key: cord- - xgmanai authors: matlock, ann marie; gutierrez, debbie; wallen, gwenyth; hastings, clare title: providing nursing care to ebola patients on the national stage: the national institutes of health experience date: - - journal: nursing outlook doi: . /j.outlook. . . sha: doc_id: cord_uid: xgmanai nan plans had been underway since july to prepare for the admission of a patient with evd, or exposure, to the nih clinical center. however, when the phone call came, the enormity of this impending admission became a reality. as nursing leadership, we knew that nurses would be at the front line and on the national stage in providing care to our patients as well as preventing transmission to caregivers or others in the hospital or community. we responded to the call by setting into action an intensively practiced response to transport, receive, assess, and care for someone with potential evd. our first patient never developed evd and was discharged after days. we received our second patient several days later, one of the nurses involved with the evd case in dallas. she had documented evd and also was discharged free of disease days later. we are ready if needed for another patient. our experience demonstrated that we could be successful in safely caring for patients with ebola in a highly specialized facility staffed by a specialized team in an extraordinary state of training readiness. our experience also raised several significant questions about if and how such an approach could be translated successfully and sustainably to the general health care system and revealed some key priorities that should inform future efforts by nursing leaders to respond to similar crises. the special clinical studies unit (scsu) at the nih clinical center was opened in to provide a resource for the study of patients with any level of isolation requirement for a documented or suspected infection. funding and resources to construct the unit within the new hatfield clinical research center were fueled by concerns about emerging unusual infectious diseases as well as the potential use of disease causing organisms in acts of bioterrorism. our role was to support research on vaccines and treatments and offer a resource for the evaluation, treatment, and study of workers with occupational exposure to these agents. the scsu includes a room that can be used for intensive care-level patient care and has multiple redundant systems for the management and disinfection of any materials or waste that leaves the unit. as a part of preparing for their role in studying highly infectious diseases, scsu staff has been trained, drilled, and observed using personal protective equipment (ppe) and has regularly rehearsed patient scenarios requiring the most intensive isolation procedures known. our team of specialists in epidemiology and infectious diseases had been tracking the unusual outbreak of ebola in west africa since its emergence in early . before the phone call in september, an interdisciplinary team had been preparing for months to be sure we could safely manage an admission of a patient with evd exposure, working through scenarios from staffing to transport of specimens to managing the trash. all employees who participated in the care of our two patients (and any who participate in any future admissions) are volunteers drawn from among our trained staff members. setting our level of isolation for patients with evd in the scsu was a major challenge because guidelines were still emerging based on the known mode of transmission, and there was limited experience in western health care facilities with the potential for transmission during invasive procedures and close quarters contact. because ebola was not previously broadly treated in the u.s. health care system, there were no published guidelines for health care worker safety. in the early s, we had developed a high level of isolation at the nih clinical center called special respiratory isolation (sri) in the event that we were going to provide care to research patients with severe acute respiratory syndrome (sars), h n , or other viruses with known airborne transmission. although ebola is not transmitted through the air, the isolation protection for sri did not leave any exposed skin on the health care worker and provided the level of barrier protection we were looking for. using the guidelines for sri, combined with what was known about ebola, isolation guidelines were updated for health care workers in the scsu who would be working with patients with known or suspected ebola infection. this approach of developing guidelines to exceed safety goals became a theme as we worked through the delicate process of balancing staff protection and patient safety with staff comfort and endurance in caregiving and institutional expense. we have had extensive experience at the clinical center with complex or rare infections requiring special isolation procedures and with the significant effort required to contain a resistant or difficult-to-treat infectious agent within a health care setting. we now commonly use "monitors" to assure adherence to barrier protections and hand hygiene when caring for patients with multidrug resistant infections. this is needed to protect our immunocompromised patients already at risk for severe infections from multidrug-resistant organisms (palmore & henderson, ) . our first information from the field in west africa was that the use of trained observers in the care process to assure there was no break in barrier protection was essential, especially during donning and doffing. this led us to the use of observers within the care process as well as during the donning and doffing of ppe. staffing was another major consideration. this period was approached as an extreme crisis, with an absolute requirement for enough resources to assure staff and patient safety and to fulfill the mandate of the nih in taking a leadership role in this global public health emergency. depending on the condition and clinical trajectory of each patient, we needed to ensure that we had staffing immediately available to provide intensive care unit-level nursing care in full isolation. to provide redundancy and constant observation, we built reserve capacity by having scsu nurses who specialize in infectious disease augmented with two other trained nurses to provide safety observation and environmental support for each patient, including critical care support if needed. staffing a unit for one critically ill patient would require . full-time equivalents for a week of / care. that is four nurses per shift! the team was adamant that our plans be built around requirement for the safety of our staff and other patients in the facility. with new information coming every week from public health authorities, other institutions, and patient care efforts in africa and the united states, we implemented staff training. we understood from consultation with clinical staff returning from the field in west africa that the constant maintenance of unbroken barrier protection was imperative to staff and community safety. we divided our training into two sessions: basic training with return demonstration of donning and doffing and an interdisciplinary simulation session of caring for a patient in full ppe with the scsu staff acting as evaluators. simulation exercises in full ppe included nursing and medical procedures, waste management procedures, communication strategies, equipment handling, and documentation requirements. one of the most useful simulation exercises, dubbed "a day in the life," was a simulation with a person playing the role of a patient with gastrointestinal distress. the day in the life was conducted after the staff went through basic and team simulation training. the exercise showed the nurse's role in caring for a patient with severe uncontrollable gastrointestinal symptoms requiring intravenous hydration with the staff in full ppe. the simulated waste was treated with a special glow gel that would show up under an ultraviolet light if not entirely cleaned up, giving the staff a clear view of the contaminated areas even after cleaning. a secondary outcome of the "day in the life" was the nurses learning by direct experience what it was like to stay in their ppe for up to hours. this was a vivid experience for those involved and brought home how careful they needed to be in caring for the patient while protecting themselves from accidental exposure. we approached the staffing for a possible patient with evd using volunteers only. given the intensive nurse to patient staffing ratios, the number of nurses in the scsu was not sufficient to provide the needed care. very explicit information about evd and our role in the crisis was provided in person and in writing to nurses on staff in the scsu and to nurses with the needed acute care competencies within our hospital. nurses who expressed an interest in volunteering to provide direct patient care were educated about ebola, trained in scsu procedures, and oriented. this provided sufficient staff although we had to "backfill" the clinical areas providing staff. the staff who volunteered became a close-knit group and weathered many difficulties caused by fear and lack of knowledge in the community and even our own facility. some nurses were told their colleagues would not willingly welcome them back to their home units after a shift with our evd patient. at least two nurses were told their children were not welcome to attend day care while they were caring for the patient and days after. from the very beginning of the crisis, constant, detailed, and up-to-date communication was essential. this included consultation with physicians who had participated in care in the field in africa, communication and verification of media reports about possible patient arrivals and the evolving outbreak in africa, and discussion of information gained from the broad network of our infectious disease team about emerging experience at other u.s. facilities who had accepted patients. when there was a lag in communicating some aspect of our preparations, media-driven fear and concerns surfaced. during each patient admission, daily huddles were held with key members from each interdisciplinary team, which allowed for quick fixes when glitches were identified in any of our processes. in both cases, our staff remained focused because there was a complex care delivery issue at hand that required precise communication, meticulous practice, and above all compassion for our patients and their families. we also have a commitment and longstanding experience preserving confidentiality both of patient-identifiable information as well as the progress of a high-profile case in the clinical center. however, as practitioners in a federal clinical research institution, we remained keenly aware that the public who we serve were looking to us for answers and guidance that could alleviate some of the rapidly proliferating misinformation about ebola and its transmission. when it became known we were caring for a patient with evd, our leadership team became the subject of numerous calls for information about how we were handling the various aspects of the admission, notably staffing and procedures for isolation and use for ppe. there was early intensive effort to collate and prepare our internal procedures for dissemination. they are now available on the web (ebola virus disease, ; palmore & henderson, ) the ebola virus was discovered in and is a filovirus known to cause hemorrhagic fever in humans. until the most recent outbreak in , evd has been confined primarily to countries in africa. this virus has four strains known to cause disease in humans. after exposure to ebola, patients can become symptomatic anywhere from to days. the average time frame for disease manifestation is to days. common symptoms are fever, severe headache, muscle pain, weakness, fatigue, diarrhea, and vomiting, with death resulting from profound dehydration, shock, and multiorgan failure. the transmission of ebola from an infected human to another occurs through direct contact with blood or body fluids. patients are considered contagious when they have symptoms and the virus can be detected in their blood (ebola virus disease, ). ebola virus disease: information for us healthcare workers ebola virus disease information for clinical center staff managing transmission of carbapenem-resistant enterobacteriaceae in healthcare settings: a view from the trenches we believe the following points are key in translating our experience to the broader nursing community: . it is possible to care for patients with evd with much better clinical results than are seen in the field and simultaneously provide protection for staff and other patients. exquisitely exact barrier protections are essential to prevent transmission to care providers or environmental contamination. procedures to care for evd within isolation are not simple and not likely to be learned through a -hour video and demonstration. intensive practice and observation as well as a chance to experience working in full gear are needed. repeated, redundant, and detailed communications to all in and around a clinical situation involving evd is essential because the associated fear and inaccuracies in the media exaggerate concerns about personal and community risk. volunteerism is a critical element in first response to this crisis, both in america and in africa.our nurses were deeply affected by the experience of caring for a nurse who had cared for an infected patient and had contracted evd. at the clinical center, we are accustomed to providing extraordinary care and precautions to protect patients from harm as well as safeguarding staff and our wider patient community because many of the treatments we support are first in human and may have little documentation of toxicity or safety. this crisis is not over, and as biomedical scientists, epidemiologists, and public health experts work to understand and control the underlying disease process and treatments and causes for the expanded outbreak, the nursing community will need to respond with rapidly developed and communicated information, guidelines, and materials to assist nurses who may be drawn into involvement. key: cord- -dhdyxnr authors: den boon, saskia; vallenas, constanza; ferri, mauricio; norris, susan l. title: incorporating health workers’ perspectives into a who guideline on personal protective equipment developed during an ebola virus disease outbreak date: - - journal: f res doi: . /f research. . sha: doc_id: cord_uid: dhdyxnr background: ebola virus disease (evd) health facility transmission can result in infection and death of health workers. the world health organization (who) supports countries in preparing for and responding to public health emergencies, which often require developing new guidance in short timelines with scarce evidence. the objective of this study was to understand frontline physicians’ and nurses’ perspectives about personal protective equipment (ppe) use during the - evd outbreak in west africa and to incorporate these findings into the development process of a who rapid advice guideline. methods : we surveyed frontline physicians and nurses deployed to west africa between march and september of . results: we developed the protocol, obtained ethics approval, delivered the survey, analysed the data and presented the findings as part of the evidence-to-decision tables at the expert panel meeting where the recommendations were formulated within eight weeks. forty-four physicians and nurses responded to the survey. they generally felt at low or extremely low risk of virus transmission with all types of ppe used. eye protection reduced the ability to provide care, mainly due to impaired visibility because of fogging. heat and dehydration were a major issue for % of the participants using goggles and for % using a hood. both gowns and coveralls were associated with significant heat stress and dehydration. most participants ( %) were very confident that they were using ppe correctly. conclusion : our study demonstrated that it was possible to incorporate primary data on end-users’ preferences into a rapid advice guideline for a public health emergency in difficult field conditions. health workers perceived a balance between transmission protection and ability to care for patients effectively while wearing ppe. these findings were used by the guideline development expert panel to formulate who recommendations on ppe for frontline providers caring for evd patients in outbreak conditions. health facility transmission is a hallmark of early ebola virus disease (evd) outbreaks and usually results in infection and death of health workers particularly before the identification of ebola virus as responsible for the clinical presentation of one or a cluster of patients [ ] [ ] [ ] . contributing factors include nonspecific clinical presentation, lack of local advanced diagnostic capabilities and suboptimal infection prevention and control (ipc) practices, amplified by poor surveillance in struggling health systems. the epidemiological pattern of the - evd outbreak in west africa revealed a similar story, but this time with an unprecedented scale and geographic spread, resulting in a record number of affected health workers, with cases and deaths by late . health workers are more likely than non-health workers to be infected: depending on the profession, the risk can be to times higher . the correct use of personal protective equipment (ppe) as part of comprehensive ipc measures contributes to the prevention of evd transmission in healthcare settings by providing a protective barrier from contaminated fluids. however, the characteristics of the material and the configuration of the equipment may lead to health worker discomfort, overheating, and concerns about dexterity and safety to perform clinical tasks when ppe is used in the typical conditions of high heat and humidity present in west african evd treatment centers , . as the united nations' international health agency, the world health organization (who) has the mandate to support member states in preparing for and responding to a wide range of public health emergencies that often require that new technical guidance is developed in short timelines with scarce evidence base. following an urgent request from affected member states, who started the production of a ppe guideline for evd outbreaks in july , shortly before declaring the evd outbreak in west africa a public health emergency of international concern. a rapid review of the efficacy and comparative effectiveness of various components of ppe was commissioned in preparation for an expert panel meeting to develop recommendations on optimal ppe for health workers in ebola treatment units (etus) in outbreak settings. it became clear very early in the process that high quality efficacy and comparative effectiveness studies addressing the use of specific ppe items for evd in outbreak settings were lacking . in addition to the paucity of data, it was critically important to gather and include the perspectives of health workers who had "real-life" experience in etus in west africa. early reports of the local conditions indicated that broader clinical questions than ppe performance as a transmission barrier were as important: usability, comfort, dexterity and impact on communication with patients, for example. the underlying principle was that evidence from efficacy and comparative effectiveness studies was necessary but insufficient for contextualization and adequate decision-making. this approach highlights the importance of understanding the way individuals exercise judgement (values and preferences) when selecting options with potential benefits, harms, and inconveniences in real life and is current best-practice in who standard guidelines . values and preferences are often informed mainly by the opinion of guideline expert panel members, however such proxies for persons affected by the recommendations in a guideline are often inadequate or even inaccurate. thus, in the early stages of the - evd outbreak in west africa, in the context of time constraints and the absence of published data, it was crucial to incorporate the values and preferences of health workers into the guideline development process. the purpose of this study was to support the development process of a who rapid advice guideline on ppe for evd care in outbreaks. the specific objectives were to understand and describe frontline physician and nurses' perspectives about ppe use, while providing direct care for evd patients in the unprecedented conditions of the - evd outbreak in west africa and to incorporate these findings into the rapid advice guideline development process. in september , we electronically surveyed international frontline physicians and nurses who participated in foreign medical teams deployed to the affected countries in early stages of the evd outbreak. the pragmatic approach was necessary given that this survey was developed and delivered at the height of outbreak and that who had very limited time available in which to produce guidance. the online, -item survey was developed specifically for this study (supplementary file ). the first section consisted of multiple-choice questions examining participant demographic characteristics, role, and experience with ppe in west africa. the next section addressed health worker exposure to the following specific components of ppe: eye protection (goggles/face shields), nose and mouth protection (medical mask/particulate respirator), gloves (single/double gloves), body covering (gowns/ coveralls), foot wear (boots/closed shoes), and head covering (hair cover/hoods). in subsequent sections, we used a four or five-point likert-scale to examine participants' perceptions about the impact of each ppe item on the following domains: safety, communication, ability to provide patient care, personal wellbeing (heat and we have made changes to the text based on the referees' comments, in particular emphasizing the connection to oxidative stress in the abstract and expanding the discussion. in response to the suggestions and comments from the reviewers we have made several edits to our research paper. first of all, we have revised table by adding categories that were previously omitted from the table. for example, in version we only presented in the table the number health workers that indicated they felt at extremely low or low risk, but in version we have added a column indicating the number of health workers feeling at high or extremely high risk. we have also added a foot note explaining how the denominator in each cell reflects missing values for that particular question. we hope that this has improved the readability of the table. second, we have added some additional references to the literature on ppe in the discussion. finally, we have added a few small clarifications and moved some text to other sections in the paper. revised dehydration), and comfort. in addition, for each of the items, participants could provide free-text comments on open-ended questions to describe any difficulties or to provide suggestions on how ppe could be improved. the final section explored specific training needs and confidence in ppe. the last question asked participants to compare two sets of ppe available in west africa shown side-by-side in a picture: one was composed of lighter items and the other had more robust components. five experts reviewed the study protocol and questionnaire during the development phase. subsequently, three clinicians with experience in the evd outbreak in west africa similar to that of the sampling frame field-tested the survey for consistency, readability, completeness, and question sequencing. the final version of the online survey incorporated all relevant feedback and comments. we obtained expedited approval of the study protocol and survey from the who ethics review committee (rpc ). we contacted potential participants via email. the first email explained the objectives, expected time commitment, and provided a link to the informed consent form and online survey on survey monkey ® . participation was voluntary and implied informed consent. a follow-up email in days reminded potential participants of the deadline ( days after launching). participants could withdraw from the study at any time without providing any justification. the study population consisted of international frontline physicians and nurses with direct field experience caring for evd patients in west africa. our sampling frame targeted international physicians and nurses deployed by who and médecins sans frontières (msf) to west africa between march and september . we used maximum variation purposeful sampling, a non-probability sampling strategy, to capture a wide range of health worker perspectives and experiences in two organizations and four different countries affected by the evd outbreak. health workers were reached through a contact individual in each organization (msf and who) who directly emailed potential participants. physicians and nurses from the affected countries and from other international organizations were not included for pragmatic reasons given the extreme time constraints and infeasibility of obtaining additional organizational approvals in the available timeline. an initial communication error led to the participation of other groups of health workers that did not have frontline clinical experience. the perspectives of these workers were considered for who quality improvement efforts, but were excluded from this analysis as these groups were not part of the approved sampling frame for this study. participants could indicate their experience with more than one item for each ppe component (e.g., both goggles and face shields for eye protection). for the purpose of statistical analysis, we considered each participant's experience with a ppe item unique and independent (i.e. we did not account for the fact that the experience came from one and the same health worker). we analysed closed-ended questions with stata (statacorp. . college station, tx) using counts, proportions, and the chi-square test when comparisons were appropriate. two independent researchers analysed the answers to the openended questions using an iterative and reflexive process. this encompassed close reading and re-reading of the answers using constant comparison within and across different participants to identify key topics. the researchers then grouped the interpretations and understanding of the participants' ideas and selected quotes to represent these findings, discussing discrepancies to achieve agreement. immediately after data collection with the survey monkey ® instrument, all information was downloaded to an anonymized spreadsheet and removed from the online database. all analyses were performed on de-identified data. informing rapid advice guideline recommendations the rapid advice guideline was developed using the grading of recommendations assessment, development and evaluation (grade) approach , . with this approach, clinical and public health recommendations are based on a systematic review and critical appraisal of the evidence on benefits and harms of an intervention, and an assessment of the balance between the two. other considerations are also taken into account when an expert panel formulates recommendations, including feasibility, acceptability and resource implications of the intervention options, and the effects on equity across subpopulations. the relative value of the potential outcomes of the intervention options and the values and preferences of persons affected by the intervention are also important considerations. the findings of the survey were presented at the guideline development meeting and incorporated into evidence-to-decision tables (supplementary file ) to inform the formulation of recommendations for ppe components in the context of an evd outbreak. evidence-to-decision tables followed the grade-decide approach and were populated by the who guideline development team in preparation for the expert panel meeting. these tables were key instruments used to present multiple sources of information to the guideline expert panel, helping to structure the discussion and to document the final judgements and decisions that underpin each recommendation. we developed the study protocol, obtained who ethics approval, contacted the participants, delivered the survey, analysed the data, and presented the findings as part of the evidence-to-decision tables at the expert panel meeting where the recommendations were formulated in a period of weeks. we invited health workers ( from msf and from who) to participate in the survey and ( %) responded. respondents from msf included logisticians and water, sanitation and hygiene experts who were excluded because they were not part of the sampling frame. thus participants ( physicians and nurses) were included in the final analysis and their characteristics are described in table . for each of the different components of ppe, one item was used by the majority of survey participants (table ) . for example, ( %) of participants had experience using goggles, while only seven ( %) had used a face shield (some participants had experience with both types of eye protection). generally, health workers felt at low or extremely low risk regardless of the type of ppe used. ppe, particularly goggles, particulate respirators, and medical masks or hoods, impaired communication (table ) . a reduction in the ability to provide care was predominantly related to eye protection equipment -both face shields and goggles. heat and dehydration were a significant or major issue for participants using goggles ( %) compared to two ( %) using a face shield (p= . ), and for ( %) using a hood compared to none using a hair cover (p= . ). heat and dehydration also were a significant or major issue for the majority of individuals using a gown (n= , %) or coverall (n= , %); however, there was no significant difference between the two groups (p= . ). goggles were considered more uncomfortable (n= , %) than face shields (n= , %, p= . ) ( table ) . participants indicated that fogging of goggles or face shields was a major issue, affecting visibility and potentially creating a hazard for health workers as well as patients. there was some indication that fogging was a bigger issue with goggles and a few participants indicated that they would have preferred a face shield. two participants indicated that the goggles caused pain after using them for extended periods. a number of participants noted that goggles did not cover sufficient skin of the face and there were requests for larger goggles, which would have the added advantage of greater visibility. other issues were the poor quality of face shield and goggles, poor fit of goggles, and the logistical challenges of waiting to clean and dry re-usable goggles. one respondent summarized it as follows: "the goggles (are) not so comfortable and (they) felt like the "unsafe" part of the ppe. they move easily, hurt on the head, and affect vision in a negative way due to sweat, etc.". medical mask and the particulate respirator were reported to cause difficulty breathing when wet (due to sweat or condensation). one participant doubted the mask's effectiveness when wet. two participants were of the opinion that respirators were excessive since evd is not airborne. the main problem regarding gloves was the risk of having them slip down, allowing fluids to contact the skin as illustrated by the following respondent: "some people found using tape over gloves (the second pair) useful as sometimes they did roll down during arduous patient care activity and in the end i also did this". other participants also attempted to solve this problem by taping gloves to the coverall, however this occasionally resulted in the tearing of gloves or the coverall. it was also mentioned that gloves were not long enough and that they tore easily. difficulties included finding the right size coverall -in several instances the available coveralls were too small, leaving the health worker to opt for a coverall of lesser quality or have difficulties removing the coverall. a number of health workers indicated that they had difficulty taking off the coverall. specific issues included having to remove the face shield first, leaving the eyes and face unprotected while undressing from the coverall, and problems taking off the coverall over large rubber boots. one respondent mentioned that coveralls with attached shoe covers could increase the risk of tripping. one respondent commented that boots were too big causing difficulty walking on irregular ground. as for reusable items (goggles and boots), it was mentioned that the time required to fully decontaminate and dry them sometimes brought challenges and put pressure on the team. training on ppe use a third of survey participants had received formal training over to days (n= , %) and four ( %) reported training duration of more than days. on the other hand, % (n= ) had received no formal or on-the-job training and another % (n= ) reported training for hours or less. the remaining % of study participants (n= ) had training of one day or less. a number of participants commented that they would have liked to have had training, more formal training, or longer training. others indicated that they would have liked to receive training before their departure, or before arriving at the treatment centre. the training topics that the survey participants would have liked included were the removal of ppe, and, how to manage eye glasses. one health worker recommended weekly refresher training, especially in the light of frequent equipment changes, which may impact the order items are put on and taken off. another health worker commented: "i believe that only experienced people can teach about ebola. teaching on the use of ppe is not about dressing and undressing. it is about using a set of behaviours with it and the understanding of all the underlying water and sanitation principles and applying them". regarding hand hygiene, alcohol-based hand-rub was not always available and there was conflicting information in different settings about which product to use. the majority of participants (n= , %) were very confident that they were using ppe correctly, ( %) were reasonably confident and ( %) was not very confident. generally, participants were least confident about goggles (fogging, moving/displacing), medical masks and particulate respirators (difficulty breathing, becoming uncomfortable), and gloves (rolling down, tearing). removing ppe was also an area that people felt less confident about (e.g., taking arms and feet out of a coverall, lack of face protection during undressing if the face shield was worn outside the hood). as one health worker illustrated: "taking off the (tyvek suit) coverall was difficult due to my height; it required me to wiggle out of it more than the average person". a respondent also mentioned feeling less confident working in the screening area where much lighter ppe was worn, while possibly also being exposed to infectious patients. when asked to indicate their preference regarding two sets of ppe depicted in a picture, ( %) participants preferred the ppe that was composed of lighter items, ( %) participants preferred the more robust components, ( %) did not have a preference and one participant did not respond to the question. the - evd outbreak in west africa required extensive local and international response and for the first time since evd was described in , a large number of organizations were directly involved in clinical and laboratory activities in the field. these interactions highlighted differences in the selection and use of ppe across the organizations. early on in the outbreak, when the cases of health worker transmission were numerous and confusion about the best available equipment was wide-spread, who was asked to provide technical guidance in a short period of time. when a public health emergency involves a new disease, or a known disease with a different presentation, there may be scarce or no evidence on the benefits and harms of potential interventions. indirect evidence (e.g., from related diseases such as other blood-borne pathogens and simulation), expert opinion, and data acquired and analysed in real-time may become the best available evidence for the guideline panel. in addition, factors other than the effectiveness of interventions may have a significant influence on the direction and strength of the recommendations. such was the situation in during the height of the evd outbreak in west africa; a rapid review of the effectiveness of different types of ppe for protecting health workers revealed insufficient evidence upon which to draw conclusions about optimal ppe . in this context and within a period of weeks, we developed and executed a survey, the results of which formed a critical part of the evidence upon which the recommendations developed by the expert panel were based . to the best of our knowledge, this approach of collecting primary data regarding the values and preferences of persons affected by clinical or public health recommendations in a guideline is novel in the extremely challenging setting of a public health emergency. overall, our findings showed that health workers perceive a balance between transmission protection and the ability to effectively care for complex patients while using ppe. health workers accept a certain degree of discomfort in return for the protection provided by ppe. the survey highlighted a slight preference of health workers for face shields compared to goggles because of less fogging, easier communication and better fit. there was no strong preference for one item of ppe over the other for all other ppe components. given the variation in preferences for different components of ppe and the absence of data on comparative effectiveness, it may be important to provide a choice for health workers. this was, in fact, a guiding principle during the development of the ppe guidelines. several issues raised by survey participants should be relatively straightforward to address, making a major contribution to health worker safety and comfort, such as providing a sufficient range of sizes, choice of equipment, and adequate training on how to put on and take off ppe in the conditions that will be faced in the field. active training, in which health workers receive face-to-face training has been shown to improve doffing procedures . we experienced a number of challenges planning and executing this study. we had to develop a survey questionnaire de novo with limited time for field testing. although this likely had a minimal impact on the results, we noted two questions that participants appeared to have difficulty comprehending (questions and ; see supplementary file ); if we had had more time for field testing we could have revised the questionnaire before formal data collection began. while our aim was to include only health workers who had provided direct patient care, such as nurses and physicians, given a communication error early in the study, we invited to participate and consequently received responses from workers without direct clinical experience who had been deployed to the evd outbreak. because these workers were not part of our pre-defined sampling frame, we excluded their responses from the analysis. similarly, our survey failed to take into account the fact that ppe consists of different components such as eye protection, nose and mouth protection, gloves and body coverings that work together to protect the health worker from the risk of infection. in the first part of our questionnaire we asked how the survey participant experienced individual components of ppe (e.g., goggles or face mask). however, it is difficult to review these components as isolated items, separate from the rest of the ppe. as one survey participant noted: "it is the combination of the respirator and the face shield which is difficult. one or the other would be manageable but both together meant major impairment". another survey participant commented: "the coverall would probably be better tolerated if we could breathe easier and see without problems". in addition, although we compared gowns and coveralls, we did not specify or ask about the materials the body coverings were made of, its level of fluid resistance, or whether the head cover was attached or not. such issues can have a significant impact on health workers' experiences. for example, a simulation study carried out in hong kong in response to the outbreak of severe acute respiratory syndrome (sars) found that ppe made of more breathable material did not lead to a significant difference in contamination but did have greater user satisfaction , . it also became clear that solutions to an issue with one component of ppe could compromise the safety of another element of ppe. for example, participants mentioned that they would improvise and tape gloves to the coverall in order to prevent them from slipping down, but then the coverall would tear when removing the tape. finally, the combination of different components of ppe may change the order in which ppe items are put on and taken off, thus end-users may perform donning and doffing procedures that are different than the training they received. this is particularly relevant if there are frequent changes in the availability of specific types of ppe, as was the case early in the outbreak response. most of the limitations of this study were caused by pragmatic decisions the research team had to make in order to complete the study in the available time. this was in and of itself an invaluable learning experience for undertaking similar projects in the future. specifically, we had to include only international health workers deployed by who and msf in our study; therefore, we did not collect information on the values and preferences of local health workers and health workers deployed by other organizations. there were two important reasons as to why we selected our sampling frame. first, we carried out the survey at the height of the evd epidemic when local doctors and nurses were fully engaged in the response efforts and we refrained from removing them from their primary work. internationally recruited health workers on the other hand, were usually deployed for shorter periods and could thus participate when they returned home. second, we had little time in which to execute the survey before the guideline meeting and we anticipated that it would be a lengthier and more complex process to identify and recruit local health workers. thus, the findings of this survey may not be applicable to local health workers. in addition, generalizability of our findings to other international health workers involved in the ebola response may be limited due to the small size of our purposive sample. in the context of the most challenging of research settings, our study proceeded very efficiently and effectively in several regards. peer reviewers for both the study protocol and draft survey made very helpful comments within to days. the who ethics review committee approved the survey in less than two weeks. by reaching out to several key managers and opinion leaders from the two organizations, we were quickly able to identify frontline clinicians that were part of the sampling frame. the online format of the survey allowed us to quickly reach a larger number of health workers in different countries who had recent personal experience with different types of ppe in the evd outbreak. the combination of different types of questions in our survey also worked well. closed and likert-scale questions made analysis of trade-offs and comparisons of health workers' preferences possible while open-ended questions allowed the survey participants to share additional thoughts and perspectives in more depth. our study highlights some of the challenges and potential limitations and demonstrates the feasibility of generating and incorporating primary data on end-users' values and preferences into a rapid advice guideline developed during the height of a public health emergency with extreme field conditions. our survey showed that health workers perceive a balance between transmission protection and their ability to effectively care for patients while wearing ppe. these findings were a critical part of the information used by the guideline development expert panel when formulating recommendations on ppe for frontline health workers caring for evd patients in outbreak conditions. we obtained expedited approval of the study protocol and survey from the world health organization ethics review committee (rpc ). as approved by the ethics committee, we provided a link to the informed consent form with the survey. participation was voluntary and implied informed consent. supplementary file : study questionnaire. click here to access the data. supplementary file : evidence-to-decision tables used in the formulation of recommendations for the who rapid advice guideline: personal protective equipment in the context of filovirus disease outbreak response. click here to access the data. author response mar , world health organization, switzerland saskia den boon i had difficulty reading the tables in the article. i thought maybe it was the way they were displaying on my computer, but nothing seemed to change when i clicked on them. please make these charts simple to read and clear. i need to see the tables to make sure your findings are adequately described. thank you for reviewing and approving our paper. we assume that you are author's response: referring to table . we have revised the table by adding the categories that were previously omitted from the table. for example, in version we only presented in the table the number health workers that indicated they felt at extremely low or low risk, but in version we have added a column indicating the number of health workers feeling at high or extremely high risk. we have also added a foot note explaining how the denominator in each cell reflects missing values for that particular question. we hope that this has improved the readability of the tables. the article is really well written. i was very pleased with the quality of the writing and the honesty of the authors about their challenges. this is important work in the area of ppe use. thanks for these kind words about our study. author's response: while i know that this was quick work in a difficulty setting, i still feel like the article needs to do justice to personal protective equipment research of the past years (at least since sars). the major section that needs more referencing is the discussion section. how do your findings compare to what we have found in epidemiological studies, simulation studies, and others on ppe. even if these studies were not done in the context of an outbreak of evd in africa, they should still be discussed. there is literature on some of these areas that would bring worthwhile context to your findings. thanks for this suggestion. we have added a number of references to the author's response: literature to our discussion section. well written paper on an important and largely ignored subject: 'health workers perspectives for guidelines'; also on top global health issue 'ebola virus disease'. study process was speedy and appropriate for the urgency needed for guidelines to be developed making this a good learning experience. however, there are a few points of attention listed below. i have also highlighted the sections relevant to my comments . here 'the - evd outbreak in west africa was initially declared a public health emergency of international concern in early august , coinciding with the decision to develop a who rapid advice guideline on the selection and use of ppe for evd care in outbreaks.' this statement will fit more within the background section, consider moving into background. 'we electronically surveyed international frontline physicians and nurses who participated in foreign medical teams deployed to the affected countries in early stages of the evd outbreak.' clearly stating time frame in the methods section within which survey was done will also be helpful for readers, although a time frame is given later under participants, it is not clear if this was for survey or the sampling. this time frame is also very early in the outbreak aq : settings is not well described, consider discussing setting in more detail under a separate title. clinicians express discomfort and safety, it may be interesting to know if at some point in the interviews they weighed in on safety versus comfort e.g. will the feeling of safety make them cope with discomfort? or does discomfort make safety inconsequential? i have answered 'partly' to the question "is the work clearly and accurately presented and does it cite the current literature?" as a small part of the methods may benefit clarity if texts are moved around. i have answered 'partly' to the question "are the conclusions drawn adequately supported by the results?" as it will be important to discuss discomfort versus safety of risk or clearly state if this was not evaluated by the study. this is an interesting piece and important in the context of infectious diseases. i will like to appreciate the authors for taking the initiative during such an emergency to collect such data. i will recommend the paper to be considered for indexing especially as it contributes towards developing guidelines for ppe which was more of a challenge to health workers during the outbreak. understanding their challenges and experiences especially in very humid temperatures is important. most importantly, the outbreak was a remarkable and most catastrophic outbreak. thus, using the outbreak as a point of focus adds value to the work considering that it pulled health workers from various countries. the work considering that it pulled health workers from various countries. why only physicians and nurses perspectives regarding ppe? i understand the relative risk for physicians and nurses as frontline workers is high, but other health workers are involved, and have recorded fatality rates, their experiences with ppe may also add value especially in the context of developing guidelines. maybe the authors should consider adding this to limitations. four or five likert is not explicit; it does not tell which questions were measured using scales of four and which used five and how they way categorize for-example., indicating low or high? agree or somewhat agree? understand the sample size was small and is actually mentioned as a limitation, however, any data on number of nurses and physicians that were deployed by who and msf during the period of data collection for background purposes and to justify the limitation? the sentence under data analysis is not clear to me, maybe rephrasing to better explain to the audience "for the purpose of statistical analysis, we considered each participant's experience with a ppe item unique and independent." the survey assumes that all the participants speak and write english? language characteristic not mentioned considering that these affected countries some are french countries. if all participants were not english speaking how was it translated? especially as the authors mentioned that respondents could not comprehend some questions due to time constraint. the literature highlights some gender differences for ppe amongst physicians and nurses especially in african context-assuming nurses are mostly women and physicians men--it would have been good to explore differences between nurses and physicians with regards to the specific ppe used. were physicians exposed to more sophisticated ppe than nurses? other comments that may be of interest to the authors: i understand the limitation of the paper is focused on participants in ebola treatment centers and only foreign deployed. however, guidelines should take into consideration local reality in terms of culture? based on previous outbreaks, most families prefer to care for patient at home and given the limited resources in this context; local materials were used at home in as ppe . http://www.cnn.com/ / / /health/ebola-fatu-family/index.html given the reality of limited resources, and the fact that most families prefer to care for patient at home it would add more value also to consider experiences of those who cared for patient at home, the type of ppe used and opportunities in incorporating local reality into evidence-based guidelines for ppe. if applicable, is the statistical analysis and its interpretation appropriate? yes settings is not well described, consider discussing setting in more detail under a separate title. we are not sure how to respond to this question of the reviewer. we did an author's response: online survey among health workers who were deployed by msf or who to respond to the ebola outbreak in west africa early on in the epidemic. health workers worked in local hospitals, clinics or ebola treatment centers, but because we did not ask further information about these settings we cannot provide a more detailed description. clinicians express discomfort and safety, it may be interesting to know if at some point in the interviews they weighed in on safety versus comfort e.g. will the feeling of safety make them cope with discomfort? or does discomfort make safety inconsequential? we assume that the reviewer is referring to question which asked, "please author's response: indicate how safe you felt by ticking a box for each aspect of personal protective equipment". as we have stated in the discussion, survey participants had difficulty answering this question because of the way the answer categories were phrased, e.g. "extremely low risk, i felt comfortable". in this answer category we wanted comfortable to mean "i am not worried about safety", but this was sometimes interpreted as "i am physically comfortable (e.g. not overheated, etc.)". if we had had more time for piloting, we would have been able to pick this up before sending out the survey. however, through comments from health workers it became clear that they indeed cope with discomfort because the ppe makes them feel safe and we have added the following sentence to the discussion: "health workers accept a certain degree of discomfort in return for the protection provided by ppe". i have answered 'partly' to the question "is the work clearly and accurately presented and does it cite the current literature?" as a small part of the methods may benefit clarity if texts are moved around. we hope that our amendments have improved the methods section. author's response: i have answered 'partly' to the question "are the conclusions drawn adequately supported by the results?" as it will be important to discuss discomfort versus safety of risk or clearly state if this was not evaluated by the study. we hope that our amendment has taken away the concern of the reviewer. author's response: this is an interesting piece and important in the context of infectious diseases. i will like to appreciate the authors for taking the initiative during such an emergency to collect such data. i will recommend the paper to be considered for indexing especially as it contributes towards developing guidelines for ppe which was more of a challenge to health workers during the outbreak. understanding their challenges and experiences especially in very humid temperatures is important. most importantly, the outbreak was a remarkable and most catastrophic outbreak. thus, using the outbreak as a point of focus adds value to the work considering that it pulled health workers from various countries. thank you for reviewing our paper and for making helpful comments and author's response: thank you for reviewing our paper and for making helpful comments and author's response: suggestions. see below our responses. why only physicians and nurses perspectives regarding ppe? i understand the relative risk for physicians and nurses as frontline workers is high, but other health workers are involved, and have recorded fatality rates, their experiences with ppe may also add value especially in the context of developing guidelines. maybe the authors should consider adding this to limitations. we agree with the reviewer about the importance of ppe for other health author's response: workers, for example cleaners, laboratory workers, burial teams and other workers. however, the focus of the who guideline which our study aimed to inform, was on healthcare workers and therefore we also focused our survey on this group. four or five likert is not explicit; it does not tell which questions were measured using scales of four and which used five and how they way categorize for-example., indicating low or high? agree or somewhat agree? we agree with the reviewer that it would have been better to have used a author's response: comparable (e.g. -point scale) for all the questions. if we had more time for piloting, we may have picked this up before sending out the survey. now, the questions on safety and comfort had a -point scale and questions on communication, ability to provide care, and heat and dehydration had a -point scale. as can be seen in the questionnaire which is included in the supplementary material, we did not use coding in the answer categories. understand the sample size was small and is actually mentioned as a limitation, however, any data on number of nurses and physicians that were deployed by who and msf during the period of data collection for background purposes and to justify the limitation? as stated in the results section, we invited health workers ( from msf author's response: and from who) to participate in the survey, but this included health workers outside the sampling frame (e.g. logisticians and water, sanitation and hygiene experts). unfortunately we do not have more detailed information on numbers deployed. the sentence under data analysis is not clear to me, maybe rephrasing to better explain to the audience "for the purpose of statistical analysis, we considered each participant's experience with a ppe item unique and independent." we have now added the following clarification to the methods section: "i.e. we author's response: did not account for the fact that the experience came from one and the same health worker". the survey assumes that all the participants speak and write english? language characteristic not mentioned considering that these affected countries some are french countries. if all participants were not english speaking how was it translated? especially as the authors mentioned that respondents could not comprehend some questions due to time constraint. yes, this is correct. we assumed that all participants could speak and write author's response: english and we did not translate the questionnaire. the miscomprehension was due to the fact that two questions were not phrased clearly, rather than the language skills of the survey participants. the literature highlights some gender differences for ppe amongst physicians and nurses especially in african context-assuming nurses are mostly women and physicians men--it would have been good to explore differences between nurses and physicians with regards to the specific ppe used. were physicians exposed to more sophisticated ppe than nurses? ppe used. were physicians exposed to more sophisticated ppe than nurses? this is a very interesting question. although our study was not designed to author's response: answer this question and the number of participants was too small to do any stratified analysis, i had a brief look at the data. we indeed found a higher proportion of physicians among males ( %) than among females ( %), but there were no obvious differences in robustness of ppe, when i compared gown or coverall use between males and females, or between physicians and nurses (varying between - % using a gown). other comments that may be of interest to the authors: i understand the limitation of the paper is focused on participants in ebola treatment centers and only foreign deployed. however, guidelines should take into consideration local reality in terms of culture? based on previous outbreaks, most families prefer to care for patient at home and given the limited resources in this context; local materials were used at home in as ppe . http://www.cnn.com/ / / /health/ebola-fatu-family/index.html given the reality of limited resources, and the fact that most families prefer to care for patient at home it would add more value also to consider experiences of those who cared for patient at home, the type of ppe used and opportunities in incorporating local reality into evidence-based guidelines for ppe. we acknowledge the importance of this issue brought up by the reviewer but it author's response: fell outside the scope of the study and the who guideline that we were aiming to inform. the benefits of publishing with f research: your article is published within days, with no editorial bias you can publish traditional articles, null/negative results, case reports, data notes and more the peer review process is transparent and collaborative your article is indexed in pubmed after passing peer review dedicated customer support at every stage for pre-submission enquiries, contact research@f .com report of a who/international study team we thank the following people for providing invaluable comments on the project proposal and questionnaire: patricia hudelson, gordon guyatt, martine verwey, doris bacalzo and elie akl. we are grateful to armand sprecher from médecins sans frontières for sending the questionnaire to his staff during the peak of the outbreak response. we are also grateful to the survey participants for making this study possible. participants could withdraw from the study at any time without providing any justification. due to the small number of survey participants, the detailed information collected, and the terms in the consent form approved by the who ethics review committee, which guaranteed participant anonymity, the individual-level data cannot be made available. requests for raw data can be dealt with on a case-by-case basis by contacting the corresponding author dr den boon, who will facilitate enquiries to the who ethics review committee.competing interests sdb and cv declare no competing interests. mf declares that his spouse is an employee at bristol myers squibb and owns company stock as part of her remuneration plan. sln declares that she is a member of the grading of recommendations assessment, development and evaluation (grade) working group, has published numerous papers related to grade, and that her career has benefited from this relationship. grade is the guideline process used by her employer, the world health organization, to develop guidelines. this study was funded by who core funds. no external funding was obtained.the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. i had difficulty reading the tables in the article. i thought maybe it was the way they were displaying on my computer, but nothing seemed to change when i clicked on them. please make these charts simple to read and clear. i need to see the tables to make sure your findings are adequately described. the article is really well written. i was very pleased with the quality of the writing and the honesty of the authors about their challenges. this is important work in the area of ppe use.while i know that this was quick work in a difficulty setting, i still feel like the article needs to do justice to personal protective equipment research of the past years (at least since sars). the major section that needs more referencing is the discussion section. how do your findings compare to what we have found in epidemiological studies, simulation studies, and others on ppe. even if these studies were not done in the context of an outbreak of evd in africa, they should still be discussed. there is literature on some of these areas that would bring worthwhile context to your findings. are all the source data underlying the results available to ensure full reproducibility? yes no competing interests were disclosed. are all the source data underlying the results available to ensure full reproducibility? yes no competing interests were disclosed. competing interests: we have read this submission. we believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. well written paper on an important and largely ignored subject: 'health workers perspectives for guidelines'; also on top global health issue 'ebola virus disease'. study process was speedy and appropriate for the urgency needed for guidelines to be developed making this a good learning experience. however, there are a few points of attention listed below. i have also highlighted the sections relevant to my comments . here thank you for reviewing and approving our paper. see below our responses to author's response: your comments. we have made a number of changes in the text in response to your comments. 'the - evd outbreak in west africa was initially declared a public health emergency of international concern in early august , coinciding with the decision to develop a who rapid advice guideline on the selection and use of ppe for evd care in outbreaks.' this statement will fit more within the background section, consider moving into background.we removed this sentence from the methods section and have added it, author's response: slightly modified, to the background section. 'we electronically surveyed international frontline physicians and nurses who participated in foreign medical teams deployed to the affected countries in early stages of the evd outbreak.' clearly stating time frame in the methods section within which survey was done will also be helpful for readers, although a time frame is given later under participants, it is not clear if this was for survey or the sampling. this time frame is also very early in the outbreak we send out the request for participation in september and have added author's response: this to the methods section. later we indicate that the survey was open for a -day period. the health workers eligible for participation were those who were deployed to west africa between march and september which was already stated in the methods section under participants. settings is not well described, consider discussing setting in more detail under a separate title. key: cord- - p n tjx authors: lambe, teresa; bowyer, georgina; ewer, katie j title: a review of phase i trials of ebola virus vaccines: what can we learn from the race to develop novel vaccines? date: - - journal: philos trans r soc lond b biol sci doi: . /rstb. . sha: doc_id: cord_uid: p n tjx sporadic outbreaks of ebola virus infection have been documented since the mid-seventies and viral exposure can lead to lethal haemorrhagic fever with case fatalities as high as %. there is now a comprehensive body of data from both ongoing and completed clinical trials assessing various vaccine strategies, which were rapidly advanced through clinical trials in response to the – ebola virus disease (evd) public health emergency. careful consideration of immunogenicity post vaccination is essential but has been somewhat stifled because of the wide array of immunological assays and outputs that have been used in the numerous clinical trials. we discuss here the different aspects of the immune assays currently used in the phase i clinical trials for ebola virus vaccines, and draw comparisons across the immune outputs where possible; various trials have examined both cellular and humoral immunity in european and african cohorts. assessment of the safety data, the immunological outputs and the ease of field deployment for the various vaccine modalities will help both the scientific community and policy-makers prioritize and potentially license vaccine candidates. if this can be achieved, the next outbreak of ebola virus, or other emerging pathogen, can be more readily contained and will not have such widespread and devastating consequences. this article is part of the themed issue ‘the – west african ebola epidemic: data, decision-making and disease control’. the - epidemic of ebola virus disease (evd), in west africa, was unprecedented in both scale and spread. the case count and death toll has surpassed the total number of cases for all previous known outbreaks. this epidemic has caused more than deaths with more than cases: figures widely thought to be underestimated [ ] . development and deployment of efficacious evd therapeutics and vaccines could have played a more significant role in limiting the - outbreak and remain a priority for the prevention of future evd epidemics [ ] . the family filoviridae includes marburg and five ebolaviruses, named for their location of recognition: zaire (now known as ebola virus, ebov), sudan (sudv), reston (restv), taï forest (tafv) and bundibugyo virus (bdbv) [ ] . the single protein expressed on the surface of filoviruses, the glycoprotein (gp), is antigenically and immunologically important and is frequently therapeutically targeted. however, bioinformatics analysis, at the structure-based and amino acid level, demarcates limited regions of homology in gp [ ] and also large areas of divergence particularly in the head domain of gp. it is therefore unclear if exposure to one member of the family filoviridae confers cross-protective immunity. it is unclear if the immune response involved in ebola virus clearance is dependent on a single aspect of the immune system (cellular or humoral immunity) or if a multifaceted response is a prerequisite and at present there is no clear correlate of protection for evd. indications from experimental infection of vaccinated non-human primates suggest a role for gp-specific igg and cd þ t cells [ , ] , and the limited analyses of convalescent samples suggest that the presence of ebola virus-specific igg and intact cell-mediated immunity (cmi) are associated with survival from natural infection [ ] [ ] [ ] . these observations are supported by immunological analysis of survivors from the current outbreak, which indicates a multi-faceted response is induced post-infection with strong humoral immunity and significantly pronounced transcriptional changes in cd þ t cells in response to several ebola virus proteins [ ] . evd vaccine development has been well established since the discovery of ebola virus and a number of different vaccine platforms have been used, resulting in at least one efficacious vaccine. these vaccine platforms include dna, recombinant or subunit proteins, virus-like particles (vlps) and recombinant viral vectors. a number of these vaccines have advanced past pre-clinical testing and are undergoing clinical testing; generally, those modalities that have demonstrated efficacy or high levels of immunogenicity in pre-clinical models. the most clinically advanced vaccines against evd are based on generating immune responses toward gp with trials ongoing in europe, the usa and africa. there are eight vaccines in clinical trials, all targeting the ebola virus gp, with some regimens employing a single dose and others using two vaccines in a heterologous prime-boost approach. prime-boost regimens have been shown to be more immunogenic than single-dose vaccinations for diseases such as malaria; however, there are financial and logistical implications associated with administering two vaccines [ ] . the ebola virus vaccines that are currently being assessed differ in the qualitative immune response postvaccination, which may be due to the use of alternate vaccine platforms. indeed, while humoral immunity may be critical for protection post vesicular stomatitis virus (vsv)-vectored vaccines in non-human primates (nhps), cmi may be key post single-shot adenovirus vectored vaccines [ ] . as both humoral and cellular immunity have been demonstrated to be protective in nhp, and are induced in man post-ebov infection, a vaccine regimen which induces long-lived and sustainable levels of cmi and antibodies is desirable. primarily, and finally, only those vaccines that are safe, efficacious and deployable will be field-effective, therefore only vaccine candidates that have progressed to published phase i studies will be reviewed here. clinical trials where results were published in peer-reviewed journals by july are summarized in table . ebolavirus disease the earliest clinical studies of vaccines against evd used plasmid dna encoding the nucleoprotein from the zaire ebolavirus and the glycoproteins from ebov and sudv [ , ] . although well tolerated with mostly mild and short-lived adverse events (aes), dna vaccines tend to be poorly immunogenic and have been largely superceded by subunit proteins, recombinant viral vectors and vlps in several vaccine development fields, including ebola virus [ ] . the vaccines most progressed for the prevention of evd use viral vector platform technology and use either the adenovirus, modified vaccinia virus ankara or vesicular stomatitis virus backbones. recombinant human serotype adenovirus (adhu ) vectors encoding gp have been evaluated in single-dose studies and have shown very acceptable safety profiles. unfortunately, adhu -seropositive volunteers demonstrated statistically significantly lower gp-specific igg titres [ ] . increasing the administered dose of vaccine appears to overcome pre-existing immunity to this serotype; however, this is associated with increased reactogenicity [ ] . unfounded concerns also still persist about a potential increase in hiv- infection rates among adhu -seropositive vaccinees, based on data from two phase ii studies of the merck rad hiv- gag/pol/nef vaccine (the step and phambili trials) [ ] [ ] [ ] . use of rarer serotypes of human adenoviruses, such as ad and adhu , can bypass pre-existing immunity [ ] and have demonstrated acceptable safety and tolerability profiles. the most widely evaluated adenoviral vector evd vaccines are based on a simian adenovirus serotype backbone (chad ) encoding either ebolavirus glycoprotein alone [ , ] and administered as a single shot or as a mixture of chad ebov and chad sudv vaccines [ ] . between september and january , four phase i studies of these vaccines were undertaken, one each in the us, uk, switzerland and mali. replication-deficient chimpanzee adenovirus vectors have been extensively evaluated as candidate vaccines for malaria, hiv, hcv, rsv, influenza and tuberculosis, in adults, children and infants, with no safety concerns [ ] . safety profiles were similar for candidate ebola virus vaccines, with higher doses eliciting more aes; however, aes were mostly graded as mild, resolving within h of vaccination. an additional vaccine modality being tested is modified vaccinia ankara (mva); both unmodified and recombinant mva vectored vaccines have been evaluated extensively as vectors for smallpox, malaria, flu and tb vaccines with excellent safety demonstrated in immunocompetent and hiv-infected participants [ , ] . in pre-clinical trials, chad was observed to provide % protection when nhps were challenged with ebola virus shortly after vaccination; however, an mva boost was required to enable uniform protection when challenge occurred months after priming vaccination. this increased durability of protection was attributed to the superior effector and memory cd þ t cell responses elicited by the mva boost [ ] . owing to the superior durability of protection demonstrated by the prime-boost regimen in preclinical trials, several phase i clinical trials were initiated to test this regimen in humans. mva-bn filo is a recombinant, replication-deficient mva vector, encoding ebov, sudv and marburg glycoproteins as well as tafv nucleoprotein. two clinical trials have assessed a chad prime with mva-bn filo boost, demonstrating acceptable safety profiles and significantly enhanced cellular and humoral immunogenicity compared with a single-shot chad vaccination [ , ] . the other vaccine modality being assessed as an ebola vaccine candidate is the recombinant vesicular stomatitis virus encoding ebov glycoprotein (rvsv-zebov), which is an attenuated replication-competent viral vector. unmodified vsv causes either asymptomatic infection or a mild, flu-like illness in humans [ ] ; however, truncation of the vsv glycoprotein results in an attenuated, avirulent form that has been shown to be safe in pre-clinical studies in macaques and mice with no evidence of viral shedding [ ] . a rvsv hiv- gag vaccine has also generated acceptable safety data in two phase i studies [ , ] . candidate vaccines using these vectors also elicited protection against both ebola and marburg viruses in a nhp model where several rvsv each encoding a single filovirus glycoprotein were mixed and injected in a single dose that elicited protection against a lethal challenge [ ] . six phase i studies of rvsv-zebov were initially performed between october and january , two in the us and one each in kenya, gabon, switzerland and germany [ , ] . almost all participants displayed transient rvsv viraemia, starting at day , and lasting beyond day in around % of participants, with mostly mild and moderate aes lasting up to h on average. in total, % ( / ) of participants across the six trials had documented fever after vaccination, significantly higher than the % observed after vaccination with chad ( / , p ¼ . , two-tailed fisher's exact (prism version , graphpad software)). although both vaccines have been evaluated across a range of doses, post-immunization fever levels are an important consideration for a vaccine that may be deployed in an outbreak of a highly febrile illness, such as evd. in the geneva trial, of participants developed arthritis lasting a median of days, with virus subsequently identified in synovial joint fluid, indicating peripheral viral replication; two cases of shorter duration were identified among participants in the other studies. a further study in geneva where a much lower dose of rvsv-zebov was evaluated in a further volunteers resulted in much lower total igg and neutralizing antibody titres and was again associated with arthritis in % of participants [ ] . transient arthritis is often observed after immunization with commonly used live vaccines, such as rubella [ ] ; however, when rvsv-zebov progressed to a large-scale phase iii cluster-randomized efficacy trial, this particular adverse event was not reported and, in addition, in an interim analysis the vaccine elicited high levels of efficacy in evd-exposed participants [ ] . incidence of post-vaccination fever in that study has not yet been reported. in summary, all of the candidate vaccines for evd that progressed to phase i studies in response to the - outbreak demonstrated acceptable safety profiles; therefore, describing the magnitude and characteristics of vaccine-induced immunity was the next scientific aim. in the absence of any gold standard for measuring humoral immunity against ebola virus, a wide variety of assays were used to evaluate antibody responses to vaccines during the recent evd outbreak. binding assays were used to quantify antibody binding to recombinant protein or inactivated whole virion while neutralization assays were used to assess the functional capacity of antibodies. binding assays, particularly enzyme-linked immunosorbent assays (elisas), are commonly used to assess the quantity of antigen-specific antibody induced post-vaccination and can additionally be used to measure qualitative aspects of the humoral immune response such as isotype profiles and in vitro avidity. ebolavirus outbreaks occur sporadically and have previously been considered too limited in size to enable assessment of vaccine efficacy prior to regulatory approval. in , the usa food and drug administration (fda) introduced the 'animal rule' enabling data from pre-clinical trials to be used to demonstrate efficacy when human trials were not possible as an alternative licensing route for drugs and vaccines against highly lethal diseases [ ] . despite the wide use of elisa assays to measure antiglycoprotein igg responses, the majority of phase i studies used an array of different antibody binding assays to assess the quantity and quality of the antigen-specific antibody response induced by vaccination (table ). the use of different assays conducted in different laboratories following different protocols hinders the comparison of humoral immunogenicity induced by different vaccine candidates. key differences in these assays that affect comparability of results include the use of glycoprotein from different strains of zaire ebola virus (kikwit, makona or mayinga), use of whole virion or recombinant protein and the use of different read-outs or units. centralized standard assays or readily available biological standards for a range of emerging pathogens would be useful tools to aid decision makers in choosing the most promising candidate to take forward for further testing and rapid deployment during outbreaks. a who reference reagent for anti-ebov igg has been established by the who expert committee on biological standardisation (ecbs) for use as a reference standard in humoral immunoassays including neutralization and elisas against ebola virus [ ] . it is now freely available from the national institute for biological standards and control (nibsc, uk) and should facilitate retrospective comparison of responses between different trials. to aid in the comparison of immunogenicity across trials, samples from a recent phase i trial of chad mva-bn filo [ ] were run on a large number of these assays and correlation analyses were conducted (table ) . a lack of correlation between some of these assays may indicate that they measure different aspects of the humoral immune response and may therefore correlate differently with protection. for example, the competition elisa used by ewer and co-workers did not correlate with neutralizing titre to live ebola virus mayinga strain or several of the glycoprotein elisas. the competition elisa measures the ability of anti-ebov antibodies in a sample to compete with the monoclonal ebov antibody (mab) g and therefore only detects activity against a single gp epitope. the lack of a correlation with neutralizing titre may indicate that antibodies binding to this epitope are non-neutralizing and that the protection that has been observed when this mab has been used in a mab cocktail in nhp models is conferred by an alternative mechanism [ ] . many of the other binding assays used in these phase i trials correlate strongly and, in particular, it is useful that the standardized glycoprotein elisa and pseudotyped lentivirus assays each correlate strongly with neutralizing titres against live ebola virus as these assays avoid the need to work at high containment levels, but may be used to indicate the presence of antibodies with neutralizing activity. in a pre-clinical nhp model, igg responses after immunization with adhu -based ebola virus vaccines were measured using an elisa against gp, where % protection against a lethal challenge was predicted by titres of or greater, while a titre of around predicted % survival. at an interim analysis of the phase iii ring vaccination study of rvsv-zebov in guinea estimated vaccine efficacy in this trial to be % [ ] . no immunogenicity data were published for this trial, due to logistical difficulties associated with collecting biological samples, therefore, it is unclear which components of the immune response to vaccination mediated this protective effect. however, phase i trials of the same vaccine at the same dose, in the usa, induced igg against zaire-mayinga gp with a geometric mean titre (gmt) of ( % ci: - ) [ ] at day post-vaccination, which is probably higher than the level achieved - days post-vaccination by which time no new cases were observed in the rvsv-zebov ring vaccination trial. a gmt of is well below the titre required to protect % of non-human primates in the experimental model. chad zebov given at a dose of  viral particles (vp) induced titres comparable to those induced by rvsv-zebov, with day gmts of ( % ci: - ) in us adults and ( - ) in malian adults [ ] . peak titres after chad is boosted with mva zebov were significantly increased to ( - ) [ ] . although the use of different assays (summarized in table ) limits comparison of immunogenicity across clinical trials, there is still much to be learnt from comparisons of groups within trials. desantis and co-workers showed a limited dose effect on anti-gp igg titres, as assessed through elisa, when chad ebov was tested at .  vp and  vp. peak titres and response rates were similar in these two groups both at peak and at day , indicating that durability was also comparable [ ] . however, in a trial by ledgerwood et. al., which compared a mixture of chad zebov and chad sudv in a : ratio, each at  or  vp, indicated that a -fold higher dose induced significantly higher geometric mean elisa titres of anti-gp igg despite similar response rates [ ] . in the same trial, % of volunteers in the high dose group developed antibody responses against the vaccine strain of zaire glycoprotein (mayinga), while only % developed responses against glycoprotein from the outbreak strain (guinea). additionally, the response rates induced against the vaccine strain sudan glycoprotein ( % in the high dose group and % in the low dose group) were lower than for zaire ( and %) despite receiving the same dose of each. this may reflect the different sensitivities of the two assays. the rapid development of multiple vaccine candidates in parallel during the recent outbreak has highlighted the need for standardization of assays that measure humoral immunogenicity. correlating responses measured by different assays and the inclusion of reference standards can aid comparisons of the quality and quantity of the humoral response induced by different vaccine candidates and support decisions on which to take forward for further development. there is a lack of discrimination between neutralizing and non-neutralizing antibody levels through elisa output and while non-neutralizing antibodies play an important role in curbing infection, there is also a concerted effort to identify neutralizing antibodies (nab) as a key determinant of infection control in many disease settings [ , ] . at present, there are data suggesting that both neutralizing and non-neutralizing antibodies are important in the evd setting and as such measuring both aspects of humoral immunity through elisa and neutralization assays will be informative. virus neutralization assays (e.g. fluorescent antibody virus neutralization (favn) assay or plaque reduction neutralization test (prnt)) can measure nab responses. however, there is a prerequisite for highly trained staff and access to containment level facilities to work with ebolavirus, which are not widely available: for example, a single laboratory based in marburg analysed samples from most of the phase i studies. additionally, these assays necessitate careful and considered planning resulting in low-throughput, expensive and timeconsuming assays to prevent accidental exposure [ , ] . to circumvent these restrictions, assays using non-pathogenic, replication-defective pseudotyped viruses (pvs) have been developed that facilitate the study of highly pathogenic viruses in standard containment level laboratories. pvs are chimeric virions, which comprise the structural and enzymatic core of one virus with a heterologous envelope protein, e.g. ebov table . relationships between different assays used to assess humoral responses to ebola vaccine candidates. spearman's rank and p-values for correlations between each of the assays tested. the same samples were run on each assay. samples were serum from healthy uk volunteers in a phase i trial of chad _mva ebo z conducted at the university of oxford [ ] . all samples were from the same time point-two weeks after mva boost. adi elisa, pseudotyped lentivirus neutralization assay and standardized elisa were carried out at the university of oxford, competition elisa at phe, neutralization assay and whole virion elisa at institute for virology, philipps university, marburg, and the nih elisa at the nih. glycoproteins [ ] . typically, retroviruses (lentiviruses and gammaretroviruses) or rhabdoviruses (vesicular stomatitis virus) are used as pseudotype cores. transduction of permissive target cells, facilitating genome transfer and subsequently reporter protein expression, allows a quantifiable read-out of transduction and produces a quantitative read-out. however, pre-incubation of pv with nab which bind an envelope protein, and can inhibit cell entry, will result in a lower level of quantifiable reporter protein expression. there are many pv assays which have been developed to assess neutralizing antibodies toward the filovirus family members and indeed a number of these assays have been used in a who collaborative study to establish a reference standard for antibodies to ebola virus [ ] . the data from this study suggest that pv assays, while offering an obvious improvement to live nab assays, may generate false positives and as such any new filovirus pv assay requires stringent standardization using validated negative and positive controls. there have been a limited number of pv assays used in recent clinical trials, which may reflect the urgent need to rank vaccine modalities during the - ebola outbreak and the concerted effort to screen using live neutralization assays. however, there are a number of informative comparisons between live ebov neutralization and pv neutralization during some of the more recent clinical trials which will help establish the usefulness and early application of these assays in screening and ranking vaccine candidates (table ) . in , neutralizing antibodies, as measured with a singleround infection assay with ebov gp-pseudotyped lentiviruses, were measured following a single im vaccination in a phase i clinical trial of adhu vaccine expressing ebov gp antigen. with the exception of one subject, sera did not inhibit virus entry [ ] . the same team also used ebov or marv gp-pseudotyped lentiviruses to measure neutralizing antibody activity after or dna vaccinations. no significant marburg virus neutralizing activity was observed following the dna vaccines, and only low-level ebov neutralizing activity was measured following the fourth dna vaccination [ ] . these data have helped evaluate vaccine regimens and have identified those vaccines and regimens which yield improved neutralizing responses. in a recent phase i clinical study in oxford, seven different assays of humoral immunity were undertaken on samples from vaccinees, providing a unique opportunity to assess the relationship between different measures of immunogenicity (table ) . volunteers were administered a single dose of chad ebov gp and a subset were then administered a booster dose of a mva strain, encoding the same ebola virus glycoprotein. two assays were used to measure neutralizing antibodies; direct neutralization of live ebov (mayinga strain) and a pseudotyped lentivirus expressing the glycoprotein from the mayinga strain, with a read-out of % inhibitory concentration (ic ). neutralizing antibody titres to live ebov (mayinga strain) were low at days after the chad dose while the levels were significantly higher days after the mva boost vaccine. again, low-level inhibition of infection was observed post-prime, using a pseudotyped lentivirus expressing the gp from the mayinga strain of ebov, and the levels of nab increased significantly post-boost. importantly, neutralizing antibody titres in the live ebov and pv assay correlated positively with each other (r ¼ . , p ¼ . ) as did titres measured by elisa and live ebov (mayinga strain) neutralization assay (r ¼ . , p ¼ . ) [ ] . nab were also assayed in vaccinees who received rvsv-zebov, through the use of vsv pseudovirions expressing the glycoprotein from the ebov kikwit strain, and a live neutralization assay with infectious ebov isolate mayinga. nab have been detected in vaccinees receiving as little as  pfu rvsv-zebov, and the two nab assays showed significant increases in neutralizing antibodies after all doses of rvsv-zebov (ranging from  pfu to  pfu) [ ] . a strong correlation between antibody titres as assessed with glycoprotein elisa and vsv pseudovirions or live virus neutralization titres were demonstrated. a significant correlation between vaccine dose and neutralizing antibody titres was also identified using the vsv pseudovirions but such correlations were not observed using whole virions or infectious ebola virus. this may reflect the lower sensitivity and thus weaker discriminatory capacity of whole virions or infectious ebola virus assays. the increased interest in measuring nab post vaccination toward highly pathogenic viruses and the suggested increased sensitivity in established and standardized pv assays will underpin the continued development and use of pv assays for broad-spectrum detection of post-vaccination humoral responses. baize and co-workers analysed samples from patients in two large outbreaks in in gabon and compared cellular and humoral responses between survivors and patients who succumbed to infection to determine the relative contribution of different immune parameters to evd outcome [ ] . survival was associated with early and rapid rises in igg directed mainly toward the viral nucleoprotein, in addition to activation of cd þ t cells with upregulation of cd , fasl, perforin and ifng. cd þ t cells specific to the ebola virus nucleoprotein are also associated with protection in a mouse model of evd [ ] and t cells induced by rad zebov gp vaccination in nhp afford protection in a lethal challenge model [ ] , while in vivo depletion of cd þ t cells using a monoclonal antibody abrogated protection in four out of five nhp, whereas passive transfer of igg did not induce protection. therefore, enumeration of antigen-specific t cell responses to candidate ebola vaccines is an important aspect of the immunological outcomes for studies in humans. many clinical trials of replicationdeficient viral vectored vaccines have reported t cell responses as measured by flow cytometry with intracellular cytokine staining (ics) using pools of peptides spanning the glycoprotein to stimulate peripheral blood mononuclear cells (pbmc). comparisons across studies are impeded by differences in sample types used (freshly isolated versus cryopreserved pbmc), variation in denominator used to report responses (memory versus total cd þ ) and differences in data analysis methodology [ , , , ] . some groups have also reported glycoproteinspecific t cell responses by ifng elispot in addition to ics; however, again differences in responses between fresh and frozen pbmc make broad comparisons difficult. although comparisons between all the trials are unreliable, limited comparisons are possible; e.g. when using fresh pbmc with ifng elispot, radhu and chad vectors encoding ebov gp induced antigen-specific t cell responses of a similar magnitude [ , ] . for the vaccine regimen where chad vectors encoding ebov and sudv gp were mixed, only the rstb.royalsocietypublishing.org phil. trans. r. soc. b : responder frequency and not the magnitude of response was reported; however, responder frequency to the mixture of vectors was similar to that observed to chad ebov gp alone. however, and possibly more importantly, comparisons between groups within the same study have yielded interesting insights into the use of viral vectors that have broader relevance beyond ebola virus vaccines. for example, a large trial in oxford comparing mva-bn filo priming and adhu zebov boosting demonstrated for the first time in humans that priming with the mva vector and boosting with an adenovirus is at least as effective at inducing antigen-specific cd þ t cells as the conventional delivery of ad-prime followed by mva boost [ ] . surprisingly, the rvsv-zebov vaccine, which to-date has been the only vaccine for which field efficacy has been assessed, has not yet been described for t cell-inducing capability [ , ] . in cynomologous macaques immunized with rvsv-zebov, cytokine-secretion from cd þ t cells stimulated with gp peptides was not detectable after immunization; however, responses were detected in vaccinated animals after ebov challenge, suggesting that immunization may have primed a response [ ] . if t cell responses to the rvsv-zebov have been assessed in phase i studies, then the absence of cmi would be of interest to the vaccine development field as maintenance of humoral immunity is obviously dependent on cmi, yet the failure to detect such a response peripherally is both surprising and interesting from the immunologist's perspective. as the immediate response to the - evd outbreak in west africa begins to wind down, scientists and policy makers involved in vaccine development can reflect on both the progress made by the field in this difficult time as well as implications for future outbreaks. notable gains and successes have been achieved, including rapid approval and completion of clinical studies for both existing and newly produced candidate evd vaccines which underpins the capacity of both ethical and regulatory authorities to expedite approvals in the context of public health emergencies. publication of data from studies undertaken in response to the outbreak has also been rapid with many journals setting aside policies relating to prior disclosure of data to allow data sharing with who and other bodies, without prejudice of future publication. that vaccines against evd existed at all is partly due to north american biodefense priorities, rather than a planned strategy of preparedness for rapid response to emerging pathogens. the efficacy of the rvsv-zebov vaccine in the phase iii trial in guinea in the context of a primarily iggmediated response suggests that an efficacious evd vaccine may be comparatively easy to produce, compared with efforts to generate vaccines for diseases such as malaria, hiv and tuberculosis. indications from the nhp vaccine model with rad ebov gp and analysis of immune responses in evd survivors indicated that a cd þ t cell component would be a prerequisite of an effective evd vaccine. yet the rvsv-zebov vaccine may not induce a significant cmi component based on pre-clinical data. an additional consideration is that passive transfer of ebola-specific antibody can fail to protect nhps from lethal ebola virus challenge, indicating that antibody titres may be a nonmechanistic correlate of protection and that qualitative aspects of the antibody response and/or cellular immunity that are not readily measured also play key roles in protection [ ] . it is likely that the mechanism of protection and protective level of a particular immune component may well differ in an experimental model in nhps, challenged in a manner that may not accurately reflect natural exposure and in humans exposed to natural infection. this highlights the importance of not being over-reliant on immunological correlates derived from pre-clinical testing. clearly, different vaccine delivery methods induce qualitatively different immune responses; induction of long-lasting humoral immunity in the absence of t cells seems unlikely, so the ability of prime-boost regimens to induce durable cmi and humoral immunity may be desirable for longevity of protection. in december , who held a workshop on the prioritization of pathogens, generating a list of seven diseases requiring urgent r&d, with a further three diseases requiring action as soon as possible [ ] . this list encompasses emerging diseases with potential to generate a public health emergency and for which no, or insufficient, preventative or curative solutions exist. crimean congo haemorrhagic fever (cchf), evd, marburg haemorrhagic fever, lassa fever, mers, sars, nipah and rift valley fever virus were identified as priorities for emerging pathogen research, with zika, chikungunya and severe fever with thrombocytopaenia syndrome (sfts) determined to be serious and necessitating further action as soon as possible. this evd outbreak has focused attention on emerging pathogens, shifting their place in the public consciousness from a theoretical emergency to a very tangible threat to global health. vaccine developers must now think in terms of addressing emerging pathogens as an entirety rather than a collection of individual highly virulent pathogens. to this end, the recent outbreak has yielded some valuable insights. firstly, in the context of an ongoing outbreak, a single dose of a viral vector vaccine could be sufficient to induce at least short-term protective immunity against filoviruses. this can usefully protect front-line healthcare workers and communities, thereby reducing the spread of an epidemic in the earliest stages [ ] . where the outbreak pathogen is readily identified a single dose of a recombinant adenoviral or vsv vector may suffice for outbreak control. however, to counter the threat of infectious outbreaks which may emerge unpredictably, large-scale prophylactic immunization of healthcare workers would be a useful first line of defence. a single-dose multivalent vaccine encoding antigens from several putative emerging pathogens could be particularly valuable in such a scenario. for example, recombinant mva would be suited to this purpose, given the potential to insert various foreign genes at numerous sites in the genome under a number of promoters [ ] , in contrast with adenovirus vectors that have a limited cloning capacity to carry foreign genes. immunity could subsequently be boosted with an adenoviral vector expressing a specific transgene, once the outbreak pathogen is identified. a study of an evd vaccine regimen employing mva as a priming vector and adhu as a boost has demonstrated that this is a feasible approach [ ] . speculatively grouping rstb.royalsocietypublishing.org phil. trans. r. soc. b : emerging pathogens according to geographical incidence may be one strategy for determining components of multivalent vaccines and an example of a potential strategy for designing vaccines using this approach is suggested in figure . almost all of the current evd vaccine candidates use gp as the antigen due to abundant expression on the surface of the virus, and there is extensive pre-clinical data reflecting promising immunogenicity and efficacy against challenge for this target antigen. studies of patients with evd in two outbreaks in gabon revealed that in survivors, igg responses were largely directed against nucleoprotein [ ] . the same observation was made in a small study of evd cases in the usa [ ] . characterization of immune responses in natural ebolavirus infection have also revealed that exposure can induce cross-reactive antibodies capable of neutralizing multiple ebolavirus species [ ] . this study of naturally acquired immunity in survivors of a bdbv outbreak in uganda in demonstrated for the first time that potent neutralizing antibodies to the glycan cap of gp could inhibit several ebolaviruses, including sudv, and protect guinea pigs from a heterologous challenge with ebov which may offer insight into immunogen design to confer heterosubtypic immunity across multiple ebolaviruses. given the very large number of survivors of the - outbreak, significant efforts should be made to characterize the immunity that afforded protection in the face of infection with such a highly lethal pathogen, to help inform antigen selection for future vaccines and advance our understanding of post-evd immunology. whether vaccines need to emulate these naturally occurring mechanisms remains to be seen, but these observations are of critical importance to help advance the field. closer examination of the priority pathogens highlighted by the who may facilitate development of broad-spectrum vaccines; viruses with small genomes that have obvious vaccine candidate antigens or where pre-clinical data are highly indicative [ ] . in this setting, data from the one health approach, which combines human, animal and environmental considerations to address global health challenges, are invaluable; for example, immunogenicity data derived from studies in zoonotic reservoirs can be applied to vaccine development [ , ] . furthermore, studies of families of viruses using technological advances such as cryo-electron microscopy, b cell cloning and antibody repertoire sequencing may yield novel targets that may be effective for tackling emerging pathogens. phylogenetically related viruses that share receptor-binding domains, and epitopes within envelope proteins may well share therapeutic and vaccine targets [ ] . as discussed above, great efforts have been made to characterize the magnitude of neutralizing antibody titres induced by vaccination, yet the detail of these entry-blocking mechanisms has not yet been fully utilized by vaccinologists. detailed understanding of host-pathogen interactions has yielded numerous opportunities for vaccines against other diseases, including malaria and hiv [ ] . in-depth understanding of the processes associated with inhibition of receptor binding, such as conformational rearrangement of glycoproteins required for viral fusion, could possibly identify ubiquitous targets for mabs that can prevent infection of multiple virus species [ ] : for example, the entry of all filoviruses into mammalian cells utilizes the same endosomal receptor [ ] , the niemann-pick c protein, presenting an obvious target for inhibition of virus entry. outbreaks of highly pathogenic diseases such as evd are devastating for the populations affected and will always focus attention on control strategies to prevent future occurrences. while it is widely acknowledged that the global public health response to the - was tragically slow to begin, immunologists and vaccinologists now have a valuable opportunity to learn as much as possible from this disaster. as well as probing the vaccine-induced responses from the many clinical trials that have taken place, detailed characterization of naturally acquired immunity in both survivors of evd and asymptomatic, ebov igg-seropositive members of communities should be systemically compiled. previous data from gabon have illustrated that substantial proportions of rural populations have evidence of ebov-specific immunity [ ] . we now have a collective responsibility to assimilate all the information that this outbreak has generated in order to be best placed when the next epidemic comes, so that we can respond effectively and robustly to curb an outbreak in its infancy. who. situation report: ebola virus disease emergency ebola response: a new approach to the rapid design and development of vaccines against emerging diseases virus nomenclature below the species level: a standardized nomenclature for filovirus strains and variants rescued from cdna structural basis for marburg virus neutralization by a cross-reactive human antibody chimpanzee adenovirus vaccine 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valley fever emerging zoonotic viral diseases zoonoses and one health: a review of the literature inhibitory antibodies targeting emerging viruses: advancements and mechanisms a pfrh -based vaccine is efficacious against heterologous strain blood-stage plasmodium falciparum infection in aotus monkeys broadly neutralizing alphavirus antibodies bind an epitope on e and inhibit entry and egress ebola viral glycoprotein bound to its endosomal receptor niemann-pick c high prevalence of both humoral and cellular immunity to zaire ebolavirus among rural populations in gabon authors' contribution. all authors contributed to the design, drafting and revision of the article and approved the final version for publication.competing interests. we have no competing interests. funding. k.j.e. is funded by a horizon award from the european union. g.b. is funded by the wellcome trust. t.l. is funded by the mrc. key: cord- - t mklwi authors: wendelboe, aaron m.; mccumber, micah; erb-alvarez, julie; mould, nicholas; childs, richard w.; regens, james l. title: managing emerging transnational public health security threats: lessons learned from the west african ebola outbreak date: - - journal: global health doi: . /s - - -z sha: doc_id: cord_uid: t mklwi background: pandemics pose significant security/stability risks to nations with fragile infrastructures. we evaluated characteristics of the west african ebola outbreak to elucidate lessons learned for managing transnational public health security threats. methods: we used publically available data to compare demographic and outbreak-specific data for guinea, sierra leone, and liberia, including key indicator data by the world health organization. pearson correlation statistics were calculated to compare country-level infrastructure characteristics with outbreak size and duration. results: hospital bed density was inversely correlated with longer evd outbreak duration (r = − . ). country-specific funding amount allocations were more likely associated with number of incident cases than the population at-risk or infrastructure needs. key indicators demonstrating challenges for guinea included: number of unsafe burials, percent of evd-positive samples, and days between symptom onset and case hospitalization. sierra leone’s primary key indicator was the number of districts with ≥ security incident. liberia controlled their outbreak before much of the key-indicator data were collected. conclusion: many of the country-level factors, particularly the who key indicators were associated with controlling the epidemic. the infrastructure of countries affected by communicable diseases should be assessed by international political and public health leaders. the nexus between risks posed by infectious disease pandemics to the stability of fragile states and international security was demonstrated dramatically by the largest reported ebola virus disease (evd) outbreak which occurred in west africa between and [ ] [ ] [ ] [ ] [ ] . underscoring its severity, the west african ebola outbreak was larger than all previous evd outbreaks combined. the epidemic began in december and the world health organization (who) was notified on march , . the who declared it a public health emergency of international concern on august , [ ] . further demonstrating the security threat posed by this public health emergency, the united nations security council resolution ( ) adopted on september , declared the outbreak was "a threat to international peace and security in the region" [ ] . the international community's response acting in cooperation with the immediately affected countries included diagnosing the disease as early as possible, contact tracing, patient isolation and care, infection control, ring vaccination, safe burial practices, and public education (e.g., messages on billboards and radio describing symptoms, hand hygiene, school closures, and avoiding close contact to prevent transmission). indeed, many of these factors comprise the majority of the who ebola situation reports' key performance indicators [ ] . the outbreak officially ended on march , . ten countries were directly impacted, three of which experienced significant outbreaks (guinea, liberia, and sierra leone), while seven countries reported one or more evd cases without widespread human-to-human transmission (italy, mali, nigeria, senegal, spain, the uk, and the us) [ , ] . we aim to systematically examine country-specific factors within the context of the larger global pandemicwith the greatest emphasis on guinea, liberia, and sierra leone. specifically, we ) conduct a quantitative analysis of country-specific factors in guinea, liberia, and sierra leone and ) conduct a qualitative analysis of patterns of disease incidence and transmission among all countries with ≥ case of evd to draw lessons learned from the west african ebola outbreak for managing emerging transnational health security threats. by march , , who reported , cases and , deaths from the west african ebola outbreak, [ ] with an overall case fatality rate of · %. cases were observed in countries across three continents (africa, europe, and north america). table summarizes the number of cases, deaths, contacts followed, and date the country was first declared ebola-free. epidemic curves for the three widely affected countries are shown in fig. . at the epidemic's peak, the doubling time was - days for cases in liberia and - days for sierra leone and guinea [ ] . although four new confirmed cases were diagnosed in guinea during march - , the who director-general declared on march , the end of the public health emergency of international concern regarding the evd outbreak in west africa [ ] . the first case likely occurred december , , but not identified as ebola until march , [ ] . the index case was traced to a two-year-old boy in meliandou, a village near gueckedou, guinea [ ] . evidence suggests his exposure was likely an infected angolan free-tailed bat [ , ] . although guinea had the highest case fatality rate ( · %, fig. ) and was the last to be declared ebola-free, it had the lowest number of cases among the widely-affected countries. the peak number of weekly cases reported was in november [ ] . eight ( · %) of the prefectures in guinea did not report any ebola cases [ ] . by march , , there were evd cases, deaths [ ] (table ) and cases among health care workers (hcws), of which died [ ] . the first sierra leone case was retrospectively identified as a female guest in the index case's home in meliandou, guinea, but returned to sierra leone and died in early january [ ] . it was not until april , that sierra leone "stepped up vigilance for imported cases when two members of the same family who had died from ebola virus disease in guinea were repatriated to sierra leone for burial" [ ] . by november , evd had been reported in each district in sierra leone [ ] and the peak number of weekly cases reported was [ ] . sierra leone had the highest number of cases ( , ) but the lowest case fatality rate ( · %). the cumulative number of deaths was [ ] (table ) and evd cases among hcw, of which died [ ] . to "implementing the full package of control interventions, including community engagement, acceptance, and ownership of the response" [ ] . ultimately there were , cases and deaths (case fatality rate = · %) [ ] . all districts in the country reported cases of evd [ ] . liberia had the highest number of hcw evd cases (n = ), but fewer deaths (n = ) [ ] than sierra leone. comparison of widely-affected countries table illustrates important demographic differences between these three countries. guinea's population ( , , ) is approximately twice sierra leone's ( , , ) and liberia's ( , , ), yet has the lowest health and education expenditures and literacy rate. guinea also has the lowest ethnic diversity. generally, we failed to detect correlations between the health indicator data (infant mortality rate, health expenditures as % of gdp, physician density, and hospital bed density) and evd-related outcomes (i.e., duration of the evd outbreak and the evd-specific mortality rate). the only statistically significant correlation was between outbreak duration and hospital bed density (r = − · , p < · ); fewer hospital beds per population was correlated with longer evd outbreak duration. country-specific information regarding the distribution of evd-related financial resources is opaque. initially, guinea received approximately half the funding sierra leone and liberia received. according to a who budget [ ] for july-december , guinea received $ , , , sierra leone received $ , , , and liberia received $ , , . nigeria, which ultimately was not widely affected, initially received nearly as much funding ($ , , ) as guinea. a who financial report covering october , reported the following geographic allocation of donor funds: guinea %, liberia %, sierra leone %, regional %, and other % [ ]. by the outbreak's end, approximately $ · billion had been dedicated to the ebola response during - [ ] . money allocation more closely correlated with country-specific incident evd cases than population size. the evd case and population-at-risk distribution was: guinea = · % cases, · % population-at-risk, sierra leone = · % cases, · % population-at-risk, and liberia = · % cases, · % population-at-risk. comparing the key indicator data provides limited insights into differences between guinea and sierra leone's country-specific epidemics; the epidemic was largely controlled in liberia (fig. ) by the time they were systematically collected. three indicators showed worse problems in guinea (number of unsafe burials, percent of tested samples that were evd positive, and days between symptom onset and case hospitalization) and one showed worse problems in sierra leone (number of districts with at least one security incident); the remaining indicators were nearly equivalent (fig. ) . evd cases were exported to seven additional countries and details regarding the country-specific outbreaks are organized by date of first confirmed evd case. of these, nigeria, senegal, and mali are west african countries with relatively high potential for ongoing transmission, particularly nigeria. however, a robust public health response prevented widespread transmission in these countries [ ] . the us, spain, the uk, and italy also had ≥ imported evd case. only the us reported in-country evd transmission. all of these countries reported their evd cases in , except italy, which was in may . table summarizes the number of cases, deaths, contacts followed, and date first declared ebola-free. the first case was reported july , in the lagos district and imported from liberia [ ] . this marks the first recorded time ebola spread to another country via airline travel. [ ] although the index case in nigeria transmitted the disease to at least five people who died, no transmission occurred on the flight, despite the infected adult male vomiting enroute [ ] . port harcourt was nigeria's second district to be affected with an evd case reported on august . nigeria was declared ebola-free on october , with a final case count of , eight deaths [ ] and ≥ contacts requiring follow-up [ ] . an adult male who travelled by road from his home in guinea to dakar was senegal's only evd case and reported on august , [ ] . he survived and senegal was declared ebola-free on october , . on september , , the first evd case in the us was reported in dallas, tx. an adult male travelling from liberia developed symptoms four days after arriving and expired on october . he transmitted evd to two female nurses. the first was diagnosed on october and discharged from the hospital on october . the second was diagnosed on october and discharged on october . she took two flights but no transmission was identified [ ] . the fourth case was in a male physician living in new york city who worked with doctors without borders. he was diagnosed october and discharged november . this physician potentially exposed multiple individuals during the first day of his illness at public places like restaurants and a bowling alley, but no transmission was identified [ ] . of these four cases, one died, two were imported, and two were from local transmission [ ] . there were an additional six evd cases acquired in west africa but treated in the us [ ] . of these, there were three hcws, an aid worker, a missionary, and a cameraman. all but one recovered. the u.s. was declared ebola-free on december , . health officials in mali investigated six suspect cases in april which helped prepare for the introduction of their first confirmed case in october . this evd case was a two-year-old female from guinea (reported on october ) [ ] . being symptomatic during her journey to mali, the girl died the following day. on october , a grand imam from siguiri prefecture in guinea was admitted to a clinic in bamako for acute kidney failure. ebola was not initially recognized and he died on october . because his symptoms began in guinea, he is reported as a guinean case. that case led to seven additional cases, with five deaths [ ] . by january , , when mali was declared ebola-free, the final case count was eight with six deaths [ ] . kayes and bamako were the only districts affected [ ] . on december , a female hcw returning from sierra leone was reported as the only evd case in the uk [ ] . she developed symptoms as she arrived in london. the people on a shared flight were classified by at least one source as exposed contacts, but were fig. indicator data from who ebola situation report treated as low risk. all passengers on board the shared flight (at from casablanca to london) and crew members were successfully contacted. public health england advised passengers sitting in the two rows adjacent (comprising passengers) to take their temperature twice daily for days [ ]. the patient survived and there were no additional cases [ ] . on may , , a case of ebola in a male italian volunteer hcw was reported. he returned from sierra leone on may , became symptomatic on may , and hospitalized on may . no inflight contact tracing was done. there were contacts to this case [ ] . on july , , italy was declared ebola-free having no additional evd cases and no deaths [ ] . who declared the ebola epidemic over on march , with , cases and , deaths across countries and three continents. of the three countries most widely affected, liberia was first to successfully control the epidemic (february ), which was before the key indicator data were collected (march ). the epidemic in sierra leone and guinea was largely controlled by april , but experienced sustained transmission into november . using the data from the present study, the key indicators that seemed to be substantially different between sierra leone and guinea were ) the number of unsafe burials, ) the percent of tested samples that were evd positive, ) the number of days between symptom onset and case hospitalization, and ) the number of districts with at least one security incident. there are a number of additional factors highlighted in the who ebola situation reports (and substantiated in the published literature). burial practices were cited as the single strongest risk factor for transmission; - % of all cases reported an exposure to a traditional burial [ ] . while previous outbreaks were largely controlled by using contract tracing, [ , ] this is the first evd pandemic with a prolonged duration where treatment and supportive care played an unquantified role in the response [ , , ] . another key difference was the strong stigma associated with evd infection in this outbreak as demonstrated by community attempts to hide cases from authorities. these areas came to be known as "shadow zones" [ ] and were accompanied by angry mobs attacking health care facilities and workers. the first such occurrence was on april , in macenta, guinea, [ ] and differences in events between sierra leone and guinea are shown in fig. . the pearson correlation estimates were limited by small sample size (three countries). the strongest country-level health indicator was between hospital bed density and the duration of the outbreak (r = − · ). increasing bed capacity was shown to contribute to controlling the ebola pandemic by two modeling studies, [ , ] however, the belated timing of the escalation of bed capacity likely limited its impact [ ] . we suggest that helping countries increase health infrastructure, particularly by having more hospital beds, as well as ongoing infection control training and capacity building, may help combat severe diseases such as evd. diagnostic equipment, largely unavailable during the early part of the outbreak, was also key for effective patient management. this pandemic highlights the need for the international community to respond to transnational outbreaks in a timely manner. despite the heroic efforts of early responders (e.g., local hcws, personnel with médecins sans frontières, cdc, and others), on a global scale, the response time was inadequately slow. this is possibly due to international politics and the sluggish turning wheels of governments who strive to do the right thing while meeting the needs of their citizens. the response by the us arguably began in march when cdc deployed personnel to investigate ebola cases in guinea, and further on july , with the activation of cdc's emergency operations center. however, because evd was largely out of the public's eye until the fall of , its response was similarly delayed. that is, the peak number of evd cases in liberia was september , ; one week after president obama's announcement to commit troops and provide additional aid to the ebola response effort [ ] and one month after who declared it a public health emergency of international concern. these events unlikely contributed substantially to controlling the evd pandemic [ ] . the us's response was impressive in terms of funding and personnel. by april , the us spent $ . billion on the ebola response effort. during - , the hhs global and domestic response mobilized more than personnel [ ] . approximately active duty commissioned corps officers in the us public health service established, operated and staffed the monrovia medical unit, an ebola treatment unit having more sophisticated medical capabilities than those in conventional ebola treatment units. the monrovia medical unit provided advanced supportive care to responders who became ill during this west african crisis and were the only us (non-private) personnel to provide direct patient care to persons infected with evd. this study is subject to certain limitations. perhaps the most substantial of which is the difficulty to quantify many factors affecting control of the outbreak. for example, the west african people educated their communities, facilitating the change of social practices, such as greetings with physical contact and modifying long-standing traditional burial practices [ , ] . education messages on fighting the epidemic were communicated through messaging in radio, billboards, etc. in conclusion, the west african ebola outbreak devastated three west african countries and propagated to seven additional countries on three continents. the public health response and subsequent control of the outbreak was different across guinea, liberia and sierra leone. the results from both the analysis of country-level data and the qualitative analysis generate hypotheses that inadequate infrastructure at the country level contributed to the delayed control of evd within the affected countries and contributed to lower survival rates. this ebola epidemic, as many in the past (such as hiv, west nile virus, sars, and cholera in haiti), shows us that epidemics can have a devastating global impact, and therefore should be considered everyone's problem. the recent zika virus epidemic followed many similar patterns highlighting that we all share the responsibility in responding to infectious outbreaks. many of the country-level factors, particularly the who key indicators were associated with controlling the epidemic. international political and public health leaders should assess the infrastructure of countries affected by communicable diseases. we used publicly available data for guinea, liberia, and sierra leone for the following demographic attributes: ) population and population density, ) median age (years), ) infant mortality rate (deaths/ live births), ) health expenditures (% of gdp), ) physician density (physicians/ population), ) hospital bed density (beds/ population), ) literacy (age + can read and write), ) education expenditures (% of gdp), ) urbanization (% urban), ) religions (% distribution), and ) ethnic groups (% distribution). pearson correlations were calculated and associated scatterplots were generated to assess associations between healthcare indicators for each country (health expenditures, physician density, hospital bed density, and infant mortality rate) and the duration of the evd outbreak (in days) and the evd-specific mortality rate. the outbreak-specific data were obtained from the weekly who ebola situation reports during which the key indicator data were uniformly published ( march , -october , . key indicators included ) number of confirmed cases, ) number of confirmed deaths, ) number and proportion of evd-positive reported community deaths, ) number of samples tested and the percent of positive evd results, ) percent of new confirmed cases from negative contacts, ) time between symptom onset and hospitalization (in days), ) case fatality rate among hospitalized cases, ) number of newly infected health workers, ) number of unsafe burials and the reported number of community deaths, ) number of districts with at least one security incident or other form of refusal to cooperate. line graphs for each key indicator were generated to assess differences between guinea, liberia, and sierra leone. we also summarize the impact of evd in the seven additional countries with limited evd transmission. the number of cases, deaths, case fatality rate, case-contacts requiring monitoring, date of first evd case, and date first declared ebola-free were summarized for each country. data were collected using index mundi, the who situation reports and internet searches, focusing on government sources, to identify relevant ebola-related information within the scope of outcome measures listed above. health and national security: a contemporary collision of cultures the routledge handbook of new security studies. london: routledge health security as a public health concept: a critical analysis the coming plague pandemics on the radar screen: health security, infectious disease and the medicalisation of insecurity ebola response team. ebola virus disease in west africa--the first months of the epidemic and forward projections security council approves threemonth extention for united nations mission in liberia accessed ebola situation report ebola situation report accessed ebola response team. after ebola in west africa--unpredictable risks, preventable epidemics estimating the future number of cases in the ebola epidemic--liberia and sierra leone one year into the ebola epidemic: a deadly accessed investigating the zoonotic origin of the west african ebola epidemic bat-filled tree may have been ground zero for the ebola epidemic ebola virus disease--sierra leone and guinea cdc classification of countries with reported ebola cases for evaluation of persons in the united states accessed ebola situation report who strategic action plan for ebola outbreak response: annex accessed accessed who: ebola response roadmap update cases of ebola diagnosed in the united states accessed how many ebola patients have been treated outside of africa accessed ebola virus disease -united kingdom accessed ebola situation report - accessed world health organization. factors that contributed to undetected spread of the ebola virus and impeded rapid containment. in: one year into the ebola epidemic. geneva: world health organization ebola --new challenges, new global response and responsibility the ebola outbreak, - : old lessons for new epidemics measuring the impact of ebola control measures in sierra leone impact of bed capacity on spatiotemporal shifts in ebola transmission impact of interventions and the incidence of ebola virus disease in liberiaimplications for future epidemics empty ebola clinics in liberia are seen as misstep in u.s. relief effort engaging 'communities': anthropological insights from the west african ebola epidemic ebola situation report accessed who: ebola response roadmap situation report ebola situation report - accessed accessed this research was supported in part by the defense intelligence agency, grant # hhm - - - (pi: regens). the views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of dia, the indian health service, or the us government. funding was provided through the defense intelligence agency, grant # hhm - - - (pi: regens). the data are publically available and the sources are referenced within the manuscript. the data collected from the weekly who situation reports were summarized in an ms excel file which will be made publically available pending acceptance of the manuscript for publication.authors' contributions amw, mm, and jlr contributed to study conception and design. amw and mm were primarily responsible for data analysis. all authors contributed to interpreting the data. all authors contributed to the drafting/revising of the manuscript for important intellectual content. all authors have provided final approval of the submitted manuscript. all authors agree to be accountable for the accuracy and integrity of the work.ethics approval and consent to participate not applicable. we did not seek approval from an ethics board/institutional review board because the data were from publically available sources. the authors declare that they have no competing interests. