Sex Disparities in Applied Force on Maxillary Incisors Among Novices During Laryngoscopy Using a High-Fidelity Simulator: A Prospective Observational Study.

Endotracheal intubation (ETI) is a common and crucial intervention. Whether the performance of ETI differs according to the sex of the laryngoscopist remains unclear. The aim of this study was to assess sex disparities in markers of ETI performance among novices using a high-fidelity simulator. This prospective observational study was conducted from April 2017 to March 2019 in a public medical university. In total, 209 medical students (4th and 5th grade) without clinical ETI experience were recruited. Of the 209 students, 64 (30.6%) were female. The participants used either a Macintosh direct laryngoscope or C-MAC video laryngoscope in combination with a stylet or gum-elastic bougie to perform ETI on a high-fidelity simulator. The primary endpoint was the maximum force applied on the maxillary incisors during laryngoscopy. The secondary endpoint was the time to ETI. The implanted sensors in the simulator automatically quantified the force and time to ETI. The maximum force applied on the maxillary incisors was approximately 30% lower in the male than female group for all laryngoscopes and intubation aids examined (all P < 0.001). Similarly, the time to ETI was approximately 10% faster in the male than female group regardless of the types of laryngoscopes and intubation aids used (all P < 0.05). In this study, male sex was associated with a lower maximum force applied on the maxillary incisors during both direct and indirect laryngoscopy performed by novices. A clinical study focusing on sex differences in ETI performance is needed to validate our findings.

Impact of Unexpected In-House Major COVID-19 Outbreaks on Depressive Symptoms among Healthcare Workers: A Retrospective Multi-Institutional Study.

The coronavirus disease 2019 (COVID-19) has significantly affected the mental health of healthcare workers (HCWs). The authors have provided psychosocial support to HCWs working in typical hospitals and nursing homes in Fukushima Prefecture, Japan, where major COVID-19 outbreaks have occurred since December 2020. This study retrospectively examines depressive symptoms before psychosocial interventions among HCWs working at typical hospitals and nursing homes experiencing in-house major COVID-19 outbreaks. We have offered psychosocial support in eight hospitals and nursing homes, obtaining data on the mental health status of 558 HCWs using the Patient Health Questionnaire-9. The study's results indicate that 29.4% of HCWs have exhibited moderate or higher depressive symptoms, and 10.2% had suicidal ideation. Multiple logistic regression analysis showed that being a nurse was associated with higher depressive symptoms and suicidal ideation compared to other HCWs. In addition, multiple logistic regression analysis of Polymerase Chain Reaction-positive HCWs showed that being a nurse and the number of COVID-19-related symptoms was associated with high depressive symptoms. These results suggest that HCWs in typical hospitals and nursing homes experiencing major COVID-19 outbreaks are more likely to exhibit severe depressive symptoms, which may worsen if infected with COVID-19. This study's findings expand the current understanding of HCWs' depressive symptoms and the importance of psychosocial support during unexpected major outbreaks in healthcare facilities.

Current situation survey for establishing personally acceptable radiation dose limits for nuclear disaster responders.

When responding to disasters, emergency preparedness is essential to ensure that disaster activities are performed smoothly, safely and efficiently. Investigations on the Fukushima accident revealed that lack of preparedness, poor communication and unsuitable emergency measures contributed to an inadequate emergency response to the nuclear disaster. In this study, we conducted a questionnaire survey on the establishment of a personal radiation exposure dose among Disaster Medical Assistance Team (DMAT) members in Japan who might be involved in the initial response to a nuclear disaster. Establishing personal exposure doses for personnel can encourage emergency preparedness and inform decisions on appropriate role assignments during nuclear response activities. Valid responses were obtained from 178 participants, and the response distribution was as follows: 'Already have own acceptable dose standard,' 16 (9%); 'Follow own institution's standard (and know its value),' 30 (17%); 'Follow own institution's standard (but do not know its value),' 59 (33%); 'Haven't decided,' 63 (35%) and 'Don't understand question meaning,' 10 (6%). We also assessed intention to engage in nuclear disaster activities among respondents via engagement intent scores (EIS) and found that participants who had established personal exposure standards had significantly higher EIS scores than those who had not decided or who did not understand the question. Thus, educating potential nuclear disaster responders on personal exposure doses may contribute to a higher intention to engage in emergency responses and improve preparedness and response efficiency.

