated lymphocytes preserved CD62L expression and engrafted effectively in the spleen. Moreover, they produced antigen-specific antibodies, whereas COR-pretreated lymphocytes did not. These results suggest that a high-P4 environment suppresses T cell activation and induces T cell migration into lymphoid tissues, where they maintain the ability to produce anti-pathogen antibodies, whereas COR does not preserve T cell function. The mechanism may be pivotal in maintaining non-fetus-specific T cell function in pregnancy.

Time boundaries of the three-phase time-sensitive model for ventricular fibrillation cardiac arrest.

AIM: Ventricular fibrillation (VF) cardiac arrest may consist of three time-sensitive phases: electrical, circulatory, and metabolic. However, the time boundaries of these phases are unclear. We aimed to determine the time boundaries of the three-phase model for VF cardiac arrest. METHODS: We reviewed 20,741 out-of-hospital cardiac arrest cases with initial VF and presumed cardiac origin from the All-Japan Utstein-style registry between 2013 and 2017. The study endpoint was 1-month neurologically intact survival. The collapse-to-shock interval was defined as the time from collapse to the first shock delivery by emergency medical service personnel. The patients were divided into the bystander cardiopulmonary resuscitation (CPR, n = 11,606) and non-bystander CPR (n = 9135) groups. RESULTS: In the bystander CPR group, the collapse-to-shock times that were associated with increased adjusted 1-month neurologically intact survival, compared with those in the non-bystander CPR group, ranged from 7 min (42.9% [244/4999] vs. 26.0% [119/458], adjusted odds ratio [aOR], 1.95; 95% confidence interval [CI], 1.44-2.63; P < 0.0001) to 17 min (17.1% [70/410] vs. 7.3% [21/288], aOR, 2.82; 95% CI, 1.62-4.91; P = 0.0002). However, the neurologically intact survival rate of the bystander CPR group was statistically insignificant compared with that of the non-bystander CPR group when the collapse-to-shock time was outside this range. CONCLUSIONS: The time boundaries of the three-phase time-sensitive model for VF cardiac arrest may be defined as follows: electrical phase, from collapse to <7 min; circulatory phase, from 7 to 17 min; and metabolic phase, from >17 min onward.