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -vqoxd i authors: rosello, alicia; mossoko, mathias; flasche, stefan; van hoek, albert jan; mbala, placide; camacho, anton; funk, sebastian; kucharski, adam; ilunga, benoit kebela; edmunds, w john; piot, peter; baguelin, marc; muyembe tamfum, jean-jacques title: ebola virus disease in the democratic republic of the congo, - date: - - journal: nan doi: . /elife. sha: doc_id: cord_uid: vqoxd i the democratic republic of the congo has experienced the most outbreaks of ebola virus disease since the virus' discovery in . this article provides for the first time a description and a line list for all outbreaks in this country, comprising cases. compared to patients over years old, the odds of dying were significantly lower in patients aged to and higher in children under five (with % mortality in those under years old). the odds of dying increased by % per day that a patient was not hospitalised. outbreaks with an initially high reproduction number, r (> ), were rapidly brought under control, whilst outbreaks with a lower initial r caused longer and generally larger outbreaks. these findings can inform the choice of target age groups for interventions and highlight the importance of both reducing the delay between symptom onset and hospitalisation and rapid national and international response. doi: http://dx.doi.org/ . /elife. . ebola virus disease (evd) outbreaks are rare and knowledge of the transmission and clinical features of this disease is sparse. as of may , the devastating outbreak in west africa has resulted in more than ten times the number of cases reported in all previous outbreaks and will ultimately provide improved insights into evd. here, for the first time, all the databases from evd outbreaks in the democratic republic of the congo (drc) have been cleaned and compiled into one anonymised individual-level dataset (see supplementary file ). the data provided are an invaluable addition to the west africa data and will allow a more complete picture of the disease. the drc is the country that has experienced the most outbreaks of evd. since the virus' discovery in , there have been six major outbreaks (yambuku , kikwit , mweka , mweka , isiro , and boende and one minor outbreak (tandala ) reported in the drc, four in the northern equateur and orientale provinces and three in the southern provinces of bandundu and kasai-occidental ( figure ) . some of these have been described in the literature (world health organization, ; heymann et al., ; khan et al., ; , maganga et al., ) . however, the individual-level data and corresponding lessons from these outbreaks have not been collated or made publicly available; by doing so, we aim to permit a more powerful statistical analysis and a fuller understanding of the disease. the end of the most recent outbreak in the drc was declared on the st of november . this provides an unparalleled opportunity to assemble all the information gathered about evd in the drc through almost four decades, learn from the congolese experience with this disease, and compare the features of evd in drc with the epidemic that has had such a devastating effect in west africa. during the last years, cases of evd have been reported in the drc, of which are reported in this dataset. the geographical context, historical timeline, and main characteristics of these outbreaks are depicted in figure and table . a detailed account of the outbreaks can be found in appendix , section b. the early accounts of all outbreaks except for mweka involved a healthcare facility. the direct epidemiological link between index cases (when known) and animal reservoirs has not been found for any of the outbreaks. the lack of systematic surveillance together with the presence of diseases with similar symptoms allows evd cases to go unnoticed for long periods of time. a repository of the interventions that led to the control of the outbreaks is outlined in supplementary file . table summarises the number of cases and deaths reported in each outbreak. the number of cases and case-fatality ratios (cfrs) varied greatly between outbreaks ( table ) . it can also be observed that laboratory confirmation became more readily available over time. across all outbreaks, % of cases were female ( % ci = . - . ). in the second mweka outbreak and in the isiro outbreak, more than % of cases were females. however, in the other outbreaks, the percentage of females was lower ( - %). when comparing the probable and confirmed cases by age with the overall drc population (figure ), we observed a high concentration of cases in the - age category compared to the baseline population. this might be because at this age individuals are more likely to be carers. the occupation was only recorded during three outbreaks: kikwit, boende and isiro. during kikwit, % ( / ) of cases were known healthcare workers (hcws) and . % ( / ) were possible hcws. during boende, the occupation was recorded for % ( / ) of cases. % ( ) were known hcws and % ( ) were possible hcws. during isiro, occupation was reported for % ( / ) of cases. % ( ) were hcw. although occupation was not recorded on an individual level, during yambuku, of the yambuku hospital workers contracted evd (world health organization, ) . elife digest ebola virus disease commonly causes symptoms such as high fever, vomiting, and diarrhoea. it may also cause muscle pain, headaches, and bleeding, and often leads to death. there have been seven outbreaks of ebola virus disease in the democratic republic of the congo (drc) since . the drc is the country that has had the most outbreaks of this disease in the world. the most recent outbreak in the drc was in ; this was separate from the outbreak that started in west africa in the same year. rosello, mossoko et al. have now compiled the data from all seven of the outbreaks in the drc into a single dataset, which covers almost patients. analysing this data revealed that people between and years of age were most likely to be infected by the ebola virus, possibly because most healthcare workers fall into this category. age also affected how likely a patient was to die, with those aged under and over more likely to die than those aged between and . delaying going to hospital once symptoms had started, even by one day, also increased the likelihood of death. rosello, mossoko et al. also examined the ebola virus effective reproduction number, which indicates how many people, on average, an infected person passes the virus on to. outbreaks that initially featured viruses with a reproduction number larger than three tended to be stemmed quickly. however, when the reproduction number was lower, national and international organisations were slower to respond to the signs of the outbreak, leading to outbreaks that lasted longer. further research is needed to understand why the likelihood of death is different for different age groups and to investigate the effect of the different routes of transmission of the virus on interventions such as vaccination. the epidemic curves were plotted for the six major outbreaks ( figure ). the date of infection was based on symptom onset when available ( / ). when it was not, hospitalisation dates were used ( / ). in cases where these were also absent ( / ), the notification dates were used as proxy. for mweka , the date of infection was mostly based on the notification date ( %), whereas in the other outbreaks, infection dates refer to onset of symptoms almost exclusively (> %). in time, case definitions became more specific. with the exception of kikwit, in which notification and the closure of healthcare facilities coincided closely in time, outbreaks seemed to peak before major interventions were initiated. the proportion of probable and confirmed cases reporting evd symptoms is shown in figure . overall, the most commonly reported symptom was fever, which was reported by % of cases ( % ci = . - . %) and at least % of cases in every outbreak. reports of vomiting were also similarly common across all major outbreaks, reported by % of cases ( % ci = . - . ) and between % and % of cases for all major outbreaks. there was considerable variation in how frequently the remaining symptoms were reported for different outbreaks. in particular, hemorrhagic symptoms were present in % ( % ci = - ) of cases during kikwit but only % ( % ci = - ) during mweka . the bundibugyo ebolavirus (isiro outbreak) did not present a symptom profile that was particularly different from that seen for the zaire ebolavirus (all other outbreaks). however, this was difficult to conclude given the large variation between outbreaks. the mean cfr overall was % ( % ci = . - . ), but there were significant differences between epidemics and within epidemics over time ( figure and in the regression model that included the delay between symptom onset and hospitalisation as a factor but excluded three outbreaks for missing data (table ) , the baseline cfr in individuals over years of age during the first month of an evd outbreak who were admitted to hospital after . days (the average time from symptom onset to admission to hospital) during the boende outbreak was % ( % ci = . - . ). the cfr was similar during the isiro outbreak but was significantly higher during the kikwit outbreak ( %). the cfr in - year olds was %, and in - year olds, it was significantly lower at %. the odds of dying declined on average by % ( % ci = . - . %) each month after the start of an outbreak and increased by % ( % ci = . - . %) per day that a symptomatic person is not hospitalised ( table ) . in the regression model that included all major outbreaks, the cfr for individuals over years of age during the first month of the outbreak during the boende outbreak was estimated at % ( % ci = . - . ). the yambuku, kikwit, and mweka outbreaks had significantly higher cfrs ( %, % and %) and the mweka outbreak had a significantly lower cfr ( %). - year olds had significantly higher cfrs ( %) than those over years of age. for the - year olds, the cfr was significantly lower ( %). the odds of dying declined on average by % ( % ci = . - . ) each month after the start of each outbreak ( table ) . changes in the effective reproduction number, r, over the course of the outbreaks were plotted in figure . in yambuku, mweka , and boende , r dropped below one within - weeks after the initial case and the outbreak was rapidly brought under control. in these settings, the spread of evd during the first weeks had been high (r > ). by contrast, in kikwit , mweka , and isiro where the initial transmission rate was lower, spread of evd was sustained for more than weeks. overall, we can see that r declines before the major interventions occurred, which could point to behavioural changes that occurred spontaneously in the populations. the delay distributions from onset of symptoms to notification, from onset of symptoms to hospitalisation, from onset of symptoms to death, length of hospital stay, and from hospitalisation to death were plotted for each outbreak (when available) in figure . the largest delays between symptom onset to notification and to hospitalisation were seen during the kikwit outbreak ( . days and . days, respectively). the largest delay between symptom onset and death and the longest duration of hospitalisation were seen during the isiro outbreak ( . and . days, respectively). however, this was only recorded for the kikwit, mweka , and isiro outbreaks. the longest delay between hospitalisation and death was observed during the mweka outbreak ( . days) ( table ). this article provides for the first time a description and a line list for all outbreaks that have occurred in the drc. this represents almost years of surveillance data, seven outbreaks, and suspected, figure . time course of the evd outbreaks in drc. confirmed cases are plotted in red, probable cases in orange, suspected in light blue, cases that were either suspected or probable cases in dark blue, and cases for whom the definition was unknown in purple. the dashed lines represent important events that occurred during the outbreaks (in orange, the first records of the disease, in red, the first notifications, and in black, important interventions carried out). for yambuku, this was the closure of yambuku mission hospital; for kikwit, the closure of all hospitals, health centres, and laboratories in the area; for mweka , the opening of two mobile laboratories; for mweka , the opening of the first isolation centre; for isiro, first the opening of the isolation centre and later the opening of the laboratory; and for boende, the opening of the first isolation centre. notification dates were when the cases were first notified to the direction de lutte contre la maladie (dlm). doi: . /elife. . probable, or confirmed cases. it is an invaluable resource for studying the epidemiology and clinical features of evd. we highlight the importance of reducing the delay between symptom onset and hospitalisation, as the odds of dying increase by % per day that a patient is not hospitalised. we also observe higher incidence in those between and years of age and a higher cfr in patients under or over years of age than in those between and years old. these trends mirror those observed during the west african outbreak, where cumulative incidence was highest in those between and years of age and cfr progressively dropped from . % in those under year of age to . % in those between and years, to rise again to . % in those over years old (who ebola response team et al., a). these distinctions could inform the choice of target age groups for interventions such as vaccination. another important finding is that during outbreaks with an initially lower reproduction number, r, (≤ ) national and international response was slower, outbreaks took longer to control, and (with the exception of yambuku, where the virus was first discovered) were larger outbreaks than those with initially high r. this occurred during the current outbreak in west africa, where the basic reproduction numbers for guinea, sierra leone, and liberia have been estimated at . , . , and . , respectively, and indicates the need for any future evd to be met with rapid national and international response (althaus, ) . our estimates largely coincide with those recently reviewed in the literature (van kerkhove et al., ) . the basic reproduction numbers reported for the kikwit outbreak ( . ) is comprised in the range found by other studies ( . - . ) (chowell et al., ; ferrari et al., ; lekone and finkenstädt, ; legrand et al., ; forsberg white and pagano, ; ndanguza et al., ) , figure . percentage of probable and confirmed cases with abdominal pain, diarrhoea, fever, haemorrhagic symptoms, headache, and vomiting. these were calculated by dividing the number of probable and confirmed cases with symptoms by the number of probable and confirmed cases with symptoms, no symptoms, and blanks for cases for who the presence or absence of at least one symptom was reported. note that the majority of cases in the mweka outbreak were diagnosed a posteriori using recorded symptoms. doi: . /elife. . and our estimate for the yambuku outbreak ( . ) is similar to that reported by camacho et al. ( . , range = . - . ) (camacho et al., ) . the mean delay of onset of symptoms to hospitalisation and to death estimated here for kikwit ( . and . , respectively) was also similar to that found by other authors ( - rowe et al., ] and . - . [bwaka et al., ; khan et al., ] ). our estimated mean delay of onset of symptoms to death during the boende outbreak ( . ) was slightly lower than that found by other authors ( . ) but included in their reported range ( - ) (maganga et al., ) . the delay between hospitalisation and death during the kikwit outbreak found in the literature ( . ) coincided with our estimate ( . ) . in addition, our estimates of the overall cfr for kikwit and boende ( % and %, respectively) coincided with other estimates reported in the literature ( - % [muyembe and kipasa, ; khan et al., ; ndambi et al., ; sadek et al., ; chowell et al., ] and % [maganga et al., ] , respectively). the remaining outbreak estimates have not been studied by other authors and are reported here for the first time. overall, cfrs and delays between symptom onset and hospitalisation, symptom onset and death, and hospitalisation and death reported in our study do not differ substantially with those reported for the current outbreak (who ebola response team et al., b) . the data presented were originally collected for the containment of the outbreaks rather than for providing the basis of an epidemiological study of the disease. as such, variables are not recorded consistently across all outbreaks and there are missing data. this dataset does not take into consideration undetected cases. a surveillance study carried out in northwestern drc between and , through clinical records and serological testing, detected cases likely to be evd, suggesting that sporadic cases do occur (jezek et al., ) . another serosurvey carried out in yambuku after the outbreak suggested that that % of the population in the village was infected asymptomatically (breman et al., ) . under-reporting may differ between and during outbreaks and may impact the calculated estimates such as cfrs, which limits the validity of direct comparisons of values between outbreaks. other limitations include the different case definitions employed in different outbreaks and that the method used to calculate the effective reproduction numbers is susceptible to changes in reporting during the outbreak (as most methods are). however, it is robust if the extent of underreporting remains constant during each outbreak. moreover, it is robust to different reporting sensitivity between outbreaks. the regular re-emergence of evd in human hosts is likely to be connected to the presence of the virus in animal reservoirs, such as bats and monkeys (leroy et al., ; muyembe-tamfum et al., ) . the presence of vast tropical rainforests covering entire regions of the drc and the strong link existing between local economies and the forest makes a re-emergence of the virus in the country in the near future very likely (pigott et al., ) . although the mweka outbreak has been linked to the consumption of fruit bats that migrate to the area (leroy et al., ) , the epidemiological link between index cases (when known) and animal reservoirs has not been found for any of these outbreaks. all outbreaks except for the mweka outbreak have involved hospital transmission during the early part of the outbreak, illustrating the amplifying effect that poor infection control can have on evd epidemics. a study of the outbreak has highlighted the importance of community infection to transmission (camacho et al., ) . traditional burials are an important mechanism of transmission of evd. funeral data can help inform mathematical models that explore the importance of this route of transmission and can help guide resource allocation. this will be explored in subsequent analysis. mweka was the shortest and smallest outbreak with the lowest cfr. this could be due to the short delay between the first notification and the opening of the isolation centre ( days). the low cfr during isiro could be due to infection by a less virulent type of virus (b. ebolavirus) and is in line with what has been reported for this virus in other outbreaks (van kerkhove et al., ) . in most outbreaks, major interventions arrived when the reproduction number, r, was less than one and the epidemic was already under control. this suggests an important role of other factors, such as changes in contact behaviour, in shaping the changes of r. for example, there is evidence that an increase in the proportion of patients admitted to hospital was associated with a reduction in the size of evd transmission chains in guinea in (faye et al., ) and the community acceptance of evd control measures in west africa improved dramatically over the course of the epidemic, which led to better infection control (dhillon and kelly, ) . the boende outbreak began whilst the west african outbreak was gaining international importance. this much smaller outbreak, with an initial r of five, which consisted of cases, lasted only weeks. the more remote setting, a background antibody presence in the area and a greater preparedness to evd (that led to its notification weeks after the first case and the opening of the first isolation centre a month later) could have contributed to the avoidance of a larger outbreak (heymann et al., ; busico et al., ; maganga et al., ) . the high number of evd cases between and years of age compared to the background demographics, the high cfr in children under five, the decrease in cfrs in those to , and the subsequent increase in cfr during adulthood are phenomena that warrant further investigation. the variation in symptoms reported during different outbreaks is also a matter for further research. the public body in charge of containing evd outbreaks in the drc. these data were designed for outbreak containment rather than for epidemiological analysis; therefore, appropriate cleaning was undertaken. the fields selected were age, sex, date of symptom onset, date of hospitalisation, date of hospital discharge, outcome, case definition, date of notification (when the case was first reported to the dlm), date of death, occupation, fever, diarrhoea, abdominal pain, headache, vomiting, hiccups, and hemorrhagic symptoms. where this information was not available, it was left blank. a unique id was assigned to each patient in the dataset. the tandala outbreak ( ) included only one reported case; therefore, only the context and history of this outbreak was analysed. we included of the cases reported in yambuku (those for which these data were available). the aggregated line lists can be found in supplementary file . according to the who evd case definitions for outbreak settings; suspected cases are all individuals (alive or dead) who had a fever and had contact with a suspected, probable, or confirmed evd case or a sick or dead animal; any individual with a fever and more than three additional evd symptoms; or any person with unexplained bleeding or whose death is unexplained (world health organization, ) . probable cases are suspected cases that have a clear epidemiological link with a confirmed case. confirmed cases are individuals who were tested positive via pcr. in the drc setting, the case definitions employed varied somewhat between outbreaks (appendix , section a). unless stated otherwise, where the case definitions distinguished susceptible cases from probable and confirmed cases, all estimates presented (cfrs, symptom delays, and reproduction numbers) were computed omitting suspected cases. for temporal comparison of patient reports, we used the date of infection. when available, we used the date of symptom onset. when these were unavailable, hospitalisation dates were used instead. if these were also absent, the notification dates were used as proxy. when calculating the proportion of confirmed and probable cases that presented with evd symptoms, we assumed that patients for whom the presence or absence of at least one symptom was reported did not display any additional symptoms unless those were also reported. the odds of dying from evd were estimated through binomial regression with age group and year of outbreak as factorial covariates and the number of months since the start of the outbreak and the delay from symptom onset to hospitalisation as continuous covariates. the age groups used were - years, - years, and > years. the delay from symptom onset to hospitalisation was present for % of probable or confirmed cases. these dates were not recorded for yambuku and mweka and only for four cases for mweka . for this reason, these outbreaks were excluded from this first analysis. a second regression model was conducted that excluded the delays from symptom onset to hospitalisation as an explanatory variable, enabling the use of data from all major outbreaks and increasing statistical power. the start of an outbreak was defined by the earliest onset of symptoms of any detected case. the cis were calculated using profiled log-likelihood. we calculated the weekly effective r, the average number of individuals that were infected by a typical evd case during the period of infectiousness, by reconstructing the transmission tree of each outbreak on the basis of date of infection for each case (wallinga and teunis, ) . to link a case to its most likely source, we assumed a serial interval of . days with a standard deviation of . days as reported during the current outbreak in west africa (maganga et al., ) . delays in care were only calculated for those outbreaks for which the necessary dates were recorded. software r- . . was used for the cleaning, analysis, and plotting of figures (r development core team, ). this study was approved by the lshtm research ethics committee (approval number pr/ / ). the funders had no role in the design, collection, analysis, and interpretation of data, or in the writing of the manuscript. the corresponding authors had full access to all the data and were responsible for the final decision to submit for publication. author contributions ar, mb, conception and design, acquisition of data, analysis and interpretation of data, drafting or revising the article; mm, pm, bki, acquisition of data, drafting or revising the article; sf, ajvh, ac, sf, ak, analysis and interpretation of data, drafting or revising the article; wje, pp, j-jmt, conception and design, analysis and interpretation of data, drafting or revising the article ethics human subjects: this study was approved by the lshtm research ethics committee (approval number pr/ / ). informed consent and consent to publish were not required as the data had no personally identifiable information. person living in the epidemic area who died after one or more days with two or more of the symptoms (headache, fever, abdominal pain, nausea and/or vomiting, and bleeding). the patient must have within the prior days received an injection or had contact with a probable or confirmed case and the illness must not have any other obvious cause. ebola virus isolated, demonstrated by electron microscopy or ifa titre of at least : within days after symptom onset. • fever+ contact with ebola virus disease (evd) case. • fever and at least symptoms (headache, vomiting/nausea, anorexia, diarrhoea, fatigue, abdominal pain, myalgia, generalized generalised joint pains, dysphagia, hiccups). • any unexplained death. all those presenting hemorrhagic symptoms. • all those (dead or alive) presenting with fever that had contact with a patient suffering from a hemorrhagic fever or any sickly live or dead animal. • all those (dead or alive) presenting with fever and any three of the following symptoms: • suspected case evaluated by a clinician. • deceased case with an epidemiological link to a confirmed case. • suspected case that is known to have travelled in an area affected by the outbreak. suspected or probable case that has been tested positive in the laboratory. • all those (dead or alive) presenting or having presented with a sudden-onset high fever that had contact with a suspected, probable or confirmed evd case or any sickly live or dead animal. • all those (dead or alive) presenting or having presented with a sudden-onset high fever of sudden onset and any three of the following symptoms: all suspected cases that cannot be confirmed biologically but have an epidemiological link with a confirmed case (as determined by the surveillance committee). suspected or probable cases with a positive result in the laboratory (presence of ebola antigen, presence of viral rna detected by pcr or presence of anti-ebola igm). all suspected cases with a negative laboratory result (no ebola antigen, no rna by pcr, and no specific anti-ebola igm detected). section b. description of the outbreaks yambuku, the first known case was a -year-old male teacher who fell ill after a trip near gbadolite and was admitted at the yambuku catholic mission hospital on the th of august with a febrile illness thought to be malaria/typhoid fever. he later developed gastrointestinal bleeding and died on the th of september. the hospital held beds and was run by medical staff including three belgian nuns. five syringes and needles were provided to the hospital outpatient workers every morning and these were re-used on different patients without appropriate sterilisation. parenteral injection was the main delivery method for the majority of the medication administered to patients in the hospital, including vitamins given to pregnant women, and greatly contributed to the spread of disease through this population. on the th of september, the yambuku mission hospital was closed and the ebola virus (z. ebolavirus) was isolated on the th of october. between the st of september and the th of october, cases and deaths were reported (world health organization, ) . the following year, in june , a -year-old girl presented to the tandala mission hospital also in the equateur province, approximately km west from yambuku. she died of an acute hemorrhagic fever, later recognised as evd (heymann et al., ) . in , cases of evd were reported in the city of kikwit, the most densely populated area affected by evd in the democratic republic of the congo (drc) to date, and home at the time to , residents . the index case was thought to be a charcoal maker who worked in the forest close to kikwit. the first cases were observed in early april at the kikwit ii maternity hospital. after a laboratory technician from this facility was transferred to kikwit general hospital and underwent two laparotomies for a suspected perforated bowel, two nurses assisting the procedure and several providing postoperative care became ill. at the end of april, an outbreak of bloody diarrhoea was reported in the kikwit general hospital. initially, shigellosis was suspected, but upon receipt of laboratory supplies sent from kinshasa, patient samples were tested and this hypothesis was discarded. blood from acutely ill and convalescent patients was collected on the th of may and sent for testing to the cdc, atlanta. all hospitals, health centres, and laboratories in the kikwit area were closed. patients were quarantined at the kikwit general hospital with no running water, electricity, nor latrines. one physician and three nurses volunteered to stay with the patients. on the th of may, the cdc confirmed the evd diagnosis. the quarantine of patients in the kikwit general hospital had limited success because food had to be provided by patients' relatives. in addition, due to the poor living conditions, many patients fled the hospital . between the th of january and the end of june, cases and deaths were reported. the first cases of evd during the mweka outbreak in were detected in the mweka, bulape, and luebo health zones of the kasai occidental province. the mweka health zone alone spans over , km and comprises over , inhabitants. these cases were initially attributed to a novel disease originally named the kampungu syndrome, a hybrid between typhoid fever, shigellosis, and ebola. however, it was later recognised that three separate outbreaks of these diseases were co-existing in the same location. the retrospective nature of the diagnosis hindered the epidemiological investigation. from april to october, cases and deaths were reported. however, only cases were confirmed. two international mobile laboratories were opened on the th of september, one in mweka (public health agency of canada, phac) and one in luebo (cdc) (ministère de la santé publique (direction de la lutte contre la maladie), ). this outbreak was later associated with the consumption of fruit bats that annually migrate in masses to the area (leroy et al., ). one year later, a new outbreak of evd was detected in the same area. the epicentre of the outbreak was kaluamba (mweka) but the outbreak spread into the neighbouring district of luebo. the first reported case was an -year-old mother who had been suffering from fever since the th of november and was hospitalized at the kaluamba health centre on the th. she died from a post-partum haemorrhage after giving birth to a premature -month-old baby who died the same day. a traditional burial was then conducted. several of her contacts including the nurse that saw her at the health centre developed evd. the epidemiologists conducting the investigation postulated that she could have been infected though the injections she had received from the th to the th of november by a clandestine nurse from kaluamba in an attempt to decrease her fever. this clandestine nurse had previously treated another patient who had died weeks before. between the th and the th of december, national and international support arrived on site and msf belgium volunteers opened the first isolation centre in kaluamba on the th of december. on the nd of january, the isolation centre was transferred from kaluamba to kampungu, where new cases were being reported and msf had built an isolation centre during the preceding outbreak with greater capacity ( patients). three mobile laboratories were opened on the th of january (ministère de la santé publique (direction de la lutte contre la maladie), ). in total, from november to january, cases and deaths were reported. on the th of july , an evd outbreak was declared in the kibaale region of uganda, east of the albert lake. on the other side of this lake lies the orientale province of the drc. due to the proximity to the outbreak, the drc reinforced evd surveillance in this region. on the nd of august, the first suspected cases were reported in the isiro and dungu health zones in the haut-uélé (a population estimated at , ), making this the first known cross-border epidemic. already in june, seven hcws had died at the chemin de fer des uélé clinic (isiro) from a gastrointestinal febrile illness. when, in july, a daughter and her mother (who was caring for her) at the isiro general reference hospital presented with a similar illness with additional hemorrhagic symptoms, samples were sent to the cdc's uganda virus research institute laboratory in entebbe. the diagnosis of evd was confirmed on the th of july. this time, the infecting pathogen was the b. ebolavirus, different from the z. ebolavirus, encountered in all other outbreaks in the drc. on the th of august, a treatment centre was established at the isiro general reference hospital that was re-organised by msf belgium and spain who arrived on site on the th of august. on the th of august, the first laboratory was installed. the last case was confirmed on the th of october and the outbreak was declared over on the th of november. in total, cases and deaths were reported (ministère de la santé publique (direction de la lutte contre la maladie), ). the last outbreak to date took place years later in the boende health zone in the djera sector (equateur province), which comprises approximately , inhabitants. in mid-august , a set of suspiciously grouped cases and deaths were reported by the military personnel of the watsi-kengo camp to the central government. a -year-old pregnant woman from the ikanamongo village who was receiving antenatal care in her village started to develop a fever in the first week of august. she was transferred to the miracle centre in isaka but died a few hours after her arrival. because it is traditional not to burry a heavily pregnant mother with her child still inside her, a post-mortem cesarean section was carried out. all the hcws participating in the procedure later died of evd. days before these events, the nurse designated to the lokolia health centre had reported cases of a disease resembling ebola to the central bureau but was told to keep quiet about his suspicions. on the th of august, the health area supervisor reported similar findings to that of the military to the direction de lutte contre la maladie (dlm). eight blood samples were collected from patients hospitalised in lokolia and watsi-kengo and sent to the inrb, kinshasa. six were found positive to z. ebolavirus. the outbreak was officially declared over on the st of (ministère de la santé publique (comité national de coordination), ). cases and deaths were reported. estimating the reproduction number of ebola virus (ebov) during the outbreak in west africa the epidemiology of ebola haemorrhagic fever in zaire prevalence of igg antibodies to ebola virus in individuals during an ebola outbreak, democratic republic of the congo van den enden e, van den enden e. . ebola hemorrhagic fever in kikwit, democratic republic of the congo: clinical observations in patients potential for large outbreaks of ebola virus disease the basic reproductive number of ebola and the effects of public health measures: the cases of congo and uganda community trust and the ebola endgame chains of transmission and control of ebola virus disease in conakry, guinea, in : an observational study estimation and inference of r of an infectious pathogen by a removal method a likelihood-based method for real-time estimation of the serial interval and reproductive number of an epidemic ebola hemorrhagic fever: tandala, zaire, - ebola between outbreaks: intensified ebola hemorrhagic fever surveillance in the democratic republic of the congo the reemergence of ebola hemorrhagic fever, democratic republic of the congo understanding the dynamics of ebola epidemics statistical inference in a stochastic epidemic seir model with control intervention: ebola as a case study human asymptomatic ebola infection and strong inflammatory response human ebola outbreak resulting from direct exposure to fruit bats in luebo, democratic republic of congo ebola virus disease in the democratic republic of congo rapport de mission. riposte contre l'epidémie de la maladie a virus ebola epidémie de fièvre hémorragiqueà virus ebolaà mweka rapport de la gestion de l'epidémie de fièvre hémorragique virale ebola dans la zone de santé de mweka gestion de l'epidémie de la fièvre hémorragique a virus ebola a isiro ebola haemorrhagic fever in kikwit ebola outbreak in kikwit, democratic republic of the congo: discovery and control measures epidemiologic and clinical aspects of the ebola virus epidemic in mosango statistical data analysis of the ebola outbreak in the democratic republic of congo mapping the zoonotic niche of ebola virus disease in africa r: a language and environment for statistical computing clinical, virologic, and immunologic follow-up of convalescent ebola hemorrhagic fever patients and their household contacts ebola hemorrhagic fever, democratic republic of the congo, : determinants of survival a review of epidemiological parameters from ebola outbreaks to inform early public health decision-making different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures ebola haemorrhagic fever in zaire case definition recommendations for ebola or marburg virus diseases this study was funded by the fischer family trust, the national institute for health research health protection research unit in immunisation at the london school of hygiene and tropical medicine in partnership with public health england, the research for health in humanitarian crises programme (managed by research for humanitarian assistance, grant ). the views expressed are those of the authors and not necessarily those of the funders. we'd like to thank all the community nurses and volunteers on the ground that collaborated with the dlm to collect this data amid challenging circumstances. the funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. all those presenting with headache and/or fever for at least hr that had contact with a probable or confirmed case within the previous days. key: cord- - ylifqo authors: kelly, j. daniel; worden, lee; wannier, s. rae; hoff, nicole a.; mukadi, patrick; sinai, cyrus; ackley, sarah; chen, xianyun; gao, daozhou; selo, bernice; mossoko, mathais; okitolonda-wemakoy, emile; richardson, eugene t.; rutherford, george w.; lietman, thomas m.; muyembe-tamfum, jean jacques; rimoin, anne w.; porco, travis c. title: projections of ebola outbreak size and duration with and without vaccine use in Équateur, democratic republic of congo, as of may , date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: ylifqo as of may , , suspected, probable and confirmed cases of ebola virus disease (evd) had been reported in Équateur province, democratic republic of congo. we used reported case counts and time series from prior outbreaks to estimate the total outbreak size and duration with and without vaccine use. we modeled ebola virus transmission using a stochastic branching process model that included reproduction numbers from past ebola outbreaks and a particle filtering method to generate a probabilistic projection of the outbreak size and duration conditioned on its reported trajectory to date; modeled using high ( %), low ( %), and zero ( %) estimates of vaccination coverage (after deployment). additionally, we used the time series for prior ebola outbreaks from to to parameterize the thiel-sen regression model predicting the outbreak size from the number of observed cases from april to may . we used these techniques on probable and confirmed case counts with and without inclusion of suspected cases. probabilistic projections were scored against the actual outbreak size of evd cases, using a log-likelihood score. with the stochastic model, using high, low, and zero estimates of vaccination coverage, the median outbreak sizes for probable and confirmed cases were cases ( % prediction interval [pi]: , ), cases ( % pi: , ), and cases ( % pi: , ), respectively. with the thiel-sen regression model, the median outbreak size was estimated to be . probable and confirmed cases ( % pi: . , . ). among our three mathematical models, the stochastic model with suspected cases and high vaccine coverage predicted total outbreak sizes closest to the true outcome. relatively simple mathematical models updated in real time may inform outbreak response teams with projections of total outbreak size and duration. a a a a a on may , , the world health organization (who) announced the occurrence of an outbreak of ebola virus disease (evd) in the democratic republic of congo (drc). [ ] from april through may , suspected evd cases were reported in iboko and bikoro, Équateur province. on may , blood samples from five hospitalized patients had been sent to kinshasa for ebola-pcr testing, and two were confirmed pcr-positive. [ ] on may , vaccination of healthcare workers started. [ ] by may , the ring vaccination campaign was being rolled out as contacts and contacts of contacts were being actively monitored. six suspected, probable and confirmed evd cases had been reported, and ( %) of probable and confirmed evd cases had died. [ ] this outbreak had several features that were worrisome for widespread transmission. cases were reported over a -kilometer distance, including four confirmed cases in thẽ , , -inhabitant provincial capital of equateur, mbandaka, which is situated on the congo river and bordering congo-brazzaville. [ ] moreover, travel to kinshasa is frequent from mbandaka. given these risk factors, early epidemic growth profiles, [ ] and evidence of unreported infection from previous outbreaks, [ , ] the risk of a substantially larger outbreak could not be ignored. the factors causing epidemic growth to peak have been debated. delayed detection of evd outbreaks and resulting widespread distributions of evd have significantly contributed to epidemic growth. [ ] in addition to traditional burial practices, ebola treatment units with low quality care and/or high mortality rates have discouraged ebola suspects from presenting to care and contribute to community-based transmission. [ ] [ ] [ ] fragile, overwhelmed public health surveillance systems have also contributed to higher rates of unreported cases, who endanger urban communities, [ ] which potentially have had higher transmission rates than rural communities. [ ] change to subcritical transmission (reproduction number below ) tends to occur when ebola response organizations deploy control, prevention and care measures, [ , ] communities adopt more protective behaviors, [ , ] and/or transmission decreases in a social network. [ , ] scientific advances with rapid diagnostics and vaccines from the west africa outbreak were deployed in the april-july evd outbreak in drc and had the potential to limit ebola virus transmission. [ ] [ ] [ ] we used reported case counts during evd outbreak in drc and/or time series from prior outbreaks to estimate the total outbreak size and duration with and without the use of vaccines. these projections were intended to help organizations anticipate and allocate sufficient resources for the duration of the april-july evd outbreak. the following methods were used to generate projections: a stochastic branching process model, [ ] statistical regression based on prior outbreaks, and gott's law. [ ] on may , evd cases ( suspected, probable and confirmed) were reported in three locations (iboko, bikoro, and mbandaka) (fig ) . based on evd situation reports from drc, we assumed the ring vaccination program started the week of may , so we used may as the time point that vaccines were implemented in the model at high and low coverage levels. data on suspected, probable, and confirmed case counts were available from who situation reports in may and used as the basis for analysis. the published situation reports reflected data available up until may , , , , and , respectively. during the outbreak, the ebola response team tested suspected cases for evd and depending on positive or negative results, cases were classified as confirmed or not a case. the final outbreak case count was probable and confirmed cases (no suspected cases). [ ] due to this reporting process, probable and confirmed cases were used to parameterize the stochastic branching process model, regression models, and gott's law. we added suspected cases to create an additional projection, using stochastic branching process model. we modeled ebola virus transmission using a stochastic branching process model, parameterized by transmission rates estimated from the dynamics of prior evd outbreaks, and conditioned on agreement with reported case counts from the evd outbreak to date. we incorporated high and low estimates of vaccination coverage into this model. then we generated a set of probabilistic projections of the size and duration of simulated outbreaks in the current setting. to estimate the reproduction number r as a function of the number of days from the beginning of the outbreak, we included reported cases by date from thirteen prior outbreaks and excluded the first historical outbreak reported in those countries (e.g., outbreak in yambuko, drc) (s table) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] as there is a difference in the ebola response system as well as community sensitization to evd following a country's first outbreak, we employed this inclusion criterion to reflect the ebola response system in drc during what is now its ninth outbreak. the wallinga-teunis technique was used to estimate r for each case and therefore for each reporting date in the outbreak. [ ] the serial interval was defined as the interval between disease onset in an index case and disease onset in a person infected by that index case. the serial interval distribution used for this estimation was a gamma distribution with a mean of . days and a standard deviation of days, with intervals rounded to the nearest whole number of days, consistent with the understanding that the serial interval of evd cases ranges from to days with mean to days. [ , [ ] [ ] [ ] given that serial interval distribution, which we can denote as a probability w (t) of a t-day interval between given primary and secondary cases, wallinga-teunis estimation works by defining a relative likelihood p ij for each possible source j of a given case i: and then deriving from that an estimated reproduction number rj for each case: after using this technique to derive estimated reproduction numbers for each case in an outbreak, we use these estimated r values and cases' onset dates d to estimate an initial reproduction number r and quenching rate τ for each past outbreak by fitting an exponentially quenched curve: to each outbreak's r and d values (s fig) . transmission was modeled using a stochastic branching process model in which the number of secondary cases si caused by any given primary case i was drawn from a negative binomial distribution whose mean is the reproduction number r: [ , ] si � nbðr; kÞ; where r is reproduction number as a function of day, k is a dispersion parameter, and nb() denotes the negative binomial distribution. all transmission events were assumed to be independent. the serial interval between date of detection of each primary case and that of each of its secondary cases is assumed gamma distributed with mean . days and standard deviation days, rounded to the nearest whole number of days, as above. the pair of parameters r and τ estimated for the different past outbreaks used, and dispersion parameter k, were used in all possible combinations (with r and τ taken as a unit) to simulate outbreaks. this model generated randomly varying simulated outbreaks with a range of case counts per day. after the ministry of health and who conducted epidemiological investigations about the beginning of the evd outbreak in Équateur province, they concluded that the outbreak began on april , , with a single case. [ ] the simulation process occurs as follows: proposed epidemic trajectories are generated in an initial step based on the above branching process, and these are then subsequently filtered by discarding all but those whose cumulative case counts match the known counts of the april-july evd outbreak on known dates. the filtration accepts epidemics within a range of cases more or less than each recorded value. this one-step particle filtering technique produced an ensemble of model outbreaks, filtered on agreement with the recorded trajectory of the outbreak to date. this filtered ensemble is then used to generate projections of the eventual outcome of the outbreak. [ ] to model vaccination coverage with respect to total transmission (unreported and reported), we multiplied the estimate of vaccine effectiveness by low and high estimates of reported cases. in a ring vaccination study at the end of the west africa outbreak, the overall estimated rvsv-vectored vaccine efficacy was % and vaccine effectiveness was . % in protecting all contacts and contacts of contacts from evd in the randomized clusters, including unvaccinated cluster members. [ ] estimates of vaccine effectiveness were used in our stochastic model. the ring vaccination study found the vaccine to be effective against cases with onset dates days or more from the date of vaccine administration, so we modeled the vaccination program as a proportionate reduction in the number of new cases with onsets days or more after the program start date. then, past estimates of the proportion of unreported cases were used to estimate the proportion of exposed individuals not covered by the vaccination process. based on a sierra leonean study from the - outbreak, [ ] we estimated that the percentage of reported cases in drc would rise over time from a low of % to a high of %. given these low and high estimates of reported cases and the estimate of vaccine effectiveness ( . %), a low estimate of vaccination program coverage was % ( % multiplied by . %) and a high estimate of vaccination program coverage was % ( % multiplied by . %). the course of the outbreak with and without the vaccination program was modeled based on approximate dates available from situation reports. [ ] for simulation based on probable and confirmed cases, from , , simulated outbreaks, , were retained after filtering on approximate agreement with drc case counts. for simulation based on probable, confirmed, and suspected cases, from , , simulated outbreaks, , were retained after filtering. the simulated outbreaks that were retained after filtering were continued until they generated no further cases. this ensemble was used to derive a distribution of outbreak sizes and durations. mean and median values and % prediction intervals were calculated using the . and . percentiles of simulated outbreak size and duration. these analyses were conducted using r . . (r foundation for statistical computing, vienna, austria). for contrast with the stochastic model above, a simple regression forecast was conducted based solely on outbreaks of size or greater. time series for all such prior outbreaks were obtained, including seven prior ones from drc, dating back to (s table; the beginning of each outbreak was not reliably characterized; therefore, all time-series were aligned on the day they reached cases. in the april-july outbreak, we observed cases over the period from april to may (day to day ). may corresponded to day since reaching reported cases. for the prior outbreaks, linear interpolation was used to obtain the number of cases on day (after reaching cases). to reduce the influence of outliers and high leverage points, and to improve linearity, we calculated the pseudologarithm transform f(x) = arcsinh(x/ ), asymptotically logarithmic but well-behaved at . we used nonparametric theil-sen regression (r-package mblm) followed by calculation of the resulting prediction interval for a new observation. [ , ] finally, we reported the median and % central coverage intervals for the prediction distribution conditional on the value being no smaller than the observed value on day . sensitivity analysis was conducted using ordinary least squares regression. these analyses were conducted using r . . (r foundation for statistical computing, vienna, austria). gott' s law was used to estimate the outbreak size using data through may and may . we included a projection using data through may because we hypothesized that this method performs better when the first situation report is posted than at later in the outbreak period. [ ] then we included a projection with the regression models using data through may for comparison. with gott's law, we assume we have no special knowledge of our position on the epidemic curve. if we assume a non-informative uniform prior for the portion of the epidemic that still remains, the resulting probability distribution for the remaining number of cases y is: the median outbreak size was estimated, along with the two-sided % prediction interval. each of the above models assigned a probability to any possible value of the total outbreak size. the final outbreak size was probable and confirmed cases, so we identified the probability of this equivalent number ( ) from each model, as of may . probabilistic projections were scored using a log-likelihood (ignorance) score. [ ] as of may , , there were suspected, probable and confirmed evd cases. bikoko had ten confirmed cases, probable cases, and one suspected case. iboko had confirmed cases, two probable cases, and one suspected case. mbandaka had four confirmed cases and one suspected case (fig ) . with the stochastic model, we projected outbreak size and duration of probable and confirmed cases. in the absence of any vaccination program, the projected median outbreak size was . cases (mean . ; % prediction interval: . , . ). median duration of projected outbreaks was . days (mean . ; % prediction interval: . , . ). using a lower estimate of % vaccination coverage, the median outbreak size was . cases (mean . ; % prediction interval: . , . ) and median duration was . days (mean . ; % prediction interval: . , . ). using a higher estimate of % vaccination coverage, the median size was . evd cases (mean . ; % prediction interval: . , . ), and the median duration was . days (mean . ; % prediction interval: . , . ). these projections with the stochastic model were repeated to estimate suspected, probable and confirmed cases (table and table with the regression based on past outbreaks, the median outbreak size was estimated to be . probable and confirmed cases ( % prediction interval: . , . ), while use of ordinary least squares produced a median size of . probable and confirmed cases ( % prediction interval: . , . ). outbreak projections were also reported using data through may in table . gott's law suggests that given probable and confirmed cases, the median estimate of outbreak size was . cases ( % ci: . , . ). using the probable and confirmed cases as of may , the median estimate of outbreak size was . cases ( % ci: . , . ). of the mathematical models employed, the stochastic model that included suspected cases and high vaccination coverage had the best probabilistic score (log likelihood of - . ). likelihood scores of each model can be found in table . when we were conducting our projections in late may, this outbreak still had the potential to become the largest outbreak in drc since . vaccine use, regardless of coverage levels, was projected to prevent more than half of the total outbreak size. vaccines, however, were only part of concurrent prevention, control, and care strategies. [ , [ ] [ ] [ ] we also found that the stochastic model with vaccine use projected that rare, large outbreaks (tail of the distribution of the model without vaccinations) were prevented, suggesting that repeat epidemics such as the - west african outbreak may have been highly unlikely once vaccines were rolled out. multiple models were used to estimate total outbreak size. this study exemplified how mathematical models, including simple regressions, can be useful for advising real-time decision making because they provided rapid projections and similar estimates of r as compared to complex models, [ ] even though real-time modeling projections historically overestimated outbreak size and duration. [ , ] our projections that included suspected cases did not suggest that vaccines had as much of an impact as our model using only probable and confirmed cases. the trends associated with suspected cases were subject to several factors, including operational choices of response teams and maturity of the outbreak. nevertheless, suspected case counts may at times provide a better glimpse into the near future of an outbreak than the confirmed and probable case counts. in our case, use of the time series of confirmed, probable, and suspect cases yielded a forecast closer to the final outbreak size. however, as model projections can be highly sensitive to inclusion of suspected cases and use of exact case counts, particularly the last few counts in the available data, conclusions must be taken with caution. thus far, there had been a strong local and international response, and deployment of vaccines and rapid diagnostic tests (rdt) occurred early in response efforts. [ ] rdts were being used to screen ebola suspects while the vaccines are being administered to high-risk groups for evd, including healthcare workers, contacts, and contacts of contacts. to further limit epidemic growth from unreported cases, particularly those who have non-specific symptoms but table . distribution of projected outbreak size from stochastic branching process model. mean, median and % prediction interval of outbreak size, by proportion of vaccine coverage, using probable and confirmed cases with and without suspected cases. probable table . distribution of projected outbreak duration from stochastic branching process model. mean, median and % prediction interval of outbreak duration, by proportion of vaccine coverage, using probable and confirmed cases with and without suspected cases. there are limitations to our projections. projection distributions were right-skewed, with long tails (and we therefore reported the median instead of the mean). while there have been observed evd outbreaks with a case count greater than ten cases, we were unable to include all prior outbreaks in our estimates due to data availability. [ , ] note that the simple regression projection is based entirely on past outbreaks of evd (measured and reported in different ways), and cannot account for the improved control measures and vaccination in the way that a mechanistic model does. we included, however, as much real-time information into our estimates as possible, but situations such as the introduction of evd into a large urban population and implementation of rdts and vaccines are new to drc. we did not include vaccination of healthcare workers in the stochastic model. our estimates of vaccination effectiveness and reported cases were obtained from west africa because these estimates were not available for the evd outbreak in Équateur. these modeling assumptions may not have been consistent with estimates in drc and should be carefully considered prior to use in other evd outbreaks. a strength of our approach was the use of multiple methods to estimate the outbreak size, although we note that gott's law has not been validated for outbreak projections in other evd outbreaks. additional limitations of the models were that they did not include parameters to address spatial spread, urban settings, conflict zone, or other factors that may have influenced the accuracy of the predictions, particularly in the - evd outbreak in northeastern drc (ongoing in january ). while it can also be useful and achievable to use models of these kinds to make short-term forecasts for evaluation of model performance and to inform outbreak response, [ ] the present study was limited to projections of final outbreak size and duration. among our three mathematical models, the model that performed the best (stochastic model with suspected cases and high vaccine coverage) predicted total outbreak sizes close to the true outcome. when evd cases were introduced into mbandaka, there was concern that the total outbreak size could exceed most prior evd outbreaks in drc. indeed, our projections were consistent with this concern because models without vaccine coverage projected higher total outbreak sizes. in our stochastic model projections, vaccine use reduced mean total outbreak size by more than half, regardless of coverage levels (p< . , welch's t-test). as vaccine coverage was scaled up, an influx of support was warranted to support and bolster the evolving rapid response; however, continued efforts to strengthen the health system are equally as warranted so that we can respond to future outbreaks before they become epidemics. relatively simple mathematical models updated in real time may inform outbreak response teams with projections of total outbreak size and duration. supporting information s table. list of prior ebola outbreaks from to by time period, country, confirmed/probable reported and time series case count, outbreak inclusion into the regression and stochastic models. world health organization regional office for africa. health topics: ebola virus disease world health organization. emergencies preparedness, response excitement over use of ebola vaccine in outbreak tempered by real-world challenges mathematical models to characterize early epidemic growth: a review minimally symptomatic infection in an ebola 'hotspot': a cross-sectional serosurvey anatomy of a hotspot: chain and seroepidemiology of ebola virus transmission after ebola in west africa-unpredictable risks, preventable epidemics the ebola suspect's dilemma biosocial approaches to the - ebola pandemic ebola virus disease in west africa-clinical manifestations and management unreported cases in the - ebola epidemic: spatiotemporal variation, and implications for estimating transmission heterogeneity in district-level transmission of ebola virus disease during the - epidemic in west africa the impact of control strategies and behavioural changes on the elimination of ebola from lofa county dynamics and control of ebola virus transmission in montserrado, liberia: a mathematical modelling analysis risk communication and ebola-specific knowledge and behavior during - outbreak a theory-based socioecological model of communication and behavior for the containment of the ebola epidemic in liberia modeling household and community transmission of ebola virus disease: epidemic growth, spatial dynamics and insights for epidemic control ebola control: effect of asymptomatic infection and acquired immunity rapid antigen test for ebola. for use under emergency use authorization (eua) only efficacy and effectiveness of an rvsv-vectored vaccine in preventing ebola virus disease: final results from the guinea ring vaccination, open-label, cluster-randomised trial (ebola Ç a suffit!) ebola control: rapid diagnostic testing on the probability of the extinction of families implications of the copernican principle for our future prospects high-resolution global maps of st-century forest cover change report of a who/international study team ebola virus disease in southern sudan: hospital dissemination and intrafamilial spread ebola hemorrhagic fever outbreaks in gabon, - : epidemiologic and health control issues the reemergence of ebola hemorrhagic fever, democratic republic of the congo prise en charge des malades et des défunts lors de l'épidémie de fièvre hé morragique due au virus ebola d'octobre à décembre a limited outbreak of ebola haemorrhagic fever in etoumbi, republic of congo ebola virus disease in the democratic republic of congo filovirus outbreak detection and surveillance: lessons from bundibugyo different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures ebola virus disease in west africa-the first months of the epidemic and forward projections a systematic review of early modelling studies of ebola virus disease in west africa transmission dynamics and control of ebola virus disease (evd): a review comparing methods for estimating r from the size distribution of subcritical transmission chains superspreading and the effect of individual variation on disease emergence ebola virus disease in the democratic republic of the congo outbreak(s) of ebola haemorrhagic fever, congo and gabon potential for large outbreaks of ebola virus disease world health organization. weekly epidemiological record. abonnement annuel university of bergen dissertation for phd ebola virus disease outbreak in nigeria: transmission dynamics and rapid control ebola (ebola virus disease): history of ebola virus disease: - ebola outbreak in west africa: case counts estimates of the regression coefficient based on kendall's tau a rank-invariant method of linear and polynomial regression analysis. i, ii, iii. nederl akad wetensch, proc scoring probabilistic forecasts: the importance of being proper beyond vaccines: improving survival rates in the drc ebola outbreak food insecurity as a risk factor for outcomes related to ebola virus disease in kono district, sierra leone: a cross-sectional study the symbolic violence of 'outbreak': a mixed methods, quasiexperimental impact evaluation of social protection on ebola survivor wellbeing estimating the future number of cases in the ebola epidemic -liberia and sierra leone models overestimate ebola cases centers for disease control and prevention. outbreaks chronology: ebola hemorrhagic fever real-time projections of epidemic transmission and estimation of vaccination impact during an ebola virus disease outbreak in the eastern region of the democratic republic of congo we thank the ebola responders for their efforts in the evd outbreak in Équateur, democratic republic of congo. key: cord- -bswndfvk authors: lalle, eleonora; biava, mirella; nicastri, emanuele; colavita, francesca; di caro, antonino; vairo, francesco; lanini, simone; castilletti, concetta; langer, martin; zumla, alimuddin; kobinger, gary; capobianchi, maria r.; ippolito, giuseppe title: pulmonary involvement during the ebola virus disease date: - - journal: viruses doi: . /v sha: doc_id: cord_uid: bswndfvk filoviruses have become a worldwide public health concern, especially during the – western africa ebola virus disease (evd) outbreak—the largest outbreak, both by number of cases and geographical extension, recorded so far in medical history. evd is associated with pathologies in several organs, including the liver, kidney, and lung. during the – western africa outbreak, ebola virus (ebov) was detected in the lung of infected patients suggesting a role in lung pathogenesis. however, little is known about lung pathogenesis and the controversial issue of aerosol transmission in evd. this review highlights the pulmonary involvement in evd, with a special focus on the new data emerging from the – ebola outbreak. ebolavirus is part of the filoviridae family, which consists of three genera: marbugvirus, cuevavirus, and ebolavirus. there are currently six known, genetically distinct, species of ebolavirus-ebola virus (ebov), sudan ebolaviurs (sudv), tai forest ebolavirus (tafv), bundibugyo ebolavirus (bdbv), reston ebolavirus (restv), and bombali ebolavirus (bomv) [ , ] . no virus has triggered fear in the general population more than the filovirus ebolavirus [ ] . ebov is categorized among the deadliest viruses, with mortality rates up to %. the zoonotic origin of outbreaks are often the result of transmission from primates, although the suspected natural reservoir for ebov, bats, is still being questioned. since it was first identified in in zaire (the actual democratic republic of congo), confirmed outbreaks, mainly in the central part of africa, have occurred, and each outbreak was accompanied by high case fatality rates up to %, including the new declared outbreak ongoing in the north kivu province of the democratic republic of the congo [ ] [ ] [ ] . the - ebola outbreak is the largest (both by number of cases and geographical extension) ebolavirus outbreak ever reported, resulting . tlr stimulates irf- and nf-κb via myd activation, leading to the release of proinflammatory cytokines and the production of ifn-α, -β, and -λ, respectively. secretion of proinflammatory cytokines and chemokines activate the immune system, through recruitment of eosinophils, neutrophils, macrophages, dendritic cells, t cells, and nk cells. most respiratory viruses have developed strategies to escape antiviral defense, mainly by interfering with the ifn system or by affecting the epithelium barrier, with the consequence of a loss of integrity and protection. furthermore, respiratory viruses can perturb (skewed or exaggerated) inflammatory responses and production of soluble mediators. ebov infection is acquired through direct contact with bodily fluids. the virus enters blood circulation through breaks in the skin and mucosa and spread to different organs, causing systemic manifestation of cardiovascular, coagulation, or inflammatory disturbances [ ] . the terminal stages of evd usually involve massive tissue injury and hemorrhage, resulting in multiorgan failure and shock, the main cause of exitus in evd patients [ ] . during evd, respiratory symptoms such as chest pain, shortness of breath, cough, and nasal discharge are signals of the multisystem involvement, but, so far, lung damage has not been directly linked to ebov replication in the respiratory tract. however, new evidences collected during the recent - ebola outbreak hypothesized shedding of the virus in the lung and identified viral replication markers in sputum samples collected from ebov infected patients [ ] . on the other hand, the high virulence of ebov is attributed in large part to the ability of this virus to interfere with the host immune response, and the high degree of variation in lung pathogenesis is usually linked to indirect damage due to endothelial and epithelial inflammation and the hyper-activation of the immune system subsequent to ebov infection. in fact, viral direct damages are always associated with indirect damages, caused by inflammatory and immune reactions elicited by the viruses through the activation of soluble mediators (cytokines and chemokines) as part of the immune response ( figure ). the acute inflammation process is characterized by increasing blood flow, which enables plasma and leukocytes to reach extra-vascular sites of injury. even though inflammation may be often restored, in evd, severe inflammation is associated with a cytokine storm and more serious pathological changes are observed. for instance, ebov in vitro infection of monocytes and macrophages triggers the robust expression of inflammatory mediators, including il- β, il- , il- , mip- a, mip- β, mcp- , and tnf-α [ , ] , whereas the dysregulation of immune mediators in humans has been associated with the secretion of other inflammatory mediators, such as il- β, il- , ccl , ccl , ccl , cxcl , cxcl , cxcl , cxcl , il , mif, spp [ ] [ ] [ ] . in addition, severe inflammatory upon entrance into the cell, viruses are recognized by the toll-like receptor (tlr) on either cell membrane or in endosomes. tlrs activate interferon regulatory factors (irfs) leading to ifn-α and ifn-β release via the toll/il- receptor domain-containing adaptor (trif). tlr stimulates irf- and nf-κb via myd activation, leading to the release of proinflammatory cytokines and the production of ifn-α, -β, and -λ, respectively. secretion of proinflammatory cytokines and chemokines activate the immune system, through recruitment of eosinophils, neutrophils, macrophages, dendritic cells, t cells, and nk cells. most respiratory viruses have developed strategies to escape antiviral defense, mainly by interfering with the ifn system or by affecting the epithelium barrier, with the consequence of a loss of integrity and protection. furthermore, respiratory viruses can perturb (skewed or exaggerated) inflammatory responses and production of soluble mediators. ebov infection is acquired through direct contact with bodily fluids. the virus enters blood circulation through breaks in the skin and mucosa and spread to different organs, causing systemic manifestation of cardiovascular, coagulation, or inflammatory disturbances [ ] . the terminal stages of evd usually involve massive tissue injury and hemorrhage, resulting in multiorgan failure and shock, the main cause of exitus in evd patients [ ] . during evd, respiratory symptoms such as chest pain, shortness of breath, cough, and nasal discharge are signals of the multisystem involvement, but, so far, lung damage has not been directly linked to ebov replication in the respiratory tract. however, new evidences collected during the recent - ebola outbreak hypothesized shedding of the virus in the lung and identified viral replication markers in sputum samples collected from ebov infected patients [ ] . on the other hand, the high virulence of ebov is attributed in large part to the ability of this virus to interfere with the host immune response, and the high degree of variation in lung pathogenesis is usually linked to indirect damage due to endothelial and epithelial inflammation and the hyper-activation of the immune system subsequent to ebov infection. in fact, viral direct damages are always associated with indirect damages, caused by inflammatory and immune reactions elicited by the viruses through the activation of soluble mediators (cytokines and chemokines) as part of the immune response ( figure ). the acute inflammation process is characterized by increasing blood flow, which enables plasma and leukocytes to reach extra-vascular sites of injury. even though inflammation may be often restored, in evd, severe inflammation is associated with a cytokine storm and more serious pathological changes are observed. for instance, ebov in vitro infection of monocytes and macrophages triggers the robust expression of inflammatory mediators, including il- β, il- , il- , mip- a, mip- β, mcp- , and tnf-α [ , ] , whereas the dysregulation of immune mediators in humans has been associated with the secretion of other inflammatory mediators, such as il- β, il- , ccl , ccl , ccl , cxcl , cxcl , cxcl , cxcl , il , mif, spp [ ] [ ] [ ] . in addition, severe inflammatory cytokines/chemokines may spill over into the circulation and result in systemic cytokine storms, which are responsible for multi-organ dysfunction and for the impairment of the vascular system and disseminated intravascular coagulation [ , ] . dendritic cells (dcs) play an essential role in the link between the innate and adaptive immune response, and their maturation is essential for the correct functionality of dcs, such as the migration, processing, and presentation of viral antigens to t-and b-cells for their activation and correct viral clearance [ , ] . ebov infection has been shown to influence these mechanisms through impairment of dcs in upregulating co-stimulatory molecules (cd , cd , and cd ) and major histocompatibility complex (mhc) class ii, as well as soluble chemokines and cytokines [ ] . ebov infection is also able to influence the adaptive immune response: severe lymphopenia and the destruction of lymphoid tissue is one of the hallmarks of ebov infection. fatal cases showed a more marked reduction of nk cells and γδ t-cell frequency, as well as a loss of peripheral blood cd + and cd + t cells [ , ] . moreover, a recent study showed that patients with fatal outcome presented lower, or often absent, levels of both ebov-specific igm and igg, which, when detected, appeared later than in survivors [ ] . overall, the alteration of the innate and adaptive response explains the paralysis of the immune system and its inability to initiate and maintain a protective immune response. at the pulmonary level, many of the pathological changes are, in fact, secondary to systemic alterations, correlating with general pathogenic mechanisms, which are the major causes of severe disease in humans, even at the respiratory level [ , ] . evd is a viral hemorrhagic fever (vhf) characterized by acute systemic manifestations with vascular damage, plasma leakage, severe inflammation, and disruption of the immune system [ ] . evd transmissibility seems to vary depending on the stage of disease [ ] . a high-level of ebov replication, associated with systemic dissemination to multiple cell types, results in a complex pathogenesis, which is linked to an increased risk of infection transmission [ ] . as stated above, these pathogenic mechanisms include detrimental immune suppression and over-activation of the immune response, disordered coagulation, and tissue damage due to direct viral and indirect host-mediated effectors. in the absence of adequate supportive care, these processes commonly result in multiple organ failure and death within about days of symptom onset in humans. it is well recognized that ebov infection is acquired by direct contact with bodily fluids. notably, studies conducted in animal models have instilled doubts about possible airborne/droplet transmission (see section . ). however, this route of infection in humans is still debated. piercy and colleagues evaluated the actual stability of the virus particles in aerosol droplets [ ] . they created ebola-containing aerosol droplets and, according to the decay rates, estimated that ebov and restv can survive in aerosols for roughly and min, respectively, at % to % relative humidity and ± • c [ ] . therefore, a key additional question to ask is whether primary pulmonary infection of ebov could be a potential scenario for the future. a fair amount of studies, based on animal experiments (table ) and clinical evidence collected during the outbreaks ( table ), suggest that pulmonary infection may be a possibility. this possibility will be fully investigated below. after its first discovery in in cynomolgus macaques imported to reston, virginia, restv was detected in domestic swine in the philippines in a co-infection with the porcine reproductive and respiratory syndrome virus (prrsv, family arteriviridae, genus arterivirus) and porcine circovirus type (pcv- ; family circoviridae) [ , ] . later on, restv was identified to cause asymptomatic infections with mild respiratory symptoms, which may result in severe mortality in cases of co-infections with other viral pathogens like viruses in the families arteriviridae and circoviridae. the virus was first isolated in lung and lymphoid tissues in the original disease investigation [ ] . however, the massive presence of the virus in the lungs may be due to the fact that restv infection in pigs has been mostly associated with other infections of the respiratory tract, which may contribute to the specific localization of the virus and the respiratory symptoms of the disease. marsh et al. [ ] conducted an experimental study to rule out the effect of other pathogens affecting pigs, using a philippines swine isolate of restv. specifically, five-week-old pigs were exposed (via the oro-nasal or subcutaneous route) to the virus, and the subsequent viral replication in internal organs and shedding of the virus from the nasopharynx was observed. the researchers detected the highest levels of virus replication in lung and lymphoid tissues, confirming previous results [ ] . the detection of restv in domestic swine raised important biosecurity concerns about the potential for the disease's emergence in humans and other livestock, mainly in animals for food consumption [ , ] . the evidence of restv seropositive individuals further increased the concern for human infections and the worries of researchers, farm owners, and the public at large (world health organization. who, , available online: https://www.who.int/csr/resources/publications/hse_ epr_ _ .pdf). interestingly, so far restv has not been seen to result in any human disease, even if there is concern that its passage through swine may allow restv to diverge and shift its potential for pathogenicity [ ] . on the other hand, several studies investigated if other ebola viruses may be transmitted through the aerosol route and may result in primary pulmonary infection [ , , ] . researchers reviewed the different animal models and offered an overview regarding the possibilities of ebola viruses causing aerosol infections in non-human primates (nhps) and other animals. experimental studies analyzed the respiratory tract involvement in filovirus infections when the animals were exposed to the virus through different aerosol routes (artificially aerosolized virus or natural aerosol transmission) [ , , , ] . in these experimental studies conducted on nhps and pigs, ebov was inoculated via the aerosol route, and, following mucosal exposure, ebov replicated, reaching high concentrations, mainly in the respiratory tract, with the development of severe lung pathology. interestingly, weingartl et al. demonstrated that piglets inoculated oro-nasally with ebov and then transferred to a different room housing macaques in an open inaccessible cage system resulted in ebov infection of all macaques, suggesting a need to revise prevention and control measures during outbreaks [ ] . viral replication was observed within alveolar spaces [ , ] , in type i pneumocytes and macrophages [ ] , and in type ii pneumocytes, bronchiolar epithelial cells, and endothelial cells [ ] , supporting the respiratory involvement. the upper and lower respiratory tract, the lymphoid tissues, and the mediastinal lymph nodes showed infection signs, as well [ ] . similarly, in experiments on cynomolgus macaques placed separately in cages with experimentally infected piglets [ ] , and on guinea pigs exposed via aerosols to a guinea pig-adapted ebov strain [ ] , viral antigens were detected within alveolar and septal macrophages, pneumocytes, epithelial cells, endothelial cells, fibroblasts, and other interstitial cells of the respiratory tree [ ] . considering the pathology of the respiratory system, the expression of disease in the lungs and the patterns of lesions seem to be influenced by the exposure routes (aerogenous or hematogenous). broncho-interstitial pneumonia, characterized by injury to both the bronchiolar and the alveolar epithelium, is commonly caused by aerogenous viral infections [ ] . moreover, such pathological features were generally not evidenced following the inoculation of ebov by other routes in nhps and laboratory animals [ , ] . as shown in animal studies, primary pulmonary infections could occur and cause active viral shedding from the respiratory tract, thus potentially setting up a cycle of ongoing respiratory transmission in humans [ , ] . overall, experimental works conducted so far have shown that ebov infection induces respiratory complications, that the virus can be shed via the respiratory secretions, and that it can cause similar pulmonary lesions both in animals exposed to aerosols and in those kept nearby in separate cages with no close contact. the pathophysiological mechanism of pulmonary disease in patients with evd is unknown. notably, autopsies were performed on a limited number of humans (about cases), primarily during the sudv and ebov evd outbreaks and revealed interesting characteristics at microscopic level. during the first known sudv outbreak, chest pain was almost universal ( % of patients), often accompanied by a dry cough. autopsies were further performed on two patients and thickening of the alveolar walls due to proliferative accumulations of alveolar cells was found [ ] . furthermore, a possible pathogenetic role of the virus in the respiratory tract was suggested by the fact that viral inclusions within alveolar macrophages and free viral particles within alveolar space were found in the lungs from fatal evd cases who showed congestion, focal intra-alveolar edema, diffuse alveolar damage, and hemorrhaging. [ , ] . one of the most common symptoms in evd patients is a cough (up to %), especially during the progression of the disease, when viral loads in serum significantly increase, and the virus is copiously emitted in most body fluids, as well as in aerosol particles of various sizes [ , ] . among the reported evd cases in the literature, respiratory symptoms were commonly reported with a wide range of symptoms, such as a cough (from % [ , ] to % [ ] ), dyspnoea or breathless (detected from % [ ] to % [ ] ), and chest pain (from . % [ ] to . % [ ] ). moreover, a who study on the first months of the epidemic in western africa found that nearly % ( out of ) of the patients experienced coughing and . % ( of ) had a bloody cough [ , ] . a study of ebov-positive patients of the - outbreak in western africa, treated in europe and usa, reported that cough and dyspnoea were present at admission in seven ( %) and five ( %) evd patients, respectively. at symptom onset, only a cough was reported in one patient. furthermore, during hospitalization, patients ( %) experienced hypoxemia while they were breathing ambient air, patients ( %) had pulmonary oedema, seven patients ( %) had pneumonia, patients ( %) had respiratory failure, and six patients ( %) had a diagnosis of acute respiratory distress syndrome (ards). of these patients, four patients ( %) received non-invasive mechanical ventilation, and seven patients ( %) received invasive mechanical ventilation [ ] . notably, the first ebov-positive patient treated in italy, mechanically ventilated for respiratory insufficiency for days, had high levels of ebov rna in the lower respiratory tract secretions. the authors concluded that the absence of other identified respiratory pathogens in broncho-alveolar lavage fluids and aspirates supported the hypothesis of a direct contribution to the lung tissues damage by ebov. notably, ebov rna was detected in bronchial aspirate fluids when the ebov rna concentration in the concomitant blood samples was barely detectable. furthermore, the blood ebov rna concentrations in the previous days were significantly lower than the concentrations detected in the bronchial aspirate samples. these findings suggest that this ebov infection is unlikely a spillover from the blood compartment, eventually accompanied by delayed clearance. instead, the most plausible explanation is that the virus actually replicated into the lower respiratory tract [ ] . in the second ebov-patient treated in italy, our group investigated the presence of ebov genetic material in the lungs and blood during the patient's treatment and recovery. the patient showed a persistence of ebov replication markers within the respiratory tract, with a prolonged detection of ebov viral rnas (negative and positive sense rnas: neg-rna and pos-rna, respectively), known to be associated with ebov replication, in the lower respiratory tract for up to five days after the ebov viral load in blood was already undetectable. these results suggest that ebov may replicate in the lungs, although it is possible that the lungs simply provided a protective environment that allowed rna to linger longer than it did in the plasma. nevertheless, the detection of pos-rna together with neg-rna in the sputum (until day and of the hospital stay, respectively) supports the concept of active viral replication within the respiratory tract, rather than plasma spill-over or prolonged rna stability [ ] . overall, the pathophysiological mechanisms of pulmonary disease in patients with evd are still uncertain, but there could be multiple contributing factors, including vascular leak from endothelial infection, cytokine dysregulation, or direct damage to ebov-infected cells (figure ). viruses , , x for peer review of of pos-rna together with neg-rna in the sputum (until day and of the hospital stay, respectively) supports the concept of active viral replication within the respiratory tract, rather than plasma spill-over or prolonged rna stability [ ] . overall, the pathophysiological mechanisms of pulmonary disease in patients with evd are still uncertain, but there could be multiple contributing factors, including vascular leak from endothelial infection, cytokine dysregulation, or direct damage to ebov-infected cells (figure ). our understanding of ebov transmission in humans mainly relies on epidemiological observations. contact with bodily fluids from evd patients remains the most likely route of transmission. notably, the number of past outbreaks and associated epidemiological studies hat carefully examine transmission patterns is small. therefore, conclusions about transmission are based on relatively limited data sets [ ] . interestingly, ( . %) of the cases in the sudv outbreak in nzara, sudan, and ( . %) of the cases during the ebov outbreak in kikwit, drc, had no direct or physical contact with an infected person or known infected dead body [ , ] , thus pointing to other possible routes of transmission, e.g., human to human respiratory tract infection through droplet and aerosols. during the - western africa epidemic, more than health care workers (hcw) were infected, with a case fatality rate of % [ ] , whereas during our understanding of ebov transmission in humans mainly relies on epidemiological observations. contact with bodily fluids from evd patients remains the most likely route of transmission. notably, the number of past outbreaks and associated epidemiological studies hat carefully examine transmission patterns is small. therefore, conclusions about transmission are based on relatively limited data sets [ ] . interestingly, ( . %) of the cases in the sudv outbreak in nzara, sudan, and ( . %) of the cases during the ebov outbreak in kikwit, drc, had no direct or physical contact with an infected person or known infected dead body [ , ] , thus pointing to other possible routes of transmission, e.g., human to human respiratory tract infection through droplet and aerosols. during the - western africa epidemic, more than health care workers (hcw) were infected, with a case fatality rate of % [ ] , whereas during the current - outbreak in drc, as of july , hcw have been already affected ( . % of total cases) [ ] . currently, full body protection is recommend by who and cdc [ , ] . all hcw involved in the care of evd patients must receive training and demonstrate competency in performing all ebola related infection control practices and procedures, specifically in proper donning and doffing ppe even if using an n mask or a powered air-purifying respirator (papr). the risk of infection via inhalation of contaminated aerosols from exposed individuals has not been documented. however, droplets containing ebov that have become aerosolized (e.g., from coughing sneezing, vomiting, invasive medical or surgical procedures, or surfaces) may have the potential to come into contact with a person's mucous membrane in their nose or mouth or non-intact skin. therefore, respiratory protection may be helpful in providing a barrier to help prevent infectious materials from contacting a wearer's mucous membranes. finally, the epidemiologic and viral evidence of ebov detection and replication in the respiratory tract raise concerns on the need of strict application of cough etiquette for patients and of droplet and/or respiratory precautions for all hcw involved in the clinical management of evd suspected and confirmed cases. acute respiratory tract infections (artis) remain a leading cause of mortality, morbidity, and economic loss, and viruses are one of the main causes of such disease. who estimates that artis cause nearly four million deaths per year, a rate of more than deaths/ , people [ ] . the microbial etiology of aris is varied, with viruses being the most common cause in humans [ ] , leading to a high level of awareness and the necessity to develop countermeasures to control them (table ) . filoviruses are not commonly considered to be viruses responsible for aris, even if respiratory symptoms may be present as a consequence of diffuse systemic alterations. interestingly, evidence collected in animal studies, in the epidemiological analysis of transmission chains, and in the most recent ebola outbreaks suggests that ebov may be able to cause primary pulmonary infection. this evidence highlights the ability of the virus to be shed in the lung, suggesting a role in lung pathogenesis. specifically, the relevant proportion of evd patients without any epidemiologic link to the exposure to contaminated biological samples or fomites, or to any contact with evd patients; the evidence of respiratory signs and symptoms commonly reported all over the clinical course; the abundance of viral antigens in the lungs in animal necropsies; the prolonged persistence of ebov detection and replication within the respiratory tract days after undetectable ebov viral load in plasma; and similar clinical patterns in several other viral respiratory tract infections are all different parameters with consistent evidence of a major role in the pathogenesis of evd in respiratory tissues [ ] . on the other hand, there is no evidence of aerosol transmission in evd. however, different studies addressing this issue have been performed [ , ] , and aerosol transmission was considered a possibility as a consequence of epidemiological observations in past outbreaks, where people showed signs of evd even in the absence of a direct or physical contact with an infected person or known infected dead body [ , ] . this hypothesis was corroborated by other studies, in which the presence of free viral particles in alveoli and within intra-alveolar macrophages demonstrated a pulmonary involvement [ ] . from a clinical point of view, the - ebov outbreak underlined the lung involvement in evd pathogenesis. in fact, only a few patients treated in europe and usa had a cough and difficulty breathing at admission. nevertheless, during the clinical progression, half of the patients experienced hypoxemia while breathing room air, one third had respiratory failure, and one fourth received invasive or non-invasive mechanical ventilation [ ] . in the italian experience at the national institute for infectious diseases "l. spallanzani" (inmi), respiratory symptoms were present in both patients, in the absence of other common respiratory pathogens [ , ] . one case required mechanical ventilation and the other presented ebov replication markers in the lungs even after clearance of the virus from the blood. the inmi experience suggests a direct role of the virus in lung pathogenesis. although lung pathogenesis in evd may be secondary to systemic alterations (correlating with general pathogenic mechanisms) the direct presence of the virus is undisputable in the lung, and its interaction with the immune system, whose hyper-activation may be the most likely explanation of the lung damage, is also indisputable. further research will be 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of the viral hemorrhagic fevers dengue viruses can infect human primary lung epithelia as well as lung carcinoma cells, and can also induce the secretion of il- and rantes pathogenesis of lassa fever. viruses pathophysiology of hantavirus pulmonary syndrome in rhesus macaques this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -g ki vyy authors: de rooij, doret; belfroid, evelien; eilers, renske; roßkamp, dorothee; swaan, corien; timen, aura title: qualitative research: institutional preparedness during threats of infectious disease outbreaks date: - - journal: biomed res int doi: . / / sha: doc_id: cord_uid: g ki vyy background: as demonstrated during the global ebola crisis of – , healthcare institutions in high resource settings need support concerning preparedness during threats of infectious disease outbreaks. this study aimed to exploratively develop a standardized preparedness system to use during unfolding threats of severe infectious diseases. methods: a qualitative three-step study among infectious disease prevention and control experts was performed. first, interviews (n = ) were conducted to identify which factors trigger preparedness activities during an unfolding threat. second, these triggers informed the design of a phased preparedness system which was tested in a focus group discussion (n = ) were conducted to identify which factors trigger preparedness activities during an unfolding threat. second, these triggers informed the design of a phased preparedness system which was tested in a focus group discussion (n = ) were conducted to identify which factors trigger preparedness activities during an unfolding threat. second, these triggers informed the design of a phased preparedness system which was tested in a focus group discussion ( results: four preparedness phases were identified: preparedness phase green is a situation without the presence of the infectious disease threat that requires centralized care, anywhere in the world. phase yellow is an outbreak in the world with some likelihood of imported cases. phase orange is a realistic chance of an unexpected case within the country, or unrest developing among population or staff; phase red is cases admitted to hospitals in the country, potentially causing a shortage of resources. specific preparedness activities included infection prevention, diagnostics, patient care, staff, and communication. consensus was reached on the need for the development of a preparedness system and national coordination during threats. conclusions: in this study, we developed a standardized system to support institutional preparedness during an increasing threat. use of this system by both curative healthcare institutions and the (municipal) public health service, could help to effectively communicate and align preparedness activities during future threats of severe infectious diseases. e four pandemics (sars, influenza a/h n , mers, ebola) that have emerged since the beginning of this century [ ] underpin the necessity of global awareness and optimal control strategies. ese outbreaks showed the potential for the worldwide spread of such severe diseases [ ] and led to social unrest and large economical consequences for the affected countries [ ] . during the spread of the ebola viral disease (evd) outbreak in west africa, the likelihood of imported cases in europe increased, and european countries advised their healthcare institutions to prepare for patients with suspicion of evd. admission of a patient suspected for evd, or another transmittable viral hemorrhagic fever (vhf), requires a large pool of trained healthcare workers and of specialized medical facilities [ , ] . erefore, in the netherlands, the care for these patients was designated to a few highly specialized hospitals. an evaluation by the harvard-lshtm independent panel on the global response to ebola concluded that international response to evd was inadequate [ ] . a multidisciplinary national evd outbreak evaluation in the netherlands concluded that better guidance on preparedness during threats of outbreaks was needed for diseases, such as evd, where patients only can be admitted to highly specialized hospitals [ ] . in the netherlands, as in other countries [ , ] , it had been unclear among curative and public health institutions which preparations during a developing threat of evd were necessary, and for which preparations, the institutional or national level should have guidance [ ] . while many studies describe preparedness for outbreaks, preparedness during a remote threat is not discussed separately in literature. e european center for disease control defines preparedness for infectious diseases as "the knowledge and capacities […] to effectively anticipate, respond to, and recover from, the impacts of a likely, imminent or current crisis" [ ] . preparedness includes the development of institutional, national or international plans, communication and collaboration among different (types of) healthcare institutions, training and simulation, and surge capacity. e evd outbreak, however, showed that successful preparedness during a threat requires flexibility and adaptations to be able to respond to differences in the probability of occurance of the disease. what these adaptations should be, has been unclear. ere is a need to clarify what preparedness entails in healthcare institutions during threats of severe infectious diseases whose patients can, due to the severity of the disease, only be admitted to designated, highly specialized hospitals (from now on described as diseases "which require centralized care"). erefore, the aim of this study was to define preparedness during an unfolding threat of an infectious disease that requires centralized care. second, we aimed to exploratively develop a standardized preparedness system describing preparedness activities for healthcare institutions in different preparedness phases. we conducted a qualitative three-step study with an iterative design of in-depth interviews (steps and ) and a focus group (step ), in order to identify the key elements of a preparedness system. e system includes (a) the triggers for healthcare institutions to initiate extra preparedness activities during different levels of a threat, which define preparedness phases, and (b) preparedness activities for each preparedness phase. we aimed at finding generic triggers for preparedness, applicable to different types of healthcare institutions, such as hospitals, ambulance services, general practitioners and the municipal health services. e outline of the preparedness system is shown in figure . in the first round of in-depth interviews, we explored the phases and triggers of the preparedness system, which we validated in the consensus meeting. in the second round of interviews, we aligned the preparedness activities per phase and grouped them per topic. we obtained ethical approval from the medical ethical committee of the umc utrecht (wag/mb/ / ). all participants provided informed consent and were informed that their responses would be used for research purposes. for all three steps, we invited professionals working at various levels and in various healthcare institutions and public health organizations. included healthcare institutions were academic and peripheral hospitals, ambulance services, general practitioners, and municipal health services. figure shows how healthcare institutions are involved in the case of a potential patient requiring centralized care [ ] . e municipal health service (mhs) was additionally involved because of their coordinating role between all partners at the regional level. professionals with the following backgrounds were invited: (i) academic hospitals: microbiologists and infectious disease specialists; (ii) peripheral hospitals: infection preventionists; (iii) ambulance services: medical managers at the regional and national level; (iv) general practitioners: respresentattives of the national association for general practitioners (lhv) and dutch college of general practitioners (nhg); (v) municipal health services: regional communicable disease control consultants and infectious disease control specialists. we used purposeful sampling by approaching the key players in the netherlands, from the above-mentioned healthcare and public health organizations, who were involved in preparedness and/or response during the evd outbreak. when the invited key player was not able to participate, we asked him or her to nominate a colleague in the same type of healthcare institution with comparable expertise. all professionals had, in this way, expertise in evd preparedness or response. for step and we aimed for one participant per healthcare institution. for step , we aimed for - participants per healthcare institution. participants were invited by e-mail and a consecutive telephone call during september-november . collection. data collection comprised three steps: individual interviews, a focus group and another individual interview round. a hypothetical scenario of a vhf outbreak was used for data collection, which was developed by experts on outbreak control of the national institute for public health and the environment (rivm). e scenario described a fictitious marburg virus outbreak in uganda that spread towards neighboring countries and continuously led to exported cases throughout the world. e outbreak scenario consisted of three stages, each hypothetically representing a preparedness phase of the preparedness system, as shown in figure . based on the identified triggers, preparedness phases for the preparedness system were developed. for each of these preparedness phases, again a corresponding scenario of the marburg virus outbreak was developed to discuss in the focus group of step . e preparedness system was adjusted based on the results from step and was sent by e-mail to the participant to discuss in step . e results of step were used to finalize the preparedness system by grouping preparedness activities into overarching topics, and in institutional and collaborative activities. step consisted of individual, in-depth, semistructured interviews. to ensure that collected data was as reliable and consistent as possible, an interview guide was developed beforehand (additional file ). e interview guide for step was piloted with a microbiologist at a dutch academic hospital. all interviews were conducted by one researcher (ddr), to safeguard inter-observer reliability. interviews took between and minutes. during the interviews, the interviewer presented the outbreak scenario to the participant. per preparedness phase, the participant was asked if and why preparedness activities would be necessary for their healthcare institution. in this way, the triggers for preparedness activities were explored. alongside, questions covered terminology for preparedness during a threat, responsibility for preparedness during a threat, and collaborative preparedness activities carried out together with other healthcare institutions. step . in step , a mixed focus group discussion with - representatives per type of healthcare institution was organized to validate the concept preparedness system. a focus group guide was developed beforehand (additional file ). e focus group was guided by two researchers (ddr and cs), and supported by an expert in guiding focus groups (re). e focus group took place at the rivm and lasted hours and mintues. per preparedness phase, the corresponding scenario was presented. participants were asked if and why preparedness would be necessary within their institutions, what they would expect the other healthcare institutions to do, and where cooperation and support between healthcare institutions was needed. in the second phase of the focus group, preparedness activities identified in step were presented to representatives of each type of healthcare institution separately. representatives of one type of healthcare institution debated if and in which preparedness phase these preparedness activities were needed. subsequently, terminology for preparedness during a threat was discussed among all participants, since the interpretation of terminology had shown to be different. step consisted of individual, in-depth, semistructured interviews. we included one participant per type of healthcare institution out of the participants in step . an during the first interview round, "scaling up" and "enhanced preparation" were used as synonyms by the interviewer for different preparedness phases. in the focus group, we observed differences in interpretation between curative and municipal health services. according to the curative partners, the dutch term for upscaling that was used, applied to the response phase "with the presence of an actual potential patient". in contrast, for the mhs, the term could also be used for preparedness during an increasing threat. e need for congruent language was highly stressed by the participants, and consensus was reached on the definition of "enhanced preparedness" to describe preparedness activities during a threat. during the first interview round several factors that trigger preparedness activities were identified for different healthcare institutions. e microbiologist at an academic hospital reported that they were at all times ready for such cases. however, they would enhance preparations if the likelihood of admitting a vhf patient increases, such as or with repatriated staff from the outbreak area. municipal health services started with preparedness activities as soon as the outbreak somewhere in the world occurred and would be further enhanced when health institutions in their region were likely to become involved. for academic hospitals, general hospitals and ambulance services, ( ) the likelihood that an unexpected potential patient was presented to their healthcare institution, and/or ( ) unrest among the general population and staff, triggered preparedness activities. for general practitioners, only an outbreak in their would lead to preparedness activities. in the focus group, trigger and were accepted as main triggers distinguishing between preparedness phases. besides, a third trigger was the situation of several (potential) patients hospitalized within the country, conceivably leading to different referral pathways between healthcare institutions. not all triggers would lead to the same intensity of extra preparations in all healthcare institutions, but all healthcare institutions would be involved in these phases. and most importantly, they all agreed upon the need for univocal communication. e final preparedness system based on these three triggers consists of four preparedness phases and is shown in figure . preparedness phase green is a situation without the presence of the infectious disease threat that requires centralized care, anywhere in the world. preparedness phase yellow is the occurrence of the disease somewhere in the world but without triggers one and two. in preparedness phase orange, trigger one or two applies, and in preparedness phase red trigger number three applies. e preparedness activities as derived from step and and tested in step and , were divided by topic as shown in the institutional preparedness column in figure . all participants needed preparedness activities on infection prevention, such as the right type and stock of personal protective equipment, donning and doffing procedures, and waste management. regarding diagnostics, academic hospitals described preparedness activities. ese consisted mostly of extra checks whether interview guide was developed beforehand (additional file ). interviews were conducted by telephone and were all conducted by the same researcher (ddr). interviews took between and minutes. e preparedness system was reviewed during the interview by discussing preparedness activities per phase. e participants discussed specific needs and adaptations per preparedness phase of the preparedness system. further analyses included comparing preparedness activities between healthcare institutions, to see whether their expectations matched. each interview and focus group was voice-recorded, with permission from the participants, and transcribed. transcription started directly a er the first interview and continued parallel to further data collection. data were processed anonymously using a coding system. a summary of every interview and focus group was sent to the participants to verify their input. all interviews and focus group sessions were coded using content analysis. a coding guide (additional file ) was developed beforehand, based on the structure of the interview guide. for each step, the guide was expanded and adapted. coding was done by two researchers independently (ddr, and dr), using atlas. ti [ ] , and differences were discussed until consensus was reached. data collected from each step of the study were analyzed and interpreted before the beginning of the subsequent step. in step , we invited participants, of whom could not be included. five experts participated in the interview round: a microbiologist of an academic hospital, an infection preventionist in a general hospital, a medical manager of the national ambulance service with extensive experience as an ambulance nurse, a practicing gp and representative of the lhv, and a regional communicable disease control consultant of a municipal health service. in step , we invited participants of whom could not be included. eleven experts participated in the focus group: microbiologist and infectious disease specialist of two different academic hospitals, infection preventionists of different general hospitals, medical managers of different regional ambulance services, gp who also was representative of the nhg, and regional communicable disease control consultants of different municipal health services. in step , we re-invited participants from step , of whom only accepted participation: one of the infection preventionists, the gp and representative of the nhg, and one of the regional communicable disease consultants. all representatives of academic hospitals and medical managers of the national ambulance services were either not responding or not able to participate due to time constraints. for all steps, reasons why professionals could not be included were the absence of reaction to the invitation (푛 = ), unavailability during the data collection period (푛 = ), completeness of inclusions (푛 = ). figure provides an overview of the different steps, the number of included participants and their backgrounds. step : individual interviews (n = ) x general practitioner at the nhg (gps) step : individual interviews considerations start in preparedness phase orange as well, but policy on this should ideally be made in the green phase. (v) for mhs, diagnostics and training are required from preparedness phase yellow on, depending on the type of pathogen. in preparedness phase orange and red, they start to prepare their internal communication and personnel capacity. considerations. during step and , ethical considerations were mentioned by representatives of all institutions except the municipal health services. e considerations of gps, academic hospitals and ambulance services described how to deal with suspected cases in life-threatening situations. ey need guidance on when concerns for their own safety would overrule their duty as a care provider, and based on which criteria. another aspect named several times by representatives of ambulance services, general hospital and academic hospitals was the priority of care: to respectively transport, temporarily accommodate, or care for one evd suspected patient, meant that many other patients could not receive care because an ambulance, an emergency department or large parts of intensive care had to close due to cleaning procedures, panic reduction or lack of staff or resources. participants explicitly stated that these were dilemmas they faced during the latest evd outbreak, and they would still face them should a case be admitted today. in addition to institutional preparedness activities, collaborative preparedness activities were discussed in all interview rounds. ese are activities that overarch individual healthcare institutions or should be performed by multiple healthcare organizations together. we identified collaborative preparedness activities in information, training and simulation, and coordination, as shown in the differential diagnoses for these patients could run. academic hospitals, peripheral hospitals and ambulance services named preparedness activities for patient care. academic hospitals and peripheral hospitals discussed the need to prepare their personnel for extra working hours, or the need for extra supplies. general practitioners and municipal health services needed preparedness for controlling unrest among their staff and the population, e.g., by informing staff and the availability of a telephone line for questions. in additional file a, an overview of identified preparedness activities that resulted from step and are shown per type of healthcare institution. we identified the following trends: (i) academic hospitals start with all preparedness activities from preparedness phase yellow on. in preparedness phase orange, a sub-commission on preparedness for the admittance of patients needs to be installed, and in preparedness phase red, there will be a need to consider more ethical challenges related to the threat and challenges related to a shortage of staff. (ii) peripheral hospitals inform triage staff and professionals at the gate during preparedness phase yellow. in preparedness phase orange, preparedness activities should start, except for diagnostics and patients' care/cure. in preparedness phase red, mainly a more intense communication among hospital departments and healthcare institution in the region is needed. (iii) for ambulance services, preparedness activities start in preparedness phase orange and no clear difference in preparedness activities were identified between preparedness phase orange and preparedness phase red. (iv) for general practitioners, phase orange is most important. e preparedness activities of general practitioners are limited to triage and primary infection prevention in all preparedness phases. ethical phases reflect the preparedness activities at a global, international and national level, rather than the institutional level within a country. e need for such specific phases for frontline institutions emerged during the evaluation of the ebola threat [ ] , since all types of healthcare institutions experienced the need to perform extra activities to stepwise increase their level of operational response as the threat evolved. healthcare institutions need thus to adapt their preparedness activities to the level of a threat. e identified triggers for enhanced preparedness match with other studies and theory. schol et al. identified higher fear among dutch healthcare workers during the threat of ebola and identifies a relation between fear and the need for information. is study provides support for our finding that unrest is a trigger for enhanced preparedness (in this case by providing additional information) [ ] . e founding risk classification theory of kinney and wiruth ( ) [ ] states that risk is the chance that something happens times the impact of that event. within this formula, the presentation of an unexpected patient is the event that could happen, and the unrest among healthcare workers and the population represents impact. together they define the risk, which is then translated in the urge to prepare. in this way, the phase system in this study builds upon the literature on risk classification. studies showed that extra preparedness was needed for countries during threats with increasing severity of outbreaks elsewhere in the world [ , , , ] . however, these studies report on disease-specific preparedness activities and, therefore were, not necessarily applicable to other threats. is study used marburg virus disease in the scenario and included experts with evd outbreak experience. we worked in the a ermath of the evd outbreak, but used a case of another disease. hereby, we strongly aimed to work towards a generic preparedness system. while specific preparedness activities differ between types of healthcare institutions and threat phases, in this study, a uniform enhanced preparedness system has been developed. during interviews, the focus group, healthcare institutions expressed the need to communicate explicitly and uniformly about preparedness activities. it became clear that there is no uniform terminology among experts from different healthcare institutions. for example, the term "scale-up" applies in curative care to the act of responding to an actual patient, while in public healthcare, the term could also be used during the preparedness. absence of uniform terminology impedes communication between public and curative health care, while smooth communication between the two is a must, especially during threats or outbreaks. with clear definitions of phases, our system offers this uniformity both within institutions, as well as among institutions. it could therefore be used to effectively arrange communication about the required specific enhanced preparedness. although this specific study was conducted in the netherlands, the results are also applicable in other countries with a comparable organization of healthcare. centralized care in dedicated health centers for patients suspected for an infectious disease requiring centralized care, is described in israel [ ] , the united states (new york state) [ ] , and in canada [ ] . besides, they can be of value in other countries, because columns headed "collaborative preparedness" in figure . e expectations of the different types of healthcare institutions regarding information and coordination match well between healthcare institutions. is implies that information exchange between organisations is reported to be adequate. furthermore, information on case definitions and information on the current preparedness phase is expected from the national centre for disease control. what did not match were the expectations of the different types of healthcare institutions regarding training and simulation exercises. e need to perform training or exercises together was mentioned by ambulance services and academic hospitals towards each other. but for peripheral hospitals, the need to practice together with ambulance services varied among participants. an overview of collaborative preparedness activities per preparedness phase is shown in additional file b. participants of all types of healthcare institutions stressed that aligned preparedness activities are preferred over institutional autonomy. however, healthcare institutions with a specific function should be able to deviate from the preparedness system activities. examples are healthcare institutions serving points of entry or those with national tasks such as the academic hospital with the reference laboratory. e aim of this study was to define preparedness during an unfolding threat of an infectious disease that requires centralized care. second, we aimed to develop a standardized system describing preparedness activities per preparedness phase for healthcare institutions. we developed this standardized system by defining phases of preparedness during a threat and their corresponding preparedness activities, within both the perspective of individual healthcare institutions and of the collaborative network in which these institutions need to function. e four identified preparedness phases were based on (a) the likelihood of presentation of an infected patient to one of the healthcare institutions and (b) the unrest among the general population and staff. phases ranged from no outbreak to the situation in which several potential or confirmed patients were hospitalized, conceivably leading to other referral pathways in the country. is system could be used for any future threat from an infectious disease requiring centralized care. using phases in preparedness to threats is not new. for terrorist attacks, for example, a level system using numbers - is common in several european countries, with being considered a low threat, and being a critical one [ ] . in the netherlands, a code system using colors is used in the weather forecasting, ranging from green ("business as usual"), through yellow and orange, to code red ("high impact on society") [ ] . and the who announced a pandemic phase system during the influenza outbreak (h n ) in , reaching from to [ ] . however, by our knowledge, explicit preparedness phases following an unfolding threat caused by an infectious disease that offers concrete measures for frontline institutions have not been identified in literature. certainly, we acknowledge the existence of the pandemic phases of the who [ ] . ese is study investigated preparedness during threats of infectious diseases requiring centralized care. is is the first study that explicitly defines preparedness activities during a threat for different frontline healthcare institutions. we reached consensus that a standardized preparedness system is required. a phased preparedness system has been developed, which can be used for improving institutional preparedness in curative healthcare institutions, and collaborative preparedness among curative healthcare institutions and the public health services. ebola virus disease gp: general practitioner lhv: national association for general practitioners md: medical doctor mhs: municipal health service n: number nhg: dutch college of general practitioners ppe: personal protective equipment rav: region of ambulance services rivm: national institute for public health and the environment vhf: viral hemorrhagic fever who: world health organization. data availability e datasets generated and/or analyzed during the current study are not publicly available due to the privacy protection of the participants, but are available from the corresponding author on reasonable request. we obtained ethical approval from the medical ethical committee of the umc utrecht (wag/mb/ / ). all participants provided informed consent and were informed that their responses would be used for research purposes. past experience with outbreaks has shown that presentation or even the likelihood of imported patients, indeed led to unrest among the general population and hospital staff [ , ] . our study has several limitations. ere was a high attrition rate between the focus group and last interview round, leading to a lack of representation