Increasing Disaster Medical Assistance Teams' Intent to Engage with Specific Hazards.

To ensure human resource availability for a smooth response during various types of disasters, there is a need to improve the intent of those involved in responding to each hazard type. However, Disaster Medical Assistance Team personnel's intent to engage with specific hazards has yet to be clarified. This study therefore aimed to clarify the factors affecting Disaster Medical Assistance Team members' (n = 178) intent to engage with each type of hazard through an anonymous web questionnaire survey containing 20 questions. Our results show that the intent to engage in disaster response activities was significantly lower for chemical (50), biological (47), radiological/nuclear (58), and explosive (52) incidents compared with natural (82) and man-made hazards (82) (p < 0.01). Multiple regression analysis showed that incentives were the most common factor affecting responders' intent to engage with all hazard types, followed by self-confidence. Thus, creating a system that provides generous incentives could effectively improve disaster responders' intent to engage with specific hazards. Another approach could be education and training to increase disaster responders' confidence. We believe that the successful implementation of these measures would improve the intent of responders to engage with hazards and promote the recruitment of sufficient human resources.

Survey about Intention to Engage in Specific Disaster Activities among Disaster Medical Assistance Team Members.

INTRODUCTION: Different disaster activities should be performed smoothly. In relation to this, human resources for disaster activities must be secured. To achieve a stable supply of human resources, it is essential to improve the intentions of individuals responding to each type of disaster. However, the current intention of Disaster Medical Assistance Team (DMAT) members has not yet been assessed. STUDY OBJECTIVE: To facilitate a smooth disaster response, this survey aimed to assess the intention to engage in each type of disaster activity among DMAT members. METHODS: An anonymous web questionnaire survey was conducted. Japanese DMAT members in the nuclear disaster-affected area (Group A; n = 79) and the non-affected area (Group N; n = 99) were included in the analysis. The outcome was the answer to the following question: "Will you actively engage in activities during natural, human-made, and chemical (C), biological (B), radiological/nuclear (R/N), and explosive (E) (CBRNE) disasters?" Then, questionnaire responses were compared according to disaster type. RESULTS: The intention to engage in C (50), B (47), R/N (58), and E (52) disasters was significantly lower than that in natural (82) and human-made (82) disasters (P <.001). The intention to engage in CBRNE disasters among younger participants (age ≤39 years) was significantly higher in Group A than in Group N. By contrast, the intention to engage in R/N disasters alone among older participants (age ≥40 years) was higher in Group A than in Group N. However, there was no difference between the two groups in terms of intention to engage in C, B, and E disasters. Moreover, the intention to engage in all disasters between younger and older participants in Group A did not differ. In Group N, older participants had a significantly higher intention to engage in B and R/N disasters. CONCLUSION: Experience with a specific type of calamity at a young age may improve intention to engage in not only disasters encountered, but also other types. In addition, the intention to engage in CBRNE disasters improved with age in the non-experienced population. To respond smoothly to specific disasters in the future, measures must be taken to improve the intention to engage in CBRNE disasters among DMAT members.

Lower maximum forces on oral structures when using gum-elastic bougie than when using endotracheal tube and stylet during both direct and indirect laryngoscopy by novices: a crossover study using a high-fidelity simulator.