of academic hospitals and ambulance services. is has led to gaps in the completeness of the review of preparedness activities per stakeholer and per phase. however, to increase validity the outcomes of this study were presented and discussed in a , -hour slot during the regular national meeting on evd preparedness. during this meeting with national representatives of academic and peripheral hospitals, ambulance services and mhs who had been involved with preparedness and response during the evd outbreak of - , the findings of this study were endorsed. is strongly supports further generalizability for both institutional as well as collaborative preparedness. another limitation is that data collection was only through interviewing, whereby direct observation of preparedness activities might yield additional findings. also conducting a simulation exercise might lead to other insights. moreover, we need to acknowledge the chance of recall bias. although we used a new scenario, participants referred to activities they had performed two years before, during the evd outbreak. is could have resulted in the identification of preparedness activities in phase yellow, orange and red that should not be performed in that phase. participants might have reported from previous evd experience where sometimes activities were performed in phase yellow, organge or red, whereas ideally these should be tackled in the green phase. an example are the ethical considerations, which indeed turn up during higher phases, but which should be covered in standard guidelines or procedures. an additional limitation is that most participants worked in the most urbanized parts of the netherlands. although regional organization might be different in the more rural regions, we have chosen to approach healthcare institutions with most experience with infectious diseases requiring centralized care. e expertise of the participants can be mentioned as a strength. since there was a strong need for a system that identifies different phases of a threat and the corresponding activities, this preparedness system could be used as a communication tool on a national or regional level. future research should focus on identifying all activities for each phase. e completed preparedness system can be used by healthcare instiutions as a checklist of all preparedness activities they should perform during unfolding threats. in addition, it can be used as an agenda-setting for regional meetings to discuss the collaboration between healthcare institutions for unfolding threats. finally, we recommend investigating the applicability of this system to other severe infectious diseases, not requiring centralized care. examples could be, the recent outbreak of plague in madagascar [ ] or the ongoing threat of the middle east respiratory syndrome-coronavirus [ ] . roles and responsibilities among types of healthcare institutions, in case of outbreaks of these diseases, vary and it is possible that other triggers and preparedness activities are required. our phased preparedness system may also be applicable in these situations. hospital preparations for viral hemorrhagic fever patients and experience gained from admission of an ebola patient clinical management of ebola virus disease in the united states and europe will ebola change the game? ten essential reforms before the next pandemic. e report of the harvard-lshtm independent panel of the global response to ebola preparing for imported ebola cases in israel european centre for disease prevention and control, public health emergency preparedness for cases of viral haemorrhagic fever (ebola) in belgium: a peer review - evaluatie van de ebolapreparatie in nederland united nations international strategy for disaster reduction rijksinstituut voor volksgezondheid en milieu. lci richtlijnen en draaiboeken atlas.ti gmbh. version . . . scientific so ware development terrorism and national emergencies kleurcodes current who phase of pandemic alert for pandemic (h n ) ebola preparedness in the netherlands: the need for coordination between the public health and the curative sector knowledge, perceptions and media use of the dutch general public and healthcare workers regarding ebola practical risk analysis for safety management preparing the health system to respond to ebola virus disease how the biggest outbreaks since the start of this century shattered some long-standing myths world health organization infectieziekten en veiligheid. toekomstige uitdagingen voor maatschappij en beleid implementation of the canadian contingency plan for a case of suspected viral hemorrhagic fever ebola virus disease cluster in the united states e first case of ebola virus disease acquired outside africa emergencies preparedness, response: revamp of the plague detection in madagascar yields quick and sustainable wins middle east respiratory syndrome corona virus (mers-cov) acknowledgments is research was supported by the utrecht university medical center. we thank our colleague joyce l. browne, md, ph.d., for assistance with the methodology of this study, for her insights regarding the clinical applicability of our research, and for here feedback on an earlier version of the manuscript.we would also like to show gratitude to our participants, for their efforts, insights and feedback during the course of this research. we thank jim van steenbergen md, ph.d., for sharing his insights on the connection of this study with earlier performed research. additional file a: guide for individual, semi-structured interviews, belonging to step (written in dutch). additional file b: guide for the mixed focus group, belonging to step (written in dutch). additional file c: guide for individual, semi-structured interviews, belonging to step (written in dutch). additional file : coding guide used for qualitative content analysis of data in step - . (written in dutch). additional file a: institutional preparedness activities per type of healthcare institution and per preparedness phase (written in dutch). additional file b: collaborative preparedness activities per preparedness phase. (supplementary materials) e authors declare that they have no conflicts of interest. ddr collected, analyzed and interpreted the data and has dra ed the manuscript. eb has been involved in designing the data collection and in revising the manuscript critically for important intellectual content. re has been involved in the conception of the data collection and guided the focus group. dr has performed coding of the data. cs has made substantial contributions to the design of the study and interpretation of data and had supervision over the research project. at has critically revised the manuscript and has given final approval of the version to be published. all authors read and approved the final manuscript. key: cord- - w j authors: hung, yuen w; law, michael r; cheng, lucy; abramowitz, sharon; alcayna-stevens, lys; lurton, grégoire; mayaka, serge manitu; olekhnovitch, romain; kyomba, gabriel; ruton, hinda; ramazani, sylvain yuma; grépin, karen a title: impact of a free care policy on the utilisation of health services during an ebola outbreak in the democratic republic of congo: an interrupted time-series analysis date: - - journal: bmj glob health doi: . /bmjgh- - sha: doc_id: cord_uid: w j background: during past outbreaks of ebola virus disease (evd) and other infectious diseases, health service utilisation declined among the general public, delaying health seeking behaviour and affecting population health. from may to july , the democratic republic of congo experienced an outbreak of evd in equateur province. the ministry of public health introduced a free care policy (fcp) in both affected and neighbouring health zones. we evaluated the impact of this policy on health service utilisation. methods: using monthly data from the national health management information system from january to january , we examined rates of the use of nine health services at primary health facilities: total visits; first and fourth antenatal care visits; institutional deliveries; postnatal care visits; diphtheria, pertussis and tetanus (dtp) vaccinations and visits for uncomplicated malaria, pneumonia and diarrhoea. we used controlled interrupted time series analysis with a mixed effects model to estimate changes in the rates of services use during the policy (june–september ) and afterwards. findings: overall, use of most services increased compared to control health zones, including evd affected areas. total visits and visits for pneumonia and diarrhoea initially increased more than two-fold relative to the control areas (p< . ), while institutional deliveries and first antenatal care increased between % and % (p< . ). visits for dtp, fourth antenatal care visits and postnatal care visits were not significantly affected. during the fcp period, visit rates followed a downward trend. most increases did not persist after the policy ended. interpretation: the fcp was effective at rapidly increasing the use of some health services both evd affected and not affected health zones, but this effect was not sustained post fcp. such policies may mitigate the adverse impact of infectious disease outbreaks on population health. abstract background during past outbreaks of ebola virus disease (evd) and other infectious diseases, health service utilisation declined among the general public, delaying health seeking behaviour and affecting population health. from may to july , the democratic republic of congo experienced an outbreak of evd in equateur province. the ministry of public health introduced a free care policy (fcp) in both affected and neighbouring health zones. we evaluated the impact of this policy on health service utilisation. methods using monthly data from the national health management information system from january to january , we examined rates of the use of nine health services at primary health facilities: total visits; first and fourth antenatal care visits; institutional deliveries; postnatal care visits; diphtheria, pertussis and tetanus (dtp) vaccinations and visits for uncomplicated malaria, pneumonia and diarrhoea. we used controlled interrupted time series analysis with a mixed effects model to estimate changes in the rates of services use during the policy (june-september ) and afterwards. findings overall, use of most services increased compared to control health zones, including evd affected areas. total visits and visits for pneumonia and diarrhoea initially increased more than two-fold relative to the control areas (p< . ), while institutional deliveries and first antenatal care increased between % and % (p< . ). visits for dtp, fourth antenatal care visits and postnatal care visits were not significantly affected. during the fcp period, visit rates followed a downward trend. most increases did not persist after the policy ended. interpretation the fcp was effective at rapidly increasing the use of some health services both evd affected and not affected health zones, but this effect was not sustained post fcp. such policies may mitigate the adverse impact of infectious disease outbreaks on population health. what is already known? ► evidence from previous outbreaks of ebola virus disease (evd) and other infectious diseases suggests that the use of primary health services usually declines among the general public, which can lead to important declines in population health. ► to our knowledge, there have been no evaluations of policies or strategies implemented to mitigate the impact of evd outbreaks on the use of health services in any international context. ► the introduction of user fee exemption or other free care policies (fcps) to incentivise health service utilisation have been evaluated in a number of sub-saharan african countries contexts, however, none have been evaluated in the context of an outbreak of evd or other infectious diseases. what are the new findings? ► our findings provide strong evidence that utilisation rates of many primary health services increased with the implementation of the fcp, although most increases were not sustained after the fcp ended. ► total visits and treatments for pneumonia and diarrhoea saw the largest increases while some services, such as those involving needles and blood, were not affected by the fcp. what do the new findings imply? ► the available scientific evidence suggests that fcps may be an effective strategy to mitigate the impact of evd outbreaks on the use of health services among the general public, even in resource poor settings. ► further research is needed to understand how such policies can be better implemented and additional strategies should also be explored. ► routine health information system data can be a useful tool to study the impact of fcps and other short-term policies in low income country settings. introduction widespread disruption to health systems has been observed during previous major outbreaks of infectious diseases. for example, during the - outbreak of ebola virus disease (evd) in west africa, the use of health services greatly declined in heavily affected countries. communities were fearful and lacked trust in the health system, which not only impeded response efforts, but also deterred health seeking behaviour. overall use of health services decreased by % during the peak of the outbreak. reductions were seen for maternal and child health services, as well as treatments for priority diseases such as malaria and hiv. it has been estimated that reductions in the use of health services led to mortality increases similar in magnitude to those directly attributable to evd. moreover, studies have shown that patterns of health seeking behaviour were disrupted for months after the outbreak. as a result, implementing policies to mitigate these impacts should be a priority. in africa, user fee exemption policies or other free care policies (fcps) have been a popular approach to incentivise health service utilisation, especially in the use of maternal and child healthcare services. however, studies have shown mixed evidence with regards to their effectiveness in various contexts. [ ] [ ] [ ] [ ] weak study designs, many of which lacked an adequate control group, may partially explain the mixed evidence. an evaluation of a previous fcp introduced in the democratic republic of congo (drc) in , unrelated to an evd outbreak, also demonstrated mixed results and the programme was not sustained. while fcps have been implemented in previous evd outbreaks in drc, to date, there have been no evaluations of their impact, where in addition to the usual concerns, additional challenges may further limit the effectiveness of such policies. fcps could provide benefits in two ways during an outbreak. first, it could encourage early identification and treatment of the disease itself-a factor that is believed to be a key predictor of ebola survivorship. second, it could help increase or maintain the use of other beneficial health services among the general population. based on the intervention theory of health user fee exemption policies developed by robert et al, a fcp should allow households to obtain health services that were previously unaffordable. however, in the context of an evd outbreak, fear of infection or a lack of trust in the health system may limit the demand for these services. in the evd outbreak in the equateur province of drc, the ministry of public health quickly implemented a temporary fcp in the three evd affected health zones as well as in four neighbouring health zones, primarily motivated by the first of the benefits described above. the implementation was supported by the ongoing health system strengthening for better maternal and child health results project funded by the world bank. in this paper, we evaluate the effect of the fcp on the use of health services at primary health centres (phcs) in equateur province using routinely collected administrative data. the drc is among the largest and most populous countries in africa and also has some of the worst health indicators in the region. the health system is highly decentralised and is challenged with very low levels of funding. to compensate, the health system relies heavily on user fees for financing. however, as over % of the population live in poverty, user fees represent a major barrier to health service utilisation. the drc has provinces which are subdivided into health zones. each health zone is further subdivided into health areas, each of which is equipped with health centres to provide primary health services. in , the drc experienced two separate evd outbreaks: the first happened in equateur province, followed by a second in the eastern region of the country a few months later. the first, which was declared on may , initially began in the ikoko-impenge health area in the bikoro health zone, where two cases of fever were confirmed to be evd and community deaths had been reported. by may , a total of cases and deaths were reported, including probable cases from the iboko and wangata health zones, a distance of nearly km, raising concerns of widespread transmission. in response to the outbreak, the drc ministry of public health, in partnership with the who, established a social awareness campaign and delivered personal protective equipment to the region by may . on may , vaccination campaigns were launched targeting front-line health workers, individuals exposed to confirmed evd cases and contacts of these individuals. additionally, to encourage people at risk to seek medical care and improve surveillance in the community, the ministry of public health implemented a temporary fcp in the health areas affected by the evd epidemic as well as in nearby health zones, beginning in june . the outbreak infected a total of people and led to deaths, including two health workers, before being declared over on july , with cases remained localised to the three health zones. we conducted a retrospective, controlled interrupted time-series (its) study using monthly data to estimate changes in the level and trend in the rate of health service utilisation between january and january at phcs during the equateur province outbreak. controlled its is a very strong quasi-experimental study design that can be used with routinely collected health system data. within equateur province, cases of evd were reported in of the health zones: bikoro (rural), iboko (rural) and wangata (urban). along with these affected zones, four neighbouring health zones (bolenge, ingende, ntondo and mbandaka) also received the fcp, bmj global health which was in effect between june and september (figure ). fcp covered consultations and medications for evd and other health conditions in the targeted areas. payments were made from the government to public health facilities (health centres and hospitals) to support the health workers and the maintenance of the facilities, using an existing payment platform that had previously been established to support a results-based financing programme in the area. the government also distributed medicines covered by the fcp to public facilities. we confirmed the enactment and implementation dates of the fcp with both provincial health administrators and local healthcare workers in equateur province. we extracted monthly data from the health management information system (hmis), an national electronic data collection system based on the district health information system (dhis ) platform. data in this system are input from health facilities' monthly health service use reports at district health offices. significant efforts have been launched in the drc to improve the quality of hmis data, including continual quality assessment activities at both the health zone and facility levels and incentives for report submission and completion. hmis data have been used to retroactively evaluate the impact of the west african evd outbreak on health service utilisation, and to evaluate the impact of other policies in other low-income and middle-income countries contexts using its analysis. for each phc, we extracted the number of visits for the following health services: . overall: ( ) total clinic visits. each health facility reported each of the indicators on a monthly basis. to enable comparisons between health zones, monthly counts were modelled as per-capita monthly rates using the estimated catchment populations for each facility reported in the hmis. these indicators were selected as they represent the majority of health services delivered in phcs ( % of total visits) and had the highest level of data completeness. although routine immunisations and malaria rapid diagnostic testing had been curtailed during the outbreak due to evd transmission concerns, we included these indicators to monitor the overall use of health services in the general population in the context of the evd outbreak. the research protocol was approved by the ethics committees at wilfrid laurier university (canada) and kinshasa school of public health (drc). we tested the following hypotheses: ( ) was the fcp associated with significant changes in health services utilisation at phcs in both evd affected and non-evd affected health zones? if so, what were the magnitude of these changes? ( ) were the changes in health service utilisation sustained throughout the period of the fcp bmj global health implementation and afterwards? ( ) were there any differential effects of the fcp in evd vs non-evd health zones? ( ) were some health services more affected by the fcp than others? our analysis included the phcs in two intervention groups that received the fcp: three evd affected health zones (evd and fcp), as well as in the four neighbouring health zones that received the fcp but were not directly affected by evd (fcp only). phcs in the remaining health zones within equateur province were included as the control group (neither). we fit our models using a two-level mixed-effects negative binomial model to adjust for the clustering of observations from the same health centres over time, and to correct for over-dispersion. all of our models included random intercepts for clinic in order to account for heterogeneity of clinic visit volumes, and an autoregressive structure of one period to account for potential correlation between observations over time. we defined three time periods: pre-intervention (january -march ), intervention (june-september ) and post-intervention (october -january ) based on the timing of the fcp. we excluded the first months of the outbreak (april and may ) from our analysis, as the time period between the onset of the outbreak and the implementation of the fcp was too short to independently test for time trends. each indicator was analysed for level and slope over time, changes in immediate (level) and gradual (slope) in the intervention and post-intervention period, and the interaction of these changes with the different study groups (evd and fcp, fcp only, neither). phcs were excluded from each analysis if data were missing for two or more consecutive months in either the pre-fcp (october and march ), or during evd and fcp (april and september ) periods. thus, we excluded phcs from one health zone (makanza) that had neither evd nor fcp due to lack of consistent reporting. we identified outliers and excluded a phc for a specific indicator if their reported data exceeded eight sd from the mean time trend (< . % of the sample). due to this rule about missing data, number of phcs included in each study group varied by indicator. the samples of phcs for each indicator is included in online supplementary table s a and s b. we then conducted separate controlled its analysis for each of the nine indicators. missing data were accounted for using standard maximum likelihood estimation in the mixed-effects models. additionally, in order to estimate the absolute change of each outcome compared to the counterfactual estimate without the fcp, we used the non-linear (exponential) combination of estimate parameters from the two-level mixed-effects negative binomial model and applied bootstrapping method to construct confidence intervals around the predicted absolute changes in outcome. we simulated data based on the estimates with normally distributed error using bootstrap statistics with resamples within each group. all analyses were conducted using sas v. . . this research was done without patient involvement. patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. patients were not invited to contribute to the writing or editing of this document for readability or accuracy. as shown in table , we found that the fcp was associated with changes in the utilisation of many types of services, majority were similar in both the health zones with evd and in neighbouring health zones with fcp only. overall relative to control health zones, rates of total clinic visits increased substantially in fcp health zones following the start of the evd outbreak and we see similar increases in both the evd and fcp health zones and the fcp-only health zones. as shown in figure , visit rates increased more than twofold in evd and fcp health zones (incidence rate ratio ( similar to overall clinic visits, the fcp was associated with a large increase in visits for pneumonia and diarrhoea, and to a smaller extent for malaria visits. figure shows the model results for the rate of clinic visits for pneumonia. compared to facilities in control health zones, clinic visits for pneumonia doubled at the beginning of fcp in evd and fcp health zones (irr: . , % ci: . - . , p< . ) and quadrupled in fcp-only health zones (irr: . , % ci: . - . , p< . ). during the implementation period, visits for pneumonia in evd and fcp health zones had no significant change (irr: . , % ci: . - . , p= . ) while the rate decreased over time in fcp-only health zones (irr: . , % ci: . - . , p< . ). following the end of the fcp, the level of pneumonia visits decreased by % in evd and fcp health zones (p= . ), with no significant difference in the trend in subsequent months (irr: . , % ci: . - . , p= . ). the % decrease in fcp-only health zones was not statistically significant (irr: . , % ci: . - . , p= . ) and the trend reversed after the end of the policy (irr: . , % ci: . - . , p< . ). changes in the levels and trends of visits for diarrhoea following bmj global health the fcp had a comparatively moderate effect on the utilisation of maternal health services both in the evd and fcp health zones and the fcp-only health zones which varied by service type. figure shows vaccination figure shows the results for the administration of first doses of the dtp vaccine. reporting of routine immunisation in the evd and fcp health zones was predominantly from the wangata health zone. compared to control health zones, dtp immunisation had no significant change in the evd and fcp health zones (evd and fcp: irr: . , % ci: . - . , p= . ) and marginal increase in fcp-only health zones (irr: . , % ci: . - . , p= . ). no significant changes were found in the trends nor level after the fcp ended. discussion during disease outbreaks, maintaining the use of health services is important both for diagnosing diseases and ensuring continuity of care for other health issues. we found strong evidence that a fcp implemented in the drc during an ongoing evd outbreak associated with large increases in the rate of utilisation of health services in phcs. the magnitude of this increase was similar in the evd zones compared to neighbouring zones with the fcp but no evd. our findings are consistent with previous studies that found short term effects of fcps in other african contexts, but in stark contrast to the finding that fear and a lack of trust greatly curbed health service utilisation in the west african evd outbreak. despite the increase in the use of health services, the fcp was not equally effective for all indicators. the largest increase was observed in curative visits for pneumonia and diarrhoea, while increases in the treatment of malaria were observed only in the fcp-only zones. preventative services such as first antenatal visit and institutional delivery showed more modest increases. this pattern generally aligns with other fcp studies that have shown greater effectiveness for curative services than preventative services. studies from west africa also suggest the use of curative services recovered and rebounded earlier in the post-outbreak period, compared to preventative services. due to the concern of evd transmission, health facilities may have curbed the delivery of services that involved needles or blood extraction. indeed, the chief medical officer of bikoro health zone reported that evd responders recommended that, during the epidemic, routine immunisation, elective surgeries and malaria rapid diagnostic testing be curbed in the epicentre health zones (dr b loleka, oral communication, may ). the restriction in routine immunisation in the epicentre may have also contributed to reduced reporting on immunisation and malaria diagnosis during the evd outbreak. although these services were not targeted by the fcp, we found some evidence that dtp vaccination and malaria diagnosis did not decrease during the evd period in the reporting phcs, suggesting that such activities were maintained in areas outside of the evd epicentre. our findings also highlight some potential challenges in implementing fcps. the rapid increases in the use of services following the implementation of the policy attenuated over the following months which may be a result of the disruption of the fcp on the local health system. in particular, the sudden increase in demand for primary health services may have overstretched the limited human resources, or disrupted regular operations due to the changes in reimbursements paid to health workers and budgetary constraints during the fcp implementation. these impacts should be considered in future uses of fcp-type policies designed to mitigate the impact of infectious disease outbreaks. our findings also provide some insights that could be useful to decision-makers contemplating setting up similar policies in other infectious disease outbreak contexts, for example, countries currently deciding how to respond to the pandemic of covid- . first, we demonstrate that the policy was effective soon after implementation which was likely due in part to the presence of an existing payment structure that had previously been established in the region and that could quickly be leveraged for this programme. without such a platform, it may be challenging for other countries to implement such a policy in a rapid manner. second, while the intent had always been for the policy to be temporary, our findings suggests that the effectiveness of the policy began to wane soon after implementation, potentially as a result of the lack of longer-term planning. decision-makers should try to better balance the need for short-term effectiveness with the sustainability of the policy, in particular when it is uncertain at the onset how long an outbreak will last. our study has a number of limitations that should be considered when interpreting our results. first, our sample included only health centres and did not include all health facilities. as health centres are the formal health system structure that provide primary health services, we did not include health posts, which provide mainly community health services and health promotion activities. our sample also excluded hospitals and private health facilities. as private facilities are not directly governed by the ministry of public health, their reporting of routine health data is limited. it was not possible for us to include hospitals as their reporting in some health zones was very inconsistent during the outbreak. however, in the appendix we present data from select hospitals and note that similar increases in use of health services were also observed. second, there was a small increase in missing data during the first few months of the evd outbreak, particularly in vaccination and malaria diagnosis. as we excluded health centres with consecutive missing data in this period, our samples for these two indicators did not include all evd health zones. hence, our findings on vaccination and visits for malaria diagnosis may not be generalisable to the entire evd outbreak area. third, we were unable to include an estimate of the level and trend changes following the ebola outbreak as there were only months between the outbreak and the start of the fcp. finally, it is possible that the intervention may have had led to some spillover effects into neighbouring health zones which we are not able to fully control for in our analysis. however, the challenging terrain and large distances to health facilities may have limited spillover effects. plus, if such spillover effects had happened, it is unclear which direction they would have gone, and could have even made it less likely that we were to find an effect. in conclusion, our study demonstrates that the introduction of a fcp was strongly associated with rapid increases in the use of health services, in particular in zones with both the policy and evd. this is in contrast to prior evd outbreaks, wherein countries did not implement fcps at scale and saw large declines in the use of health services, suggesting that such policies may be effective at mitigating the impact of future evd outbreaks. however, the increases were not uniform across all health services and the rapid increases in the use of health services did not continue over the full fcp period. fcps may be an effective way to mitigate the impact of future outbreaks, including the current pandemic of covid- that is now threatening many countries including the drc, on population health, however, more research is needed to better understand the impact in different contexts and how such policies can be effective over time. access to all the data in the study and had final responsibility for the decision to submit for publication. disclaimer the funders of the study had no role in study design, data collection, data analysis, interpretation of data, or writing of the report. map disclaimer the depiction of boundaries on this map does not imply the expression of any opinion whatsoever on the part of bmj (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. this map is provided without any warranty of any kind, either express or implied. competing interests mrl has consulted for health canada, the health employees' union, the conference board of canada, and provided expert witness testimony for the attorney general of canada. bluesquare has ongoing contracts with a variety of organisations in drc including the ministry of health and the world bank. si, la-s, smm, and hr were paid as individual consultants as part of their collaboration with this project. patient and public involvement patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. provenance and peer review not commissioned; externally peer reviewed. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. orcid ids the - ebola virus disease outbreak and primary healthcare delivery in liberia: timeseries analyses for - the impact of the sars epidemic on the utilization of medical services: sars and the fear of sars women and babies are dying but not of ebola': the effect of the ebola virus epidemic on the availability, uptake and outcomes of maternal and newborn health services in sierra leone health-care access during the ebola virus epidemic in liberia patterns of demand for non-ebola health services during and after the ebola outbreak: panel survey evidence from community-based reports of morbidity, 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epss - rapport final [democratic rebublic of congo evaluation of health services epss acknowledgements we acknowledge that this manuscript was prepared on the haldimand tract, traditional territory of the neutral, anishinaabe and haudenosaunee peoples. we are grateful to all of our key informants, including those in the democratic republic of congo (drc) and elsewhere to helping us obtain information on key parameters related to the outbreak. we also acknowledge qamar mahmood and sofia rossell at international development research centre for their support, jess wilhelm's research assistance on the project, and nicolas de borman's facilitation in facilitating the project and data access.contributors mrl, si, smm and kg conceived the idea. ywh, mrl, si, la-s, gl, smm, hr and kg developed the protocol and contributed to the study design. gl and ro provided study data and assisted with data management. ywh and lc managed and analysed the data, in collaboration with mrl. ywh and kg drafted the manuscript. all authors reviewed the manuscript and contributed to the revision of the manuscript, and approved its final version. the corresponding author had full michael r law http:// orcid. org/ - - - sharon abramowitz http:// orcid. org/ - - - lys alcayna-stevens http:// orcid. org/ - - - grégoire lurton http:// orcid. org/ - - - romain olekhnovitch http:// orcid. org/ - - - gabriel kyomba http:// orcid. org/ - - - hinda ruton http:// orcid. org/ - - - x karen a grépin http:// orcid. org/ - - - key: cord- -qwxkn j authors: aceng, jane ruth; ario, alex r.; muruta, allan n.; makumbi, issa; nanyunja, miriam; komakech, innocent; bakainaga, andrew n.; talisuna, ambrose o.; mwesigye, collins; mpairwe, allan m.; tusiime, jayne b.; lali, william z.; katushabe, edson; ocom, felix; kaggwa, mugagga; bongomin, bodo; kasule, hafisa; mwoga, joseph n.; sensasi, benjamin; mwebembezi, edmund; katureebe, charles; sentumbwe, olive; nalwadda, rita; mbaka, paul; fatunmbi, bayo s.; nakiire, lydia; lamorde, mohammed; walwema, richard; kambugu, andrew; nanyondo, judith; okware, solome; ahabwe, peter b.; nabukenya, immaculate; kayiwa, joshua; wetaka, milton m.; kyazze, simon; kwesiga, benon; kadobera, daniel; bulage, lilian; nanziri, carol; monje, fred; aliddeki, dativa m.; ntono, vivian; gonahasa, doreen; nabatanzi, sandra; nsereko, godfrey; nakinsige, anne; mabumba, eldard; lubwama, bernard; sekamatte, musa; kibuule, michael; muwanguzi, david; amone, jackson; upenytho, george d.; driwale, alfred; seru, morries; sebisubi, fred; akello, harriet; kabanda, richard; mutengeki, david k.; bakyaita, tabley; serwanjja, vivian n.; okwi, richard; okiria, jude; ainebyoona, emmanuel; opar, bernard t.; mimbe, derrick; kyabaggu, denis; ayebazibwe, chrisostom; sentumbwe, juliet; mwanja, moses; ndumu, deo b.; bwogi, josephine; balinandi, stephen; nyakarahuka, luke; tumusiime, alex; kyondo, jackson; mulei, sophia; lutwama, julius; kaleebu, pontiano; kagirita, atek; nabadda, susan; oumo, peter; lukwago, robinah; kasozi, julius; masylukov, oleh; kyobe, henry bosa; berdaga, viorica; lwanga, miriam; opio, joe c.; matseketse, david; eyul, james; oteba, martin o.; bukirwa, hasifa; bulya, nulu; masiira, ben; kihembo, christine; ohuabunwo, chima; antara, simon n.; owembabazi, wilberforce; okot, paul b.; okwera, josephine; amoros, isabelle; kajja, victoria; mukunda, basnet s.; sorela, isabel; adams, gregory; shoemaker, trevor; klena, john d.; taboy, celine h.; ward, sarah e.; merrill, rebecca d.; carter, rosalind j.; harris, julie r.; banage, flora; nsibambi, thomas; ojwang, joseph; kasule, juliet n.; stowell, dan f.; brown, vance r.; zhu, bao-ping; homsy, jaco; nelson, lisa j.; tusiime, patrick k.; olaro, charles; mwebesa, henry g.; woldemariam, yonas tegegn title: uganda’s experience in ebola virus disease outbreak preparedness, – date: - - journal: global health doi: . /s - - - sha: doc_id: cord_uid: qwxkn j background: since the declaration of the th ebola virus disease (evd) outbreak in drc on st aug , several neighboring countries have been developing and implementing preparedness efforts to prevent evd cross-border transmission to enable timely detection, investigation, and response in the event of a confirmed evd outbreak in the country. we describe uganda’s experience in evd preparedness. results: on august , the uganda ministry of health (moh) activated the public health emergency operations centre (pheoc) and the national task force (ntf) for public health emergencies to plan, guide, and coordinate evd preparedness in the country. the ntf selected an incident management team (imt), constituting a national rapid response team (nrrt) that supported activation of the district task forces (dtfs) and district rapid response teams (drrts) that jointly assessed levels of preparedness in designated high-risk districts representing category ( districts) and category ( districts). the moh, with technical guidance from the world health organisation (who), led evd preparedness activities and worked together with other ministries and partner organisations to enhance community-based surveillance systems, develop and disseminate risk communication messages, engage communities, reinforce evd screening and infection prevention measures at points of entry (poes) and in high-risk health facilities, construct and equip evd isolation and treatment units, and establish coordination and procurement mechanisms. conclusion: as of may , there was no confirmed case of evd as uganda has continued to make significant and verifiable progress in evd preparedness. there is a need to sustain these efforts, not only in evd preparedness but also across the entire spectrum of a multi-hazard framework. these efforts strengthen country capacity and compel the country to avail resources for preparedness and management of incidents at the source while effectively cutting costs of using a “fire-fighting” approach during public health emergencies. a week after declaring the end of the th ebola virus disease (evd) outbreak in equateur province of the democratic republic of congo (drc) on july th, , the ministry of health of the drc confirmed a new evd outbreak in the eastern drc, north kivu province on august , [ ] . six health zones, including beni, butembo, oicha, mabalako, and musienene in north-kivu province, and mandima in ituri province have since reported confirmed and probable evd cases. within a month, evd cases ( confirmed, probable), including deaths ( % case-fatality rate) had been reported with an additional nine suspected cases pending laboratory testing for evd [ ] . north kivu province shares borders with uganda in the east, and there is frequent cross-border movement due to trade, farming, healthcare, and social activities. in addition, north kivu and ituri provinces have been the centre of interethnic clashes for some time now, and harbor over a million displaced persons, with active rebel activities causing prolonged insecurity. since december , there has been a continuous influx of refugees into uganda, resulting in a high risk of evd introduction into the country. evd is a severe, often fatal illness in humans. initial human infection with ebola virus (ebov) occurs through contact with an infected animal, such as a fruit bat or non-human primate [ ] . the virus spreads from person to person via direct contact with the blood or body fluids of an ebov-infected symptomatic person or dead body. entry of the body fluids (urine, saliva, sweat, faeces, vomit, breast milk, vaginal fluid, and semen) through broken skin or mucous membranes in the eyes, nose, or mouth can lead to infection [ ] . the spread of ebola zaire strain can be effectively prevented through vaccination, as demonstrated by a ring vaccination trial held in guinea during the west african evd outbreak [ ] . guinea was the epicenter and the initial site of the largest-ever evd outbreak, leading to intense transmission in guinea as well as the neighbouring countries of liberia and sierra leone. transmission to neighbouring countries was associated with illprepared health systems and poor inter-governmental coordination, factors that led to poor disease surveillance, insufficient infection prevention and control and clinical care. liberia, guinea and sierra leone had a long history of socio-economic underdevelopment due to civil conflict leading to very weak and severely underresourced health systems. the outbreak was further exacerbated by infected persons crossing the highly porous borders of the countries involved [ , ] . as a result, this outbreak caused significant mortality, with reported case-fatality rates of up to %. evd outbreaks have also occurred in the central african nations of gabon ) , the democratic republic of congo (drc) ( , , , , , , , , ) , sudan( ), and uganda ( , , , ) [ , ] . uganda's largest documented evd outbreak occurred in - in gulu district, registering cases and deaths [ ] . in this paper, we describe uganda's experience in preparedness to prevent evd introduction into the country and limit its spread in case of an outbreak. the approach adopted by the country focused on comprehensively addressing objectives of epidemic preparedness and reponse, including anticipation/prediction so that epidemics do not occur, early detection, and rapid and effective response. the epidemic preparedness process constituted all the activities that were undertaken by moh and its partners from national to health facility levels to enable readiness to effective response to evd outbreak in uganda from august when evd outbreak was declared in the drc to the time of writing this paper. the reports of the national task force (ntf) and its subcommittees were reviewed to inform the content of the paper. the preparedness efforts included activation of coordination mechanisms, functionalising subcommittees of the ntf, classifying districts by risk level and conducting risk assessment and mapping exercise which informed development of the national evd response plan. to assess the country readiness, a major simulation exercise was conducted. the moh activated the public health emergency operations centre (pheoc), ntf and district task forces (dtfs) for coordination of the evd preparedness. the ntf is multi-sectoral and multi-disciplinary in nature and comprises key ministries, agencies, and departments as well as partners and relevant stakeholders and works through its subcommittees (fig. ) . the ntf which is chaired by the director general of health services and co-chaired by who, held an urgent meeting on the nd of august to discuss evd preparedness and prevention of spillover from drc into uganda. the ntf developed a multi-agency incident management system (ims) to coordinate preparedness efforts and guide central and field evd activities. the major ims components are command and management of preparedness activities, resource management, communication, and information management. the ntf assigned an incident management commander (imc) and team, made of technical subcommittee team leads encompassing the eleven key who evd preparedness components, including: ) epidemiological surveillance (contact tracing, capacities at poes, and laboratory incorporated); ) case management and infection prevention and control (ipc) including psycho-social support, waste management and safe and dignified burials; ) risk communication and community engagement; ) vaccination, therapeutics, and research; ) emergency coordination including budgeting and resource mobilisation; and ) logistics [ ]. the imt was responsible for planning and managing preparedness resources and activities, guiding activity implementation through the dtfs, and reporting back progress from each district to the ntf. after the initial risk assessment, districts bordering north kivu and ituri provinces were categorized as high-risk for evd importation, as moderate-risk, and the remaining districts as low-risk. through the ims, all high-risk and moderate-risk districts were supported to formulate and/or reactivate their dtfs to constitute sub-committees for the core preparedness and coordinate interventions at district level. the dtfs comprised the district political, civic, security, and health leadership as well as technical advisors from different partners working in the districts. as a result of the complexity of the evd situation in drc, civil unrest and refugee influx, several national development partners became involved in evd preparedness. the ntf, with support from who, developed a partners' coordination matrix to avoid duplication of efforts, facilitate identification of preparedness gaps, support monitoring of implementation of the preparedness plan and realise the importance of impact on competing health interests. the matrix specified who should be doing what, where, and when (also known as the ws), as well as the evd preparedness goal, objectives, strategies, budget, funding sources, funding gaps, donors, and implementing agencies in the respective high-risk districts. guided by this matrix, the moh and partner institutions provided district-level financial and technical support for preparedness activities (figs. and ). figure shows total amount of money spent by each implementing partner while fig. shows the contribution by each donor to the preparedness efforts. the matrix was updated regularly based on feedback from ntf members. a dashboard was developed and updated promptly to display the financial and technical progress as well as the ws. the ntf classified district evd transmission risk into categories. category included high-risk districts that have physical borders, direct routes, and refugee influx from the affected provinces in drc as well as the central business disticts of kampala capital city and wakiso. category included moderate-risk districts that have physical borders with drc but no direct route to evdaffected regions, and category included low-risk districts in the rest of the country (fig. ) . the ntf deployed the nrrt to the districts to conduct rapid risk assessments and report within the first h of deployment followed by subsequent updates as the outbreak situation evolved. the ntf adapted and used the who evd preparedness checklist to assess the districts' level of preparedness. the checklist is composed of key components and core capacities and tasks for both districts and health facilities that are required for a district to be operationally ready [ ] . through face-to-face interviews with key informants and discussions with the drrt, the nrrt scored activities under each core capacity of preparedness. the assessment team verified responses by looking at documented evidence and implementation of the recommended core capacities at the district and health facility level. the nrrt held group discussions with health facility teams on epidemiological surveillance, case management, ipc, laboratory and contact tracing. scores were assigned to each of the core capacity components (green for complete/in place and red for incomplete/not yet in place) and then percentages of the total tasks that were completed for each core capacity were computed for fig. national budget and financial contribution to evd preparedness by implementing partner each district. any district with a level of preparedness component at ≤ % was considered unprepared (red), between and % was considered as fairly ready (yellow), and those above % were considered prepared for that component. the nrrt used the assessment results to identify capacity gaps for additional support to strengthen alert and response in the high and moderate risk districts. to establish drc population movements and patterns across the drc-uganda border, the population connectivity across borders (pop-cab) tool developed by us cdc was used to document, record, analyze, and map risks associated with population movements across borders. the nrrt held key informant interviews with the district health team (dht), which included the district health officers, surveillance focal persons, health inspectors and health educators, and local leaders at known border poes and along priority porous borders. several official and non-official high-risk crossing points for population movement from drc across border districts were identified. trained facilitators also interviewed township chairpersons, town clerks, subcounty chiefs, mayors, and transport operatives in the high-risk locations. in addition, focus group discussions (fgds) with village leaders, community health workers in the cited high-risk locations for drc population were held. the fgds were guided by an adapted popcab fgd guide to gather information about the type of people crossing the border, their points of origin, congregation points, reasons for entering uganda, duration of their stay and destinations. gps coordinates for each of the locations were recorded. we developed summaries from key informant interviews and focus group discussions aided with sketch maps to track crossborder movements and indicate key locations for the drc population. the facilitators integrated participatory mapping with spatially-accurate, printed maps in the key informant interviews and focus group discussions to identify location information for priority points of interest and travel routes. respondents described population movement patterns associated with refugees who leave the uganda settlements to visit their relatives in drc and return back to uganda. in addition, they described the patterns of persons newly-arriving from the drc to established refugee reception centers and resettlements areas in uganda such as kyangwali in hoima district or kyaka ii in kyegegwa district, as well as drc traders traveling across lakes albert and george to major markets in towns in the ugandan border and non-border districts for business, and others who fly directly to entebbe international airport from goma, eastern drc. the drrt used the results to identify several official and non-official high-risk border locations with population movement from drc into border districts. these exercises revealed multiple drc travelers' destinations to towns as far as uganda's capital city of kampala. a mapping exercise was conducted by the international organization for migration (iom) to establish the numbers, locations, and traveler flow of the numerous non-official border crossing points that exist between the drc and uganda through which people travel for social, business, and health reasons. this enabled with support from development partners and relevant stakeholders, the ntf developed the national evd contingency plan to address the identified gaps in preparedness, and to support timely detection, response, and immediate containment of a potential evd case in uganda. this plan was developed in line with guidance provided in the international health regulations (ihr) for countries to develop core capacities to prevent, protect against, and rapidly respond to public health threats, including evd. the plan was developed based on the rapid assessment preparedness reports, past experiences, and lessons learnt during the previous evd outbreaks in uganda [ ] . the plan was also developed based on the one health approach to global health security at both national and subnational levels. this approach requires coordination across multiple sectors of government including human and animal health, agriculture, wildlife, water and environment, security, immigration and law enforcement. framework for each of the components of preparedness and was costed accordingly. it highlighted a package of interventions for the districts in the risk categories. after several cross-border contacts were made and points of entry coordination exchanges took place at local levels, the ntf and moh engaged with the drc ministère de la santé publique (ministry of public health) to convene a cross-border health meeting. attendees included the east african countries at risk of introduction of evd cases from the drc in october . following this meeting, a bilateral ministerial meeting was held in goma, drc, in december . the first meeting was designed to formalize crossborder collaboration and local-level exchange of information between affected countries, meanwhile the second meeting was meant to result in developing and signing of the uganda-drc memorandum of understanding (mou) on cross-border collaboration for public health preparedness and response. the mou enabled establishment of four surveillance zones between uganda and the drc. the nrrt trained dhts, health and non-health frontline workers including members of security forces, village health teams (vhts) and political leaders on evd case definitions and distributed copies of case investigation forms and contact tracing guidelines in assessed health facilities. health facilities formed surveillance teams to heighten surveillance and active case search in order to detect any alert or suspect cases. volunteers were trained on evd screening at border poes and refugee reception centers with support from various partners. a poe coordination committee developed a poe toolkit which was approved by the ntf and adapted for use by moh. the poe teams screened everyone crossing into uganda from drc with infrared thermometers for body temperature, including all refugees at reception centers. persons found with elevated body temperatures (> degrees celsius) were further screened for ebolalike symptoms. the nrrt trained laboratory health workers on specimen collection from suspected evd cases and triple packaging for transportation to the uganda virus research institute (uvri) for testing. with support from partners, ambulances were stationed in each of the category high-risk districts for rapid transportation of specimens to the uvri viral haemorrhagic fever (vhf) program laboratory in entebbe, ensuring delivery of samples within h of collection. in addition, the moh conducted a pilot of an electronic system to track collected samples to improve the monitoring of laboratory results turnaround time. other actions undertaken in the preparedness period include modifications of the specimen collection, sample chains of custody and packing list forms. these modifications aimed to strengthen the existing biosecurity mechanisms of the national laboratory services. by end of may , ebola alerts were verified countrywide (fig. ) . although up through june, no specimen collected from an alert tested ebola positive, other vhf pathogens were detected in samples from alert cases including crimean congo haemorrhagic fever [ ] and rift valley fever [ ] . the dtfs identified clinical staff including clinicians and community health workers whom the nrrt trained on evd case definitions, transmission, clinical presentation, community surveillance, reporting, ipc, and case management including dignified safe burial. the trainings included simulation exercises such as donning and doffing of evd ppe for case management and safe burial. during the trainings, the nrrt disseminated evd guidelines and standard operating procedures (sops) for patient management and, safe and dignified burial. the nrrt also helped the dtfs to designate and setup evd isolation units at specified hospitals and health facilities ready to provide care to evd patients. with support from partners, moh constructed ten ebola treatment units (etus) at designated hospitals in highrisk districts. the nrrt conducted ipc assessments and instituted hand-washing and disinfection measures and positioned hand-washing stations at major health care facilities, official and high-risk unofficial poes, refugee transit and reception centers, and other relevant public places in the high and moderate risk districts. with support from partners, moh trained district-based ipc trainers who trained and mentored all relevant health facility workers on ipc practices in handling suspect, probable and confirmed evd patients including safe waste management, and safe dignified burials. the ntf logistics sub-committee conducted logistics assessments in at least five of the high-risk districts to determine a baseline, and then used the data for forecasting and quantification for medical, ipc, ppe, and laboratory needs for the districts. with support from the nrrt, the dtfs developed emergency contingency plans and budgets to facilitate evd preparedness activities, which were reviewed and approved by the ntf. the moh with support from partner agencies purchased and distributed ppe and other relevant supplies to all designated district hospitals and health facilities for case management. a number of development partners and international agencies supported the moh financially to avail the preparedness logistics and supplies to the districts. the ntf generated a press statement which was read by the minister of health on rd august to inform the public about the evd outbreak in drc and increase alertness for surveillance in the high-and moderaterisk districts and the rest of the country. the ntf risk communication subcommittee developed subsequent press releases for the minister of health, the committee also developed the risk communication plan, radio spot messages, reviewed, printed and translated iec materials which were translated in fifteen most spoken local languages in the high-and moderate-risk districts across the western border of uganda to ensure reach to the general public. information specified signs and symptoms of evd, the need to seek urgent medical care in case symptoms arise, and the importance of safe burial of the dead. evd information was disseminated regularly through local newspapers, popular radio, and television stations. in addition, the dtfs disseminated iec on evd through regular radio talk shows, spot messages, and posters in high-risk communities. they also supported trained community volunteers to carry out communal and door-to-door evd health education. the ntf sought ethical and institutional approval for prophylactic use of the rvsv-zebov vaccine currently used in the drc based on its demonstrated protective efficacy against the ebola virus-zaire type. this particular vaccine was being administered in drc and had demonstrated positive protective results and potency against the ebola virus-zaire type [ ] . the aim of the initial ebola vaccination campaign was to protect frontline health and non-health workers in uganda under a compassionate-use strategy to protect persons at potential risk for evd in advance of an outbreak. once approval was granted, the moh, with support from the who, secured vaccine doses, established and trained national vaccination teams, organized cold chain logistics, selected districts and mostat-risk workers in health care facilities, poes and other locations (laboratories, airport, etc.), and commenced voluntary vaccination. vaccination proceeded according to a site-by-site plan ranking highest-to lowest-risk sites for evd case introduction from the drc. the vaccination campaign planning committee used popcab results from identified districts to inform their decisions about which heath care facilities and poe to target during the initial vaccination campaign. an additional doses of vaccines were later secured to scale up the vaccination exercise. by the end of april , uganda had vaccinated health workers in high-risk districts (fig. . the vaccination team in their wisdom selected health workers they considered more at risk compared to others and targeted those for vaccination rather than vaccinate all health workers. this was the first time ebola vaccination was conducted as part of a country's preparedness response. a who joint monitoring and assessment of evd preparedness in uganda conducted in december showed significant progress, with up to % readiness nationally. the moh therefore recommended a fullscale simulation exercise to test the operational capabilities of all components of the preparedness and response plan. a full-scale simulation exercise (fsx) was conducted in april to test the preparedness and response systems at three levels of operation: community, district, and national. the exercise was conducted in a highly stressful environment, simulating actual response conditions. the exercise simulated three suspected cases of evd. the first case tested the response systems at a designated land poe in kasese district (mpondwe border point), and referral to an ebola treatment unit (etu), while the second came through entebbe international airport. the third case tested community surveillance and reception of an evd suspected case in a non-etu facility in kasese district, and subsequently safe and dignified burial when the patient died. the coordination structures at national and district levels were also tested. in all scenarios, detection of a suspected evd case was timely, though reporting from the community to the national level was delayed. the simulation exercise identified strengths and gaps in the development and implementation of preparedness and response measures. the exercise also identified areas for improvement in coordination of the response at district level, safe referral of evd suspected cases, infection prevention and control, and management of severely ill patients. it was recommended that preparedness efforts prioritize skilling health care providers through intensified supervision, mentorships and drills. the conflation of political instability and rebel activities coupled with community mistrust in the outbreak response in eastern drc have made it very difficult for the drc and its partners to control what has now become the second-largest and -longest evd outbreak recorded in history [ ] . as a result, the outbreak continues to rage on and on many months after it was declared, and the number of confirmed evd cases in the drc have been increasing, with new cases being declared closer to the ugandan border [ ] . at the same time, uganda continues to receive a large influx of people from drc through official and unofficial poes, posing a huge strain on the border screening efforts put in place. moreover, evd preparedness efforts are showing multiple signs of fatigue from all sides and is thus becoming increasingly hard to sustain, with funding and resources still inadequate to cover all high-risk districts, and yet the need to sustain the preparedness momentum at both national and district levels is greater than ever. a day after the official declaration of the th evd outbreak in the drc, uganda's moh initiated a quick evd preparedness response by activating the ntf and pheoc to a response level and mandating its members and partners to plan, mobilize resources and coordinate implementation of the full range of evd preparedness pillar activities. with support from several partner organizations, uganda was able to activate the ntf and create an active ims and a partner coordination matrix, mobilize resources and carry out preparedness activities in designated high-and moderate-risk districts on its western border with drc as well as on adjacent borders with rwanda and south sudan and the central urban hubs of kampala and entebbe, linked to population movements from and to the drc's outbreak hotspots. in addition, uganda has established multi-sectoral and multidisciplinary national and district task forces, and technical subcommittees for each preparedness pillar that advise the ntf and act as liaisons between the ntf and the high-and moderate-risk districts. these quick actions were most influenced by uganda's experiences with four previous evd outbreaks [ ] . with this experience and support from partners, activation was quick and was established with relative ease. the lasting impact of these efforts is a high likelihood that it could generate momentum towards national and partners' commitments to support long-term emergency preparedness for future outbreaks. the who recommends evd preparedness activities in countries with close proximity to evd epicenters to enable them respond should there be any importation of evd cases. uganda is among nine priority countries neighboring drc since the present th evd outbreak started [ ] . after the evd outbreak in west africa, the who proposed an agenda for changing its strategy in the face of epidemic and pandemic threats, which has been largely accepted by who member states, including uganda. through this agenda, who was able to support uganda with a quick, proactive, result-driven, resourced and well-equipped team. indeed, uganda, supported by its internationally recognized national vhf program at uvri, was the first neighboring country in the who-afro region to initiate and engage in a fully-fledged emergency preparedness and response program, which also included prophylactic use of ebola vaccination. the preparedness assessment found that all highand moderate-risk ugandan districts had less than a % score for evd readiness at baseline. it also found that the average score for evd preparedness was highest in laboratory and lowest in budgets, safe burials, and contact tracing. these findings were similar to who's initial assessments done across evd african countries neighboring drc during the evd outbreak as well as what was found by who in the evd preparedness assessment for west african countries ( ). the unhcr, iom and medical teams international (mti) that provide active health, border, and mobility care for refugees in the settlements had already put in place measures to strengthen evd preparedness such as evd trainings, evd screening, ipc measures, and dissemination of evd iec materials. following the idsr guidelines, the national surveillance system was strengthened with training of all national and district surveillance focal persons and facilitation for timely detection, reporting, and investigation of evd alerts with focus on cross-border surveillance and early patient triage at high-risk referral health care facilities. the eoc continues to provide timely information about disease epidemics while the ntf closely continues to guide, monitor, and supervise the preparedness activities. the country has built capacity and established a good laboratory network within districts, regional referral hospitals, and at the national level to collect, package, store and transport samples to the national vhf program laboratory at uvri. the vhf program laboratory at uvri is a regional diagnostic referral laboratory for vhf and routinely screens all suspect specimens for ebola (bundibugyo, sudan), marburg, cchf and rvf. there is also well-developed local capacity for social mobilisation during epidemics with engagement of political, local and religious leaders. many health workers have been trained in evd case management and provided with updated guidelines and sops with support from several partner agencies. nine months after the declaration of the th evd outbreak in the drc, uganda continues to conduct preparedness activities to prevent introduction and spread of evd into the country. while who continues to support this effort, the duration and extent of this outbreak has come as a surprise to many. as a result, governments, donors, and partners have all been stretched to a point where the preparedness strategy needs to be revisited. specifically, it is important to redefine strategies in order to both maintain the readiness momentum at a time where the risk of outbreak spillover has increased, as well as to plan for the human, technical, and financial resources needed to balance this protracted effort with the rest of the national health security agenda. this agenda requires at least equal time, efforts, and resources as evd preparedness, yet the capacity of an atrisk country like uganda is limited and cannot address both needs fully. a who meeting on strengthening partnership for improving ebola preparedness and readiness took place at the end of april and this issue was addressed. as the evd outbreak continues in drc, the risk of cross-border transmission remains imminent. subsequently, the country has plans to expand and intensify preparedness activities to additional districts, with a special focus on the use of universal precautions and ways to strengthen and sustain ipc practices at all health facilities in high-risk districts. the broad evd preparedness workgroup continues to strengthen cross-border collaboration and to engage the community in door-todoor risk communication and surveillance in all highrisk districts. there is also need to accelerate vaccination of at-risk frontline health workers in the other high-risk districts. the moh, with support from partner agencies, has started to conduct drills and simulation exercises in the most at-risk districts bordering the drc to evaluate preparedness and response capacity. the moh also plans to improve sample transportation and re-establish a national border health unit that has been inactive for many years. within the first month of declaration of the th evd outbreak in drc, uganda's moh had established a strong coordination and surveillance system to effectively alert and respond to any evd suspect case and to mitigate risk of importation of evd into uganda. with continued technical and financial support from many partners, the country has strengthened evd preparedness and timely detection, investigation and response to evd alerts. sustained efforts are required to support refreshing of health workers, provision of infection control supplies, maintenance of infrastructure, provision of equipment for case referral and isolation, regular drills and simulation exercises in key technical areas, continued risk communication, community engagement, resource mapping as well as countrywide coordination. on june , uganda detected its first cases of evd as a result of a spillover event from the drc. while the details of the cases will be presented in another paper, cases were quickly recognized, specimens safely collected and efficiently transported for diagnostic testing and confirmation at uvri. case patients were rapidly relocated to an etu for isolation and care. as of june , no secondary transmission from these three cases have occurred in uganda, a clear demonstration of the effectiveness of the uganda preparedness program. afenet: african field epidemiology network africa centres for disease control and prevention; china cdc: chinese centre for disease control and prevention; dfid: department of international development dho: district health officer; dht: district health team; drc: democratic republic of congo; drrt: district rapid response team; dtf: district task force; etu: ebola treatment unit; evd: ebola virus disease; fao: food and agriculture organisation of the united nations; fgd: focus group discussion; ghsa: global health security agenda; idi: infectious diseases institute, uganda; ihr: international health regulations; imc: incident management commander iom: international organisation for migration makerere university school of public health; moh: ministry of health mti: medical teams international; muwrp: makerere university walter reed project; nrrt: national rapid response team; ntf: national task force undp: united nations development program; unhcr: united nations high commissioner for refugees; unicef: united nations children's fund; urcs: uganda red cross society; usaid: united states agency for international development; us-cdc: united states centers for disease control and prevention; uvri: uganda virus research institute; vhf: viral haemorrhagic fever; vht: village health team; wfp: world food program; who: world health organisation organisation, country office, kampala, uganda. world health organization -afro african risk capacity, kampala, uganda. united nations children's fund, kampala, uganda. civil aviation authority, entebbe, uganda. united states agency for international development democratic republic of congo: ebola virus disease -external situation report ebola virus: symptoms, treatment, and prevention signs and symptoms | ebola hemorrhagic fever | cdc ebola vaccine to help tackle drc outbreak ebola virus disease) | cdc [internet] a systems view and lessons from the ongoing ebola virus disease (evd) outbreak in west africa outbreak of ebola virus disease in guinea: where ecology meets economy years of ebola virus disease outbreaks | - outbreak west africa | history | ebola (ebola virus disease) | cdc [internet] efficacy and effectiveness of an rvsv-vectored vaccine expressing ebola surface glycoprotein: interim results from the guinea ring vaccination cluster-randomised trial ebola virus disease) | cdc [internet] ebola viral hemorrhagic disease outbreak in west africa-lessons from uganda who-regional-strategic-evd-operational-readiness springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all partners for the technical and financial support which made the country prepare for an evd outbreak. special appreciation goes to the following organisations and agencies: afenet, africa the moh/ntf undertook the planning, coordination, and implementation of the preparedness activities. jra, ara, anm, im, mn and ytw participated in design development, data collection and management, and manuscript writing. all authors offered technical assistance for data management, manuscript development and reviewed the manuscript for intellectual content. all authors contributed to the write up, read and approved the final manuscript. the evd preparedness activities were supported by the uganda ministry of health, international agencies and development partners. the data sets and the reports that support this write up belong to the moh uganda. due to confidentiality reasons, the data sets and reports are not publically available. however, the data sets and the reports could be availed upon reasonable request and with permission from the moh uganda.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -nuep nim authors: dewald, lisa evans; johnson, joshua c.; gerhardt, dawn m.; torzewski, lisa m.; postnikova, elena; honko, anna n.; janosko, krisztina; huzella, louis; dowling, william e.; eakin, ann e.; osborn, blaire l.; gahagen, janet; tang, liang; green, carol e.; mirsalis, jon c.; holbrook, michael r.; jahrling, peter b.; dyall, julie; hensley, lisa e. title: in vivo activity of amodiaquine against ebola virus infection date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: nuep nim during the ebola virus disease (evd) epidemic in western africa ( ‒ ), antimalarial treatment was administered to evd patients due to the high coexisting malaria burden in accordance with world health organization guidelines. in an ebola treatment center in liberia, evd patients receiving the combination antimalarial artesunate-amodiaquine had a lower risk of death compared to those treated with artemether-lumefantrine. as artemether and artesunate are derivatives of artemisinin, the beneficial anti-ebola virus (ebov) effect observed could possibly be attributed to the change from lumefantrine to amodiaquine. amodiaquine is a widely used antimalarial in the countries that experience outbreaks of evd and, therefore, holds promise as an approved drug that could be repurposed for treating ebov infections. we investigated the potential anti-ebov effect of amodiaquine in a well-characterized nonhuman primate model of evd. using a similar -day antimalarial dosing strategy as for human patients, plasma concentrations of amodiaquine in healthy animals were similar to those found in humans. however, the treatment regimen did not result in a survival benefit or decrease of disease signs in ebov-infected animals. while amodiaquine on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of amodiaquine when used in combination with artesunate or another antiviral. antiviral activity of amodiaquine and artesunate and their metabolites in cell culture. the antimalarial treatment asaq that was administered to evd patients in , is a coformulation of artesunate (as) and amodiaquine (aq). as and aq are rapidly metabolized in the liver to dihydroartemisinin (dha) and desethylamodiaquine (deaq), respectively. prior to in vivo evaluation, the drug asaq, its components, and the metabolites were characterized for their inhibitory effects on ebov (makona variant, ebov/mak) replication in cell culture ( table ). the data confirm previous reports that both aq and the metabolite deaq block ebov replication with similar activity (ic = . to . µm) in huh and vero e cell lines (ic = . to µm). in primary human macrophages, both aq and deaq exhibited elevated cytotoxicity, which precluded any interpretation of antiviral activity. in contrast, activity of as and its metabolite dha was weak or undetectable. combinatorial testing of aq and as or the metabolites, deaq and dha, did not reveal in vitro synergistic effects against ebov replication (data not shown). based on the in vitro data, the decision was made to evaluate aq in the nhp model of ebov infection. nhps with an aq dosing regimen similar to that used for evd patients in ebola treatment centers in . treatment consisted of a -day course of as-aq with the dose determined according to age of the patient. the dose range for aq in humans is . to mg/kg corresponding to a rhesus macaque equivalent dose range of . to . mg/kg based on body surface area . a pharmacokinetic (pk) study in rhesus macaques ( groups of males and females) was performed to monitor plasma concentrations of aq (fig. a ) and the active metabolite deaq (fig. b) . the study evaluated three daily oral doses of aq, using mg/kg or mg/kg. pharmacokinetics were determined by collecting blood samples at , . , , , , , , , , and hours (h) following dosing on day and day ( fig. ) . after days of dosing with mg/kg in healthy male and female macaques, aq was well-tolerated. the higher dose of mg/kg resulted in a variety of clinical observations including hypoactivity, shivering (muscle tremors) and/or diarrhea. extreme hypoactivity was observed in a single male of the mg/kg group that resolved after dosing ceased. animals in both the mg/kg and mg/kg groups had lower blood pressure readings than at predose on both dosing days, typically at and/or h post-dosing. clinical chemistry and hematology parameters for both doses were analyzed and fell within normal ranges with the exception of liver enzymes. alanine aminotransferase (alt) and aspartate aminotransferase (ast) were elevated . -to . -fold on day at h after the rd dose. the increases in alt and ast were seen in both male and female animals at both the and mg/kg dose regimens, though changes were not dose-related. these increases were considered toxicologically significant. aq and the metabolite deaq reached peak concentrations at . to h (t max ) after administration for both day and day dosing (supplementary tables and ). the elimination phase half-life (t / ) varied among the individual animals, ranging from to h for aq and to h for deaq. plasma concentrations of the metabolite deaq were higher than concentrations of the parent drug resulting in auc last , and auc inf values that were . -to -fold higher for deaq than for aq. the mg/kg aq dose resulted in c max for aq ( . - . ng/ml) and deaq ( - ng/ml) that were in a similar range as reported for the mg/kg dose in humans (aq: c max = . ± . ng/ml and deaq: c max = . ± . ng/ml) . based on the results of the pharmacokinetics study, the mg/kg aq dose was chosen for a study to evaluate the in vivo effect of aq in the nhp model of evd (study outline, supplementary fig. ). rhesus macaques were challenged intramuscularly (im) with a target dose of plaque-forming units (pfu) of ebov/mak (measured dose of pfu) on study day . the control group (n = , female, males) received vehicle treatment on days , , , , and postexposure. treatment group (n = , females, males) received a -day course of mg/kg of aq by oral administration on days , and after exposure to ebov. treatment group (n = , females, males) received a -day course of mg/kg of aq by oral administration on days , , and after exposure to ebov. all animals were euthanized or succumbed to disease by day postexposure (fig. a) . median times to disposition were days for placebo and treatment group , and days for treatment group with no significant difference between the placebo or treatment groups versus the treatment group (p = . and . , respectively). the animals in all groups became febrile by day or postexposure, followed by a marked decrease in body temperature preceding death (fig. b) . no significant difference in febrile illness or weight loss was observed between control and treatment groups (fig. b,c) . nhps had a mild reduction in activity and responsiveness by www.nature.com/scientificreports www.nature.com/scientificreports/ day postexposure with a severe decrease observed for most animals on day postexposure ( table ). loss of appetite and lymphadenopathy began on day to followed by dehydration and rash (petechial, maculopapular) on day postexposure. clinical signs did not differ significantly between the groups. viral loads in plasma were not reduced in treated animals. plasma viremia was quantified by rt-qpcr, and viral titer was determined by plaque assay. viral rna was first detected in the serum of some animals days after exposure, with a rapid and substantial increase by day for both placebo-and aq-treated animals. rna levels at necropsy were in the range of - viral rna copies/ml for all nhps (fig. a) . infectious viral titers followed a similar trend for all groups with a sharp increase in viral titer starting on day postexposure and reaching a peak plateau by day before animal death (fig. b ). viremia correlated with the onset of clinical signs of disease such as loss of appetite, lymphadenopathy, and fever. aq treatment did not reduce plasma viral rna copies or infectious virus titer regardless of when treatment was initiated. no significant difference in viral titers was observed between groups. amodiaquine-treated animals present with abnormal hematology and biochemical profiles and pathological disease that corresponds with ebola virus disease. the animals showed a similar hematological profile regardless of treatment. complete blood counts and serum chemistry analysis were performed at scheduled sampling points, before (days - , - , and ) and after (days , , , and at necropsy) exposure (figs. , ) . the chemistry values for aq-treated nhps followed the same trends as the control animal values. similar hematological and biochemical profiles were observed for all animals regardless of treatment both in aq-and placebo-treated animals. concurrent neutrophilia and thrombocytopenia were observed for aqand placebo-treated animals on day postexposure with ebov (fig. ) . as animals reached endpoint criteria, neutrophil levels decreased (fig. a) . the low-level neutrophil values on day postexposure were from necropsy samples only. nhps from all treatment groups exhibited a concomitant increase in serum creatinine and blood urea nitrogen levels, indicative of renal dysfunction often noted in nhps with concurrent evd (fig. a,d) . other biochemical abnormalities consistent with evd were also observed beginning on day postexposure, including substantial elevation of serum alt, ast, and gamma-glutamyl transpeptidase (ggt) levels that indicate hepatocellular damage (fig. b ,e,f). necropsies were performed on all animals to evaluate pathological disease associated with ebov infection following aq or placebo treatment. the pathologist was blinded to the group identification during necropsy and tissue evaluation. the pathological findings were similar in type and severity between treated and untreated animals, and the gross and histopathologic findings in all animals were consistent with typical evd in rhesus macaques. common gross findings included a cutaneous rash on the face, often extending to other regions of the body, dehydration, discoloration of the liver with increased friability, turgid spleen, and enlarged, often congested kidneys. at the microscopic level, all animals exhibited lymphoid depletion of the axillary lymph nodes, lymphoid depletion and necrosis of the spleen, and hepatocellular degeneration and necrosis. panniculitis and necrosis were observed at the virus challenge site of animals. samples from infected animals collected on days , , , and postexposure and on day of necropsy (days , or ) were analyzed for determination of plasma levels of aq and its metabolite deaq. data indicate negligible levels of aq in all but five plasma samples, each from a different animal and day (fig. a) . as the samples were diluted by a factor of . for decontamination protocol, the concentrations were likely below the limit of detection. plasma levels of the metabolite deaq were higher than aq and detectable in all treated animals from both nhp nhp nhp nhp nhp table . clinical scores for responsiveness of animals. responsiveness of unanesthetized animals was scored using the following criteria: (white) = alert, responsive, normal activity, free of disease signs or exhibits only resolved/resolving disease signs; = slightly diminished general activity, subdued but responds normally to external stimuli; = withdrawn, may have head down, fetal or hunched posture, or reduced response to external stimuli; = recumbent but able to rise if stimulated, or moderate to dramatically reduced response to external stimuli; = persistently recumbent, severely or completely unresponsive, or may have signs of respiratory distress. www.nature.com/scientificreports www.nature.com/scientificreports/ groups and (fig. b) . deaq was evident through day postexposure and/or necropsy in of animals in group and in all animals in group . plasma levels of deaq in ebov-infected nhps were compared at different time points (fig. ) . animals that were treated on days , and (group , fig. a ), had plasma deaq levels ranging from to ng/ml on days , , and postexposure. the highest deaq levels were detected in necropsy samples on day ( and ng/ ml). for animals treated on days , and postexposure (group , fig. b ), plasma concentrations ranged from - ng/ml on day . higher concentrations were detected on day ( - ng/ml) and day postexposure ( - ng/ml). plasma levels of deaq in infected nhps and healthy nhps were compared at select time points that were identical in the pk and the efficacy study. plasma samples from infected group animals on day correspond to pk-plasma samples taken at h after the rd dose. healthy animals had higher plasma levels of deaq ( - ng/ml) than infected animals ( - ng/ml) (fig. a) . similarly, plasma samples on day from infected group animals were in a lower range (n = , - ng/ml) than those of healthy animals at the corresponding time point ( h after rd dose, n = , - ng/ml) (fig. b) . on day , h after the rd dose, deaq levels in the plasma of two animals from group were in a similar range (n = , - ng/ml) as found in healthy animals (n = , - ng/ml) (fig. c,d) . repurposing drugs continues to be of interest to the healthcare professional community for the treatment of emerging and re-emerging hemorrhagic fever viruses such as ebola, marburg, and lassa viruses. extensive efforts to screen approved and established drugs for antiviral activity led to a panel of drugs with broad-spectrum antiviral activity profiles that are available, affordable, have well-characterized pk/safety profiles and could be used under the emergency use authorization (eua) mechanism , , , . while a number of fda-approved compounds have proven to be efficacious against ebov in vitro or in murine models of disease, clinical evaluation or evaluation in more relevant disease models, such as nhps, has been limited. aq is a well-known antimalarial drug with wide usage in the countries that experience outbreaks of evd. the drug has activity against several human pathogens of other virus families including corona-, flavi-, and bunyaviruses [ ] [ ] [ ] [ ] . a recent report showed that entry of lassa-gp pseudotyped virus was blocked by aq, indicating that the drug may also have value for the treatment of other viral hemorrhagic fevers . aq is known to have in vitro antiviral activity against ebov - . multiple mechanisms for antiviral activity have been proposed. aq may block ebov entry, which depends on the acidification of endosomes. as a cationic amphiphilic drug, aq can accumulate in the late endo/lysosome and, as a weak base, neutralize the acidic environment, thereby inhibiting cathepsin b activation required for fusion of the viral and endosomal membrane . aq has also been reported to bind and inhibit cathepsin b directly . in silico binding studies revealed that aq may also bind to the viral protein vp . we found that aq inhibits ebov replication in multiple cell types, including huh and vero e cells and primary human macrophages, with ic 's ranging from . - . um depending on experiment and the cell type (table ) . aq is rapidly metabolized to the active metabolite, deaq, following oral administration. in vitro studies confirmed that the active metabolite also has anti-ebov properties in huh and vero e cells, and primary human macrophages, with ic 's ranging from . - . µm µm depending on experiment and the cell type. in contrast, as and its metabolite dha demonstrated minimal to no in vitro antiviral activity against ebov when tested side-by-side to aq using our assay parameters. when used in combination, as and aq did not have a synergistic effect on ebov replication in vitro. whereas as could possibly act with aq to impact the whole body-system in response to ebov in a way that cannot be replicated in the in vitro assays, this study assumed that aq was the main contributing factor of the drug combination resulting in anti-ebov activity. www.nature.com/scientificreports www.nature.com/scientificreports/ the goal of the study was to treat animals with aq using a similar dosing strategy as for human patients, with a target blood concentration range of the parent compound aq of . ± . ng/ml . indeed, we found that a mg/kg aq dose using the -day treatment regimen resulted in correlating plasma levels of . - . ng/ ml in healthy nhps. however, this treatment regimen did not result in a survival benefit or decrease of disease symptoms in ebov-infected animals. these results are disappointing and highlight the importance of utilizing relevant animal models of evd to evaluate potential antivirals, including detailed characterization of pharmacokinetics and tolerability in the context of evd. whereas aq treatment did not lead to detectable beneficial effects on evd progression in nhps, there may be value in investigating novel aq derivatives that have been improved for anti-ebov potency and/or improved tolerability . a possible impact from aq side effects needs to be considered. rare instances of acute liver injury usually after prolonged treatment have been reported , . for this reason, aq and the combination drug asaq are recommended for use as a malaria treatment in endemic areas, but not for prophylaxis against malaria. the onset of hepatic injury is often associated with agranulocytosis. elevated liver enzymes, alt and ast, were observed in the healthy nhps during the pharmacokinetics study. given that the evd patients in were given a co-formulation of aq and as, it would have been of interest to test the combined regimen rather than just aq to evaluate potential implications of the two drugs on disease progression. whereas as has no measurable anti-ebov effect when tested in combination with aq in vitro, the drug could have an in vivo effect that is not captured in cell culture assays. as and artemether are derivatives of artemisinin and are both metabolized to dha, the active metabolite for the treatment of malaria. however, as www.nature.com/scientificreports www.nature.com/scientificreports/ is water soluble, and reaches peak concentration more rapidly with higher plasma c max than artemether, which could impact in vivo activity against ebov. another consideration is that as and aq may affect each other in terms of pk, drug metabolism, or disposition. for example, as co-administration with aq has been reported to reduce exposure to aq . questions remain on the possible contribution of as to the beneficial effect of the asaq treatment observed in evd patients . therefore, testing the co-formulation would have value, but without testing each drug singly as well, attribution of any observed effect to a specific component will be challenging. other confounding factors not measured in the gignoux study could have accounted for the beneficial effect of asaq . the potential impact of concurrent malaria and the type of antimalarial used in evd patients was not addressed in our study. in conclusion, treatment with aq did not have a beneficial effect on survival or the symptoms of evd in rhesus macaques under the conditions tested. whereas aq on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of aq when used in combination with another antiviral. www.nature.com/scientificreports www.nature.com/scientificreports/ cells and virus. vero e (atcc crl- , manassas, va), hela (atcc ccl- ), and huh (human hepatocellular carcinoma) cells were maintained following recommended protocols. human monocyte-derived macrophages (mdms) were generated as previously described . ebola virus/h.sapiens-tc/gin/ /makona-c (ebov/mak, genbank accession no. kx . ) was propagated in vero e cells (bei resources, niaid, nih: vero c (e ), african green monkey kidney, working bank #nr- ) as previously described . virus stock and challenge inoculum titers were determined by plaque assay on vero e cells as previously described . drugs and treatment preparation. in vitro studies. the antimalarial artesunate-amodiaquine (asaq winthrop) (sanofi-aventis, gentilly cedex, france) was solubilized by crushing the tablets and resuspending in dimethyl sulfoxide to prepare a solution with the aq component at a concentration of mm. the compounds, amodiaquine dihydrochloride dihydrate (#a ), artesunate (#a ), and dihydroartemisinin (#d ) were purchased from sigma-aldrich (saint louis, mo). n-desethylamodiaquine hydrochloride (#sc- ) was obtained from santa cruz biotechnology (dallas, tx). drugs were prepared as mm stocks in dimethyl sulfoxide. animal studies. source, formulation, and preparation of amodiaquine hydrochloride was the same for the pk and the efficacy studies. amodiaquine hydrochloride was obtained from us pharmacopeia (rockville, md; cat. ; lot j ) and a mg/ml aq (free base) solution was prepared in sterile water for injection (usp). cell-based testing of ebov antiviral agents. the cell-based ebov drug screen and cytotoxicity assays were performed as previously described . briefly, vero e and huh cells were seeded at × cells/well, and mdms at × cells/well in -well plates. after h, cells were treated with compounds at -fold dilutions starting from µm. the starting concentration of the asaq tablet suspension corresponded to µm of the aq base component. cells were infected with ebov/mak h after the addition of the drugs in biosafety level (bsl ) containment at multiplicity of infection (moi) of . - . . after h, plates were fixed with % neutral buffered formalin (richard-allan scientific), and ebov/mak was detected with a mouse antibody specific for ebov vp protein (#b-md -bd -ae , usamriid) followed by staining with alexa fluor ® goat anti-mouse igg (heavy + light chain) antibody (life technologies, grand island, ny) or with anti-mouse igg-peroxidase labeled antibody (kpl# - ). fluorescence or luminescence was quantified on a plate reader (infinite ® m pro, tecan us, morrisville, nc). the signal of treated infected wells was normalized to uninfected control wells and measured (in percent) relative to untreated infected wells. non-linear regression analysis was performed, and the % inhibitory concentrations (ic s) were calculated from fitted curves (log [agonist] versus response [variable slope] with constraint to remain above %) (graphpad software, la jolla, ca). the ebov drug screen assay was performed with three replicates for each drug concentration, and the assay was repeated at least twice for confirmation. to evaluate cytotoxicity, cells were treated with compounds as described above in absence of virus. at h after drug addition, cell viability was quantified using the celltiter glo luminescent cell viability assay kit (promega, madison, wi). www.nature.com/scientificreports www.nature.com/scientificreports/ pharmacokinetic analysis of amodiaquine in nonhuman primates. rhesus macaques (macaca mulatta) were obtained from covance research products (princeton, nj). two groups (n = , females and males per group) were dosed with or mg/kg amodiaquine hydrochloride (us pharmacopeia, rockville, md; cat. ; lot j ) orally via nasogastric intubation once daily for days. nhps were housed in stainless steel primary enclosures singly or in pairs if compatible. nhps were provided teklad certified global % protein primate diet (# c) and purified water ad libitum. clinical observations were conducted for days including the day of dosing. blood (maximal μl) was collected from cephalic vessels on day and day . on day , blood was collected pre-dose, . , , , , , , , and h post-dose (immediately prior to dosing on day ). on day , blood was collected h after dose (or h after dose ), immediately prior to dosing on day , and . , , , , , , , and h after dose . drug concentrations of aq and its metabolite, deaq, were determined in collected plasma samples using liquid chromatography with tandem mass spectrometry (lc-ms/ms). plasma samples (volume μl) were prepared by adding ml of methyl t-butyl ether. each tube was vortexed for approximately minutes (min) at maximal speed and centrifuged for min at , g to facilitate separation of the liquid phases. upper layers ( μl) were transferred to new tubes, and the solvent was removed under vacuum in a centrifugal evaporator. the dried residues were reconstituted with μl of internal standard solution ( ng/ml risperidone and ng/ml chloroquine in : [v:v] acetonitrile:water). the tubes were vortexed min and clarified by centrifugation ( , g) for min. the clarified extracts were transferred to high performance liquid chromatography vials containing glass inserts for subsequent lc-ms/ms analysis. lc-ms/ms was performed using a lc- ad pump system (shimadzu, columbia, md) and a qtrap mass spectrometer (sciex, concord, ontario, canada) in multiple reaction monitoring mode and a polaris c -a column ( × . mm, μm; agilent, ca), using gradient elution with . % formic acid in water and . % formic acid in acetonitrile as the mobile phase. the lower limit of quantitation for aq and deaq of the method was ng/ml. the following parameters and constants were determined: maximal plasma concentration (cmax), time to maximum plasma concentration (tmax), area under the plasma concentration-time curve to the last time point and extrapolated to infinity (auc last and auc inf ), terminal elimination half-life (t / ), apparent volume of distribution (v/f), and total clearance (cl/f) after oral administration. pk parameters were analyzed using phoenix ® winnonlin ® software (v . ; certara, princeton, nj) to perform noncompartmental data analysis for extravascular administration. for clinical pathology (serum chemistry, hematology), blood ( ml) was collected prior to dosing on day and approximately h after the final day dose. treatment and challenge of nonhuman primates. rhesus macaques of chinese origin (n = , adult, < years of age) were obtained from charles river laboratories (frederick, md). animals were singly housed in stainless steel primary enclosures and provided chow and purified (reverse osmosis) water ad libitum. the vehicle control group (group ; n = ) was treated with sterile water. two treatment groups were treated with aq orally once daily as a consecutive -day course of mg/kg free base ( mg/kg amodiaquine hydrochloride (us pharmacopeia, rockville, md; cat. ; lot j ). treatment began on the day of ebov exposure (group ; n = , females and males), or on day postexposure (group ; n = , females and males). all groups were challenged im with a target dose of pfu) of ebov/mak (actual dose = pfu). the plaque assay back-titration of the challenge material was initiated on the day of preparation (study day ) on vero e cells, and plaques were fixed with % formalin and stained with crystal violet days later. animals were observed and weighed daily. the vehicle control group (group , n = ) received an equivalent volume of sterile water (gibco, cat. a , lot ). weight was recorded on day - and day - , then daily starting one day before challenge until primates succumbed to disease. responsiveness of the animals was monitored following -point range, in which a score of met primary endpoint criteria and initiated secondary criteria evaluation (table ) . when nhps scored a for primary euthanasia criteria and their temperature was above °c, secondary euthanasia criteria were reviewed. an nhp had to meet at least two secondary criteria, blood urea nitrogen ≥ mg/dl, calcium ≤ . mg/dl, ggt ≥ u/dl, and/or creatinine ≥ . mg/dl, for required euthanasia. two rhesus macaques were euthanized based on their secondary criteria. six of the fifteen rhesus macaques were euthanized based on veterinary discretion, not based on their clinical score or secondary criteria. hematology and serum chemistry. complete blood count with leukocyte differential was performed from peripherally collected blood samples using vacuette k ethylenediaminetetraacetic acid (edta) tubes and a sysmex xt- iv hematology instrument using a preprogrammed monkey species profile (sysmex america, ny). plasma and serum were prepared by separation for min at ambient temperature with centrifuge set to rcf. serum chemistries were performed using the piccolo xpress analyzer and general chemistry discs (abaxis, abbott point of care, nj) from vacuette z serum clot activator tubes (greiner bio-one, monroe, nc). pathology and histology. all animals were humanely euthanatized in accordance with defined experimental endpoints, and gross necropsy was performed. tissue samples were inactivated by fixing for h in % neutral buffered formalin. following fixation and removal from the bsl- laboratory in accordance with standard operating procedures, tissue samples were routinely processed in a tissue-tek vip- automated vacuum infiltration processor (sakura finetek usa, torrance, california, usa) followed by paraffin embedding with a tissue-tek model tec unit (sakura finetek usa, torrance, ca, usa). using a standard semiautomated rotary microtome and lighted water flotation bath (leica biosystems, wetzlar, germany), tissue sections were cut at a thickness of µm and mounted on positively charged uncoated glass slides (thermofisher, waltham, ma, usa), air-dried at room temperature, stained with hematoxylin and eosin (h&e), and coverslipped for microscopic evaluation by the pathologist. plasma samples from rhesus macaques that had received a dose of aq at integrated research facility/ niaid (fort detrick, md) were analyzed for concentrations of aq and the metabolite deaq. prior to shipment to sri, the samples were diluted : . and irradiated at mrad using a cobalt- source to destroy any pathogens that may have been present in the plasma samples. a pilot study with spiked quality control standards confirmed that irradiation does not appreciably alter the level of aq in the plasma (data not shown). a liquid:liquid extraction method with methyl t-butyl ether was used to separate aq and deaq from rhesus macaque plasma. samples were analyzed by lc-ms/ms with a lower limit of quantitation (lloq) of ng/ml ( . ng/ml × . dilution factor) in plasma for both aq and deaq. aq and deaq concentrations were adjusted for the dilution factor of . for analysis in figs. and . the virus working stock ebov/makona used for exposure (genbank accession no. kx . , biosample: samn ). clinical management of patients with viral haemorrhagic fever effect of artesunate-amodiaquine on mortality related to ebola virus disease effect of mass artesunate-amodiaquine distribution on mortality of patients with ebola virus disease during west african outbreak the clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry identification of compounds that block ebola virus-like particle entry via a repurposing screen of approved drugs a systematic screen of fda-approved drugs for inhibitors of biological threat agents evaluation of ebola virus inhibitors for drug repurposing identification of agents effective against multiple toxins and viruses by host-oriented cell targeting the antiviral activities of artemisinin and artesunate nonhuman primate models of ebola virus disease a simple practice guide for dose conversion between animals and human pharmacokinetics and tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers identification of combinations of approved drugs with synergistic activity against ebola virus in cell cultures a screen of approved drugs and molecular probes identifies therapeutics with anti-ebola virus activity establishment of an antiviral assay system and identification of severe fever with thrombocytopenia syndrome virus inhibitors antiviral activities of selected antimalarials against dengue virus type and zika virus amodiaquine, an antimalarial drug, inhibits dengue virus type replication and infectivity repurposing of clinically developed drugs for treatment of middle east respiratory syndrome coronavirus infection arbidol and other low molecular weight drugs that inhibit lassa and ebola viruses antiviral activity of cationic amphiphilic drugs a common feature pharmacophore for fda-approved drugs inhibiting the ebola virus novel amodiaquine derivatives potently inhibit ebola virus infection amodiaquine induced agranulocytosis and liver damage tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated plasmodium falciparum malaria: two open-label, randomized trials in nimba county evaluation of the activity of lamivudine and zidovudine against ebola virus high dose sertraline monotherapy fails to protect rhesus macaques from lethal challenge with ebola virus makona pathology of experimental ebola-zaire (mayinga) virus infection transmitted to guinea pigs by oral, conjunctival and tonsillar routes the findings and conclusions in this report do not necessarily reflect the views or policies of the us department of health and human services or of the institutions and companies affiliated with the authors. the authors declare no competing interests. supplementary information is available for this paper at https://doi.org/ . /s - - - .correspondence and requests for materials should be addressed to j.d.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- -fz wydz authors: bezek, sarah; jaung, michael; mackey, joy title: emergency triage of highly infectious diseases and bioterrorism date: - - journal: highly infectious diseases in critical care doi: . / - - - - _ sha: doc_id: cord_uid: fz wydz emergency medical services are a key element in health systems for the evaluation and treatment of patients exposed to highly infectious diseases or bioterrorism agents. triage and early identification at any point of care can have a significant impact on the prevention and management of these diseases. this chapter reviews triage practices, including early isolation and decontamination, of highly infectious diseases and bioterrorism agents at different health system levels. effective triage systems that protect patients and staff require a well-functioning health system with integrated referral and communication pathways between community/prehospital, outpatient, emergency department, and hospital settings. the pandemic influenza and ebola virus disease (evd) outbreaks had a global impact, and they revealed gaps in triage and health surveillance systems in low-and high-resource countries alike. other high-visibility events are attacks with biological and chemical agents such as the sarin nerve gas attack in tokyo, the anthrax attacks in the usa, and the ongoing use of chemical weapons in conflicts in the middle east. no community is immune to a future outbreak or attack, and preparations require proper planning among healthcare workers, government officials, private businesses, and community leaders. this chapter will approach the triage of highly infectious diseases and terrorist attacks in two sections. the first will focus on general considerations at each point of the health system with examples of specific triage practices from select disease outbreaks. the second will emphasize biological agents of interest and the use of decontamination units and personal protective equipment. health departments, pharmacies and medical supply manufacturers, traditional healers and alternative medicine practitioners, universities and research laboratories, and schools and childcare centers. these health systems may interact with or be a part of larger systems at local, regional, national, and international levels. disease control policies and programs can strengthen infectious disease and bioterrorist attack care and surveillance at each of these levels. this chapter will focus on system points staffed by health workers: prehospital response and transport, outpatient facilities, emergency departments, hospitals and specialized treatment units, facilities in response to disasters and conflict, and the public health surveillance service. in health systems with established prehospital emergency medical service (ems) systems, ems health providers and other responders are an essential first point of contact for ill patients seeking care. there is a wide variance in the structure of ems systems and training of responders from country to country as well as means of transport, dispatch, and communication ( fig. . ). the world health organization (who) emergency care framework identifies the key prehospital components of bystander response, ems dispatch, on-scene provider response, and patient transport with on-board transport care. during the evd outbreak, governmental agencies like the us centers for disease control and prevention (cdc) developed specific recommendations to guide local ems systems in responding to possible cases and prevent spread of the infection [ ] [ ] [ ] . the modifications occur at multiple points of care: • developing a case definition for person under investigation • standardized questions for dispatchers to identify possible infection • preparation for and evaluation upon arrival on scene by ems personnel • precautions while transporting patients and contacting appropriate receiving hospital • monitoring of potentially exposed ems personnel • maintenance of transportation vehicles and equipment • decontamination processes similar peer-reviewed frameworks have been proposed for a pandemic of influenza and other respiratory illnesses [ ] . during a pandemic or a surge in patients that requires rationing of ems response, an additional consideration is the implementation of minimal resuscitation criteria for patients in possible cardiac arrest on initial call to the dispatcher or other inclusion and exclusion criteria for care and transport. an algorithm that is decided at the local level, well-communicated to the public, and uniformly followed by ems system and healthcare facilities is necessary for equitable rationing. although it is out of the scope of this book chapter, separate and effective mortuary services to transport deceased patients from the prehospital setting can be important to prevent overwhelming ems dispatch and response systems. in the event of a biological or chemical terrorist attack, the prehospital ems systems may respond differently if it is an overt or covert attack. a set of algorithms was developed from military and civilian sources for use to evaluate patients from an attack with known or unknown agents [ ] . initial triage and treatment are based on symptomatology without a definitive diagnosis, and they highlight the importance of isolation and decontamination to prevent further spread or exposure to patients and responders while transporting patients for definitive treatment. appropriate implementation of these principles can potentially help prevent further spread of disease or agent exposure, initiate appropriate care of ill patients, protect essential ems responders, and promote efficient use of healthcare resources. ambulatory clinics are often the first place that patients seek medical care. this may be a clinic for primary care, pediatrics, antenatal care, urgent care, or specialist care, or it could be the general outpatient department of a hospital. in many health systems, patients may reach a clinic's nurse-on-call and undergo triage by telephone. this is an opportunity to direct the patient to an appropriate care facility for evaluation and give hygiene and isolation instructions at home for cases that may not need immediate attention. during an outbreak, additional screening questions can be instituted for patient presenting to any outpatient facility. one example is the screening protocol was described by a multifacility academic health system in the usa during the evd outbreak [ ] . all patients presenting to the facilities were asked screening questions, and patients that met the cdc definition for "person under investigation" were then triaged to either a tropical medicine clinic, emergency department, or specialized evd treatment unit depending on symptomatology and time of day of presentation. of the patients who met the inclusion definition, the majority were triaged to the clinic or emergency department, and no patients were diagnosed with evd. patients may seek care at clinics following a terrorist attack by biological or chemical agents either in the event of a widespread attack with varying degrees of illness or a covert attack with an agent that has an insidious onset of symptoms. facilities should have reporting and referral pathways in place if healthcare workers detect a pattern in presenting cases. many emergency departments (ed) use standardized and validated triage tools in order to prioritize patients who are most sick on presentation. examples of commonly used instruments include the emergency severity index, the south african triage score, and the emergency triage assessment and treatment for pediatric patients. these and other similar tools use easily observable physical exam signs, with or without measured vital signs and rapid diagnostic tests such as a fingerstick glucose measurement, to quickly identify patients needing immediate evaluation and treatment. additionally, specific triage instruments and scores such as the systemic inflammatory response syndrome (sirs) criteria, quick sepsis-related organ failure assessment (qsofa), and the national early warning score (news) are tools that have been used in the ed to identify patients who have infection resulting in sepsis or septic shock (table . ) [ , ] . initial ed triage includes early identification of patients for isolation and decontamination. at the beginning of the outbreak of severe acute respiratory syndrome (sars) in , an ed in singapore activated the decontamination area outside its entrance as a screening and consultation area of at-risk patients identified by triage nurses immediately on arrival and registration [ ] . similarly, a mobile pediatric emergency response team was stationed outdoors during the influenza pandemic in the usa to evaluate low acuity patients with influenza-like symptoms [ ] . the rationale of both of these responses was to prevent disease transmission and absorb increased patient volumes with minimal impact on the care for other ed patients. the ed has also been used as a place for continued treatment in cases that require prolonged isolation while awaiting confirmation of a diagnosis. during the evd outbreak, a referral hospital in the usa developed a mobile containment unit staffed with ems personnel adjacent to the ed as an extended treatment area for patients under investigation for evd [ ] . by separating the unit from the ed and integrating the unit with the ems referral system, the arrival and initial evaluation of patients were more confidential and streamlined. the resource-intense unit also had dedicated laboratory, portable radiology, and staff decontamination equipment. in the event of a bioterrorist attack, ed needs will depend on the extent of exposure and agent used. bioterrorist attacks can be covert or announced. the detection of a covert attack can be delayed depending on incubation period, access to healthcare facility, and location of the attack [ ] . triage systems should alert providers in the case of unusual patterns of illness, such as geographical clusters, an unusual number of deaths or critically ill patients, or sudden rise in a specific syndromic presentation. once a bioterrorist attack is suspected, local and national authorities should be notified, and an emergency preparedness plan should be initiated. this is discussed in greater detail in the section "the threat of bioterrorism: triage in setting of suspected attack". additional triage after initial entry into the ed may be implemented to stratify treatments for patients who may present with similar symptoms and to formalize the criteria for hospitalization. these triage systems can assist in prioritizing available resources based on patient needs in an equitable manner and not solely relying on clinical judgment. in mexico during the pandemic influenza, a large referral hospital implemented an adapted scoring system for adults presenting with an influenza-like illness (ili) to determine hospitalization and oseltamivir use [ ] . the ili score elements included patient symptoms, comorbidities, number of previous healthcare facility visits, and results from labs and imaging, and they found the score complemented clinical judgment. in the uk, the simple triage scoring system (stss) was applied retrospectively to patients admitted for pandemic influenza [ ] . the stss adds mental status and age to vital signs and had similar predictive value for intensive care unit (icu) admission and mechanical ventilation compared to the full sepsis-related organ failure assessment (sofa) score which requires laboratory exam values. there is also a role for critical care triage for patients requiring hospitalization in general or specialized wards such as icus or isolation units. the american college of chest physicians published a consensus statement on tertiary triage for the critically ill and injured in pandemics and disasters in [ ] . they recommended critical care and acute care physicians be designated as triage officers or in triage teams, and they emphasized the role of clinical decision support tools that are agreed upon at the health facility and regional levels. in pandemics and disasters that result in severe resource scarcity, triage teams may need to consider excluding patients from intensive care units who have a predicted mortality of greater than % but allow for reassessment and an appeal mechanism. identifying patients who will require intensive care should also be accompanied by streamlining and increasing available hospital resources to treat the influx of patients. this has been characterized as surge capacity and is a basic element of disaster and epidemic preparedness and described further in the section on bioterrorism [ ] . another mechanism for increasing resources among hospitals is regional coordination of treatment centers. in response to the evd outbreak, the us department of health and human services created a regional treatment network for evd and other special pathogens [ ] . hospitals across the country were designated as frontline facilities that provide stabilizing treatment for the first - hours after presentation, assessment hospitals capable of evaluation and treatment in the initial hours to confirm or rule out illness, treatment centers that can care for patients during the entire duration of illness, and regional treatment centers with enhanced capabilities for multiple patients. this tiered plan allowed for distribution of regional resources and limits healthcare worker exposure to patients with confirmed illness. triage for highly infectious diseases and bioterrorism attacks may occur in nonhealth facilities in specific contexts such as at ports of entry, during mass gatherings, and among populations displaced by humanitarian emergencies. health screening at ports of entry is a public health surveillance function aimed at delaying and reducing the spread of disease by international travelers (fig. . ) . modeling for screening of passengers arriving on international flights at us airports during a simulated pandemic influenza estimated that the program would identify about half of infected individuals and reduce the rate of new us cases [ ] . during the evd outbreak, the cdc implemented health border screening of passengers coming from other evd-affected countries arriving at select us airports with referral to designated health facilities for possible cases, and the agency also worked with multiple west african countries to strengthen ground and air border health strategies [ , ] . another special consideration for triage is surveillance during anticipated mass gatherings and migrations. one example is the annual hajj pilgrimage to saudi arabia. a systematic review of prevalence studies of acute respiratory infections among pilgrims while in saudi arabia and on return to their origin countries spanned the pandemic influenza and emergence of middle east respiratory syndrome coronavirus (mers-cov) [ ] . although there was a high incidence of acute respiratory infections among pilgrims, there was a low prevalence of pandemic influenza, and no cases of mers-cov were reported among hajj pilgrims during the review period. humanitarian emergencies from man-made and natural disasters can lead to large and unexpected population displacement within and between countries. disease surveillance, prevention, and treatment can be challenging in informal communities and during times of protracted conflict with disruption of governmental health services [ ] . although the burden of disease during the crisis often reflects pre-crisis disease prevalence, populations affected by humanitarian disasters are vulnerable to specific respiratory and diarrheal illnesses such as measles and cholera because of crowded living conditions, malnutrition, and lack of adequate water and sanitation. the sphere project is a multiorganizational effort to establish minimum standards for health, nutrition, shelter, and water and sanitation interventions to improve quality and accountability [ ] . although there is specific emphasis on implementation of vaccine measures to prevent disease, surveillance and triage are essential to identify and manage health risks in these vulnerable populations. the use of biological agents as weapons of war or terrorism has been in practice for centuries. the threat of bioterrorism has heightened in the past several decades as our population has become highly mobile and the means to implement a bioterrorist attack have become readily accessible due to increased access to technology and biological agents. the use of chemical and biological weapons as means of terrorism has drastically increased in the past three decades, including the japanese sarin attack in the s, the anthrax attacks in the usa in the s, and the use of chemical agents against civilians in the syrian civil war this decade all demonstrate the need for emergency preparedness and a clear triage protocol for healthcare settings in the setting of a suspected attack. densely populated areas, such as urban centers, are traditionally at higher risk of bioterrorism threat due to easier dissemination and greater exposure than more sparsely populated rural areas, leading to a potential mass casualty incident. in the event of a mass casualty incident due to a recognized bioterrorist attack, it is imperative that hospitals have adaptability to divert resources and space to accommodate the influx of patients, e.g., "surge capacity." surge capacity is generally divided into three components: human resources, physical space, and equipment [ ] . the most impactful of the three is human resources, such as calling in off-duty staff to increase the personnel on site in anticipation or response to a mass casualty event. in addition to increasing personnel, streamlining hospital resources, such as expediting inpatient discharges to increase available beds, cancelling elective procedures, and mobilizing equipment to the areas where it is most needed (such as the emergency department and critical care units), is also key to a successful response. with the exception of the plague (yersinia pestis), anthrax (bacillus anthracis), and smallpox (variola major), the majority of biological agents utilized in bioterrorist attacks are not aerosolized or spread from person-to-person contact and do not require strict isolation protocols aside from typical universal precautions, so open spaces such as parking lots or cafeterias can be converted into temporary triage or patient treatment areas to increase the physical space utilized for patient care. national agencies including the cdc recommend cohorting patients who present with similar syndromes, limiting access or transportation to what is necessary to provide patient care, and exercising standard precautions while cleaning equipment or utilizing personal protective gear [ ] . in addition, hospital protocols that allow for deviation from standard of care in order to provide basic critical care for the maximum number of people, including utilizing noncritical care providers, converting noncritical care areas to critical care treatment areas, and having access to basic mechanical ventilation, intravenous fluids, and vasopressors for at least the first hours without outside support, have been advocated by expert working groups in the setting of a mass bioterrorist attack [ ] . bioterrorist attacks can be covert or announced. an established surveillance network and reporting system is key to enable early detection of potential covert attacks. surveillance typically takes place at the state (health department) and national (cdc or equivalent agency) level. once notified of an unusual presentation or pattern or disease, an epidemiological investigation is initiated to determine the underlying cause and potential exposures. initial notification has historically relied upon the individual practitioner to recognize an aberrant or concerning presentation and notify the respective authorities. however, recognition of covert bioterrorist attacks can be delayed depending on incubation period, access to healthcare facility, and location of the attack. surveillance systems should account for response time, incubation period, and population density [ ] . initial cases can present with vague, generalized complaints that can be difficult to distinguish from seasonal illnesses such as influenza. in addition to relying on the individual practitioner to recognize potential covert attacks, triage systems should also be designed to alert the appropriate personnel in the case of unusual patterns of illness, such as geographical clusters, an unusual number of deaths or critically ill patients, or sudden rise in a specific syndromic presentation. this is also known as a "sentinel monitoring system" [ ] . once a bioterrorist attack is suspected, local and national authorities should be notified, and an emergency preparedness plan should be initiated. this would include a case definition that should be disseminated and utilized for screening purposes and infection control measures specific to the suspected agent. children are disproportionately affected by bioterrorist attacks due to differences in their anatomy, physiology, and development as well as a lack of pediatric-specific research and planning in the event of an attack. children have higher metabolic and respiratory rates, an immature immune system, decreased physiological reserve, and underdeveloped cognitive capacity (leading to a child being less likely to recognize or flee a dangerous situation). for instance, aerosolized agents that are heavier than air are more toxic to children than adults due to a higher concentration at the child's stature and greater intake due to a child's faster respiratory rate compared to an adult [ ] . children have more permeable skin and a proportionally greater body surface ratio and eat more food and drink more milk on a per-kilogram basis than adults, making them more vulnerable to biological agents spread via contact or ingestion. in addition to having a greater risk via exposure, most current public health surveillance and treatment systems in the event of a bioterrorist attack have major gaps in the management of children. schools and childcare facilities have been largely ignored in planning for a bioterrorist event, and most lack an emergency preparedness protocol or personnel trained in the initial triage or stabilization of children following an attack. likewise, common medications utilized by first responders in the event of an attack, such as the rapid administration of antidotes by autoinjectors, are not available in pediatric appropriate dosing [ ] . other antidotes or antibiotics may have unknown pharmacokinetics in children, having only been tested in adults, or may not be available in liquid formulations for children who have difficulty swallowing pills [ ] . national organizations, such as the american association of pediatrics (aap), have made great strides in advocating for pediatric inclusion in future bioterrorism research and strategic planning and creating pediatric-specific resources. the cdc classifies biological agents into three categories: a, b, and c. category a agents are most concerning as they can be easily disseminated and are highly fatal. these will be the agents addressed in this section, with the exception of ricin, which is a category b agent. the most alarming of these potential biological agents are those that can be disseminated via aerosol and persist in the environment. these include the plague (yersinia pestis), anthrax (bacillus anthracis), and ricin. other agents are disseminated via direct contact or ingestion. for the purposes of triage, a brief syndromic description, route of dissemination, and recommended contact precautions are summarized (table . ). please refer to chap. for more detailed descriptions of syndromes and treatments. a decontamination unit is designed to remove any gross contamination from the clothing and body of patients or exposed first responders to an aerosolized, liquid, or solid agent prior to further contact with other patients or healthcare personnel. ideally, a unit should be located near the receiving area of the healthcare facility and have access to running water, detergent, and clean linens [ ] . patients presenting with a suspected exposure should be quickly triaged for emergent interventions (e.g., impending respiratory or cardiac failure, seizure) and then directed to the decontamination unit to remove all items of clothing. patients should also remove contact lenses. some exposures also require cutting off hair that would otherwise serve as a reservoir for the agent (typically, chemical or radiation exposures). after disrobing, patients should wash from head to toe in soap and clean water before dressing in clean linens and entering the rest of the healthcare facility. the usual standard precautions should be utilized for personal protection in all cases while triaging potential highly infectious diseases. this includes handwashing and personal protective equipment (ppe). ppe will vary depending on the exposure. when contact with blood or bodily fluids is expected, gloves and a gown should be worn. when splashing of blood or bodily fluids is expected, ppe should be expanded profuse nausea, vomiting, diarrhea followed by multiorgan failure or seizures sources: [ , , ] to include a mask and eye protection such as goggles. for aerosolized sources, a respirator such as an n or hood should also be worn [ ] . for the initial triage of most highly infectious suspected respiratory or cns illnesses, full precautions should be taken. with the exception of the plague, anthrax, and smallpox, most biological agents used in a terrorist attack are not transmittable person to person and do not require specialized ppe aside from the usual standard precautions [ ] . hemorrhagic fevers require more extensive ppe and is covered in chap. . effective triage practices at all levels of the health system is essential in the management of highly infectious diseases and response to bioterrorism attacks. strong emergency triage systems require well-trained health workers; adequate 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countermeasures for children in public health emergencies, disasters, or terrorism guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings clinical management of potential bioterrorism-related conditions emergency department and receiving areas international society for infectious diseases key: cord- -p xjq authors: bindenagel Šehović, annamarie title: introducing ebola (evd): an unnecessary surprise date: - - journal: coordinating global health policy responses doi: . / - - - - _ sha: doc_id: cord_uid: p xjq chapter tackles the ebola (ebola virus disease, evd) pandemic of / . it notes that coming in the wake of the ongoing hiv pandemic, the rights of those infected with ebola to be identified and treated were largely uncontested. the questions of who would be treated, by whom, with what, remained however extremely contentious. the international response to the pandemic also saw, for the first time, not only non-state actors involved in mediating and mitigating a health crisis, but also military intervention. this chapter lays out both the uses and the dilemmas of military response. it explores the impact of these interventions in this ebola pandemic, with a view towards possible future military deployments against health threats, and offers an initial analysis of the consequences thereof on the relationship between individual and state rights and responsibilities. the - outbreak of ebola virus disease (evd) in west africa (again) caught the world off guard. it should not have. one the hand, hiv and aids should have served as a warning of emerging infectious diseases (eids), and on the other, ebola had actually been recorded in west africa before. yet the outbreak still surprised and very quickly overwhelmed all levels of response: local, national and international. by the time it abated (small clusters of cases continue to be identified,), , people had been registered as infected, and , had died. the - ebola pandemic in west africa morphed into a global crisis beyond health. although locally concentrated, it demanded global intervention. the continued spread of the disease is subject to changing prognoses, contradictory reports, and deep angst. fears pertain to medical as well political and economic implications. ebola, and further emerging infectious diseases (eids), are associated with a host of negative consequences in terms of life expectancy and development in affected societies, states and economies, and also pose a threat to peace and security directly and beyond the region of west africa. the three west african countries most affected by the - edv outbreak were guinea, liberia and sierra leone. all three share porous see who ebola situation reports, available at: http://apps.who.int/ebola/ ebola-situation-reports. author's translation of "die ebola-pandemie westafrikas wurde insbesondere in den jahren und zu einer krise globalen ausmaßes und anlass zu weltweiter sorge. räumlich konzentriert, verlangte sie lokale maßnahmen mit weltweiter reichweite. ihr verlauf war und ist thema wechselnder prognosen, widersprüchlicher nachrichten, und auch großer Ängste. besorgnisse richten sich sowohl auf medizinische als auch politische und wirtschafliche implikationen. ebola, sowie weitere sogenannte "emerging infectious diseases" (eid) sind verbunden mit gravierenden folgen für die lebenserwartung und entwicklung der betroffenen gesellschaften, staaten und die Ökonomien sowie eine bedrohung für frieden und sicherheit innerhalb und jenseits der unmittelbar betroffenen regionen westafrika." in Šehović, annamarie bindenagel und stephan klingebiel ( ). "eine funktionsfähigere globale gesundheitspolitik: empfehlungen vor dem hintergrund der ebola-krise," in herdegen, matthias, karl kaiser and james bindenagel (eds). borders; each ranks among the lowest on the human development index (hdi); in addition, all three are still recovering from nearly decade-long civil war(s) that raged throughout the s. however, it is worth noting that from to , numerous outbreaks of evd were recorded throughout the african continent, notably on the borders between bat and human habitats. it should have been no surprise then that the zoonosis evd jumped the bat-human barrier (again) in , leading to infection. the local outbreak became an epidemic and then a regional pandemic as a result not so much of the potency of the infectious agent as the bungled response to it. what is it? how is it transmitted? evd is hosted by pteropodidae bats, who themselves do not fall ill. it belongs to the family of filoviruses. as with hiv transmission, or any zoonosis, the virus jumps the animal-human barrier. in this case it does so when infected saliva, including on fruit, blood, urine or feces mingle with human secretions. as with hiv, this is most likely to happen where animal and human settlements collide: at the borders of cities, in camps lacking hygiene and sanitation facilities, where the human population encroaches upon the forest. evd had been seen in west africa previously. as early as the s, ebola antibodies were detected in the blood of west african patients. these findings were published in a issue of the journal, annals of virology, and further confirmed in . according to these results, liberia should have been included in the so-called "ebola zone." this did not happen. in addition, researchers in the region were themselves unaware of the findings, which were not shared, and subscription to the journal was not affordable. danger, fearing international travel sanctions which could cripple their tourist-dependent economies still struggling to gain ground after the years of civil war. it was a fatal combination of disjointed priorities. west africa has various regional characteristics that exacerbated the challenge. the ratio of doctors to patients is about per . civil war and state-wide turmoil, mainly in the s, still leave footprints in the damage to hospital facilities and to roads, and in a whole cohort of young adults who missed out on schooling and limit their trust in political leaders. but most of all, the populations of west africa are rampantly mobile. to have relatives that need regular visiting in nearby countries is commonplace, and people zip around, unimpeded by porous national borders. "ebola stood still for us in the past, and we could set up an operational machine in one area," explains armand sprecher, a public health specialist with msf who has worked in all three countries during this outbreak. "if you have a contact tracing system, what do you do when your contact picks up and moves km away one morning without telling you? if ebola moves from location a to location b, suddenly you need to duplicate everything." this explains a large part of why the control systems were overrun so quickly. once the virus gained a foothold, which occurred in guinea, it spread like wildfire. it was propelled not only by particular customs, but by porous borders, social mistrust of politicians, and political mistrust among the regional leaders in this fragile post-conflict zone. this intersection of war and recovery, of human and animal, of city and forest, of zoonotic transmission, is precisely where and what happened when the so-called "index case", patient zero, a small boy in guinea, came into contact with a fruit bat, likely eating it or at least injuring it and coming into contact with its bodily fluid(s). the little boy died within a few days in guinea in december . the ebola virus is a simple virus. mimicking sugar, it is absorbed by the human body entering the bloodstream, where it replicates rapidly. once the immune system recognizes the virus not as a sugar molecule but as an infection, it mounts an immune reaction which quickly becomes an overreaction. as the body fights the virus, infection proceeds in two phases. phrase one provokes symptoms of fever and muscle aches/cramps. phrase two elicits the loss of bodily fluids, up to liters a day. while previous ebola outbreaks also featured haemorrhaging, the - pandemic in west africa was characterized more by vomiting, diarrhea and hiccups. the causative mechanism of the last symptom is unknown. an infected person either dies within ca. days of exhibiting symptoms, or lives, taking roughly days (after developing symptoms) to initially recover. the only known antidote, which sometimes helps and sometimes does not, is the provision of fluids. while different ebola strains, during separate outbreaks, have had varying mortality rates, the average appears to be percent. at death, the corpse harbors the highest viral load of the course of infection. touching, or ritually cleansing the body is thus when most transmissions take place. by contrast, hiv and aids remains nearly percent deadly. however, whereas hiv needs to be transmitted intravenously, via sexual contact, or from mother to child, ebola can be transmitted through the skin by contact with contaminated bodily fluids. yet whereas hiv infects on average an additional . people, ebola infects "only" . to . this is largely because unlike hiv, which can take up to years (on average) to reach the stage of aids, without the provision of arvs, ebola reaches its final stage within days. one "advantage" of ebola infection is that those who have become ill, and infectious, are visibly sick. those with hiv are not always so identifiable. when the little boy died, the ebola virus went on to infect his mother and sister and grandmother, all of whom subsequently died. their funerals, aided and abetted by cleaning rituals, served as catalysts for the first transmission chains of the ebola outbreak of - . all this occurred before the cause of the infection, evd, was identified, or confirmed. lacking this first responsive step, no further could reliably follow. the fact that so many of the symptoms of ebola are also those indicative of malaria, which is endemic in the region, delayed initial identification. yet the cluster of dead indicated an infection other than malaria, whose infection pattern is erratic: following mosquitoes' flight rather than human interaction. high death rates and the close clustering pointed away from malaria, but not to the actual culprit. the delay in identification, medically but especially politically, enabled the virus to spread. transmission was all but guaranteed, due to funeral rituals initially, and then through the porous borders between guinea, liberia and sierra leone: as people travelled to and from funerals, as well as to trade and to work, the virus accompanied them. warned that without american assistance the disease could send liberia into the civil chaos that enveloped the country for two decades. . . . "i am being honest with you when i say that at this rate, we will never break the transmission chain and the virus will overwhelm us." she requested , additional beds in new hospitals across the country and urged that the united states military set up and run a -bed ebola hospital in the besieged capital, monrovia. until president johnson sirleaf's request, the head of a sovereign state asking the head of another sovereign state to intervene militarily in order to combat a disease was unheard of. in doing so, the president did two things: first, she acknowledged the security threat to her populationexplicitly citing the physical, economic and political (civil war) threatsand her state (its integrity, especially in the event of a recurrence of ensuing political violence); and second, she voluntarily invited a foreign state violate her state's westphalian (border/ territorial) sovereignty by sending not humanitarian aid workers, but the military. working under the direction of the national government, liberia's domestic sovereignty and its responsibility for security and health (security) remained untouched. september , : building on the precedent set in the global response to the hiv and aids pandemic, the united nation's security council (unsc) passed resolution ( ), in which it called upon immediate measures to respond to the spreading outbreak. resolution ( ) placed the onus for ebola response on the national state. yet president johnson sirleaf's request highlighted the incapacity and inadequacy of many such responses. september , : the un called into being the un mission for ebola emergency response (unmeer). unmeer, like unaids before it, represented a first: the first un emergency health mission. preceding its establishment, beginning on august , the un's ebola emergency response operated under the oversight of the who, under the "direct authority of the who director-general," margaret chan. coming into its own, unmeer was set up as "a temporary measure to meet immediate needs related to the unprecedented fight against ebola," and was responsible for deploying "financial, logistical and human this has caused all kinds of theoretical and practical controversy; the consequences of johnson sirleaf's request are still being grappled with. october , : president obama appointed ronald "ron" klain as ebola "czar." his assignment pointed directly to the concern over security driving the us ebola response: he will report directly to the president's homeland security advisor, lisa monaco, and the president's national security advisor, susan rice, as he ensures that efforts to protect the american people by detecting, isolating and treating ebola patients in this country are properly integrated but do not distract from the aggressive commitment to stopping ebola at the source in west africa. december : treatment centers commence being built in guinea, liberia and, to a lesser extent, sierra leone. however, they are completed only after the epidemic has crested. july , : mission accomplished: unmeer ceased its activities, having achieved its goals. with the dissolution of unmeer, international attention to the ebola pandemic largely dissipated. the pandemic, and especially its aftermath, no longer have policy prioritization. this is despite the mounting clinical evidence that the infection can linger, causing long-term health complications, and can also be transmitted (notably through seminal fluid) months after someone has recovered from the infection. furthermore, the longterm consequences and costs to social cohesion, to economic investment, development and productivity, (including impact on food security, for instance) and to political stability (where one state or subregion (re)gains investment and/or tourism while another does not) remain underacknowledged, underresearched, and underappreciated. with each, the likelihood of a future outbreak-or related crisis-rises. beyond that, the myriad experimental vaccine and treatment initiatives that proliferated during the ebola response illustrated the potential and possibility of conducting high-caliber research and implementation of interventions amidst a crisis. the successful vaccine administration further indicates an ethical standard and an anthropological acceptance that was not foreseeable at the outset of the epidemic (when ebola teams were being attacked). june : in a second attempt, the who declares the end of ebola virus transmission in the republic of guinea and in liberia. even prior to the june declaration of the end of the ebola pandemic in west africa, the world's attention turned elsewhereaway from sustaining the specialized ebola treatment units that were set up to respond to the acute crisis as multipurpose medical centers (as requested by sirleaf johnson, among others). also in peril are long-term commitments to health systems strengthening (hss) initiatives which would invest in and build, literally, the facilities, and from the purchase, maintenance and use of the equipment. the international community has also failed to consider the costs of (not) training and retaining professionals. instead, the private (ngo) sector, and international programs (such as through the uk's national health service, nhs) court have long trained technicians, nurses and doctors, and lured them from local health systems with lucrative contracts abroad. in the case of the nhs this is especially egregious, since the postcolonial structure of many african health systems means that medical staff trained there adhere to uk standards: so staff hired away do not need additional training or certification to be able to practice in the uk. similarly, if intended to be more short-term, the german government has an agreement with the egyptian government: the latter sends doctors to work in german hospitals, their salaries paid by the egyptian government. in both cases, the local (west african or egyptian) health systems are left bereft of medical professionals. the host (national) health systems benefit, but little or no transfer of knowledge takes place. this leads to perverse situations wherein, for instance, there are more malawian doctors practicing medicine in london than in malawi; it is more likely that someone with malaria will be properly diagnosed in london or frankfurt than in east africa because of the concentration of expertise in identifying malaria symptoms. given the high mortality rate for evd in west africa, this is likely to be the case with ebola infection as well: that medical specialists in atlanta and madrid are attuned to ebola, while no doctors are even available in, notably, sierra leone. the world's wandering attention also means waning focus and funding for establishing and monitoring the supply chains of necessary surveillance, and medications necessary to keep ebola, and other diseases, at bay. the myriad systems' failures arising from the world's averted attention to the post-ebola reality of west africa also fails to address the concomitant shortages and medical challenges which undermine effective local and national response to an epidemic /pandemic threat. in addition, from this vantage point-that of the "end" of the ebola pandemic in west africa-it appears that the only epidemics /pandemics to which an international or global response will be mounted are those with resonance in the developed world-including in germany. germany treated three patients infected with ebola during the - pandemic. these were transferred to and isolated in specialized treatment units in frankfurt am main, hamburg and leipzig. despite the fact that evd is relatively difficult to transmit, and only infectious in the last acute phase of the disease trajectory, and then only via direct contact with infected bodily fluids, extraordinary precautions were taken to ensure the virus's containment. thus the transportation alone of the evd patients-via sierra leone lost its one specialist for infectious disease to the ebola outbreak. see "leipziger patient gestorben," süddeutsche zeitung (october , ), available at: http://www.sueddeutsche.de/gesundheit/ebola-leipziger-patientgestorben- . . specialized medical evacuation-made headlines. such medically unnecessary measures, while effectively guaranteeing that the virus could not-and did not-spread, spiked the level of fear felt by the population. this combination of overcaution and fear did a disservice to the tasks of identifying the infectious agent, informing the public about real threats and genuine dangers, and of coordinating an effective, proportionate response. though not much publicly proclaimed-having kept the very presence of evd on german territory more or less hushed (despite the photos of the special transports splashed across newspaper pages)-german clinical teams were able to cure two of the three patients. the level of medical intervention available to respond to evd in germany, as in western europe and the united states and canada is incomparably better than that in west africa. still, it can be counted as progress in the wake of the hiv and aids pandemic that neither local, national and international experts nor publics questioned the right of people infected with evd to be treated and cared for in as comprehensive way as possible. nonetheless, without adequate, timely identification of an infection, and a coordinated response, even the comprehensive german health system would reach a limit in terms of the number of patients it could treat at such a level of care: in isolation, with large medical teams present around the clock, and with plenty of protective suits and other equipment. given growing international connectivity, another infectious disease outbreak is preordained. anticipatory preparation is thus a must. it would benefit all actors involved, especially in high-stakes infectious disease outbreaks, to review and revise the elements of and the decisions involved in response in order to optimize a plan before the next outbreak. as the timeline above indicates, decisions, and non-decisions, reflect multiple elements of health security: the rights of those ill to be treated; the rights of those offering help to be safe; the need for states to protect and provide both of those components to their citizens; and the need for citizens even of states which cannot offer such protection and provision to be met. decision-making reflects all these factors, as well as the pressure to "do something" applied to both affected and aiding states. the decisions taken, or not, also change the relationships between each one of these elements. at moments of epidemic danger, one naturally focuses on the actions of nations to control the outbreak. but turn that question around: what are the likely actions of an epidemic on a nation? epidemics change governments. political leaders could have no clearer signal that it is their responsibility to protect the health of their people (governments, not doctors, defeat epidemics). those leaders understand that their nation's political, economic, and social stability depends on health. liberia's president johnson sirleaf certainly demonstrated this understanding of the state's stability as dependent upon the state of the health of the population. she also understood the limitations of liberia's ability to respond according to its state responsibility to its citizens. msf itself admitted it was overwhelmed with its emergency response to the burgeoning epidemic and called for military intervention to shore up the response. johnson sirleaf herself asked for such intervention. thus, local, including ngo, responses at the acute level try to stem the tide of the outbreak and implement coping mechanisms. where individual cases occur, as is the case now in the post-ebola phase, and contacts can be traced, isolated and monitored, this response is sufficient and rests at this level. where this is not adequate, further response measures are needed. they include the local, national, international and global levels of response. at the national level, this means coordinating response plans and delegating specialists. liberia, for one, wrote a policy plan and collected and coordinated as many medical professionals as possible to be deployed to respond as the epidemic expanded. bridging the gap between local and national level were msf and the ministry of health and social welfare. the exponentially rising infection rates and concomitant mortality rates, especially of frontline medical personnel, raised the alarm at the international level: sounding the siren at the who, the unsc were the president of the country and the president of the much-respected msf. at the international level, the who and the unsc, establishing unmeer, furthered the cause. in addition, the united states, as well as germany, appointed so-called "ebola tsars," charged with identifying needs on the ground, and advocating for and coordinating those country's bilateral and multilateral assistance to the countries who requested help. in keeping with the international system wherein sovereign states have the ultimate decision-making power, supplemented by both ngos (advocacy) and influential external actors (such as peter piot and richard holbrooke for hiv and aids), the decisions on when, and how, to request help in responding to the ebola outbreak lay with the most affected countries themselves. they did not have any prominent international actor to rely on to carry their cause-until president johnson sirleaf stepped into the spotlight. but, reflective of the system, she only pleaded (and only could have pleaded) for assistance for her struggling country. that johnson sirleaf requested help from the united states is itself an interesting political decision. liberia is the result one of the two settlements founded by freed american slaves. the country also received support from the uk. the other such freed slave settlement, which became sierra leone, received support from cuba and the uk. the third west african country, guinea, received some assistance from its former colonial master, france. given these fraught historical relationships, and the lingering mistrust between the three west african countries due to the s civil wars fought there, it is all the more surprising that military aid was requested, both by msf and johnson sirleaf. such military support is also the most contentious of the post-ebola political debates. the ebola pandemic of - illustrates how rapidly an unexpected infectious disease can get out of control. the implications include excessive rates of morbidity and mortality, agricultural losses, food insecurity, productivity losses in everything from mining to production, and those for the tourist industry, as well as political instability. they also include social changes. bonds of trust suffer at all levels of personal interaction. medical burial teams wore protective gear to disinfect and prepare evd infected corpses for burial. these burials, deemed necessary to break the viral transmission chains, violated the cultural practices of the region. failure by external aid workers and/or professionals to adequately explain and support their adoption resulted in mob attacks on these workers. in august a see petherick ( ) . "ebola in west africa: learning the lessons." mob stormed a clinic and accused the foreign medical staff working there of having imported ebola into guinea. hidden burials were common at some times and places, which inevitably resulted in more ebola infections. taking local customs into account is vital for effective disease response. the national response needs to take these social practices into account and to cue both the local populations, for instance by cooperating with local healers, and external actors in order to render any response culturally palatable as well as medically and politically effective. in order to be politically and medically effective in turn, national governments need to realize, invest and negotiate the capabilities and capacities they require in order to anticipate, identify and react to infectious diseases, of which evd is a case in point. this includes, at the national level, investment in the global outbreak alert response network (goarn), the who system which draws on government information sharing, but also allows ngos and social media platforms access in order to report and monitor, in real time, (im)pending disease outbreaks. goarn is meant to operate as an event-management system, the event being an outbreak of potentially international health concern. when it works optimally, it features: • comprehensive databases on epidemic intelligence, verification status, laboratory investigation and operational information. • tracking and recording outbreak history, critical decisions, important actions by who and partners and key documents. • management of logistic support and specialized response equipment, materials and supplies. • integrated database on the skills, experience and availability of international experts for response teams. • profiling of technical institutions in the goarn concentrating on readiness and capacity to support international outbreak response. • standardized information products for member states, public health officials, media and the public. • communications with goarn to enhance operational readiness. at the international /global level, goarn provokes a response by the who, which in turn can issue guidelines and alter, evaluate and if deemed necessary declare a pheic in order to set into motion a cascade of informational support and technical expertise. also at the international level, the international health regulations (ihrs) ideally inform and coordinate global infectious disease response. the latest ihrs, announced in and which came into force in , stipulate the reporting requirements for emerging infections, and outline the necessary measures to be taken in response. however, they have two shortfalls: while a treaty obligation, they rely primarily on voluntary compliance; they have been invoked overwhelmingly with regard to airborne diseases such as avian flu and sars, the subject of the following chapter; and they have no additional, automatic enforcement mechanism(s). the ihrs were of little help in the midst of the ebola pandemic. in the wake of the ebola outbreak in west africa, and in anticipation of future eid outbreaks in particular, the remarks of david nabarro, the un's special envoy on ebola remain undisputed: there will be more: one, because people are moving around more; two, because the contact between humans and the wild is on the increase; and maybe because of climate change. the worry we always have is that there will be a really infectious and beastly bug that comes along. indeed, such a beastly bug might yet emerge from avian flu and sars should their airborne transmissibility become more efficient. ebola clinic in guinea evacuated after attacked: angry mob claims doctors without borders int roduced deadly disease to country ebola: burying the bodies this was done in south africa with regard to hiv and aids. author's professional collaboration with professor ruben in the context of africare in eastern cape province guiding principles for international outbreak alert and response key: cord- -btaxvmsr authors: di paola, nicholas; sanchez-lockhart, mariano; zeng, xiankun; kuhn, jens h.; palacios, gustavo title: viral genomics in ebola virus research date: - - journal: nat rev microbiol doi: . /s - - - sha: doc_id: cord_uid: btaxvmsr filoviruses such as ebola virus continue to pose a substantial health risk to humans. advances in the sequencing and functional characterization of both pathogen and host genomes have provided a wealth of knowledge to clinicians, epidemiologists and public health responders during outbreaks of high-consequence viral disease. here, we describe how genomics has been historically used to investigate ebola virus disease outbreaks and how new technologies allow for rapid, large-scale data generation at the point of care. we highlight how genomics extends beyond consensus-level sequencing of the virus to include intra-host viral transcriptomics and the characterization of host responses in acute and persistently infected patients. similar genomics techniques can also be applied to the characterization of non-human primate animal models and to known natural reservoirs of filoviruses, and metagenomic sequencing can be the key to the discovery of novel filoviruses. finally, we outline the importance of reverse genetics systems that can swiftly characterize filoviruses as soon as their genome sequences are available. infections with viruses of the mononegaviral family filoviridae (in particular, members of the genera ebolavirus and marburgvirus) are an increasing threat to mankind. until recently, the infrequent spillover of these viruses into humans and the fact that spillover often occurred in remote locations, coupled with a limited knowledge of non-human reservoir hosts, the use of low-output genomic sequencing, and biosafety and bio security restrictions on filovirus research, contributed to the paucity of publicly available data on filovirus genome sequences . in december , complete genome sequences for only ebolaviruses and marburgviruses were available despite the fact that outbreaks of natural filovirus disease had been recorded . since december , atypically extensive filovirus disease outbreaks, from to in western africa and from to present in the democratic republic of the congo, have profoundly impacted public health systems. at least , fatalities from filovirus disease were reported between december and april , (refs , ). by leveraging the continued development and improvement of next-generation sequencing technology, > complete filovirus genome sequences and over , draft genomes (that is, genomes with > % coverage) across classified and unclassified filovirus family members have become available since (ref. ). indeed, among high-consequence, risk group viruses, the genomic diversity of filoviruses is arguably becoming the best characterized. the impact and importance of genomics in pathogen characterization is routinely demonstrated, but the rapid prediction of, response to and mitigation of outbreaks requires more detailed genomic information than virus consensus-genome sequencing. indeed, as predicted , metagenomic sequencing has become a powerful tool for identifying novel viruses and, crucially, for predicting pathogen emergence . targeted or unbiased sequencing of individual clinical samples aids in the identification of outbreaks, the determination of outbreak aetiology and the definition of virus transmission chains by identifying chain-defining single nucleotide polymorphisms (snps). furthermore, field transcriptomics improves our understanding of host responses to virus infection and will be important in deciphering the differences between asymptomatic and symptomatic disease states and in predicting whether patients with acute and chronic disease will survive . functional genomics is becoming the tool of choice for the rapid characterization of patient-specific viruses that have not been isolated in culture or that cannot be equitably shared among laboratories across borders . finally, the genomic analysis of patient-specific viruses also enables precision medicine by predicting the efficacy of available medical countermeasures (mcms) against these individual viruses. here, we review how recent advances in genomic technologies have shaped past and current responses to outbreaks of ebola virus disease (evd), including insights into filovirus diversity and evolution. we emphasize the importance of accurate and rapid large-scale data generation and its implications for the development of mcms and outbreak response. we also examine the phenomena of ebola virus (ebov) persistence in human hosts and provide an overview of recent genomic advances in threat characterization, vaccine development a collection of continuously evolving technologies and techniques that allow for the digitalization of genomic material. the sequencing of genetic material recovered directly from an environmental or clinical sample that allows the identification of all organisms and mobile genetic elements represented in the sample. and immunotherapy. although we focus primarily on ebov, these practices can apply to all pathogenic filoviruses and other high-consequence viruses capable of sustaining human-to-human transmission. although the global distribution and diversity of filoviruses remains largely undefined, metagenomic sequencing is becoming a valuable tool for identifying filovirus reservoirs. until , disease outbreaks owing to infection by ebolaviruses (including ebov, sudan virus (sudv) and marburgviruses (including marburg virus (marv) and ravn virus (ravv)) had only been recorded on the african continent ( fig. ). as the natural reservoir hosts of all of these viruses remained unidentified, despite extensive ecological studies, filoviruses were thought to be african viruses . this view changed after , when reston virus (restv; of the genus ebolavirus) was discovered and repeatedly identified as a lethal pathogen of captive crab-eating macaques (macaca fascicularis) in non-human primate (nhp) breeding facilities in the philippines - ( fig. ). however, although restv can infect humans, it appears to be apathogenic . restv was subsequently considered to be an asian anomaly to the african filovirus dogma. classical filovirus-targeted genome sequencing and, later, unbiased broad-scale metagenomic sequencing, shed new light on filovirus ecology. in , the sequencing of samples obtained from egyptian rousettes (rousettus aegyptiacus) in africa revealed that these bats, which are cavernicolous and frugivorous pteropodids, are natural reservoir hosts of both marv and ravv. coding-complete or complete genomic sequences of both viruses were repeatedly obtained from egyptian rousette populations in uganda, sierra leone and south africa [ ] [ ] [ ] [ ] , and genomic fragments of these viruses were also detected in populations of these bats in the democratic republic of the congo and in zambia . around and after , sequence-based evidence obtained using a range of techniques began to support the hypothesis that restv is an asian virus. restv genome sequences were obtained from captive dome stic pigs (sus scrofa domesticus) in the philippines and china , , and restv genome fragments were sequen ced from samples from molossid, pteropodid and vespertilionid bats in the philippines . next-generation sequencing further enabled the discovery of a highly divergent filovirus, lloviu virus (llov, genus cuevavirus), in deceased schreibers's long-fingered bats (miniopterus schreibersii) in hungary and in spain . the ebolavirus genus was expanded owing to the discovery (via next-generation sequencing) of bombali virus (bomv) in molossid little free-tailed bats (chaerephon pumilus) and angolan free-tailed bats (mops condylurus) in guinea, kenya and sierra leone [ ] [ ] [ ] in short, genomics has clarified that highly divergent filoviruses, frequently with unknown pathogenic potential, are likely to be distributed widely over the african, asian and european continents in highly diverse host reservoirs ( fig. , box ). furthermore, expanded animal sampling and unbiased host virome sequencing is likely to enable this diversity and distribution to be described in more detail. of note, the natural host reservoirs of three ebolaviruses that are human pathogens, namely bundibugyo virus (bdbv), sudv and taï forest virus (tafv), are still unclear. furthermore, although bats are suspected to be hosts of ebov owing to the detection of short ebov genomic fragments and/or antibodies to ebov in certain bats , no complete ebov genome has yet been sequenced from any bat sample. the genomic investigation of archived or newly acquired samples could also support or refute the often-repeated hypothesis that middle african central chimpanzee (pan troglodytes troglodytes), duiker (cephalophus spp.) and western lowland gorilla (gorilla gorilla gorilla) populations are frequently decimated by ebov infection [ ] [ ] [ ] . thus, genomics may enable the prevention of future filovirus disease outbreaks by identifying filovirus natural hosts and by limiting host-human contacts as well as the initial introduction of filoviruses into the human population. identifying and characterizing outbreaks genomics-based techniques have been central in the identification and characterization of filovirus disease outbreaks. the largest known filovirus disease outbreak occurred from to in western africa and was caused by a novel ebov variant, makona (ebov/mak) ( fig. ). genomic sequencing efforts during this evd outbreak showcased various platforms and strategies to characterize thousands of human clinical samples containing ebov/mak . early efforts relied on exporting positive samples to high-complexity genomic centres abroad , (box ). however, in december , ebov/mak genome sequencing using benchtop sequencers, such as the miseq system (illumina) and the ion torrent system nature reviews | microbiology r e v i e w s (thermo fisher scientific) in-country (namely, in liberia and sierra leone), became standard practice [ ] [ ] [ ] . in addition, field laboratories used the iseq (illumina), a portable bench-top sequencer with low error rates that can be transported in a suitcase, to obtain complete ebov genome sequences to determine virus transmission in the democratic republic of the congo , . use of the portable nanopore sequencing technology minion (oxford nanopore technologies) markedly reduced the time required to obtain the genome sequence from patient samples and enabled the reintroduction of ebov into guinea and sierra leone to be rapidly confirmed . similarly, the ebov variants causing the Équateur province evd (ebov/"tum") and the ongoing nord-kivu/sud-kivu/ituri province evd outbreak caused by ebov/"itu" in the democratic republic of the congo were quickly identified by the use of minion , . the timing and establishment of in-country genomic sequencing capabilities determine which information can be captured and disseminated during an evd outbreak. early sequencing efforts can provide an informative 'snapshot' of the genomic epidemiology of ebov during the initial phase of the outbreak . the extent of the genomic diversity of the virus at the beginning of an outbreak can be used to determine whether single or multiple virus spillover events have occurred and to provide a crude estimate of the time at which a virus emerged in a human population , , , . highly accurate genomic data have been used to characterize intra-host ebov populations and genetic drift and even to evaluate, in silico and in real time, the available diagnostic measures and mcms , , . as an outbreak progresses and the sampling size increases, phylodynamic and spatiotemporal analyses reveal broader trends in the intra-outbreak evolutionary rate of the virus, its geographical migration and factors contributing to virus transmission, disease outcome and virus-host adaptation , [ ] [ ] [ ] [ ] [ ] [ ] . ideally, the viral agent is initially identified using highly portable sequencing platforms on site. after this identification, considerations other than sequencing speed (for example, sequencing accuracy and processivity) become paramount in determining virus transmission networks and in detecting changes in the viral genome (between cases in the current outbreak and between the current and previous outbreaks) that could subvert mcms. however, whereas unbiased sequencing approaches using high fidelity platforms can lead to the discovery of co-infections and reveal important clinical considerations during the treatment of patients near the point of need, targeted methods of pathogen characterization using the portable sequencing platforms iseq and miseq (which use bait-enrichment techniques) and minion (which uses amplicon sequencing) can still provide useful genomic data albeit with a lower sequencing output (that is, a lower number of reads) than unbiased sequencing. sequencing only a single target during an enduring and large outbreak of evd may result in the detection of co-infections and/or superinfections being missed. the earliest evidence of an ebov co-infection was obtained in gabon in , where a patient with evd also tested positive for human immunodeficiency virus (hiv- ; a lentivirus of the retroviridae family) the change in the frequency of an existing gene variant (allele) in a population owing to the occurrence of random mutations. of the family hepadnaviridae) and epstein-barr virus (a lymphocryptovirus of the family herpesviridae) were reported [ ] [ ] [ ] . additionally, ebov infections in patients with a gram-negative septicaemia or with bacterial translocation have been described [ ] [ ] [ ] . moreover, an extensive infectious disease due to one particular virus could plausibly conceal a simultaneous outbreak caused by a different pathogen . notoriously, there have been outbreaks of cholera, plague, measles and malaria, and sporadic cases of monkeypox and yellow fever, alongside the -present evd outbreak in the north-eastern region of the democratic republic of the congo. detecting and characterizing co-infections during a disease outbreak can provide clinicians with crucial point-of-care information and identify differences in patient outcomes that may result from co-occurring infections. the characterization of unexpected, co-circulating viruses during large-scale viral outbreaks requires established and reliable sequencing strategies that can be applied without knowledge of which virus is present. the discovery of novel viruses is ideally facilitated by metagenomic sequencing, which often relies on the pre-processing of clinical samples by depleting host-derived genomic material, followed by single or random primer amplification by pcr and deep sequencing [ ] [ ] [ ] . however, metagenomic sequencing is limited by the requirement for computational and bioinformatics resources, which are not always readily available under field conditions. instead, target-enrichment approaches using a wide breadth of bait probes for known pathogenic viruses, including filoviruses, have led to the successful characterization of known viruses in clinical samples from patients with disease of unknown etiology [ ] [ ] [ ] . moreover, target-enrichment sequencing is more cost-effective than metagenomic approaches. the percentage of sequencing data matching the target pathogen or pathogens can range from % to % with target enrichment, whereas with metagenomics approaches often < % of sequencing data matches the target , . punctual and highly accurate sequencing efforts have revealed the molecular genomic epidemiology of disease and thus enabled the characterization of pathogen transmission during disease outbreaks . the first application of in-country, real-time genomic epidemiology started well into the evd outbreak of - in western africa; portable sequencing was performed and data were analysed in tangent with up-to-date public health data . the abundance of ebov genome sequences determined during recent large-scale evd outbreaks (including the - outbreak and the -present outbreak in the democratic republic of the congo) enabled real-time and retrospective investigations, using median-joining haplotype network establishment and phylodynamic inferences, to reveal cryptic human ebov transmission chains in humans , , , . in coordination with classical epidemiological data (for example, that obtained by manual contact tracing), individual virus transmission events identified by genomic analysis such as median-joining haplotype networks can be temporally and spatially linked to determine likely transmission pathways, including the mode of virus diffusion and the identification of 'superspreaders' (as reviewed in ref. as the quality and quantity of avail able, complete genome sequences improves, new methods identifying intra-host snps may provide more granular analyses of person-to-person transmission than previous techniques . such snps can distinguish between almost identical consensus sequences of two or more patients . however, acute infections resulting from direct contact with a recently infected and symptomatic individual, and for which primary infection occurred < days before the onset of symptoms, is not the only route for sustained person-to-person transmission during filovirus disease outbreaks. ebov initially infects monocyte-derived macrophages and dendritic cells, which disseminate the virus through the circulatory system to all main target organs, including the liver, spleen and kidneys. after infecting and damaging the vascular endothelia, ebov infiltrates the parenchymata of these organs, resulting in focal necroses and inflammation. such damage can eventually lead to multi-organ dysfunction syndrome and ultimately death , . however, in some cases, the intrinsic, innate and adaptive immune responses can contain viral replication and dissemination, resulting in the survival of the patient . until recently, it was hypothesized that survivors of filovirus diseases effectively abolished filovirus infection. however, new evidence indicates that ebov can persist in certain sites of the body in the absence of viraemia and that this persistence could cause disease flare-ups (for example, see ref. ). some of these sites, including the brain, eyes and testes, are immune-privileged box | endogenous filovirus elements the bioinformatic analysis of higher animal genome sequences, the number of which is steadily increasing, reveals that a marked percentage of these sequences are derived from ancient retroviruses . many animal genomes are mosaics that are likely to have evolved through the accidental integration of retroviral genes or gene fragments into germ cell genomes and the subsequent inheritance of this genetic material by descendants. in some cases, these sequences were positively selected for and were (or are still) expressed and their functions were exapted by hosts for novel functions . a famous example of exaptation is the use of the human endogenous retrovirus w-derived syncytin, which was once a retrovirion surface glycoprotein that mediated virion host cell entry but is now essential for placental morphogenesis in pregnant women . during the past decade, scientists have been increasingly aware that such 'viral fossils' or 'paleoviruses' can derive from viruses other than retroviruses. indeed, non-retroviral integrated rna viruses (nirvs; also known as endogenous viral elements) were derived from the ancestors of numerous extant virus families . prominent examples of negative-sense rna virus-derived nirvs are bornavirus sequences, which are found in the genomes of bats, fish, hyraxes, marsupials, primates, rodents, ruminants and elephants , , and rhabdovirus sequences, which are found in the genomes of crustaceans, mosquitoes, ticks and plants , . interestingly, filovirus-derived nirvs also appear to be widespread as they have been located in the genome of afrosoricids, bats, eulipotyphlans, marsupials and rodents , , . the function of these stably inherited filovirus sequences remains to be determined. however, the existence of nirvs indicates that filoviruses are at least several million years old and that highly divergent mammals were exposed to, and at least occasionally infected by, these viruses and perhaps by the descendants of these viruses that exist today. the novel use of an evolved trait for a different function. a minimum spanning tree analysis of recombinant-free genomic sequences that infers ancestry-descendant relationships using haploid genotypes that can be visualized in a single unrooted, reticulate network. the study of how evolutionary processes interact with epidemiological and immunological factors to influence phylogenetic estimations. because they are physically separated from tissues and cells that are under immune surveillance ( fig. ) . thus, foreign antigens such as ebov particles are tolerated within these sites without eliciting an inflammatory immune response . prior to the outbreak of evd in western africa, evidence of persistent ebov infection had been sparse probably owing to the small number of spillover events arising from this persistence ( fig. ). nevertheless, infectious ebov and marv and/or filoviral rna had been detected in the eyes and semen of convalescent survivors prior to this outbreak [ ] [ ] [ ] [ ] . the large pool of survivors following the - outbreak of evd (specifically, , individuals) was different. disease flare-ups or re-emergences were reported in at least nine individuals and attributed to sexual transmission or breast-feeding . sexual transmission of persistent ebov was implicated in the initiation of new ebov transmission chains , , [ ] [ ] [ ] . genomic analyses revealed that the evolutionary rate of ebov persisting in testes during convalescence is reduced relative to the rates of ebov persisting in blood and plasma , . all these observations prompted a notable number of studies of the long-term effects of persistent ebov infection in evd survivors. indeed, ebov persistence can be accompanied by various sequelae, colloquially often referred to as 'post-ebola [virus] syndrome' . studies of ebov persistence in humans and experimentally in nhps have revolutionized our understanding of ebov infection and changed the guidelines of clinical operation as well as the recommendations of the world health organization for evd survivors. the impact of genomics on understanding the persistence of ebov is broader than next-generation sequencing; advances have also revolutionized the field of pathology by allowing the rapid exploration of transcriptional expression in a chosen site of filovirus infection. the development of multi-labelled and targeted 'probes' that allow multiplex immunopathological hybridizations in sites of interest have also boosted our knowledge of ebov persistence. indeed, studies using novel histopathological tools have benefited genomic research in immune-privileged and non-immune-privileged sites. immune-privileged sites. various neurological complications have been noted in survivors of evd . in experimentally infected rhesus monkeys (macaca mulatta), encephalitic ebov persistence is always accompanied by various degrees of encephalitis or meningoencephalitis . persistent infection of ebov in the brain may lead to evd relapse and late-onset encephalitis in human survivors several months after acute disease , . in experimentally infected nhps, ebov enters the brain by breaking down the blood-brain barrier by directly infecting and damaging endothelial cells (fig. a) . interestingly, ebov primarily infects and persists in microglia . ocular complications, including uveitis, are some of the most common findings during evd convalescence , and persistent ebov and persistent marv have been isolated from the aqueous humour of human survivors with uveitis , . in experimentally infected nhps, ebov infects blood vessels during the acute phase of infection and later infects parenchymal eye tissues. however, in rhesus monkeys surviving the experimental infection of ebov with various degrees of uveitis, retinitis and vitritis, ebov only persisted in cd + cells (monocytes or macrophages) in the vitreous chamber and in the inner limiting membrane of the retina to which it is adjacent (fig. b ). whether ebov isolated from the aqueous humour of human survivors originates from the vitreous chamber and its adjacent structures, as appears to be the case in nhps, remains unknown . the first recorded sexual transmission of a filovirus occurred in , when a male survivor of marburg virus disease transmitted marv to his wife . ebov genomic rna was repeatedly detected in the semen of evd survivors up to months after acute infection , , , [ ] [ ] [ ] , and infectious ebov was isolated from a few semen samples . ebov infects the seminiferous tubules of both human and nhps ( fig. c) , which are the immune-privileged sites of sperm production, during the acute phase of disease . persistent ebov infection was detected in the epididymis of a single rhesus monkey survivor with epididymitis, whereas marv persistence in seminiferous tubules was multifocal in of crab-eating macaques that survived , . recent studies indicate that testicular persistence is not restricted to filoviruses, as potential cases of the sexual transmission of crimean-congo haemorrhagic fever virus (cchfv; an orthonairovirus of the family nairoviridae) and uveitis inflammation of the uvea (the pigmented layer between retina and the fibrous layer composed of sclera and cornea of the eye). over the past two decades, high-throughput benchtop platforms (for example, sequencing (roche), miseq, nextseq and hiseq (illumina), sequel and rs (pacbio) and ion torrent (thermo fisher)) have been the backbone of metagenomics and targeted sequencing approaches for pathogen identification . genomic centres generally had to allocate a notable portion of space to house and maintain sequencers and transporting sequencers was impractical. for example, miseq, which is the smallest of the sequencers, weighs kg and occupies ~ , cm . recently, 'capacity building' efforts have established on-site genomics centres in low-resource settings , . however, the international shipping of oversized sequencers that rely on precise optical alignments for functionality can be challenging and cost-prohibitive and may cause irreparable damage to the sequencer. the maintenance and repair of internationally shipped sequencers may also be challenging as they do not come with in-country service contracts from the manufacturers. moreover, in low-resource settings, trained local staff may not be permanent, and they will periodically require guidance and retraining in sample handling and storage and in how to ensure the continued service and activity of the sequencers. the technological improvements in, and practicality of, portable sequencing technologies have been embraced in recent viral disease outbreaks, including in the -present ebola virus disease outbreak in the democratic republic of the congo and a lassa fever outbreak in nigeria. the iseq (illumina) and minion (oxford nanopore) platforms both conform to on-site field requirements as they are miniature, rapid and easy to use. the zibra zika virus (zikv; a flavivirus of the family flaviviridae) sequencing project in brazil also demonstrated the feasibility of a 'trailer laboratory', but produced limited complete genome sequences owing to the small amounts of zikv rna in clinical samples . several commercialized mobile laboratories incorporated into trucks or trailers shield equipment and temperature-sensitive reagents from austere conditions while providing ample power and laboratory workspace for sequencing. within such mobile laboratories, smaller pcr thermocyclers, such as the programmable mini thermal cycler with a smartphone (minipcr bio™), and miniature centrifuges further bolster portability and ease space requirements. other innovations that limit the need of a 'cold chain' for supplies will greatly improve on-site sequencing in hot climates and remote communities that are prone to outbreaks of ebola virus disease. arenaviridae) have been reported [ ] [ ] [ ] . sertoli cells, the supporting cells of spermatogenesis, are the main cellular reservoir of testicular marv and cchfv persistence in experimentally infected nhps , , and they may also be the reservoir of testicular lasv. the majority of cases of filovirus persistence have been associated with immuneprivileged sites. however, in several evd flare-ups originating from asymptomatic survivors of evd that were persistently infected with ebov, identifying the exact sites of viral persistence in the index cases was not possible , . thus, it is expected that sites of ebov persistence that are not immune-privileged will be discovered. ebov can be detected in breastmilk of female survivors of evd and in various tissues, including the blood and liver, of laboratory mice that have been experimentally infected with ebov and have partial immunity up to days post-exposure , . persistence in sites that are not immune-privileged has also been recently reported for cchfv and lasv , . interestingly, cchfv persists within granulomas of nhp survivors with latent tuberculosis . lasv persists in the smooth muscle cells of blood vessels with vasculitis in both crab-eating macaque and domesticated guinea pig survivors , , suggesting that a local altered immunological environment may sustain viral persistence. genomics is uniquely suited to study the pattern of transmission from patients who are asymptomatic or paucisymptomatic. genomic studies of persistent infections revealed distinct evolutionary dynamics that might result in patterns that can when viral diversity cannot be explained by spillover and spatial-temporal estimations, a secondary spillover may be possible (top left). persistent infections through sexual transmission present with low genetic diversity (that is, with a slow evolutionary rate) over periods (bottom right) that are much longer than expected for acute reintroduction at the expected evolutionary rate (top right). a similar analysis was performed during the first discovery of sexual transmission during the - western african evd outbreak , and a theoretical example is shown (bottom right). this example indicates the number of days after the initial presentation of symptoms at which an acutely infected male is sampled (day ) and the day at which he recovers (day ). on day , the sexual partner of this male becomes symptomatic owing to a very similar ebov genotype, confirmed with epidemiological information and visualized using a median-joining haplotype network. help identify the source of the flare-ups . during the - evd outbreak, an unexpectedly low genetic diversity and complementary epidemiological data provided the first evidence of ebov sexual transmission , . recent pathogenesis studies elucidated the persistent infection of ebov and marv in seminiferous tubules , and epididymides , but niche-specific genomic studies (or single-cell sequencing efforts) have yet to be reported. certain ebov mutations may be tissue-specific and may therefore be required to establish persistence; genomics will be key in identifying these mutations. for instance, the sequencing of ebov genomes present in the plasma and cerebrospinal fluid of a patient with evd during a relapse revealed that only two non-coding changes to the genome had occurred compared to the originally obtained ebov genomes sequenced from plasma during the acute phase of disease . multiple or even single nucleotide changes may permit ebov to transverse the blood-brain barrier by directly infecting endothelial cells and microglia cells and establishing a persistent infection . although ebov and marv have been detected and isolated from the aque ous humour of evd survivors with uveitis , and in breastmilk of survivors , genomic studies have not yet investigated the evolutionary dynamics in these niches. in nature, diverse biotic communities constantly interact and evolve within an ecosystem in response to environmental factors. microorganisms, pathogenic or not, participate in these relationships and constantly react and evolve to changes within the environment. in highly complex organisms such as mammals, immune responses against viruses are inherently complex and involve humoural and intracellular mediators and diverse cell types. in turn, viruses such as ebov evolve sophisticated and diverse strategies to evade the host immune response. by studying host-pathogen interactions, we may improve our understanding of the mechanisms that govern infection, immunity and immune evasion. even though ebov is highly virulent and lethal in humans, some individuals survive infection. furthermore, some individuals who were exposed to ebov or who tested seropositive for the virus never reported disease. the seroprevalence rate of these individuals, categorized as asymptomatic or paucisymptomatic, has been reported to be > % throughout africa [ ] [ ] [ ] [ ] [ ] [ ] . transcriptomics offer insight as to why certain factors, such as the source, viral load, and infectivity of ebov or host genetics, contribute to the range of disease severity and survivorship in patients. host 'immune gene signatures' in patients infected with ebov/mak have been associated with clinical prognosis , . indeed, data generated from patients infected with ebov/mak ( survivors and fatal cases) revealed that interferon response-related genes and acute-phase responses were dysregulated in patients who did not survive . however, natural killer cell populations were increased in evd survivors, suggesting a crucial role for natural killer cells in controlling ebov infection. furthermore, low levels of inflammation and robust t cell responses with an upregulation of cytotoxic t lymphocyte-associated protein (ctla ) and programmed cell death (pd ) expression in t cells also correlated with survival from evd . additional transcriptomic studies focusing on the population dynamics of ebov in infected humans and possibly in naive nhps will complement earlier characterization of host responses to evd and provide a greater understanding of the mechanisms of evd pathogenesis and disease outcome. bringing transcriptomics tools to the field, facilitated by our ability to perform genomic sequencing in outbreak areas, will allow the promises of precision medicine to be realized in an outbreak setting. the genomic characterization of an outbreak pathogen is only the first step in characterizing a threat, a process that can be facilitated by reverse functional genomics. classical reverse genetics has focused on the virus rescue of filoviruses based on cloning a reference (that is, a consensus) filovirus sequence or using a replicating filovirus isolate to clone filovirus sequences , . however, synthetic reverse genomics can rapidly rescue individual virus haplotypes or genotypes from a virus population in the absence of replicating isolates, using gene and genome synthesis based on sequence information alone. these rescued viruses can be used to evaluate the functional aspects of individual filovirus genome mutations. thus, functional genomics can facilitate the rapid and precise functional characterization of a newly emerging filovirus or filovirus mutant. given that natural filovirus isolates must be studied while fulfilling strict biosafety and biosecurity requirements that are frequently not available in areas of filovirus disease outbreaks, the availability of in-country and field-deployable sequencing platforms increases the ability of researchers to gather crucial information about the virus without the need to export biological specimens across national borders. to succeed, field sequencing needs to produce highly accurate finished filovirus genome sequences (for example, sequences that include the complete genomic leader and trailer regions of the virus) from a variety of sample sources , , . filoviruses rescued from synthetic reverse genetics systems can then be used to study host adaptation and attenuation as well as the efficacy of therapeutics - . the de novo generation of ebov from the ongoing evd outbreak in the democratic republic of the congo (that is, of ebov/"itu") demonstrates the value of synthetic reverse genetics (fig. ). after the development of modular reverse genetic systems that are even more efficient than those available today, even high-throughput phenotypical characterizations of large numbers of minimally divergent filoviruses are likely to be possible even in the absence of a biological isolate. multiple mcms against ebov infection have been developed, including small molecules, monoclonal antibodies (mabs), antibody cocktails and vaccines , and clinical trials have yielded promising results. however, the population dynamics and evolution of ebov are influenced by mutations in rna, rna recombination rates, virus population bottlenecks, natural selection and fitness (including diversifying and purifying selection), host range and mode of transmission . these traits re-adjust depending on the environment in a natural host, a naive accidental host, a previously exposed accidental host (owing to infection or vaccination) or an accidental host that received an mcm. therapeutic pressures will force the selection of individual ebov genotypes, and thereby adaption, to ensure virus survival or persistence. highly accurate genomic data can be used to evaluate available mcms in silico prior to in vitro and in vivo testing and to characterize host responses to specific therapeutic interventions in real time. the erosion of genetic diversity and concomitant reduction in individual fitness and evolutionary potential. for example, accurate sequencing data from ebov/"itu" allowed for the rapid in silico assessment of the ability of the mab (national institutes of health) and zmapp (mapp biopharmaceutical) mabs to bind to the receptor-binding domain of the ebov spike glycoprotein gp , , predicting that these mabs should be effective against circulating ebov/"itu" . using genomic approaches to understand how mcms influence ebov population dynamics and to identify mutant viruses that escape mcms could augment future therapeutic designs and filovirus-targeting strategies. correlates of protection for different vaccines and vaccination regimens against ebov have not been fully determined. however, both humoural and cellular immunity independently correlate with the protection of nhps from ebov infection and disease , . the use of a recombinant vesicular stomatitis indiana virus vaccine expressing ebov gp , , rvsvΔg-zebov-gp (sold under the brand name ervebo), the first ebov vaccine to be approved by the fda , , diminished evd case fatality rates in a limited ring-vaccination trial performed in guinea in (ref. ) and it is currently administered to people living in the area of the current evd outbreak. however, unfortunately, some vaccinated individuals still present with clinical signs of mild evd. the exact reasons for these 'breakthrough cases' are not completely understood; however, they are thought to result from ebov infection within the first days after vaccination. a breakthrough could be due to the individual having an insufficient immune response to control the virus (that is, when the vaccine induces a low titre of anti-ebov antibodies and/or scarce effector cells) or to ebov adapting to escape the immunological pressures produced by the vaccine. the characterization of the genomic ebov population in patients who developed evd after vaccination could help address these questions. immunotherapy has also been successfully used as a therapy for evd, most notably during the ongoing outbreak in the democratic republic of the congo . the pamoja tulinde maisha (palm) randomized controlled trial recently evaluated four investigational therapeutics (zmapp, remdesivir (gilead sciences, inc.), mab and regn-eb (regeneron pharmaceuticals)) in the treatment of evd . mab (a single mab) and regn-eb (a cocktail of three mabs) were significantly more effective than zmapp (a cocktail of three mabs) reverse functional genomics facilitates external support in the response to outbreaks of ebola virus disease (evd) that occur in remote areas that lack in-house resources to test available medical countermeasures. rapid, high accuracy , complete genome sequences determined in-country are shared with out-of-country collaborators to evaluate key genomic and proteomic changes in ebola virus (ebov) that may affect the efficacy of available therapeutics (part a). for example, changes in the double-stranded rna (dsrna)-binding site of the ebov polymerase cofactor viral protein (vp ), a protein targeted by several therapeutics, can be identified from the sequencing data obtained for a new ebov isolate. changes in this region of vp may compromise the efficacy of treatments. indeed, if two available therapeutic agents (hypothetical treatment a and hypothetical treatment b) target vp , reverse genetic systems can produce replicative ebovs de novo that contain the changes identified in vp (part b). these replicative ebovs can then be used for the in vitro and in vivo therapeutic evaluation of both hypothetical treatments; data obtained using this approach can inform on which treatment is potentially more efficacious against the ebov isolate causing the outbreak. in treating evd (p = . and p = . , respectively) and were also more effective than remdesivir (a nucleoside analogue); the effect of zmapp and remdesivir on evd was not significantly different. mab , obtained from a evd survivor from the democratic republic of the congo, is one of several recently identified ebolavirus-neutralizing antibodies that are being developed as therapeutics for evd [ ] [ ] [ ] [ ] . this mab protected nhps from ebov-induced disease and death, even when administered days after inoculation with ebov . as mab binds to the ebov glycoprotein gp , , the risk of escape mutants arising might be constrained by viral fitness. regn-eb also showed promising results in ebov-exposed nhps, and no mutant viruses were reported to escape this mcm , . by contrast, ebov mutants that escape zmapp have been characterized . a mutation in amino acid residue of ebov gp , abrogated its binding to two of the mabs within zmapp, and a mutation in amino acid residue of ebov gp , abrogated its binding to the third mab . moreover, epitope mapping of ebov gp , using an alanine-scanning assay identified several residues that are crucial for antibodies to bind to ebov gp , , although none of these mutations was tested for fitness. ( ) . as ebov continually replicates, expanding intra-host diversity can create heterogeneous subpopulations ( , blue circles). once exposed to treatment ( , dashed line), ebov intra-host populations may be countered and eliminated, demonstrating an effective treatment without further intra-host replication or diversification (green circles). however, a small subpopulation surviving the therapeutic bottleneck may allow escape mutants to subvert treatment ( ) and continue diversifying into novel, treatment-resistant genotypes ( , red circles). (~ - ) reduces the analytical power of comparative virus-host interactions and inter-host population-level genomics. in addition, experiments aimed at understanding the appearance of antiviral resistance are restrictive; precise protocols to measure and evaluate ebov and the host immune response to infection without violating established policies are urgently required. furthermore, the possibility that a more virulent or less treatable virus may evolve during such experiments and be accidently released is a concern, which is why institutional biosafety committees are cautious in approving experiments aimed at creating such viruses. additionally, concerns may arise from other nations that are parties of the biological weapons and toxins convention. convincing national rivals that experiments resulting in ebov strains that are resistant to mcms were actually intended to strengthen mcms, and not to deliberately create biological weapons, is not straightforward. the advancement of targeted and unbiased genomic sequencing has profoundly impacted our biological knowledge of, epidemiological preparedness for, and response strategies to known and unknown high-consequence filovirus infections. greater investments in in-country genomic infrastructure and mobile sequencing platforms have reduced the time from sample to viral genome sequence and simultaneously informed local clinicians, epidemiologists and public health officials of genome-guided information on the virus responsible for a current outbreak. advances in large-scale and timely data generation encourage future genomic studies to go beyond consensus-level pathogen genome sequencing during an outbreak. for example, persistent infections in immune-privileged sites of survivors can be characterized using single-cell sequencing technologies. additionally, an increased focus on host responses in an infected individual and the contribution of host genome characteristics to disease outcome and transmission would potentially further benefit the development of mcms and improve the outbreak response. complete pathogen-host genomic investigations could be applied to infected individuals, nhps and known natural host reservoirs of filoviruses. the successful integration of current and future genomic tools will rely on the establishment of new long-term partnerships between government, academia and public health agencies and on maintaining in-country genomic capabilities where the threat of filovirus outbreaks is imminent. in silico modelling using the three-dimensional structure of ebov gp , was used to predict which mutations in ebov would enable it to escape antibody binding , . initially, mab kz was analysed, followed by mab , mab and mab f - - . a list of mutations predicted to interfere with kz -ebov gp , binding was expanded to mutations predicted to disrupt the binding of other mabs to ebov gp , . three of the predicted mutations were found in ebovs infecting humans or experimental animals , , showing that viruses may escape current mcms under investigation. despite the proven efficacy of two therapeutics assessed in the palm trial, namely mab and regn-eb , none of the treatments achieved complete protection against evd . we hypothesize that the characterization of the ebov population in individuals who did not benefit from treatment in the palm trial might help elucidate the reasons for this failure. a clear demonstration of the power of genomics for this purpose was the investigation of two nhps that succumbed to experimental ebov exposure despite experimental treatment with mb- , a cocktail of three mabs. two clusters of genomic mutations (a cluster of five non-synonymous changes in one animal and a cluster of four non-synonymous changes in the other) reduced the binding of the three mabs to ebov gp , ( fig. ). viral isolates obtained after mb- treatment recapitulated the observed 'escape' phenotype. the mutations, all located in the ebov glycoprotein (gp) gene, abrogated antibody binding to gp , . although this study was restricted in size, it highlights mechanisms by which ebov can evade immuno therapies. first, adaptation to a selection pressure can occur rapidly. second, methods to monitor the appearance and phasing of viral mutants that can escape immunotherapies are crucial. third, with the use of reverse genetics systems, scientists can acquire pertinent information on the therapeutic efficacy of sequence-based mcms during an ongoing outbreak of evd (fig. ). for example, phenotypical changes resulting from clade-defining non-synonymous mutations (for example, alanine to histidine substitution at residue in nucleoprotein or isoleucine to methionine substitution at residue in viral protein , both in ebov/"itu") or positively selected non-synonymous mutations identified in the ongoing outbreak can be investigated. unfortunately, not many studies have investigated the resistance of ebov to candidate vaccines or to mcm. cost is a consideration, but 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rousette bats isolation of genetically diverse marburg viruses from egyptian fruit bats isolation of angola-like marburg virus from egyptian rousette bats from west africa studies of reservoir hosts for marburg virus marburgvirus in egyptian fruit bats discovery of swine as a host for the reston ebolavirus reston virus in domestic pigs in china molecular evidence of ebola reston virus infection in philippine bats re-emergence of lloviu virus in miniopterus schreibersii bats first filovirus discovered by next-generation sequencing in the absence of virus isolation bombali virus in mops condylurus bat the discovery of bombali virus adds further support for bats as hosts of ebolaviruses bombali virus in mops condylurus bats filovirus rna in fruit bats characterization of a filovirus (měnglà virus) from rousettus bats in china genetically diverse filoviruses in rousettus and eonycteris spp. bats, china the evolutionary history of vertebrate rna viruses unexpected metagenomic discovery of filoviruses in fish fruit bats as reservoirs of ebola virus ebola outbreak killed gorillas multiple ebola virus transmission events and rapid decline of central african wildlife isolates of zaire ebolavirus from wild apes reveal genetic lineage and recombinants this review summarizes the sequencing efforts and evolutionary studies performed during the - western african evd outbreak emergence of zaire ebola virus disease in guinea genomic surveillance elucidates ebola virus origin and transmission during the outbreak rapid outbreak sequencing of ebola virus in sierra leone identifies transmission chains linked to sporadic cases monitoring of ebola virus makona evolution through establishment of advanced genomic capability in liberia this report describes the establishment of the first in-country genomics centre in liberia during the - western african evd outbreak real-time, portable genome sequencing for ebola surveillance medical countermeasures during the ebola virus disease outbreak 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shared genomic variants: identification of transmission routes using pathogen deep-sequence data the pathogenesis of ebola virus disease filovirus pathogenesis and immune evasion: insights from ebola virus and marburg virus characterization of host immune responses in ebola virus infections tissue-based class control: the other side of tolerance uveal involvement in marburg virus disease spermatogene Übertragung des persistence and genetic stability of ebola virus during the outbreak in kikwit, democratic republic of the congo marburg-virus disease in kenya ebola virus transmission caused by persistently infected survivors of the - outbreak in west africa resurgence of ebola virus disease in guinea linked to a survivor with virus persistence in seminal fluid for more than days new evidence of long-lasting persistence of ebola virus genetic material in semen of survivors ebola virus persistence in semen of male survivors active ebola virus replication and heterogeneous evolutionary rates in evd survivors post-ebola syndrome sequelae of ebola virus disease: the emergency within the emergency identification and pathological characterization of persistent asymptomatic ebola virus infection in rhesus monkeys ebola virus disease complicated by late-onset encephalitis and polyarthritis late ebola virus relapse causing meningoencephalitis: a case report an update on ocular complications of ebola virus disease persistence of ebola virus in ocular fluid during convalescence ocular immune privilege and transplantation ebola rna persistence in semen of ebola virus disease survivors -final report clinical, virologic, and immunologic follow-up of convalescent ebola hemorrhagic fever patients and their household contacts, kikwit, democratic republic of the congo a longitudinal study of ebola sequelae in liberia persistence and sexual transmission of filoviruses tissue and cellular tropism, pathology and pathogenesis of ebola and marburg viruses persistent marburg virus infection in the testes of nonhuman primate survivors a case of human lassa virus infection with robust acute t-cell activation and long-term virus-specific t-cell responses possible sexual transmission of crimean-congo hemorrhagic fever lassa fever: epidemiology, clinical features, and social consequences persistent crimean-congo hemorrhagic fever virus infection in the testes and within granulomas of non-human primates with latent tuberculosis persistence of ebola virus after the end of widespread transmission in liberia: an outbreak report persistent infection with ebola virus under conditions of partial immunity ebola virus persistence in breast milk after no reported illness: a likely source of virus transmission from mother to child immune-mediated systemic vasculitis as the proposed cause of sudden-onset sensorineural hearing loss following lassa virus exposure in cynomolgus macaques persistence of lassa virus associated with severe systemic arteritis in convalescing guinea pigs 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rna editing of the gp gene and viral cytotoxicity use of reverse genetics to inform ebola outbreak responses therapeutic strategies to target the ebola virus life cycle effects of life history and ecology on virus evolutionary potential role of antibodies in protection against ebola virus in nonhuman primates immunized with three vaccine platforms immune parameters correlate with protection against ebola virus infection in rodents and nonhuman primates properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses identification of the ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury efficacy and effectiveness of an rvsv-vectored vaccine in preventing ebola virus disease: final results from the guinea ring vaccination, open-label, cluster-randomised trial (ebola Ça suffit!) independent monitoring board recommends early termination of ebola therapeutics trial in drc because of 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initiating a watch list for ebola virus antibody escape mutations expanding the watch list for potential ebola virus antibody escape mutations emergence of ebola virus escape variants in infected nonhuman primates treated with the mb- antibody cocktail origins and evolutionary consequences of ancient endogenous retroviruses syncytin is a captive retroviral envelope protein involved in human placental morphogenesis systematic survey of non-retroviral virus-like elements in eukaryotic genomes unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes paleovirology of bornaviruses: what can be learned from molecular fossils of bornaviruses widespread endogenization of genome sequences of non-retroviral rna viruses into plant genomes endogenous viral elements are widespread in arthropod genomes and commonly give rise to piwiinteracting rnas evolutionary maintenance of filovirus-like genes in bat genomes filoviruses are ancient and integrated into mammalian genomes sequence-based evidence of a long co-evolutionary history of filoviruses and mammalian filovirus hosts clinical metagenomic next-generation sequencing for pathogen detection establishment and cryptic transmission of zika virus in brazil and the americas we thank laura bollinger (nih/niaid integrated research facility at fort detrick, frederick, md, usa) for critically editing the manuscript and william discher (usamriid, fort detrick, frederick, md, usa) for the diagram used in fig. . in no event shall any of these entities have any responsibility or liability for any use, misuse, inability to use or reliance upon the information contained herein. the us departments do not endorse any products or commercial services mentioned in this publication. these authors researched data for the article, contributed to the writing and discussion of the content, and reviewed and edited the manuscript prior to submission, focusing on the following sections: introduction (n.d., j.h.k. and g.p.); identifying filovirus reservoirs (j.h.k.); identifying and characterizing outbreaks (n.d., j.h.k., g. p. and x.z.); genomics in threat characterization (n.d. and g.p.); and genomics in prevention and therapy (m.s.-l. and g.p.). all of the authors contributed to the conclusions. all authors declare no competing interests. nature reviews microbiology thanks miles carroll and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. fda news release on the first fda-approved vaccine for the prevention of ebola virus disease: https://www.fda.gov/ news-events/press-announcements/first-fda-approvedvaccine-prevention-ebola-virus-disease-marking-criticalmilestone-public-health key: cord- - hnaiyc authors: cieslak, theodore j.; herstein, jocelyn j.; kortepeter, mark g. title: communicable diseases and emerging pathogens: the past, present, and future of high-level containment care date: - - journal: bioemergency planning doi: . / - - - - _ sha: doc_id: cord_uid: hnaiyc high-level containment care involves the management of patients with highly hazardous communicable diseases in specialized biocontainment units possessing a unique collection of engineering, administrative, and personnel controls. these controls are more stringent than those found in conventional airborne infection isolation rooms and provide additional safeguards against nosocomial disease transmission. borne amidst a convergence of events in , the employment of hlcc units was validated during the – ebola virus disease outbreak, and the united states (as well as many other nations) is in the process of expanding its hlcc capacity. beyond ebola, however, the specific diseases that might warrant care in a hlcc unit remain unclear. we review here the fascinating history of hlcc and of biocontainment units and make recommendations regarding those highly hazardous communicable diseases that might optimally be managed in these units. the past few decades have witnessed a number of outbreaks of communicable disease caused by novel or emerging pathogens with the potential to produce significant morbidity and mortality in humans. although highly hazardous communicable diseases (hhcds) such as smallpox and plague date to antiquity, the year saw a convergence of events that brought such diseases, and the pathogens that cause them, into the forefront of public consciousness. the publication, that year, of michael crichton's fictional work, the andromeda strain, magnified concerns initially raised by media coverage surrounding the decision to shutter the us offensive biological weapons program. the success of the apollo mission later that year and the possibility that returning astronauts might bring extraterrestrial pathogens back to earth upon their return further heightened these concerns and was partly responsible for the decision to build the first specialized units dedicated to the isolation of patients potentially harboring highly hazardous communicable pathogens [ ] . these units, the lunar receiving laboratory at the johnson manned spaceflight center in houston and the "slammer" at the us army's medical research institute of infectious diseases (usamriid) at fort detrick md, would usher in a new era of "high-level containment care" (hlcc) and foster a reexamination of institutional infection control procedures. nearly simultaneously, an emphasis on improved laboratory safety would be prompted by the discovery of the contagious and deadly viral hemorrhagic fever virus, lassa, by researchers at yale [ ] . after a yale technician died of laboratory-acquired lassa fever, research activities were relocated to a new maximum-security laboratory (the predecessor of today's biosafety-level- laboratories) at the communicable disease center (now the centers of disease control and prevention [cdc]) in atlanta. usamriid's "slammer" was a two-bed unit that employed engineering controls analogous to those seen in bsl- laboratories. designed with the ability to isolate (care for patients infected with hhcds) and quarantine (observation of individuals potentially exposed to these diseases), the unit was utilized for the latter role times over its -year existence [ ] , but was never required to isolate a symptomatic patient, a fact which likely factored into its decommissioning in . in the meantime, partly in response to bioterrorism concerns raised by the anthrax attacks, as well as to the subsequent outbreaks of severe acute respiratory syndrome (sars) and monkeypox, civilian hlcc units were constructed at emory university and at the university of nebraska. these two facilities cared for seven ebola virus disease (evd) patients during the - outbreak, while another two were cared for at the national institutes of health's special clinical studies unit, which had also developed hlcc capability. a tenth evd patient was successfully managed under improvised hlcc conditions at new york's bellevue hospital. while us etcs have, as of this writing, cared for a handful of evd victims and a single patient with lassa fever [ ] , it is expected that such facilities will be ready to manage patients with a number of additional hhcds. in this regard, we envision that four broad categories of patients might be viewed as candidates for admission to a hlcc unit (table . ). we briefly discuss each of these categories, as well as the pathogens contained therein, allowing that the list of such pathogens is designed to be neither under-nor over-inclusive. in this regard, we acknowledge that some institutions may elect to care for patients in a hlcc setting even though the disease they harbor may not be included on this list, and the same patient might not necessarily be managed under hlcc conditions at another institution. similarly, we realize that new diseases may emerge and be cared for under hlcc conditions until a certain level of confidence with their management is gained. finally, we acknowledge that future developments in vaccinology and therapeutics may well lead to the removal of some diseases from the current list. first, patients harboring diseases caused by pathogens that require handling under bsl- conditions in the laboratory would seem to be obvious candidates for clinical management under hlcc conditions. several taxonomic families contain such highly hazardous viruses: of these, we advocate that patients infected with any except the flaviviruses be considered for movement to a hlcc facility. the latter do not require containment because they lack person-to-person (ptp) transmission, with naturally occurring disease being acquired solely through the bite of an arthropod vector. with the exception of variola and the henipaviruses, the remaining bsl- pathogens produce a clinical syndrome of viral hemorrhagic fever (vhf) in humans, and all are transmissible, to varying degrees, from ptp. in addition to the bsl- pathogens, there are several other diseases that cause high morbidity and mortality, which are potentially communicable and thus might prompt management in a hlcc unit. while a lower risk to laboratorians permits the causative agents of these diseases to be handled utilizing bsl- or even bsl- precautions, in many cases, the precise nature of ptp transmission risk is unknown. we thus propose that the optimal management of patients harboring these agents take place under hlcc conditions. included in this category are persons infected with a number of viral pathogens: the sars or mers coronaviruses, highly pathogenic avian influenza (hpai) and other seemingly morbid novel influenza strains, and the orthopoxvirus, monkeypox. in addition, while pneumonic plague, caused by the bacterium yersinia pestis, is treatable with antibiotics, its high degree of contagion, almost universal lethality in the absence of prompt intervention, and narrow window of opportunity for successful postexposure treatment or prophylaxis make its management in a conventional hospital setting dangerous. moreover, its history as a cause of frightening global pandemics and its past association with biological warfare make it a public perceptual and surety risk (see below). finally, while most patients with pulmonary tuberculosis caused by conventional strains of mycobacterium tuberculosis are readily cared for in a negative-pressure isolation room within a conventional medical facility, the recent emergence of strains of extensively drug-resistant tuberculosis (xdr-tb) provides justification of the need for high-level containment. we allow for the certainty that new diseases will continue to emerge and that these new diseases may initially be severe yet insidious, their causative agents unidentified, and optimal means of their control unknown (the andromeda strain problem). in such circumstances, it may, on occasion, be prudent to manage and study victims in a hlcc environment. in this regard, sars, mers, nipah, hendra, and most of the vhfs could have been considered "andromeda strains" at the time of their initial appearance. finally, we acknowledge that newly emerging and highly lethal diseases raise security and surety issues and that these are compounded by fears of biological warfare and terrorism. there may be circumstances, then, when it would be reasonable to manage patients in a hlcc unit in response to political, public assurance, and risk management concerns. the - outbreak of ebola virus disease (evd) in west africa involved at least , cases with , deaths [ ] . the th such outbreak, larger than the previous combined [ ] , resulted in the infection of several western aid workers, led to their repatriation to the united states and europe [ ] , and prompted the current ongoing expansion of hlcc facilities and capabilities. evd is caused by viruses of the genus ebolavirus in the family filoviridae; the viruses derive their name from the ebola river in the democratic republic of the congo (drc, then called zaire), from whence the first cases were described in . while the - outbreak was caused by the same ebola virus (the type species, previously known as ebola zaire), evd is also caused by at least three additional members of the ebolavirus genus, bundibugyo, sudan, and tai forest viruses. a fifth species, reston virus, produces fatal disease in nonhuman primates and has resulted in seroconversions among laboratory workers, but is not known to cause overt disease in humans. to date, all outbreaks of evd have arisen in a small handful of african nations; guinea, liberia, and sierra leone accounted for the vast majority of cases during the - outbreak, while previous outbreaks occurred in the drc, congo, gabon, uganda, and south sudan. while the ecology of evd remains unclear, fruit bats likely serve as a reservoir host for the viruses [ ] ; outbreaks may begin when humans acquire the disease through contact with these bats or with duikers and nonhuman primates (who are also susceptible to evd) consumed as bush meat. evd is then transmitted from ptp through infected blood and body fluids. given the profuse amount of vomitus and diarrhea often seen among victims, along with the high concentration of virus in those fluids, the risk of such transmission is quite high, especially among family caregivers and those involved in funeral preparations. similarly, patients with evd pose an extraordinary risk of nosocomial transmission through exposure to blood and other bodily fluids during medical procedures. finally, ebola virus persists in semen for many months after recovery, raising the possibility of sexual transmission. ebola has an incubation period of - days (mean - days), after which patients develop fever, headache, myalgia, and gastrointestinal symptoms. hemorrhagic manifestations may be mild or profound, with hematemesis and hematochezia, purpura, and ecchymosis sometimes seen. death typically occurs as a result of multi-organ failure rather than hemorrhage per se, and the mortality rate has ranged from % to %, depending on the species. supportive care is the cornerstone of evd management, and meticulous attention needs to be paid to hemodynamics, respiratory status, fluid balance, and electrolyte abnormalities. while no licensed antiviral therapy exists, monoclonal antibodies [ ] and other experimental treatments have demonstrated great promise, and a vaccine candidate has been shown to be % efficacious in a postexposure vaccination trial [ ] . ebola viruses should be handled in the laboratory using bsl- safety measures, and the processing of clinical specimens potentially harboring these viruses should involve at least bsl- precautions, as would be the case with all of the pathogens discussed in this chapter. the corpses of evd victims are teeming with virus and pose an extreme risk to handlers and family members; they should only be handled by trained persons wearing appropriate ppe. patients infected with ebola were managed under hlcc conditions in multiple countries that evacuated infected expatriate healthcare and aid workers from west africa, including germany, switzerland, britain, france, norway, italy, netherlands, spain, as well as the united states. the infection of two nurses who cared for an evd patient in a conventional hospital setting in dallas, texas, and the more favorable mortality rates of patients treated in hlcc conditions ( . % compared to - % in west africa) [ ] underscore the value of hlcc units in evd management. marburg virus was first described as the cause of a lethal outbreak of viral hemorrhagic fever among laboratory workers in marburg, germany, in . the prototype member of the newly described family filoviridae, marburg, caused deaths among the victims ( % mortality rate) managed in modern german medical facilities, of whom represented secondary cases attributable to ptp transmission. only rare sporadic cases of marburg were seen subsequently until , when an outbreak occurred in congo in which of known cases died (mortality rate %). a second large and very lethal outbreak occurred in angola in ( deaths among victims, mortality %). marburg disease typically begins, following a - -day incubation period, with the onset of fever, headache, myalgia, and gastrointestinal symptoms (vomiting and diarrhea). rash, hemorrhage, and thrombocytopenia are common, and uveitis often occurs; death results from multi-organ failure. nosocomial transmission is well documented. management is supportive; there are no licensed therapeutic agents available to treat marburg hemorrhagic fever, although immune plasma has been used [ ] , and experimental therapies have proven efficacious in nonhuman primates [ ] . laboratories should handle marburg virus under bsl- conditions. the management of patients with marburg infection in hlcc settings has occurred in both the netherlands [ ] and germany [ ] . lassa virus is a member of the family arenaviridae and is an important cause of viral hemorrhagic fever in west africa. endemic in the same region affected by the - evd outbreak, lassa causes as many as , - , human infections annually in nigeria, guinea, liberia, sierra leone, and other nations in the region, where it accounts for - % of all hospitalizations [ ] . seroprevalence rates in these countries range as high as %, attesting to the fact that many infections are mild or silent. among patients ill enough to require hospitalization, mortality typically ranges from % to %. while most lassa infections result from exposure (via ingestion or inhalation) to the urine and feces of mastomys rats, ptp transmission is well documented, and the risk of nosocomial spread via exposure to blood and body fluids is high. like ebola, lassa virus can persist in semen for several months, thus promoting sexual transmission. symptomatic lassa fever begins, following a - -day incubation period, as a non-specific flu-like illness. fever, myalgia, sore throat, and cough are followed by gastrointestinal symptoms and, often, by a maculopapular rash. in severe cases, manifestations of vascular leak (edema, ascites, pleural effusion) occur during the second week, as do neurologic symptoms such as seizures and coma. overt hemorrhage occurs in only about % of patients [ ] , and death results from shock and organ failure. an elevated serum aspartate aminotransferase portends a poor prognosis, and levels above iu/liter have been associated with a % mortality rate. it is in this group, however, that ribavirin was initially studied [ ] . when administered intravenously within the first days of illness, it reduced mortality to %. the use of ribavirin is also advocated for postexposure prophylaxis. lassa is a bsl- pathogen and should be handled accordingly in the laboratory. until the west africa evd outbreak, lassa fever had been the most common vhf treated in an hlcc setting. multiple hlcc units in germany, sweden, and the united kingdom have experience managing lassa fever patients, as does emory university hospital's serious communicable diseases unit, which treated a patient with lassa in . while three lassa fever patients treated in the european facilities were medically evacuated from endemic countries, most were imported cases that were locally hospitalized and later transported to an hlcc facility [ , ]. lujo virus, an old world arenavirus closely related to lassa, was first described in as the cause of a single outbreak of viral hemorrhagic fever involving five patients in lusaka, zambia, and johannesburg, south africa (the name, lujo, derives from the two cities) [ ] . four of these patients died (mortality rate %), and there was evidence of spread to medical caregivers. of note, the lone survivor was the only patient to receive ribavirin. no other cases have been reported as of this writing. laboratories should handle specimens containing lujo virus as they would those containing lassa. guanarito, junin, machupo, and sabia are members of the family arenaviridae and the causative agents of venezuelan, argentinian, bolivian, and brazilian hemorrhagic fevers, respectively. the new world arenaviruses all have rodent hosts, and humans are incidentally infected, likely through exposure to aerosolized rodent excreta. only a single case of naturally occurring (and two cases of laboratoryacquired) sabia has been reported, and its potential for ptp and nosocomial transmission is thus unknown. data supporting ptp transmission of guanarito is likewise sparse. the close relationship of these agents to junin and machupo, however, both of which are known to be transmitted from ptp in nosocomial and other settings, prompts us to advocate for the management of patients infected with any of the four viruses under hlcc conditions. the incubation periods of these diseases are generally thought to range from to days (shorter in the case of parenteral exposure such as via needle stick injury), after which time patients develop fever and malaise, accompanied by headache, myalgia, vomiting, and diarrhea. neurologic manifestations may differentiate new world arenaviral infections from other vhfs, where they are far less common. these manifestations may include hyporeflexia, tremor of the tongue and upper extremities, gait abnormalities, seizures, and coma. leukopenia and thrombocytopenia can be profound, and signs of vascular leak, such as proteinuria and large ecchymoses, are often prominent. mortality is approximately - % in the case of junin or machupo [ ] . as with lassa, however, ribavirin appears quite beneficial in the treatment of new world arenaviral infections, as does convalescent plasma [ ] . although not licensed in the united states, a junin virus vaccine has been widely employed in argentina and is thought to be more than % efficacious [ ] . limited animal data supports the possibility that it may protect against machupo infection as well. all four of these viruses warrant the use of bsl- precautions in the laboratory. chapare, another virus closely related to the abovementioned four, was isolated from a single fatal case of hemorrhagic fever in bolivia [ ] , and three fatal hemorrhagic fever cases in california were attributed to another closely related arenavirus, the whitewater arroyo virus [ ] , which is widely distributed among woodrats in the american southwest. whether these two viruses can be transmitted from ptp is unknown, and while many additional arenaviruses have been discovered in rodents, their role in human disease likewise remains unknown. it would seem prudent to manage patients potentially harboring such diseases under hlcc conditions when feasible and to handle their causative viruses in a bsl- laboratory. although reports of a disease consistent with crimean-congo hemorrhagic fever (cchf) date to the twelfth century, the illness derives its name from a large outbreak of hemorrhagic fever in - among soviet troops serving in the crimea and a subsequent outbreak in the belgian congo [ ] . the causative agent of cchf is a nairovirus in the family bunyaviridae, the only member of this taxon requiring bsl- handling. spread largely via the bite of hyalomma ticks, it is endemic throughout much of this vector's range in africa, central asia, the middle east, and the balkans [ ] . nonetheless, it also poses a significant risk of ptp transmission (the only bunyavirus apparently capable of this), with over cases having occurred among healthcare personnel. on a global scale, cchf is the most important tick-borne infection of humans, responsible for over separate outbreaks since isolation of the virus in . while % of human infections are thought to be subclinical, symptomatic cchf presents in similar fashion to most other vhfsfollowing an incubation period of - days after a tick bite (or - days after exposure to the fluids of an infected person), patients typically experience the abrupt onset of fever, myalgia, and headache, often accompanied by neck stiffness and photophobia. gastrointestinal symptoms (nausea, vomiting, diarrhea) are frequently seen, and thrombocytopenia with hemorrhagic manifestations (petechiae, ecchymoses) is often prominent. although cchf has a mortality rate of - % in the absence of therapy, ribavirin may be beneficial in reducing mortality and in the prophylaxis of exposed contacts [ ] . despite a relatively wide geographic distribution, confirmed cases of cchf in western europe are relatively rare. in and , imported cases of cchf were treated in hlcc units in france and the united kingdom, respectively [ , ] . two autochthonous cases of cchf occurred in spain in : the first patient was initially admitted to an icu before being transported to an hlcc facility, and the second patient was a nurse who had cared for the first patient in the conventional icu [ ] . another bunyavirus, rift valley fever (rvf) virus, is a relatively common cause of disease outbreaks throughout africa and the arabian peninsula. although it can cause a hemorrhagic fever syndrome in a small minority of cases, there is no evidence for ptp transmission of rvf and hlcc management is thus unnecessary. nipah virus infection is caused by a paramyxovirus in the genus henipavirus. it was first described in as the cause of an outbreak of respiratory illness and encephalitis in malaysia and singapore; during the initial malaysian outbreak, at least of cases resulted in death [ ] , for a mortality rate of %. subsequent outbreaks have been limited to bangladesh and neighboring areas of india. while virtually all cases of nipah infection in malaysia and singapore are thought to have resulted from close contact with infected pigs, ptp transmission appears to be a factor in the spread of disease during bangladeshi outbreaks [ ] . the malaysian pigs presumably acquire the disease from pteropus bats which roost in the orchards where pigs are permitted to feed on fallen fruit. in bangladesh, a muslim-majority nation in which pigs are seldom raised, disease appears instead to be spread via the consumption of raw date palm sap contaminated with bat excrement. nipah has an incubation period of - days, after which time patients develop fever and headache, followed by drowsiness, confusion, and, in some cases, respiratory distress. permanent neurologic sequelae, including personality changes and seizures, occur frequently. treatment of nipah is generally supportive, although ribavirin appears efficacious in vitro. laboratories should handle nipah virus under bsl- conditions. like nipah, hendra virus infection is caused by a henipavirus in the family paramyxoviridae. the virus was discovered in as the cause of fatal infections among horses in hendra, a suburb of brisbane, australia. similar to the situation with nipah, the horses appear to have contracted the disease through exposure to the secretions of infected pteropus bats. although human infection has been exceedingly rare (only seven cases have been reported as of this writing), mortality is high ( / , %). hendra appears to have an incubation period of - days, and clinical disease involves a severe respiratory illness accompanied by encephalitis. ribavirin has in vitro activity against the virus but has not been studied in vivo. while ptp transmission of hendra has not been documented, we feel that the similarities between this virus and nipah, coupled with scant clinical experience, warrant extreme prudence. we thus advocate for the management of human hendra virus infection in a hlcc setting: laboratory handling should be done under bsl- conditions. the severe acute respiratory syndrome (sars) first appeared as a distinct clinical entity in the guangdong province of china in . the disease was ultimately attributed to a newly described coronavirus, a taxonomic family previously associated with the common cold. while % of the - , cases associated with the epidemic occurred in china, global travel resulted in infections in nations, with a mortality rate of approximately %. toronto, canada, experienced roughly cases, with evidence of local ptp transmission. the disease then disappeared, and there have been no reported cases anywhere in the world since . bats appear to be the reservoir for the sars coronavirus (sars-cov) and are thought to have spread the pathogen to civet cats; early human infections resulted from contact with these cats [ ] . although animal hosts may be asymptomatic, human infection with sars-cov results, after a - -day incubation period, in an initial flu-like illness with fever, cough, sore throat, myalgia, and lethargy. this typically progresses to a severe viral pneumonia, sometimes with secondary bacterial involvement. diarrhea and other gastrointestinal symptoms occur in a significant minority of patients. laboratory findings often include lymphopenia, as well as elevated transaminases, lactate dehydrogenase, and creatine phosphokinase. the treatment of sars is supportive, and bsl- precautions should be employed by laboratories. during the sars outbreak, cases were imported into western europe, and most were treated in hlcc settings in germany, france, italy, sweden, and the united kingdom [ ] . at the epicenter of the outbreak, isolation capabilities in beijing and singapore were exhausted quickly, and hospital complexes with hlcc capability were built for increasing numbers of sars patients [ , ] . in singapore and taiwan, insufficient space led to the temporary designation of sars hospitals, where engineering controls were installed, contamination zones established, and ppe donning and doffing areas designated [ ] . the middle east respiratory syndrome is caused by another coronavirus (mers-cov) closely related to sars-cov and was first described as the cause of an outbreak of severe and often fatal respiratory disease on the arabian peninsula in . while autochthonous cases have been reported only in the middle east, travelassociated cases have occurred in the united states, western europe, and east asia. as of this writing, the outbreak is still ongoing, with well over cases reported; although asymptomatic infection does occur, the mortality rate of mers is - % among symptomatic patients. person-to-person transmission occurs frequently. following an incubation period of - days, mers begins with non-specific flulike symptoms and progresses, much like sars, to a severe viral pneumonia, acute respiratory distress syndrome, and respiratory failure. laboratory findings are similar to those seen in patients with sars, and clinical management is likewise supportive. the world health organization has published comprehensive guidance for the provision of supportive care to patients with mers [ ] . mers-cov isolates, as well as specimens from patients suspected of having mers, should be handled in the laboratory using bsl- precautions. influenza is caused by a number of viruses in the family orthomyxoviridae. human infections are attributed to three genera, influenza viruses a, b, and c. while influenza b and c are known to cause seasonal disease in humans, only influenza a has the potential for causing devastating pandemics. this potential results from the virus's ability to exchange genes among strains, a process resulting in "antigenic shift." the most important of these genes are those coding for two viral proteins, hemagglutinin (h) and neuraminidase (n). viral strains are characterized by these proteins, with h n and h n currently circulating as causes of seasonal influenza among humans. while most viruses are somewhat species specific, both human and avian strains have the ability to infect pigs; simultaneous infection of pigs risks the exchange of genetic material between human and avian strains within the porcine host. such an exchange caused the h n swine variant outbreak and, while this outbreak was milder than some feared initially, the devastating potential of novel influenza strains is best highlighted by the global spanish flu pandemic, which is estimated to have caused - million deaths worldwide ( - % of the world's population) [ ] . even in the absence of a pandemic, seasonal influenza causes a mean of , excess deaths annually in the united states alone, largely among the elderly. although most patients recover from seasonal human influenza, disease caused by avian strains among poultry and aquatic birds can be devastating. highly pathogenic avian influenza (hpai) h or h strains can have mortality rates of - % in chickens, turkeys, and ducks. while most avian influenza viruses are not particularly infectious for humans, there is fear that a novel emerging influenza strain might combine the infectivity for humans with mortality rates seen in birds. seasonal influenza has an incubation period of - days, and patients may be contagious h prior to the onset of symptoms, which poses a challenge to infection control efforts. initial symptoms include fever and respiratory complaints (cough, sore throat, rhinitis), accompanied by myalgia, headache, and malaise. primary viral and secondary bacterial pneumonias occur frequently and are often the cause of death in fatal cases. avian influenza strains, when they do produce symptomatic disease in humans, often result in rapid progression to severe respiratory distress and respiratory (as well as other organ) failure. while supportive care is a mainstay of treatment for all forms of influenza, adamantanes (amantadine, rimantidine) and neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) have been beneficial in some cases. susceptibility to these drugs varies greatly among strains, however, and their use should be considered in view of guidelines put forth annually by the cdc and world health organization. annual influenza vaccination will not protect against novel and avian strains but is useful in lowering the prevalence of seasonal influenza in the community, thereby potentially providing diminished opportunities for viral reassortment events. the sporadic occurrence of a case of influenza caused by a novel, seemingly highly pathogenic strain might merit isolation and care under hlcc conditions. in the face of a pandemic, however, hlcc bed capacity would quickly be overwhelmed, and alternative management strategies would need to be employed. seasonal influenza virus strains, and clinical specimens harboring such strains, can be handled under bsl- conditions. non-contemporary and hpai strains warrant bsl- handling. smallpox ranks as, perhaps, humanity's greatest killer. responsible for the deaths of several hundred million people over the course of history, its eradication, the result of an intense and coordinated global effort, similarly ranks among public health's greatest achievements. naturally occurring smallpox was last seen in somalia in , and worldwide vaccination against the disease was halted in the early s. a case today would likely be the result of a laboratory accident, a bioterror attack, or a reawakening of dormant virus (e.g., from a corpse preserved in permafrost). smallpox is caused by variola virus, a member of the orthopoxvirus genus in the family poxviridae. its control was enabled by the use of a vaccine derived from vaccinia, a related, but far less pathogenic virus in the same genus. unusual among viruses, variola is quite stable ex vivo and can survive (e.g., in crusted scab material) for decades. smallpox is transmissible via both contact (e.g., with scabs) and droplet nuclei. following an incubation period of - days, initial symptoms include fever, malaise, prostration, headache, and myalgia [ ] . these symptoms are followed very closely by a characteristic exanthem and enanthem (lesions can be seen in the mouth and other mucosal surfaces and are present on internal organs). the rash progresses in synchronous fashion from macules to papules to vesicles to pustules to tense painful lesions said to mimic pellets embedded in the skin. the lesions are centrifugal in distribution and involve the palms and soles, differentiating them from those of chickenpox. when the disease was endemic, smallpox had a % mortality rate (from multisystem organ failure), and survivors were left with deep scars from these lesions. historically, supportive care served as the primary means of treatment for smallpox patients, although recently cidofovir [ ] , licensed for the treatment of cytomegalovirus retinitis, has shown promise in treating other orthopoxviruses in animal models and in immunocompromised humans. similarly, tecovirimat has been used under an investigational new drug protocol to treat persons with complications arising from receipt of live vaccinia virus and has also demonstrated efficacy in animal orthopoxvirus models [ ] . as evidenced by its past success, vaccination is quite effective in preventing smallpox, and the us strategic national stockpile contains robust quantities of vaccinia vaccine. administering vaccine promptly postexposure (within days) may prevent or ameliorate disease, an unusual attribute among vaccines. despite these countermeasures, an outbreak of smallpox today, occurring in an immunologically naïve population, would likely pose a significant risk of mortality, and a single case would constitute a grave public health emergency. smallpox stores are held in only two authorized laboratories at the centers for disease control and prevention (cdc) and at the state research center of virology and technology in koltsovo, russia. any handling of clinical materials potentially containing virus should only be done under tight security and bsl- conditions. monkeypox is caused by an orthopoxvirus closely related to variola and was only differentiated from smallpox in during efforts to eradicate the latter [ ] . while its primary host appears to be macaque monkeys, it can infect humans and a number of other animals, notably rodent species. while monkeypox is endemic in the democratic republic of the congo, contact with infected rodents has resulted in cases elsewhere. in , an outbreak of monkeypox in the upper midwestern united states was traced to the importation of infected gambian giant rats. the rats transmitted the disease to prairie dogs; exposure to these rodents resulted in the infection of over people [ ] . in fact, fear among clinicians and refusal to care for infected patients during this outbreak [ ] was one factor leading to the university of nebraska's decision to build its hlcc unit. human monkeypox presents a clinical picture very similar to that of smallpox, albeit with a milder course and lower mortality rate (< %). in addition, monkeypox produces significant generalized lymphadenopathy whereas smallpox does not, perhaps indicative of more effective immune recognition [ ] . it is principally for this reason-the need to rule out smallpox-that we advocate for the management of suspected monkeypox patients under hlcc conditions. monkeypox is transmissible from ptp, and special caution is warranted until such time as smallpox is ruled out. vaccinia vaccine administration appears protective against other orthopoxviruses, including monkeypox, and hlcc unit personnel can thus be protected through immunization. monkeypox should be handled in the laboratory using bsl- precautions. few diseases conjure up images of fear and destruction as vividly as plague. the disease was first described as the cause of a great pandemic that began in egypt in ad. known as the "plague of justinian," it led to the death of - % of the population of europe and is said to have sealed the fate of the eastern roman empire. a second pandemic, known as the "black death," struck europe in and wiped out one-third of the existing population. a third pandemic began in china in and killed at least million. plague, caused by the gram-negative bacillus, yersinia pestis, presents clinically in multiple forms, with bubonic, septicemic, and pneumonic being the most common. bubonic plague is most often contracted by the bite of an infected flea, particularly xenopsylla cheopis, the oriental rat flea; in the united states, prairie dogs often serve as a reservoir. pneumonic plague can be acquired primarily through exposure to infectious droplets (as might be generated by coughing or sneezing) or secondarily following the seeding of the lungs of a septicemic patient. it is this form of the disease that is readily transmissible from ptp. pneumonic plague typically begins following an incubation period of just - days, when patients experience the abrupt onset of high fever, chills, and rapidly developing tachypnea and dyspnea. hemoptysis, a hallmark finding in