BACKGROUND: Applying excessive force during endotracheal intubation (ETI) is associated with several complications, including dental trauma and hemodynamic alterations. A gum-elastic bougie (GEB), a type of tracheal tube introducer, is a useful airway adjunct for patients with poor laryngoscopic views. However, how the use of a GEB affects the force applied during laryngoscopy is unclear. We compared the force applied on the oral structures during ETI performed by novices using the GEB versus an endotracheal tube + stylet. METHODS: This prospective crossover study was conducted from April 2017 to March 2019 in a public medical university in Japan. In total, 209 medical students (4th and 5th grade, mean age of 23.7 ± 2.0 years) without clinical ETI experience were recruited. The participants used either a Macintosh direct laryngoscope (DL) or C-MAC video laryngoscope (VL) in combination with a GEB or stylet to perform ETI on a high-fidelity airway management simulator. The order of the first ETI method was randomized to minimize the learning curve effect. The outcomes of interest were the maximum forces applied on the maxillary incisors and tongue during laryngoscopy. The implanted sensors in the simulator quantified these forces automatically. RESULTS: The maximum force applied on the maxillary incisors was significantly lower when using a GEB than when using an endotracheal tube + stylet both with the Macintosh DL (39.0 ± 23.3 vs. 47.4 ± 32.6 N, P < 0.001) and C-MAC VL (38.9 ± 18.6 vs. 42.0 ± 22.1 N, P < 0.001). Similarly, the force applied on the tongue was significantly lower when using a GEB than when using an endotracheal tube + stylet both with the Macintosh DL (31.9 ± 20.8 vs. 37.8 ± 22.2 N, P < 0.001) and C-MAC VL (35.2 ± 17.5 vs. 38.4 ± 17.5 N, P < 0.001). CONCLUSIONS: Compared with the use of an endotracheal tube + stylet, the use of a GEB was associated with lower maximum forces on the oral structures during both direct and indirect laryngoscopy performed by novices. Our results suggest the expanded role of a GEB beyond an airway adjunct for difficult airways.

Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA.

Oct4 is a master regulator of the induction and maintenance of cellular pluripotency, and has crucial roles in early stages of differentiation. It is the only factor that cannot be substituted by other members of the same protein family to induce pluripotency. However, although Oct4 nuclear transport and delivery to target DNA are critical events for reprogramming to pluripotency, little is known about the molecular mechanism. Oct4 is imported to the nucleus by the classical nuclear transport mechanism, which requires importin α as an adaptor to bind the nuclear localization signal (NLS). Although there are structures of complexes of the NLS of transcription factors (TFs) in complex with importin α, there are no structures available for complexes involving intact TFs. We have therefore modeled the structure of the complex of the whole Oct4 POU domain and importin α2 using protein-protein docking and molecular dynamics. The model explains how the Ebola virus VP24 protein has a negative effect on the nuclear import of STAT1 by importin α but not on Oct4, and how Nup 50 facilitates cargo release from importin α. The model demonstrates the structural differences between the Oct4 importin α bound and DNA bound crystal states. We propose that the 'expanded linker' between the two DNA-binding domains of Oct4 is an intrinsically disordered region and that its conformational changes have a key role in the recognition/binding to both DNA and importin α. Moreover, we propose that this structural change enables efficient delivery to DNA after release from importin α.

Human and equipment resources for difficult airway management, airway education programs, and capnometry use in Japanese emergency departments: a nationwide cross-sectional study.