pneumonic plague, occurs within - h of symptom onset and heralds an almost universal and rapidly impending death. as a bacterial disease, plague is amenable to treatment with antibiotics; aminoglycosides (streptomycin, gentamicin), fluoroquinolones, doxycycline, and chloramphenicol are typically effective but must be started very early in the course of disease. we advocate for the management of patients with pneumonic plague under hlcc conditions due to plague's extreme infectivity, short incubation period, very rapid progression from the onset of symptoms to death, and futility of treatment once patients have become symptomatic. preexposure and postexposure prophylaxis with oral doxycycline or ciprofloxacin may be useful in protecting healthcare workers caring for a plague victim. a licensed vaccine is currently out of production; while it provided some efficacy against bubonic plague, it was ineffective at protecting against disease acquired via inhalation. bsl- controls should be employed by clinical laboratories handling yersinia pestis or specimens potentially containing the organism. tuberculosis (tb) is caused by infection with the bacterium mycobacterium tuberculosis (and occasionally by m. bovis) and has been a scourge of mankind since antiquity. responsible for the deaths of % of adults in eighteenth-century europe, the disease was brought under control with the discovery of streptomycin in and isoniazid in . most isolates of m. tuberculosis remain susceptible to these drugs today and to others such as rifampin, ethambutol, and pyrazinamide. nonetheless, the recent emergence of multi-drug-resistant tb (mdr-tb) strains, defined as having resistance to both isoniazid and rifampin, is a cause for concern given the limited number of effective tuberculocidal drugs available. even more ominous are strains of extensively drug-resistant tb (xdr-tb), defined as having resistance to isoniazid, rifampin, and fluoroquinolones, plus at least one of three "second-line" drugs (kanamycin, amikacin, and capreomycin, all of which are only effective when administered parenterally). patients harboring such strains pose significant treatment challenges and only - % achieve cure. even in cases where treatment is ultimately successful, the period of contagion may be prolonged, and patients may require airborne isolation for many months. one-third of the world's population has tb, although the vast majority of these persons have latent infection and are asymptomatic (and noninfectious). while tuberculous disease may involve lymph nodes, kidneys, spine, bone, and other organs, it is the pulmonary form of tb which is most common among symptomatic patients, however, and the form which poses the greatest risk of ptp transmission. patients with symptomatic pulmonary tb typically present with chronic cough, night sweats, low-grade fever, and weight loss. radiographic findings vary considerably, but often include hilar and paratracheal lymphadenopathy, as well as pulmonary cavitary lesions and upper lobe atelectasis or infiltrates. most patients with pulmonary tuberculosis caused by susceptible strains are readily managed in a negative-pressure isolation room using airborne precautions. we believe, however, that disease due to mdr-tb should prompt consultation with an expert in tb management. we further advocate that disease due to xdr-tb should be considered for management in a hlcc unit; the agent, and clinical specimens potentially containing it, should be handled under bsl- conditions. the list of pathogens that might warrant care under hlcc conditions is short, and the incidence of disease caused by the majority of these pathogens, at least in developed settings, is low. this is fortunate given the very limited capacity to provide such care. while we foresee that this capacity will increase in the coming years, driven in large part by the collaborative efforts of the national ebola training and education center (netec), we expect that their principal benefit will derive from a reexamination and a strengthening of "conventional" infection control practices throughout the healthcare system. while some might call for a more dramatic expansion in hlcc capacity, further additions to the list of diseases managed in hlcc units, or even a return to bsl- -like care, there is reason to proceed cautiously. hlcc, and especially bsl- -like care, is not without disadvantages. the most obvious of these are economic. it is estimated that the average cost incurred by us ebola treatment centers in acquiring hlcc capabilities during the - evd outbreak exceeded $ . million per hospital [ ] . while some of these are one-time investments (e.g., unit construction and planning), others are ongoing operational costs, such as staff training and the maintenance of supply stocks. moreover, the provision of care under hlcc or bsl- -like conditions creates numerous challenges for caregivers: ppe ensembles can be awkward and clumsy and can lead to claustrophobia. they also limit the time that caregivers can spend performing direct patient care activities, and they decrement auditory and tactile sense. all of these factors risk decreasing, rather than improving, patient and provider safety. while intense training and frequent exercising assist in mitigating against these risks in existing hlcc units, they may be impractical on a larger scale. conversely, the management of these hhcds outside the hlcc environment is fraught with hazard. cases have been successfully treated in conventional hospitals when an hlcc setting was unavailable or there was a delay in diagnosis; a woman with undiagnosed marburg virus infection was successfully managed at a community hospital in colorado [ ] . institutional responses to such exigencies have involved modifying policies, adapting infrastructure, and relying on universal standard precautions. such approaches, however, heighten the exposure risk to healthcare workers and can cause critical delays in treatment and laboratory testing. documented nosocomial transmission of many of the aforementioned diseases and high infection rates among healthcare workers during the sars and evd outbreaks reinforce the importance of engineering controls and highly trained staff to provide safe, quality care to patients harboring highly hazardous contagious pathogens. therefore, while these diseases may be managed safely in a conventional facility if absolutely necessary, in most cases transfer to an hlcc unit is warranted to ensure the safety of healthcare workers, other patients, and the general public. in summary, the hlcc unit incorporates a broad range of infection control measures, engineering modifications, and personnel considerations (detailed in another chapter in this text) that differentiate it from the "conventional" negative-pressure hospital isolation ward. these serve to: . protect patients by providing care in a self-contained unit staffed by selected individuals with expertise in critical care and infectious diseases . protect families by removing difficult decisions about visitation . protect other patients from the threat of contagion . protect laboratory personnel handling specimens containing highly hazardous communicable pathogens . protect the community by offering an additional level of safety, surety, and confidence . protect the healthcare worker against nosocomial transmission this latter protection is especially vital given that at least cases of nosocomial ebola occurred during the - west african outbreak [ ] , a risk to clinical personnel - times that of the general population [ ] . a brief history of biocontainment the invisible enemy: a natural history of viruses managing potential laboratory exposure to ebola virus by using a patient biocontainment care unit emory hospital admits lassa fever patient. the emory wheel ebola outbreak in west africa ebola and marburg haemorrhagic fever clinical management of ebola virus disease in the united states and europe fruit bats as reservoirs of ebola virus multi-national prevail ii study team, et al. a randomized controlled trial of zmapp for ebola virus infection efficacy and effectiveness of an rvsvvectored vaccine in preventing ebola virus disease: final results from the guinea ring vaccination, open-label, cluster-randomized trial viral hemorrhagic fever: initial management of suspected and confirmed cases marburg virus infection in nonhuman primates: therapeutic treatment by lipid-encapsulated sirna response to imported case of marburg hemorrhagic fever, the netherlands european network of infectious disease physicians lassa fever in west african sub-region: an overview lassa fever: another threat from west africa lassa fever: effective therapy with ribavirin european centre for disease prevention and control. lassa fever in nigeria clinical features and patient management of lujo hemorrhagic fever viral hemorrhagic fevers and hantavirus infections in the americas antiviral treatment of argentine hemorrhagic fever protective efficacy of a live attenuated vaccine against argentine hemorrhagic fever: ahf study group chapare virus, a newly discovered arenavirus isolated from a fatal hemorrhagic fever case in bolivia centers for disease control and prevention. fatal illness associated with a new world arenavirus-california crimean-congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome, and genetic diversity crimean-congo hemorrhagic fever health care response to cchf in a us soldier and nosocomial transmission to health care providers first confirmed case of crimean-congo haemorrhagic fever in the uk imported crimean-congo hemorrhagic fever european centre for disease prevention and control. crimean-congo haemorrhagic fever in spain outbreak of hendra-like virus-malaysia and singapore, - nipah virus encephalitis reemergence a review of studies on animal reservoirs of the sars coronavirus a curriculum for training healthcare workers in the management of highly infectious diseases the sars epidemic: treatment; beijing hurries to build hospital complex for increasing number of sars patients epidemiology and control of sars in singapore rapid creation of a temporary isolation ward for patients with severe acute respiratory syndrome in taiwan clinical management of severe acute respiratory infections when novel coronavirus is suspected: what to do and what not to do influenza: the mother of all pandemics smallpox as a biological weapon: medical and public health management cidofovir activity against poxvirus infections tecovirimat for smallpox infections human monkeypox update: multistate outbreak of monkeypox-illinois why were doctors afraid to treat rebecca mclester status of human monkeypox: clinical disease, epidemiology, and research initial costs of ebola treatment centers in the united states imported case of marburg hemorrhagic fever-colorado world health organization. health worker infections in guinea world health organization. ebola health worker infections key: cord- -zeok hn authors: biddinger, paul d.; shenoy, erica s. title: evaluation of the person under investigation date: - - journal: bioemergency planning doi: . / - - - - _ sha: doc_id: cord_uid: zeok hn a person under investigation (pui) is defined as a patient who presents with both clinical and epidemiological risk factors for a specific infectious disease. in the case of infectious diseases that present risks of transmission to healthcare workers (hcws) and patients, the use of the identify-isolate-inform framework is essential to protect staff and patients and the delivery of safe and effective care. this includes early identification of puis, institution of appropriate transmission-based precautions including use of specific personal protective equipment (ppe) and isolation, and prompt notification of relevant personnel, including relevant experts and authorities. depending on the specific infection suspected, once appropriate infection control measures have been implemented, clinical evaluation of puis can vary in complexity. in the case of ebola virus disease (evd), the need for specialized ppe and training, well-developed procedures, and dedicated space can be extremely resource-intensive and costly for facilities. in addition, depending upon the need to reduce risks to other patients and hcws, regular laboratory and imaging equipment may not be available (or available at the standard frequency or turnaround time) to support medical care. lastly, diagnostic tests needed to confirm the diagnosis may not be available at the healthcare facility and may instead be accessible through public health authorities. this testing may take several days to confirm the diagnosis or rule out the presence of the suspected infection. thus, the potential period of evaluation for a pui can extend well beyond a typical clinic or emergency department (ed) visit. thoughtful and coordinated planning efforts are required across the community and across the hospital to be able to adequately care for the pui. the ability to detect and diagnose patients infected with a highly hazardous communicable disease (hhcd) must be a priority for healthcare facilities in order to limit the morbidity and mortality of infection and to ensure the safety of staff and other patients through the early initiation of appropriate infection prevention measures. a patient presenting to healthcare facilities with specific clinical and epidemiological risk factors for infection with one of these pathogens may be termed a person under investigation (pui) for the disease, and healthcare staff should utilize carefully developed protocols and procedures to guide their subsequent isolation and clinical evaluation practices until the disease has been ruled in or out. unfortunately, many factors challenge the appropriate early identification and appropriate isolation of puis in practice. these include lack of familiarity with pui definitions and lack of knowledge regarding necessary actions once a pui is suspected or identified. in addition, evolving pui definitions from public health authorities, as well as changes in clinical guidance regarding recommended actions, as can occur with a new or newly emerging pathogen, further complicate pui assessment. inadequate early implementation of appropriate infection prevention measures can have severe consequences, and prior delays have resulted in nosocomial transmission [ ] [ ] [ ] [ ] [ ] [ ] . therefore, rational and thoughtful approaches to identifying, evaluating, and providing care for hhcd puis are essential. healthcare facilities must support vigilance in the suspicion of these diseases and support safe and effective care for all patients. plans developed to support the evaluation of puis must also minimize the potential disruptions to routine facility operations, since puis will most likely outnumber actual confirmed cases, creating substantial operational and economic costs for institutions if not managed efficiently. the identify-isolate-inform framework introduced by the cdc during the - ebola virus disease (evd) outbreak can serve as a basic framework upon which further planning for the evaluation of puis for any hhcd, not just evd, and can be used in any setting [ ] . in this chapter, we will discuss features of pui definitions and their implementation by healthcare providers, the various clinical settings that may be used for evaluation of the pui, an approach to puis using the identify-isolate-inform framework, the specific evaluation and management methods that may be used in evaluating puis, and the clinical and operational challenges encountered during evaluation and management. we will conclude with a look to the ongoing challenges in pui evaluation and areas where future advances in knowledge and policy are needed. evaluation of the pui requires an understanding of each of the factors required to meet the definition. for well-known diseases, the term clinically compatible case [ ] may sometimes be used instead of pui, since formal pui definitions have only typically been developed during more recent outbreaks such as severe acute respiratory syndrome (sars, (sars, - [ ] , middle east respiratory syndrome (mers, -present) [ ] , and evd (during the - west african outbreak) [ ] . when new diseases emerge (such as sars or mers) or reemerge and new information is learned (such as evd), a clear and complete clinical description of the disease may not be completely known. therefore, in such conditions, public health and medical authorities initially develop case definitions to attempt to identify all of the suspect cases in the community according to standardized and current knowledge of the disease. a case definition is a set of uniform criteria used to define a disease for public health surveillance, and the details of the case definition usually form the foundation of the definition of the pui [ ] . case definitions include the demographic risk factors of persons who may have the disease (age, sex, etc.), the locations where exposure may be occurring, the length of the incubation period of the disease, and the symptoms associated with the disease [ ] . a case definition is not equivalent to diagnostic criteria used for a particular disease. instead, a case definition is intended to ensure maximum sensitivity for disease detection and not necessarily for maximum specificity. maintaining current working knowledge with specific pui criteria can be extremely challenging for providers, as the case definition may change frequently as new knowledge is learned about the disease. pui definitions may also be complex and include multiple combinations of risk factors and symptoms to define levels of risk or severity of disease. symptoms and risk factors may be added to or removed from the formal definition as this process evolves. for example, following two cases of mers that were diagnosed in healthcare workers from saudi arabia traveling to the united states, cdc altered its guidance to emphasize testing for mers in persons with mild symptoms but with strong epidemiologic risk factors, including particularly prior healthcare exposure [ ] . in addition, travel to selected countries or regions may also be included or excluded as a risk factor for disease as an outbreak evolves. during , after the emergence of a nosocomial outbreak of mers in south korea, this country was briefly included in the list of countries in the mers pui definition and then was subsequently removed when the outbreak ended. when the case definition changes rapidly, information that was recently shared with staff in lectures, webinars, or emails can quickly become obsolete. unfortunately, it is not uncommon for printed and posted pui criteria to remain in use long after the content is outdated. in the setting of evolving pui definitions, healthcare facilities must focus efforts to encourage patients to identify themselves to staff and to ensure that all those staff who may encounter puis have access to the most current information, know how to access that information, and know how to implement necessary actions when a pui is identified. first, well-placed, clearly written signage in public areas, ambulatory waiting rooms, and ed settings should direct patients to immediately notify specific staff (depending on specific location) if they have either a relevant clinical syndrome (i.e., fever and a cough or fever and a rash) on arrival or if they have traveled internationally during a specified period. the precise time frame for international travel, corresponding to specific infectious incubation periods, will differ based on infection; however a window of travel within the prior weeks will capture the incubation periods of mers, sars, novel avian influenza, and evd and other viral hemorrhagic fevers, which simplifies the message to patients. whenever possible, paper or electronic triage forms should be used to prompt staff to ask arriving patients about epidemiologically important risk factors such as travel at each point of entry to the facility and then document the answers prominently in the medical record. however, while prompts can help to increase clinicians' ability to ask about relevant symptoms compatible with hhcd and epidemiologic risk factors (such as travel), it may be challenging for clinicians to remember if the answers they receive from their patients are actually of concern. this is especially true of travel histories, where clinicians may not know which countries are actively affected by outbreaks. some medical systems have built decision support tools into their electronic medical forms to assist with this challenge and also to guide the subsequent actions a clinician should take whenever a clinical symptom or travel question is answered affirmatively about selected hhcd. four toronto hospitals have described their experience in successfully developing a triage protocol for rapid isolation to limit transmission during the sars outbreak [ ] . the university of nebraska ed evd pui protocol contains electronic prompts which allow for travel screening completed either by a greeter nurse for walk-in patients or by assigned nurse for patients transported by ambulance services. the travel questions include country of travel and time frame. if the travel screen is positive and the patient has a temperature > . °f, two highly visible alerts appear on the screen, providing specific instructions regarding the immediate next steps including patient isolation and consultation with infectious diseases [ , ] . even if decision support tools are not used, providing clinicians with an easily accessible, electronic, expertly maintained list of current infectious diseases of high concern, plus a list, the relevant geographic and other exposure risk factors for each disease can be of tremendous value [ ] . such a list could be curated by hospital infectious diseases or infection prevention staff, local or state public health officials, or others and could be hosted on a local intranet page. clinical leaders should also consider how they may better direct staff to access expert websites such as that of the cdc, since such sites can sometimes be challenging to navigate for the infrequent user. quick links built into the electronic medical record (emr) with bookmarks of relevant internal and/or external website pages related to pui criteria may be helpful to clinicians and speed their access to relevant information. in addition to building robust electronic aids into providers' common clinical workflows that can facilitate improving providers' identification of puis, it is also essential that frontline clinicians clearly know how to access expert local decisionmakers when deciding whether a person meets pui criteria. such experts may be infectious disease consultants from the institution where the clinicians work, or a nearby community or tertiary care hospital (if such remote consultation services have been arranged), or may be local or state health department officials. these expert opinions are indispensable to help make the correct determination of whether a patient actually meets pui criteria. for both patients and staff, in the absence of an ongoing major outbreak during which public attention is highly focused on a specific disease, facilities need to address the challenges of waning interest and vigilance that are likely to occur. during these periods, the continual use of updated signage in public areas, conduct of periodic educational activities, and increasing use of clinical decision support and other types of prompts within the emr are needed to maintain a consistent level of readiness. puis may be identified, and potentially assessed, in several different types of clinical environments. the first environment, which is safest for limiting subsequent disease transmission to others, is telephone or internet triage. through a remote medical encounter, patients may describe their symptoms to a nurse or other medical provider through a phone conversation, a website questionnaire, or a remote home visit, and it can likely be quickly determined if the patient meets pui criteria with the required combination of symptoms and exposure risk factors. if the patient does not meet pui criteria, then his or her triage may be continued as normal. if, however, the patient does meet pui criteria, then she or he may be directed to a safe portal of entry at an appropriate nearby clinical site for further evaluation and care without unnecessarily exposing other people in a waiting room or other public setting. if ems is required to help transport the patient to the clinical site, they should be alerted so that they can don the appropriate personal protective equipment (ppe) for transport to limit their own risks of exposure to the disease. in order for this process to be effective, telephone triage staff and providers must have ready access to the most current case definition and pui criteria. puis may also present in person to a primary care or urgent care office. primary and urgent care clinics are unlikely to have on-site subject matter expertise in infectious diseases or infection prevention, making the establishment of simple, sustainable protocols essential. these should include ( ) use and maintenance of clearly visible signage for arriving patients to instruct them to quickly identify themselves if they have concerning symptoms or risk factors, such as travel, and ( ) training of staff who are able to quickly take action (especially including isolation of the patient) should a patient either self-identify with risk factors for an hhcd or be identified as such during triage. in the case of many of the diseases discussed here (mers, sars, novel avian influenza), placement in an airborne infection isolation (aii, "negative pressure") room is required as soon as possible. however, since many ambulatory care settings will not have access to aii rooms, in these cases it is recommended to offer the patient a mask, instruct them to put the mask on, and then direct them to a private exam room with a closed door. after the patient has been safely isolated, senior clinic staff must be notified and must contact appropriate subject matter experts for direction on next steps including ( ) whether (based on information already available) the patient meets pui criteria or if additional information is required; ( ) if the latter, direction on the safe use of ppe and distancing from the patient; ( ) advice on what types of care can safely be provided in that setting for patients confirmed as puis; and ( ) instructions on transferring the patient to another more appropriate location for further clinical evaluation and management if deemed necessary. as with primary care and urgent care settings, emergency departments must also be able to identify and isolate patients with infectious diseases, who may arrive as walk-ins, referrals from local primary care or urgent care offices, or by ambulance. transferring facilities or clinicians should contact the receiving emergency department staff prior to sending a pui to ensure appropriate isolation space is available, that the patient is immediately taken to the isolation space in a route that is least likely to expose others, and that staff don the appropriate ppe to protect themselves. further, at the time of transferring a pui, local public health authorities must be involved in the decision in order to provide expertise as well as logistical and communications support. once the patient has been confirmed to meet pui criteria and appropriate infectious disease and/or public health experts have been notified, the patient will require transport to an ed capable of fully evaluating the patient (if the patient is not already located in such an ed). for many outpatient practices and clinics, this may be a local ed or perhaps a regional ed. no matter which ed is chosen, it should be assured that they have appropriate plans and resources available to safely clinically evaluate the pui. in some regions, the selection of the receiving ed is made jointly between the transferring hospital/clinic and public health officials. in other regions, the decision is left solely to the transferring providers. no matter how the decision process is conducted, protocols for the safe transfer of puis to the correct clinical setting must be developed in advance and exercised. this means that primary and urgent care centers should have formal plans for transfer of puis to an appropriate ed in their area. in addition, the ems services and receiving eds involved in these plans should be fully aware of the plans and their roles within them. community eds without the capabilities for evaluating puis should have similarly established relationships and plans in place to transfer puis to predesignated regional tertiary care centers. ems must be made aware of the suspected infectious disease when planning a transfer, so that their staff is able to utilize appropriate ppe and other infection control precautions. receiving hospitals and their surrounding ems services should meet to review plans for supporting doffing of ppe by emts and paramedics, for management of waste generated in transit, and for the procedures to be used to clean the ambulance and return it to service. while arrangements are being made to transfer the patient, appropriate infection control precautions must be maintained. personnel should avoid unnecessary contact with the pui, and all personnel should wear appropriate ppe if they must be near the pui. selection of ppe for clinical staff should be selected based on the known (or suspected) routes of transmission for the suspected infection and the resources available. it is not realistic to expect all ambulatory clinics to stock and for staff to maintain proficiency in the correct and consistent use of ppe required in the long-term care of patients for specific infectious diseases such as evd; however, in the setting of a clinically stable patient, staff should be expected to safely don and doff ppe appropriate for limited patient contact. this may include impermeable gown, n respirator, gloves, and face shield. all personnel who wear ppe in this setting must have been previously properly trained to do so. when the patient is transferred out of the sending facility, the path that ems personnel will travel out of the clinic should be cleared of other patients, visitors, and other medical personnel to reduce potential exposures. after the patient leaves the facility, the patient care area should be cleaned using preexisting protocols created with input from infection control and public health authorities. depending on the specific infection suspected, the clinical evaluation of the pui can range from being relatively straightforward to being extraordinarily complex. in , one hospital's experiences in evaluating ebola virus disease (evd) puis were summarized as the following: . staff was unfamiliar with donning, doffing, and working in personal protective equipment (ppe) appropriate for care of these patients and therefore was apprehensive about their roles. . disproportionate space in clinical areas had to be dedicated exclusively to isolation and care of puis, decreasing overall ed capacity. . presence of puis in the ed was highly disruptive as the spectacle of cordonedoff spaces and staff in ppe could not be disguised, and large numbers of ancillary personnel congregated in the vicinity of the patient. . patients fearing for their own and family members' safety left the ed waiting area and avoided hospital facilities known to have evd or puis present. . the intrusiveness of the media imposed access and flow problems and made it very difficult to protect the identities and protected health information of the puis [ ] . other challenges in the evaluation of the pui have been documented as well. indeed, during the - evd outbreak in west africa, initiation of even basic lab testing and radiologic studies was delayed by - days in some cases for puis in us hospitals, and it was observed that some patients who were puis for evd had poor outcomes because the concern for evd infection negatively influenced their clinical evaluation and care [ , ] . lastly, because the definitive diagnostic tests needed to confirm the presence of hhcd infection may not be available at many hospitals and clinics, and may also take days to confirm or rule out the presence of the suspected infection, the potential period of evaluation for a pui can extend well beyond a typical clinic or ed visit, further taxing the healthcare system. hospitals must carefully select and prepare the most appropriate location for managing puis, ideally well in advance of being asked to care for such a patient. some hospitals choose to evaluate their puis in an ed treatment area, while others use a separate, specialized, inpatient, or other isolation area. when a site within the ed is chosen, there are a few questions that are especially worthy of consideration for planning purposes. first, is the room appropriate to support the care of a patient-is the room aii and is there a private bathroom (or other appropriate individual toileting procedure) available? second, does the location of the room (or rooms, if multiple rooms will be used) support both safe entry of clean clinical personnel into the room and safe exit for contaminated clinical personnel? additionally, does the space have a clearly demarcated area for doffing of ppe? one advantageous practice that has been observed is to select a room (or to modify an existing room) that has a separate entrance and exit, so that contaminated staff will not traverse the clean entrance to the room when exiting. third, is the room in a location within the ed where its use for evaluation of the pui will not excessively disrupt other ed activities? evaluation of the pui can be a labor-and material-intensive process, creating congestion as well as visible distractions for other patients and staff. therefore, it is advisable, when possible, to choose a room to evaluate puis that is located away from the center of the ed to minimize interference to the other important ongoing ed activities and use physical barriers when possible to reduce disruption to routine care. some facilities plan to keep puis in their ed room only until the initial assessment and first round of testing is completed, while other facilities plan to keep their puis in the ed room until the diagnosis has been definitively ruled in or out, which can potentially take several days (up to days in the case of evd). if it is anticipated that the patient will be required to remain in the room for more than a few hours, plans must consider how both medical waste will safely be removed from the room. waste management procedures for the pui must follow the same protocols as for a confirmed patient until the disease is ruled out. if specialized disposal of the waste prior to confirmation of disease is cost-prohibitive for the facility, they must have plans to safely store and secure the waste while awaiting confirmation. one hospital has described the successful use of a portable facility they named a "mobile containment unit" to limit the impact of pui needs on the main ed while supporting safe patient care [ ] . a planning team consisting of an emergency department physician, ed nurse, infectious diseases physician, infection preventionist, facilities manager, and laboratory leadership (at a minimum) should convene to review these questions and begin planning their use of space for pui evaluation. the team may also wish to explore the utility of video teleconferencing capabilities in the room, which can limit entry to only essential caregivers, allowing others, such as consultants, public health officials, and family members, to remain outside the patient care environment. all unnecessary medical equipment and materials should be removed from the room prior to admission of a pui, leaving only those supplies that will assist with the care and evaluation of the patient. this may include specialized medical equipment, such as a disposable stethoscope or electronic stethoscope, ultrasound machine, or other diagnostic equipment, as well as cleaning supplies and solidification agents for liquid waste if deemed necessary. biomedical waste receptacles should also be placed in the room. all of the room preparation activities should be guided by the use of predeveloped and exercised checklists, which can ensure that the room and staff are properly prepared to care for the pui. once the pui has arrived in the appropriate clinical location for evaluation, two important parallel processes must begin. the first is to ensure that the patient receives appropriate medical evaluation and care. the second is to undertake the appropriate diagnostic testing to establish a diagnosis. because the pui may have immediate medical needs, the receiving clinical facility must be able to provide stabilizing medical care to the patient if necessary, including airway and respiratory support, venous access, and administration of intravenous fluids, parenteral antibiotics, and vasopressor support. the cdc requires that hospitals designated by their states as assessment hospitals for evd must be able to appropriately manage puis, undertaking the necessary diagnostic assays to ensure that other causes of fever (i.e., malaria) are identified and treated in a timely manner [ ] . it is important to note that in one hospital's experience, % of puis who did not ultimately have the hhcd infection suspected did have a life-threatening alternative diagnosis [ ] . receiving facilities must ensure that clinical staff is properly trained to don and doff the necessary ppe in order to provide routine and stabilizing clinical care. in order to do this, hospitals must establish regular training schedules that allow providers to demonstrate proficiency in donning and doffing ppe as well as provide clinical care, manage waste, and obtain laboratory studies according to hospital protocols. the range of specific resuscitative and potentially invasive medical services and procedures that will be offered to a pui before the specific hhcd is ruled out is a highly challenging decision and is one that should be approached carefully. hospital administrative, medical, legal, and ethical leaders must consider whether they will be able to offer surgical operations (including cesarean sections), hemodialysis, endoscopy, or other procedures that present elevated risks to staff and the facility. these decisions should be made prospectively as part of the hospital planning and preparedness program. if challenging care decisions arise during the care of a specific pui, an appropriate leadership team should be able to assemble immediately to ensure a fully informed decision-making process. if a specific necessary procedure is not available at the hospital assessing the pui, public health officials may assist in determining if it may be available elsewhere, such as at one of the ten regional ebola and other special pathogen treatment centers (resptcs) in the united states [ ] . laboratory testing for puis may be extremely challenging and requires extensive preplanning in order to support clinical care and establish the diagnosis of specific hhcds. prior to the - evd outbreak, federal guidance stated that all lab testing on patients suspected to have certain highly infectious pathogens (such as evd) could only be performed in a biosafety level (bsl)- laboratory, while most hospitals only have bsl- laboratory facilities. although the cdc provided guidance during the evd epidemic that was intended to permit appropriate clinical testing outside of bsl- labs, these changes were not accepted by many. many laboratory leaders were concerned about staff safety and impact on use of equipment for routine laboratory studies after processing a sample that could contain evd [ ] . therefore, clinical and laboratory leaders must jointly decide on the basic menu of laboratory tests to support and to ensure adequate clinical care of the patient with the resources available. some hospitals have elected to rely on bedside point-of-care testing devices to support much of this need, as the devices eliminate the need to utilize the large, automated laboratory machines. because malaria is commonly in the differential diagnosis for many puis for evd or other viral hemorrhagic fever, it is important that the hospital have a mechanism for testing for malaria as part of the basic clinical evaluation. to limit the potential spread of biological contamination outside of the patient's room, special procedures must be developed to properly clean and package blood and other biological samples before they leave the room for transport to the hospital lab. testing for the pathogen of concern is likely to be coordinated through the state public health laboratory. while commercial assays are available for some of these pathogens, public health laboratories will assist in confirmation of the diagnosis or excluding the diagnosis. hospital staff must be trained and certified in packaging of specimens for transport to state laboratories. radiographic imaging is an essential component of the evaluation of most febrile patients. whenever possible, bedside ultrasound is the imaging modality of choice, since it does not require the patient to leave the room and can be interpreted immediately. portable x-ray imaging can also be used, but may require the use of special protective covers for the machine and the cassette [ ] . the decision about whether to offer additional advanced imaging services, such as ct or mri, depends on variables such as the specific infectivity and transmission of the infectious disease for which the patient is being evaluated. if there is concern about the hospital's ability to offer such imaging services, a multidisciplinary committee, such as the one used to determine the medical and surgical procedures that can be offered, should be utilized. if the patient is to be transported to an imaging area within the hospital, or to any other area of the hospital, the clinical staff must have a protocol to determine in advance the safest method of doing so. the decision to transport the patient for this purpose should be made by clinical leadership with all relevant parties involved, weighing the risks and benefits of movement of the patient outside of the area of isolation. hospitals should plan to be able to clear the corridors and elevators of patients, visitors, and others during patient transport when needed and must also have plans in place to decontaminate the transport corridors if necessary following an unintended spill or other event. the selection and crossmatching of blood products is challenging, because most current practices require use of open blood tubes. some programs may choose to utilize uncrossmatched type o blood to avoid this risk when transfusion of red blood cells is needed, though others have successfully used a manual slide agglutination test for blood typing as well [ ] . hospitals should also plan for special social and legal circumstances that may arise when evaluating the pui. hospitals should anticipate how and where they will screen and care for any family members or others who are transported with the pui to their facility. hospitals should also consider how they will plan to support the parents and families of pediatric puis and whether they can or cannot safely permit family members to stay with a young pui (or any other pui) during his or her evaluation [ ] . hospitals should have the ability to utilize language translation services in the area where the pui assessment occurs. additionally, hospitals should anticipate how they will respond in the event that a pui does not wish to comply with the recommended evaluation and/or wants to leave the facility. the university of nebraska medical center has developed a protocol for the noncompliant puis [ ] . their protocol was developed following a joint meeting with local law enforcement, public health officials, hospital security, risk management, and ed and hospital leadership. hospitals should also consider how they will support all of these efforts if they receive more than a single pui at the same time. ensuring the availability of appropriate space and trained staff, as well as all of the other tremendous resources required for multiple puis, may seem insurmountable but nonetheless requires forethought and planning. facilities may wish to consider engaging their neighboring hospitals and their public health partners in crafting plans for these efforts. the use of the identify-isolate-inform framework is essential when patients present to healthcare facilities with symptoms and exposure risk factors of hhcds. identification of these patients as early as possible in their presentation, institution of appropriate transmission-based precautions including use of specific ppe and isolation, and prompt notification of relevant experts and authorities are all essential actions in the care for puis with hhcds. because the potential period of evaluation for a pui to rule in or rule out disease can extend well beyond a typical clinic or ed visit, thoughtful and coordinated planning efforts are required across the hospital and across the community to be able to adequately care for the pui. mers-cov outbreak following a single patient exposure in an emergency room in south korea: an epidemiological outbreak study sars outbreak in the greater toronto area: the emergency department experience epidemiologic study and containment of a nosocomial outbreak of severe acute respiratory syndrome in a medical center in kaohsiung factors associated with transmission of severe acute respiratory syndrome among health-care workers in singapore ebola virus disease cluster in the united states active tracing and monitoring of contacts associated with the first cluster of ebola in the united states identify, isolate, inform: background and considerations for ebola virus disease preparedness in u.s. ambulatory care settings key terms used in case classifications clinical guidance on the identification and evaluation of possible sars-cov disease among persons presenting with community-acquired illness (version ): centers for disease control and prevention interim patient under investigation (pui) guidance and case definitions case definition for ebola virus disease (evd): centers for disease control and prevention outbreak case definitions: centers for disease control and prevention evaluation of patients under investigation for mers-cov infection ebola triage algorithm: a tool and process for compliance emergency department processes for the evaluation and management of persons under investigation for ebola virus disease a highly infectious disease care network within the united states healthcare system patients under investigation for ebola virus disease in the united states: hospital preparedness planning and alternate care facilities early identification and prevention of the spread of ebola -united states clinical inquiries regarding ebola virus disease received by cdc-united states development and use of mobile containment units for the evaluation and treatment of potential ebola virus disease patients in a united states hospital institutional preparedness to prevent future middle east respiratory syndrome coronavirus-like outbreaks in republic of korea ebola or not? evaluating the ill traveler from ebola-affected countries in west africa committee on infectious diesease. parental presence during treatment of ebola or other highly consequential infection key: cord- -fv n v authors: hewlett, angela; vasa, angela m.; cieslak, theodore j.; lowe, john j.; schwedhelm, shelly title: viral hemorrhagic fever preparedness date: - - journal: infection prevention doi: . / - - - - _ sha: doc_id: cord_uid: fv n v the – outbreak of ebola virus disease (evd) in west africa marked the th such occurrence but was noteworthy in its massive scope, causing more human morbidity and mortality than the previous recorded outbreaks combined. as of april , there were , cases resulting in at least , deaths, nearly all in the three nations of guinea, liberia, and sierra leone (centers for disease control and prevention. http://www.cdc.gov/vhf/ebola/outbreaks/ -west-africa/index.html. accessed june ). moreover, the – outbreak was the first in which patients, albeit few in number, were afforded sophisticated intensive care in the united states and in europe. this “high-level containment care” (hlcc) was provided in specially designed purpose-built biocontainment units (bcus). in this chapter, we explore the history and evolution of biocontainment, discuss its unique engineering and infection control modalities, and offer recommendations for the clinical and operational management of ebola and other viral hemorrhagic fevers (vhfs). the - outbreak of ebola virus disease (evd) in west africa marked the th such occurrence but was noteworthy in its massive scope, causing more human morbidity and mortality than the previous recorded outbreaks combined. as of april , there were , cases resulting in at least , deaths, nearly all in the three nations of guinea, liberia, and sierra leone [ ] . moreover, the - outbreak was the first in which patients, albeit few in number, were afforded sophisticated intensive care in the united states and in europe. this "high-level containment care" (hlcc) was provided in specially designed purpose-built biocontainment units (bcus). in this chapter, we explore the history and evolution of biocontainment, discuss its unique engineering and infection control modalities, and offer recommendations for the clinical and operational management of ebola and other viral hemorrhagic fevers (vhfs). the modern concept of biocontainment had its birth in with the convergence of four separate events. in may of that year, michael crichton published the andromeda strain, and, while the work was clearly fictional, it debuted amidst a series of discussions leading up to president nixon's decision in november of that year to abandon the us offensive biological weapons program. nixon's decision was a prelude to ratification of the biological weapons convention and to the us ratification, in , of the geneva protocols. at the time, nixon stated that "the united states has decided to destroy its entire stockpile of biological agents and confine its future biological research program to defensive measures." implicit in that decision was a shift in the focus of us efforts to defensive and medical countermeasure development that would include an emphasis on the management of patients potentially infected with highly hazardous human pathogens. this medical defense program would fall largely upon the newly created us army medical research institute of infectious diseases (usamriid), an entity which would inherit its defensive mission from the old army biological laboratory (abl). the year also witnessed the discovery of lassa virus by dr. jordi casals-ariet at yale university [ ] . while attempting to characterize the new virus, dr. casals contracted lassa fever himself and fell critically ill but survived following the administration of convalescent serum from one of his patients. unfortunately, one of his technicians, juan roman, succumbed to the disease while conducting laboratory studies, causing dr. casals to move his research to a new maximum-security laboratory at the communicable disease center in atlanta (now the centers for disease control and prevention) and ushering in a new era of laboratory safety. finally, saw man's first journey to the moon, aboard apollo . in order to guard against the remote possibility that extraterrestrial pathogens might inadvertently accompany the returning astronauts, a new facility, the lunar receiving laboratory (lrl), was constructed, in consultation with abl experts, at the johnson manned spaceflight center in houston. the facility would receive spacecraft, equipment, and lunar samples from apollo and from future apollo missions. moreover, it would serve as a quarantine facility for the returning astronauts from the apollo , , and missions. included among the assets of the usamriid facility was a novel two-bed high-level containment care unit [ ] . this unit, often referred to as "the slammer," presumably owing to the sound produced by the closure of its heavy steel airlock doors, opened in and included engineering controls analogous to those employed in biosafety level (bsl- ) laboratories. the facility was designed to treat infected patients but also to provide confidence and a sense of security to scientists and to the community of frederick, maryland, in which it was located. during the period - , individuals were admitted to the slammer following laboratory or field exposure to a variety of bsl- pathogens [ ] . a st patient (exposed to ebola in the laboratory) was admitted in [ ] . of note, none of the patients developed clinical evidence of infection. the slammer was decommissioned in ; a new usamriid building, slated to open in , will not house a containment care unit. the intentional dissemination of anthrax via contaminated mail in october , occurring just weeks after the world trade center assault and, ironically, attributed to a troubled usamriid scientist, convinced some civilian experts to move in the opposite direction and propose the creation of academic medical center-based hlcc facilities. outbreaks of severe acute respiratory syndrome (sars) and monkeypox in the spring of added impetus to these construction projects, sars because of its high mortality and apparent transmission via droplet nuclei and monkeypox owing to a resistance among fearful healthcare providers to treat victims of the disease [ ] . during - , a two-bed facility at emory university in atlanta and a ten-bed facility at the university of nebraska medical center in omaha opened; the facilities employed some (but not all) of the engineering controls contained within the usamriid facility. in , leaders from these facilities, as well as usamriid and the centers for disease control and prevention (cdc), published consensus guidelines for the employment of hlcc units [ ] . in that same year, the national institute of allergy and infectious diseases (niaid) contracted with saint patrick hospital in missoula mt to construct the first hlcc unit housed outside of a large university-based medical center in order to care for scientists exposed to bsl- and bsl- pathogens at the niaid's rocky mountain laboratories in nearby hamilton [ ] . as of this writing, no patients have been cared for in this facility. in , the special clinical studies unit at the national institutes of health adapted its seven-bed clinical research unit in order to provide hlcc. this facility, along with those at emory and nebraska, cared for of the victims of the - west african ebola outbreak managed in the united states. one patient was managed under hlcc conditions at bellevue hospital in new york, and one patient was managed at dallas presbyterian hospital. germany possesses seven hlcc facilities, four of which cared for evd victims during the - west african outbreak. some of these units have experience in treating patients infected with marburg and lassa viruses as well. biocontainment units in britain, france, spain, the netherlands, norway, switzerland, and italy also successfully cared for expatriate patients during the recent evd outbreak, and european nations have been pioneers in the development of hlcc doctrine [ , ] . finally, china, at the height of the sars outbreak in , constructed a bed infectious disease treatment facility equipped with engineering controls designed to ameliorate the risk of airborne transmission of the sars coronavirus [ ] . other nations in the region, such as singapore and south korea, are constructing hlcc facilities as well. the viral hemorrhagic fevers (vhfs) are caused by a heterogeneous group of viruses belonging to four taxonomic families and include: -the filoviruses, ebola, and marburg -the arenaviruses, which can be divided into old world (lassa) and new world (guanarito, junin, machupo, sabia) agents, the latter causing venezuelan, argentinian, bolivian, and brazilian hemorrhagic fevers, respectively -the flaviruses, yellow fever, dengue, kyasanur forest, and omsk -the bunyaviruses, crimean-congo hemorrhagic fever (cchf), rift valley fever (rvf), and a number of hantaviruses which cause hemorrhagic fever with renal syndrome (hfrs; hantaan, dobrova, seoul, and puumala) yellow fever has been known since at least ; is distributed throughout tropical africa, asia, and south america; and was the first disease shown, by walter reed, to be transmitted by mosquitos [ ] . the remaining vhfs have, for the most part, been discovered within the last half-century and remain quite limited in their geographic distributions. although the vhf viruses share certain microbiologic characteristics (all are lipid-enveloped single-stranded rna viruses) and derive their name from the fact that some (but not all) patients experience clinically significant hemorrhage, they produce a diverse array of clinical symptoms and vary widely in their virulence. while massive hemorrhage occurs frequently with new world arenaviral infections, as well as rvf, cchf, certain hantaviruses, and yellow fever, it occurs less frequently with infections due to the filoviruses and rarely in lassa infections. renal failure is characteristic of hfrs and yellow fever but otherwise rare. rash is seen with dengue, lassa, and filovirus infections, but not with most other vhfs. icterus is prominent with yellow fever; tremors with the new world arenaviruses; deafness with lassa. pulmonary disease is prominent with kyasanur forest and omsk, as well as with certain hantaviruses. in addition, laboratory findings vary considerably among the vhfs. new world arenaviral infections characteristically cause a profound leukopenia, while hfrs patients often exhibit significant leukocytosis. thrombocytopenia can be marked in most vhfs but is usually not a prominent feature of lassa fever. these notable differences in presentation and symptomatology have implications for clinical care and infection control. the prodigious amount of vomiting and diarrhea seen in patients during the - evd outbreak, coupled with the very low infectious dose and high quantity of viral particles within these bodily fluids, makes meticulous attention to personal protection imperative. guidelines for the employment of such protection, as well as engineering and other controls, provide the basis for the remainder of this chapter. it is important to note that the causative agents of most vhfs need be handled under biosafety level (bsl- ) conditions in the laboratory [ ] . exceptions include yellow fever, rvf, and the hantaviruses, which require bsl- precautions. patients harboring any of these agents that present the risk of person-to-person transmission ideally should be managed under hlcc conditions. these agents would include the hantaviruses, as well all of the bsl- agents except rvf, kyasanur forest, and omsk viruses, which are transmitted to humans only via the bite of infected arthropods. high-level containment care facilities include enhanced engineering controls with the goal of providing safe and effective care to patients while optimizing infection prevention and control procedures [ ] . two [ , ] . however, formal standards for hlcc facility design features have not been established. the design of a hlcc unit should serve to minimize nosocomial transmission of infectious diseases by establishing a contained clinical isolation unit capable of housing all facets of patient care. hallmark hlcc engineering controls include care units that are physically separated from normal patient care spaces and maintained at negative pressure by independent air handling systems. at least air exchanges per hour in patient rooms are accomplished using dedicated exhaust systems with high efficiency particulate air (hepa)-filtered effluent air. it is recommended that pressure status of patient care rooms be monitored with audible and visual alarms [ , ] . individual patient care rooms should have the equipment necessary to support critically ill patients, self-closing doors, and handwashing sinks [ ] . it is important to have established zones for employee donning and doffing, storage of personal protective equipment (ppe), and staff shower-out capability [ ] . additionally, selection of nonporous and seamless construction materials is an ideal design component of hlccs that both minimizes the risk of environmental contamination and maximizes the ability to clean surfaces when contaminated. hlcc units should delineate high-risk areas ("hot" or "red" zones: patient room, laboratory), intermediate-risk areas ("warm" or "yellow" zones: anteroom, decontamination area, waste processing, doffing), and low-risk areas ("cold" or "green" zones: nurse station, clean supply room, staff egress changing area). establishment of these designated zones guides healthcare worker flow as well as implementation of protocols for cleaning, packaging of waste or clinical specimens, and decontamination of medical devices, reducing the potential for contamination as personnel and devices move through the hlcc. inclusion of laboratory and waste sterilization capabilities within hlcc units are also key features that help minimize the potential of transmission throughout the hospital [ , ] . a double door pass through autoclave was identified as mandatory for hlcc unit through both consensus efforts [ , ] . analogous pass through "dunk tanks" filled with disinfectant solution is useful in moving specimens from the hlcc to the laboratory and is particularly useful in facilities which lack a dedicated "in-unit" laboratory. implementation of telehealth strategies that enable communication with healthcare workers as well as provide a platform for remote patient assessment is important in reducing the number of healthcare workers with direct patient contact, thus limiting risk. the intermittent and sporadic utilization of hlcc units necessitates strong leadership. ideally, a hlcc leadership team should possess a robust set of diverse skills to include expertise in infectious disease and critical care, nursing, emergency management, industrial and environmental hygiene, research, laboratory, hospital administration, and public affairs. this leadership team should meet regularly to strategize and define drill objectives, plan educational efforts, promote research projects, and synchronize collaborative endeavors [ ] . a robust activation checklist should be developed and drilled intermittently to assure that departments followed through on tasks assigned and that necessary items can be obtained in a timely fashion. this checklist should address unit stockage and supplies, equipment, medications, facilities activation procedures, and notification of departments and key individuals who will be involved in the activation of the unit and the care of the patient(s). numerous communication strategies are adaptable for use by hlcc team members. an electronic alert system with individual key numbers can be used to notify the hlcc team of drills and activation. an email distribution list can be used for less urgent information sharing. in order to organize the response for arriving patients, a modified hospital incident command system (hics) can be utilized, and the incident commander (ic) can support hlcc leaders in completing the activation checklist. moreover, the ic can facilitate coordination among the multiple agencies often involved in air and ground transport of patients to the patient care unit. although each facility may wish to tailor the composition of the hics team to their own particular needs, and each situation may require adjustment, key team members would typically include logisticians to plan to replenish ppe supply levels and address waste management issues, a public information officer (pio), medical technical specialists to include infectious disease physicians and nurse leaders to manage the clinical care of the patient and staffing within the patient care unit, a laboratorian to address testing logistics and specimen transport challenges, a clinical research expert to facilitate the use of experimental therapies when necessary, a nurse concierge or other dedicated individual to support family needs, and a behavioral health expert to address staff well-being as well as the psychological and emotional needs of patients and families. the pio is charged with responding to media requests, including those from social media sources. internal messaging within the organization should be done prior to release of any external information. internal messaging may be directed at administration, employees, and also patients (inpatients and outpatients) and their family members. press conferences with infectious diseases experts and others involved in patient care should be held to provide timely updates. it is also helpful to establish an information phone line staffed by the state or local health department to answer questions and provide education to the community. during activation, a concierge nurse or other patient advocate may prove helpful in the support of families of patients. this individual can assist by making advance contact with family members and arranging services such as airport transportation, accommodations, and meals. they can also serve as the liaison with family in the coordination of meetings to discuss the status of the patient, media information, and various other details. pastoral care staff should be available upon request during activation. the hlcc facilities in the united states that admitted patients infected with ebola virus disease (evd) have well developed teams of nurses who are able to provide skilled and effective patient care within their isolation units. recruiting and retaining qualified nursing staff willing and able to provide care for patients under emotionally and physically demanding hlcc conditions is the cornerstone to building a successful team. the staffing model must take into account the need for specialized nurses to provide quality care. the virulence of the disease in question, its mortality rate, the advanced levels of ppe required, and the propensity for infected patients to require complex interventions all influence the profile of staff selected to care for patients with vhf or other highly hazardous communicable diseases. the composition of the hlcc nursing team should reflect these needs. the centers in the united states that provided care for evd patients each required that a percentage of their core nursing staff possess critical care experience, with some institutions relying solely upon critical care nurses to staff their units [ ] . in addition to critical care experience, it is essential to have nurses on the core team who have expertise in infectious diseases and have expressed an interest in caring for patients with highly hazardous communicable diseases [ ] . the success of the nursing staff starts with a robust selection process. utilizing a formal interview process to determine qualifications and interest has been proven to be an effective method of selecting staff. once the interview is complete, the nursing leadership should contact the employee's current manager to discuss their clinical skills, teamwork skills, adaptability, dependability, and critical thinking skills. when staffing a unit that is only activated intermittently, an important consideration involves creating a process by which staff members can designate their availability on any given day. this can be accomplished in a multitude of ways; however, maintaining a consistent process is key to ensuring staff availability when needed. as the provision of nursing care must occur h a day, days a week, it is important that a schedule be created that accounts for all times. one way to achieve this is to mandate on-call shifts for dedicated staff. the on-call nurses are required to be at the unit within min of being notified of activation. another option is to have each staff member fill out their availability and maintain a balanced schedule several weeks in advance. this allows staff members a level of autonomy to self-schedule. considerations for creating a nursing staff matrix include the design of the unit, the waste management strategy, the disease being treated, the acuity of the patient, the level of personal protective equipment (ppe) required, and the time that could be spent in the ppe [ , ] . an important consideration is the need to minimize the number of staff that enters into the patient care area. the ability to utilize nursing staff in multiple roles can facilitate effective infection control by minimizing the footprint within potentially contaminated areas. in this effort, nursing staff become responsible for tasks that would typically be assigned to ancillary services within the standard hospital system, including routine cleaning and environmental services, phlebotomy, coordinating care needs, and unit clerk roles [ , ] . consideration must also be given to the nurse-to-patient ratio necessary to provide safe care to a patient with vhf. the number of staff members required for a standard h nursing shift must take into account the time limitations imposed on each staff member due to the use of advanced ppe. when providing the level of intensive care that these patients can require in addition to wearing ppe, it is necessary to adjust shift times and staffing ratios [ ] . the staffing matrix utilized within hospitals that successfully cared for evd patients differed significantly from standard staffing ratios. within the nebraska biocontainment unit, six staff members were present on a day shift and five on the night shift (usually three nurses along with respiratory therapists and/or patient care technicians). healthcare staff was scheduled for h shifts which were broken up into h blocks to allow for the limitation of not wearing ppe for greater than - h at a time. designation of roles for each staff member on each shift can clarify expectations and ensure consistency within each role. the use of an autoclave for waste processing may necessitate the inclusion of a dedicated staff member to operate the machine. the special communicable diseases unit (scdu) at emory university utilized two to three nurses to staff the unit at all times when occupied, and it was recommended that nurses remove ("doff") ppe every h to allow for personal needs and a break. at the highest level of ppe and patient care, three nurses were working in the scdu at one time, in -h shifts. they rotated in -h shifts between the patient room, the anteroom, and the nursing desk with each having designated responsibilities [ ] . within each treatment facility, there are unique circumstances which will dictate the most efficient and safe nursing staffing practices. it is important to consider both staff safety and patient safety when determining which guidelines will be used to operate a unit caring for patients with vhf or other highly hazardous communicable infectious disease. nurses that join these teams must be individuals able to operate outside their normal routine by utilizing critical thinking skills, flexibility, and autonomy. these nurses are required to take responsibility for a wide array of clinical and nonclinical tasks and perform these in demanding clinical situations, which are skills that require practice, exceptional communication, and teamwork. caring for patients with highly hazardous communicable diseases is a true multidisciplinary effort, and choosing and maintaining an effective physician team illustrates this concept well. each center should tailor their physician team to fit their needs and the culture of the facility. in general, infectious diseases specialists have often led physician teams in the biocontainment setting; however this may not be appropriate in every facility. infectious diseases specialists monitor and manage infectious complications and coinfections and oversee the administration of antimicrobial agents, including experimental products. specialists in critical care medicine are an important asset in the care of patients with vhf, since some of these patients may have critical illness and require icu-level care, including mechanical ventilation, vasopressors, and other supportive care measures [ ] . since invasive procedures are often necessary as well, it is critical to ensure that the physician team includes individuals who are experienced and comfortable performing these procedures. this skillset should be assessed by direct consultation with these physicians, since some may not feel comfortable performing invasive procedures in a high-risk isolation environment. training and drills involving critically ill patients, including performing invasive procedures in ppe, are an integral part of skill assessment and maintenance for the physician team. it is also important to involve other groups of physicians who may be needed in the care of a patient with vhf. pediatricians and pediatric intensive care specialists should be identified in the event that a pediatric patient must be cared for under hlcc conditions. similarly, obstetricians are an important part of the physician team since it is possible that a pregnant and/or laboring patient with suspected or confirmed vhf will need care in the isolation setting. nephrology specialists have been involved in the care of patients with vhf who developed renal failure, especially those who required dialysis [ ] . relationships with other physician groups, including but not limited to surgery, emergency medicine, general internal medicine, and pathology, should be established as necessary in case consultative needs arise. it is important to note that some physician consultations can occur via telemedicine without the physician entering the patient care room. this serves to limit the number of physicians required to directly evaluate the patient at the bedside in order to decrease the possibility of exposure. when considering physician staffing models, it is important to note that physicians providing care to patients with evd or other vhf in the biocontainment setting may be unavailable for prolonged periods of time. this makes the ability to provide clinical care to other patients very difficult. thus it is important to consider backfilling other clinical responsibilities in order to provide dedicated time to the complex processes of donning and doffing ppe, performing procedures, and other aspects of biocontainment care. the most appropriate way to provide -h on-call coverage for patients with vhf must be evaluated, and this will vary depending on the current call structure in the medical facility [ ] . the involvement of physicians in training (fellows, residents, etc.) in the care of patients with vhf in the biocontainment setting has been discussed, and generally it is felt that trainees should not be compelled to provide direct care for patients with vhf as a requirement of a clinical rotation due to excessive risk. however, physicians in training have entered the biocontainment setting on a volunteer basis to observe and assist in the management of patients with vhf via the telemedicine system, which provides educational opportunity without excessive risk. the use of ppe in clinical care to prevent the transmission of infectious diseases is not a new concept, yet in the context of viral hemorrhagic fever, ppe became the topic of much debate during the - evd outbreak. facilities who were tasked with providing care to infected individuals with evd faced multifaceted challenges related to the selection, procurement, and proper utilization of ppe, along with changing guidelines. personal protective equipment is worn to minimize exposure to infectious material and to protect the skin and mucous membranes from exposure to pathogens. ppe reduces, but does not eliminate, the risk of skin and clothing contamination with pathogens among healthcare personnel [ ] . examples of ppe include items such as gowns, gloves, foot and eye protection, respirators, and full body suits. the occupational safety and health administration (osha) requires that employers protect their employees from workplace hazards that might cause injury. controlling a hazard at its source is the best way to protect employees. depending on the hazard or workplace conditions, osha recommends the use of engineering or work practice controls to manage or eliminate hazards to the greatest extent possible [ ] . installing negative pressure air handlers to place a barrier between the hazard and the employees is an engineering con-trol; changing the way in which employees perform their work is a work practice control. when engineering, work practice, and administrative controls are not feasible or provide insufficient protection, ppe must be utilized to protect healthcare workers who are providing care to patients with infectious diseases. there are many variations of ppe available for purchase, and selecting the best version for the environment in which care must be delivered can be daunting. the versions of ppe used in hlcc units differed in the individual pieces used; however, the guiding principles remained the same. for healthcare workers caring for patients with evd, ppe that fully covers skin and clothing and prevents any exposure of the eyes, nose, and mouth is recommended to reduce the risk of accidental self-contamination of mucous membranes or broken skin [ ] . varying levels of ppe are appropriate for use based upon the acuity of the patient, the volume of infectious bodily fluids (blood, vomitus, diarrheal stool) present, and the potential for aerosolization of these fluids [ ] . providing this level of protection often requires that many pieces of ppe be worn; this can lead to an increased risk of fatigue and overheating. centers in the united states that treated patients with evd in utilized varying levels of ppe based on this stratified risk assessment [ , , ] . in the nebraska biocontainment unit (nbu), the first level of ppe used completely disposable, and the second level incorporated the use of a powered air-purifying respirator (papr). first-level ppe consisted of fluid-impervious association for the advancement of medical instrumentation (aami) level gown, n respirator, surgical hood, face shield, knee-high fluid-impervious boots, three pairs of gloves, and the addition of a second splash-resistant apron as needed (fig. . ) . the second level of ppe consisted of fluid-impervious coveralls, inner boot liners, outer boot covers, three pairs of gloves, and the papr hood with accompanying belt and blower motor. in the emory university special communicable diseases unit (scdu), varying levels of ppe based upon the risk assessment consisted of a completely disposable ensemble as well as a papr ensemble. the disposable ppe included a coverall, apron, booties, double gloves, face shield (goggles if face shield is not available), and a surgical mask. the papr level of ppe was comprised of a coverall, double gloves, booties, an apron, and the papr hood [ ] ( fig. . ) . the equipment available for purchase through each institution may have differed; however, making selections based upon disease transmission and risk factors related to patient care rather than brand-specific products helped to ensure healthcare worker protection. the donning and doffing procedures require both vigilance and attention to detail. while ppe is effective at decreasing exposure to infected bodily fluids among healthcare workers, these healthcare workers are still at risk if this equipment is not removed in a manner that prevents exposure [ ] . detailed guidance with the correct order of donning and doffing equipment should be readily visible on a chart posted within the patient care area. the process used to don and doff ppe should be followed exactly by all personnel every time it is performed and should be guided by a checklist. all staff members, regardless of title or position, are expected to hold one another accountable for adhering to the policies and procedures, including the appropriate use of ppe [ , , ] . the donning and doffing process should incorporate the use of a donning partner who assists the healthcare worker in appropriate placement of ppe and a doffing partner who assists the healthcare worker in removing their ppe. this doffing partner helps to ensure that all steps in the process are completed in the proper order and technique. the physical exhaustion and emotional fatigue that can accompany the provision of care for patients infected with vhf may further increase the chance of an inadvertent exposure to bodily fluids on the outside of the ppe when performing the doffing process [ ] . the cdc also recommends the presence of a trained observer when performing the doffing process [ ] . the trained observer is available to provide immediate feedback if there is any inadvertent contamination of the healthcare worker. the doffing process can be complex and is considered to be a vulnerable area in which the healthcare providers may be inadvertently contaminated. simulation studies conducted using donning and doffing scenarios have shown high rates of self-contamination during the doffing process, especially during the removal of the gown and gloves, emphasizing the need for stringent protocols and supervision during this process [ ] . the safe transport and prehospital care of patients with evd or other highly hazardous communicable diseases require enhanced infection control practices, which necessitate sound administrative policies, work practices, and environmental controls implemented through focused education, training, and supervision [ ] . hlcc hospitals require partner emergency medical services (ems) capable of ensuring the safety of the hlcc transport medics and the public through implementation of infection control practices, policies, and procedures [ ] . the ambulance environment is defined by confined space with limited air handling, and care is provided with reusable medical devices in acute situations. emergency vehicles have many compartments, shelves, patient care beds, and other high-touch areas that are difficult to clean. ambulance cleaning protocols have been established, but environmental contamination with nosocomial organisms continues to be documented [ ] [ ] [ ] . a variety of specialized approaches have been established for hlcc transport. these include specialized truck and trailer ambulances (used in germany), hepa-filtered ground ambulance positioned aboard a hercules c aircraft (sweden), road ambulances with stretcher-based isolators (italy), and road ambulances draped to minimize contamination potential (united states) [ , ] . hlcc transport medics should receive enhanced education and training on modes of transmission, the availability of vaccines, pre-and postexposure prophylaxis, and treatment modalities. competencybased training has also been recommended to develop and maintain ppe donning and doffing competency [ , , ] . the transporting hlcc ambulance is commonly supported by an external transport team with extra supplies that facilitates communication with external support agencies (which may include law enforcement, airport operations, public health, and emergency management) and provides guidance for clinical decision-making when required [ , ] . transition of the patient from the hlcc transport team to the hlcc unit team should be a highly scripted event, rigorously tested through planning and exercise [ ] . following transition of care, the emergency vehicle should be decontaminated. hlcc facilities have utilized different decontamination methods; however the general principles of surface cleaning performed by personnel in ppe followed by appropriate waste disposal are maintained. vaporized hydrogen peroxide, chlorine dioxide, and ultraviolet light have all been used or proposed as adjunct decontamination strategies for emergency vehicles [ , , ] . the clinical care of patients with vhf is largely supportive, and the ability to provide supportive care varies depending on the capabilities of the individual healthcare facility. generally, healthcare centers caring for patients with vhf should be ready to provide general supportive care and additional aggressive intensive care modalities when necessary and available. up until recently, little information regarding these care modalities was available given that outbreaks of vhf occurred in resource-limited settings. however during the - evd outbreak, patients who were managed in resourced settings in the united states and europe where aggressive supportive care was available had a much lower mortality rate when compared with that noted in previous reports from africa [ ] . the clinical presentation of vhf may vary according to the etiology, the wide range of clinical severity, and multiple patient factors. it is important to note that the clinical presentation of vhf is non-specific; therefore it is important to evaluate patients with possible and confirmed vhf for other causes of symptoms, notably including malaria if the patient has a history of travel to an endemic area. the delivery of aggressive supportive care requires intravenous access, and the availability of this depends on the resource limitations of the healthcare facility. in resourcelimited settings, only peripheral iv placement may be feasible, whereas in resourced settings, central venous catheters (cvcs) are generally utilized. the placement of a cvc also enables healthcare workers to obtain blood samples without repeated venipuncture, reducing the risk of sharps injuries. antipyretic agents have been utilized to manage fever in patients with vhf. oral rehydration solutions and/or intravenous fluids may become necessary given the profound volume depletion that can result from vomiting and diarrhea. pharmacologic controls such as antiemetic and antidiarrheal medications have been utilized to control nausea, vomiting, and diarrhea. physical controls such as emesis bags and fecal management systems have been employed as well, since controlling these secretions is an important infection control modality in the healthcare setting. the monitoring and replacement of electrolytes is also an important aspect of supportive care in patients with vhf, since significant electrolyte disturbances have been observed [ ] . nutritional support is often necessary, and when available, total parenteral nutrition has been utilized in patients with anorexia, nausea, and vomiting. patients with respiratory symptoms may require supplemental oxygen. bleeding complications can be treated with blood products and correction of coagulopathy. cases of encephalitis have been observed, and patients with agitation may require sedating medications. patients with vhf may also develop secondary infectious complications including bacterial sepsis, and these infections may be managed with antimicrobial therapy, which is often empiric since the availability of blood cultures is limited [ ] . patients with vhf may present with, or may progress to, critical illness involving multi-organ failure and may require advanced life support including mechanical ventilation and dialysis. these interventions were utilized during the care of patients with evd in the united states and europe during the - outbreak [ ] . in patients with respiratory failure, airway management was accomplished via intubation by rapid sequence induction and video laryngoscopy [ , ] . renal failure was managed with continuous renal replacement therapy (crrt) in some centers. vasopressors have been utilized for blood pressure support in patients with vhf. an assessment of the use of other advanced cardiac life support measures like cardioversion and chest compressions should be discussed by healthcare facilities preparing to care for patients with vhf, with consideration of the potential benefits to the patient and the risks to healthcare workers. there are currently no fda-approved therapeutic agents available for the treatment of ebola or marburg virus disease, although many experimental drugs were used in the treatment of patients with evd during the - outbreak. since most of the use of these agents was employed in individuals and very small groups of patients, no definite conclusions can be made regarding efficacy. nonrandomized single-arm trials were conducted in africa evaluating certain therapeutics; however one was unable to reach any conclusions on the potential benefit of the viral rna polymerase inhibitor favipiravir, and another evaluating the small interfering rnas product tkm- did not demonstrate improvement in survival [ , ] . a randomized trial involving the triple monoclonal antibody cocktail zmapp was conducted, but although the estimated effect appeared beneficial, the result did not meet the statistical threshold for efficacy [ ] . similarly, convalescent serum has been used in the management of patients with evd; however one study did not demonstrate a significant improvement in survival in patients administered convalescent plasma [ ] . ribavarin has been shown to be effective in treatment of lassa fever [ ] . the hospital discharge of patients with vhf is a complicated process and is dependent on many factors, including resolution or significant improvement of symptoms along with correlative virologic laboratory data. consultation with local and state health authorities and the cdc and/or who should occur to determine the recommended disease-specific discharge criteria for patients with vhf. the monitoring of laboratory parameters is a vital part of providing supportive care to patients with vhf, since these patients may have significant laboratory abnormalities on which clinical management is based. this is especially important in patients who are critically ill who require interventions like dialysis where laboratory parameters must be evaluated frequently and closely monitored. the ability to perform laboratory testing in a safe and effective manner requires significant planning prior to implementation. as a first step, the clinical care team should discuss which laboratory studies are necessary in order to care for the patient with vhf. this potential testing menu should be communicated to laboratory leadership, who should assess each test to determine if the sample can be processed safely. it is essential that the clinical care team have access to a menu of available laboratory tests and detailed information on the collection of specimens, including any special media required or recommended collection times. determining the location of the laboratory should take into account the capabilities of the facility. if feasible, laboratory testing should be performed in close proximity to the site of clinical care to eliminate the need for specimen transport, thereby increasing safety and decreasing turnaround time [ , ] . point-of-care testing is desirable but is often not comprehensive, and additional testing may need to occur in the core laboratory or a special containment laboratory. it is important to note that some special containment laboratories may not have the equipment necessary to perform routine laboratory studies such as complete blood counts or metabolic panels, so these tests may need to be performed in the core laboratory if point-of-care testing is not available. a careful risk assessment should occur prior to implementation of any testing in order to minimize risk to the instruments and most importantly the laboratory staff [ ] . viral load monitoring is helpful in patients with vhf, as the degree of viremia may predict the initial severity of disease and provide information on progression of disease during the treatment phase. the viral load is generally a component of discharge criteria as well [ , ] . the transport of samples to the appropriate reference laboratory for viral load testing is a complicated process, and significant preplanning is necessary in order to facilitate this. the importance of stringent infection prevention and control, including environmental infection control, is heightened when providing hlcc for patients with vhf due to factors such as low infectious dose and potentially large volume of body fluids containing high concentrations of viral particles. these elements contribute to the significant yet manageable hazards posed by such care. perspectives and waste management strategies of two hlcc facilities have been reported [ ] . robust packaging and disinfection procedures were employed by these two facilities in order to process evdassociated solid and liquid patient waste, contaminated patient linens, healthcare worker ppe and linens, contaminated medical devices, and other general medical waste. waste, linens, medical equipment, and other items potentially contaminated with pathogens such as ebola, lassa, marburg, and select other vhfs are categorized as category a infectious substances through the united nations and us department of transportation's hazardous materials regulations [ ] . category a infectious substances require enhanced packaging and labeling along with security plans in preparation for transport [ ] . materials that are sterilized by autoclaving or incineration are not required to be packaged and shipped as category a infectious substances. the quantity of waste generated through hlcc is significant with reports of over , lb of waste generated per patient [ ] . management of such large quantities of infectious waste requires scalable strategies for packaging, storage, and security. solid waste disposal strategies include autoclaving and incineration. it is important to maintain autoclave validation logs to ensure appropriate function. several strategies have been employed for the transport of waste from the patient care room, including double bagging of waste and wiping the outside of the bag with bleach prior to transport. storage in waste-holding containers may be necessary while awaiting transport to the autoclave or incinerator. according to current recommendations, liquid waste can be safely disposed of in the sewer system. however, during the - ebola outbreak, some facilities utilized pretreatment strategies with a hospital-grade disinfectant prior to disposal of liquid waste [ ] . fluid solidifiers were also used at some facilities in order to dispose of liquid waste into the solid waste stream. waste should only be handled by trained individuals in full ppe [ ] . environmental cleaning during and after the care of patients with vhf is an important part of protecting healthcare workers, as well as other patients in the facility by maintaining the highest infection control standards. environmental cleaning for many vhfs, including ebola, should only be performed by trained individuals, and full ppe should be worn at all times during this process. daily cleaning of hlcc facilities generally consists of surface cleaning with an eparegistered disinfectant approved for use against non-enveloped viruses [ ] . the terminal cleaning process varies by facility but generally consists of disposal of waste followed by surface cleaning with a hospital-grade disinfectant and disinfection of medical equipment. some facilities utilize a final decontamination step involving ultraviolet germicidal irradiation or vaporized hydrogen peroxide [ , ] . this process should be monitored and documented by a trained infection control expert to ensure compliance with all procedures. the remains of a patient with ebola virus disease (evd) are considered highly infectious. it is important to remember that although the patient is deceased, the viral load may remain very high, and body fluids may remain infectious for an extended period of time postmortem [ ] . there is significant risk for those who are handling the body if proper procedures and barriers are not employed. preparing the body for transportation to the mortuary must be done by trained staff in the patient care room as close to the time of death as possible [ ] . when providing care for the deceased in the united states, it is most likely that these patients will be in a hospital setting and more stringent controls can be implemented. in addition to federal laws and guidelines that apply to mortuary workers, mortuary practices may also be subject to a variety of state, tribal, territorial, and local regulations. cdc recommends close collaboration with public health officials in the state or local jurisdiction, as well as with the licensed funeral director who has agreed to accept the bagged remains, to safely implement each step of the process [ ] . the presence of a memorandum of understanding (mou) with key ancillary partners can facilitate safe and timely transfer of the remains of deceased patients. it is beneficial for any insti-tution that may provide care for patients with vhf to have an mou in place with a local mortuary service, crematorium, or cemetery. the highly infectious nature of the remains of a deceased victim of evd demands the use of increased protection for the healthcare worker. the recommended ppe for handling such remains includes a powered air-purifying respirator (papr), fluid-impervious coveralls, double gloves, and use of an outer apron [ ] . adequate staffing during the care of the deceased is essential for safe execution of the procedures. the patient remains are first prepared and packaged within the patient room (hot zone) and transferred out into the hallway or anteroom (warm zone) and out of the patient care area (cold zone) for transport to final disposition [ ] . the body of the deceased should not be washed or embalmed, medical devices should remain in place, and healthcare workers should not attempt to remove them. autopsies should not be performed unless specifically directed by the state health department and only after consultation with the cdc and state health department officials [ ] . patient remains should be securely contained within the patient care area. the remains should be packaged using established guidance, which currently includes the use of multiple layers [ ] . the first layer to form a protective barrier is a standard hospital issued mortuary bag, followed by a heat sealable chlorine-free material, and final securement is achieved by the use of a heavy duty morgue bag. each protective barrier that is added should be thoroughly disinfected before moving to the next step and again before being transported out of the hot zone. the patient remains should be transferred out of the hot zone with special attention paid to minimizing the cross contamination of zones. when the remains have been safely processed out of the patient care area, the transport team will assume care of the deceased. the composition of the transport team will vary; however it is important to consider state requirements for chain of custody when developing protocols. personnel serving on the transport team may include the servicing mortuary staff, state medical examiner, healthcare worker or leadership staff, and law enforcement personnel. cremation is recommended [ ] . upon completion of cremation, the ashes may be returned to the family of the deceased as the risk of transmission of infection is no longer present [ ] . when providing care for the deceased patient, the utmost level of dignity and respect for the deceased patient and his/her family should be maintained. during the - ebola outbreak, many healthcare facilities were faced with caring for patients who presented with symptoms compatible with evd and met certain epidemiologic criteria as defined by the cdc [ , ] . these patients were termed "persons under investigation." in order to properly address quick isolation and care of persons under investigation for evd or other vhf, a travel and symptom triage tool is needed at check in areas within the healthcare environment. the tool can be a paper instrument with simple questions related to travel history and symptoms. alternatively, a more robust tool can be built within the electronic health record (ehr) to assess travel history, identifying specific countries and providing decision support prompts that then are matched up with presenting symptoms and correlated with cdc case definitions. alerts then appear within the ehr to notify caregivers of additional precautions required (e.g., give patient mask to wear, notify infectious diseases experts, isolate patient in a negative pressure room, etc.). whatever tool is used, it must be agile and quickly adapted to meet ever-changing emerging pathogen threats. once a patient screens positive for travel history and symptoms matching the cdc case definition, a process map can be used to provide step-by-step guidance to healthcare providers using a standardized approach. a protocol should be created for the emergency department, as well as for other ambulatory locations (outpatient clinics, radiology, etc.) where patients may present with symptoms. a positive screen result for epidemiologic risk and signs or symptoms consistent with viral hemorrhagic fever should trigger escalating personal protective equipment use and movement to a designated isolation area. the choice of isolation area is determined by each individual facility. a predetermined area within the emergency department can be utilized since this is often the point of entry for patients [ ] . notification of appropriate personnel should then occur, including infection control professionals, area leadership, a designated infectious diseases physician, public health officials, and the laboratory. once the patient is isolated, security should be summoned to control the area and to maintain a log of staff entering the isolation zone. staff in ppe then perform an initial assessment of the patient and obtain additional details and history, including confirmation of epidemiologic history. specialists may be called in to assess the patient as well, or alternatively this may be accomplished via video technology in an effort to limit the number of individuals who enter the room. once the exam is completed, a consultation with local public health and cdc should be conducted, and testing requirements should be determined. it is important to ensure that the appropriate collection methods are utilized; these should be clarified with the public health laboratory prior to specimen collection [ ] . a pui may require imaging studies. bedside studies are preferred from an infection control perspective but are not comprehensive, and additional studies that cannot be per-formed at the bedside may be necessary. robust predefined plans for patient transport to cardiac catheterization, ct, mri, and endoscopy should be developed. in addition, a pui may require surgical intervention. a predefined plan should be created, which outlines the preoperative timeout briefing, intraoperative care considerations to include type of ppe to be used by the surgical team, instrument handling and care, recovery of patient in the operating room, and subsequent cleaning and disinfection of the space, instruments, and waste management [ ] . although there are no formal guidelines for the management of patients with suspected vhf in the operating room, there is information available from the american college of surgeons, who recommends against elective surgical procedures but states that emergency operations can be considered [ ] . development of these processes along with defined drills involving the operating room staff will enhance the capability to successfully navigate through care of puis in need of surgical care. children differ from adults in myriad ways which potentially impact their vulnerability to the viral hemorrhagic fevers and present challenging management issues. developmentally, children are likely to be frightened by the sight of caregivers in ppe and may flail, tug, and pull at such equipment, creating additional risk for these caregivers. similarly, young children are unable to cooperate with their management, and the usual pediatric paradigm of family-centered care, which would enlist parents in assisting with such care, may be prohibitively hazardous in the setting of transmissible vhf such as ebola, marburg, or lassa. from a policy perspective, multiple factors complicate the care of children. certain medications that might be used in adults are contraindicated in children, are unavailable in liquid preparations, or are unfamiliar to pediatric practitioners. similarly, the use of investigational drugs may be more problematic in children. finally, pediatric-specific equipment, doctrine, and hlcc beds are often lacking. despite these apparent disadvantages, children have been consistently underrepresented among ebola victims. in the kikwit outbreak, children accounted for of the cases ( %), despite constituting % of the zairean population [ ] . similar findings were obtained during the outbreak in gulu, uganda, where children represented of the cases ( %) [ ] . moreover, these children had a case fatality rate of %, not dissimilar to the rate among adults. finally, in a study performed in guinea during the - outbreak, of cases ( %) occurred in children, again despite the fact that children constitute % of the population of guinea [ ] . while these findings raise the possibility that children may be less susceptible to infection with ebola (and, perhaps, with other vhfs), it is likely that this diminished susceptibility derives mainly from social factors; young children are less likely to function as primary caregivers to dying family members, are thus less likely to have contact with body fluids, and are less likely to participate in intimate funereal preparations. management of the pregnant or laboring patient with vhf is similarly problematic; maternal and infant mortality are extraordinarily high in virtually all of the vhfs, although maternal survival has been reported following fetal loss associated with ebola infection and uterine evacuation has been shown to improve survival of pregnant women with lassa fever [ , ] . fetal and neonatal loss among women with lassa fever has been reported to be as high as %, and there are no reports of neonates born to ebola-infected mothers surviving beyond days [ , ] . vertical transmission of yellow fever appears to occur very rarely, and few reports of affected pregnant women exist for the remaining vhfs [ ] . in light of this paucity of information, it is difficult to make specific recommendations for the management of the pregnant woman with vhf. nonetheless, meticulous planning must be undertaken by facilities that might be called upon to care for pregnant vhf patients. such planning should address, among others, questions regarding where and when delivery should occur, what equipment is required, and how complications like bleeding should be managed. this final question that raises, perhaps, the most vexing issue associated with the care of newborns and children with contagious vhfs is under what circumstances might parents or other nonmedical caregivers be permitted to remain at the beside of an infected child. parents might assist in reducing the anxious flailing of a toddler, thereby diminishing risk to hcws. they are also afforded the opportunity to participate in family-centered care, thus emotionally benefitting both parent and child. these considerations must be balanced, however, against the reality that parents then become, in a sense, additional patients, requiring assistance in donning and doffing ppe and running the risk of inadvertent breaks in containment by non-skilled individuals. an expert panel recently met to discuss these considerations, although the subject is likely to remain controversial [ ] . training healthcare workers in the provision of care to patients with vhf presents many challenges. one of the challenges involves maintaining readiness and keeping team members engaged when these specialized patient care areas are not activated. the implementation of a consistent and structured training schedule facilitates staff engagement by incorporating activities of varying intensity. incorporating complex functional exercises, tabletop exercises, skill-focused drills, competency evaluations, and team-building activities builds a strong foundation from which the patient care team can further develop. educational sessions on emerging infectious diseases may also be helpful to maintain readiness and interest. developing an annual training calendar that is available to team members in advance sets the expectation for the team members and also helps to minimize scheduling conflicts for required attendance. bringing healthcare workers together to train regularly enables the formation of a cohesive functional team rather than a collection of individuals. when considering the provision of intensive care to patients with evd, the challenges are heightened. these patients often require invasive interventions which involve the skills of anesthesiologists and critical care physicians, as well as nurses proficient in managing the ongoing care of critically ill patients. the interventions must be implemented while wearing advanced levels of ppe, thus potentially limiting the dexterity of the providers. training regimens for healthcare workers should allow for the development and refinement of specific policies and procedures, addressing critical issues like donning and doffing ppe, waste processing, the insertion of central venous catheters, endotracheal intubation, the use of continuous renal replacement therapy, advanced cardiac life support (acls) and pediatric advanced life support (pals) plans and protocols, and the plan for extraction and provision of care for a provider who has a medical emergency in the patient care area. providing routine training for key personnel ensures the opportunity for healthcare workers to gain confidence in their ability to perform the procedures, as well as to build a firm foundation of processes for many aspects of care [ ] . developing and exercising detailed policies to guide cares within the unit, as well as maintaining an expert staff, are key components to maintaining preparedness. training ensures that healthcare workers are knowledgeable and proficient in donning and doffing ppe before caring for a patient with vhf. comfort and proficiency when donning and doffing are only achieved by repeatedly practicing correct use of ppe. when providing training and assessing competency in ppe, healthcare workers should perform required duties while wearing ppe. this could include inserting an intravenous device, assisting with perineal care after an incontinent episode, processing waste in the patient care area, or charting an assessment. training should be customized for the intended audience and effectively relay essential information. healthcare workers who are unwilling or unable to fulfill these requirements should not be included in the patient care team. with regard to maintenance of skills, it is imperative that a culture of safety be fostered within the care team, where the focus is on effective teamwork to accomplish the goal of safe, high-quality patient care [ ] . all staff must feel empowered to identify and take action to prevent errors from occurring and to improve the patient care environment. this sense of empowerment can be developed during routine training and preparedness exercises in preparation for the reality of patient care. the provision of care for patients with evd or other vhf is a complex process necessitating that close attention be paid to multiple infection control modalities. engineering and facility controls such as negatively pressurized rooms within designated care areas are ideal; however the most important assets needed to provide safe and effective care for patients with vhf or other highly hazardous communicable diseases are a trained team and a collection of well-developed and practiced protocols. in order to increase preparedness for highly hazardous communicable diseases in the united states following the ebola outbreak of - , the cdc and department of health and human services (dhhs) developed a three-tiered system to screen and manage patients with suspected or confirmed evd. under this system, facilities with high-level containment care capability are designated as "ebola treatment centers" (etc). as of this writing, approximately such centers have applied for designation and funding; among them are ten designated as regional referral centers by dhhs (one in each of its ten geographic regions) [ ] . in addition, other hospitals would be designated as "ebola assessment hospitals" (eah), able to manage and isolate persons under investigation (pui) until a diagnosis of ebola virus disease (evd) can be confirmed or refuted. finally, remaining hospitals ("frontline facilities") would receive training in order to improve their ability to isolate potential ebola victims until they could be transferred to an eah or etc. within this network, the provision of patient care can be optimized, protocols practiced and improved, and research on investigational drugs and products streamlined. although this system represents a vast improvement in hospital preparedness in the united states, isolation bed capacity remains limited [ ] . the us department of health and human services, the assistant secretary for preparedness and response (aspr), the centers for disease control and prevention (cdc), and emory university, nebraska medicine, and bellevue hospital center comprise the national ebola training and education center (netec) [ ] . initiated in , the netec program supports the education and training of healthcare facilities in order to enhance preparedness for ebola and other highly infectious diseases. although there remains a significant amount of education and work to be done in this area, this collaborative effort, along with the tiered network of hospitals, represents a significant improvement in preparedness. the invisible enemy: a natural history of viruses isolation and biocontainment of patients with highly hazardous infectious diseases the "slammer": isolation and biocontainment of patients exposed to biosafety level pathogens managing potential laboratory exposure to ebola virus by using a patient biocontainment care unit why were doctors afraid to treat rebecca mclester? new york times designing a biocontainment unit to care for patients with serious communicable diseases: a consensus statement preparing a community hospital to manage work-related exposures to infectious agents in biosafety level and laboratories framework for the design and operation of high-level isolation units: consensus of the european network of infectious diseases infection control in the management of highly pathogenic infectious diseases: consensus of the european network of infectious diseases the sars epidemic: treatment; beijing hurries to build hospital complex for increasing number of sars patients yellow jack and geopolitics: environment, epidemics, and the struggles for empire in the american tropics biosafety in microbiological and biomedical laboratories guideline for isolation precautions: preventing transmission of infectious agents in health care settings guidelines for design and construction of hospitals and outpatient facilities environmental infection control considerations for ebola safety considerations in the laboratory testing of specimens suspected or known to contain ebola virus facing highly infectious diseases: new trends and current concepts planning and response to ebola virus disease: an integrated approach emory healthcare ebola preparedness protocols ebola virus disease: preparedness and infection control lessons learned from two biocontainment units critical care for the patient with ebola virus disease: the nebraska perspective the nebraska biocontainment unit policies and procedures preparing for critical care services to patients with ebola successful delivery of rrt in ebola 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patient in intensive care experimental treatment with favipiravir for ebola virus disease (the jiki trial): a historically controlled, single-arm proof-of-concept trial in guinea experimental treatment of ebola virus disease with tkm- : a single-arm phase clinical trial evaluation of convalescent plasma for ebola virus disease in guinea lassa fever laboratory test support for ebola patients within a high-containment facility criteria for discharge of patients with ebola virus diseases in high-income countries clinical management of patients with viral haemorrhagic fever. a pocket guide for the front-line health worker department of transportation. cfr parts , , , and hazardous materials: infectious substances; harmonization with the united nations recommendations department of transportation. dot guidance for preparing packages of ebola contaminated waste for transportation and disposal nebraska biocontainment unit perspective on disposal of ebola medical waste safe handling, treatment, transport and disposal of ebola-contaminated waste interim guidance for environmental infection control in hospitals for ebola virus nebraska biocontainment unit patient discharge and environmental decontamination following ebola care new who safe and dignified burial protocol -key to reducing ebola transmission. world health organization guidance for safe handling of human remains of ebola patients in u.s. hospitals and mortuaries guidance on personal protective equipment (ppe) to be used by healthcare workers during management of patients with confirmed ebola or persons under investigation (puis) for ebola who are clinically unstable or have bleeding, vomiting, or diarrhea in u.s. hospitals, including procedures for donning and doffing ppe the nebraska biocontainment unit. the nebraska biocontainment unit policies and procedures centers for disease control and prevention. case definition for ebola virus disease (evd) ebola or not? evaluating the ill traveler from ebola-affected countries in west africa development and use of mobile containment units for the evaluation and treatment of potential ebola virus disease patients in a united states hospital emergency department processes for the evaluation and management of person under investigation for ebola virus disease ebola surgical protocols enhance safety of patients and personnel surgical protocol for possible or confirmed ebola cases ebola hemorrhagic fever: why were children spared? ebola hemorrhagic fever among hospitalized children and adolescents in northern uganda: epidemiologic and clinical observations ebola virus disease and children: what pediatric health care professionals need to know dilemmas in managing pregnant women with ebola: case reports a prospective study of maternal and fetal outcome in acute lassa fever infection during pregnancy live neonates born to mothers with ebola virus disease: a review of the literature perinatal transmission of yellow fever, brazil parental presence at the bedside of a child with suspected ebola: an expert discussion teaching the culture of safety centers for disease control and prevention. hospital preparedness: a tiered approach current capabilities and capacity of ebola treatment centers in the united states infect key: cord- -b r authors: labrunda, michelle; amin, naushad title: the emerging threat of ebola date: - - journal: global health security doi: . / - - - - _ sha: doc_id: cord_uid: b r ebola is one of the deadliest infectious disease of the modern era. over % of those infected die. prior to , the disease was unknown. no one knows exactly where it came from, but it is postulated that a mutation in an animal virus allowed it to jump species and infect humans. in simultaneous outbreaks of ebola occurred in what is now south sudan and the democratic republic of the congo (drc). for years, only sporadic cases were seen, but in a new outbreak occurred killing hundreds in the drc. since that time the frequency of these outbreaks has been increasing. it is uncertain why this is occurring, but many associate it with increasing human encroachment into forested areas bringing people and animals into more intimate contact and increased mobility of previously remote population. this chapter will navigate ebola in the context of global health and security. there are multiple objectives of this chapter. first is to provide a basic understanding of ebola disease processes and outbreak patterns. second, is to explore the interplay between social determinants of health and ebola. the role of technology in spreading ebola outbreaks will be explained as will ebola’s potential as a bioweapon. readers will gain understanding of the link between environmental degradation and ebola outbreaks. this chapter will be divided into five main sections. these are ( ) a case study; ( ) ebola disease process; ( ) social determinants of health and ebola; ( ) ebola in the modern era, and ( ) the link between ebola and environmental degradation. who contracts ebola. the story will be told from her perspective. she will describe from her why she thinks the outbreak has occurred. her husband has died of ebola despite efforts of traditional healers. she will discuss burial rites in the context of her religious beliefs. the next section looks at the disease itself. the history, epidemiology, transmission, and signs/symptoms will be described. prevention measures including the use of personal protective equipment and vaccination strategies will be discussed. the basics of diagnosis and treatment will be covered. the section will end with a discussion of ebola epidemics. social determents of health play an important role in the epidemiology and transmission of ebola. factors impacting spread include, high population mobility, porous international borders, and ongoing conflict resulting in displaced populations. poverty, cultural beliefs and practices and prior ineffective public health messages have all played a role in the emergence of ebola. the following section will explore ebola in the era of technology. the role of air travel in disease spread and the effectiveness of airport screening measures will be discussed. ebola's potential for use in bioterrorism will also be discussed in this section. the relationship between environmental encroachment and disease emergence will be explored. global warming, and the impact of a growing population in ebola outbreaks will be explored. the chapter will end with a discussion of future directions. in this last section the important of international collaborations for disease prevention and public education programs will be discussed. sia waited nervously in the small one room house where she lives. she was waiting for her brother-in-law to return with the body of her dead husband, saa. he had died yesterday of the bush illness that was killing so many in her community, ebola the outsiders called it. just weeks ago, the world had seemed a different place. sia had sat with the other women of the kissi tribe at church joking and planning for the upcoming rice harvest. yes, they practiced christianity, but also followed the traditions of their ancestors. women in her village prayed to jesus and god, but also to their ancestors. outsiders sometimes questioned how the kissi could follow both christianity and their old traditions, but sia had never seen a problem. ancestors after all, were the ones who communicated with god. when someone in the family died, they were escorted to the realm of the ancestors where they were able to protect the living family and speak to god on their behalf. ancestors continued to live in the village, but in their new form. sia shivered thinking of what happened to those who died and were not escorted to the realm of the ancestors. ceremonies were usually performed by the brother of the deceased. if the ceremonies were not done properly, a loved one would become a wandering ghost instead of an ancestor. wandering ghosts torment the living bringing misfortune to everyone in the village, especially to the family that failed to perform the proper rights. sia did not like to think of such things, but there had been several deaths in a nearby village and she could not help but to wonder if it was the work of a wandering ghost. that was the day it started. saa was fine when he woke up, but while they were at the church, he started to get sick. he got sick so quickly that sia suggested that they return home early so he could rest. it wasn't a far walk, but by the time they arrived home, saa was having chills, headache, nausea, and said his joints hurt. while saa rested, sia prepared a tonic to ease the pain and ward off evil spirits. saa's eyes were red and he felt hot to touch. "a powerful spirit must be involved", sia thought to herself. she couldn't imagine who would have cursed her husband this way. he hadn't argued with anyone that she knew. for days sia cared for her husband with special food, potions, and prayers. she had even sacrificed a chicken, but instead of getting better he started vomiting and having diarrhea. obviously, she needed assistance from someone with greater influence in the spirit realm. kai, a local medicine-man of conservable powerful agreed to help but needed time to make the necessary preparations. by that evening saa had stopped eating altogether and his gums started to bleed. kai belonged to a secret society that added to his powers. sia was not allowed to attend kai's ceremony but was told that saa had cried blood and started to hiccough uncontrollably. kai was notable to defeat the evil spirits even with his most powerful incantations. some of the villagers wanted to take saa to a treatment center set up by some foreigners to see if they could help him. sia was hesitant, but by the next morning saa had developed a yellow color to his skin and was having black diarrhea, so she agreed. after a bunch of questions saa was taken into the camp that the foreigners set up, but they would not let sia or anyone else in the family enter. that was the last time she had seen saa alive. two days later sia was informed that saa had died. he was to be buried in a mass grave and no one was allowed to see his body. saa's brother said that he thinks the foreigners killed him. they weren't really there to help but part of a government plan to destroy the kissi. workers in the camp were removing the internal organs of the sick while they were still alive and selling them. that is why no one was allowed into the camp or to bury the bodies properly. they weren't just attacking the living, but also trying to destroy the ancestors by preventing the death ceremony from happening. luckily saa's brother knew people. it had cost everything that the family owned, but the man driving the truck full of bodies agreed to meet a short distance from the foreigners' camp. he would give them the body there, but there were not to tell anyone. as saa's brother walked into the house carrying saa's body, sia felt an overwhelming sense of relief. all the worry gave her a headache and made her feel weak. now that they had saa's body it will be better. they will do the rituals this evening and burry saa in the morning. he will be able to walk with the ancestors. one of the world's deadliest pathogen, the ebola virus made its first appearance in in not just one but two simultaneous outbreaks. the first of its deadly attacks were in what is now known as nzara, south sudan while the second occurred in a small village community near the ebola river bank in yambuku, democratic republic of congo (drc) [ ] . of the known to be infected, lost their lives. since that time, we have learned much about the ebola virus and the disease it causes. ebola virus is an uncommon virus which infects both human and non-human primates. it belongs to the family filoviridae, a negative stranded rna virus. when magnified, it appears as a filamentous structure fig. . the ebolavirus genus has six known species, zaire, sudan, tai forest (formerly côte d'ivoire ebolavirus), bundibugyo, reston, and the recently described bombali [ ] . reston is highly pathogenic for non-human primates and pigs, and bombali has been discovered in free-tailed bats as part of ongoing research to discover the ebola reservoir. the zaire species was responsible for the first ebola virus outbreak in and is considered to be the deadliest of the six [ ] . initially the disease caused by ebola virus was called ebola hemorrhagic fever, but later studies showed that the hemorrhagic manifestations were less common than initially thought and subsequently the name was changed to ebola virus disease (ebd). until , the ebola virus isolated sporadic outbreaks occurred only in central africa with counts numbering in the hundreds or less, and only lasting days to weeks. however, in march the who confirmed an epidemic of the zaire species of ebola virus emerging in west africa. this outbreak lasted years and grew to be one of the world's deadliest epidemics. there were , case and , fatalities documented by the world health organization (who). the index case of this epidemic is thought to be a -year-old child who became ill in late . the child eventually succumbed to the illness with symptoms of fever, chills, vomiting, and black-tarry stool [ ] . this was in guinea, west africa a country where ebola supposedly did not exist. from here it spread to liberia, sierra leone, nigeria, and mali. the natural reservoir of ebola virus is not known with certainty, although research has suggested that it may be bats. human infection may occur through direct contact with the mystery reservoir or through contact with infected primates. this can occur when hunting and preparing bush-meat or via contact with body fluids from an infected person. ebola is highly transmissible. the disease pattern of evd has shifted over the last years. currently, ebola has been found across central and west africa, with occasional exported cases to other regions. for obscure reasons, outbreaks seem to be occurring with increasing frequency. this may be linked to environmental degradation and increasing mobility of local populations. ebola spread is through contaminated body fluids. unfortunatly, traditional funerary practices across africa put funeral attendees in contact with body fluids from those who have died of ebola. initial international efforts to control ebola spread during outbreaks have often resulted in clashes and conflict as control measures confront tradition. inadequate public health messages, distrust of those providing the health messages, political instability, and regional conflict have allowed ebola to spread and kill thousands when early containment could have been within reach. ebola is one of the most fatal infectious diseases humans have encountered. even with the best medical care the disease is deadly. unfortunatly, the developing countries where evd occurs are not equipped with optimal medical or public health facilities. to complicate the situation further, survivors of evd are not hailed as heroes, but instead may be left with chronic illness and stigmatized in their communities. transmission of ebola disease is still being studied, but it is known that person-toperson contact is the most common form of spread. infection occurs primarily through direct contact with body fluids from infected people or animals (fig. ). viral antigens have been isolated from the skin of those infected suggesting that skin contact alone may be sufficient to spread disease [ ] . it has also been shown that, at least in primates, ebola can be spread through intramuscular injection, and inoculation can occur through contact of the conjunctiva or oral mucosa with infected body fluids [ ] . blood, vomitus, and feces are the body fluid most likely to spread infection because of the frequency with which they are encountered during the course of the illness, but other fluid such as urine, semen, vaginal fluid, tears, sweat, and breast milk also have potential for viral transmission [ , , , , , ] . caring for an infected person with ebola, whether at home or in the hospital has been identified as a high-risk activity for acquiring ebola. household members who provide direct care to an ebola victim are - times more likely to contract ebola than household members who share a residence but do not participate in patient care [ , ] . healthcare workers are also at high risk for acquiring ebola. one study found the risk of developing evd for healthcare workers to be times that of the general community during an outbreak of ebola in sierra leone [ ] . there are many factors contributing to the spread of ebola amongst healthcare workers. the presentation of ebola is non-specific so early on in the disease process it may be diagnosed as malaria, influenza, or other non-specific viral illness. if a patient is initially misdiagnosed, then proper protective measures to limit the spread of ebola will not be initiated. also, the use of personal protective equipment (ppe) including gloves and gowns for routine patient care is less common in developing countries than in more developed countries due to financial restriction. there is a risk of iatrogenic spread of ebola. in the initial outbreak of , health care workers reusing glass syringes and needles in a community clinic may have inadvertently caused spread of infection. the facility consisted of a -bed hospital and a busy outpatient center which treated between and , people per month. at the beginning of each day, nurses were given five syringes each which were reused after a warm water rinse. unfortunatly, this is where ebola made its first appearance. potentially hundreds were exposed from this clinic alone [ , ] . there have been many other instances where hospitals have turned into epicenters for ebola outbreaks [ , ] . early detection and isolation is key to preventing similar incidents in the future. the greatest risk of transmission of evd from human to human occurs when a patient is acutely ill. risk also corelates with severity of illness. the sicker a patient is the more infective she is. in early phase of acute illness, the viral load is relatively low, however it increases exponentially during the latter part of the acute illness, and high viral loads are associated with high mortality rates and infectivity [ ] . those who handle corpses of ebola victims after death also run considerable risk of acquiring the disease. many funerary customs in ebola-prone regions involve extensive physical contact with the dead body. despite the risk of transmission, many still engage in these traditional practices. without these preparations, some local traditions hold that misfortune will plague the living and the dead will not be able to pass into the spirit realm. family who do not engage in expected funerary practice may be viewed negatively in the communities where they live. one funeral ceremony alone has been linked to additional cases of ebola [ ] . transmissibility of ebola virus depends on the phase of infection of the ill-person. the viral load corresponds to the severity of illness [ ] . in other words, the sicker a person is, the higher concentration the concentration viral particles in the blood stream. as an ill person succumbs to ebola, they become more debilitated and require more care. at the same time, the viral load increases as the victim declines. because of this, family caring for the ill are more likely to be infected in the later stages and corpses of those killed by ebola are highly infectious [ ] . even after a person has recovered from ebola and no virus can be isolated from blood, it may still be found in other tissues and able to transmit disease. live virus has been isolated from breastmilk after recovery raising the issue of transmission to mother to infant [ ] . ebola has been isolated from semen up to months after onset of symptoms, in urine for days, sweat for days, aqueous humor of the eye for weeks, and in cerebral spinal fluid for months [ , , , , ] . there has been at least one case where a man who recovered from ebola transmitted the infection to a sexual partner days after his initial illness [ ] . to prevent sexual transmission of ebola, the who recommends systematic testing for ebola virus in semen. for the first months after infection, the semen of male ebola survivors should be assumed to be infectious. three months after the day symptoms started semen testing for ebola should be initiated. if the result is negative, then it should be repeated in week. if the test is positive, then it should be repeated monthly until a negative result is obtained. once two consecutive negative results have been obtained sexual activities can be resumed [ ] . vaginal secretions have been found to contain virus up to days after the initiation of symptoms, but no official testing recommendations exist for vaginal secretions [ , ] . other methods of ebola spread have been postulated, but do not appear to be significant sources of transmission. surfaces contaminated with body fluids produce a theoretical risk of transmission, but no confirmed documented cases of fomite transmission of ebola exist. ebola virus has been shown to persist in the environment supporting the need for close attention to decontamination of surfaces [ , ] . medical procedures can augment disease spread if proper precautions are not taken [ ] . hunting and capturing infected animals for bush meat or for trading in black market as exotic pets can result in exposure and transmission of ebola. there have been numerous instances of human infection resulting from contact with dead primates [ , ] . contact with wild primates, especially those found dead should be avoided to curb the risk of contracting ebola. there is another step in ebola transmission that continues to be elusive. humans and other primates can catch ebola from each other, but they are not the reservoir. the reservoir is not known with certainty, but there is some evidence linking bats to ebola [ ] . the evidence for bats as the ebola reservoir is suggestive but not compelling. antibodies against ebola have been found in bat species, but the significance of this is unclear. antibodies are formed when an organism has been exposed to an infectious organism. this is evidence of exposure and immune response, but not of long-term infection or viral shedding [ ] . only one small study has ever isolated ebola rna from bats [ ] . attempts to infect bats then isolate viral rna or shedding have not met with success [ , ] . as the systematic search for the reservoir continues, negative findings are as important as positive one. plants and arthropods have not been shown to harbor ebola [ , ] . ebola virus disease is an acute febrile illness that has been associated with hemorrhagic manifestations. it has an incubation period of - days, but presentation of symptoms is most common between day and after exposure [ ] . it is unclear whether or not infected people can transmit disease prior to developing symptoms, but those with symptoms should be assumed to be contagious. evd typically begins with abrupt onset of malaise, fever, and chills. it is also common to experience vomiting, headache, diarrhea, and loss of appetite early in the disease course. the diarrhea can be profuse and water losses of up to l per day have been reported [ ] . dehydration and hypovolemic can result. relative bradycardia can also be seen in ebola [ ] . a maculopapular rash commonly develops - days after onset of illness. the rash is not a consistent finding and seems to vary from region to region [ ] . hemorrhage is the most dramatic symptom associated with evd but is not as common as first feared. usually it manifests as gastrointestinal bleeding, but petechia, ecchymosis, bleeding oral mucosa can also be seen [ ] . bleeding is multifactorial and likely due to a combination of thrombocytopenia, coagulopathy from liver involvement, and in some instance disseminated intravascular coagulation (dic). evd can cause involve a number of different organ systems. neurologically, it can cause meningoencephalitis, confusion, chronic cognitive decline, and seizures. neurological symptoms typically occur - days after onset of illness [ , ] . cardiomyopathy and respiratory muscle fatigue have been described [ ] . eye involvement is also common early in the disease course and may persist. patients frequently report blurred vision, photophobia and blindness [ ] . laboratory findings during the course of the infection can include leukopenia, elevated renal profile, abnormal coagulation panel, thrombocytopenia, anemia, and elevated liver function tests [ ] . hiccoughs are common late in the acute phase of illness. symptoms typically abate after weeks of illness. even after the acute illness has resolved, ebola victims can have long term symptoms. these include fatigue, insomnia, headaches, myalgias, arthralgias, cognitive decline, and hair loss. uveitis and hearing loss are both common after recovery from evd [ , ] . even after the resolution of acute evd, new symptoms can develop. in a study looking at early clinical sequela, % of ebola survivors developed arthralgias, % ocular symptoms, % auditory symptoms, and % uveitis [ ] . studies evaluating the long -erm sequela of evd are ongoing. prevention strategies for ebola are numerous, but essentially boils down to avoiding all contact with skin and body fluids that could potentially harbor the ebola virus. of course, this is more easily said than done especially in health care settings, and for families of those infected. health care providers deal with rapidly changing conditions often in limited resource settings and are at high risk for contracting ebola if prevention protocols are not followed. families of ebola victims face similar, but even more daunting challenges. ebola may be found in secretions of those who have recovered for months or even years after the acute illness has resolved. while not common, cases of transmission have occurred months after a person has recovered. active ebola virus can persist in urine, vaginal secretions, breast milk, semen, ocular fluid, and cerebrospinal fluid even after recovery making prevention more challenging. while not heavily researched as an effective prevention strategy, people who eat bushmeat should be encouraged to take precautions to prevent ebola infection. this means avoiding contact with fluids from slaughtered animals as much as possible. ebola virus is inactivated by thorough cooking, so through cooking of bush meat should be encouraged [ ]. ebola is highly pathogenic and easily transmitted. both the who and the center for disease control (cdc) have published detailed guidelines on prevention which are freely available online [ , , ] . the who recommends the following key elements to prevent transmission of ebola virus in the hospital setting: • hand hygiene • gloves • facial protection (covering eyes, nose and mouth) • gowns (or overalls) • sharps safety • respiratory hygiene for both health care providers and patients • environmental cleaning • safe linen transport and cleaning • proper waste disposal • proper sanitation of patient care equipment ebola prevention requires attention to and special training in donning and removing personal protective equipment (ppe). specific instructions and videos for use of this equipment is available at the who prevention cdc websites. health care workers who use ppe equipment properly are safe from ebola infection, but can develop other health issues from the ppe itself. the ppe suits are hot, uncomfortable, and require constant surveillance to ensure that all the equipment remains in place and undamaged. areas prone to ebola outbreaks tend to be hot, humid, and lack resources for air conditioning, wearing ebola suits creates a risk for development of heat related illness and dehydration. the cdc has published guidelines for preventing heat related illness for those providing care to ebola patients in hot african climates [ ] . as previously mentioned, people have survived initial ebola infection may still be able to transmit the disease to others. with proper preventive measures the risk of transmission can be ameliorated. as with other aspects of ebola, both the cdc and who have published extensive guidelines available on their websites. for healthcare workers, no special precautions are needed for basic patient care. the cdc does recommend that additional ppe be used when caring for ebola survivors if contact with testes, urine, breast, breast milk, spinal fluid, or intraocular fluid is anticipated during patient care [ ] . in the home, additional precautions may be needed. cases of transmission through sexual contact and breast milk have been describe in the literature [ , ] . cdc guidelines recommend abstinence from sexual activity of all types including oral, anal, and vaginal. if abstinence is not possible then condoms and avoidance of contact with semen is recommended. the who has recommended that semen be tested months after the onset of disease in men. if the test is negative, then it should be repeated in week. after two negative test sexual activity can be resumed. if the test is positive, it should be repeated every month until a negative test is obtained. once a negative test occurs, it should be repeated in week, and after two negatives sexual activity can be resumed [ ] . maternity issues around ebola are complex. it is unclear when it is safe for a woman to become pregnant after recovering from ebola. some organizations have suggested that a woman wait a few months prior to becoming pregnant, but so far this recommendation has not been supported by clinical data. breastmilk can transmit ebola virus from a mother who has recovered from evd to her child. if feasible, breastfeeding should be avoided. the data on ebola transmission through breasting is limited, and resources in ebola-prone areas make repeat testing of breastmilk impractical. suggested strategies have recommended avoiding breasting feeding for months after recovery [ ] . travel restrictions may occur during ebola outbreaks. it is generally accepted practice that those who have potentially been exposed to ebola virus not travel for days after the last possible day of their exposure. as an alternative for those at low risk, close monitoring with no restrictions on travel may be done. balancing individual rights with community safety creates ethical and regulatory challenges in cases of potential exposure. additional information on monitoring and travel restriction can be found at both the cdc and who websites. vaccination development is in place, but there is currently no federal drug administration (fda) approved vaccination for ebola. currently, there are different clinical trials running with the goal of developing a safe and effective ebola vaccine [ ] . an investigational vaccine called rvsv-zebov is presently being used in drc under "compassionate use". this vaccine is specific for the zaire strain of ebolavirus. this same vaccine was previously administered to , volunteers during an outbreak in . so far, the vaccine appears safe with few side effects, but insufficient data is available for licensing [ ] . preliminary reports suggest an efficacy of %, but duration of protection is currently not known [ ] . even though there are no specific therapies to treat ebola, diagnosis is important to prevent spread and to ensure administration of appropriate supportive care and monitoring. anyone who has had any potential exposure to ebola in the last days should be evaluated if symptoms of ebola develop. while awaiting the result of ebola testing, appropriate infection control practices should be implemented. diagnosis is done by reverse-transcription polymerase chain reaction (rt-pcr). the test should be done days after the onset of symptoms [ ] . false negatives can occur if the lab is collected before h of symptom onset. a positive test confirms ebola virus disease and that the patient is infective. considering repeat testing in patients whose clinical picture is highly suspicious of ebd and have a negative initial test. ebola virus disease has a broad differential, and simultaneous testing for other illnesses should be undertaken as clinically warranted. this differential includes, malaria, lassa fever, typhoid fever, influenza, meningococcal meningitis (neisseria meningitidis), measles, crimean-congo hemorrhagic fever, yellow fever, marburg, and the familiar travelers' diarrhea among many others [ ] . supportive care is the only treatment for ebola. there are no antimicrobial agents proven to be effective in ebd. when possible, care should be provided at a facility familiar with the clinical progression of ebola. supportive care in ebola is no different than for any other critically ill patient. give intravenous fluids to prevent dehydration and shock. patients with ebola suffer from vomiting and diarrhea and may easily dehydrate. if intravenous fluids are unavailable or prohibitively expensive, oral hydration should be undertaken. ebola can lead not only to hypovolemic shock, but also septic shock [ ] so close patient monitoring is warranted. electrolytes will require close monitoring and should be repleted as needed. vasopressors may be required if blood pressure cannot be maintained. ebola can result in significant hematological abnormalities [ , ] . it can also lead to liver failure followed by coagulopathy [ ] . thrombocytopenia, leukopenia, and anemia are all common and treatment should be based on the specific abnormality encountered. other management may include antipyretics, respiratory support, analgesics, antimotility agents for diarrhea, antiemetics for nausea and vomiting, antibiotics, nutritional support and renal replacement therapy. these and other supportive measures must be tailored to the individual patient need. the first reported outbreak of ebola-like illness occurred in in sudan and zaire [ ] [now south sudan and the democratic republic of congo (drc)]. it is probable that sporadic outbreaks happened earlier but were not identified. outbreaks appear to be occurring more frequently than before. this is not only due to improved detection techniques, but also due to environmental encroachment, increasing population mobility, and changing weather patterns. the following section will summarize data on known ebola social determinants of health are the conditions in which a person lives and grows. there is no one list of these factors, but they are generally considered to include influences such as school, (un)employment, the community where one resides, food, and transportation. the factors are driven by forces outside of one's sphere of control such as poverty and war as well as some potentially self-directed choices such as belief system and friend circle. for example, social determinants of health are a way of describing why when a . magnitude earthquake hits haiti buildings collapse and people die and when a . magnitude earthquake and the same earthquake on guam causes no damage. social determinants of health significantly affected how ebola has impacted affected countries. poverty affects every aspect of life for most. according to world bank data, the rate of poverty in sub-sahara africa is trending downwards but is still over % of the population. poverty leads to lack of education, limited medical resources, poor nutrition, and crowded living conditions. people in poverty will eat a dead animal if they find one because it may be all they have to eat. they are unlikely to seek medical care outside of traditional healers because it is all they know and can afford. they may insist on washing the bodies of the dead because their only knowledge of science are traditions passed from generation to generation. all of which contributes to the spread of ebola. anyone who reads the history the countries that make up the peri-equatorial regional of africa will quickly notice that the region has suffered from nearly continuous war since even before the european occupation. there are pockets of stability in the region, but conflict is a way of life for many. conflict leads to destruction of infrastructure, fear, stress, distrust, and population displacement. currently, an ebola outbreak is occurring in drc. refugees from drc continually flee into neighboring countries, especially uganda. conflict driven human movement is a means by which ebola can be spread. no widespread outbreak of ebola has occurred in a refugee camp, but these types of settlements are fertile soil where an outbreak could start and flourish before an alarm is raised. the ugandan government is working with the international federation of the red cross and red crescent societies (ifrc), unicef, and the who collaborating to develop an ebola emergency preparedness plan [ ] . political and economic instability across have resulted in a debilitated medical and public health infrastructure. official data is limited, but media sources have reported that liberia has experienced a severe shortage of trained health workers within the country. media sources list general practitioners, public health specialists, pediatricians, surgeons, obstetrician-gynecologists, ophthalmologists, internists, dentists, psychiatrists, family medicine specialists, orthopedic surgeons, radiologists, pathologist, ear-nose-throat specialist, veterinarian, and dermatologist as comprising the entire formally trained health community (excluding nursing professionals) [ ] . the cia world factbook lists the number of physicians per people to be . for liberia, . for sierra leona, . for guinea, . in drc, and . in uganda [ ] . even some of these numbers are almost years-old making it difficult to assess the actual situation in the region. regardless, it is a safe conclusion that none of these countries are even close to having the recommended physician per residents recommended by the who. each of these countries is unique in the health care challenges it faces, and only are mentioned here because they have all been touched by ebola. infrastructure development is generally associated with improved health and decreased disease burden, but this is not always the case. while lack of infrastructure such as water and sanitation is thought to lead to increased transmission. increased connectivity via road and boat is thought to increase the risk of transmission through increased number of contacts [ ] . one of the most fascinating aspects of ebola occurs at the intersection of culture and public health. for generations, a mixture of traditional beliefs and mainstream religion has served as a cultural foundation in many tribal areas across central and western africa. funerary practices in these tribes are some of the most important in their belief system. it is these practices that have been exploited by the ebola virus allowing it to spread. exposure has been associated with attendance of funerals and contact with dead bodies in multiple countries [ , , ] . as public health and medical personnel tried to curb ebola spread, conflict has occurred. those most at risk for ebola suddenly felt threatened not only by the disease itself, but also by those where were trying to help as their core beliefs were suddenly targeted. from the perspective of the health care workers trying to save lives, the cultural beliefs were generally considered as just another barrier to be surmounted. this lack of understanding between those at risk and the health care workers lead to conflict, distrust, which at times drove ebola victims into hiding rather than seeking care. bribes were made, bodies were stolen, aid workers were attacked, and ebola spread. some of the cultural beliefs common in central and western africa will be discussed here with the goal of fostering cultural understanding of disease. given the diversity of human beliefs, it is likely that future events will again put disease control against traditional beliefs. a good starting point in cultural sensitivity is viewing an idea from the point-ofview of the other party. in the case of ebola, it is important to understand what different groups of people believe to be the etiology of disease. most educated health professionals view disease as an understandable biological process. infections are caused by microbes. in the case of ebola, it is a filovirus. in many traditional african cultures, disease is believed to be due to witchcraft [ ] . consultation with traditional healers is a common practice across africa. in many regions traditional healers are the only locally available medical provider. even if modern medical facilities exist, many will turn to the traditional healers first because they are more trusted, and their beliefs tend to align more closely with those of the community. there are many different traditional healing practices, sometimes traditions are passed down through generations in specific families. one description of a traditional medical ceremony in sudan describes a medicine man and his assistants. first, ritualistic dance and chants are performed. next the medicine man shows his spiritual power by having a large rock placed on his abdomen and broken by an ax while he remains still. once his strength has been established, his attention can be turned to his patient. the medicine man's diagnosis is mental illness caused by evil ancestors who have returned with the purpose of tormenting the patient. incantations are the treatment [ ] . beliefs and practices such as this are common in rural central africa. in these societies, illness is viewed as a disruption in the relationship between god, ancestors, and the person affected. witchcraft, sorcery, angry ancestors, and evil spirits may all be at the root of disease and a powerful medicine man can restore the proper balance in these relationships thus curing disease [ , ] . the individual customs and beliefs associated with the cause and treatment of disease is too long to be included here, but those interested in additional information should read the articles cited in this section for additional details. traditional healers can be a great asset to a community, but there have been unfortunate instances where they actually promoted the spread of ebola. some traditional healers claimed to be able to cure ebola. unfortunatly, their attempts at cure have been known to spread the disease to those in attendance of curative ceremonies as well as to themselves [ ] . traditional healers can also charge a significant amount of money putting a family who is already dealing with the loss of a loved one in additional financial stress [ ] . not all traditional healers seek the good of the community but instead are motivated by personal gain. many societies in central africa practice religious beliefs based on a combination of mainstream religion and ancestor worship. occult ceremonies, secret societies, and rituals are common, and the details of these practices are often covert, only known to a small subpopulation. the ceremonies may be benign such as the one described in the preceding paragraph or may involve animal or human sacrifice [ , ] . while many of these practices involve sacrifice and exposure to blood no studies have been published linking these activities to ebola transmission. it is the traditional funerary practices that have been most closely associated with the spread of ebola. many central and western african cultures view the death ceremony as one of the most important. when people die, they must be guided to the realm of the ancestors. from this realm, ancestors are able to hear the requests and see the needs of the living family and communicate these needs to god. the living family prays directly to the ancestors. if death rights are not done correctly then instead of becoming an ancestor, the deceased may become an angry ghost which torments the family [ ] . a common funerary practice in liberia is for an elder family member to bathe the body of the deceased. it is common for mourners to touch the face and kiss the forehead of the deceased. in some traditions the spouse of the deceased continues to share a bed with the corpse until the time of burial. another tradition involves dance. on the night prior to the funeral, men dance with the dead body while women wail. several traditions involve sacrifice and exposure to the blood of a bull as part of their ceremony [ ] . to prevent the spread of disease the governments in liberia and guinea passed laws requiring safe burial teams or cremation when the number of grave sites was insufficient for the number of bodies. numerous reports of bribing health workers responsible for collecting and properly disposing of the bodies allowed ebola to persist in this region [ ] . people stopped going to the health care facilities, and families would try to hide the cause of death from officials. at the height of the epidemic in sierra leone, the number of ebola care beds was insufficient for the number of patients. many were transferred from facility to facility and their families were not notified. rumors began to spread that the ebola facilities were harvesting organs and killing people [ ] . poor communication resulted in suspicion and distrust. it took thousands of deaths, but finally both sides began to compromise. the government and health care workers started to work with local religious leaders and traditional healers to find solutions that would let the people honor the dead without exposing themselves. many muslim leaders told their followers to abstain from washing bodies until the outbreak ended. bodies were buried with families nearby and although the could not touch the bodies prayers could be said. burial teams started to dress corpses in clothing requested by the family and often placed requested jewelry. once all sides compromised and started working together the epidemic was able to be contained [ ] . even if someone survives ebola the battle is not over. there is poor understanding of disease and disease transmission. survivors may be ostracized and shunned by their communities because there is fear that they can spread disease. survivors have had their houses burned, families attacked, and lost their jobs due to irrational community fear. during the west african ebola outbreak survivors were issued certificates stating that they were no longer contagious in an attempt to combat social stigma. this is not to say that it is all gloom-and-doom in countries that have experienced ebola outbreaks. social determinants of health are not isolated static elements. technology and globalization are bringing health improvements at an unprecedented rate. if one reviews data for the countries where significant ebola outbreaks have occurred, guinea, uganda, drc, south sudan, and liberia. all of these countries have had a decrease in infant mortality rates, decrease in maternal mortality rates, and extreme poverty rate have been steadily dropping over the last years despite the presence of ebola [ ] . anyone interested in additional information on measurable global trends, whether they be economic, or health based is encouraged to visit gapminder (www.gapminder.org). not every country that faces ebola descends into a public health crisis. in july multiple cases of evd were diagnosed in lagos, nigeria. lagos is a densely populated city and the capital of nigeria. the nigerian ministry of health was able to rapidly contain the situation before a full-scale epidemic began. the nigerian government had access to trained health care providers able to do contact tracing, able to mobilize a rapid efficient response, and worked closely in cooperation with the who to implement standardized epidemiologic practices. the epidemic in nigeria was halted before it was able to start [ ] . ebola in the technology era the concept of quarantine was first developed in the fourteenth century to control the spread of plague [ ] . quarantine is a required separation of incoming people or animals prior to mixing with the local population with the goal of preventing the spread of disease. it is one of the oldest and most effective public health measures, but very unpopular with those whose movements are restricted by quarantine. recently, kaci hickcox, a nurse volunteering in sierra leone returned to the us. she possibly had been exposed to the ebola virus. ms. hickcox was placed on a mandatory home quarantine of days, but she defied the quarantine order and proceeded with her day-to-day activities [ ] . in reality, she was at very low risk for developing the disease, and there was essentially no risk for widespread ebola transmission in the us, but her unwillingness to comply with the quarantine brought attention to many public issues surrounding quarantine. specifically, the conflict between individual civil liberty and the well-being of the general public [ ] . since when quarantine laws were first written technology has expanded drastically. surely there exists a technology that allows us to abolish the antiquated quarantine system. whether an intentional act of terrorism or through accidental contagion spread, travelers pose a significant threat to homeland security. various measures have been attempted to try and identify sick travelers with the goal of limiting epidemic spread. the following is a discussion of currently available boarder control measures aimed at preventing the spread of disease, and evaluation of the effectiveness of these measures, and a discussion of technologies that may be of utility in the future in preventing cross-border ebola spread. two-point-five million people fly in or out of the united states every day [ ] and an estimated one-million more per day cross via land and sea [ ] . with millions of border crossings daily, transmission of communicable disease between remote locations is inevitable. the vast majority of communicable diseases spread by travelers are upper respiratory viruses such as the common cold or influenza. generally, these are self-limited illnesses with few long-term consequences. every few years though, something new with greater lethality emerges and threatens the security of the us travelers, their contacts, and the broader population at home. ebola, severe acute respiratory syndrome (sars), and even the relatively benign zika virus have made media headlines with travelers seen as potential harbingers of disease. another factor that must be taken into account is the increasing population density and urbanization. the united nations (un) predicts that % of all people will live in cities by the year [ ] . a megacity is defined as an urban population of over ten million people. the first to reach megacity status was new york city in the 's [ ] . by , the megacity count rose to [ ] . large numbers of people in a small area constitute a vulnerability when looking at epidemic risk assessment. a single ill traveler arriving to a megacity has the potential to start a local chain of infection that could rapidly spread to millions. with the widespread availability and affordability of trains, planes, automobiles, buses, and boats it is easy for microbes as well as humans to travel rapidly across the globe. travel provides individual freedom for pleasure and commerce but, at the expense of national security. small disease outbreaks are continually occurring across the globe. multiple international monitoring systems are in effect and the center for disease control (cdc) has issued official recommendations for travel restrictions for persons with higher-risk exposure to communicable diseases of public health concern [ ] . briefly, these guidelines state that a person who meets the following criteria will have their travel restricted [ ] : be known or likely infectious with, or exposed to, a communicable disease that poses a public health threat and meet one of the following three criteria: . be unaware of diagnosis, noncompliant with public health recommendations, or unable to be located. or . be at risk for traveling on a commercial flight, or internationally by any means. or . travel restrictions are warranted to respond effectively to a communicable disease outbreak or to enforce a federal or local public health order. while the above criteria may be the best legally available option, it leaves a multitude of holes by which a person with a communicable illness could slip into a us city and start a new epidemic. ideally, additional layers of protection would allow potentially ill travelers to be identified and detained prior to entry to the united states. an infectious agent can travel across the globe in h if spread via airplanes [ ] . this has important implications for those trying to prevent disease from spreading. land and boat entry into the united states present other challenges. the sheer number of people crossing by land on a daily basis makes any screening difficult. boat traffic can also present unique screening challenges. a cruise boat, for example, may arrive with thousands of people who all debark within a short period of time. though screens are impractical in these situations. even if screening technology was employed allowing security agents to detect fever there are so many causes of fever that timely interpretation of the data would be difficult. with so much international travel occurring, there is a continual search for ways to improve screening for ill travelers with the goal of preventing importation of disease. many different methods have been tried, most centered around a specific pandemic rather than continual monitoring. none have had great success. these methods have included entry-screens, exit-screens, and post-entry monitoring. the us division of quarantine is not only authorized, but required to identify and detain anyone entering the country with actual or suspected diphtheria, any viral hemorrhagic fever including ebola, cholera, tuberculosis, small pox, plague, novel influenza strains or yellow fever [ , , ] . in theory, this is an excellent regulation, but how can millions of travelers be efficiently screened and detained if needed? after the outbreak of sars in many countries starting using boarder screening to try to identify possibly ill people in hopes of limiting spread of infectious disease, others jumped on board after the h n influenza pandemic. the issue then resurged in the wake of the ebola outbreak in west africa. as with many things, there must be an understanding of the costs, potential benefits and effectiveness of programs aimed at preventing a possible public health disaster. an article by the cdc, published around the same time as the article recommending travel restriction for high-risk individuals, concludes that border screens are expensive and not effective in preventing the spread of disease [ ] . while point-of-care screens are not yet considered an effective means of controlling certain biosecurity threats, progress is being made. temperature screens have been developed with the goal of identifying people with fever. what happens when a fever is detected depends on where a person is traveling to and from, and the current state of outbreaks occurring in the world. there are several types of temperature readers including ear gun thermometers, full body infrared scanners, and hand-held infrared thermometers [ ] . none of these methods is highly effective and most screening devices can be fooled with minimal training and effort. once study found that thermal screens were only about % effective in detecting fever. the authors of this study concluded that temperature screens were ineffective in identifying ill travelers [ ] . the european center for disease control (ecdc) has also investigated the feasibility of using temperature screens to identify ill travelers and came to similar conclusions. this report was done during the ebola of and geared towards diagnosing travelers potentially infected with ebola. they estimate that even under ideal conditions % of symptomatic illness would be missed due to low sensitive of temperature devices [ ] . additionally, it was concluded that those intentionally trying to mask their temperature could easily do so and that those who had not developed symptoms would be missed by the screen. even if fevers screens were accurate and difficult to manipulate that would still be a poor screening measure. first of all, with many illnesses including chicken pox, flu, the common cold and countless others, people can be contagious before a fever starts. it is not yet known if an infected person can spread ebola before symptoms begin. secondly, not all fevers indicate an infectious disease. fevers can be due to drug reactions, blood clots, and even cancer. third, not everyone reacts to an infection the same way. some people naturally tend to have fever and others tend not to. one expression commonly taught in medical schools across the us is, "the older the colder". this is a reminder to students that elderly patients may never have a fever even if they are extremely ill with an infectious disease. lastly, what determines what constitutes a fever? the medical field defines fever as a temperature of degrees celsius ( . f) or higher. are these same numbers valid for travelers or should different cut offs be used? while temperature screens may have their place in emergency settings, they are far from an ideal way of detecting an ill passenger and the day to day use of temperature screens is not generally considered an effective means of identifying ill travelers. when foreign agencies are cooperative screening may be done prior to departure. exit screening was done during the ebola outbreak of for travels from west africa to the united states. the goal of exit screening is to identify those potentially infected with a specific disease and prevent them from departing for the united states until they can be medically cleared. the cdc considers this to be one of the more effective forms of preventing disease importation to the united states [ ] . departure screens are not routinely used except during times of known outbreaks. during the west african ebola outbreak exit screening measures were implemented. the general process used for screening during the outbreak was as follows. travelers were instructed to arrive earlier than they normally would for their travel due to increased processing times. general instructions to travelers instructed them to postpone travel if they were ill. in addition to the regular airport screening, all travelers were required to have their temperature taken and fill out a "traveler public health declaration". travelers who were febrile or considered at risk based on the answers to their health declaration forms were detained and their travel delayed [ ] . during the ebola outbreak the who provided resources for predeparture screening that were detailed yet used easy-to-follow language and including flow charts for those performing the screen. basic information on ebola and its symptoms so that the illness was more well understood and the disease symptoms familiar. directions for using personal protective equipment for those performing the screening. written tools and the public health declaration form were provided. additional resources included a data collection log and a traveler information card that could be distributed to travelers [ ] . the ebola screening was done in two steps, a primary screen and a secondary screen. the primary screen included three questions: ( ) is the traveler febrile?; ( ) is the traveler demonstrating symptoms of ebola?; and ( ) has the traveler marked "yes" to any questions on the health declaration form? an affirmative response to any of these questions resulted in secondary screening. secondary screening involved a public health interview and filling of the secondary health screen form, repeat temperature measurement preferably with an accurate thermometer, and focused medical exam. if the secondary screen found a temperature < . , no risk factors for ebola in the public health interview, and no symptoms of ebola on the public health interview they were allowed to proceed to check-in. if the above criteria were not met, check-in was denied until health clearance could be obtained [ ] . this strategy was considered effective. the limitations include the time and money required to implement the program, frustrating travel delays for travelers, and the inability to identify illnesses other than ebola or similar diseases. its usefulness is limited to known and identified epidemics. this strategy will likely continue to be used in future outbreaks to prevent exportation of disease [ ] . temperature screens have been used during five epidemics to date, dengue, sars, ebola, and influenza during both the entry and exit process. screening for fever in taiwan entry points during a dengue outbreak was reported to be effective. one research study reports that % of imported dengue cases were able to be identified through airport screening [ ] . during the sars outbreak, singapore entry points screened , people and identified no cases, canada entry points screened . million people and identified no cases, and hong kong entry points screened . million people identifying only two cases of sars [ ] . fever screening was used during the - influenza pandemic and even with a low threshold for defining fever was found to have a sensitivity in the . % range. exit screening done in west africa during the ebola outbreak identified fever in out of , travels screened. of these, none had ebola [ ] ). active monitoring is another technique that can be used in preventing disease spread within ebola naive countries such as the united states. it involves allowing a traveler freedom to come into the us, freedom from quarantine, but also allows health authorities to monitor the health status of potentially infected people. if someone begins to develop symptoms then measures can be taken to isolate, diagnose, and treat the ill person. this method is best applied to those who are reliable and at low risk for developing illness. there has not been much experience with widespread use of active monitoring systems with the exception of the western africa ebola outbreak. during this outbreak, travelers from liberia, sierra leone, and guinea to the us were given care (check and report ebola) kits upon arrival to the us [ ] . care kits provided resources to travelers from ebola affected countries. travelers were given information on the signs and symptoms of ebola, educated on the basic pathophysiology of ebola, provided a thermometer with detailed use instructions and given a cell phone to ease the communication process. travelers were allowed to travel freely but were required to check in with public health officials daily. during these check-ins, Àhealth reports were given including the development of any new symptoms, and daily temperature readings for days. ebola has a highly variable incubation period. twenty-one days was the longest interval between exposure and disease presentation to have been reported accounting for its use in both care packages and quarantine [ ] . while the cdc coordinated active monitoring programs, the programs were managed at the state level. all states eventually participated, but with varying start dates. new york, pennsylvania, maryland, virginia, new jersey, and georgia were those to first initiate the program. seventy percent of travelers from west africa enter through these states making them logical starting points for the program [ ] . after much legal debate and unwanted publicity, ms. hickcox mentioned in the introduction, eventually went into active monitoring program which restored most of her personal freedoms while at the same time protecting public interests. currently available technology is considered insufficient to prevent entry of ill individual into ebola naive countries. the general public continues to demand protection of civil liberties that include the freedom to travel and protection of privacy. despite recommendations by the cdc, it is difficult to identify an ill traveler either before a person embarks for the us or at the point-of-entry. post entry monitoring of reliably low risk travels is a socially acceptable alternative to quarantine and considered reliable although not widely tested. screening technologies such as infrared screens may not be considered useful on a daily use basis but may prove of utility under certain circumstances such as an active ebola outbreak. as research continues, technology advances, and better models to study patterns of disease spread are developed, new methods of pointof-entry biosecurity are sure to emerge. bioterrorism is the intentional spread of disease with the goal of destabilizing an opposing group. it is thought to have roots extending back to at least bce when the hittites used infected sheep to spread infection and destabilize their opponents [ ] . since that time, technology has improved and along with it the threat of bioterrorism has augmented. the center for disease control (cdc) divides bioterrorism agents into three separate categories a, b, and c. category a agents are those which are considered to be of highest risk. characteristics group a pathogens are, easy transmission, high mortality rate, protentional for social disruption, and require special action. category b agents are of concern, but considered to have a lower potential for disease than those in group a. this category is comprised of pathogens that are moderately easy to spread, have moderate morbidity, low mortality and require specific diagnostic and surveillance tools. group c are agents of some concern. this group is made of pathogens that are easily available, easy to produce and disseminate, and potentially have significant medical and public health implications. emerging infections also fall within group c pathogens. ebola is considered to be a high threat level a biothreat [ ] . bioweapons are at least as large a threat to homeland security as are traditional weapons. biological weapons are attractive to potential terrorists because they are relatively inexpensive to manufacture, easy to encounter, and easy to distribute [ ] . in the biological weapons convention went into effect. it has been signed by countries and prohibits the development of biological agents for the purpose of warfare. unfortunatly, terrorists fail to abide by this convention, and it is rumored that even some of the countries that signed the convention document continue to engage in clandestine research into biological agents for warfare. characteristics of a pathogen with bioterrorism potential are those with consistent disease induction and progression, high infectivity, are easily transmissible between people, are difficult to diagnose, and have a high mortality rate [ ] . it is also important that the pathogen be stable during production, storage, and distribution [ ] . lack of immunity in the targeted population and diseases that are difficult to diagnoses are also attractive to would-be terrorists. ebola possesses many of these characterizes. ebola possesses many features of an ideal bioterrorism weapon. in the early stages, ebola presents as an acute viral illness. by the time clinical features unique to ebola infection have developed, it is likely that the illness will already have be transmitted to others. particularly vulnerable are those caring for infected patients including family members and health care workers. despite being limited to transmission through body fluids, ebola is highly contagious. ebola has a high mortally rate and is attractive to terrorists because there is already widespread fear associated with ebola infection. reston virus, a non-human pathogen in the ebola family, can be transmitted. there is concern that with genetic manipulation evd could be transformed into an airborne illness and distributed as a bioterrorism weapon [ ] . ebola is one of the many pathogens that could potentially be converted into a biological weapon. preparedness plans at the local, state, and national level all include sections applicable to ebola. all hospitals in the nation have received training on ebola identification and response. continued vigilance and repetitive training sessions are required to ensure that should ebola be used as a biological weapon, it will be rapidly identified and contained. ebola virus is an agent that could be used as a bioterrorism agent. it is deadly, can result in long term infection in survivors, and non-specific clinical presentation make it an attractive choice for would be terrorists. also, for many people, the word ebola creates fear out of proportion to the actual risk of disease. this visceral reaction and exaggerated fear make ebola a tempting agent. on the other hand, the lack of airborne spread and existence of effective vaccine (even if not licensed) are deterrents to its use. it is impossible to know with certainty when the first ebola infection occurred. most likely it was in a remote african jungle and those infected died without a diagnosis other than that provided by the local traditional healer. what can be said with certainty is that the outbreaks are occurring with more frequency. no one knows with certainty why this is. hypothesis tend to center around issues of environmental degradation in association with increased population mobility. increasing population, global warming, and continued human encroachment into forested areas have been put forth as potential contributing factors. increasing population is theorized to be contributing to the increasing frequency of ebola outbreaks. increasing populations, particularly in developing countries, tend to lead to congesting living conditions and rapid disease spread, but this would not explain how the index case in an outbreak becomes infected. experts opinion often lists expanding population as contributing to the ebola outbreak, and intuitively it is credible, but there is little in the way of direct evidence to support this theory. literally hundreds of studies have been conducted on ebola since the outbreak, but none directly addresses the relationship between population growth in africa and increasing frequency of ebola outbreaks. it is likely that the impact of increasing human populations in endemic areas will not be fully understood until the reservoir of ebola has been determined. what we can say with certainty is that once started, ebola spreads more quickly than it did in the past and is killing more people. population level research on ebola has yielded interesting results. for a start, risk of ebola infection has been associated with a higher level of education [ , ] . lower risk for acquisition of ebola at the population level has been associated with urban residence, households with no or low-quality sanitary system, and married men in blue-collar professions in the outbreak in west africa [ ] . other studies have found different results when examining the interplay between population dynamics and the emergence of ebola. for example, in contrast to the study by levy & odoi, ebola transmission has been positively correlated with population density, and proximity to ebola treatment centers in other investigations [ ] . another study found that . % of people who tested positive for ebola cases lived within a -km of roads connecting rural towns and densely populated cities [ ] . basic public health principles hold that increasing population density allows infectious disease to spread more quickly, but it is unclear what the impact is on the emergence of ebola. it is safe that there is a relationship between population density, population distribution, and ebola but the exact nature of that relationship remains elusive. climate change has been cited by mass media sources as the source of emerging disease such as ebola. elevated atmospheric temperature have been associated with the development of evd, but then so have low temperatures [ ] . there does appear to be a relationship between ebola and temperature, but the character of that relationship is not clear. ebola virus is sensitive to high temperatures so intuitively, higher temperatures would not create a more active form of the virus. what may change is the human response to higher temperatures. when it is hot, people sweat more, drink more, and may wear different clothing. it may be that the human response to hot weather is responsible for the noted difference rather than changes in viral activity. it is also possible that temperature changes correlate with other phenomena such as rain storms and that rain, or the response of vegetation to rain somehow impacts the emergence of ebola. climate change, whether due to human activities or natural climatic cycles will change patterns of disease across the globe. how changing weather patterns may affect the distribution and frequency of ebola cases remains to be seen. possibly once the reservoir of ebola virus has been discovered scientists can predict with greater certainty how climate change will impact the emergence of ebola. it is also postulated that ebola is occurring with greater frequency due to increasing human activities within previously untouched natural areas. at least one study has linked deforestation to evd outbreaks [ ] . again, there are limited studies confirming this idea, but logic does suggest that it would be true. expert opinion, and the mass media purport that the increasing frequent outbreaks of ebola are due to environmental encroachment [ ] . as roads are build, forests are cut, and mineral resources exploited humans are in more intimate contact with the forest and its inhabitants including the reservoir for ebola. the reservoir is unknown, but it is probably found in african jungles. a study looking at vegetation cover, population density and incidence of ebola found that vegetation was protective until the population reached people per square km. at this population density vegetation became associated with and increase incidence of evd [ ] . there is a relationship between environmental encroachment and the emergence of ebola, but until the reservoir is found it will be difficult to determine the exact nature of this relationship. the frequency of ebola outbreaks has been increasing. international collaboration is essential to better understand how and why this is occurring. traditional tribal regions do not always follow country lines and both official and unofficial border crossing are common. contact tracing is essential for containment of ebola outbreaks requires countries to coordinate as people cross borders. epidemiological evaluation and experience in treating the disease also require a global rather than country approach. the study of ebola requires systematic evaluation and intercountry coordination to most effectively predict outbreaks and limit their spread once they do occur. the global community would also benefit from international standards for diagnosis, prevention, and treatment. luckily, framework already exists for this collaboration, at least in times of epidemics with pandemic potential. the international health regulations (ihr) agreement is legally binding accord signed by countries. it stipulated that these countries must act to contain the threat if a public health emergency of international concern (pheic) is declared by the who director general. a pheic was declared in august in response to the ebola outbreak in west africa [ ] . the ihr helps to ensure that an appropriate global health response will be made once a public health disaster is well underway. intervention at this level will help curb progression of the disaster. along this same line of thinking, mitigation and preparedness efforts are needed prior to development of a public health disaster. if a pheic is declared, then local measures have failed. improved regional collaboration is needed to help minimize the impact of ebola in the region. many countries at risk for outbreaks of evd would benefit from bolstering of their public health and medical programs. outside assistance is a starting point, but capacity building is required for long term solutions. in countries with weak public health infrastructure international efforts need to focus on programs to develop a sustainable public health system. the challenges are considerable particularly in areas of chronic conflict, but progress has already been made and with continued support will continue into the future. a basic public health infrastructure will help contain ebola as well as whatever threat comes next. when an ebola outbreak hits the general public needs to be educated on how to respond. if ebola preparedness is part of the local education, then lives can be saved. the public can help with surveillance efforts. this would require the population to trust the public health community, believe that their input is useful, and that they be trained to recognize potential ebola in the community. public health education can also assist with limiting spread if an outbreak does occur. this education can be provided through schools, community outreach campaigns, or religious institutions. the education does not need to be complex, just consistent, concise, true, and culturally appropriate. outbreaks of evd have been occurring with increasing frequency. thousands have died and thousands more have been lives have suffered because of the disease. the disease is highly fatal, but even more insipid, it exploits traditional ceremonies and death-rights as a means of spread. poverty, both at personal and national level has resulted in an infrastructure ill-equipped to deal with events such as ebola. overcrowding promotes transmission and lack of financial incentives have delayed vaccine development. despite the barriers, evd is slowing being more well understood, thousands of research articles have been published, and guidelines for every aspect of the disease have been published by the who, cdc, or other government level organizations. progress is being made. esposure patterns driving ebola transmission in west africa: a retrospective observational study assessment of the risk of ebola virus 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a two-year-old child died from viral haemorrhagic fever in méliandou village in the south-east of guinea, and constituted the likely index case of a major epidemic. when the virus was formally identified as ebola, epidemiologists started to investigate the chains of transmission, while local people were trying to make sense out of these deaths. the epidemic control measures taken by national and international health agencies were soon faced by strong reluctance and a sometimes aggressive attitude of the affected communities. based on ethnographic work in macenta (forest region) in the autumn of for the global outbreak and alert response network (goarn) of the world health organization, this chapter shows that while epidemiologists involved in the outbreak response attributed the first ebola deaths in the forest region to the transmission of a virus from an unknown animal reservoir, local citizens believed these deaths were caused by the breach of a taboo. epidemiological and popular explanations, mainly evolving in parallel, but sometimes overlapping, were driven by different explanatory models: a biomedical model embodying nature in the guise of an animal disease reservoir, which in turn poses as threat to humanity, and a traditional-religious model wherein nature and culture are not dichotomized. the chapter will argue that epidemic responses must be flexible and need to systematically document popular discourse(s), rumours, codes, practices, knowledge and opinions related to the outbreak event. this precious information must be used not only to shape and adapt control interventions and health promotion messages, but also to trace the complex biosocial dynamics of such zoonotic disease beyond the usual narrow focus on wild animals as the sources of infection. at the end of december with the death of a two-year-old child in the village of méliandou in guéckédou prefecture, four days after the onset of symptoms (fever, black stools and vomiting). this patient would be considered from now on as the 'case zero', the index case stemming the severe ebola virus disease (evd) epidemic of west africa from apparently a single zoonotic transmission event. but then, with the idea of the spillover taking central stage the question arises: which animal species, the mythic 'animal zero', came to bear the burden of epidemic blame this time? while this retrospective epidemiological study was perceived as essential for limiting high-risk exposures and for quickly implementing the most appropriate control interventions, these investigations (biomedical experts deployed from the rich north) were tempted to mimic and fulfil the 'outbreak narrative' imposed by the global health governance. in this endeavour, rather than discovering the epidemiological origin, what becomes crucial is to quickly identify the carriers-'these vehicles necessary to drive forward the plot', which often function as the outbreak narrative's scapegoats. historically always located at the boundary of the human social body, the ideal candidate to carry this role in the evd epidemic of - was once again the wild and villainous non-human animal. because the pathways for emergence are in any way 'natural' or 'sylvatic', according to the dominant western biomedical model, the inclusion of wildlife in the epidemiology and the evolution of emerging infectious diseases is justified, yet its role is often misrepresented. although the probability of a humans contracting the disease from an infected animal still remains very low, certain cultural practices sometimes linked with poverty, especially 'bushmeat' hunting, continue to be seen as the main source of transgression of species boundaries. in the african context, research into emerging infections from animal sources implicates nonhuman primate 'bushmeat' hunting as the primary catalyst of new diseases. since the virus of ebola was identified for the first time in zaïre in and qualified as the first 'emerging' virus according to the new world clinic called 'global health', the link between animal and human health appears based on an 'us vs. them'. after the formal confirmation of the aetiological agent in march , the epidemic quickly took on an unprecedented scale and severity in several respects. it was declared by the who as an 'extraordinary event' because of its duration, the number of people infected, and its geographical extent which made it the largest ebola epidemic recorded in history until then. to these quantifiable impact measures were added sociological, ecological, political and economic phenomena that are much more complex to decrypt. these have had a profound impact on society, well beyond the remote rural environment that was typically affected by preceding epidemics. by threatening major urban areas, these 'geographies of blame' or 'hotspots' (usually at the margin of modern civilisation and configuring specific areas of the world or the environment into the breeding grounds of viral ontogenesis) have been mapped by 'virus-hunters' to update 'predictions about where in africa wild animals may harbour the virus and where the transmission of the virus from these animals to humans is possible'. in addition to this epidemic's extraordinary character, by spreading beyond the capacities of humanitarian aid, this new biomedically unsolved complexity conferred upon it a status of 'exceptionality' also by 'proclaiming the danger of putting the past in (geographical) proximity with the present'. this status had the effect, among others, of the most intense involvement, perhaps more visibly than before, of different disciplines, from human and animal health to the social sciences, in the international response. anthropology's response in particular was 'one of the most rapid and expansive anthropological interventions to a global health emergency in the discipline's history'. yet it is very critical that the collective social science experiences acquired during this west african ebola epidemic remained engaged to addressing future outbreaks and beyond. they translated and shared anthropological knowledge between scholars by including translation for public health specialists, transmitting that knowledge to junior scientists, and engaging in ongoing work to develop relevant methodology and theory. among the three west african countries most affected by the epidemic, guinea-conakry has been more marked by this dual 'exceptionality', that is to say, both epidemiological and social. beside the exceptionalism described by the senegalese anthropologist faye on the strong and sometimes violent demonstrations of popular reticence with regard to the activities of the 'riposte', guinea was also marked by a higher case fatality rate, as shown in the who report of march . globally raised up to more than % (while knowing that the number of cases and deaths was probably underreported), this case fatality rate confirmed the seriousness of the disease in a guinean context where the ebola virus had never hit before. neither the medical community, nor the population, nor the authorities had so far experienced it. despite all the measures implemented, to the question, why did we observe a higher case fatality rate in guinea compared to that of other countries, a multitude of factors can be advanced. the latter deserve to be the subject of multidimensional analyses, especially as this global lethality has manifested itself differently according to the geographical region of the country. the highest fatality rate was observed in forest guinea ( . %, / ), the region of origin of the index case and main epicentre of the epidemic. was this due to exclusively biomedical factors, such as a lower level of immunity among the guinean population? or was it because of late care that would have given patients less chance of surviving and fighting the virus? but then, why did people infected with the virus later arrive at ebola treatment centres (etc) in guinea? was it due to a poorer and more limited health system and frailer medical and health infrastructure than liberia and sierra leone at the time of the epidemic? or was it due to less effective coordination work by international and national teams in responding to the epidemic? or simply because in guinea the local communities were much more reluctant and intentionally opposed to the deployment of humanitarian and health assistance? although sharing broadly similar cultural worlds, what can therefore explain this notable difference of social resistance between the affected countries? combined with a divergent political practice and lived experiences of the state, especially between sierra leone and guinea, the working hypothesis drawn from my ethnographic observations in macenta and related literature review is that part of the continuing episodes of hostility and social resistance manifested by guinean communities regarding the adoption of the proposed control measures against the scourge of ebola has its origins in the divergence between explanatory systems of the disease; on the one hand, biomedical explanatory systems, and, on the other hand, popular explanatory systems. in march , when ebola hemorrhagic fever was formally identified a few months after the first death, epidemiologists and local populations each actively began to trace and understand this first human-to-human transmission chain of the disease, as well as its triggering event. evolving most often in parallel, and overlapping at times, these epidemiological and popular investigations generally refer to different explanatory models, some more biomedical ('natural') and others more mysticoreligious ('supernatural'). the purpose of this chapter is to trace and reflect on the interpretations of the origin and transmission of the ebola disease, as perceived and explained by the population, and to contrast them with the explanatory model of epidemiologists. in order to interrupt the two routes of evd transmission, namely from animal reservoirs to humans and between human infection, humanitarian responses followed the following public health logic: 'bushmeat' hunting, butchering and consumption should be banned and the ill should be isolated within etcs and burials should be made safe. yet, the interventions related to this reasoning had unattended consequences and, together with the ebola disease itself, they 'disrupted several intersecting but precarious social accommodations that had hitherto enabled radically different and massively unequal worlds to coexist'. carriers, in the case of human-to-human transmission, are generally perceived as the ones promulgating the epidemics and are marked with transgressive attributes intrinsic to their 'contagiousness' (e.g. wanton or deviant sexuality for the hiv epidemic, uncleanliness for the cholera epidemic, immigration for typhoid). however, in zoonosis-related diagnostic discourses, pathogens have the potential to reverse relations between humans and animals in such a way that the carrier becomes the victim. located at the 'interface' between humans, animals and the (natural) environmentalready proved to be a virtual place where deadly pandemic risks lie waiting for humanity-'forest people' from guinea were rendered both carriers of the disease and victims of the villainous role of nonhuman animals. the response to the fear of pandemics has been made unmistakable: we have to shield off humanity from nature. this mindset strongly adheres to the prevailing 'culture-nature divide' which is also depicted through zoonotic cycles diagrams further operating both as pilots of human mastery over human-animal relations and as crucial sites of unsettlement for the latter. wild animals became public enemy number one, together with those who were supposedly facilitating the transgression of the boundaries between the cultural and natural world with (or because of) their culturally 'primitive' or 'underdeveloped' practices. by framing 'bushmeat' hunting, as well as local burials, as the main persisting cultural practices among the 'forest people' to explain (or to justify) the maintenance of the evd transmission during the west african epidemic, the notion of culture that fuelled sensational news coverage has strongly stigmatised this 'patient zero' community both globally and within guinea, and has been employed to obscure the actual, political, economic and political-economic drivers of infectious disease patterns. appointed by my former institute, the institute of tropical medicine of antwerp, belgium (itm), to the who, i was sent to guinea-conakry from the end of october to the end of november for a four-week mission by the global outbreak alert and response network (goarn). since august , the country had been in the largest and longest phase of the epidemic, the second recrudescence which would also be the most intense one up until january . i first spent a week in conakry to follow the implementation of a social mobilisation project (project of monitoring committees at the level of each commune in the urban area). then, following an evaluation of the situation qualified as catastrophic by the national coordinator of the who, it was in macenta, forest guinea, where i was deployed. macenta, located east of guéckédou, was the prefecture considered to be the epicentre of this new outbreak of ebola and where transmission was the most intense. this district would remain one of guinea's most affected regions. by october , macenta, where catastrophic scenarios seemed possible, had already a cumulative number of almost cases since the beginning of the epidemic. the epidemiological situation was out of control, with a lack of material, human and financial resources. on arrival, there was still only one transit center (cdt). a new etc was being finalised by msf belgium. its management would be taken over a few weeks later by the french red cross. due to the long rainy season, the road used for bringing confirmed cases from macenta to the guéckédou treatment centre was in a deplorable state, slowing down the start of treatment and increasing the risk of transmission during transportation. it is as a medical anthropologist that i have been involved in guinea's national coordination platform for the fight against ebola and this within the commission of 'social mobilization and communities engagement', also named locally the 'communication' unit, in order to document, better understand and help to address the reluctance manifested by the local community. without going into the debate about the instrumentalisation of anthropologists as simple 'cultural mediators' at the service of humanitarians, i will simply recall here the specific objectives assigned for the mission. they consisted, on the one hand, in an analysis of rumours and crisis situations in order to propose responsive actions and, on the other hand, in adapting the responses and protocols of the various national and international institutions to local conditions, giving priority to comprehensive and participatory approaches. by integrating the 'communication' unit, i tried to support and animate the meticulous and sensitive work of a whole team working to rebuild trust with communities and to 'open' villages reluctant to receive care interventions. under the authority of unicef guinea, this communication team also hosted many local associations previously working for the prevention of infectious diseases, such as hiv/aids, in the region. the latter had already been mobilised to serve as a relay and to mitigate the unpredictable consequences of the epidemic not foreseen by the riposte, such as, among other things, sensitisation and reception of healed people and orphans of ebola, food distribution, and support for people and villages stigmatised by the disease for whom access to the market-purchase and sale of products-was forbidden. religious representatives of protestant and muslim communities also voluntarily joined this platform to learn and then preach preventive behaviour, to comfort the population, as well as to deconstruct and addressed rumours. their main message was to convince the public that ebola did indeed exist and 'was a real disease'. subsequently, the communication unit was finally able to associate the prefectural direction of traditional medicine of macenta counting traditional healers and distributed in the subprefectures of macenta. the main objective of this new activity was to engage all traditional healers in the fight against evd by raising the awareness of their patients and their entourage thanks to their high level of credibility in their respective communities. they also undertook to refer their patients directly to the tc if they came to present even one of the symptoms of evd (fever, diarrhoea [with blood], vomiting [with blood], loss of appetite). a 'health promotion' team managed and financed by msf belgium also acted on the ground. each morning, the different commissions and stakeholders of the riposte present in macenta were meeting at the prefectural health directorate (dps) to discuss and coordinate their activities in the field. alongside a guinean sociologist, consultant for the who and the assistant coordinator of the mission philafricaine, i was quickly immersed in the realities of the field and in the local strategies elaborated with respect of traditional hierarchies, despite the emergencies. their goal was to restore dialogue with the various village representatives who, since the officialisation of the epidemic, had decided to resist ebola interventions. this was, for instance, the case of the village of dandano, where deaths had risen to ; a village whose access was authorised the day after my arrival in macenta. although tragic, this coincidence made me earn some legitimacy from the other national and international 'fighters'. it is in this intense and difficult context that the ethnographic observations and their preliminary analysis, presented in this chapter, were collected. the methods employed are based on participant observation, including many informal discussions during meetings with villagers (representatives of youth/notables/sages/women), with religious representatives (protestant pastors, and imams), with drivers and partners of the coordination community (e.g. doctors without borders, guinean red cross, unicef among others). some formal interviews were also conducted with key informants such as healed individuals (ebola survivors), traditional healers, pastoralists and local actors in the fight. biomedical scientific literature and reports on epidemiological data, as well as observational notes, photographs and audio recordings collected in the field, allowed me to trace the interpretations of the origin and transmission of ebola in a dual perspective: that of epidemiologists, on the one hand, and that of the population on the other. it is through the concept of explanatory models or 'cultural models of the disease' developed by arthur kleinman that i attempted to interpret the observations ( fig. . ) . this is a conceptual framework that has already been used by barry and bonnie hewlett, alain epelboin and pierre formenty in their respective interventions during the previous outbreak of ebola haemorrhagic fever in the congo in . to be able to adapt the response and interrupt transmission, it is essential to know and understand how the population perceives the introduction of a disease, especially when it is such a deadly one. explanatory or cultural models refer to the explanations of an individual or a culture and to predictions about a particular disease. these are social and cultural systems that construct the clinical reality of the disease. culture is not the only factor that shapes their forms: political, economic, social, historical and environmental factors also play an important role in disease knowledge construction. in kleinmann's model, care systems are composed of three sectors (popular, professional, and traditional) that overlap. in each healthcare system, the disease is perceived, named and interpreted, and a specific type of care is applied. the sick subject encounters different discourses about the illness as she or he moves from one sector to another. kleinman defines the existence, in each sector, of explanatory models of the disease for the sick individual, for his/her family and for the practitioner, whether professional or not. in general, only one part of an explanatory model is conscious, the other is not. although the explanatory models seek from the health district mbomo in congo in , they identified five different cultural models including a sorcery model (sorcerer sending spiritual objects into victims), a religious sect (la rose croix, a christian sect devoted to study of mystical aspects of life), an illness model (fever, vomiting, diarrhoea with blood), an epidemic model (illness that comes rapidly with the air/wind and effects many people) and a biomedical model (ebola haemorrhagic fever). interestingly, none of the integrated non-biomedical models identified a specific non-human animal as potential source and/or carrier of evd or hunting and butchering as specific health risk activities for such illness. this further supports the epistemic dissonance observed during many epidemics (including the west african evd epidemic in this case), between the public health framing of wild meat as hazardous and the practical and social significance of the activities that occasion contact with that hazard. in the case of evd, it is the biomedical cultural model that prevails among western health workers. when the alert was launched by the local health authorities on march , two and a half months after the beginning of the disease of the index case, it was virologic investigations that were conducted at first, following the many deaths that occurred during this socalled silent phase. when the zaïre ebolavirus was identified as the causative agent, retrospective epidemiological investigations of the cases took place, which are crucial during the outbreak of an infectious disease responsible for such high mortality rate. the first chains of transmission of evd are presented in the below graph adapted from baize et al. ( ) (fig. . ). these investigations are mainly based on the identification of patients and the analysis of hospital documents and reports (results of blood tests carried out in the laboratory), as well as on testimonies and interviews with the affected families, the inhabitants of the villages where the cases occurred, suspected patients and their contacts, funeral participants, public health authorities and hospital staff members. virologic analyses suggest a single introduction of the virus into the human population. but the exact origin of the infection of this two-year-old child has not yet been definitively identified, even though the role of bats as natural hosts of the ebola virus, including this time also the insectivorous species, remains one of the most probable scientific hypotheses. up to now, the precise nature of the initial zoonotic event in guinea remains undetermined and the natural reservoir of the ebola virus more generally is not yet certain, beside for three species of fruit bat and other insectivorous african bat species known to carry ebola antibodies and rna. therefore, this informational gap was from the start filled with assumptions during the west african outbreak. among these assumptions, the elusive link between bats, wild animals and humans triggered high concerns over handling, butchering and consuming wild animals, commonly referred to as 'bushmeat'. consequently, these concerns were integrated into public health messages on disease prevention and were translated into a 'bushmeat ban' by governments across the region and enforced during the entire outbreak. this raises the question of the value of focusing on zoonotic transmission, in particular by fruit bats and non-human primates, which was quickly (s ) child, years-old onset dec. dotted arrows: the epidemiological links have not been well established deemed to be of minimal risk, when the biggest threat of infection was from other humans. furthermore, it raises the question of whether there is evidence to indicate and confirm that 'bushmeat'-related information included in public health campaigns in the region actually reduced ebola transmission. first, hunting and consuming 'bushmeat' for food have long been a part of human history occurring worldwide, serving as an important source of protein, and household income, especially where the ability to raise domestic animals is limited. the term itself encompasses an extensive list of taxa that are harvested in the wild (ranging from cane rats to elephants and including duiker, squirrels, porcupine, monkeys, non-human primates, bats and hogs) for food, medicine, trophies and other traditional, cultural uses. yet, designating the consumption of wild animal meat through the use of the term 'bushmeat' for west africans instead of 'game', as is the case for europeans and americans, by the media, scientific literature and public health campaigns that prohibit this practice, participates in 'semiotics of denigration' and has the effect of perpetuating 'exotic' and 'primitive' stereotypes of africa. although involuntary, the immediate and visceral effect produced in western minds by the thought of someone eating a chimpanzee, a dog or a bat, for instance, creates a feeling of disgust which downgrades this person, his/her needs and his/her claims on us. this issue has led to calls to replace the term with 'wild meat' or 'meat from wild animals'. secondly, while the term 'bushmeat' typically refers to the practice in the forests of africa, the trade of 'bushmeat', which has expanded over the past two decades, is considered as an example of an anthropogenic factor that provides opportunities for the transmission of diseases from wildlife to humans. the unsolved reconciliation between present policies and practices and the different values at stake (ecological, nutritional, economic and intrinsic values of wildlife hunted for food) in the actual 'bushmeat crisis', have accentuated the national and global conservation, development and health (infectious disease transmission related) concerns over hunting, eating and trading wild meat. thirdly, because of the many competing interests and realities involved, the proscription of hunting and consuming certain species of wild animals-in particular fruit bats and nonhuman primates during the west africa ebolavirus outbreak-has resulted in several unintended consequences, has incurred great cost and has had only a limited effect. in addition to being vague, inconsistent with scientific research and targeted to the wrong audience, messaging that unilaterally stressed the health risk posed by wild meat and fomite consumption contradicted the experiences of target publics, who consume wild meat without incident. consequently, in addition to having a negative impact on the livelihoods of people living at the frontlines of animal contact, the ban ran the risk of eroding public confidence in the response efforts and fuelling rumours as to the cause of evd (e.g. that the government was attempting to weaken villages in areas supporting the opposition party, as wild meat is considered an important source of physical 'strength' and energy). by focusing exclusively on the risk of spillover, we are distorting and concealing aspects of the dynamics at play. what if species boundaries are not perceived in the same way by everyone? what if the transgression of this 'invisible enemy' is spotted at a different intersection, beyond the nature/society binary? the first chains of human-to-human transmission led to the conclusion that the main vector of contamination was a health professional (s ) who spread the ebola virus in macenta, nzérékoré and kissidougou in february . the fifteenth patient, a doctor (s ), would have also contaminated his relatives in the same areas. the aetiological agent of this deadly disease (the ebola virus for some, the transgression of a taboo for others) remained hidden until then and finally became apparent because of clusters of cases in the hospitals of guéckédou and macenta. indeed, even though the high risk of exposures was elucidated, the problem remained hidden for a number of months, mainly because no doctor or health official had previously witnessed a case of ebola and because its clinical presentation was similar to many other endemic diseases experienced in guinea, such as cholera, which affects the region regularly. but these signals could also have been blurred by another narrative of the causative agent of these same symptoms. this is very similar to what genese marie sodikoff has identified during the recent bubonic plague epidemic in madagascar, when scientists elicited survivors' memories of dead rats in the vicinity to reconstruct the transmission chain. not only were these clues imperceptible to most, but residents had also constructed an alternative outbreak narrative based on different evidence. indeed, the mystico-religious beliefs deeply rooted in this region, even within the medical profession, have offered a different interpretation of causality according to a cultural model other than the biomedical model used by epidemiologists. following james fairhead, it is important to note that 'cultural' model does not tend here to slip into more totalising ideas of 'culture', such as a model being a 'kissi culture' (see below) nor its strict symmetrical opposite (e.g. a model of the 'humanitarian culture' or of a 'western culture'). origin and transmission chain according to an 'animist' model at the beginning of the epidemic, for some, the first deaths in forest guinea were due to the transmission of the filovirus through contact with animals' and/or patients' body fluids; while for others, these deaths originated from the transgression of a taboo related to the touch of a fetish belonging to a sick person, a member of a secret society belonging to one of the ethnic groups of the region. as a result, susceptibility to ebola was initially perceived to be restricted to this particular ethnic group, labelling ebola as an 'ethnic disease'. i decided to name this explanatory model of evd in forest guinea, the 'animist' model, not to further racialise this epidemic, but because it refers to the genies and fetishes that constitute principal aspects of the ancient religions of west africa and also because it describes a belief in a dual existence for all things-a physical, visible body and a psychic, invisible soul. according to a young pastor from macenta who i interviewed, and as confirmed by several other sources of key informants, the population of macenta initially attributed the origin of the disease (in this region at least) to a curse that was only affecting the kissi ethnic group because the first deaths solely affected people belonging to this ethnic group. here is what was stated: … on arrival with all the rumours we heard in conakry, i really did not believe in the beginning that it [the ebola virus disease] must be true because i thought it was an issue of the kissi (…) because it had started in macenta with the kissi, the first deaths were almost only kissi. so we thought it was something related to it … and so we, as toma, it was not going to touch us, it is like that at the beginning we perceived things (…) not something genetic, we thought about the fetishism and idolatry activities that people exercised and that can influence them in one way or another … the first rumour that was there, in macenta, the first death was the doctor who was dead in front of everyone's views. people said they have an idol called 'doma' and so when a person dies of that according to the tradition and according to what is done. and those who are on the thing [those who belong to the secret society of 'doma'] have no right to touch, to manipulate the corpse, or to see it otherwise they may die (…) and that, it existed before. it is a kind of secret society, so they have told us that it can certainly be that, that it is why they [the kissi] are just dying successively. according to these discourses, a health worker from guéckédou hospital (s ), who had gone to seek treatment at his friend's house at macenta hospital (s ), belonged, like him, to a secret initiation society called 'doma' which is also the name of a very powerful fetish; so powerful that it can cause a very fast death for its owner if it has been touched by someone else belonging to the same secret society. when the guéckédou health worker's body was moved, the doctor from macenta would have touched this fetish, idol, sacred object, often hidden in the owner's boubou (traditional clothing). by touching the sacred, the fetish got upset causing the brutal death of the director of macenta's hospital very soon after this event. at that point, in order to repair this transgression and calm the anger of the fetish, six more deaths must succeed each other to reach the symbolic number of seven. if the number of sudden and rapid deaths reaches eight, it means that the fetish is very powerful, and, as a result, seven additional deaths must occur to reach deaths to restore harmony and repair sacrilege. if we reach deaths, we must go to deaths before the disturbed order is restored and moreover that the stain is 'washed', and so on. since the first deaths of this second chain were indeed members of this kissi ethnic group (fig. . ), the 'animist' explanatory model of the disease was quite consistent with people's observations and gained legitimacy among the population at the expense of the biomedical discourse of the existence of evd. as the susceptibility of dying from ebola was initially and predominantly perceived as restricted to this particular ethnic group, no preventive measures were adopted by the non-kissi population of the region. among the kissi, the consequent epistemic dissonance between the public health logic and the transgression to be restored led between june and july twenty-six kissi-speaking villages in guéckedou prefecture to isolate themselves from ebola response, cutting bridges and felling trees to prevent vehicle access, and stoning intruding vehicles. because it is a disease of the social-of those who look after and visit others, and of those who attend funerals-there are of course many reasons why the ebola phenomenon was likely to be associated with sorcery. it is also not a coincidence that the triggering event, the transgression, in this explanatory model was attributed to medical doctors. as elite africans generally educated in european ways and relatively wealthy, this social group displays many characteristics of sorcerers (they lead a secluded life, do not share their gains, exchange abrupt greetings, eat large quantities of meat and eat alone). moreover, the intense preoccupation throughout this region with 'hidden evil in the world around you that finds dramatic expression in the clandestine activities of witches and the conspiracies of enemies' is exacerbated by tiny pathogens remaining largely invisible to our routine social practices, hence attracting suspicions of sorcery (fig. . ) . following the investigation of this 'animist' model in relation to the strong community resistance manifested in forest guinea, i interviewed a member of the riposte communication unit originating from macenta about the dandano case : yes, there is the specificity of dandano. (…) [in] dandano there was a great witch doctor who had gone to greet his counterpart witch doctor where there were a lot of cases. and that is where he got infected. he returned to dandano. three days later he developed the disease and died. afterwards, as he is a great, recognised witch doctor, people said to themselves, because he died, it was not ebola that killed him but his fetish that is taking revenge on him because it is a betrayal to leave one's domain to greet one's friend. maybe he went to spy on his friend and his friend hit him … well, there have been many versions. (…) among the old people who knew the drug he had, euh… his fetish, the grigri that he had, and that if it was his grigri who killed him, it means that all those who saw him, who saw his body, must also suffer. (…) [we could] see his dead body because he was not protected, because we had to wash him and there were medicines that had to be poured to annihilate his fetishes' power before burying him. so there must have been deaths, hence it was already premeditated. then there were deaths, as it was said, and they were successive deaths. that means there were deaths, two days, three days, so people put more anathema on what happened. and that is how dandano lived things. so there were deaths, we said it is the fetish that woke up because dandano is known as a village of powerful fetishes, that is known. (…) even all the sensitisation we do, we never stop in dandano on a manager, a notable, otherwise they can do something to you … so it is well recognised (…) dandano, is not where you have to go joking. (…) at the end, with a lot of deaths, a lot of funerals, they saw that no, it is not that [the fetish anger] anymore, and with the information here and there, it is ebola. and it is like that with all the negotiations (…). notably, these explanatory models are distinct from general beliefs about diseases and care techniques in the region. we cannot argue then that 'biomedicine' and 'kissi culture' are somehow distinct and opposed. chain of transmission according to the 'animist' cultural model. s and s are the two suspect cases as presented in the 'biomedical' chain of transmission (see fig. . ); the grey blocks are the kissi people of the 'animist' transmission chain these beliefs belong to the ideology of different sectors of the care system and exist independently of the illness of a subject. explanatory models are collected in response to a particular episode of illness in a given subject in a given sector and can evolve over time, depending on how the experience, knowledge and risk exposure of the concerned individual develop. this is precisely what has been reported to us and what has been observed in forest guinea. as the number of deceased progressed, and according to the religious and/or ethnic affiliation of the deceased, a new explanatory model was put in place as stated in this conversation: yes, at first it was said, when i was in conakry, since our country is predominantly muslim, it was said that it is a matter for christians since muslims do not eat apes. muslims do not eat the bat. it's only the foresters who eat that. and that's why this disease hits only the kissi and toma who are from the forest. so it's a kaf disease. -kaf? (séverine thys) -from unbelievers, pagans who do not know god. we call kaf, all those who do not believe in the god of muslims. this last extract particularly highlights the fact that these explanatory models are not fixed in time and space and are not impervious to each other either. indeed, the first health messages communicated to the population and built on the biomedical model were intensely focused on the need to avoid the consumption of 'bushmeat', especially wild animals identified as potential primary sources of contamination, namely monkeys and bats. the content of these messages gave birth to another popular model, in which the food taboos or eating habits observed by members affiliated to a certain religion allowed them to explain why this disease was affecting certain groups and not others. this quote also perfectly illustrates how popular discourses have integrated medical interpretations or public health messages. in the study conducted by bonwitt et al. about the local impact of the wild meat ban during the outbreak, all participants, irrespective of age or gender, were aware of wild mammals acting as a source of transmission for ebola. yet a confusion remained about which species in particular could transmit the ebola virus, which may be due to the content of public health messages that were inconsistent as regards the species shown to be potentially hazardous. messages are being absorbed, but in such chaos and fear, people process information according to their own worldview, according to the sources available to them, and following their personal experiences and instincts. furthermore, the criminalisation of wild meat consumption, which fuelled fears and rumours within communities, did entrench distrust towards outbreak responders and also exacerbated pre-existing tensions within villages, ethnicities and religions. following the kissi, it seemed that it was the muslim community that was hit by sudden and numerous deaths. to cope with this new upheaval, this new incomprehension, the operated explanatory model of these deaths' origin was, consequently, first that of a 'maraboutage': it started like that until a certain moment. and then it turned upside down. there have always been upheavals. it turned upside down, and instead of being weighed at a certain moment on the toma and the kissi, it was rather on the manyas, who are entirely, %, % even muslims. and so people started saying 'ha! that only attacks muslims, why not christians?'. so there has always been upheaval in all the procedures of this disease evolution. as noted by hewlett et al., 'patients, physicists, caregivers and local people in different parts of the world have cultural patterns for different diseases. providing care and appropriate treatment for a particular disease is often based on negotiation between these different models'. to be able to negotiate, it is necessary that each one, doctor and patient, partakes in the knowledge of the explanatory model of the other. while most health professionals rarely assume that people have and construct their own interpretation of the causal chain, my ethnographic observations presented in this chapter demonstrate that the a priori on which all interventions of sensitisation are based is not only incorrect, but also a source of blockages for the adoption of prescribed behaviours. this is because, to return to hewlett et al., 'people do not just follow the continuous thread of learning; they also develop an ability to articulate adherence to prescribed behaviours with the refusal of others, to cooperate at certain times and to show reluctance to others, inviting the analysis to move towards a sociology of compromise'. through the example of funerals, wilkinson and leach have also cast light on the presumption that the knowledge needed to stop the epidemic is held by public health experts and scientists, and not by local people. this very often leads to the development of protocols and procedures that completely negate the contribution of communities. this asymmetrical reflection between caregivers and care receivers, the structural violence that has cultivated inequalities in this region, the heterogeneity of experiences seen by the populations as fundamental contradictions between words and facts, the confidence and trust crisis since the 'demystification' programme initiated during sékou touré's time, and the traumas inflicted by a transgression of usages in the name of urgency and the exceptional nature of the ebola epidemic, are all realities that have fueled community reluctance and resistance. the late involvement of traditional healers, primarily consulted by guineans when experiencing illness, in the activities of the response in macenta, is another example of this asymmetry, which too often omits to acknowledge and relate to these other categories that support the social fabric, even if since alma ata in these stakeholders should no longer be on the margins of the health system. although the concept of explanatory models is not sufficient to explain all the failures of response in the context of guinea, or the bordering regions with sierra leone and liberia, nevertheless it allows to move past linear technical discussions of 'weak health systems' as the main reason for the scale of the disaster. the use of this conceptual framework for understanding popular interpretations of the origin of the disease and its transmission reveals the complex, historically rooted and multidimensional picture of the ebola crisis. several authors agree that, 'in any case, it is not a question of archaic beliefs or outlier depictions, but good answers -which can be called rational in this context -to a vital emergency situation, interpreted in the light of past and present experiences'. a better knowledge and comparison of these discourses and different cultural models of the disease, sometimes incorporated, sometimes hermetic, could nevertheless contribute considerably to the success of the fight against the epidemic, especially when it concerns the improvement of knowledge of the chains of disease transmission, the identification and understanding of the behaviours of local populations, and of the sources of denials and rumours. explanatory models proposed by the biomedical sciences are very often in competition and in contradiction with diagnoses made by traditional healers and especially with rumours involving divine punishments, breaches of prohibitions, the misdeeds of wizards or genies, or virologic warfare. if this 'animist' model is not identified nor recognised as making sense for others at the key moment, there will also be no negotiation and no understanding of the distances and proximities existing between the thought systems present in the concerned ecosystems. an anthropological approach remains essential to adapting this response to local realities. epelboin further argues that 'local models of causation regarding misfortune, often the most predominant, involve not only the virulence of the virus and human behaviour, but the evil actions of human and non-human individuals. the virologic model is then only one explanatory model among others, leaving the field open to all social, economic and political uses of misfortune'. following the re-emergence of this infectious disease of zoonotic origin in a whole new social ecosystem, a cross-sectoral research agenda, the so-called one health integrated approach, has finally emerged in the field of viral haemorrhagic fevers, also enabling the role of anthropology to be expanded to times of epidemic outbreak. until then, anthropologists were mandated to contribute to the adaptation and improvement of immediate public health interventions in relation to human-to-human transmission. yet, the growing interest of anthropologists in the interaction between humans and non-humans has made it possible to extend their research topic to the complex dynamics of the primary and secondary transmission of the virus. in addition, this anthropological interest has provided a new cross-cultural perspective on the movement of pathogens and has therefore improved knowledge about the mechanisms of emergence, propagation and amplification of a disease located at the interface between humans and wildlife. such was the role of almudena marí saéz and colleagues who, in a multidisciplinary team, conducted an ethnographic study in the village of the ebola epidemic's origin, the index case village, to better understand local social hunting practices and the relationships between bats and humans. however, the realm of the human-animal-disease interaction has been limited to 'natural versus cultural' domains and frequently conceived as a biological phenomenon in one health studies instead of a biocultural one integrating the social and cultural dimensions generated by human-animal relations. incorporating anthropology into one health approaches should provide a more nuanced and expanded account of the fluidity of bodies, categories and boundaries as drawn up by existing ethnographies on cattle in east and southern africa for example. epelboin et al. have stressed that, 'the anthropological approach in previous epidemics has confirmed that the urgency and severity of an epidemic must not prevent people from listening to them and thinking throughout the epidemic of taking into account indigenous codes, customs, knowledge, skills and beliefs'. by taking seriously the possibility that affected people in the places where we do research or implement control measures might not see things in the same way, we have to be willing to have our categories (such as culture/nature, human/animal, mind/body, male/female, caregivers/care receivers) unsettled, and to grapple with the practical implications of this for engagement in field sites, for knowledge-sharing and for the design of interventions, in the hope that such improvements might contribute to a future prevention of ebola and to public health policies more suitable to respond to people's basic needs. it also allows the affected people themselves to have a say in the matter. as philippe descola and other anthropologists have argued, on the basis of a comparative analysis of a wide range of ethnographic work across the continents, native classificatory systems usually offer a continuum, rather than sharp divisions, among humans and other animal species. indeed, human dispositions and behaviours are attributed not only to animals but also to spirits, monsters and artefacts, contrasting to modern western models, which generally see the categories of human and non-human as clearly defined and mutually exclusive. the ability to sense and avoid harmful environmental conditions is necessary for the survival of all living organisms and, as paul slovic has argued, 'humans have an additional capability that allows them to alter their environment as well as respond to it'. as regards the emerging violence in conservation as either against nature (e.g. culling bats) or in defence of it (e.g. rearranging landscapes within an inclusive 'one health' approach), james fairhead proposes that such violence is increasingly between 'the included' and 'rogues' in ways that transcend the nature/society binary. while the 'white', and african elites were seen by the affected population as 'antisocial' intruders or rogues, suspected of sorcery and using ebola as a tool for political manipulation, those involved in the struggle to address the ebola epidemic were not fighting just against the virus but also against the natural world that harboured it: the rogues which included villainous bats but moreover habitat destroyers, namely hunters, bushmeat traders and deforesters. these were the humans casted as the ones invading the habitat of the virus. since evd will be constantly reconceptualised, and because of new scientific discoveries (e.g. on natural reservoir, or vaccine development), control interventions must listen to and take into account popular perceptions as well as the socio-cultural and political context and their respective evolution. rumours must be identified and managed on a case-by-case basis without global generalisation that could reinforce misinterpretations on the assumption that ignorance alone generates these rumours, con-flicts, lack of trust and resistance. moreover, zoonotic epidemic fighters should follow macgregor's and waldman' recommendations by starting to think differently with and about animals and about species boundaries in order to generate novel ways of addressing zoonotic diseases, allowing for closer integration with people's own cultural norms and understandings of human-animal dynamics. and medicine ( ) ebola virus disease in guinea-update (situation as of aspects épidémiologiques de la maladie à virus ebola en guinée (décembre -avril emergence of zaire ebola virus disease in guinea investigating the zoonotic origin of the west african ebola epidemic zoonosis: prospects and challenges for in this outbreak story, a disease emerges in a remote location and spreads across a world highly connected by globalisation and air travel to threaten 'us all'-read the globally powerful north: see a entre science et fiction' contagious: cultures, carriers, and the outbreak narrative: wald priscilla the global focus on wildlife as a major contributor to emerging pathogens and infectious diseases in humans and domestic animals is due to reports which are not based on field, experimental or dedicated research but rather on surveys of literature and research regarding human immunodeficiency virus (hiv) and aids, severe acute respiratory syndrome (sars) and highly pathogenic avian influenza (hpai), all of which have an indirect wildlife link: r. kock, 'drivers of disease emergence and spread: is wildlife to blame on how and why 'bushmeat' hunting leads to the emergence of novel zoonotic pathogens see bushmeat hunting, deforestation, and prediction of zoonoses emergence uncovering zoonoses awareness in an emerging disease "hotspot"'. social science attempt of the zoonotic niche of evd, see contagious: cultures, carriers, and the outbreak narrative the term 'exceptionality' is borrowed from s. l. faye, 'l' "exceptionnalité" d'ebola et les "réticences" populaires en guinée-conakry. réflexions à partir d'une approche d'anthropologie symétrique to-plague-and-beyond-how-can-anthropologistsbest-engage-past-experience-to-prepare-for-new-epidemics. for the policy relevance of anthropological expertise and a (self-)critical reflection on ebola and on anthropological (and more broadly social scientific) engagements with humanitarian response, see a. menzel and a. schroven the term 'riposte' is the french name used to designate the official national mobilisation settled to respond to the evd crisis, structured into two poles, an inter-ministerial committee and a national coordination committee grouping together the international actors and the national non-governmental organisations; see m. fribault heterogeneities in the case fatality ratio in the west african ebola outbreak challenges in controlling the ebola outbreak in two prefectures in guinea: why did communities continue to resist? comparison of social resistance to ebola response in sierra leone and guinea suggests explanations lie in political configurations not culture understanding social resistance to the ebola response in the forest region of the republic of guinea: an anthropological perspective contagious: cultures, carriers, and the outbreak narrative zoonosis: prospects and challenges for medical anthropology the good, the bad and the ugly: framing debates on nature in a one health community understanding social resistance to the ebola response in the forest region of the republic of guinea: an anthropological perspective sustainability and contemporary man-nature divide: aspects of conflict and alienation on the visual ethnographic examination of the ebola zoonotic cycle transformed into tools of public health communication by the us cdc during the outbreak of medical anthropology and ebola in congo unintended consequences of the "bushmeat ban emergence of zaire ebola virus disease in guinea maladie à virus ebola: une zoonose orpheline?'