BACKGROUND: Although human and equipment resources, proper training, and the verification of endotracheal intubation are vital elements of difficult airway management (DAM), their availability in Japanese emergency departments (EDs) has not been determined. How ED type and patient volume affect DAM preparation is also unclear. We conducted the present survey to address this knowledge gaps. METHODS: This nationwide cross-sectional study was conducted from April to September 2016. All EDs received a mailed questionnaire regarding their DAM resources, airway training methods, and capnometry use for tube placement. Outcome measures were the availability of: (1) 24-h in-house back-up; (2) key DAM resources, including a supraglottic airway device (SGA), a dedicated DAM cart, surgical airway devices, and neuromuscular blocking agents; (3) anesthesiology rotation as part of an airway training program; and (4) the routine use of capnometry to verify tube placement. EDs were classified as academic, tertiary, high-volume (upper quartile of annual ambulance visits), and urban. RESULTS: Of the 530 EDs, 324 (61.1%) returned completed questionnaires. The availability of in-house back-up coverage, surgical airway devices, and neuromuscular blocking agents was 69.4, 95.7, and 68.5%, respectively. SGAs and dedicated DAM carts were present in 51.5 and 49.7% of the EDs. The rates of routine capnometry use (47.8%) and the availability of an anesthesiology rotation (38.6%) were low. The availability of 24-h back-up coverage was significantly higher in academic EDs and tertiary EDs in both the crude and adjusted analysis. Similarly, neuromuscular blocking agents were more likely to be present in academic EDs, high-volume EDs, and tertiary EDs; and the rate of routine use of capnometry was significantly higher in tertiary EDs in both the crude and adjusted analysis. CONCLUSIONS: In Japanese EDs, the rates of both the availability of SGAs and DAM carts and the use of routine capnometry to confirm tube placement were approximately 50%. These data demonstrate the lack of standard operating procedures for rescue ventilation and post-intubation care. Academic, tertiary, and high-volume EDs were likely to be well prepared for DAM.

Difficult airway management resources and capnography use in Japanese intensive care units: a nationwide cross-sectional study.

PURPOSE: The availability of difficult airway management (DAM) resources and the extent of capnometry use in Japanese intensive care units (ICUs) remained unclear. The purpose of this study was to clarify whether: (1) DAM resources were adequate, and (2) capnometry was routinely applied in Japanese ICUs. METHODS: This nationwide cross-sectional study was conducted from September 2015 to February 2016. All ICUs received a mailed questionnaire about their DAM resources and use of capnometry. Outcome measures were availability of: (1) 24-h in-house backup coverage; (2) a supraglottic airway device (SGA); (3) a dedicated DAM cart; and (4) surgical airway devices, and (5) routine use of capnometry to verify tube placement and for continuous monitoring of ventilator-dependent patients. The association between these outcomes and ICU type (academic, high-volume, closed, surgical) was also analyzed. RESULTS: Of the 289 ICUs, 196 (67.8 %) returned completed questionnaires. In-house backup coverage and surgical airway devices were highly available (89.3 and 95.9 %), but SGAs and dedicated DAM carts were not (60.2 and 60.7 %). The routine use of capnometry to confirm tube placement was reported by 55.6 % of the ICUs and was highest in closed ICUs (67.2 %, p = 0.03). The rate of continuous capnography monitoring was also 55.6 % and was highest in academic ICUs (64.5 %, p = 0.04). CONCLUSION: In Japanese ICUs, SGAs and dedicated DAM carts were less available, and capnometry was not universally applied either to confirm tube placement, or for continuous monitoring of ventilated patients. Our study revealed areas in need of improvement.

Are prehospital airway management resources compatible with difficult airway algorithms? A nationwide cross-sectional study of helicopter emergency medical services in Japan.

PURPOSE: Immediate access to the equipment required for difficult airway management (DAM) is vital. However, in Japan, data are scarce regarding the availability of DAM resources in prehospital settings. The purpose of this study was to determine whether Japanese helicopter emergency medical services (HEMS) are adequately equipped to comply with the DAM algorithms of Japanese and American professional anesthesiology societies. METHODS: This nationwide cross-sectional study was conducted in May 2015. Base hospitals of HEMS were mailed a questionnaire about their airway management equipment and back-up personnel. Outcome measures were (1) call for help, (2) supraglottic airway device (SGA) insertion, (3) verification of tube placement using capnometry, and (4) the establishment of surgical airways, all of which have been endorsed in various airway management guidelines. The criteria defining feasibility were the availability of (1) more than one physician, (2) SGA, (3) capnometry, and (4) a surgical airway device in the prehospital setting. RESULTS: Of the 45 HEMS base hospitals questioned, 42 (93.3 %) returned completed questionnaires. A surgical airway was practicable by all HEMS. However, in the prehospital setting, back-up assistance was available in 14.3 %, SGA in 16.7 %, and capnometry in 66.7 %. No HEMS was capable of all four steps. CONCLUSION: In Japan, compliance with standard airway management algorithms in prehospital settings remains difficult because of the limited availability of alternative ventilation equipment and back-up personnel. Prehospital health care providers need to consider the risks and benefits of performing endotracheal intubation in environments not conducive to the success of this procedure.