. bulletin de l'académie vétérinaire de france inclusivity and the rogue bats and the war against "the invisible enemy about the natural reservoir for ebola virus see the evolution of ebola virus: insights from the - epidemic' a review of the role of food and the food system in the transmission and spread of ebolavirus mammalian biogeography and the ebola virus in africa for information on the 'bushmeat ban', see bonwitt et al., 'unintended consequences of the "bushmeat ban ebola virus disease epidemic emergence of zaire ebola virus disease in guinea'; world health organization, 'one year into the ebola epidemic: a deadly, tenacious and unforgiving virus caring for critically ill patients with ebola virus disease ebola-myths, realities, and structural violence'; and olival and hayman the threat to primates and other mammals from the bushmeat trade in africa, and how this threat could be diminished origins of major human infectious diseases'; centers for disease control and prevention take-a-semiotician-or-what-we-talk-aboutwhen-we-talk-about-bush-meat-by-adia-benton/. the kellogg institute on the feeling of disgust as a sentiment with powerful political valences, see also j. livingston, 'disgust, bodily aesthetics and the ethic of being human in botswana the anatomy of disgust world organisation for animal health the bushmeat trade: increased opportunities for transmission of zoonotic disease bushmeat crisis' is caused by the dual threats of wildlife extinctions and declining food and livelihood security of some of the poorest people on earth and whether the hunting of bushmeat is primarily an issue of biodiversity conservation or human livelihood, or both, varies according to perspective, place and over time; see unintended consequences of the "bushmeat ban impact of the ebola virus disease outbreak on market chains and trade of agricultural products in west africa'. food and agriculture organization of the united nations sending the right message: wild game and the west africa ebola outbreak bushmeat ban" in west africa during the - ebola virus disease epidemic'; p. richards, ebola: how a people's science helped end an epidemic les errances de la communication sur la maladie à virus ebola zoonotic semiotics: plague narratives and vanishing signs in madagascar' understanding social resistance to the ebola response in the forest region of the republic of guinea: an anthropological perspective one year on: why ebola is not yet over in guinea encyclopedia of medical anthropology : health and illness in the world's cultures extracts of the individual interview conducted with the pastor on the cultural and political role of initiation societies in the forest region and the related experiences of local citizens in relation to both the manding (often islamic) world to the north, and to the 'white' (often christian) colonial and neo-colonial order, see fairhead purity and danger, an analysis of concepts of pollution and taboo communication with rebellious communities during an outbreak of ebola virus disease in guinea: an anthropological approach understanding social resistance to the ebola response in the forest region of the republic of guinea: an anthropological perspective memories of the slave trade: ritual and historical imagination in sierra leone lifeworlds: essays in existential anthropology for more information about dandano village 'surrendering their sick and dead after being battered by the virus', see a. nossiter extracts of the individual interview conducted with a voluntary of the communication unit of macenta new therapeutic landscapes in africa: parental categories and practices in seeking infant health in republic of guinea extracts of the individual interview conducted with the pastor for similar narrative about muslim communities and food taboos regarding bats, see f. batty, 'reinventing "others" in a time of ebola unintended consequences of the "bushmeat ban extracts of the individual interview conducted with the pastor medical anthropology and ebola in congo: cultural models and humanistic care ebola en guinée: violences historiques et régimes de doute briefing: ebola-myths, realities, and structural violence l' "exceptionnalité" d'ebola et les "réticences" populaires en guinée-conakry ebola en guinée: violences historiques et régimes de doute'; wilkinson and leach traiter les corps comme des fagots' production sociale de l'indifférence en contexte ebola (guinée approche anthropologique de l'épidémie de fhv ebola en guinée conakry zoonosis: prospects and challenges for medical anthropology extending the "social": anthropological contributions to the study of viral haemorrhagic fevers investigating the zoonotic origin of the west african ebola epidemic views from many worlds: unsettling categories in interdisciplinary research on endemic zoonotic diseases animal spirits and mimetic affinities: the semiotics of intimacy in african human/animal identities annexe . contribution de l'anthropologie médicale à la lutte contre les épidémies de fièvres hémorragiques à virus ebola et marburg'. in world health organisation, Épidémies de fièvres hémorragiques à virus ebola et marburg: préparation, alerte, lutte et évaluation the morning after: anthropology and the ebola hangover beyond nature and culture biosecurity and the topologies of infected life: from borderlines to borderlands nature and society: anthropological perspectives by perception of risk inclusivity and the rogue bats and the war against "the invisible enemy views from many worlds acknowledgements i would like to thank tenin traoré, a guinean sociologist and consultant to who, and joseph kovoïgui, assistant coordinator of the philafrican mission and then consultant to who, for their commitment and engagement in the fight against ebola, their generosity, their knowledge, their experience and our fruitful collaboration in many respects. i would also like to thank the coordination team and the dps (prefectural health direction) of macenta for their welcome and sincere attention; goarn/who, antwerp institute of tropical medicine, and in particular prof. marleen boelaert for emotional, financial and logistical support; dr. alain epelboin for field preparation and numerous sharing with the francophone anthropological platform; and christos lynteris for his invitation to connect and exchange with the anglophone 'anthro-zoonoses' network and contribute to this timely collection. key: cord- -pnd ipd authors: bleasdale, susan c.; sikka, monica k.; moritz, donna c.; fritzen-pedicini, charissa; stiehl, emily; brosseau, lisa m.; jones, rachael m. title: experience of chicagoland acute care hospitals in preparing for ebola virus disease, – date: - - journal: j occup environ hyg doi: . / . . sha: doc_id: cord_uid: pnd ipd during the – ebola virus disease (evd) outbreak, hospitals in the united states selected personal protective equipment (ppe) and trained healthcare personnel (hcp) in anticipation of receiving evd patients. to improve future preparations for high-consequence infectious diseases, it was important to understand factors that affected ppe selection and training in the context of the evd outbreak. semistructured interviews were conducted with hcp involved with decision-making during evd preparations at acute care hospitals in the chicago, il area to gather information about the ppe selection and training process. hcp who received training were surveyed about elements of training and their perceived impact and overall experience by email invitation. a total of hcp from hospitals were interviewed, and hcp completed the survey. factors affecting ppe selection included: changing guidance, vendor supply, performance evaluations, and perceived risk and comfort for hcp. cost did not affect selection. ppe acquisition challenges were mitigated by: sharing within hospital networks, reusing ppe during training, and improvising with existing ppe stock. selected ppe ensembles were similar across sites. training included hands-on activities with trained observers, instructional videos, and simulations/drills, which were felt to increase hcp confidence. many felt refresher training would be helpful. hands-on training was perceived to be effective, but there is a need to establish the appropriate frequency of refresher training frequency to maintain competence. lacking confidence in the cdc guidance, interviewed trainers described turning to other sources of information and developing independent ppe evaluation and selection. response to emerging and/or high consequence infectious diseases would be enhanced by transparent, risk-based guidance for ppe selection and training that addresses protection level, ease of use, ensembles, and availability. though the last major threat of ebola virus disease (evd) in the united states occurred in - , acute care hospitals must remain prepared to respond to outbreaks of high-consequence infections. although classified as low global risk, the current evd outbreak in the democratic republic of congo (congo), combined with the recurring emergence of high-consequence infections (e.g., severe acute respiratory syndrome [sar] , middle east respiratory syndrome, h n influenza), highlights the need for ongoing preparations. [ ] healthcare personnel (hcp) are particularly vulnerable to occupationally-acquired infection during outbreaks of emerging infectious diseases, including evd and sars owing, perhaps, to uncertainty about the route of transmission and necessary personal protective equipment. [ , ] after the infection of two hcp with evd, for example, the centers for disease control and prevention (cdc) revised their recommendation for personal protective equipment (ppe) to eliminate skin exposure, though ppe guidance continued to be updated through . [ , ] the purpose of this study was to understand how acute care hospitals in the chicago, illinois area prepared for the - evd outbreak, focusing on issues related to occupational health. more specifically, questions included: ) how ppe ensembles were selected, ) considerations for ppe acquisition and use, and ) how training in the use of ppe ensembles and evd patient care was developed and delivered. while there is a growing body of literature describing preparations for the - evd outbreak, this study is unique because it allows comparison of experiences across different types of acute care hospitals (with different roles in the regional evd plan), and between hcp who planned and received training. [ ] [ ] [ ] [ ] the study objectives were achieved using semistructured interviews with hcp involved with evd preparations, and surveying hcp who participated in training for the use of enhanced ppe ensembles for evd. twenty-six of the acute care hospitals in the chicago area were selected for recruitment using a purposeful sampling strategy (table ) . hospitals were classified into categories based on their role in the regional evd response plan (ebola treatment center [etc] or ebola assessment center [eac] and non-etc/eac), type, location, and size (small with < beds, medium with - beds, and large with > beds). in each category, if there were hospitals, all hospitals were selected for recruitment; otherwise, four hospitals were randomly selected. two hospitals were excluded from analysis because members of our research team were involved in evd preparations at these hospitals. individuals were eligible for participation if they were employed at a chicago area acute care hospital and participated in decision-making about ppe and/or contributed to the design or delivery of training during the - evd outbreak. participation in the interview was incentivized by a $ gift card. attempts were made to contact up to eight individuals (up to three phone calls and three e-mails each) at each hospital, starting with individuals in infection prevention or emergency management. one to three individuals were interviewed at each hospital between september and february . when more than one individual participated from a hospital, attempts were made to identify people with different disciplinary training and/or role in evd preparations. a semistructured interview guide was prepared. [ , ] questions and follow-up probes were organized into four domains: participant characteristics, institution organization and culture, training experiences, and experience with personal protective equipment. the interview guide is available in the online supplemental materials. interviews were performed over the telephone, digitally recorded and transcribed. interviews were periodically reviewed to evaluate saturation of question or topic and identify the need for further probes for clarity. [ ] a codebook for the interview transcripts was developed iteratively and validated by application to selected interviews by five investigators with tabulation of inter-rater reliability. [ ] the final codebook is included in the online supplemental materials. final coding was performed on each interview transcript by two people, with a third adjudicated conflicting codes to select the five most relevant codes or subcodes for each response. the focused conversation method was used for group analysis of coded text: two analysis meetings were conducted focused on the objectives related to ppe and training, respectively. [ ] the focused conversation method involves the group addressing a series of objective, reflective, interpretative, and decisional questions. more details are provided elsewhere, and the conversation guides are included in the online supplemental materials. [ ] observations and themes identified in the focused conversation were further explored by identifying text that supported and challenged the findings, including identification of illustrative quotes. quantitative data from interviewed trainers is described at the hospital level by the percentages of hospitals interviewed. referral sampling was used to recruit survey respondents. an online survey using qualtrics xm (seattle, wa) was distributed by the interviewed trainers to colleagues and through the state of illinois rapid electronic notification system from october to june . eligible respondents had received training in the use of ppe in the context of the - evd outbreak. survey respondents (trainees) were a different population than interviewees (trainers). the survey included questions organized around six themes: ) trainee characteristics, ) ppe donning and doffing training received, ) perceived impact of training, ) training received regarding performing care activities while wearing ppe, ) experience with specific types of ppe, and ) experience with caring for suspected or confirmed evd patients. multiple choice answers were used to describe characteristics of the trainees and the training. likert scales were used for perceived impact and experience. the survey was piloted by trainers and trainees within our research institution and iteratively adapted to the final version. the survey is available in online supplemental materials. participation was incentivized by a $ gift card. the study was approved by the university of illinois at chicago institutional review board, protocol # - . recruitment of trainers occurred from september to february and resulted in interviewed trainers from of the ( %) hospitals identified for recruitment (table ) . trainers from additional hospitals were not recruited because preliminary review of transcripts suggested that saturation was achieved on most questions. trainers broadly fell into the following categories: infection prevention (n ¼ ), emergency management (n ¼ ), education (n ¼ ), executive leadership (n ¼ ), biosafety (n ¼ ), and risk management (n ¼ ). a total of trainees completed the online survey between october and june . thirty-four ( %) surveyed trainees identified that they worked at academic or tertiary care centers, while the remaining surveyed trainees were from nonacademic urban/suburban hospitals ( %), va hospitals %), and the fire department ( %). surveyed trainees identified as nurses (n ¼ ), physicians (n ¼ ), other clinical personnel (n ¼ ), or nonclinical personnel (n ¼ ). the majority worked in an emergency department ( %), followed by interfacility transportation ( %). interviewed trainers from hospitals identified the cdc as a source of information about ppe for use with evd patients. cdc recommendations, however, were used with other resources including: biocontainment centers, expert consultants, in-house experts, and colleagues at other hospitals in the same healthcare network; occupational health agencies were rarely mentioned. multiple resources were used in part owing to concern that initial cdc recommendations to use standard and contact precautions were "inadequate" or "unreliable." [ ] the evolution in cdc recommendations had significant implications: hospitals had to evolve with the recommendations, the changes decreased credibility of the personnel selecting ppe and delivering training and influenced hcp attitudes toward possible care of an evd patient. one interviewed trainer explained that the changes from cdc "messed with our credibility." another trainer described that changes from cdc resulted in training hcp on the use of three different ppe ensembles, which meant that "the caregivers weren't particularly happy." the overall delay in clear recommendations from cdc was felt to add "unneeded anxiety." interviewed trainers from all hospitals indicated that inadequate ppe supply affected preparations when the cdc recommendations moved to the use of enhanced ppe ensembles. [ ] the common theme was that trainers used what "we could get our hands on." some hospitals initiated training with available equipment while waiting for preferred equipment, like powered air purifying respirators (paprs) and fluid-impermeable coveralls, to become available; others adapted or "cannibalized" equipment from specialty units (e.g., orthopedic surgery), such as surgical helmets with shrouds and longer gloves. interviewed trainers from one hospital described the plan to use suits designed for hazardous materials (hazmat) response as a "last resort option" if they ran out of other ppe supplies. these strategies, however, could not overcome limitations in available ppe sizes, a challenge expressed by many interviewed trainers. limited supply of paprs was specifically identified by interviewed trainers from several hospitals, though the majority of interviewed trainers described training with paprs. some hospitals substituted shrouded surgical helmets for paprs because the helmets provided the same cooling effect as the airflow in paprs but included n respirators in the ensemble because the helmet does not provide respiratory protection. one interviewed trainer described that the hospital (non-etc/eac) did not have paprs and did not initially seek to acquire the highest levels of recommended ppe, including paprs, because they did not anticipate receiving an evd patient. this was the only interviewed trainer that described the use of this type of risk-based decision making for ppe selection and training. some interviewed trainers from smaller hospitals felt that their hospitals were at a disadvantage relative to larger hospitals with respect to acquiring ppe. one interviewed trainer described, "we didn't have a lot of the resources that some of the bigger facilities did. [ … ] we can't really compete with the big dogs if you will." supply shortages were minimized among smaller hospitals that were part of a healthcare network, as interviewed trainers from networked hospitals described plans for just-in-time delivery of ppe and centralized patient care, which decreased the need for ppe stockpiling and training at the smaller hospitals. interviewed trainers did not describe the cost of ppe as a limiting factor in preparations, and many cited worker safety as sole criteria for ppe selection. the resources were described in a carte blanche fashion: "we're buying the best for our employees," "the cadillac of everything," and "i don't care what the price is we just have to do this." interviewed trainers postulated reasons for the extent of financial support in both positive and negative terms. positive expressions about the availability of financial resources centered on the organization's commitment to safety, "there was no hedging on the commitment of the organization for the safety of all of our employees across the board." negative expressions centered on the organization's fear of failure, "i think they just got the money because no hospital wanted to be caught not doing anything about it." interviewed trainers from % of hospitals described evaluating and modifying ppe ensembles in ways characterized here as improvisation, and these activities were often described as involving the hcp who would provide care to evd patients. the impermeability of body coverings, including at junctions between pieces of ppe, was a common concern. some interviewed trainers described finding it difficult to identify or evaluate fluid-impermeability ratings, describing a body covering as being made of "an impermeable-like type of material but, there's no signage or anything." interviewed trainers from two hospitals described independently evaluating the permeability of ppe or the connections of ppe ensembles with surrogates for blood with water or kool-aid. an interviewed trainer described evaluating an ensemble to figure out, "how do we do this so that it doesn't leak around the edge of the tyvek suit?" and, that after identifying a potential ensemble through a trialand-error approach, the interviewed trainer said that staff answered the questions, "what do you think? can you get in? can you get out? how should we modify it? does this work?" concerns extended to breaching ppe and contributed to decisions to use hooded paprs or shrouded surgical helmets in an attempt to prevent hcp from touching their face. while interviewed trainers from % of the non-etc/ eac hospitals felt they did not serve a population at risk for evd, interviewed trainers from all hospitals described fear as common emotion among hcp. as one interviewed trainer described, " … [hcp] kept thinking about the nurse that was in texas that seemed to have had all the protection that she needed but she still got exposed somehow." fear led to decisions about ppe that some interviewed trainers characterized as "irrational." as one participant described, "[hcp] were not paying attention to the different risks between a wet and a dry patient. they heard ebola, ebola wet, highly contagious, everybody dies, and they wanted to be encased like a mummy." another participant described specific requests from hcp who "said that they would refuse to take care of anybody unless they were provided with this absurd amount of protection [ … ] not levels of ppe required or requested by the cdc … ." comfort and ease of use interviewed trainers described heat as the main factor affecting comfort during use of the enhanced ppe ensembles. heat management motivated the use of paprs and shrouded surgical helmets, which move cool air over the head of the wearer. these devices also have less impact on the visual field of the wearer than goggles or face shields. interviewed trainers at a couple of hospitals indicated that suits for hazmat response were not preferred because they are hot and heavy and would be reserved for emergencies. the final ppe ensembles selected at the different hospitals were quite similar, and were described by interviewed trainers as involving head-to-toe coverage consistent with the cdc recommendations for "no skin exposure". [ ] the use of paprs and tyvek coveralls or fluid-impermeable gowns were identified by interviewed trainers at and hospitals, respectively, including all etcs. head coverings (e.g., shrouds or hoods) were described by interviewed trainers at of the hospitals that did not use paprs. interviewed trainers at hospitals ( etcs), described the use of surgical helmets. interviewed trainers at hospitals described training the majority of hcp at the hospital in ppe donning/ doffing, regardless of whether they were expected to care for evd patients. more commonly, interviewed trainers indicated that ppe donning/doffing training was limited to hcp anticipated to be in the patient care workflow. hcp in the emergency department were most frequently identified by interviewed trainers as recipients of ppe donning/doffing training (n ¼ hospitals interviewed), followed by environmental service workers (n ¼ ) and intensive care or isolation room workers (n ¼ ). other hcp groups described by interviewed trainers as included in training were: laboratory, radiology, respiratory therapy, security, transportation, and emergency medical technicians. training about donning/doffing ppe was described by interviewed trainers from all hospitals. while a variety of training methods for ppe donning/doffing were described, interviewed trainers at the majority of hospitals interviewed indicated use of hands-on practice. this is consistent with surveyed trainees, % of whom reported receiving hands-on training in ppe donning and doffing in a group setting. instructional videos about ppe donning and doffing were also identified frequently by interviewed trainers, and by % of surveyed trainees. interviewed trainers from the majority of hospitals interviewed identified that existing staff participated in delivery of training about ppe donning/doffing. the staff most frequently identified included: infectious diseases clinicians and infection control personnel ( %), clinical educators ( %), and clinical staff ( %). forty-percent of hospitals interviewed specifically described using a train-the-trainer model to distribute training. all hospitals interviewed indicated that the ability of hcp to don/doff ppe was evaluated using observation, including return demonstration. interviewed trainers at some hospitals described using check lists to aid observation or markers (glow germ or chocolate syrup) to evaluate self-contamination during ppe doffing. the vast majority of surveyed trainees ( %) received instructions on a specific order for donning/ doffing ppe. of the surveyed trainees who indicated their ability to don/doff ppe was evaluated during training, % reported demonstration for trainer and % reported demonstration for a fellow trainee. no surveyed trainees reported taking a written quiz. training in the care of evd patients was described at % of hospitals interviewed, including the etcs and eac, while training in logistical protocols (intake procedures, communication protocols, etc.) were described at %. surveyed trainees most frequently indicated that they received training in: cleaning patient care areas or spills ( %), transporting patients ( %), transportation of body fluids ( %), blood draw ( %), and emergency medical procedures ( %). one surveyed trainee wrote in that s/he was trained to not provide resuscitation to evd patients. five surveyed trainees indicated receiving training in the use of electronic devices, including: a bluetooth stethoscope, telemedicine equipment, and/or ipads/tablets. simulations and/or drills of care activities and logistical protocols were described by interviewed trainers from the vast majority of hospitals and identified as opportunities to: increase the speed of response, increase the comfort and ease of hcp to use ppe (e.g., learning the "physical boundaries" imposed by the ppe), identify gaps in preparations, increase hcp confidence, and revise operating procedures. that is, the simulations were part of a continuous improvement process, rather than a summative assessment of hcp competency. hcp were viewed "as active learners and trainers because of their contributions [to the care process] and what they had to say." changes described as arising from simulations and drills included: installation of phones in patient rooms to improve communication, changes in staffing requirements, creation of a "all call" page of hcp who would respond to an evd patient, and adoption of a risk tiered approach to ppe. two interviewed trainers from different hospitals described negative consequences of unannounced simulations involving mock patients. specifically, fear among hcp during the simulation affected how they performed their work and/or resulted in emotional distress. in a hospital where the interviewed trainer noted the first drill was "incredibly stressful," the trainer described that a staff member in the patient room "panicked and tried to come out [ … ] tried to take off his ppe and get out" during a drill. interviewed trainers described that fears were assuaged through "town hall" education and information sessions and through training. one interviewed trainer said town halls were used " … to keep people updated on what we learned through cdc [ … ] because there was all sorts of [ … ] misinformation going on." the impact of training, particularly simulation, reduced fear and led to revisions of the ppe ensembles. for example, an interviewed trainer from a hospital where hcp "wanted to be encased [in ppe] like a mummy" noted that preferences "started to change after like the th or th simulation where people were like, '[m]an, [i] can't work like this.'" when asked to identify the three training modalities that had the greatest positive impact on their confidence to care for an ebola patient, surveyed trainees most frequently identified: hands-on activities in group (n ¼ ) or individual settings (n ¼ ), trained observers (n ¼ ), instructional videos (n ¼ ), training in a simulated care area with (n ¼ ) or without task trainers (n ¼ ), and using markers for evaluation of self-contamination during ppe doffing (n ¼ ) ( table ). the majority of surveyed trainees were very ( %) or moderately ( %) confident in their ability to don ppe and to doff ppe as instructed; and the majority ( %) reported that the presence of an observer would increase their confidence in doffing ppe as instructed. the majority of surveyed trainees were very ( %) or moderately ( %) confident in their ability to work as an individual or in a group to care for an evd patient. interviewed trainers from the etcs and two other hospitals reported that their hospital has performed some skill maintenance training since the outbreak ended (interview period september to february ). the value of skill maintenance was linked with the need to be "always prepared for things like ebola" and/or a trend toward improved emergency management and business continuity planning. barriers to skill maintenance training identified by interviewed trainers at etcs included debate about who should be trained, and how frequently hcp should be trained. interviewed trainers from non-etc hospitals identified staff turnover as a barrier. the majority of surveyed trainees ( %) perceived a need for refresher training, but the perceived need for training differed with time since last training (v p < . ). among surveyed trainees who indicated a need for refresher training about patient care activities % wanted the training twice per year or more frequently, and % wanted the training annually. thirteen of the interviewed hospitals described some historical education on ppe, however many interviewed trainers described how evd preparations made them aware of deficiencies in routine training and use of ppe. deficiencies included needed "clarification on how to don and doff", lack of experience with elements of the ensemble, limited training to only a subset of providers, lack of hands-on training, and lack of retraining after hire. despite these identified gaps, interviewed trainers from only two hospitals indicated a change in routine training, specifically, new employee orientation was changed to include hands-on training in ppe donning/doffing. hospitals in the chicagoland area were resourceful in their occupational health preparations for the - evd outbreak were able to select ppe ensembles they judged appropriate for the hospital's role in the regional evd plan and trained hcp in the use of enhanced ppe ensembles and/or evd patient care. interviewed trainers at all hospitals interviewed indicated that at least some training involved enhanced ppe ensembles. this is consistent with the response that half of the non-etc/eac interviewed hospitals had some expectation of receiving an evd patient, and with the federal policy recommending that all hospitals be able to provide care for an evd patient for up to hr. [ , ] fortunately, only suspected evd patients were treated in chicagoland hospitals, so the ability of preparations to protect hcp from occupationally-acquired evd was not tested. our results, however, do not suggest that substantial changes in routine practices have occurred outside of etcs that would ease preparations for the next outbreak of an emerging or high-consequence infectious disease of a similar scale, as limited refresher training is ongoing, and only two hospitals interviewed have modified routine training in the use of ppe. interviewed trainers expressed the perception that the immediacy of the threat of a high-consequence infectious disease has decreased, which is likely a driver to decreased institutional commitment to preparedness activities, and failure to institutionalize changes resulting from lessons learned in the evd preparations. in addition, with the - evd outbreak in congo at a low global risk, there has not been a response to initiate refresher training at non-etcs. interviewed trainers were frequently critical of cdc guidance for ppe ensembles for care of evd patients. the initial recommendations from the cdc for standard and contact precautions were perceived as inadequate, and repeated revisions created challenges for hospitals to acquire equipment and maintain trust with hcp. lacking confidence in the cdc guidance, interviewed trainers described turning to other sources of information, particularly the biocontainment units and individuals perceived to be experts (in-house and external). few interviewed trainers mentioned referencing occupational health agencies, such as the national institute for occupational safety and health and the occupational safety and health administration. this is disappointing as occupational health experts can contribute substantially to the prevention of infection among patients and hcp, and since the - evd outbreak there has been movement to increase the availability of information about ppe from these and other federal occupational health agencies. [ ] [ ] [ ] [ ] there remains, however, a need to provide further guidance on how to evaluate ensembles, not just individual pieces of ppe, for their level of protection against infectious diseases and for their comfort and usability. in the face of ppe shortages and changing ppe guidance, most hospitals utilized multiple sources of information and improvised to select ppe ensembles that met their needs. this approach is consistent with the spirit of standard precautions. standard precautions require hcp to perform specific behaviors (e.g., hand hygiene), select ppe and use work practices that are appropriate to the nature of anticipated contact with body fluids. [ ] application of standard precautions to the care of a symptomatic evd patient leads to the enhanced ppe ensemble ultimately recommended by the cdc. more specifically, given the large volumes of body fluid emitted in late-stage evd and the large number of sites where ebola virus may initiate infection, it is necessary to protect the dermis, facial mucous membranes and (controversially) the respiratory tract from contact with patients' bodily fluids. [ ] [ ] [ ] [ ] furthermore, the high evd mortality rate observed in africa requires a precautionary approach to worker protection. [ ] in this context, standard precautions would identify the need for fluid-impermeable ppe to protect the entirety of the dermis, the mucous membranes, and the respiratory tract. the lower rates of evd mortality observed in the united states and europe and improved understanding of virus shedding in the early stages of evd could allow a change in the ppe ensemble under the standard precautions framework, such as the two-tier, symptom-based, ppe recommendations. [ , ] the reliance on ppe to protect hcp from occupationally-acquired infectious diseases is unfortunate, as ppe is the lowest strategy in the hierarchy of controls. research objectives for this study were focused on topics related to ppe, so other types of control strategies employed were not explore with interviewed trainers, but a few surveyed trainees described receiving training in electronic devices to reduce patient contact, such as telemedicine equipment or bluetooth tm stethoscopes. since the - evd outbreak, there has been evaluation of the environment and how it contributes to risk and can be optimized for protection of hcp. [ ] there should be increased efforts to identify engineering and administrative controls to reduce pathogen emission and limit pathogen transport through the environment. until that time, however, it is critical that hcp have access to and correctly use ensembles of ppe that effectively interrupt disease transmission. hands-on practice was the most common modality for training in ppe donning/doffing and evd patient care activities described in our sample and was valued by trainees. others have found that workers desire hands-on training about ppe donning and doffing, and this type of training is consistent with principles of adult education because it actively engages the worker in a realistic, relevant activity. [ ] [ ] [ ] hands-on training also offers opportunity for evaluation, which is particularly important when self-perceived proficiency is not correlated with performance, such as has been observed for doffing of ppe ensembles. [ ] hands-on training can provide real-time feedback to correct behaviors in the moment with observer interventions or surrogates for contamination. [ , ] in this sample, skills maintenance training was limited and primarily occurred at etcs. a barrier identified was debate over the appropriate frequency of training, though surveyed trainees who wanted refresher training, wanted it to occur - times annually. the annual interval for many occupational health trainings is driven by logistical concerns rather than evidence of skill retention. training in complex activities like ppe donning/doffing may need to occur more frequently than annually. this study is subject to a number of limitations. while this study used a stratified random sampling scheme to identify hospitals for recruitment of interviewed trainers to help ensure that varied experiences were represented, individuals declined to participate or were not responsive to recruitment efforts. some individuals specifically cited negative experiences during the evd preparations as a reason to not participate, which may have led to a bias in our sample towards individuals with positive experiences. however, all interviewed trainers described the period of the - evd outbreak as extremely stressful, and some described negative experiences. amongst our sample of interviewed trainers, however, there was consistency among responses, suggesting that saturation was reached for many of our questions, despite the modest sample size. the trainee survey was distributed through referral sampling, and received a small number of responses, but there is no reason to believe that interviewed trainers distributed the survey to a specific subset of potentially eligible colleagues. given the limited sample size, inferences from the survey were limited, but findings were consistent with interviewed trainers. this mixed methods approachan effort to triangulate the true experience of hcp involved in evd preparationsis the strength of the research approach. by design, the study captured the experience in the chicagoland area and was conducted after the conclusion of the - evd outbreak. thus, experiences described herein may be specific to chicago and subject to recall bias. a strength of our approach to this qualitative research was the use of multiple coders applying a codebook to interview transcripts and the focused conversation method for data analysis and interpretation. these methods ensured that the data were reviewed by multiple people from the research team through different disciplinary perspectives. themes emerging from the focused conversation were verified by reviewing the interview text to identify supporting and challenging quotes and, to the extent feasible, tabulating quantitative information. though hospitals in the chicagoland area were able to select ppe ensembles and train hcp to use these ppe ensembles while providing care to evd patients, it is not clear that the preparations have resulted in lasting changes that will ease preparations for the next high-consequence infection outside of etcs. refresher training is essential for maintaining preparedness, and there is a need to determine, through research, a training interval that maintains skills while minimizing cost and administrative burden. hospitals were able to improvise and identify other sources of information to guide ppe selection in the face of dissatisfaction with initial cdc recommendations, using an approach consistent with the philosophy of standard precautions. occupational health agencies could and should fill the need for guidance for ppe selection and evaluation that is relevant to diverse infectious diseases, and acknowledge the need to consider: protection level, ease of use, ensembles, and availability. such guidance could result from revisiting ppe selection in the context of standard precautions and/ or the development of a tool to guide decision making. world health organization: ebola virus disease -democratic republic of congo ebola virus disease cluster in the united states occupational deaths among healthcare workers cdc: infection prevention and control recommendations for hospitalized patients under investigation (puis) for ebola virus disease (evd) healthcare workers on personal protective equipment for ebola. cdc online newsroom addressing infection prevention and control in the first u.s. community hospital to care for patients with ebola virus disease: context for national recommendations and future strategies preparing the health system to respond to ebola virus disease rapid development and deployment of ebola readiness training across an academic health system: the critical role of simulation education, consulting and systems integration chicago ebola response network (cern): a citywide crosshospital collaborative for infectious disease preparedness rigour and qualitative research qualitative research in health care -analyzing qualitative data (reprinted from qualitative research in health care) saturation in qualitative research: exploring its conceptualization and operationalization the place of inter-rater reliability in qualitative research: an empirical study the art of focused conversation utilizing the focused conversation method in qualitative research: a team-based approach to data analysis and interpretation guidelines for isolation precautions: preventing transmission of infectious agents in healthcare settings the emergency medical treatment and active labor act (emtala): what it is and what it means for physicians hospital preparedness for patients under investigation (puis) or with confirmed ebola virus disease (evd): a framework for a tiered approach j ebola hemorrhagic fever j cdc national institute for occupational safety and health: niosh personal protective equipment information (ppe-info) personal protective equipment for preventing highly infectious diseases due to exposure to contaminated body fluids in healthcare staff (review) isolation gowns in health care settings: laboratory studies, regulations and standards, and potential barriers of gown selection and use osha: fact sheet: ppe selection matrix for occupational exposure to ebola virus guideline for isolation precautions in hospitals part ii. recommendations for isolation precautions in hospitals assessment of the risk of ebola virus transmission from bodily fluids and fomites protecting health workers from airborne mers-cov -learning from sars uncertainty, risk analysis and change for ebola personal protective equipment guidelines epidemiology of ebola virus disease (evd) and occupational evd in health care workers in sub-saharan africa: need for strengthened public health preparedness successful delivery of rrt in ebola virus disease guidance on personal protective equipment (ppe) to be used by healthcare workers during management of patients with confirmed ebola or persons under investigation (puis) for ebola who are clinically unstable or have bleeding, vomiting, or diarrhea in u.s. hospitals, including procedures for donning and doffing ppe j ebola hemorrhagic fever making the invisible visible: why does design matter for safe doffing of personal protection equipment? cdc safety training course for ebola virus disease healthcare workers acceptability and necessity of training for optimal personal protective equipment use use of remote video auditing to validate ebola level ii personal protective equipment competency the association between self-perceived proficiency of personal protective equipment and objective performance: an observation study during a bioterrorism simulation drill violet': a fluorescence-based simulation exercise for training healthcare workers in the use of personal protective equipment assessing viral transfer during doffing of ebola-level personal protective equipment in a biocontainment unit we would like to acknowledge isabel farrar with the uic survey research laboratory for assistance and advice with the interview and survey instruments, agnes kalat for programming our survey, and yu-kai huang for analyzing the survey responses. the data generated by the interviews in this study are not publicly available because it is not possible to effectively de-identify these data, which were sampled from a small geographic region. extended and additional quotes are available in the supplementary materials, and survey data will be available within mo of publication at uic indigo, indigo.uic.edu. the authors have no conflict of interest to disclose related to this manuscript. key: cord- - n hml authors: brown, colin s.; garde, diana; headrick, emily; fitzgerald, felicity; hall, andy; harrison, hooi-ling; walker, naomi f. title: ebola virus disease in the obstetric population date: - - journal: ebola virus disease doi: . / - - - - _ sha: doc_id: cord_uid: n hml the clinical management of ebola created a significant challenge during the outbreak in west africa, due to the paucity of previous research conducted into the optimum treatment regimen. that left many centres, to some extent, having to ‘work out’ best practice as they went along, and attempting to conduct real time prospective research. médecins sans frontières (msf) [ ] were the only organization to have provided relatively in depth practical guidance prior to the outbreak and this manual was the basis of further planning between the who, national ministry of health and sanitation in sierra leone, and other relevant stakeholders. additionally, guidance changed over the epidemic as experience grew. this chapter will describe four key areas in the management of ebola in west africa. firstly, it outlines the most recent who guidance; secondly, it looks back at how ebola was managed in differing low and high resource settings; thirdly it outlines possible and optimal options for managing complications, paying particular attention to some of the controversies faced; fourthly it describes recent and ongoing studies into potential novel therapies that may shape future practice. the clinical management of ebola created a significant challenge during the outbreak in west africa in / , due to the paucity of previous research conducted into the optimum treatment regimen. that left many centres, to some extent, having to 'work out' best practice as they went along, and attempting to conduct real time prospective research. médecins sans frontières (msf) [ ] were the only organization to have provided relatively in depth practical guidance prior to the outbreak and this manual was the basis of further planning between the who, national ministry of health and sanitation in sierra leone, and other relevant stakeholders. additionally, guidance changed over the epidemic as experience grew. this chapter will describe four key areas in the management of ebola in west africa. firstly, it outlines the most recent who guidance; secondly, it looks back at how ebola was managed in differing low and high resource settings; thirdly it outlines possible and optimal options for managing complications, paying particular attention to some of the controversies faced; fourthly it describes recent and ongoing studies into potential novel therapies that may shape future practice. there is, as yet, no specific cure for evd and the mainstay of treatment is supportive care and managing complications, alongside ring-fence vaccination of close contacts. however, due to many tropical illnesses masquerading as ebola, and thus requiring isolation and evd testing, it is worth bearing these diagnoses in mind as empirical treatment for them should be considered in the undifferentiated patient (table . ). this is particularly important in contexts lacking diagnostic resources, and additionally, with the current absence of a rapid diagnostic test that has been widely used or field tested. as an example, o'shea et al. [ ] reviewed patients who presented with suspected evd but tested negative, at the uk ministry of defense etu at kerrytown, sierra leone. eleven had malaria ( . %), shigella spp. or e. coli, a respiratory infection and , an undifferentiated febrile illness supporting the need for empirical malaria and antibiotic treatment. the who released their most recent guidance on the management of ebola in february . this is recognised as the gold standard in the low-income setting, however, it is possible that the capabilities of many centres will not meet these targets. the who classifies the patient into three categories of severity; mild, moderate and severe. these are briefly summarised here, but for specific guidance the most up to date version of the who manual should be referred to. the patient will be haemodynamically normal, able to eat and drink, have no complications nor evidence of dehydration. empirical oral broad-spectrum antibiotics, anti-malarials and oral rehydration solution are recommended. treatment for symptoms such as pain, fever and dyspepsia can be provided orally. patients often have vomiting and diarrhoea, are weak and look dehydrated with sunken eyes and a skin pinch slow to return. antibiotics and anti-malarials should ideally be given intravenously, however, if there are contraindications to intravenous line insertion, can be administered intramuscularly. fluids should be given intravenously with additional oral rehydration solution. severe this patient will be severely dehydrated and shocked from either dehydration, sepsis or bleeding, although haemorrhage in the west african outbreak was seen in as little as - % of cases. empirical broad-spectrum antibiotics should be administered intravenously within the first hour of presentation, along with anti-malarials, and effective intravenous fluid resuscitation is essential. tables are provided in the who guidelines to calculate fluid requirements, however, as a rule of thumb an adult who is severely dehydrated or shocked would be treated with a bolus of l in the first min. monitoring the patient for acute fluid overload with regular vital sign measurement and fluid balance charts is required. in ill patients, the who advocates testing for malaria and hiv, and measuring potassium, sodium, bicarbonate, blood glucose, creatinine, and lactate. for women of a childbearing age, a pregnancy test should be performed as a priority. if possible, magnesium, haemoglobin or hematocrit, platelet count, inr and aptt should also be tested. in all instances management of symptoms and signs is required-these are described in the management of complications section below. there was great variation in evd management in practice, influenced in part by resource discrepancies, differences in case load and staffing, and disagreements in best practice that developed due to the void of evidence. here we discuss some of the different evd management settings, the type of care that was provided and the impact that these differences may have had on patients' outcomes. table . describes the variation in care across the three most affected west african countries at low and high resource centres, and those repatriated or treated within europe and the united states. there was a wide variation in reported mortality rates. however, the heterogeneity of populations studied, demographics, geography, time period (early versus late in the outbreak), survivor bias (only trans cut pacing- , none cpr uyeki et al. [ ] patients who made it as far as hospital settings were included) most likely explain most of this variation, rather than the effect of differing management strategies. therefore, drawing a meaningful conclusion from these mortality trends about the effect of treatment strategies is very difficult, though expanded access to staffing, therapeutic monitoring, blood product support, and critical care is almost certainly contributory to improved survival. there was a range of the care delivered from differing facilities across the world. as aforementioned, the most recent who manual outlines categorizing the patients into mild, moderate and severe, however, this was not available at the start of the outbreak and many centres used their clinical judgment to determine appropriate therapy. additionally, there was variation across laboratory testing, diagnostic abilities, clinical management and discharge criteria. this was due to multiple factors including the human resource and funding allocation, geography of the unit and specific patient factors (such as time of day they presented and agitation levels) which affected the safety of procedures. a key component to the mohs operational plan for country preparedness was the establishment of isolation facilities at every hospital admitting suspected, rather than just confirmed cases. ehu's such as at connaught hospital in freetown provided a point of access to basic health care where unfortunately in practice the highest levels of management generally only reached intravenous lines and iv fluid and antibiotic therapy, due to resource constraints, leaving laboratory testing and closer monitoring to the etcs. isolation in these facilities was expected to be for less than h, while waiting for blood results and transfer, however, patients were often waiting much longer due to delay in diagnostics and limited bed availability and thus received basic care for this period of time. additionally, at the height of the outbreak when the number of suspected cases exceeded bed availability, there were many patients who were forced to wait outside hospitals, etcs or at home, receiving only ors, until a beds became available. it is clear now that this time window was critical for patient resuscitation and the ability to check laboratory results and correct electrolyte imbalances would have been of significant benefit. even once a patient reached an etc, the level of care differed widely. for example kenema etc, in the east of sierra leone, one of the first etcs set up by msf and a h drive away from the ehus in freetown was able to perform basic laboratory tests but often was so overburdened with cases that optimal management was challenging. however, in kerrytown, sierra leone, where the british funded two etc sites, one staffed by save the children and the other through the ministry of defense, patients could receive a higher level of care from onsite laboratory services measuring and correcting electrolyte imbalances and a lower patient to staff ratio allowing more time and a safer environment for monitoring and delivering intravenous fluid resuscitation. unfortunately, epitomizing the global delay in rapid response to the outbreak, kerrytown opened in late november providing a mere two months of care during the height of the outbreak. in addition, the uk mod etc at kerrytown limited its patients through selecting only health care workers who had become infected, and with a high level of resources were able to do all supportive interventions apart from intubation and ventilation and renal replacement therapy. from the review conducted by ukeyi et al. [ ] on the care of patients with ebola in the us and europe, it is clear that in all centres regular monitoring and laboratory testing were available and management was tailored to results. five patients received renal replacement therapy, nine received non-invasive and invasive ventilation and transcutaneous pacing was conducted on one patient. none of the patients in any of the settings received cardiopulmonary resuscitation as it was deemed that once a patient had lost cardiac output, resuscitation would be futile. complications (table . ) at the start of the outbreak there was reluctance to provide intravenous fluid therapy mainly due to the risk to health care workers and challenges surrounding observing patients for bleeding complications, and therefore oral rehydration solutions were relied upon. however, over the course of the outbreak there developed an understanding of the mechanisms of death from ebola through shock, with high lactate (values reported as ranging from to mm/l [ ] ), hypoxia from late multi-organ failure, renal failure and electrolye imbalances, in particular hypokalaemia from diarrhoea. this led to a consensus that the basic principles of resuscitative supportive care should be applied with aggressive management of intravascular volume depletion, the correction of electrolytes and prevention of complications associated with shock (hunt et al). in one well-documented case managed in a german intensive care setting, diarrhoeal output exceeding l in h was reported, with intravascular collapse, and was managed aggressively with fluid repletion ( - l per day). intravascular leak did occur (pleural effusions, pericardial effusion, ascites) but overall, the treatment was successful [ ] . certainly dallatomasinas et al. [ ] noted that % of deaths occurred within days of admission, when supportive therapy is most likely to impact survival. there still is, however, uncertainty on how much, what type and how fast, fluid should be given promoting suggestions that further research is required in these areas, to optimize simple interventions, including resuscitation with a pre-mixed ebola specific fluid [ ] . there were very few complications related to fluid overload in the west african setting, and perner et al. [ ] commented on minimal capillary leak and less hypoxaemia/ards than in western sepsis, suggesting that perhaps not enough fluids were given as opposed to too much. unfortunately, the challenges faced from high patient to staff ratios, limited time inside the unit and concerns over bleeding risks through iv cannulation, (although clinically significant gastrointestinal bleeding was reported in less than % [ ] ) meant that patients were likely not receiving optimal medication. electrolyte disturbances are common in evd, although electrolyte monitoring was not widely available in west african holding units and treatment centres. case [ ] . hyperkalaemia was associated with acute kidney injury and mortality. in the same series, hyponatraemia was also prevalent, in over % patients. [ ] . the uk's ebola referral hospital, the royal free, is now prepared to perform haemodialysis and intubation. there are still no standardised guidelines for use in high income settings, however, the current recommendations are that organ support should be available but that interventions should be limited with a do not resuscitate (dnr) order place. there are no specific treatments with proven efficacy for ebola. the rapid and unpredictable onset of evd outbreaks, together with their often remote location and hazards to health workers prove a major challenge to therapeutic trial implementation. a series of eight symptomatic patients in kikwit, in , given convalescent whole blood, was the largest reported attempt at a an ebola therapeutic intervention study, prior to the west african ebola outbreak [ ] . however, this has been a rapidly evolving field. the scale and duration of the west african evd outbreak, involving patients in urban and high resource settings, provided the opportunity and incentive for accelerated research into therapies and clinical trials. efficacy studies to date have consisted of: . in vitro and animal studies . case reports/small case series of occasional or "compassionate" human use . phase ii clinical trials interventions have been either post-exposure prophylaxis (pep) in asymptomatic exposed individuals, and/or treatment in symptomatic cases. candidate drugs that have made it into human clinical use currently fall into four categories: . novel specific antiviral agents e.g. small interfering rnas . repurposed anti-infective agents, e.g. favipiravir . other repurposed agents e.g. amiodarone . specific immune therapies, e.g. convalescent plasma, convalescent whole blood, monoclonal antibodies such as zmapp in summary, an impressive effort to generate human trial data on therapeutic inventions, the results of which are summarized in table . (taken from brown [ ] ) has to date identified no clearly efficacious agent. there was a reluctance to attempt double-blind, placebo-controlled trials, for questionable ethical and logistical reasons (see lanini [ ] -this includes a good review of clinical trials and a discussion of the ethical issues). an opportunity to collect data on the efficacy of supportive interventions e.g. threshold for iv fluids, loperamide for diarrhea, was largely missed due to inadequate human resources, and no systematic controlled studies of such were performed to our knowledge. as evd is most likely to affect the low income setting in future, further research into interventions, such as the safety of intravenous lines, usual care versus laboratoryguided care, effectiveness of anti-diarrhoeals, empirical antibiotics and oral potassium supplements would be beneficial. provisional plans for trials should be agreed prior to the next outbreak, to improve rapid implementation when the need arises. this is a moving field and more trial data is likely to be available in the upcoming years. we suggest consulting the following useful resources for up-to-date information: https://ebolaclinicaltrials.tghn.org http://www.ukcds.org.uk/resources/ebola-research-database http://www.who.int/medicines/ebola-treatment/emp_ebola_therapies/en/ https://clinicaltrials.gov small interfering rnas, have shown potential in treatment and prevention, in non-human primates and humans. tkm- (by tekmira), was fast-tracked due to encouraging animal and phase data for a clinical study in sierra leone. however, the trial was terminated early, as demonstration of efficacy was deemed unlikely, and the product discontinued by the manufacturer [ ] . other sirna molecules are in development with encouraging data efficacy in non-human primates (limiting symptoms, abrogating mortality-siebola- , see thi [ ] ). brincidovir, a small molecule nucleotide analogue, orally available lipid conjugate of cidofovir (chimerix, inc.), was used occasionally in repatriated patients and in an open-label, single arm phase ii clinical trial (in liberia) which stopped early, favapiravir (toyama, japan), is a broad spectrum anti-viral, approved for treatment of influenza, in japan. a therapeutic effect was reported in ebola virus-infected mice and supported by relatively good outcomes in some cases of occasional human use in repatriated patients (pep and treatment). since then two historically-controlled, open-label, single arm phase ii clinical trials have been undertaken: a multi-centre study in guinea (the jiki trial, see sissoko [ ] ) and a single-centre study in freetown, sierra leone [ ] . conclusions are limited by the chosen study design and the challenges of trial implementation under the circumstances. the former, larger study did not demonstrate a treatment effect of favapiravir on mortality, whereas the latter reported survival benefit and viral load reduction in treated patients. together these results support prioritization of a randomized placebocontrolled trial of favapiravir, when the opportunity presents. there is some evidence (and a widely held belief) that an ebola-specific antibody response is protective, providing the rationale for attempted treatment and prevention with ebola virus-specific antibodies. specific monoclonal antibodies were available but in short supply and were not easily amenable to rapid scale up. one such antibody cocktail, zmapp, was initially used compassionately in repatriated patients and when increased supply became available, the only randomized control clinical trial was performed, in us, guinea, liberia and sierra leone. the results suggested that there was some evidence of treatment effect, and again this agent will certainly be a likely candidate for prioritization in any future outbreaks [ ] . other monoclonal antibodies, (zmab and mil ) were also used in selected cases as pep [ ] . due to encouraging results during the earlier kikwit outbreak (albeit in selected patients, see mupapa [ ] ) there was considerable enthusiasm for a trial of convalescent plasma and/or whole blood from evd survivors. phase ii trials were commenced in guinea and sierra leone, but neither trial recruited enough patients, and the guinea trial did not ascertain whether any neutralizing antibody was present [ , ] . additionally, a pilot study of interferon β- a for evd enrolled only patients in the intervention arm (reference konde et al plos one interferon β- a for the treatment of ebola virus disease: a historically controlled, singlearm proof-of-concept trial. it remains to be seen whether there are long term side effects or other consequences of therapeutic manipulation of the natural immune response to evd. it is difficult to assess the effect of different interventions on outcomes, due to the lack of formal studies involving rigorous prospective data collection and appropriate controls. the epidemiology of the disease and the response changed significantly, and so historical comparisons are relatively unhelpful. we have concluded that, in the absence of evidence and the lack of opportunity to generate evidence, it should be the priority to optimize supportive therapy, including intensive care therapy when available. other specific interventions may be used when they are readily accessible, likely to provide benefit based on extrapolation from other diseases, and very unlikely to do harm, in pragmatic studies. other interventions, including novel drug therapies and immunotherapies should be evaluated in randomized, adequately controlled clinical trials, prior to use. diana garde and emily headrick care for the pregnant and postpartum patient in the context of an ebola virus disease (evd) epidemic presents unique and challenging clinical, ethical and logistical considerations. since the first recognized epidemic of evd in zaire in , subsequent outbreaks have occurred in sub-saharan africa (ssa) [ ] where access to robust maternal health care services has been limited. an evd epidemic superimposed on an already weakened health system further exacerbates extremely poor outcomes for the obstetric population. in general, % of all women are expected to experience obstetric complications [ ] . the - west african evd epidemic is the largest to date, with approximately , cases in three countries-guinea, sierra leone and liberia. prior to the - evd epidemic, these countries demonstrated some of the worst health care indicators due to inadequate infrastructure, human resources and lack of access to basic medical resources [ ] [ ] [ ] [ ] . in sierra leone, it is estimated that prior to the evd epidemic, one in every women would die in childbirth-related incidents in her lifetime, [ , p. ] with the maternal mortality ratio at per , live births in -the highest in the world [ ] . in addition, all three countries fell within the lowest density of medical personnel per capita, resulting in the smallest and least-skilled healthcare workforce in the world [ ] . both the number of in-hospital deliveries and cesarean sections declined as the incidence of evd increased [ ] . ultimately, it was predicted at the end of the epidemic in west africa, that the greatest impact of evd would be on maternal health due to the loss of medical staff to ebola (physicians, midwives and nurses). by september , the three countries had lost medical personnel from their already significantly small workforce [ ] . from that data, it was estimated that there would be an increase of at least % (guinea) and as much as % (liberia) in maternal mortality [ ] . it has been asserted that women are at an increased risk for evd infection, both physiologically and socioculturally. traditionally, they are the caregivers for ill family and community members, and they responsible for burying the dead, and as such have significant potential for interaction and contact with the virus via body fluids [ ] . if a woman is pregnant during an evd epidemic, routine health care encounters for antepartum or intrapartum care places women at high risk for exposure to infected patients also seeking care. there is a higher prevalence of female medical staff, namely nurses and midwives, both inside government facilities and in the community who would then be more likely to have (knowingly and unknowingly) direct contact with positive evd patients in an epidemic. in addition, females in ssa have historically had less authority over their reproductive health and are at higher risk of gender based violence or coercion [ ] ; sexual intercourse with an infected or surviving male also places women at increased risk of infection [ ] . natural immunosuppression occurring in pregnancy [ ] may play a role in a higher acuity of illness observed in presenting obstetric patients with positive evd, contributing to very poor maternal outcomes. considering the expectation of an excess of . million pregnancies per year [ ] across guinea, sierra leone and liberia, a significant number of women who had direct contact with the virus were either pregnant or postpartum. during the - west african evd epidemic, pregnant women presenting for health care services-either for routine peripartum care or in the event of obstetric complications-often met case definition for evd (see table . ).where proactive clinical management would have been appropriate in a non-epidemic table . clinical and epidemiological factors in initial evd case definition screening epidemiological factors considerations for screening for general populations early: fever, profound weakness or malaise, headache, myalgia, arthralgia, conjunctivitis, nausea or anorexia, throat pain or difficulty swallowing, abdominal or epigastric pain, diarrhea (bloody or nonbloody) exposure/contact: infected animals, bushmeat or fruit also fed on by bats, healthcare workers/ traditional healers also treating evd, items soiled or touched by positive evd patient, deceased evd bodies sexual intercourse with evd-positive male or evd survivor late: confusion and irritability, hiccups, seizures, chest pain, diarrhea (watery or bloody), vomiting (with or without blood), skin rash, internal or external bleeding, shock, respiratory distress additional considerations for screening obstetric population vaginal bleeding of unknown origin, spontaneous abortion, premature labor and/or rupture of membranes, preterm labor, antepartum and postpartum hemorrhage, intrauterine fetal demise, stillbirth, loss of consciousness exposure to products of conception or deceased fetus of evd positive patient being a pregnant woman with history of contact with confirmed evd patient, recent evd survivor with an intact pregnancy, newborn of an evd positive mother, infant breastfed by a recent evd positive mother who library cataloguing-in-publication data [ ] setting, women were often left untreated or were provided minimal intervention by frightened medical staff working in an overwhelmed, under resourced health care system in crisis. even as the emergency response resources became more established, an unfortunate number of women were isolated based on presenting symptoms; the majority of these women ultimately tested negative for evd, yet they languished and died in evd isolation centers due to the limitations of obstetric interventions available in this setting. it is in this context that clinical care for obstetric patients in an evd setting be specifically considered. culture, health infrastructure, access to resources, geography and physiology are all complex forces that must be considered when managing individuals and populations alike. treatment of the pregnant or postpartum patient who meets case definition for evd should be offered without haste and with the highest level of quality interventions possible, while maintaining safety of healthcare workers and the community. this chapter aims to achieve the following objectives, informed by previous research on evd outbreaks and by field experiences from the to west african evd epidemic: -examine the unique risks and needs of the obstetric patient in the context of the an evd epidemic -review clinical management of the obstetric patient infected with evd as well as the unconfirmed or suspect obstetric patient being managed in a red zone (rz) setting -provide technical guidance for establishing a safe and effective setting for triage, screening, isolation and treatment of the pregnant patient and mother/baby dyads. one of the key challenges when evaluating a pregnant patient in the context of evd is that symptoms suggestive of evd infection (i.e. abdominal pain, vaginal bleeding) may mask a true obstetric emergency. conversely, the clinical presentation of what initially appears to be an obstetric complication often confounds the accurate identification of potential evd infection. however, evd infection can be the precursor to obstetric complications and a patient presenting for care may in fact require appropriate interventions for both. the basic evaluation of suspected evd patient must consider both clinical presentation (signs and symptoms) and an accurate history to evaluate risk of exposure. due to this unique overlap in symptom presentation for the pregnant patient, additional considerations for the obstetric population must be made in addition to the general screening (table . ). it is of note that not all evd-infected patients presented with or manifested a febrile state during their illness. it is estimated that only between % [ ] and % [ ] of patients actually presented with fever greater than c. likewise, patients did not regularly demonstrate coagulopathies or overt hemorrhagic symptoms [ ] , as is frequently assumed as a common presentation for a viral hemorrhagic fever, with only one study finding these as a presenting symptom in only % of patients [ ] . in the - west african evd epidemic, it was frequently observed that evdpositive pregnant patients were presenting with tachypnea and tachycardia, sometimes in the absence of any other symptoms, and could be repeatedly seen "hitting the floor," or favoring a position on the floor rather than in bed. it is postulated that this behavior may be due to agitation, or to alleviate fever by lying on a cool surface, but was routinely observed among this population [ ] . although many guidelines for screening include fever and bleeding as dominant symptoms in the algorithm, suspect cases can present without either and evd illness can be missed during initial clinical evaluation. in fact, there are multiple documented cases of pregnant women with known evd exposure and/or infection who do not manifest these common symptoms as expected. in these cases, the potential for an evd positive fetus/neonate is %, thus increasing the risk to unsuspecting healthcare workers during routine intrapartum care [ ] . the majority of obstetric complications outside of an evd epidemic involve the following: postpartum hemorrhage (pph), antepartum hemorrhage, obstructed labor, postpartum sepsis, complications of abortion, severe preeclampsia or eclampsia, ectopic pregnancy and ruptured uterus [ ] . in , approximately women in ssa died each day as a result of obstetric complications, the majority from pph [ ] . in addition, the stillbirth rate in ssa is approximately times higher than in developed countries at / [ ] . as such, an evd-negative obstetric patient can easily meet current who case definition, resulting in the isolation and testing of a high proportion of women who are actually in need of basic obstetric care. given that overlap of presenting symptoms may be commonly seen in both evd and non-evd obstetric cases, astute clinical decision making is required to ensure that obstetric patients are not being overwhelmingly screened and disproportionately isolated for evd when the absolute risk in the community is low. conversely, great effort must be made to ensure that symptomatic obstetric patients are not being treated outside of isolation when the absolute risk of evd is high. in west africa, it was estimated that only . % of the pregnant patients admitted to isolation were evd positive; the . % who were not merely needed intervention for obstetrical complications or normal delivery [ ] . epidemic: in an epidemic setting it can be argued that the likelihood of infection transmission or the public health risk from evd is greater than the risk of morbidity or mortality from obstetric complications. you must first consider general screening for the basic symptoms of evd infection, with additional symptoms to be considered for the obstetric patient (table . ): any of these additional obstetrical complications, particularly in combination with symptoms included in routine evd screening, should warrant isolation and polymerase chain reaction (pcr) testing. in addition, screening methods must capture any patient who presents to a healthcare facility who has recovered from evd with an intact pregnancy and is in labor or in the immediate postpartum period. given the absolute likelihood of viremia in products of conception from a patient who recovered from evd while pregnant, delivery must take place in isolation. in a post-epidemic setting the general screening criteria changes, but the obstetric screening considerations remain largely the same. contrary to epidemic settings, the risks of poor obstetrical outcomes are overwhelmingly thought to outweigh the risk of evd infection or transmission of disease; strong clinical judgment should be employed. in the general population, initial screening uses fever as a determinate for case definition. this tool is used for any acute hemorrhagic fever (table . ). the fever must have persisted despite treatment with appropriate medications for the symptoms (i.e. treatment for presumed malaria), prescribed by a qualified medical professional. the patients meeting criteria must be isolated and pcr tested. pregnant women pose a challenging dilemma during the initial months after an epidemic has been declared over. those who conceived during the epidemic could potentially carry an evd infected fetus into a post epidemic setting given the average weeks of gestation. in a post-epidemic setting however, one might argue for a higher level of scrutiny and clinical judgment prior to admission. the singular obstetric complication alone as criteria for admission for evd testing cannot be justified given the numbers of patients that present for care for pph, iufd and sab under non-epidemic conditions. in either an epidemic or post-epidemic setting, obstetric patients with highly concerning presenting symptoms should be admitted for testing in isolation, regardless of whether they fit the established criteria. consultation and collaboration is recommended with other obstetric providers, surveillance officers, and evd medical professionals who should be made aware of these cases. the evaluation and planning for a patient presenting with symptoms of evd is wholly dependent on whether there is a declared epidemic present, or if there are definitive laboratory-confirmed positive cases in the population. where there is any concern for evd or other hemorrhagic fevers, triage and screening should be established at the entry point to every tier of health care facility in the affected area per guidance of government mandates or international recommendation. during a declared epidemic or in cases where there is a high suspicion of infection, an obstetric-specific screening area should be staged at all peripheral health units, community clinics, and hospitals ( i.e. anywhere obstetric patient may present). all pregnant, postpartum and lactating women should have an accurate temperature taken, and basic and obstetric-specific screening questions addressed before entry to the facility. trained maternity nurses should complete the initial screening and evaluation to allow for experienced clinical judgment in this special population. ideally, screening should be operational for as many hours in a day as the facility is active. staff should have clear protocols for documenting patient information to ensure multiple opportunities for confirmation of triage status upon entry into the health care encounter. we recommend standardized forms that can be made in duplicate or triplicate for record keeping. staff should also have ways and means of communication to other colleagues so as not to leave the triage post in the event of a positive screen, an emergency in triage, or need for consultations or technical/ operational support. this station should have access to electricity or reliable lighting, and a source of water for hand washing stations and cleaning. while the triage area should ideally remain a calm environment for efficient yet thorough screening, the possibility of emergent screening is eminent. triage staff should be prepared to prioritize emergent or critical cases while adhering to screening protocol and ultimately prioritizing safety for themselves, colleagues and patients in the immediate surrounding area. patients may present to the facility in critical condition on foot, by private car or by ambulance from another facility. if the patient is unconscious or unable to give a clear history of the present condition, immediate isolation should be the most likely triage decision. if family members or an accompanying health care worker can provide a clear history that places the patient at a lower suspicion for meeting case definition, clinical judgement can be exercised judiciously. a secondary screening area can be used when staff determines that a patient is going to isolation, but more history taking and assessment must be made. an open window with a one-meter buffer can be placed between the staff area and patient secondary screening room. a patient can be removed immediately from the primary screening area and obstetric-specific information can then be gathered from safely behind the window. if the situation warrants, nursing staff can use the space in secondary screening to allow for observation to assist in determining if the patient meets case definition. when a patient enters the secondary screening, it should be considered a red zone until suspect status is otherwise ruled out, or the patient is transferred into the appropriate isolation ward and the secondary screening cleaned. in some situations, emergent or non-emergent, a thorough screening is not feasible prior to delivery and in cases of unknown history care must be administered as if the patient meets case definition. it is beneficial to design and stock the secondary screening facility to immediately turn into a safe red zone in the case that a patient exhibits an emergent illness (i.e. actively bleeding, loss of consciousness) or in cases of imminent delivery. if the patient cannot be transferred into the secondary screening area, triage nurses must have the ability to close the primary screening zone from pedestrian traffic, offering privacy to the patient, room for nurses to work and separation from the general public until the emergency is resolved. clinical and ipc staff must have ready access to all necessary materials in the triage/secondary screening area to safely and effective care for patients requiring immediate attention. we recommend the following: • nurses must have a donning and doffing area and the means to handle blood borne waste or body fluids. • delivery kits, fluid resuscitation supplies, comprehensive ppe and medications for pph should be maintained in the nursing area and access to a hospital bed in secondary screening is optimal for patient care. • there should be the means for transferring a non-ambulatory patient to either isolation or to the hospital after the appropriate screening is completed, or postpartum. this may include a wheelchair or a stretcher. there are known cases of pregnant women presenting to a health care facility in labor who do not meet case definition at admission, but who then develop higher-acuity symptoms during/after labor and are subsequently test positive for evd [ , ] . it is crucial that health care administrators, staff and supporting partners collaborate to establish and implement protocols to increase the chances of early identification, rapid isolation, adequate treatment and effective ipc in the health care facility. ongoing assessments must take place for the in-patient population throughout their stay in the hospital. there must be q-shift assessments completed to determine if a patient is showing signs of becoming ill or demonstrating the classical obstetric warning signs. medical personnel must also screen neonates post-delivery q-shift, during their entire stay and discharge instructions must offered to caregivers regarding warning signs after discharge. given the potential for a scenario in which a patient has subclinical asymptomatic infection, but passes evd to the fetus, clinicians must be watchful for and proactive in isolating and treating as soon as symptoms arise. during an active evd epidemic, every patient must be treated as potentially infected, no matter where they may suddenly require care. while care should never be withheld from a patient requiring attention, appropriate ipc measures must be available before care is delivered. given the rapid progression of obstetric emergencies and precipitous labors, rapid response protocols should be established. any area can be rapidly turned into an ad-hoc red zone. all first responders should be comfortable with ipc principles and with the concept of red zone/green zone, which can theoretically be established with or without physical barriers. multiple sets of complete ppe should be available at multiple locations in and around health care facilities and in ambulances. care should not be rendered without appropriate ppe and ipc materials. we recommend delivery kits also be easily accessed or assembled for imminent deliveries. support staff should be available to secure a perimeter around an ad-hoc red zone to maintain crowd control, for delivery of additional materials and medications, to establish a line of communication between ad-hoc red zones and surrounding areas, and to initiate the next steps of transfer into a facility once immediate care is rendered. hygienists/ipc support staff should don full ppe and prepare to decontaminate the ad-hoc red zone once the patient is stabilized and transferred. in the event of potential exposure or contamination to others in the community, every attempt to identify potential contacts is crucial for ongoing contact tracing and surveillance. while this can be difficult when an ad hoc red zone must be established in a large facility, in a crowd, or involving methods of transportation, it is crucial in the midst of an outbreak. the - west african ebola epidemic catapulted the research and development of innovative designs for the structures and materials used to combat this virulent disease. while the relative quality of infrastructure used as ebola treatment centers ranged from sticks and tarps to military grade modular isolation units to modified existing structures to multimillion dollar bsl biocontainment facilities at prestigious academic medical facilities in the united states, the guiding principles of infection prevention and control remain the same across sites. the guiding principles of an ebola treatment center include: -limited entry and exit points, for both patients, staff, materials and corpses. -double barriers between red zone and external environment. -flow of movement from green zone, to suspect case areas, to confirmed case areas, to morgue, thus reducing the risk of transmitting virus from confirmed evd positive patients to possibly uninfected patients. -multiple points for decontamination between patients -adequate distance/barriers between patients and between "suspect" and "confirmed" wards -clinical principles that prioritize safety of staff, minimizing risk of contact with infected fluids. -around-the-clock bedside care is very difficult to realize given staffing constraints and limits of length of time in ppe. regularly scheduled "rounds" to administer patient care is more feasible [ ] . these principles remain the same for an ebola treatment center serving the obstetric population. however, in our experience, we recommend the following considerations to the design and utility when caring for pregnant or laboring women in a red zone. • etcs are generally separated into suspect vs. confirmed wards, and/or "wet" versus "dry," meaning patients with active vomiting or diarrhea should be separated from those who do not to reduce the risk of transmission of highviremia fluids. we recommend that in an obstetric red zone, every attempt should be made to arrange patient beds so that actively laboring or unstable patients occupy an additional "ward," ideally one that can be visually monitored at all times. in the ob red zone setting, intrapartum patients are considered highest-risk in terms of potential of evd transmission (in known positive or unknown pcr status), but regardless of their evd status, will require the most focused care until they are stabilized. • it is likely that staff will not be able to provide hour support in the red zone, but particularly when a patient is actively laboring, every attempt should be made to schedule teams of two to rotate through "red zone rounds" to assist with labor without interruption of bedside care. deliveries can be precipitous, and forgoing constant bedside care in active labor increases the risk that simple complications (i.e. shoulder dystocia, pph) result in death. • in the event that staffing support does not allow for constant bedside care during an active labor, we highly recommend designing the ob red zone with multiple access points to visualize patients from the green zone, either through windows or utilizing camera or video recording equipment if available. being able to visually assess the status of a patient to determine the best time to don ppe for bedside care can be crucial to improving outcomes. • every red zone should be equipped with the appropriate materials to care for the obstetric patient. there are several key items that will be necessary to have in abundance: -menstrual pads and diapers (adult and infant) -infant formula and feeding cups -cotton sheets (or suitable substitute) to cover patient for warmth and privacy, also to anticipate multiple bed-linen changes, and several rags, towels, linens for cleaning large amounts of blood/amniotic fluid. -bassinette which can serve as sleep area for neonate or set up as neonatal resuscitation surface post delivery (must have cleanable surface) -suture materials, needle holder, blunt tipped scissors, speculum or retractor -manual vacuum extractor or forceps -individual blood pressure cuff and thermometer at each bedside, able to be sanitized. -sharps container at each bedside -iv poles, both and short (short for patient who must be placed on the floor for safety) -bell, intercom or other means of calling for assistance. this is particularly helpful for women in early stages of labor who may not require constant monitoring to alert staff that assistance is needed. -wall clock to monitor contraction intervals, as well as time limits for staff in the red zone. -scale for infant weights or for measuring maternal blood loss -ready-made and easily accessible kits with necessary equipment to rapidly manage normal deliveries, postpartum hemorrhage, and eclampsia/seizures the acuity and complexity of patients entering into the red zone is such that a standard medication protocol is warranted. given the lack of immediate diagnostic capacity in many settings, it is recommended that all patients receive empiric treatment of antibiotics, antiprotozoal and antimalarial medications until bacterial, amoebic or malarial infections can be definitively ruled out, or the entire course completed. even in the case of evd, one cannot rule out co-infection with malaria or other common infectious disease. as such, evd suspect and positive patients should be continued on all medications unless testing confirms absence of co-infection. clearly, it would be optimal to have an extensive medication formulary at the disposal of clinical staff in an epidemic, however the historical outbreaks occurring in low resource countries have forced makeshift pharmaceutical supply. the following are suggestions for coverage of the potential needs in isolation or treatment centers. planning should include at minimum medications from the following categories. all medications listed are from the who model list of essential medicines [ ] , unless otherwise noted. clinical judgment must be made as to the relative benefits and risks involved and the acuity of the individual patient when choosing medications (table . ). for purposes of simplicity and as a model for the ideal facility, the following will be addressed as if both suspect and confirmed cases are in isolated and treated within the same site. at admission, it must be determined where the patient should be placed within the unit based on their status. "wet" suspect patients, or those with active bleeding, vomiting or diarrhea should be separated from "dry" suspect patients. all suspect women awaiting test results should be physically separated from probable confirmed patients. laboring patients should be given privacy and placed inside intrapartum rooms for delivery, containment of body fluids and a higher level of care and observation. infants should be with their mothers and not in a nursery. bassinet sharing must be avoided. it is critical for every patient who enters into an isolation or treatment center, that complete demographic and symptom history information be completed at the time of admission for care planning, data collection and tracking purposes. first name, last name, and birthdate should be verified and patients given a wrist name band including those three identifiers. patient information can be entered onto a whiteboard or other central documentation record for clinical planning with the following information: bed number, name (first and last), age, birthdate, pregnancy status (pregnant and gestational age, postpartum or lactating), presenting symptoms, and date of onset of symptoms. this record can also include pregnancy outcomes that are updated in real-time (i.e. delivery date and time, gender of neonate, complications, etc.). it is advisable to have an admission book, or means of keeping patient status updated and relevant data logged. the goal is that all staff members can quickly assess and interpret the status of all patients in the etc, as status can change rapidly. another whiteboard or central documentation record can also be used to track lab tests completed (date and time), when the next confirmatory tests are due and results. in order to create a care plan for individual patients, a complete head to toe assessment must be completed to the best ability of the clinician, given time and patient load constraints. information that should be collected can be divided into two categories-objective and subjective. a clinician with experience in obstetric care should collect the objective information. the subjective information is dependent on patient consciousness, the ability of a patient to be an accurate historian or in some cases must be pieced together from family members. the clinician inside the red zone is responsible for collecting gaps in history that has not been addressed before admission (table . ). all information must be documented in patient charts after each assessment in the red zone and on the central documentation record/whiteboard. patients in labor should have a partograph started if over - cm dilation. to date, pcr has been the testing method of choice for evd infections. approval for use of a rapid screening test (rst) or genexpert for evd would allow access to results that could rule out evd quickly. choice of testing method must be made according to current international standards, national regulations and pharmacy board approvals. all patients entering into the center should be pcr tested on admission. if the symptom onset is less than h, then a second test is needed at or after the h mark. suspect and confirmed patients having either a spontaneous abortion or iufd must have products of conception swabbed and tested (fetus, placenta-fetal side, associated tissue or amniotic fluid). an neonate delivered in isolation, or admitted with a suspect patient must also be tested. a patient who is deceased prior to serum collection should have oral swabs collected prior to burial. iufd at full term can also have oral swabs collected. like any other evd suspect or confirmed patient, pregnant, postpartum or lactating women must be assessed and treated based on presenting symptoms. given the nature of fluid loss, offer appropriate replacement fluids (ors or iv/io) based on the severity of dehydration and level of consciousness. consider differential diagnoses and offer antibiotic and antimalarial therapy as discussed above. symptomatic relief must also be included in the care plan for pain, nausea, vomiting, agitation etc. obstetrical care in the context of evd has historically been limited to expected management given extremely high viral load present in amniotic fluid, blood, and placental tissue. as a result the inherent risk to health care workers it was determined to be too high for interventional care. the following were considered high risk in the past and healthcare workers were cautioned against engaging in: cesarean section, artificial rupture of membranes (arom), episiotomy or deinfibulation of scarring related to female genital mutilation, manual vacuum aspiration, manual removal of a retained placenta, suturing, vacuum extraction, and craniotomy in the case of obstructed labor. anticipated delivery in isolation should be managed with caution ensuring the utmost safety of staff while offering the highest level of care to the patient and her fetus. adequate staffing numbers and skill level and immediate availability of needed delivery supplies and medications will eliminate some of the risks associated with deliveries in a limited resource setting. in serious cases where life is threatened or suffering is unmanaged, a higher level of intervention should be considered when qualified staff are present, adequate supplies are on hand and ipc measures can be adhered to. in this way, risks can be mediated and the potential for survival increased. for management of all deliveries in the red zone, protocols must be created with respect to the local ministry of health clinical guidelines and who recommendations for ob care in limited resource settings. additionally, the following considerations must be made to care for patients with evd filovirus or other hemorrhagic fevers: • an adequate intrapartum setting must be prepared before delivery to decrease the risk to staff and patients in the red zone. safety must always be a priority and clinicians must not place themselves at risk in the event a lack of appropriate water, lighting, or ppe should occur. • red zone staff should prepare the bedside when there is an impending delivery and have iv fluids, delivery kit, resuscitation equipment and neonate blanket and bedding at the ready. • staffing should be adequate for deliveries; ideally, there should be a nurse or midwife for the delivery, a nurse for the neonate and one other clinical staff member to monitor ipc and assist where needed. presence of a hygienist is also advisable. roles should be assigned prior to entry into the red zone. • a second team in the green zone must be ready and able to relieve red zone staff when they are exiting and there must be a system of report to update status of the patient before the change of shift. if able, the exiting ipc clinician should update the incoming team before they enter. • there must always be staff in the green zone to hand in needed medications, consult and support red zone clinicians. the green zone staff must help to monitor total time in the red zone and give adequate warning when doffing is required. a "sign in" whiteboard at the entrance to the red zone area allows for accurate monitoring of time in ppe and identification, location and duties of staff in the red zone. -it is optimal for clinical staff to visualize laboring patients from the green zone if there are not enough staff for round the clock care in ppe. a communication tool is also advised so that the patient can call for help if needed, or give status reports to staff. • elbow length gynecologic gloves are preferred for deliveries. in addition to standard ppe, a heavier and thick reusable apron is recommended for the delivering clinician to protect the front of the coverall from body fluid, and to reduce the movement of a lighter, thinner apron. have all needed ppe in the red zone and readily available. -treat all body fluids as potentially infected -place iv before delivery if possible in anticipation of likely ivf resuscitation and to reduce risks to staff associated with an urgent/emergent iv placement. • fresh . % chlorine must be available for immediate decontamination of soiled gloves and gown. hands must be washed or outer gloves changes between procedures. • limit the number of vaginal exams during labor to the initial assessment and intermittent progress checks q h if needed, or the to fewest number possible. • a partograph and/or detailed charting and adequate care planning must be maintained so as to monitor labor progression and anticipate potential interventions for complications. • regularly monitor fetal heart rate or movement. • refrain from using fundal pressure during second stage • a clear plastic sheet should be used as a drape during delivery to separate the clinician from the neonate and placenta. the delivering clinician is avoid sitting or standing at the end of the bed or between the legs of the laboring patient to limit contact with blood or amniotic fluid exposure. • limit the number of sharps in the red zone. use blunt tipped scissors if available for cord cutting. prioritize single use instruments over multi-use. if multi-use instruments are used, a system for cleaning must be employed. a rinse in . % chlorine will ensure adequate decontamination. a fresh water rinse and immediate drying will delay corrosion of metal instruments. if available, an autoclave is optimal. • suturing should be available and employed only when adequate lighting and experienced staffing are available and only in cases where the patient is cooperative (not agitated) and there is a risk of negative outcome without intervention. -blood loss and uterine tone should be monitored closely after every delivery, regardless of gestation. • po medications are preferred, but if needed progress to iv, im or io. all postpartum patients should have iu of slow iv push or im oxytocin (after confirmation of single fetus) to decrease the chances of pph. • if delivery of live baby (or with retained placenta), tie off and cut the cord under plastic. in cases of fetal demise, leave the cord intact, deliver the placenta and place both placenta and fetus together into a body bag, using recommended ipc measures. • a team of postpartum clinicians should be available to monitor vitals and infant transition in the hours after delivery -referral for hiv or tb testing or pmtct services should be offered at discharge if there is a known or suspected secondary infection. given the nature of a viral hemorrhagic fever superimposed on pregnancy, the likelihood of obstetric complications and coagulopathy is very high. safety of staff members must be prioritized, however, we recommend the consideration that more interventions may be appropriately rendered to improve patient outcomes than were recommended in the - evd outbreak. • adequate iv fluids must be on hand for volume resuscitation in high acuity cases. • consider induction of labor in emergent cases only; otherwise, defer induction if a suspect case is highly suspicious of having evd. this is in an effort to reduce unnecessary exposure of staff to body fluids. • deinfibulation of type female genital mutilation (fgm) is discouraged, but may be performed if it is considered a life saving measure. if proceeding with procedure, perform at the patient's side, under plastic sheeting and with adequate anesthesia or pain relief. • perform fundal massage (with support of lower uterine segment) and iu of oxytocin in l of iv fluids ( gtt per minute) for initial pph management and be prepared to offer higher levels of intervention if bleeding persists, including: external aortic compression and uterine balloon tamponade. -in cases of antepartum or postpartum hemorrhage, consider having an established system for basic blood typing within the unit and a process in place for collection and administration of blood products. no suspect or confirmed patient blood can leave the unit unless a process is in place to transfer to a evd specific lab. staff must be trained to type patient blood and to monitor for transfusion reactions. inadequate training would disqualify a treatment center from transfusing. • patients who are suspect and acutely ill are often placed in situations that are life threatening while they wait for pcr results. consider establishing a site for isolation surgery (dependent on trained personnel, equipment and adherence to ipc measures) so that patient needs can be addressed in emergencies and the option of cesarean section be made available. • consider administration of nifedipine over terbutaline (may have more serious side effects and requires higher level of monitoring) for delay of early onset preterm labor or onset of uterine hyperstimulation. consider antepartum corticosteroid (acs) administration in cases where preterm delivery ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) weeks gestation) appears to be unavoidable. • proactively treat prom or pprom with prophylactic antibiotics. • do not delay treatment of hypertensive emergencies. offer antihypertensives (po or iv) if systolic exceeds and diastolic exceeds and monitor regularly. address severe preeclampsia or eclampsia immediately with im magnesium sulfate and continue until h post-delivery or last seizure (whichever is later). the risk of fluid overload must be balanced with the propensity of evd patients to be fluid depleted and anuric. monitor for symptoms of pulmonary edema and defer diuretics unless severe edema [ ] . rapid delivery can resolve symptoms of eclampsia and induction or augmentation should be considered. • in cases of iufd, deliver as with a live infant under plastic sheeting. in many cases, symptoms of infection are present and mimic evd, particularly if labor has been delayed or obstructed. treat with antibiotics for chorioamnionitis and monitor. induce or augment labor to expedite delivery if the risk of puerperal sepsis is high. given the extremely high risk of fetal death with positive evd mothers, pregnancies must be monitored and ultimately delivered in isolation or in an etu. even if the patient is recovered, her products of conception will have high viral load and must be treated as infectious waste. • spontaneous abortions must also be treated with suspicion and poc from suspect or positive patients treated as infectious waste. • vacuum delivery and episiotomy can be considered for obstructed labor when it is believed to be a life saving measure. ipc measures should be maintained at all times. referral for cesarean should be made when available, if failed assisted delivery. • in the case surgical intervention is needed and not available, all attempts at supportive care and potentially palliative care must be administered until lab results are returned. transfer of a non-infected patient with confirmed negative pcr to non-isolation facility can be arranged when lab results are returned. this patient who has been identified as not having filovirus must be advocated for outside of isolation or treatment units and reassurance given to medical staff that they are uninfected and safe to be operated on. • confirmed evd-positive patients with no access to surgery must stay in the treatment center until recovery and two confirmed negative results have been received. the fetus, regardless of gestation, will very likely not survive and will need to be delivered within the isolation facility. -depending on the location of the epidemic, there may be access to high intervention medical care and drug therapy for neonates born from an evd positive mother and though the fatality rate has historically been almost %, priority for should be given to advances in clinical care and vaccines. however, in the absence of adequate interventions, the option of therapeutic medical abortion before discharge should be offered if an evd positive patient has an intact pregnancy, the patient lives far away from a evd treatment center and there is a risk that she will not return for delivery (thereby risking further infection in the community). given that the majority of women entering into the etc will be evd negative, the majority of care should mimic the expectations for infant care in a non-epidemic setting. fetal monitoring during labor and delivery should be provided for early detection of complications and immediate care of the infant is essential to ensure optimal outcomes and reduce the risk of infant mortality. • immediately after delivery, vigorously stimulate and dry the neonate • oropharyngeal/nasopharyngeal suction only if secretions suction only if secretions are obstructing the airway; there is no need to suction a vigorous neonate, even if meconium present • perform basic assessment (airway, breathing, circulation) and offer resuscitation if needed • allow delayed cord clamping and cutting in non-emergent settings, tie and cut cord under plastic sheet to minimize contact with blood • clean and dry infant and allow skin to skin/kangaroo care and bonding if the mother is capable • assess initial apgar score and then complete routine vital signs: respiration rate, heart rate (umbilicus or brachial pulse) and temperature q min  after delivery and q shift (at least with every assessment of mother thereafter). complete newborn assessments as thoroughly as possible given time restraints in ppe and check for jaundice, tone, retractions and feeding. stethoscopes cannot be utilized in a red zone. • ensure that the infant bassinet is covered with mosquito netting to decrease the risk of malaria infection • offer vitamin k injection im ( mg) at birth, ophthalmic tetracycline ointment bilaterally, and chlorhexidine cord care per who recommendations • delay washing for h is possible and dress infant in weather-suitable layers ( - layers more than adults) to stabilize body temperature. • offer other treatments based on individual symptoms-consider im antibiotic treatment for bacteremia for days if concerns regarding infection survival of neonates delivered to evd positive patients in or out of an etu is close to % mortality rate. at the end of the - west african epidemic, one documented infant of a deceased evd positive patient survived after an intensive antibody, broad spectrum antiviral and antibiotic regimen [ ] . one can assume that a neonate is exposed to filovirus in utero, during delivery or during breastfeeding (though it has appeared based on documented cases of live births that neonates seroconvert shortly after delivery with unknown data around the impact of breastfeeding [ ] ). recommendations then include keeping the mother and infant as a treatment dyad and allow the mother to care for the infant if able. communication with the mother about her evd status and expected outcome of the neonate should occur as early as possible, with adequate psychosocial support as needed. there are several factors that must be considered when reviewing recommendations for breastfeeding a neonate after delivery in an isolation setting and before maternal pcr results are obtained. in resource low areas, the risk of unsanitary water to make powder formula, the unavailability of ready to use infant formula (ruif), the lack of hygienic means to sterilize bottles, or the prohibitive cost to families to obtain artificial feeding or animal milk products for the neonate for up to years after delivery must be weighed with the immediate risk of continued breastfeeding and exposure to evd. who recommends that in cases where the mother is symptomatic and awaiting results that her breastfeeding be suspended. in these cases a discussion with the patient about the risks, benefits and options must be had. where the mother is unable to give informed consent one way or the other, family members must be brought into the conversation and clinical decisions be made also taking into account the current prevalence of infection in the community. if the patient's result is positive, it can be assumed that the neonate will be positive. there are questions about the initiation of breastfeeding and whether the infant is already infected and would ( ) benefit from any maternal antibodies, ( ) will get an increased viral load through breastfeeding, or ( ) be likely to die regardless of feeding. who recommends suspending breastfeeding and starting ruif (ready to use infant formula) until breast milk samples test negative  by pcr testing after which the mother should be encouraged to initiate or resume breastfeeding exclusively for at least months. for patients who suspend breastfeeding until results are returned, interim supply can be maintained with pumping. however, all expressed milk must be treated as contaminated material and discarded per appropriate ipc protocols. if the patient expires during or after delivery but prior to maternal serum testing, oral swabs of the corpse are to collected prior to burial. collect a serum sample for pcr testing of the neonate as soon as possible , however note that the infant must be in the care of isolation facility for days following delivery. a neonate can be infectious but present as being asymptomatic days prior to becoming ill and even then symptoms are atypical or non-specific. accounts of live newborns delivered to positive mothers were all documented to be deceased within the th day of life [ ] . the -day cut off allows for monitoring for the entire contact exposure period. if neonate is positive, treat per pediatric evd protocol or arrange transfer to an appropriate treatment facility via local government regulations. planning the psychosocial impact of the - west africa ebola epidemic is an immeasurable burden for thousands of people. a common sentiment often expressed both from patients admitted to etus and health care workers alike was the dehumanization and trauma of being isolated. the human element of direct patient care was covered by multiple layers of plastic, only eyes visible behind foggy masks. while novel efforts to humanize health care workers rapidly spread by word of mouth among first responders, the experience of being cared for in an isolation center is undeniably traumatic. we strongly advocate for early and robust psychosocial resources as part of a comprehensive evd response. care for the pregnant patient also requires unique psychosocial considerations. while practices may vary across cultures, childbirth is a global phenomenon laden with tradition, ritual and social norms. universally, the laboring woman is at her strongest, and yet at her most vulnerable. effort should be taken to understand and support the unique sociocultural norms surrounding pregnancy and birth in a way that maintains dignity in delivery while adhering to all safety and ipc protocol in the context of evd care. in times of crisis, it may be common for the quality of patient care to suffer as safety or allocation of resources is prioritized. we assert, however, that quality can be incorporated into emergency response service delivery in a way that does not jeopardize safety or waste valuable resources. discharge planning and patient education are components of emergency response service delivery that may be neglected in the height of an emergency, but in the context of evd, these practices can be a crucial component to breaking the chain of transmission as well as improving the overall quality of patient care beyond the etu. the obstetric population has unique needs upon discharge from an evd treatment or isolation facility that should be incorporated into the development and implementation of any program working with women of reproductive age. resources and protocols should be developed early so that staff are prepared to guide patients when they are discharged from the facility. all patients discharged from a red zone should receive clear instructions that they are, by default, considered possible contacts and should monitor their signs and symptoms for days after discharge. examples of unique obstetric patient pathways are summarized in table . . the development of clinical guidelines and practical health care delivery strategies to address the unique needs of evd survivors presented grand challenges for the community serving guinea, sierra leone and liberia in the recovery phase of the - west african evd epidemic. even verifying the number of evd survivors in west africa is a daunting, occasionally political task, but estimates are currently that out of , documented cases of evd, there are approximately , survivors [ ] . to date, there are no strong data to approximate how many of those survivors have become pregnant since recovering from evd, but it may be asserted that the pregnant evd survivor represents the nexus of vulnerability. in , before the a patient should be aware that these are similar presentations and may result in repeat isolation evd epidemic, sierra leone had a baseline maternal mortality ratio of deaths out of every , deaths [ ] ; that number has almost certainly risen, with some estimates by as much as % simply by virtue of the decimated health care system and decreased utilization of services [ ] . combining these baseline maternal health indicators with the pervasive stigmatization and fear of pregnant evd survivors lends an extraordinarily high risk for neglect and mistreatment of the pregnant evd patient, despite the fact that there have been no data to show active virus in the amniotic fluid or products of conception in the subsequent pregnancies of women who survived evd. it should be noted that the risk for stigma affecting care for evd survivors is not limited to the west african nations where the outbreak occurred; a case study detailing management of a pregnant evd survivor planning to deliver in the united states reports marked discomfort and concern from hospital staff despite no evidence of risk for transmission of virus [ ] . furthermore, there are limited data about subsequent pregnancy outcomes for women who became pregnant after surviving evd, with a small cohort study in liberia showing a slightly higher incidence of miscarriage or stillbirth in liberian evd survivors as compared to the overall rate in both the developed and developing world [ ] . however, national data for baseline miscarriage/stillbirth rates are not available in liberia, sierra leone or guinea, making data specifically reflecting the evd survivor population murky. recommendations addressing breastfeeding for evd survivors in subsequent pregnancies were initially limited due to lack of data regarding viral persistence in breastmilk. anecdotal evidence suggests that ebola virus may persist for several months in breastmilk of survivors, but breastmilk was not routinely included in the major viral persistence studies conducted in the immediate post-epidemic period. there are no known cases of a breastfeeding infant presenting with evd contracted from a lactating mother. given the overwhelming benefit to breastfeeding, particularly in resource-poor settings, current cdc guidelines support routine breastfeeding of the neonate born to evd survivors, with case-by-case evaluation to neonates born to suspect or confirmed evd patients [ ] . there are multiple circumstances complicating the approach to and delivery of quality care for the pregnant evd survivor, largely due to emerging research regarding viral persistence, clinical sequelae in evd survivors and sociologic trends of stigma and access to resources for pregnant evd survivors in their communities. with the data available, we support the following recommendations: • evd survivors presenting with subsequent pregnancy outside of a known evd epidemic should be treated as a non-infected patient. antepartum and intrapartum care should not be delivered with any more ppe than would be used for a non-survivor patient (universal precautions). • status as an evd survivor should be considered as a relevant part the patient's history to inform any abnormal clinical presentation, and treated with astute clinical judgement. other key components of a thorough history taking for a pregnant evd survivor include: survivor status of the father of the baby, any recent illness/complications, social support status. • the heightened vulnerability of a pregnant evd survivor should inform a broader and more comprehensive approach to high-quality antepartum, intrapartum and post-partum care. treatment of the pregnant or postpartum patient who meets case definition for evd is controversial and is often an ethically charged debate due to the overlap in clinical presentation of evd and obstetric complications. the - west africa ebola epidemic illuminated the desperate need for adequate preparedness for infectious disease outbreaks in the obstetric population, with dedicated protocols, adequate training, and unique considerations for these extremely vulnerable patients. the safety and protection of the healthcare worker must be balanced with the commitment to deliver the highest degree of quality clinical intervention possible for the pregnant patient, with the theoretical risk of transmission of evd incorporated into every aspect of clinical and care management. we recommend that the lessons learned from the - west african epidemic, where an unknown, yet unfathomable number of evd negative women and infants lost their lives in ebola treatment centers due to inadequate obstetric care, be considered in the development of all future emergency preparedness and response protocols. with committed partners implementing informed protocols, safe and high-quality maternal/child health can and should be prioritized in the midst of an emergency. nearly children were confirmed or suspected to be infected with evd during the west african - outbreak, just under % of the total [ ] . it appears that in this as with previous outbreaks, confirmed diagnoses were fewer in children than adults [ ] [ ] [ ] . the reasons underlying this apparent sparing of children are poorly understood. firstly, it could be that diagnoses are being missed, due to underreporting or poor diagnostic sensitivity in children [ , ] . it is possible that against a background of high infant mortality as with most countries affected by evd, and fear of seeking health care during an outbreak parents did not bring their unwell children for testing [ ] . alternatively, it may be that the diagnostic tests such as both pcr (polymerase chain reaction for evd dna or serological testing) were less sensitive for small children [ ] . for example, small children, particularly infants, are often challenging to take blood samples from so it may be that smaller samples were sent, or that less sensitive mouth swabs were used for pcr as an alternative early in the outbreak [ ] . however, the difference may be true biological sparing of children, where children are either less exposed or less vulnerable to exposure, or finally that children were more likely to have asymptomatic infection. from glynn et al.'s study of seroprevalence of evd immunoglobulin g (igg, evidence of previous infection) in households of evd survivors, they found no evidence of asymptomatic infections in children under years of age, and a slight excess of symptomatic undiagnosed infections in younger children: i.e. it appears that younger children were slightly more likely not to be taken to hospital despite symptoms [ ] . bower et al. investigated age-specific attack rates in the same cohort of evd survivor households in sierra leone, and found that after adjustment for exposure type, children and adolescents aged - years were less vulnerable to infection than either younger children or adults [ ] . therefore it appears from available evidence that in the west african evd outbreak at least, the apparent sparing of children was due to a combination of younger children not being brought for medical attention and true biological sparing in older children and adolescents, the mechanisms for which remain to be explained. routes of exposure are similar to adults with the additional exposure of breast milk for infants, and vertical transmission from mother to neonate (see obstetric chapter). it appears that close contact with a sick mother/primary caregiver is a key risk factor in children over and above other household or community exposures [ ] . regarding breast feeding, ebola virus has been detected in breast milk up to months post-infection [ ] [ ] [ ] . indeed, in one case, investigation into the death of a -month old infant from evd led to the discovery of ebola virus in the mother's breast milk although the mother had had no preceding symptoms [ ] . however, bower et al.'s study of mother-child pairs (children aged < years) found no excess risk from breast feeding over and above contact with a sick mother [ ] . contact with an evd-infected mother was by far the greatest risk for the child, risk ratio (rr) compared with infections in the same household excluding mother . , % confidence interval (ci) . - . , p < . ) [ ] . interestingly, household crowding and sanitation had little impact on transmission risk, and none of the children included had contact with a dead body, indicating close proximity to the mother/primary caregiver as the most important causal factor in acquisition of evd. the authors therefore agree with current who guidelines that asymptomatic infants and children should be separated from infected mothers to limit onward transmission [ , ] . regarding children themselves as sources of the virus, the data is conflicting. one modelling study based on data from burials indicated that children might be "super-spreaders" of the virus, but this has not been substantiated by epidemiological data from liberia or sierra leone [ ] . in liberia, a contact tracing study showed no difference between children and adults in terms of transmission, and a study of transmission chains indicated that children were less likely to pass on the virus [ , ] . this was mirrored in sierra leone where children were more likely to be infected in later generations within households, rather than being the primary source within a household [ ] . it seems likely therefore that children may be less, rather than more likely to transmit the infection compared to adults. in terms of mortality, infants are the most vulnerable, with case fatality rates (cfrs) varying between and % [ ] [ ] [ ] [ ] . the prognosis improves with age, such that mid-late teenagers have amongst the lowest case fatality rates. table . shows cfrs for children in studies from both the west african and prior outbreaks by age. risk factors for mortality are discussed further below. evd is notoriously non-specific in presentation, particularly in children. indeed, even fever which was key to the who clinical case definition in the west african outbreak was absent in - % of cases in three studies [ , [ ] [ ] [ ] . in most studies from the west african and previous outbreaks, features in children have included (in order of frequency) fever ( - %), fatigue/weakness ( - %), appetite loss ( - %), vomiting ( - %) and diarrhoea ( - %) [ ] [ ] [ ] [ ] ] . abdominal, muscle, joint and chest pain as well as headaches have been reported in - %, although in younger children pain is difficult to localise and so recording of pain from various body sites has been compounded into the symptom of generalised distress, seen in % of a younger cohort [ ] . conjunctivitis was recorded in - % and hiccoughs in - % [ , , , ] . difficulty breathing and swallowing were seen approximately - % of patients [ , , ] . bleeding from various body sites tended to be rarer in the west african outbreak in children than previous outbreaks ( - % compared with %) [ , , , ] , although two cohort studies recorded bleeding in % [ , ] , and a large study of guinean children recorded bleeding in % [ ] . interestingly, one younger cohort (children aged up to years) recorded cough in up to % of children, although this was less frequently seen in other cohorts [ ] . blood tests have revealed dramatic leucocytosis, deranged liver and renal function alongside raised inflammatory markers (e.g. c-reactive protein) particularly in children who died [ , ] . hypoglycaemia, often severe, was common among both children who died ( %) and those who survived ( %) in one cohort [ ] . more detailed description of electrolyte and haematological disturbances over the course of disease can be seen in fig. . [ the mean duration of incubation of evd is shortest in younger children: estimated to be week in children < year compared to . days in children aged - years [ ] . similarly, duration from symptom onset to death is shortest in younger children-under days in those < year, compared with nearly days in those aged - years [ ] . however, care must be taken with these estimates as many children were admitted unaccompanied to treatment facilities, so data regarding [ ] symptom duration may be unreliable particularly in younger children. duration between symptom onset to attendance was days [ ] . time from presentation at a treatment facility to death can also be short (a median of days in one study) so there is a small window for intervention [ ] . features at admission that are consistently associated independently with mortality across several studies include younger age and a high viral load (low cycle threshold (ct) with a viral polymerase chain reaction) as with mixed age cohorts [ , - , , , , ] . shah et al. record a hazard ratio of . ( % confidence interval . - . ) for death with a ct value < at admission [ ] . however, in interpreting viral ct values, discrepancies between laboratories and assays used should be borne in mind, as there is currently no universally used assay. bleeding at admission and diarrhoea have also been reported to be associated with an increased risk of death [ , ] . finally, in mixed age cohorts, concomitant infection with malaria has also been significantly associated with mortality [ ] . during admission, development of bleeding, shortness of breath and diarrhoea at any point are all independently associated with mortality, as well as tachycardia within the first week of admission [ ] . dysphagia was more common those who died and in shah et al.'s younger cohort (children under years), hiccoughs, confusion and bleeding were only present in children who died [ ] . for those patients who recovered, there was a period of defervescence over - days [ ] . no children died after day of admission in one study [ ] . median duration of admission those who survived varies between and weeks [ , ] . palich et al. have thoroughly documented the progress of a year old with severe evd managed at a treatment centre with facilities of laboratory monitoring and intravenous fluid and electrolyte replacement. late complications during admission include tonic-clonic seizures, which can be prolonged and severe [ , ] . in at least two cases, children were left with severe disabilities after a prolonged seizure including blindness and paraplegia [ ] (howlett et al. in review). in bower et al.'s study of late deaths within a cohort of evd survivors, one year old and one year old died after discharge from an ebola treatment centre [ ] . the year old had symptoms consistent with tuberculosis, although also had a post-mortem mouth swab that was borderline positive for ebola virus [ ] . the year old died weeks after discharge with weight loss, night sweats and dysphagia with a post-mortem swab negative for ebola virus [ ] . it appears that true recrudescence of virus as has been seen in adult patients may be very rare although possible [ , ] as can be seen by both the breadth of symptoms exhibited by children with evd, the variations in frequency of symptoms between cohorts even within the west african outbreak, and the non-specificity of these symptoms against a backdrop of high malaria prevalence and other childhood illnesses, the clinical case definition for evd is key. a sensitive and specific clinical case definition for evd in children would allow rapid access to appropriate treatment for children with evd, crucial when early mortality is so high, and also protect children without evd (with a different illness) from exposure to evd while awaiting laboratory test confirmation. to date there has been only one attempt at deriving a paediatric-specific case definition using multicentre data on over children from the west african outbreak, and this case definition has not yet been validated on wider datasets [ ] . it also does not include malaria rapid diagnostic test results which have been shown to be an important discriminator in a mixed age study [ ] . however, these limitations aside, the paediatric ebola predictive score (pep) score derived had excellent discrimination (area under receiver operating characteristics curve (auroc) ¼ . ). the scores for each clinical feature within the score are shown in table . , along with the coefficient from the multivariable model used to derive them and associated p values. as the score has not yet been externally validated, it is presented here for information rather than recommendation for use. it is envisaged that the pep score could be used together with evd rapid diagnostic tests, several of which were trialled during the outbreak, to expedite rapid accurate diagnosis of evd [ , ] in the stressful environment of an evd outbreak, the needs of children can be overlooked. certain considerations should be planned for in advance to ensure initial assessment for emergency clinical signs should take place using the emergency triage and assessment treatment (etat) algorithm for children [ ] . assessment for dehydration is key. weighing can be a challenge in facilities with limited resources, so we would suggest using a set of scales within a ziplock plastic bag (or similar) to promote easy cleaning, prevent contamination and prolong the lifespan of the scales when being cleaned with high concentration chlorine. signs of severe or moderate dehydration should be assessed clinically on admission and at least daily (preferably more frequently during the gastrointestinal phases of disease) during admission as per guidelines in the who pocket book of hospital care for children [ ] . pain and distress is common in children with evd and should be specifically assessed for and treated both at initial admission and on reassessment. blood should be taken for evd pcr as per who recommendations for exposure prone procedures, ideally by at least two staff [ ] . this is particularly important for children who need to be held still during phlebotomy. a malarial rdt should be performed if possible in high prevalence areas, as coinfection is not infrequent [ , ] . a glucose test should also be performed as a priority if feasible. any initial emergency clinical features noted during etat assessment should be managed as per the relevant treatment algorithm. placing a laminated version of the algorithm on the wall in triage will prove useful for treating clinicians. fever should be managed with antipyretics dosed as per weight/age, and again a laminated list of age/weight appropriate commonly used medications will prove useful for clinical staff both in and outside the "red zone". adequate hydration is a mainstay of therapy for those with both mild and severe evd. all children should be offered oral rehydration solution and be supported to drink it, either by a caregiver or a dedicated staff member as they may be too weak to drink it themselves [ ] . if the child is severely dehydrated or malnourished, or unable to tolerate oral fluids, intravenous fluid resuscitation and maintenance will be needed. this should be carried out according to the presence/absence of shock, severe malnutrition and severe anaemia according to the detailed protocols in the who pocket guide to clinical management of patients with viral haemorrhagic fever. these include recommendations for the volume and rate of fluid replacement and are not reproduced here in the interests of space, but we recommend that laminated versions of the fluid replacement protocols be available both in the "red zone" and outside where fluids and medications are prepared and prescribed [ ] . in brief, the three signs of shock considered are: cold extremities, weak and fast pulse and a capillary refill time of over s; severe anaemia is diagnosed with a haematocrit < or a haemoglobin less than g/dl; and severe acute malnutrition is diagnosed with a muac of < mm [ ] . although in the context of large gastrointestinal fluid losses, the benefits of intravenous fluid resuscitation is unequivocal and recommended by the who, fluid resuscitation should ideally be carried out with input/output monitoring and using a paediatric giving set [ ] . aggressive fluid resuscitation in african children with signs of severe infection (excluding gastrointestinal infections) is not proven to be safe, so every effort should be made to monitor both the volume of fluid given and the clinical impact on the child [ ] . ongoing assessment of hydration status is therefore key, and should be planned for in daily staffing allocations. if possible, electrolytes should also be monitored and abnormalities corrected, as large derangements in sodium, potassium and calcium have all been seen in children with evd [ , ] . hypoglycaemia has been demonstrated to be common in children with evd and should be monitored for as a priority if feasible, but if monitoring is not feasible, glucose should be given intravenously empirically in the case of seizure, coma or lethargy [ ] . five percent dextrose should be used in all maintenance fluids [ ] . for persistent vomiting, ondansetron (or if unavailable, promethazine, though with care to monitor for extra pyramidal side effects) may limit symptoms and permit oral intake [ ] . if a malarial rdt is not available or the result is positive, children should receive a weight-or age-appropriate dose of artesunate combination therapy (act) or intravenous/intramuscular artesunate if there are signs of severe malaria for at least hours followed by a day course of oral act [ ] . owing to the overlap of symptoms of evd with sepsis, it is both the who and our recommendation that all children under years of age admitted with suspect evd should be treated with empirical antibiotics on admission. who guidelines are that all under s should receive intravenous or intramuscular broad spectrum antibiotics (e.g. ceftriaxone), although evidence is limited as to whether in relatively well younger children parentral antimicrobials will provide a benefit over enteral [ ] . for older children, the decision to start antibiotics lies with the treating clinician as evidence is lacking, but the local prevalence of other common childhood illnesses such as pneumonia and gastroenteritis should be taken into consideration. if used locally, the empirical treatment guidelines laid out in the who pocket book of hospital care for children and the integrated management of neonatal and childhood illness should be utilised [ ] . all those receiving antiretroviral or antituberculous therapy should continue it, and restart as soon as possible if treatment is interrupted. pain and distress has been noted frequently in children with evd (see section on clinical features at presentation and disease progression) and should be managed expectantly with age/weight appropriate doses of simple analgesia (paracetamol), or opiates (tramadol followed by morphine if available) if there is ongoing pain or