EARLY STAGE RESPONSES OF INTENSIVE CARE UNITS DURING MAJOR DISASTERS: FROM THE EXPERIENCES OF THE GREAT EAST JAPAN EARTHQUAKE.

The present study investigated the role of intensive care units (ICU) during disasters, including the responses of our ICU following the Great East Japan Earthquake on March 11, 2011. Our ICU comprises 8 beds for postoperative inpatients and those with rapidly deteriorating conditions; 20 beds in an emergency unit for critically ill patients; and 17 beds for neonates. It is important to secure empty beds when a major disaster occurs, as was the case after the Great Hanshin Earthquake, due to the resulting large numbers of trauma patients. Therefore, each ICU section cooperated to ensure sufficient space for admissions following the Great East Japan Earthquake. However, unlike the Great Hanshin Earthquake, securing beds was ultimately unnecessary due to the nature of the recent disaster, which also consisted of a subsequent tsunami and nuclear accident. Therefore, air quality monitoring was required on this occasion due to the risk of environmental radioactive pollution from the nuclear disaster causing problems with artificial respiration management involving atmospheric air. The variability in damage arising during different disasters thus requires a flexible response from ICUs that handle seriously ill patients.

Comprehensive analysis of the dynamic structure of nuclear localization signals.

Most transcription and epigenetic factors in eukaryotic cells have nuclear localization signals (NLSs) and are transported to the nucleus by nuclear transport proteins. Understanding the features of NLSs and the mechanisms of nuclear transport might help understand gene expression regulation, somatic cell reprogramming, thus leading to the treatment of diseases associated with abnormal gene expression. Although many studies analyzed the amino acid sequence of NLSs, few studies investigated their three-dimensional structure. Therefore, we conducted a statistical investigation of the dynamic structure of NLSs by extracting the conformation of these sequences from proteins examined by X-ray crystallography and using a quantity defined as conformational determination rate (a ratio between the number of amino acids determining the conformation and the number of all amino acids included in a certain region). We found that determining the conformation of NLSs is more difficult than determining the conformation of other regions and that NLSs may tend to form more heteropolymers than monomers. Therefore, these findings strongly suggest that NLSs are intrinsically disordered regions.

Establishment and implementation of an effective rule for the interpretation of computed tomography scans by emergency physicians in blunt trauma.

INTRODUCTION: Computed tomography (CT) can detect subtle organ injury and is applicable to many body regions. However, its interpretation requires significant skill. In our hospital, emergency physicians (EPs) must interpret emergency CT scans and formulate a plan for managing most trauma cases. CT misinterpretation should be avoided, but we were initially unable to completely accomplish this. In this study, we proposed and implemented a precautionary rule for our EPs to prevent misinterpretation of CT scans in blunt trauma cases. METHODS: WE ESTABLISHED A SIMPLE PRECAUTIONARY RULE, WHICH ADVISES EPS TO INTERPRET CT SCANS WITH PARTICULAR CARE WHEN A COMPLICATED INJURY IS SUSPECTED PER THE FOLLOWING CRITERIA: 1) unstable physiological condition; 2) suspicion of injuries in multiple regions of the body (e.g., brain injury plus abdominal injury); 3) high energy injury mechanism; and 4) requirement for rapid movement to other rooms for invasive treatment. If a patient meets at least one of these criteria, the EP should exercise the precautions laid out in our newly established rule when interpreting the CT scan. Additionally, our rule specifies that the EP should request real-time interpretation by a radiologist in difficult cases. We compared the accuracy of EPs' interpretations and resulting patient outcomes in blunt trauma cases before (January 2011, June 2012) and after (July 2012, January 2013) introduction of the rule to evaluate its efficacy. RESULTS: Before the rule's introduction, emergency CT was performed 1606 times for 365 patients. We identified 44 cases (2.7%) of minor misinterpretation and 40 (2.5%) of major misinterpretation. After introduction, CT was performed 820 times for 177 patients. We identified 10 cases (1.2%) of minor misinterpretation and two (0.2%) of major misinterpretation. Real-time support by a radiologist was requested 104 times (12.7% of all cases) and was effective in preventing misinterpretation in every case. Our rule decreased both minor and major misinterpretations in a statistically significant manner. In particular, it conspicuously decreased major misinterpretations. CONCLUSION: Our rule was easy to practice and effective in preventing EPs from missing major organ injuries. We would like to propose further large-scale multi-center trials to corroborate these results.

Repeated embolization of intercostal arteries after blunt chest injury.

To deal with an arterial bleeding from the chest wall after a blunt chest injury, embolization of the bleeding arteries can be a valuable therapeutic option, which is less invasive than a thoracotomy. However, its results are variable, being highly operator-dependent. In the present case, we performed successful emergency embolization of the 4th and 5th intercostal arteries for persistent hemorrhage following blunt trauma to the chest. Several days after the first embolization, secondary embolization was required for treating a pseudoaneurysm that was formed in the 5th intercostal artery. Although the mechanisms underlying pseudoaneurysm formation are not clearly understood, its rupture is potentially fatal. Therefore, it is essential to carefully follow-up patients who experience blunt chest injury to avoid this serious complication.

Development of takotsubo cardiomyopathy with severe pulmonary edema before a cesarean section.

Takotsubo cardiomyopathy is an acute syndrome involving apical ballooning and consequent dysfunction of the left ventricle. Most cases of left ventricular dysfunction resolve within 1 month. We present the case of a 40-year-old woman who developed severe heart failure caused by takotsubo cardiomyopathy with severe left ventricular dysfunction during the perinatal period. Because of the presence of multiple myomas, she was scheduled to undergo a cesarean section under general anesthesia. However, after induction of general anesthesia, she had to be awakened because of the presence of a difficult airway. Because she exhibited insufficient oxygenation, she was transferred to the emergency center. Upon hospital admission, she expectorated large amounts of pink sputum, indicating severe pulmonary edema. Cesarean section was performed immediately. Echocardiography revealed severe left ventricular dysfunction. Full recovery of cardiac function required almost 1 month, after which she was discharged from the hospital without further complications. This is the first reported case of takotsubo cardiomyopathy induced by a failed intubation during a scheduled cesarean section. Takotsubo cardiomyopathy usually shows a good prognosis, but if this myopathy develops during the perinatal period, it can worsen because of excessive preload following the termination of fetoplacental circulation.

Patient questionnaire following closure of tracheotomy fistula: percutaneous vs. surgical approaches.

BACKGROUND: Tracheotomy is an indispensable component in intensive care management. Doctors in charge of the intensive care unit (ICU) usually decide whether tracheotomy should be performed. However, long-term follow-up of a closed fistula by these doctors is rarely continued in most cases. Doctors in charge of the ICU should be interested in the long-term prognosis of tracheotomy. The purpose of this study was to evaluate whether different tracheotomy procedures affect the long-term outcome of a closed tracheal fistula. METHODS: We mailed questionnaires to patients undergoing tracheotomy in Fukushima Medical University Hospital between January 2008 and December 2010. Questions concerned problems related to perception, laryngeal function, and the appearance of a closed fistula. Patients were classified into percutaneous tracheotomy (PT) group and surgical tracheotomy (ST) group. We evaluated the statistical significance of differences in the frequency and degree of each problem between the two groups. A door-to-door objective evaluation using the original scoring system was then performed for patients who replied to the mailed questionnaire. We evaluated the percentage of patients with high scores as well as the mean scores for problems with function and appearance. RESULTS: We received completed questionnaires from 28/40 patients in the PT group and 35/55 patients in the ST group. There were no significant differences in age, mean hospital stay, or APACHE II score between the groups. Regarding problems with appearance, the outcomes of PT were significantly better than those of ST with respect to self-evaluation (p = 0.04) and the frequency (p = 0.03) and degree (p = 0.02) of scar unevenness according to door-to-door evaluation. However, there were no significant differences in the frequency or degree of self-evaluation in problems with perception and function between the two groups. There were no significant differences in the frequency or degree of door-to-door evaluation of problems with function. CONCLUSIONS: This study shows that PT might be superior to ST with respect to problems with long-term appearance. Continuous follow-up of closed tracheal fistulas can help assure that patients recovering from a critical condition experience a better return to their former lives. A systematic follow-up of post-critical-care patients is required.

Activation intervals for a helicopter emergency medical service in Japan.

INTRODUCTION: Prehospital time is crucial for treating acute disease; therefore, it is important to activate helicopter emergency medical services (HEMS) promptly. We investigated the differences in the activation intervals (the time elapsed from receiving the emergency call to the time of HEMS request) under various conditions to evaluate the current status of HEMS-related prehospital triage in Japan. METHODS: We retrospectively investigated activation intervals under exogenous (trauma, n = 553; intoxication, n = 56; and burns, n = 32) and endogenous conditions (acute coronary syndrome [ACS], n = 47; and stroke, n = 173) between January 31, 2008, and January 31, 2012, by reviewing flight records. RESULTS: Activation intervals were trauma (14.3 ± 11.5 min), intoxication (10.3 ± 8.6 min), burns (15.0 ± 13.1 min), ACS (17.9 ± 14.6 min), and stroke (19.1 ± 13.1 min). One-way analysis of variance showed a significant difference between exogenous and endogenous groups (P < .001). Post-hoc analysis using Tukey's honestly significant difference test showed significant differences between ACS and intoxication (P < .05), stroke and intoxication (P < .001), and stroke and trauma (P < .001). CONCLUSIONS: Endogenous conditions had longer activation intervals, which may reflect a lack of mechanisms assessing their severity. We are considering developing new triage criteria for dispatchers.

Dynamical excimer formation in rigid carbazolophane via charge transfer state.

Formation dynamics of intramolecular excimer in dioxa[3.3](3,6)carbazolophane (CzOCz) was studied by time-resolved spectroscopic methods and computational calculations. In the ground state, the most stable conformer in CzOCz is the anti-conformation where two carbazole rings are in antiparallel alignment. No other isomers were observed even after the solution was heated up to 150 °C, although three characteristic isomers were found by the molecular mechanics calculation: the first is the anti-conformer, the second is the syn-conformer where two carbazole rings are stacked in the same direction, and the third is the int-conformer where two carbazole rings are aligned in an edge-to-face geometry. Because of the anti-conformation, the interchromophoric interaction in CzOCz is negligible in the ground state. Nonetheless, the intramolecular excimer in CzOCz was dynamically formed in an acetonitrile (MeCN) solution, indicating strong interchromophoric interaction and the isomerization from the anti- to syn-conformation in the excited state. The excimer formation in CzOCz is more efficient in polar solvents than in less polar solvents, suggesting the contribution of the charge transfer (CT) state to the excimer formation. The stabilization in the excited state is discussed in terms of molecular orbital interaction between two carbazole rings. The solvent-polarity-induced excimer formation is discussed in terms of the CT character in the int-conformation.

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.

Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras⋅GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras⋅GTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras⋅GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-Ras⋅GTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras⋅GTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target Ras⋅GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.