distress in younger children. dysphagia has been noted to be associated with retrosternal chest pain in adults, and should be managed in children with management of bleeding can include transfusion of packed red cells or components (e.g. fresh frozen plasma if required), and particularly for malnourished children supplementation of vitamin k (enterally or parentrally) should be considered. however evidence is limited, particularly as regards antifibrinolytics [ ] . other empirical management for shortnesss of breath (oxygen via nasal cannulae if available); seizures (glucose if hypoglycaemic or monitoring unavailable and benzodiazepines); confusion (reassurance, possibly sedation if agitation severe) should be given as needed/available depending on context. in the unfamiliar and frightening environment of the treatment centre, reassurance from staff or other caregivers cannot be overemphasised as a crucial therapeutic intervention. given the gastrointestinal symptoms of evd and the background prevalence of malnutrition in the countries evd has affected, assessment for malnutrition at admission is advisable. who guidelines are that a mid-upper arm circumference (muac) should be checked and oedema assessed for at a minimum if it not feasible to assess anthropometry in more detail [ ] . as weight of children is key both in assessing hydration and nutritional status, we would suggest checking weight on admission in addition to muac and presence/absence of oedema. as above, scales could be kept within a ziplock plastic bag to protect from high concentration chlorine and ease of decontamination after use. if severe acute malnutrition is present, fluid resuscitation should be given according to who guidelines using smaller volumes and resomal™ as opposed to standard oral rehydration salts [ ] . for asymptomatic breastfed infants whose mother is unwell with evd, current recommendations based on available evidence are to separate the mother and infant and use replacement ready to use infant formula [ , ] . if the infant also has signs/ symptoms of evd, or a confirmed diagnosis, the current guidelines are that the benefits of continuing breastfeeding are likely to outweigh the risks and so breastfeeding should be continued if the mother is well enough to do so [ ] . the challenges of caring for unwell, frightened children within a "red zone" have been well documented during the west african outbreak [ , , , , ] . this problem is amplified as many children were admitted unaccompanied by a caregiver (up to % in one study [ ] ), either because family members had already succumbed to disease or because fear of nosocomial infection prevented either relatives from wishing to enter the "red zone" or unit policies forbade the admission of asymptomatic caregivers. apart from the risk of nosocomial infection between suspect evd patients posed by unaccompanied children (who were difficult to keep in their allocated bed space); there were also the hazards of sharps bins and high concentration chlorine within the red zone. units developed different practices to mitigate these risks. one treatment centre had a nursing round specifically dedicated to paediatric care times a day, to manage intravenous infusions and ensure that unaccompanied small children were fed times daily with therapeutic milk [ ] . other units started to develop protocols to employ survivors (believed to be at low risk of re-infection with evd) to care for unaccompanied children, but none, to our knowledge put the protocols into practice before the end of the west african outbreak. the possibility of either dedicated paediatric clinicians or a specific paediatric area with risks e.g. sharps and chlorine buckets minimised have both been discussed, and were put into limited practice towards the end of the west african outbreak. one study collected data post-discharge from caregivers admitted to ebola holding units with children who subsequently tested negative for evd [ ] . it was possible to contact approximately % of caregivers admitted, and of those contacted, none were subsequently readmitted with evd. for the overwhelming majority of those who it was not possible to contact, this was due to a lack of contact details. this indicates that it may not be as dangerous as anticipated to admit asymptomatic caregivers with their children, although this should be done in the context of very clear instructions about hand hygiene and strict isolation between patients. in the event that admitting caregivers with children is not possible or not felt to be safe, alternative mechanisms for managing the pastoral care needs of children have included using stretches of clear plastic sheeting between "red" and "green" zones to enable frequent communication with staff/relatives outside with children inside (heldermann t., personal communication); 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ebola virus disease late ebola virus relapse causing meningoencephalitis: a case report development of a pediatric ebola predictive score predicting ebola infection: a malaria-sensitive triage score for ebola virus disease evaluation of a point-of-care blood test for identification of ebola virus disease at ebola holding units diagnosis of ebola virus disease: past, present, and future pocket book of hospital care for children: guidelines for the management of common childhood illnesses ebola outbreak in conakry, guinea: epidemiological, clinical, and outcome features ebola response in sierra leone: the impact on children mortality after fluid bolus in african children with severe infection moving towards a more aggressive and comprehensive model of care for children with ebola being a pediatrician in an ebola epidemic risk in the "red zone": outcomes for children admitted to ebola holding units in sierra leone without ebola virus disease west african ebola crisis and orphans key: cord- -kck e ry authors: nan title: th annual meeting, neurocritical care society, october – , , vancouver, canada date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: kck e ry nan aging is associated with greater stroke risk and diminished stroke recovery. while the effect of aging on stroke recovery is well defined, the influence of aging on neuronal network activity and its correlation with stroke recovery is poorly understood. to study this, we performed serial whole-cortex imaging of spontaneous and evoked neuronal activity before and after stroke in young and aged mice and correlated those findings to behavioral outcomes. young ( - m, n= ) and aged ( m, n= ) thy -gcamp mice, underwent behavioral assessment and imaging before and , , , and weeks after infarct. infarcts were induced via exposure of somatosensory cortex to a laser ( mw, m) after injection of the photosensitive dye rose bengal. imaging followed placement of plexiglas windows and consisted of awake ( m) and anesthetized sessions ( m) with gcamp excitation via flashing of a nm led and acquisition via an emccd camera ( . hz framerate). somatosensory activation was via forepaw shock ( ma at hz for s x blocks). behavioral response was assessed by quantifying forepaw use during cylinder exploration ( m). aged and young mice exhibited similar baseline contralateral forepaw use (aged . ± . %; young: . ± . %) and evoked somatosensory cort . ± . x - ). whole-brain gcamp flourescence power in delta ( - hz) and infraslow ( . - . hz) ranges was significantly (p< . ) lower at baseline in aged mice. after stroke, aged mice developed greater long-term dependence on the unaffected limb (wk : aged . ± . %; young: . ± . %) - ). -stroke decrement in whole-brain gcamp fluorescence power was observed in aged animals. stroke in aged mice is associated with a greater decrement in local network activation, global mechanisms underlying age-related differences. hypernatremia and hyperchloremia is common after moderate-severe traumatic brain injury (mstbi) from saline resuscitation, osmotherapy administration, fever with insensible losses, limited free water administration, and diabetes insipidus. in isolation, hypernatremia and hyperchloremia are independent predictors of mortality in critically-ill patients; but this association has not been studied in mstbi, or in combination as physiologically occurring in patients. we examined whether hypernatremia and hyperchloremia in combination are independent predictors of in-hospital mortality in mstbi patients. we retrospectively analyzed prospectively collected data of consecutive mstbi patients enrolled in the optimism-study over a -year period. a semi-automated process provided all sodium and chloride values from the index hospitalization. time-weighted-average(twa)-sodium and chloride representing their "burden" over the entire hospitalization were calculated using a published formula. univariate and multivariable logistic regression were applied adjusting for impact-model-variables as validated predictors of mstbi mortality, osmotherapy, icu length-of-stay and ventilatory days. of patients analyzed, ( %) died. unadjusted mortality rates had a dose-response relationship with increasing sodium and chloride ( % for twa-sodium - mmol/l and % for twa-sodium > mmol/l; % for twa-chloride - mmol/l and % for twa-chloride > mmol/l; all p< . ). separately, twa-sodium (per mmol/l increase adjusted-or . ; %ci . - . ) and twachloride (per mmol/l increase adjusted-or . ; % ci . - . ) independently predicted mortality. in combination, however, twa-chloride remained an independent predictor of in-hospital mortality (per mmol/l increase or . , % ci . - . ), while twa-sodium did not (c-statistic . ; hosmer-lemeshow p< . ). to our knowledge, this is the first study to show that when concomitantly adjusting for hyperchloremia and hypernatremia burden, only hyperchloremia is independently associated with early mortality in mstbi. while not proving cause-and-effect, this suggests that hyperchloremia, and not hypernatremia as previously reported, deserves further attention in mstbi. if validated, this may have treatment implications for mstbi patients in the acute care phase. hyperosmolar therapy, with hypertonic sodium chloride (nacl) solution is often used in the treatment of cerebral edema and elevated intracranial pressure. recent reports have demonstrated that in patients with subarachnoid hemorrhage (sah) treated with hypertonic nacl, hyperchloremia is associated with the development of acute kidney injury (aki). we report a trial which compared two hypertonic solutions with different chloride content on the resultant serum chloride concentrations in sah patients. a low chloride hypertonic solution for brain edema (acetate), is a single center, double-blinded, double-dummy, pilot clinical trial comparing bolus dosing of . % nacl versus . % nacl/na-acetate for the treatment of cerebral edema in patients with sah. randomization occurred once patients who received hypertonic treatment for cerebral edema and/or elevated intracranial pressure (icp) developed hyperchloremia (serum cl- group, and to the hypertonic nacl/na-acetate one. the groups were well balanced in terms of severity of the sah, age, gender and risk factors. differerences between the serum chloride and sodium measurements, assessed from randomization to maximum during the icu course, were comparable between the nacl and nacl/acetate groups (cl: . ± . vs. . ± . , p= . ; na: . ± . vs. . ± . , p= . , respectively). nacl/acetate had a more prominent effect on immediate post dose sodium (increase of . ± . vs. . ± . ,p< . ). the rate of aki was lower in the na-acetate group ( . % in the nacl group vs. . % in the na-acetate group, p= . ). hyperchloremia preceded aki in . % of the cases; however, the time interval between hyperchloremia and aki was only a median of . days ). intention to treatment analysis demonstrated that treatment with hypertonic nacl/na-acetate hypertonic versus standard hypertonic nacl solution for patients with mild hyperchloremia, resulted in less events of a -center trials are needed to corroborate these results. up to . million people in the united states are living with physical, cognitive, and psychological sequelae after tbi. patients that sustain a moderate to severe tbi (mstbi) are heavily reliant on caregivers during their inpatient stay and for post-discharge care. there are limited data on how best to support caregivers in their role. the purpose of this study was to develop a checklist based on qualitative data that can be utilized by caregivers and clinicians to re-examine the particular needs of the caregiver at different periods in the acute, subacute, and chronic timeframe. patients with mstbi and their caregivers were recruited from two intensive care units (icus) in one institution to participate in semi-structured interviews at hours, one month, three months, and six months post-injury. transcripts of each interview were analyzed by two investigators who independently coded responses using a predetermined code list adapted from previously identified needs and concerns of other similar populations. based on the particular coded segments, a checklist and a list of strategies were derived to address the needs and concerns of caregivers. a total of patient-caregiver dyads were enrolled from x-y, with interviews completed; interviews with caregivers and with patients. caregiver interviews resulted in unique codes that corresponded to varying caregivers' needs and concerns which were developed into a checklist and list of strategies. the needs and concerns of mstbi caregivers should be assessed over time to provide the support necessary to assist in the care of mstbi survivors. implementation of a checklist, as well as a list of strategies, can allow for tailored interventions that improve the transitions of mstbi survivors from the icu to subacute/chronic care environments. malignant cerebral edema (mce) develops in a subset of those with hemispheric strokes, precipitating neurological deterioration and death if decompressive hemicraniectomy (dhc) is not performed in a timely manner. however, prediction of which patients will develop mce is imprecise based on baseline clinical and radiographic features imaging quantifies development of cerebral edema. we employ a recurrent neural network that learns from serial clinical and imaging data to enhance early prediction of mce. we identified patients with hemispheric stroke who had nihss and ct scans performed at baseline automated algorithm; midline shift (mls) was measured at the level of the septum pellucidum. we trained a recurrent neural network that incorporates sequential data and compared its performance to those of traditional models. we tried to maximize sensitivity for predicting mce (dhc or death) while optimizing prediction of those not requiring dhc (negative predictive value, npv). nine patients required dhc or died from mce. a linear classifier incorporating age, baseline nihss, and serum glucose had high npv ( %) but only % sensitivity for mce. a probabilistic gaussian mixed model (gmm) improved sensitivity to %. incorporating -hour nihss into gmm improved prediction (sensitivity %, npv %). the neural network was able to predict all cases of surgery and all of those not requiring surgery with % accuracy prediction. recurrent neural networks incorporating sequential clinical and imaging data from the first -hours after stroke may enhance our ability to predict which patients will need dhc. our promising pilot evaluation of this approach study requires validation in larger external stroke cohorts. aneurysmal subarachnoid hemorrhage(sah) survivors live with long term residual physical and cognitive disability. we studied whether neuromuscular electrical stimulation(nmes) and high protein supplementation(hpro) in the first two weeks after sah could preserve neuromotor and cognitive function as compared to standard of care(soc) for nutrition and mobilization. sah subjects with a hunt hess(hh) grade> , assigned to soc or nmes+hpro. nmes was delivered to bilateral quadriceps and gastrocnemius muscles daily during two minute sessions along with hpro(goal: . g/kg/day) between post bleed day(pbd) and . primary endpoint was atrophy in the quadriceps muscle as measured by the percentage difference in the cross sectional area from baseline to pbd on ct scan. all subjects underwent serial assessments of physical(short performance physical battery,sppb) cognitive(montreal cognitive assessment scale,moca) and global functional recovery(modified rankin scale,mrs) at pbd , , and . twenty-five subjects(soc= ,nmes+hpro= ) were enrolled between december and january with no between group differences in baseline characteristics( years old, % women, % hh> ). median duration of interventions was days(range - ) completing % of nmes sessions and % of goal protein intake. no difference in caloric intake between groups, but hpro+nmes group received more protein( . +/- . g/kg/d v . +/- . g/kg/d,p< . ). muscle atrophy at pbd was less in nmes+hpro group( . +/- . % vs . +/- . % ,p= . ). on univariate analysis, higher atrophy was correlated with lower daily protein intake (r=- . ,p= . ); and worse month moca (r=- . , p= . ),sppb(r=- . ,p= . ) and mrs(r= . ,p= . ). nmes+hpro subjects performed better on sppb(p= . ), were observed to have a lower mrs(p= . ) and obtained a higher moca(p= . ) than soc at pbd . nmes+hpro may reduce acute muscle wasting in lower extremities with a lasting benefit on recovery after sah. to better understand whether nmes and/or hpro are responsible for observed benefits, a larger, multicenter study is underway. increasing authorization rates for organ donation is the best way to grow the number of organs available for life-saving transplants. in order to improve our authorization rates and thereby provide more organs for life-saving transplants, our organ procurement organization (opo) partnered with donor hospitals to -led donation conversations and intensified the focus on a collaborative donation process. ned in the the opo during the authorization process by providing a timely notification of a potential donor and by work together on the timing of the donation discussion. the overall authorization rate has improved from % in to % currently. during this time frame, --led conversations has been compelling and a significant factor in improving authorization rates. equally impactful to improved authorization rates has been a % increase in cases involving a collaborative donation process (measured by timely referral and collaborative mention of donation). developing a strong partnership between an opo and a donor hospital is paramount to a successful donation process. critical factors such as timely referral notification and collaboration regarding the timing of the donation discussion can positively influence authorization outcomes. moreover, we -led donation conversations will lead to further increases in authorization which results in more lives saved through donation. quantitative eeg analysis is one part of multimodal monitoring in the intensive care unit due to high temporal resolution and ease of deployment. previously we have shown that dynamical properties of eeg signals can be used to differentiate focal vs. diffuse causes of coma (kafashan et al., ) , and that the intrinsic reactivity of eeg signals -a measure of responsiveness of the eeg to endogenously rare events -correlates with gcs score (inri, khanmohammadi et al., ) . here, we explore the possibility of localizing brain lesions using these dynamical features of eeg signals. we collected retrospective data from comatose patients (gcs< ) defined to have a focal injury. the patients underwent eeg recordings and imaging for routine purposes at barnes-jewish hospital nnicu. index (inri) , which consists of identifying intrinsic events, obtaining brain-state trajectories, and quantifying brain-state trajectories. we then used a neural network-based classifier to map the inri to lesion location using supervised learning paradigms with cross-validation. we used imaging to identify anatomical location of lesions and project them to a two-dimensional headmap. we trained a neural-network classifier to predict d lesion location from the inri dynamics of each eeg channel. we then assessed the correlation between predicted location and actual location using a cross-validation protocol. predicted locations significantly correlated with injury location (r> . ) when compared to correlations with randomly selected patients (r~ ). the results point to a systematic change in underlying neuronal-dynamics induced by brain lesions, that was captured through eeg dynamics and the concept of intrinsic reactivity. here we developed and evaluated a framework to localize brain injury through novel analysis of eeg dynamics. the results here, together with our previous work, suggest brain injuries can be detected and localized using eeg recordings. to examine whether changes in intracranial pressure (icp) waveform morphologies can be used as a biomarker for early detection of ventriculitis. of consecutive patients enrolled prospectively in a hemorrhage outcomes study from to , ( %) patients required external ventricular drainage (evd). only the culture-positive ventriculitis seen in ( % of all evds) patients were included in current analysis. based on our es per week, and additionally if infection was suspected. evds were left open for drainage, with icp monitored hourly by clamping. using wavelet analysis, we extracted uninterrupted segments of icp waveforms. we extracted dominant-pulses from continuous high-resolution data using morphological clustering analysis of icp pulse (mocaip). then we applied hierarchical k-means clustering using dynamic time warping distance to obtain morphologically similar groupings. we applied a top-down approach to split the clusters further, which stops when the mean distance of the waveforms to the centroid is less than a pre-clusters and further-split clusters (when equipoise existed) were categorized for broad comparison by clinician consensus. we extracted , dominant pulses from . hours of evd data. , pulses ( . %) occurred before positive culture, , pulses ( . %) were during culture positivity, and , pulses ( . %) occurred after clinical diagnosis was made. k-means identified clusters, which were further grouped into meta-clusters: tri/biphasic (green), single-peak (yellow) and artifactual (red) waveforms. . % of dominant pulses were tri/biphasic before ventriculitis, which reduced to . % during and . % after (p< . ). one day before the first positive cultures were collected, the distribution of meta-clusters changed to include more single-peak and artifactual icp waveforms (p< . ). the distribution of icp waveform morphology changes significantly prior to the clinical diagnosis of ventriculitis, and may be a potential biomarker. inducing normothermia with temperature modulating devices (tmds) is often associated with significant shivering. we tested the ability of a novel transnasal tmd to induce and maintain normothermia with minimal shivering in endotracheally intubated (et) cerebrovascular patients. single center study utilizing coolstat transnasal cooling device to achieve core temperature reduction by inducing an evaporative cooling energy exchange in the turbinates and upper airway thru a high flow of dehumidified air into the nasal cavity and out the mouth. primary goal was the ability to induce normothermia(t<= . c) within hours in et patients with fever(t>= . c) refractory to acetaminophen. continuous temperature measurements were obtained from tympanic and core(esophageal or bladder) temperature sensors. safety assessments included continuous monitoring for hypertension, tachycardia, and raised icp(when monitored). ent evaluations monitored for any device related nasal mucosal injury. shivering was assessed every minutes using the bedside shivering assessment scale(bsas). duration of device use was limited to hours, as regulated by the e care for temperature management. ten subjects(median age: years, bmi: . kg/m , %men) were enrolled with normothermia achieved in % of subjects. one subject did not achieve normothermia and was later refractory to other tmds. median baseline temperature was . +/- . c, with a reduction noted by hours( . +/- . v. . +/- . , p< . ) and sustained at hours( . +/- . v . +/- . , p= . ). time to normothermia was . +/- . hours. the median bsas was (range: - ) with only episodes necessitating meperidine across hours of study monitoring. no treatment was discontinued due to safety concerns. ent evaluations noted no device related adverse findings. inducing normothermia with a novel transnasal tmd appears to be safe, feasible and not associated with significant shivering. a multicenter trial testing the ability to maintain normothermia for hours is currently underway. traumatic coma is thought to be caused by disruption of the subcortical ascending arousal network (aan). this hypothesis has not yet been tested because tools to map aan connectivity in living humans have only recently become available. we implemented high angular resolution diffusion imaging (hardi) on an mri scanner in the intensive care unit to determine whether patients presenting with traumatic coma have disrupted aan connectivity. we performed high angular resolution diffusion imaging (hardi) in patients with acute severe traumatic brain injury who were comatose on admission and in matched controls. we used probabilistic tractography to measure the connectivity probability (cp) of aan axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus and basal forebrain. to assess the spatial specificity of cp differences between patients and controls, we also measured cp within four subcortical pathways outside the aan. compared to controls, patients showed a reduction in aan pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain (patients: median . , iqr [ . , . ] controls: . [ . , . ], p = . ). examining each pathway individually, brainstem-hypothalamus and brainstem-thalamus cps (pc < . ), but not brainstemforebrain cp (pc = . ), were significantly reduced in patients. only one subcortical pathway outside the aan showed reduced cp in patients. we provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. our findings support current conceptual models of coma as being caused by subcortical aan injury. aan connectivity mapping provides an opportunity to advance the study of human coma and consciousness. limited knowledge about the physiology underlying coma recovery has decreased clinicians' ability to identify patients likely to benefit from continued intensive therapy. machine learning using quantitative eeg (qeeg) has shown potential to improve outcome prediction in cardiac arrest, but the relationship between qeeg trends and coma recovery had limited evaluation in large multicenter studies. seven hospitals contributed clinical and eeg data from comatose adult subjects with cardiac arrest who underwent continuous eeg and targeted temperature management. qeeg features evaluated included background frequency, burst-suppression ratio(> %), epileptiform discharges, and entropy. we utilized random forests to predict good (cpc - ) vs. poor (cpc - ) outcome at -months. model performance was evaluated using the auc at h intervals up to h. we analyzed , hours of eeg (+ tb) for , subjects ( good outcomes). unfavorable eeg features were common in subjects with good or poor outcomes (epileptiform discharges: %, % and burst-suppression: %, %, respectively). epileptiform discharge frequency peaked after rewarming in subjects with good outcome ( spikes/min at h), but continued increasing during cooling and rewarming for those with poor outcome ( - spikes/min from h- h). shannon entropy was always higher in subjects with good outcome. burst-suppression strongly predicted outcome for all centers but during different times, while epileptiform discharges predicted outcomes in five centers, entropy in three, and alpha-background in only one. outcome prediction was best with qeeg during cooling rather than after rewarming (auc . vs. . at h and h, p< . ). maximal auc at h for individual centers ranged from . - . . early qeeg trends carry useful information for coma recovery prediction, but marked heterogeneity in qeeg trends across centers can limit performance and reproducibility of machine learning prognostication algorithms. coexistence of favorable and unfavorable qeeg features in the same patient is common, suggesting that generalizable models for coma recovery prediction must leverage temporal trends. human consciousness depends on ascending projections from the brainstem. brainstem lesion mapping studies have identified a coma-specific sub-region of the dorsolateral pontine tegmentum. however, loss of consciousness (loc) can also occur following injury to cortical regions remote from the brainstem, a phenomenon that commonly occurs after penetrating head trauma but remains poorly understood. andexanet alfa has been shown to reduce anti-factor xa activity however outcome studies are lacking. we compare the efficacy of four-facto -pcc) vs andexanet in patients with factor xa inhibitor related bleeding. retrospective study was performed january to march , including patients with factor xa inhibitor related bleeding of whom wer -pcc vs treated with andexanet. outcome was analyzed using glasgow outcome scale (gos) at discharge, presented as good (score - ) and poor ( - ); length of stay (los) and invariables, and t-test for continuous variables. -pcc or andexanet were included in the study. bleeding source --pcc; vs andexanet cases, % of total -pcc n= , andexanet n= ) and trauma ( -pcc -pcc group was . d vs . d in the andexanet group; icu stay corresponded to . vs . days, respectively. outcomes evaluated through gos did not differ -pcc group vs % in andexanet group, -pcc group vs . % on andexanet group, p= ). unexpectedly, in-hospital mortality was higher on andexanet group -pcc group ( . %); with a similar trend observed in the cns subgroup. -pcc as a factor xa inhibitor related bleeding reversal agent was as effective as andexanet based on outcome scale, constituting an essential option for hemostatic control as cost differences can limit the use of andexanet. the mechanism by which early administration of tranexamic acid (txa) reduces mortality in traumatic brain injury (tbi) is poorly understood. in-vitro models suggest the glycocalyx is preserved with early txa administration, indicating that txa may inhibit glycocalyx breakdown. we hypothesized that early txa administration would result in vascular endothelial preservation as evidenced by lower levels of thrombomodulin, syndecan- , icam, and vcam. we analyzed a subset of subjects from the prehospital txa for tbi trial, which examined the efficacy and safety of prehospital administration of txa compared to placebo in patients with moderate or severe tbi who were not in shock. blood samples were collected upon admission and at hrs. glycocalyx breakdown markers were quantified using a luminex analyte platform. clinical variables were compared using wilcoxon rank-sum tests for non-parametric continuous data and chitests for categorical data. differences in median marker levels were evaluated using t-tests performed on log-transformed variables. significance was set at . . data from patients [placebo (n= ), txa (n= )] were analyzed. groups were well-matched for age, sex, injury mechanism, admission injury severity score, head abbreviated injury score, and presence of intracranial hemorrhage (ich) on admission ct. no differences were observed in any median marker levels on admission or at hours. however, admission levels of syndecan- in patients with ich (n= ) who received txa were lower than those in the placebo group ( . pg/ml [ . - . ] v. . pg/ml [ . - . ], p= . ). no differences in thrombomodulin, icam, or vcam levels were detected at either timepoint in the ich subgroup. administration of txa early after injury may attenuate endothelial release of syndecan- in patients with moderate or severe tbi and ich, potentially suggesting a selective role for txa in endothelial gl despite a rapid increase in the use of the oral factor xa inhibitors rivaroxaban and apixaban over recent years, there remains no standard management for associated life-threatening hemorrhage. andexanet -approved reversal agent available but its place in therapy remains controversial due to its high cost and a lack of head-to-head trials comparing it to four-factor prothrombin complex -pcc). we conducted a retrospective review of adult patients admitted with ich associated with rivaroxaban or apixaban and -pcc for anticoagulation reversal between may and april . the primary outcome was hemostatic efficacy using the annexa- study rating system (excellent, good, or poor) based on initial and repeat non-contrast ct head imaging within hours. secondary outcomes included the occurrence of thromboembolic events and -day all-cause mortality. we excluded patients whose hematoma was surgically evacuated before the -hour ct or who received multiple reversal products. ich patients met the inclusion criteria: andexanet patients ( spontaneous and traumatic) and -pcc patients ( spontaneous and traumatic). ( %) andexanet patients achieved excellent -pcc patients ( -pcc patients, ( %) achieved good (p= . ) and ( %) achieved poor (p= . ) hemostasis. thromboembolic events following -pcc patients (p= . ). thirty-day all-cause mortality occurred in ( %) andexanet patient and ( %) -pcc patient (p= . ). -pcc for reversing ich associated with rivaroxaban and apixaban. limitations include our small sample size and -pcc in this population now that andexanet alfa is widely available. a quality improvement project was undertaken to understand the risks of central venous catheter associated venous thromboembolism (vte) in the neuroicu setting. all patients who were admitted to the neuroicu and required a central venous catheter from / / to / / were included in the study. all catheters were placed under ultrasound guidance using the seldenger technique. the site of catheter insertion, duration of dwell time and subtype were recorded for each catheter that was placed. catheters were categorized as cooling catheters, large bore and dialysis catheters, or standard multi-lumen infusion catheters. clinical suspicion for vte such as extremity edema or unexplained hypoxemia triggered the standard of care use of ultrasound and/or lung ct angiography for diagnosis. vtes with an appropriate chronology and in the same vascular distribution as the suspected catheter were categorized as catheter associated. catheters in patients were included in the analysis representing catheter*days. a total of catheter related vtes were observed in our cohort. in a mixed neuroicu cohort the overall vte rate was . per patient days which is in line with prior published rates. multi-lumen infusion catheters had the highest rate of vte ( . ± . ) and cooling catheters had the lowest rate ( . ± . ). surprisingly, the highest rate of vtes was observed in catheters placed in the subclavian vein across catheter types ( . ± . ). we observed that multi-lumen infusion catheters had a higher rate of vte compared with cooling and large bore catheters. this finding may be related to longer dwell times for multi-lumen catheters ( . ± . vs [cooling] . ± . and [large bore] . ± . ). the subclavian vein was the site with the highest rate of vte which may be related to more lateral approach taken with ultrasound guided subclavian catheter placement. patients on direct acting oral anticoagulants (doacs) have high mortality after intracranial hemorrhage (ich). prothrombin complex concentrate (pcc) has been used off-label to treat ich while on doacs. pccs effect on laboratory markers of anticoagulation have varied. whether or not a change in laboratory markers of anticoagulation impact outcome is unknown. retrospective, single center design assessing patients on doacs that presented with ich and received pcc. the primary outcome is to describe changes in anti-thrombelastography (teg) parameters before and after receiving pccs. hemostatic efficacy (defined by international society on thrombosis and haemostasis criteria), and thrombosis rate are also reported. thirty five patients were included. patients were . +/- . years old and % were male. . % had traumatic brain injury related hemorrhage, % had primary intracerebral hemorrhage, . % had subdural hemorrhage, and . % had subarachnoid hemorrhage. median glasgow coma score at was . units/ml +/- . units/ml. on average teg r time decreased +/- seconds and teg act time decreased +/- seconds. hemostatic efficacy was excellent or good in % of patients and poor in %. thrombosis rate was . %. overall mortality was %. there was a modest response in laboratory parameters after giving pcc to patients with doac associated ich. the mortality in this cohort was high. whether a laboratory response in coagulation dosing, laboratory response, hemostatic efficacy and patient outcomes. in critically ill patients with tbi, agitated behaviors may often be threatening for patients safety and for clinical teams. antipsychotics are commonly used for the acute management of these agitated behaviors. however, animal tbi models suggest that repeated use of antipsychotic agents reduce cognitive and functional recovery. it remains unknown if the use of these agents negatively impact the functional recovery of tbi patients. our objective was to describe the use of antipsychotic agents and agitation/delirium monitoring practices in critically ill tbi patients. we conducted a retrospective observational study of adult icus in canada that manage tbi patients. consecutive adult patients with moderate/severe tbi admitted to icu between january and december were included. data were collected using standardized forms for up to a maximum of days in icu or until transfer out of icu. the primary outcome was incidence of antipsychotic use. we included patients ( patient-days) with a moderate ( %) or severe ( %) tbi. the majority tbi included falls ( %), mva ( %) and assaults ( %). antipsychotics were used in % of patients for a total % of patient-days. quetiapine, haloperidol, olanzapine, and risperidone were used in a %, %, %, % of patient-days, mostly for agitation, an unclear reason or delirium ( %, % and % of total patient-days, respectively). a delirium monitoring tool was used % of patient-days whereas the rass and sas were used in % and % of patients-days, respectively. despite uncertainties regarding their efficacy and safety, antipsychotics are frequently used in critically ill moderate/severe tbi patients in canada, mostly for the management of agitation. sedation/agitation tools are mostly used for the monitoring whereas delirium tools are more rarely used. traumatic venous sinus thrombosis (tvst) is increasingly detected on neuroimaging in acute head trauma, and may be an important contributor to elevated icp refractory to standard medical/surgical treatment, and in turn, higher morbidity/mortality and more complex icu course. we sought to identify clinical and neuroimaging features predictive of refractory icp issues in tvst patients treated in an urban level i trauma center. retrospective query of electronic radiology database from to using the phrase "venous sinus thrombosis". cases were reviewed and scored by a fellowship-trained neuroradiologist to define degree of occlusion (partial vs complete) and cause of sinus occlusion (extrinsic compression vs intrinsic thrombus vs both). additional patient characteristics included demographics, mechanism of trauma, cerebral venous sinus involvement, laterality, skull fracture, extra-axial hemorrhage and invasive neuromonitoring. refractory icp was defined as at least one spontaneous icp elevation >= minutes during icu stay despite use of first tier therapies for icp control. odds ratios were computed and adjusted by multivariate logistic regression for patient age, gender and initial gcs to determine association with refractory icp. among patients with radiologic diagnosis of tvst, developed refractory icp ( / = . %). statistically significant variables associated with refractory icp included involvement of internal jugular vein (aor= . , % ci . - . ), involvement of transverse sinus (aor= . , % ci . - . ) and presence of temporal bone fracture (aor= . , % ci . - . ) . potentially protective factors included sinus pathology secondary to extrinsic compression (aor= . , % ci . - . ) and coexisting epidural hemorrhage (aor= . , % ci . - . ). involvement of the internal jugular vein or transverse sinus and temporal bone fracture may represent sensitive features of tvst predisposing to refractory icp issues, while extrinsic compression of a sinus alone was found to be protective. monitoring cerebral autoregulation in traumatic brain injury (tbi) patients can indicate an individual cerebral perfusion pressure (cpp) target for which autoregulation is best preserved (cppopt): this offers a precision medicine approach with hypothetical advantage over the current 'one size fits all' strategy. large retrospective data suggest that managing cpp close to cppopt has a benefit in outcome. a prospective evaluation of cppopt guided therapy is needed, but before performing an outcome study it is necessary to assess the feasibility and safety of such a protocol. the primary objective of cogitate (cppopt guided therapy assessment of target effectiveness) is to demonstrate feasibility of individualising cpp at cppopt in tbi patients, expressed as the percentage of monitoring time for which cpp is within mmhg of regularly updated cppopt targets during the first days of intensive care unit (icu) admission. secondary objectives are to investigate the safety (increases of the treatment intensity level) and physiological effects of this strategy (changes in autoregulation indexes, organ function parameters). cogitate is a phase ii non-blinded, randomised controlled trial currently ongoing in the icu of cambridge, leuven, nijmegen and maastricht. severe tbi patients requiring intracranial pressure directed therapy, are enrolled in the first hours after icu admission and allocated into two groups. in the intervention group the cpp target (cppopt) is calculated using a (modified) algorithm previously described by liu x et al. and clinically reviewed -hourly. the control group uses a fixed cpp target ( - mmhg). patient re have been recruited so far. randomising between a fixed and variable cpp is feasible. after completion of recruitment and follow up in terms of assessment of safety and physiological parameters, we will consider progressing to a phase iii study. selective reduction of non-classical monocytes has been associated with reduced neutrophil activation in murine traumatic brain injury (tbi) models. similarly, cd -/cd -t cells or double negative t-cells (dnt) may exacerbate ischemic brain injury. this study sought to assess the expression of peripherally isolated t-cells and monocytes after acute tbi. all patients admitted with primary tbi to the neurotrauma icu between november and november were eligible for study. consent was obtained and blood samples were obtained within hours of injury. samples were compared to healthy age-and sex-matched controls. conventional flow cytometry techniques gating on all patients admitted with tbi to the neurotrauma icu between november and november were eligible for study. consent and blood samples were obtained within hours of injury. samples were compared to healthy age-and sex-matched controls. conventional flow cytometry techniques, gating on cd + and cd + were employed to identify t-cell and monocyte populations, respectively. data were analyzed using cytometric fingerprint binning and t-sne embedding, which captures the set of multivariate probability distribution functions and generates maps that facilitate quantitative comparisons. patients were compared to controls. after computational analysis, distinct t-cell phenotypes were identified, of which were statistically significantly different between patients and controls expressed as a fraction of cd + cells. three of these eleven subsets had a cd -/cd -(double negative) phenotype that were depressed among patients: cd -/cd -/cd + . % versus . %, p= . ; cd -/cd -/ + . % versus . %; p= . ; cd -/cd -/ +/ + . % versus . %; p= . . there was a three-fold decrease in the fraction of type , non-classical monocytes in patients than in controls [ . (iqr . - . ) versus . (iqr . - . ); p= . ]. similar patterns in monocyte expression were observed for the patients who had repeat analysis at hours. in this preliminary study, there were notable reductions in dnt populations and non-classical monocytes in patients with acute tbi, which may suggest recruitment to the cns. prior studies suggest that dnt play a critical role in the perpetuation of cerebral ischemia after acute stroke and that type monocytes modulate neutrophilwarranted. much of the secondary injury that occurs after traumatic brain injury (tbi) results from coagulation derangements related to disseminated intravascular coagulation (dic). extracellular vesicles (evs) are small ( . transduction. evs are released from all cell types, including platelets, endothelium, and granulocytes which are responsible for dic. we hypothesized that specialized flow cytometry techniques could identify a unique ev signature of dic in acute tbi. ev fluorescence panels were created assessing for endothelial cells (cd +, cd +), platelets (cd , cd a+, cd b+), erythrocyte markers (cd +) as well as brain specific biomarkers (s b). using a modified flow cytometry instrument for detection of small particles, side scatter signal is used to estimate ev size. samples were treated with triton, which disrupts vesicular membranes, abolishing evs. samples were prepared in trucount tubes with a known number of lyophilized beads, which enabled the determination of the plasma volume. all combinations of positive/negative expression were counted. there was no significant difference in the total number of evs in the panels between the patients and controls. of combinatorial analyses in the first ev panel, the following were significantly elevated after bonferroni correction: cd +/cd + . evs/ul plasma v controls (wilcoxon rank sum p= . ); cd +/cd + . evs/ul plasma v . controls (p= . ); cd +/cd a+ . evs/ul plasma v . controls (p= . ). brain biomarkers were also elevated: s b . evs/ul plasma v. . controls (p= . ). evaluate whether this expression correlates with secondary microvascular brain injury. s b evs (membrane bound, not free soluble protein) are significantly elevated in tbi patients; if reproducible, the significance of this remains to be elucidated. diabetes insipidus (di) following transsphenoidal craniotomy may lead to significant metabolic derangements. serum sodium imbalances are frequent and important; both hypo-and hypernatremia can be devastating neurologically. a project aimed at improving di management through predictive assessments and ddavp protocols could potentially improve patient outcomes. however, few predictors for the postoperative development of di have been reported. after institutional irb exemption, the records of patients undergoing endonasal transsphenoidal craniotomy between july and december were retrospectively reviewed. demographics, preoperative medical or radiologic diagnoses, medications, and laboratory values as well as intraoperative blood loss, urine output, and ddavp administration were assessed for correlation with the incidence of postoperative development of di using logistic regression. development of postoperative di was defined as postoperative ddavp administration and/or ddavp use upon or after discharge from hospital. of the patients developed postoperative di. patients . , and . , respectively). similarly, patients with increased intraoperative blood loss, increased intraoperative volume administration, nd intraoperative ddavp or vasopressin administration were also more likely to develop postoperative di (pwith logistic regression modeling adjusted for associations between outcome and potential risk factors, patients having a documented or clinical suspicion for a preoperative endocrinopathy had seven times higher odds of developing postoperative di compared to their peers (p-value . , % ci . - . ). in administration, and ddavp were independently associated with an increased risk of postoperative di; the odds of postoperative di were seven times higher in patients with a documented or clinical suspicion findings. the seminal mechanical thrombectomy (mt) trials had a median age of years. though some of these trials included nonagenarians, there is little data on their outcomes. we aimed to compare the procedural, discharge outcomes and complications, of mt for acute ischemic stroke (ais) in patients with ais admitted to two comprehensive stroke centers were enrolled prospectively in a mt, procedural outcomes, complications, and discharge disposition were compared in propensity scorematched groups (matched for nihss, pre-stroke mrs, ivdefined as a discharge to home/acute rehabilitation. of the ais patients, / ( %) nonagenarians underwent mt compared to / ( %) ) were propensity score-matched with a median admission nihss of and , and median aspects ( % vs %, p= . ), whereas ica ( % vs %, p= . ), and m ( % vs %, p= . ) occlusions were similar between the two groups. time to groin puncture ( ± vs ± ; p= . ), revascularization time ( ± vs ± ; p= . ), complication rates ( vs . %; p= . ) and inhospital deaths ( % vs %; p= . ) were similar among the two groups. % of nonagenarians had we present one of the largest series of mt among nonagenarians with % successful recanalization rates. in propensity score analysis almost half of nonagenarians ( %) were discharged to home/rehab, which is comparable to a younger cohort ( %). aggressive management is warranted in the oldest of the old. early neurologic deterioration (end) occurs in up to one third of stroke patients and is associated with poor outcome. no consistent definition of end exists regarding degree of nihss decline and timeframe. we evaluated the definition of end, predictive factors, and day outcomes in a cohort of critically ill stroke patients. this study is a retrospective review of consecutive ischemic stroke patients with nih stroke scale (nihss) intervention factors were obtained. end was defined as a delta nihss > at hours from admission. reperfusion was defined as a thrombolysis in cerebral infarction (tici) score of > b, cerebral edema treatment as any icp-lowering therapy, and poor outcome as mrs > at days. multivariable logistic regression analyses were performed to assess factors associated with end and poor outcome. patients (median age years, % women, median nihss ) met study criteria. % experienced end. admission nihss, administration of tpa, receipt of intraarterial therapy, and successful reperfusion were not associated with end. end was independently associated with older age (p= . ), sex (p= . ), and treatment of cerebral edema (p= . ) after adjusting for cerebral herniation and tracheostomy. poor outcome was associated with older age (p= . ), higher delta nihss (p< . ), not receiving tpa (p= . ), and placement of percutaneous endoscopic gastrostomy tube (p= . ). end patients had a higher median day mrs (p< . ). end as defined by a delta nihss > at hours predicts poorer outcome, but was not associated with tpa or intraarterial therapy, which contrasts with prior literature. this variance could be attributed to the end timeframe defined as hours rather than the typical samples sizes and comparison of end timeframes could clarify observed findings. annexa- was a single-arm, prospective, open-label study of andexanet in patients presenting with major bleeding within patients with spontaneous intracranial hemorrhage (ich). brain imaging was performed at baseline, and at and hours post andexanet treatment. subdural hemorrhage (sdh) thickness and ich volumetric analysis was performed using quantomo software. co-primary efficacy outcomes were change in anti- of patients enrolled in annexa- , nontraumatic ich was present in patients, including intracerebral +/-intraventricular in patients, subarachnoid in patients and subdural in patients. in this cohort, mean age was years (sd . ) administration was . hours (iqr . - . ); median time from symptoms to ct was . hours (iqr . - . ); and median time from ct to andexanet administration was . hours ). median intraparenchymal volume was . ml (iqr . - . ). among efficacy evaluable patients (baseline anti-treatment overall. in patients treated < hours after baseline imaging, hemostatic efficacy was . %; - hours after baseline imaging, . %; > hours, . %. within days, death occurred in patients ( . %). andexanet reduced anti--or apixaban-associated nontraumatic intracranial bleeding and with a high rate of hemostatic efficacy up to hours after treatment. spontaneous intracerebral hemorrhage (ich) is associated with high rates of mortality. multiple scoring systems exist however the original ich score remains most commonly used. we hypothesize that patients undergoing scuba, compared to medically managed patients, would have lower -day mortality than predicted. we performed a retrospective observational cohort study of consecutive nontraumatic spontaneous ich patients treated at a single, tertiary care, academic center from december to june . patients for each patient based on the admission ich score. a total of ich patients were included. the median age was (q = , q = ), gcs ( , ), and nihss ( , ) . sixty-three were deep hemorrhages and had intraventricular hemorrhage. median pre-operative volume was . ml ( . , . ). the expected -day mortality was . % while the observed mortality was %. on -day follow up, a mrs of - was seen in % of patients. patients undergoing scuba have an absolute risk reduction of . % in mortality than predicted by the ich score. good outcome to moderate disability, defined as mrs - , was achievable in almost half the introduction andexanet (coagulation factor xa [recombinant] inactivated-zhzo), a specific reversal agent for factor xa % of patients with major bleeding in the annexa- trial. however, little is known about the clinical factors associated with a hemostatic response in patients with intracranial hemorrhage (ich) receiving andexanet. annexa- was a prospective, single-arm, open-label study of andexanet in patients with acute major treatment was rated by an independent adjudication committee as excellent, good, or poor/none based on pre-specified criteria. all ich patients with evaluable he were included in the analysis. univariate and indication for anticoagulation, baseline antianti-platelet use, time from last dose to andexanet (and other time intervals), neurologic function, and hematoma characteristics were performed to identify factors predictive of he. of ich patients enrolled, ( . %) had evaluable he. in patients with ich, baseline antitime from symptoms to andexanet were all significantly associated with he. in multivariate analysis, time from last dose ( . h for excellent/good; . h for poor/none), time from symptoms to andexanet ( . h for excellent/good; . h for poor/none), and time from symptoms to scan ( . h for excellent/good; . h for poor/none) were independently associated with he. in ich patients treated with andexanet in the annexa- study, various time intervals were predictive of hemostatic efficacy. these findings suggest that shorter time intervals are associated with lower he and are consistent with the known relationship between time from symptoms and the risk of hematoma expansion. alterations in functional connectivity are associated with persistent cognitive deficits in survivors of aneurysmal subarachnoid hemorrhage (sah), but causation remains unknown. therefore, we sought to and behavior could be assessed. we used functional optical intrinsic signal imaging to measure spontaneous hemodynamic fluctuations -operated (n= ) and sah (n= ) mice. we tested behavior using the morris water maze, open field test, y-maze, and rotarod. timepoints were from days to months. we used the anterior prechiasmatic injection model of sah. . ), and visual cortex ( . vs. . ) at day following sham procedure or sah, as measured by the proportion of brain surface with a correlation coefficient > . (sham vs. sah, respectively, p< . ). -independent ng sah. a global connectivity index remained decreased until month following sah ( . vs. . , p< . ). an interhemispheric connectivity index was also he hidden platform test on the morris water maze (p= . ) and open field test ( vs. m, p= . ) at approximately weeks. there were persistent deficits on the y-maze for at least months ( % vs. % alternation, p= . with repeated measures at and months). there was no significant effect of sah on rotarod performance. we studied whether high-protein supplementation (hpro) and neuromuscular electrical stimulation (nmes) after subarachnoid hemorrhage (sah) could be a safe and feasible approach to reduce muscle wasting and improve long term recovery. assigned to standard of care (soc) or nmes + hpro. nmes was delivered to bilateral quadriceps and gastrocnemius muscles during two -minute sessions daily along with hpro (goal . g/kg/day) between post bleed day (pbd) and . tolerability was measured during each nmes session by assessing for agitation or discomfort. safety measurements included increased heart rate, blood pressure, or intracranial pressure (when monitored) during nmes. stimulation sites were assessed after each nmes for muscle injury or skin trauma. hpro tolerability was assessed by monitoring for gastric retention or emesis. safety measures included aspiration and evidence of acute kidney injury. nmes and hpro were discontinued if subjects refused. the goals were to administer at least % of nmes and hpro. muscle wasting was assessed with serial ct scans of the thighs. twenty-five subjects (soc= , nmes + hpro= ) participated with no differences in baseline characteristics ( years old, % women, % hh> ). median intervention days were (range: - ), with % of nmes sessions completed. two subjects had transient muscle soreness but no other adverse events. no adverse events were associated with hpro. the hpro group received % of the goal and more protein than soc (mean difference: . +/- . g/kg/d, p< . ). muscle atrophy at pbd was greater in soc group ( . +/- . % vs . +/- . %, p= . ). nmes and hpro are safe and feasible after sah. a larger pilot study is underway to understand whether nmes and/or hpro may beneficially impact neuromotor recovery after sah. lipocalin- (ngal) is released by activated neutrophils and astrocytes and mediates neuro-inflammation and iron regulation in hemorrhagic stroke models. blood ngal is an early biomarker in human ischemic l and neurofunctional outcome in sah patients. magnetic luminex assay, r&d systems) and assessed modified rankin scale (mrs) every months. patients with renal or severe liver dysfunction, active malignancy or intracranial infections were excluded. poor outcome is defined as mrs> . vasospasm was defined as > % reduction any vessel caliber on cerebral angiogram. continuous variables were compared with student's t or wilcoxon rank sum test depending on data distribution. one-way anova was used for multi-group comparison. sah cohort has mean age of . years, % women, % with poor -month outcome and % developed vasospasm. higher plasma ngal on post--sah days - (p= . ) and (p= . ) are associated with poor -month outcome. higher plasma ngal on postand ngal on post-sah days -- . ) early elevation of plasma ngal on post-sah day is associated with vasospasm and poor -month -sah - are associated with poor -month outcome. larger population studies are needed to validate plasma ngal as a potential sah biomarker. patients with aneurysmal subarachnoid hemorrhage (asah) are at risk of rebleeding prior to aneurysm obliteration. while placebo-controlled studies have shown that administration of either -aminocaproic acid (eaca) or tranexamic acid (txa) can decrease rebleeding, there has not been a comparison of the two in this patient population. because of a national shortage of eaca in , our hospital changed to txa. the purpose of this study is to describe the outcomes of asah patients treated with either eaca or txa. this is a retrospective chart review of patients who presented with an asah between / / and / / and were treated with either eaca or txa to prevent aneurysm rerupture. descriptive statistics were used. there were patients with asah who received eaca and who received txa. the groups were eaca group and . % in the txa group. the average time from admission to drug initiation was . ± . hours in the eaca group and . ± . hours in the txa group. no patient in either group experienced aneurysm rerupture after receiving the drug. similar numbers of patients in both groups had cerebral ischemia (eaca: % vs. txa: %) and extracranial thrombosis (eaca: % vs. txa: %). although txa is known to lower the seizure threshold, we found no increased incidence of seizures (eaca: % vs. txa %). there was a modest cost difference in favor of txa vs. eaca. there does not appear to be any major differences in outcomes in patients with asah treated with either eaca or txa for the prevention of aneurysm rerupture and a slight cost savings favoring txa. a larger prospective study is required to confirm these results. outcome prediction after aneurysmal subarachnoid hemorrhage (asah) is based on scores, which are determined once at admission. however, the occurrence of delayed ischemic neurological deficits (dind) depends on multiple concomitant and continuously changing factors. the goal of the study was to establish an automated analysis pipeline to predict dind from multimodal data. multimodal data (patients' history, imaging and laboratory values among others) from patients with asah were analyzed. dind was defined as new ischemia or perfusion deficits in native or contrastenhanced ct/mri and/or cerebral vasospasm in conventional, ct-/mr-angiography. a ranking of the features was performed by univariate regression analysis. only cases with < % of missing values were included in the model. among the tested features, the top , with a false discovery rate < . , were selected. missing values were imput random forest machine learning algorithm was applied. the performance of the prediction was estimated on the fly by predicting the observations that were not used for building the tree ("out-ofbag") across all trees. the final data matrix contained events described by features from patients. in the final model, the out-of-bag estimate of error rate was %, which reflected a % accuracy. the importance plot for different features revealed the importance of some parameters known in the context of inflammatory response, which is linked to the pathophysiological cascade leading to dind. these included counts of leucocytes, monocytes, neutrophils, and lymphocytes. however, other laboratory parameters, such as zinc and selenium, appeared to be of high importance in the model, which was somewhat unexpected. machine learning algorithms may be helpful to filter out predictive features from a large number. these features might be subsequently investigated regarding their predictive value on the occurrence of dind after asah. innate inflammation is a recognized mediator of dci after sah. we have shown that neutrophils and the neutrophil-derived enzyme, myeloperoxidase (mpo), mediate memory deficits in dci. how mpo affects memory is unclear. there is evidence that mpo, and its substrate h o , may act through astrocytes or directly on neurons. here we test mpos action on astrocytes and neurons. primary neuronal and astrocyte cultures were developed from wt and c bl/ thy -gcamp mice. to test if mpo or h o are toxic to neurons or astrocytes, cells were incubated with mpo ( . u/ml), h o ( . %), and mpo/ h o and evaluated with live/dead cell viability assay (thermofisher). to test if neuronal firing is affected by mpo, the same experimental conditions were examined in c bl/ thy -gcamp using video microscopy. neuron activation was stimulated with kcl (final concentration mm). addition of h o led to death in neurons and astrocytes. mpo did not affect cell death in either group. interestingly, mpo/ h o showed less cell death than h o alone suggesting a neuroprotective benefit of mpo. in neurons, kcl administered to untreated neurons led to continuous firing as evidenced by intense calcium signal. mpo addition did not change the firing rate when compared to baseline. after . hours of mpo pretreatment, activation with kcl showed a suppressed firing rate suggesting neuronal depression. the addition of mpo/ h o showed the same firing rate suppression as mpo alone. this study suggests that mpo acts directly on neurons to decrease function. in our model of neutrophilinduced development of dci, mpo is released in the meninges, diffuses to the brain parenchyma and acts directly on neurons to affect memory. this needs to be tested more thoroughly in an in vivo model of sah. how mpo specifically affects memory in neurons is an area of interest in our laboratory. delayed cerebral ischemia (dci) is a feared complication of subarachnoid hemorrhage (sah), leading to worse outcomes. electroencephalography (eeg) provides a useful, continuous monitoring tool for dci risk (claassen ; kim ; rosenthal ) and late-onset epileptiform discharges (ed) have high predictive value for dci (kim ; rosenthal ) . however, optimal parameters to assess ed contribution to longitudinal dci risk are unknown. we hypothesize that the evolution of ed frequency after sah can provide early identification of those at high dci risk. we analyzed continuous eegs from patients with moderate to severe aneurysmal sah. ed were identified using a commercial detection algorithm (scheuer ). we calculated ed frequency (per hour) after sah and compared mean ed frequencies between dci and control patients. we also evaluation, we performed group based trajectory analysis (gbtm) and calculated hourly receiver operating curves (roc). ed rates were higher in both dci and control groups during the clinical dci "risk period" of day - . overall mean ed frequency were significantly higher in dci patients (t-test, p= . ), including only pre-dci ed assessment (t-test, p< . ). hourly mean ed rates remain higher in dci patients from days - . using gbtm, we identified three distinct trajectories associated with dci ( %, %, %, p= . ), with group number selection optimized based on bayesian information criteria. hourly area under the roc (auc) calculations of ed frequency yielded a maximum performance of . . natural history of ed frequency in all sah patients coincides with the "high risk" time-period of dci. patients with dci have higher mean frequencies that remain elevated throughout this dci risk period. gbtm and auc calculations suggest longitudinal analysis of discharge frequency can differentiate dci risk, but integration of other waveform characteristics are needed to optimize prediction. aneurysmal subarachnoid hemorrhage (sah) has high morbidity and mortality. time to aneurysm repair, whether earlier or later in the course of the disease, may impact outcomes. however, optimal timing remains controversial. our goal was to describe the association between time to aneurysm repair and mortality and functional outcome. this study was conducted in two reference centers -one in rio de janeiro and one in porto alegre july to march , every adult patient admitted to the icu with aneurysmal sah was enrolled in the study. data were collected prospectively during the hospital stay. patients were divided into four groups according to the moment of aneurysm repair after bleeding: < days, to days, > days and not repaired. the primary outcome was in-hospital mortality. dichotomous variables were analyzed using twomortality as the reference group ( to days). a total of patients were included. median age was years, mostly female ( %). in the univariate analysis hydrocephalus, rebleeding, postoperative neurological deterioration (up to hours after procedure), delayed cerebral ischemia, as well as mortality and poor outcome, were associated with the different timing of aneurysm repair. in the multivariate model for mortality, poor grade sah, hydrocephalus, post-procedure neurological worsening and dci were independently associated with higher mortality. additionally, late repair was associated with lower mortality (or . ) as compared with occlusion between to days. our study shows higher mortality in patients submitted to aneurysm occlusion procedure between days and after ictus, when compared to late repair. more studies are needed to define the best timing of aneurism repair in patients that are not submitted to early occlusion. the biological mechanisms that influence abnormal cortical neurophysiology after aneurysmal subarachnoid hemorrhage (sah) are uncertain. we hypothesized that soluble st (sst ), a plasma marker of the innate immune response, is associated with events of electroencephalography (eeg) deterioration including new epileptiform abnormalities (eas) or new eeg background deterioration. -approved biospecimen repository, we evaluated patients with at least days of eeg monitoring and an early sst measurement (collected < days following sah). eas were defined as sporadic epileptiform discharges, lateralized rhythmic delta activity (lrda), lateralized periodic discharges (lpd), or generalized periodic discharges (gpd). background deterioration was defined as decreasing alpha delta ratio (adr), relative alpha variability (rav) or worsening focal slowing. the association between sst level and eeg-identified eas or new background deterioration was compared using the wilcoxon rank sum test. patients met inclusion criteria. early sst was collected at mean . ± . days after sah; patients had a subsequent sst measurement at ± . days. ( %) patients developed new eas during eeg monitoring, ( %) developed new background deterioration, and ( %) developed neither. median sst in patients developing new eas was higher ( . ng/ml ]) than in patients who did not develop new eas ( . ng/ml ], p= . ). this association between elevated sst and new eas was not present for sst samples collected at later time points. there was no difference in sst levels between patients who developed new background deterioration ( . ng/ml ) compared with those who did not ( . ng/ml ], p= . ). among patients admitted with aneurysmal sah, elevated sst in the first days is associated with the development of new eas on eeg monitoring. this association was not present at later time points, suggesting that the early inflammatory response may be linked to abnormal cortical neurophysiology. glial-mediated inflammation occurring early after status epilepticus (se) in rodent models has been implicated in the subsequent development of spontaneous recurrent seizures (srs). while this suggests anti-inflammatory strategies may be a target for therapeutic intervention, the appropriate timing for such an intervention is unclear. the aim of this work is to define the timing of early inflammatory changes using pro-inflammatory mir- and anti-inflammatory mir- a as biomarkers in a kainic acid mouse model of se. se was induced in - week old male c bl/ j mice (n= per timepoint) using intraperitoneal injections of mg/kg kainic acid. the onset of se was defined as the first class seizure using a modified racine scale. the intensity of the se episode was estimated by the total number of discrete class v seizures observed. after hours, the se was aborted with diazepam, and hippocampal tissue was harvested at hr, hr, hr, hr and hr. rna was isolated using trizole (life technologies) followed by qrt-pcr analysis to define the steady-state expression levels of mir- and mir- a and their targets, socs we observed a > fold increase in expression levels of mir- , reaching peak levels at hours. expression levels of mir- directly associated with the intensity of se. the level of socs mrna expression decreases after the peak expression of mir- . as the levels of mir- a were only conclusions mirna- expression shows an early increase within hours of se, reaching a peak at hours. mir- a shows a non-mir- initiated after se to determine if this can prevent the development of srs. nurses routinely screen for changes in neurologic status with serial clinical assessments. the objective of this study was to employ mixed methods to determine inter-rater reliability (irr), protocol adherence, and acceptability of a new tool we developed called serial neurologic assessment in pediatrics (snap) compared to the glasgow coma scale (gcs). snap assesses mental status, cranial nerves, communication, and four-extremity motor function/strength, with scales for children < -months, -months to -ye -years-old. snap was designed for use in a diverse population, including patients who are intubated, sedated, and/or have developmental disabilities. irr of independent snap assessments by pairs of trained nurses was assessed with multilevel cohen's kappa and linear weighted kappa, calculated through clustered bootstrap method to account for multiple assessments. we assessed protocol adherence with standardized observations. we conducted semi-structured interviews to assess acceptability and feas we thematically analyzed interviews in accordance with modified grounded theory framework. critical care nurses performed paired snap assessments on patients ( < -months; months to --years). there was substantial agreement between nurses (average kappa= . < -months; . -months to --years), and irr was unchanged for children who were intubated, sedated, and/or had developmental disabilities. irr was unchanged based on degree of experience using snap and for day vs. night-shift nurses. nurses had % protocol adherence. snap was easier to use and more precise at describing neurologic status of patients who were intubated, sedated, and/or had developmental disabilities than gcs. % of nurses preferred to use snap over gcs. when utilized by nurses, snap has substantial irr, excellent protocol adherence, and is acceptable and feasible to i neurologic decline. several studies demonstrate significant gender disparities in professional societies for critical care and neurology, but data for neurocritical care is lacking. we examined gender representation trends within the neurocritical care society (ncs), the largest international professional society for this subspecialty. we hypothesized that female representation has increased with achievement of gender equality in . a multidisciplinary writing group obtained approval from the ncs executive committee and endorsement by the women in neurocritical care (wincc) section. after review by the rush university irb, access was granted for the following rosters: general membership, board of directors, officers, committees, annual meeting speakers, grant, fellowship and other award recipients. we differentiated between female, male and unidentified gender. available membership rosters from listed members, with gender unknown for > %. in , of members . % were females, . % males, and . % unidentified. as of , / presidents ( . %) and - , female committee members increased from % to %; female committee chairs increased from % to %. to date, / ( . %) christine wijman young investigator awardees were female with no female recipients of the best scientific abstract award ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . % of presidential citation awardees - % from -e representation in guidelines writing groups ranged between %- % ( - ), and - % in consensus statements writing groups ( ) ( ) ( ) ( ) ( ) ( ) . - % ( awardees were women. within the ncs, a longitudinal increase in female representation has occurred over the last years but gender equality has not been achieved. we recommend focused efforts to facilitate inclusion and gender equity within ncs. with the push toward using large data sets in critically ill patients, the use and management of registries is becoming more relevant. clinical registries provide insight about associations and patterns in diagnosis, disease, and treatment. the integrity of the data is of utmost importance. this poster describes the quality control and data management methods for maintaining the integrity of a multicenter trial registry. we employed modifications to van den broeck's method of data organization to clean and manage the end-panic registry. the data management consisted of five phases: ) screening phase, ) data organization , ) diagnostic phase, ) treatment phase, and ) missing data phase. the screening phase consisted of distinguishing missing and extraneous data elements, outliers, inconsistent patterns/distributions and unexpected analysis results. the data organization phase consisted of treating blank cells and highlighting errors with data input. the diagnostic phase was used to clarify the true nature of the data points, and make sure the data presented was biologically possible. the treatment phase consisted of correcting variables. the missing data phase consisted of determining whether the missing data was informative or noninformative. currently the multi-center registry houses ~ . million discrete data points from , patients. there was a high correlation between the texas, ohio and california locations, and npi, dvl, cvl, mcvl, and pupil size. there was a low correlation between the texas, ohio and california locations, and pupil latency and presence/absence of cataracts. missing data was informative for age, race and ethnicity, and distribution of missing data caused an inquiry into methods for collecting data and implementation plans for change. this interdisciplinary method for cleaning and managing the end panic registry was able to identify and rectify errors. we would recommend others to use the methods to build, clean and manage clinical registries. objective was to describe current state of quality improvement (qi) processes implemented in neurocritical care units (nccu). a -question-survey was sent to members (physician, nurses, and pharmacists) of the neurocritical care society. we describe factors affecting the presence of nccu qi, barriers to qi, awareness of stroke (stk, cstk), stroke get with the guidelines (gwtg), trauma quality improvement program (tqip) and american academy of neurology (aan) performance measures, and examined factors affecting satisfaction with current practices. the response rate was . %; . % of respondents were from us teaching hospitals, . % practiced in dedicated neurocritical care units, and . % in a program with a neurocritical care fellowship. . % reported a dedicated nccu qi program. comprehensive stroke center (rr . , % ci . - . , p = . ), dedicated nccu (rr . , % ci . - . , p = . ), and ncc fellowship programs (rr . , % ci . - . , p = . ) were more likely to report dedicated ncc qi staff. external ventricular drain infection was the most commonly tracked ncc qi metric ( . %). respondents indicated the highest level of awareness for cstk ( . %), stk ( . %), and gwtg ( . %), but indicated a relative lack of awareness for tqip ( . %), and aan ( . %) perform satisfaction with existing ncc qi were: presence of a hospital qi program (rr . , % ci . - . ), p = . ), presence of a formal ncc qi program (rr . , % ci . - . ), p = . , and dedicated ncc qi staff (rr . , % ci . - . ), p < . ). insufficient hospital ( . %) and departmental support ( . %) were reported common barriers to the successful implementation of an nccu qi program. a dedicated staffed nccu qi program occurs in a minority of neurocritical care units, and the lack of such programs may lead to clinician dissatisfaction. institutional and departmental support may be critical elements of a successful and satisfactory implementation of nccu qi. the development and implementation of a nurse driven rounding model was instituted in the neuro icu of an academic medical center to increase effectiveness of team communication, practice autonomy and integration of nursing input into the interprofessional care plan. clinical nurses and neuro-intensivists developed a structured rounding tool to guide the nursing presentation of clinical information on rounds. the interprofessional team underwent education on expectations and processes. the rounding tool underwent a number of revisions over a -month period based on feedback from all team members and evolving patient care priorities. all team member roles in the rounding process were clearly defined with nursing leading patient assessment and goals. nursing satisfaction surveys assessed nursing attitudes regarding autonomy, decision making and rn-md communication via a point likert scale; mean values for each question domain were compared pre-and post-implementation. in total, nursing surveys were analyzed, pre-implementation and nurses postimplementation. mean response values evidenced significant improvement across all domains in the post-implementation group: autonomy ( . vs . , p< . ), rn decision making ( . vs . , p< . ), p< . ) . survey participation was good in both groups ( % pre-and % post-implementation). nursing satisfaction across multiple important domains improved following implementation of a nurse driven structured rounding model. application of a nurse-facilitated, structured model creates a standardized reliable process that can be observed by all team members in order to deliver data driven, high quality, efficient and effective care. multiple models for program development and care delivery in pediatric neurocritical care (pncc) have been proposed with varying degrees of success. here we present a unique model for building a dedicated pediatric neuro-intensive care unit (pnicu) through creation of a community of practice (cop). cop represents a mechanism for collective learning and production of repertoire of best practices through knowledge sharing, development of social capital, and support for organizational change. we utilized a bolman and deal -frame for organizational functioning (structural, human resources, political, symbolic) to describe the development of our pncc cop. we evaluated our pnicu with the standards outlined by the neurocritical care society (ncs) for a level neuro-intensive care unit. structural factors included forming pncc leaders across specialties (neurology, critical care, neurosurgery, radiology, nursing), opening (in ) a state-of-the-art, unique pnicu which includes wired rooms for continuous eeg monitoring and multimodal neuro-monitoring, meeting / ( %) of ncs standards. human resource factors included creating core groups of physicians and nurses with a primary role in pnicu, providing ongoing education through workshops, lecture series, and certification including enls and tncc, meeting / ( %) of ncs standards. politically, a pncc fellowship-trained, board-certified physician serves as medical director coordinating conception of collaborative partnerships across multidisciplinary experts. simultaneous creation of other specialty cohorts in pediatric critical care aided in departmental acceptance for the program, meeting / ( %) of ncs standards. symbolically, we set forth our shared purpose and strong commitment to foster cop that advances knowledge and best practices for pncc. using cop principles, we have accomplished many of the ncs standards over a relatively short period of time. we plan to further develop the program with particular focus on education, certification, and expansion to include allied health professionals. our roadmap may be applicable to any institution interested in developing a pncc cop/pnicu. intravenous (iv) anti-hypertensive infusions are often used acutely in patients with intracerebral hemorrhage (ich). there is a lack of standardization of titration and variation in goal blood pressure, and therefore their use is associated with increased icu length of stay (los) and cost. we examined the use of anti-hypertensive infusions in ich patients in our institution and developed a quality improvement intervention to reduce duration of infusion, icu los, and cost. patients were included if they were admitted to our icu from september -march with an icd- diagnosis of non-traumatic ich and received iv antihypertensive infusions. interventions introduced starting in november included interdisciplinary task force formation, provider education, updated rounding checklist, and emr order with clear blood pressure target. the primary outcome measure was duration of anti-hypertensive infusions determined by retrospective chart review, and secondary outcome measures of icu los and cost data were obtained from our finance department. over months, mean antihypertensive infusion duration reduced from . hours (n= ) to . hours (n= ). icu los reduced from . to . days. proportion of cases with discordant blood pressure goal documentation reduced from . % to . %, while discordance in documented goals to actual orders reduced from . % to . %. there were no significant increases in countermeasures (infusion restarts, icu readmission, and aki due to blood pressure lowering). extrapolating from finance data, and our baseline infusion duration and icu los data, iv antihypertensive infusions cost ~$ /hour. our improvement suggested $ in estimated cost savings in months. icu accommodation cost was approximated at $ /hour, for an estimated $ additional cost savings. a quality improvement based intervention targeting management of hypertension resulted in reduced duration of anti-hypertensive infusions, icu los, and cost. the intervention was feasible and ongoing data collection is warranted to assess sustainability. mortality and long-term-disabilities secondary to stroke are high. educating high-risk population with early stroke symptoms has been outstanding. however, education of post-stroke consequences (requiring resuscitation codes and goals-of-care awareness) is lagging. this study evaluates the understanding of such concepts by the admitted stroke patients (high risk population) and visitors (general population). were asked to answer a preliminary question about their original code status then read a self-explanatory sheet followed by revealing their revised code and goals-of-care choices. we used within-group logistic-regression-analyses to determine changes of codes among original coders and types of novel codes among post-survey coders. this included proposition of new short-term resuscitation (str-strp [partial]) codes. we used between-group chi-square-analyses to determine differences in education between groups. the odds of changes in no-coders were . , . in patients and visitors, (p-value= . , < . ) respectively. the odds of changes in dnr-coders= . , . , partial-coders= . , . , full-coders= . , . times those of the no-coders respectively (p-value< . ). the odds of novel-dnr-coders= . , and . , , . , . , . times those of novel-no-coders respectively (p-value< . ). str-coders originated from other-codes> no-coders. between-group analyses showed %, % of patients versus visitors changed their code status respectively (p-value= . ). goals-ofcare choices indicated tolerance towards temporary measures (tracheostomy and feeding-tube placement) and hemiplegic disabilities without poor mentation among the majority (~ - %) as a target for continuing care. pre-event (stroke) documentation of code status was approved among the majority of participants ( %). there is a misunderstanding of the resuscitation codes among both admitted stroke patients and general population. however, the difference between both indicates reception of some education among the stroke patients. str-strp are a good alternatives for many people. pre-event documentation -stroke outcome awareness are needed. early integration of palliative care improves communication, decision-making and social support in patients with acute stroke in the neurocritical care unit. the primary objective of this study was to analyze how early palliative involvement impacts communication between the healthcare team and patients/families. in this ongoing prospective study, patients with moderate to severe ischemic and hemorrhagic strokes were randomized into control and intervention arms. the control arm received routine icu care and the intervention arm received an early palliative care consultation. study assessments with the patient or surrogate decision maker were obtained at day - , and day - of icu care. comparisons were made for total scores on the questionnaire on communication (qoc), decisional conflict scale (dcs), and hospital anxiety and depression scale (hads). we performed an interim analysis utilizing the student's t-test and chi -square test on spss , with results below as mean + standard deviation. of patients enrolled ( intervention and control), % and % were female (p = . ). the average age was + and + years (p = . ). the majority ( % and %) were ischemic strokes (p = . ). admission nihss was + and + (p = . ). there was no difference in total qoc ( + , + , p = . ), hads ( + , + , p = . ), or dcs ( + , + , p = . ) scores. when comparing responses to individual questions, a trend toward improvement in qoc responses was observed "using words you can understand" (p = . ) and "answering all questions about illness" (p = . ). early integration of palliative care may improve communication between healthcare providers and patients/families, specifically with regards to using appropriate language that is understandable. routine daily chest radiographs (cxr) in mechanically ventilated patients (mvp) are often performed in the icu for "monitoring" purposes, despite lack of specific indications. routine daily tests are of questionable value and may increase costs without clinical benefit. the society for critical care medicine and choosing wisely campaign promote indication-based test ordering. studies involving medical-surgical icus demonstrate that indication-based versus routine daily cxrs in mvps results in cost-savings without jeopardizing outcomes. we implemented a quality improvement initiative targeting reduction of routine daily cxrs in mvps in the nsicu. we convened an interprofessional team of attending physicians, fellows, medical students and nurse practitioners. we conducted educational campaigns promoting evidence-based cxr utilization practices. standardized discussion of indication for cxr was incorporated into rounds. iterative process improvements were adopted beginning june . cxr utilization rates in mvps were measured the first weeks of , and and compared pre/post-intervention. hospital length of stay (hlos) was evaluated to monitor for complications resulting in prolonged hospitalization. implementation of indication-based ordering strategies decreased cxr utilization in mvps in the nsicu without increasing hlos. value-based care quality improvement initiatives can reduce costs without compromising clinical outcomes. patients transferred from nsicu to lower acuity units are vulnerable to readmissions and hospital acquired complications. standardized handoffs may help reduce this risk within academic institutions where physician trainees possess varying levels of clinical experience. we sought to implement a standardized handoff (i-pass) within inpatient neurology, focusing on high risk patient populations. residents and attendings were surveyed about inpatient handoff practices to inform implementation of i-pass. an electronic survey was administered in to residents and inpatient attendings in neurology at university of north carolina (unc). handoff practices among inpatient services (wards, consults, nsicu, and epilepsy) were evaluated. surveys assessed perceived quality of handoffs, as well as problems with handoffs leading to adverse events. surveys were sent to physicians ( residents, inpatient attendings); responses ( residents, inpatient attendings) were obtained (response rate, . %). -six percent of residents and % of attendings reported that problematic handoffs had been the primary or contributing factor to one or more adverse events. overall quality of handoffs involving nsicu patients transferred to lower acuity units was reported as a concern, with % of residents indicating the quality of these handoffs to be poor. in ranking inpatient services for prioritization of handoff interventions, % of residents identified nsicu handoffs as either their first or second highest priority. we also found residents exhibited a self-performance bias, with % reporting that they provided all pertinent information during handoffs most of the time, and only % reporting that they received all pertinent information during handoffs most of the time. inpatient handoffs are perceived as problematic by residents and attendings, with handoffs involving transfer of nsicu patients identified as high priority for targeted intervention. unc neurology has since implemented i-pass protocols to improve the safety of handoffs involving nsicu patients. targeted temperature management (ttm) to - c is the standard of care for post-cardiac arrest patients. recent literature has demonstrated a new trend of worsening morbidity and mortality postarrest due to under-utilization of ttm. management of post-arrest patients is a multidisciplinary health care effort, and knowledge of ttm rationale and protocol varies. normothermia ( - . c) also could have neuroprotective benefit in other clinical scenarios and is another indication for ttm. we hypothesized that a focused educational intervention would improve ttm protocol compliance. a multidisciplinary team developed a standard educational presentation and a question exam given as a pre-and post-test to residents, fellows, and critical care nurses. baseline data on ttm use was established followed by month prospective data collection post-intervention. data was extracted from arctic sun® machines on all ttm cases (post cardiac arrest and normothermia). the primary outcome was compliance with the ttm protocol measured by correct temperature target goals and appropriate duration, assessed by chi-square analysis. the secondary outcome measure was individual score improvement, evaluated by -variable students t test. there was a total of ttm cases pre-intervention, and ttm cases post intervention. there was a trend toward increased ttm protocol compliance ( % to %), however this was not statistically from pre-test (n= ) to post-test (n= ) after the education presentation (p< . , ci . to . ) among all health care participants. the resident, fellow, and nursing scores increased from % to %, % to %, and % to %, respectively. educational interventions for physicians and nurses caring for post-cardiac arrest and neurocritical care patients improved knowledge gaps and helped improve compliance with ttm protocol. additional education and process improvement activities are warranted to further improve protocol compliance, which may improve patient outcome. identifying the appropriate level of care needed for a patient presenting with acute intracerebral hemorrhage (ich) is often imprecise. the utility of prior work in triaging patients is limited by exclusion of non-primary ich patients, which is often difficult to determine prior to admission. this study aims to identify which admission factors are associated with icu level of care on presentation. this is a single-center retrospective review of patients admitted to our institution with ich in , regardless of etiology. all patients were admitted to the neurocritical care unit (nccu). icu level of care was defined as the need for mechanical ventilation, administration of vasoactive or insulin infusions, continuous renal replacement therapy, ventriculostomy, treatment of cerebral edema, temperature management, management of status epilepticus, or neurosurgical intervention. logistic regression was used to identify characteristics associated with icu level of care. patients (median age , % female, median admission gcs , median ich volume ml, % with ivh, % lobar, % infratentorial) were admitted with ich. ( . %) required intensive care. the most common interventions required were mechanical ventilation ( patients, . %), antihypertensi with need for intensive care included age ( vs. ), admission gcs ( vs. ), deep location of ich ( . % vs. . %), ich volume ( ml vs. ml), and presence of ivh ( . % vs. . %). on multivariate analysis, age (p = . ), admission gcs (p < . ), and deep location (p = . ) were independently associated with the need for intensive care. among all patients presenting with ich, age, admission gcs, and location of hemorrhage may help identify ich patients who need icu level of care. the impact of emergency neurological life support (enls) course on provider knowledge and selfreported comfort in management of neurocritically ill patients in a low-middle income country such as cambodia is unknown and explored in this study. in-person enls courses with english to khmer translated slides were conducted in hospitals in phnom penh, cambodia in may, . wilcoxon signed rank test and matched paired t-test were used to examine pre and post-course scores on translated knowledge-based multiple choice tests. a descriptive analysis was performed to evaluate provider comfort in management of neurocritically ill patients pre and post-course and amongst individual enls modules. overall, / healthcare providers participated; ( . %) physicians and ( . %) nurses. thirtythree ( . %) had acquired base specialty training in cambodia, ( . %) had completed subspecialty training in critical care medicine and ( . %) previously cared for neurocritically ill patients. pre-test sores were % [iqr ]; post-test scores were . % [iqr ]. though not statistically significant, posttest scores were higher for providers who had base specialty training in cambodia ( . % vs. . %, p = . ), subspecialty training in critical care medicine ( . % vs. . %, p = . ) and previous experience caring for neurocritically ill patients ( . % vs. %, p = . ). most ( %, n = ) reported that enls training had prepared them for management of neurocritically ill patients. enls courses may enhance the knowledge and comfort of healthcare providers in managing neurocritically ill patients in low-middle income countries, however this may depend on prior experience and minimizing language barriers. the impact of enls courses on outcomes in neurocritically ill patients in low-middle income countries warrants further study. neurocritical care has become increasingly subspecialized.yet, due to limited availability of dedicated neurocritical care units (nccus), often patients may need to be admitted to icus other than nccus. this survey based study was conducted to explore self-reported knowledge in recognizing and managing some common neurological emergencies such as stroke, status epilepticus, raised intracranial pressure etc among critical care nurses at a comprehensive stroke center. in january , we engaged nurses from icu units in this qi project-which included medical, surgical, neurocritical care, cardiac and cardiothoracic units as well as post-anesthesia care unit (pacu) and interventional radiology units. using institutional redcap anonymized surveys were sent to the nurses.information on demographic and critical care work experience was recorded. all participants answered questions with a likert type scale on their knowledge of several common neurological emergencies. nurses ( females, males) participated in the survey. ( %) had been working in an icu for years or longer. their self-reported level of knowledge in managing neurological emergencies revealed that more than half the participants did not feel comfortable managing patients with evds, ich, sah, raised intracranial pressure, tbi and traumatic spine injury patients. more than % of nurses were not satisfied with their current level of training to deal with neuroemergency and supported the need for dedicated training/ study time. icu nurses report gaps in fundamental knowledge in recognizing and managing common neuroemergencies. this highlights the need for providing ongoing training and education about neuroemergencies to critical care nurses to help maintain competencies. simulation training has been increasingly adopted in critical care specialties to promote active learning and create a reproducible platform for feedback. the role of advanced simulation as a core component of training in neurocritical care remains unclear, which may be due to uncertainty about the degree of fidelity needed. our objective was to determine if trainee knowledge and/or confidence differs when using standardized patients as compared to a multi-media simulation platform in a neurocritical care concepts training course. methods junior neurology residents engaged in simulated neurologic emergencies: a right mca stroke case, status epilepticus case, and a pontine hemorrhage/coma case. the mca stroke and status epilepticus cases were portrayed by trained standardized patients for half of the residents (group sp), while the other half interacted with the manikin supplemented with video clips of pertinent neurologic exam findings (group mv). both groups interacted with the manikin for the pontine hemorrhage/coma case. before and after the course, residents completed a -question multiple-choice test on management of neurologic emergencies and a survey about their confidence in managing neurologic emergencies. a detailed task checklist was used to assess decision making during the simulations. both resident groups had statistically significant higher knowledge and confidence scores after their training sessions (knowledge: pre: % vs post: %, p< . ; confidence: average pre: . to post: . , p< . ). however, there was no statistically significant difference between the two groups in either knowledge or confidence. the task checklist demonstrated significant variations in treatment practices and provided individualized areas for teaching. this pilot study suggests that trainees' knowledge and confidence in the management of neurocritical care concepts increases following simulated encounters, regardless of whether an actor-patient or multi-media simulation platforms is used. use of a task checklist uncovered important variations in protocol adherence among novice physicians. the accurate evaluation and determination of brain death has broad consequences on life-saving organ donation, closure for families, and length-of-hospital-stay. we have observed a concerning variability of brain death testing knowledge and comfort amongst neurology attendings and trainees at our institution. we aimed to create and apply a combined didactic and simulation training program to increase the knowledge and comfort in brain death evaluation, using our approved institutional brain death policy as reference. we hypothesized that participants who attended the training would show a measurable increase in their knowledge and comfort in the clinical evaluation of brain death. an experienced neurointensivist (> years of clinical practice) presented a -hour didactic session on brain death criteria, evaluation, and pitfalls to neurology residents and attendings. a high-fidelity simulation was implemented to allow practicing the brain death examination. knowledge and comfort levels were measured before and after learners had attended both sessions using electronic -exact-tests were applied to examine changes in knowledge and comfort in brain death testing pre-and post-exposure to the educational sessions. participants ( residents, attendings) completed pre-exposure, and ( residents, attendings) have completed post-exposure questionnaires thus far. knowledge significantly improved from pre-to post-exposure ( % correct, range - % improved to % correct, range - %; p= . ). comfort levels in performing the brain death examination pre-exposure also increased from pre-to postexposure (pre: "very comfortable- %","somewhat comfortable- %","neutral- %","somewhat or very uncomfortable- %" to post: "very comfortable- %", "somewhat comfortable- %","very uncomfortable- %" [p= . ]). exposure to a single combined didactic and simulation session improved the knowledge and comfort levels immediately post--exposure questionnaire response rates, as well as measurements of knowledge retention over a -and -month period and accurate application in practice. the safety and benefit of early mobilization in general intensive care units (icu) has been found to improve outcome and decrease length of stay. however, there is a lack of literature on early mobilization in the neuro icu (nicu) specifically, due to the complexity of the patients in the nicu and their disease processes. traditionally, patients were kept on bedrest after subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, and neurotrama, due to neurologic limitations such as fluctuation in mental status, requirement for sedation and paresis. additional challenges associated with mobility in this population include the potential for positional changes to impact intracranial pressure physician comfort level and concern for adverse neurological outcomes such as vasospasm or increased bleeding also decrease mobilization. while it is imperative to be cautious with nicu patients, prolonged bedrest and restricted mobility come with its own set of complications including muscle atrophy, decreased activity tolerance, delirium, pressure sores, nosocomial infections and deep vein thromboses. we sought to develop an early mobilization guideline that would help multidisciplinary staff identify which patients in the nicu should be mobilized early. a nicu physical therapist and the director of the nicu identified criteria for patients who were appropriate/inappropriate for early mobilization. all patients in the nicu should be mobilized early with the exception of the following exclusion criteria: unstable respiratory status, status epilepticus, contraindication to holding sedation, rass - , changing/worsening neuro exam, icp > mm hg, mean arterial pressure < or > mm hg, oxygen saturation < %, acute myocardial infarction, > vasopressors, clinical vasospasm, perfusional state, guidelines on early mobilization in the nicu can optimize patient mobility while minimizing complications associated with mobilization. introduction delivery, nurses must develop leadership skills and serve as full, collaborative partners with physicians and health professionals ( ). registered nurse (rn) inclusion into rounds has been shown to: improve interdisciplinary collaboration, incorporate learning in the workplace, increase leadership skills and improve team members' perception of unit flow and culture. attending physicians, rns, neurocritical care fellows, nurse practitioners, pharmacists and respiratory therapists were surveyed via surveymonkey to examine opinions regarding current rounding processes and potential opportunities in the neurocritical care unit (nccu). responses were aggregated to create scores for each topic, with the priority areas being the lowest relative scores based on a -point likert scale. survey responses were collected from nccu staff members ( % response rate). based on survey results, priority areas to enhance rounding satisfaction included: increasing collaborative decision making, creating entire team efficiency, completing rounds in a timely manner, increasing engagement and minimizing extraneous conversations and activities. other targeted areas for improvement included reserving time for prolonged family meetings for post-rounds, as well as focusing educational time and consistently utilizing the rounding checklist. based on areas of opportunity, a multidisciplinary committee was developed. one item created to enhance processes was the development and implementation of an rn facilitated presentation tool. to support this, a standardized presentation script and handoff tool were created and executed. six-month follow up survey results are pending at the time of submission. strategies to improve communication in multidisciplinary rounds are key to decreasing errors and improving care delivery. it is likely that a systematic data presentation by bedside rns will improve: staff perceptions of rounds, collaboration among all multidisciplinary staff members and rounding efficiency. the department of neurosurgery has a readmission rate goal of less than . for the fiscal year and less than . for the fiscal year of . over the past four fiscal quarters there has been an increase in the department's readmission rate, always exceeding the institutional goal. all readmissions in the institution's dashboard for q and q for and q and q of were reviewed by way of chart review. these were divided into spine vs cranial, planned vs unplanned readmission, reason for readmission and consistency vs inconsistency with the institution's dashboard. in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . the most common reason for unplanned n reason for planned readmissions were shunt placements after lumbar drain trials. the dashboard was correct in predicting planned vs unplanned readmissions . % of the time. the coding on the backend of the institution's dashboard is missing many staged and planned readmissions and is only accurate in coding planned vs unplanned readmissions half of the time. this is resulting in falsely elevated readmission rates. despite the initial uptrend in readmissions, the actual readmission rates of the department are down trending and always below the institutional goal. this likely translates to other departments within the hospital. there needs to be a more efficient way to improve the coding and accuracy of the institution dashboards. the critically-ill neurological patients managed by specialized neurocritical care team is associated with improved outcome. in korea, limited data are available on improved outcomes after initiation of neurointensivist co-management in neurocritical care units (ncu). we evaluated the impact of a newly appointed neurointensivist on the mortality of patients admitted to the ncu. the study was conducted in intensive care unit (icu) beds of a large academic tertiary care hospital. neurointensivist co-management was initiated in march . the retrospective observational study compared the outcomes of patients before and after neurointensivist co-management. a total of patients were included, prior to and after the initiation of neurointensivist comanagement. patients admitted after neurointensivist co-management were older and had higher apache ii scores. icu mortality was significantly decreased in patients managed by neurointensivist ( . % vs . %, p= . ). the length of icu stay and duration of ventilator days were shorted in patients without co-management. neurocritically ill patients managed by specialized neurointensivist showed better clinical outcomes despite increased severity. social media has changed the way individuals communicate with each other and has altered the way society obtains information. in the past ten years, multiple articles have been published highlighting the ability to utilize social media for education of medical, nursing and pharmacy students. to our knowledge, cross discipline education utilizing these platforms has yet to be evaluated. with over . to implement a pharmacist led, social media based nursing education program and evaluate the perceived value of this education. a curriculum consisting of basic pharmacy related issues was developed and topics were posted to the ok users weekly. a pre-and post-education survey was sent out evaluating the program's effectiveness. email. of those nurses who received the pre-and post-education survey, a total of % and % completed the survey respectively. of those who completed the survey % received education via -education survey, there were no statistically significant differences in nursing performance on fact based questions after receiving education (p-value > . on all assessment questions). overall, % of the respondents reported a positive learning experience and wanted to continue this method of education delivery. the educational content. this project demonstrates the potential of utilizing social media as a means of cross discipline education; however, the solitary utilization of this platform should be used cautiously as this did not improve performance on assessment questions. consequently, targeted temperature management (ttm), either to maintain normothermia or induce hypothermia, is often advocated as a therapy to improve outcomes in brain injured patients. the physiological pathways that promote fever associated brain injury, and how these pathways might be modulated by ttm, remain unclear. this study examined the effect of fever and hypothermia on cerebrovascular pressure reactivity, a validated proxy of cerebral autoregulation. we included patients treated for brain injury from a single academic center. all patients had intracranial pressure (icp), invasive brain temperature, and arterial blood pressure (abp) recorded patient, mean prx over all periods of fever (> °c), normothermia ( - °c), and hypothermia (< °c) were calculated. differences in mean prx during normothermia, fever, and hypothermia epochs were then analyzed using paired student's t-test. the relationship between prx differences and total time spent normothermic was analyzed using linear regression. spent at a normal brain temperature (p = . , r = . ). in contrast, hypothermia was not associated with impaired cerebral autoregulation (p = . ). this study supports the hypothesis that impaired cerebral autoregulation may be one mechanism through which fever worsens outcome in brain-injured patients. the effect of fever on cerebral autoregulation appears to be more pronounced in patients that spend a longer amount of time in a normothermic state. interestingly, hypothermia was not associated with reduced prx, suggesting that the possible benefits of therapeutic hypothermia do not occur by improving the autoregulatory state. veno-arterial extra corporeal membrane oxygenation (va-ecmo) provides hemodynamic support in patients with refractory cardiogenic shock. these patients have a % incidence risk of cerebrovascular complications according to the extracorporeal life support organization database. reliable neuroassessments and neuroimaging are often limited by heavy sedation and risks of transporting these patients. transcranial doppler (tcd) can be a useful tool for cerebral hemodynamic assessment in these patients. we present four va-ecmo patients where tcd spectral waveforms provided key information on cerebral blood flow despite non-pulsatile flow. interpretable spectral waveforms were obtained in three of four patients. extensive embolization obscured flow patterns in one patient but clear cerebral perfusion with non-pulsatile waveforms was seen in the rest. two of the three remaining patients had high intensity transient signals (hits), suggesting cerebral microembolization. one patient showed pulsatility in cerebral waveforms despite no gross change in cardiac output on echo that helped guide decision to initiate ecmo wean. ecmo settings included flow at - l/min, map - mmhg, and paco between - mmhg. mca mean flow velocities were comparable to the systemic bp, and ranged from - cm/s in three patients and - cm/s in one patient. one patient suffered cerebral edema and two expired from withdrawal of care on sedation after multisystem organ failure without a chance neurological or neuroimaging assessment. the fourth patient retained consciousness and the ability to follow commands, but died from a massive gi bleed. tcd spectral waveforms can be useful bedside tools for patients on va-ecmo to assess for cerebral perfusion patterns. presence of hits reflecting microembolization can guide perfusionists to check for pulsatile flow, their relationship with systemic hemodynamics and va-ecmo settings is needed. cranial ultrasonography has a long history of use in neonates, but inadequate windows have limited its use in adults. a hemicraniectomy provides an obvious window for point-of-care intracranial imaging, providing similar views traditionally seen on ct and mri. we describe a standard approach and settings, presenting sample imaging demonstrating key anatomic landmarks. the hemicraniectomy ultrasonography preset was created and optimized using a phased array transducer with a - mhz frequency range. imaging parameters were tested and saved for d grayscale mode, with an emphasis on tissue harmonic imaging, adaptive image processing, and dynamic range. axial views are obtained from the ipsilateral temporal window, approximating the pterion, adjusting the probe to display a well-aligned view using the lateral ventricles as a landmark. by convention, the probe marker is placed anteriorly. the depth and focus are set to visualize the brain he probe craniocaudally permits visualization of the entire cranial vault. parasagittal and coronal views are obtained by placing the probe at the vertex, off midline, ipsilateral to the hemicraniectomy. several structures are clearly visualized and are available as landmarks for orientation. the ventricular system can be easily identified as hypoechoic spaces similar in appearance to ct or mr imaging. the brainstem and cerebellum, with its associated folia and peduncles are also easily seen. the thalami are identified as strongly hypoechoic paramedian structures. pathologic findings that can be easily seen include hydrocephalus, hemorrhage, and edema. aneurysm clips are hyperechoic with streak artifact, and ventriculostomy catheters can be seen as subtle hypoechoic areas within the cortex. hemicraniectomy pocus can be used to visualize the intracranial vault to facilitate evaluation of structural lesions and pathology at the bedside. the authors advocate adding hemicraniectomy pocus to the neurocritical care imaging arsenal in patients where this view is available. pain assessment is a challenge in critically ill patients with impaired consciousness, either because of sedation or concomitant severe brain injury. automated pupillometry has been used to assess the response to noxious stimulation in such patients. skin conductance, which has been used in the operative setting, has not been tested in this setting yet. the purpose of the study was to compare the pupillary response and skin conductance to pain stimulation in critically ill unconscious patients. prospective ongoing study including adult (> years) patients admitted to the intensive care unit of a university hospital and who were unconscious (glasgow coma scale < with a motor response < ) for several reasons. automated pupillometry (algiscan, idpupillary reflex dilation during tetanic stimulation. the tetanic stimulation ( hz) was applied to the skin area innervated by the ulnar nerve and was stepwise increased from to ma until pupil size had increased by % compared to baseline. the maximum intensity value allowed the determination of a pupillary pain index score ranging from (no nociception) to (high nociception): a pupillary pain peak per second ( concomitantly to tetanic stimulation. twelve patients (median age [ranges= - ] years; male gender / ) were included so far; eight patients had a primary brain injury ( / anoxic injury) and others were sedated because of shock with concomitant respiratory failure. all patients were under continuous intravenous sedation and analgesia; / were on vasopressors and / on continuous neuromuscular blockade. median gcs at the moment of pain assessment was [ - ] and median ppi was [ - ]; patients ( %) had adequate pain control. no changes of skin conductance variables were reported during pain stimulation. skin conductance was unable to detect insufficient nociception in critically ill unconscious patients. the cerebral arterial time constant (tau) reflects the time it takes to fill the cerebral arterial bed with blood during one cardiac cycle, and is derived from arterial blood pressure (abp) and middle cerebral artery flow-s with/without vasospasm (vsp) and delayed cerebral ischemia (dci) after aneurysmal subarachnoid hemorrhage (asah). ( ) ( ) . angiographic vsp and dci were adjudicated by neurointensivists. artifact-free cerebral arterial compliance and resistance. statistical comparisons were made using a two-tailed mann-whitney u-test. of asah patients, ( %) developed vsp and ( % of vsp) developed dci. patients had unilateral and bilateral vsp ( & % of vsp). one patient with unilateral vsp was available for monitoring prior to diagnosis. this patient had increased asymmetry in tau over time prior to diagnosis (slope: . s/day, r¬ : . ). tcd measures in patients were available prior to angiographic diagnosis of bilateral vsp, showing initial marginal asymmetry similar to the unilateral vsp case, then slightly decreasing asymmetry over time (mean slope: - cm/s higher in dci (p< . ). tau was . s greater for dci patients, however this did not reach significance (p= . ). explore the relationship of tau asymmetries with vsp and dci after asah. these may provide further insights into the pathomechanisms of vsp and dci while also having potential as a tool for earlier diagnosis of these important complications. pupillometry is more accurate and has higher inter-rater agreement than subjective pupil size and reactivity estimation. limitations include using a single high-intensity flash to evaluate the direct pupillary response only. we present preliminary data on using virtual reality-based pupillometry (vrp) with graded-intensity flashes and bilateral pupillary recording to monitor patients with large hemispheric infarction (lhi). we utilized a virtual reality headset-based system, i-pas (neurokinetics, pittsburgh, usa) to perform pupillometry. a total of homogeneous illumination flashes ( . to . cd/m², . sec on, . - . sec off) were presented to each eye while infrared cameras recorded pupillary area (mm ) continuously at samples/sec. this permits measurement of latency, magnitude and velocity of direct and consensual pupil constriction and dilation at each light intensity. : we performed pupillometry as described above in patients admitted with lhi from middle cerebral artery strokes. patients required decompressive craniectomy (dc) during the hospital course while the other patients did not require dc. bilateral graded-intensity pupillometry detected subtle changes in pupillary reactivity (peak constriction velocity in mm /s) prior to clinical deterioration, which were very pronounced when compared to normal control performance. singleneuropupillary index (npi) did not detect a change in pupillary reactivity in all but the most severe deterioration. virtual reality-based, graded intensity pupillometry is feasible in the intensive care unit and appears ed to set cutoff values that may aid in clinical decision making. limited access to conventional eeg results in significant delays to important diagnostic information, especially in patients with suspected non-convulsive seizures (ncs). recently, the rapid response eeg technology has proven to be clinically valuable. however, the economic aspect of this new technology has not been studied in detail. we retrospectively reviewed the use of the rapid response eeg device in our small community hospital over months since its launch in december . we performed limited chart review and collected information regarding eeg diagnosis, length of stay, and transfer to mothership hospital. we evaluated the clinical and economic impact of the device by considering the patients' clinical outcome and the estimated cost of hospitalization (~$ - /day) and transfer ($ - , ). metrics are not precise and are only estimates. the device was used in a total of patients. the treating physician or the nurse applied the device with and one with post-anoxic burst suppression. in patients with status epilepticus, seizures were aborted successfully, and median length of stay was . (national average of days). all patients were treated locally without requiring transfer to the main university hospital. considering the cost of rapid response eeg infrastructure and disposables (<$ , ) compared to conventional eeg systems (~$ , - , ) and eeg technologists (estimated to cost ~$ , - , ), and estimated range of $ , to $ , in annual savings because of shorter los and lesser transfers, this new technology seems economically advantageous. rapid response eeg system enabled significantly faster and easier access to eeg and helped detect a relatively high number of patients with gross eeg abnormalities. adopting the rapid response eeg improved emergent ncs detection and treatment in a cost-effective manner. patients requiring neurocritical care frequently have neurologic fluctuations of uncertain significance. we hypothesized that severe and prolonged events of neurologic deterioration (nd) have the greatest impact on discharge neurologic status and serve as intermediate indicators of poor outcome. we extracted nurse-documented gcs scores from electronic health record (ehr) data of consecutive patients admitted to a neurosciences intensive care unit (icu) or undergoing intracranial pressure monitoring (april - ) best initial -hour gcs (bestgcs- h), ) maximum magnitude of gcs decline (maxgcsdecline), ) duration of the episode of maximum gcs decline (dur-max), and ) the maximum duration of any gcs decline >= points (max pt-dur). we fit a -fold cross-validated logistic regression model predicting the final gcs - (vs. - ) and tested it in a % hold-out sample. we then evaluated the rates of poor outcome for combinations of these parameters. , consecutive admissions ( , unique patients) met inclusion criteria ( % with severe bestgcs- h ( - ), % with moderate bestgcs- h ( - ), and % with mild bestgcs- h ( - )). bestgcs- h, maxgcsdecline, dur-max, and max pt-dur, respectively, were independently associated with poor discharge gcs (or per standard deviation were . [ %ci . - . ], . [ . - . ], . [ . - . ], and . [ . -with a -point maxgcsdecline, the rate of poor outcome was % for patients with a severe bestgcs- h and >= -hour max-dur; % for patients with a severe bestgcs- h and < -hour max-dur; . % for patients with a mild bestgcs- h and >= -hour max-dur; and . % for patients with a mild bestgcs- h and < -hour max-dur. both the magnitude and duration of nd events are independently associated with neurological status at discharge. these empiric, informatics-derived thresholds may serve as useful intermediate outcomes facilitating the testing of biological associations and therapeutic interventions aimed at promoting neurologic recovery. unit. deteriorati worsening. we hypothesized that nonearlier than clinical deterioration. we prospectively collected data from patients with acute brain injury who are at a high risk of perfusion disturbance (sah, mmd, and severe anterior circulation ischemic stroke) between may and may . non--ry seconds neurological worsening were assessed using perfusion imaging and were categorized as hypoperfusion group and hyperperfusion group. baseline compared. non-monitoring should be highlighted in patients with high risk of deterioration. intracranial cerebral pressure (icp) monitoring is an integral part of acute brain injury management. while invasive icp monitor is the gold standard, there are several medical conditions that preclude its placement. non-invasive icp assessment tests (e.g. optic nerve sheath diameter, optic nerve disk elevation, pulsatility index, pupillary reactivity etc) have moderate accuracy when used individually. the aim of the present study is to validate a multimodal approach for intracranial hypertension detection. in this prospective study, patients with acute brain injury who had an evd placement for both icp measurement and treatment were included since march . we measured bilateral optic nerve sheath diameter (onsd) by ultrasound, bilateral optic nerve disk elevation (onde) by ultrasound, bilateral middle cerebral artery (mca) pulsatility index (pi) by using transcranial doppler and assessed pupillary reactivity with or without pupillometer as part of multimodal assessment for measuring intracranial pressure. we assessed the correlation and agreement of these values with icp measured by the evd. we included measurements in patients with acute brain injury. the presence of two or more values of mean onsd greater than mm, unilateral or bilateral presence of onde and mean mca pi greater than . has % sensitivity ( % ci . - . ) and . % specificity ( %ci . - . ) for predicting icp greater than mmhg. non-invasive multimodal assessment can be easily done by bedside, requires minimal training and seems to correlate well with increased icp. raised icp following acute brain injury is associated with poor outcome. monitoring with early detection is important in reducing sustained icp crisis. previous studies demonstrated rheoencephalography (reg) reflects cerebrovascular reactivity and may substitute invasive monitoring techniques. we hypothesized using a correlation coefficient between slow spontaneous changes in reg and systolic arterial pressure to calculate regx. reg measurements were obtained from ten patients with acute brain injury. analog waveforms of reg and arm bioimpedance pulse waves were recorded with a bioimpedance amplifier. we used the icm+ program (prx) calcu bioimpedance pulse waves (regx) instead of icp and invasive arterial pressure. visualized by previously established waveform changes on reg. a change in mean regx greater than the previous recording's mean regx value was clinically significant as opposed to absolute mean regx . one patient with a right ica infarction clinically deteriorated from moving all extremities to extensor posturing on the right and flaccid paralysis on the left with significant delta mean regx. another with bilateral aca distribution ischemic infarctions worsened from flexor to extensor posturing with significant delta mean regx. lastly, a patient with ventriculoperitoneal shunt malfunction repair improved from gcs to with multiple significant delta mean regx values between recordings. our series demonstrated clinical significance of patient specific delta mean regx suggesting importance of presenting mean regx for detection of changes in intracranial compliance. like presenting blood pressure and relative changes in blood pressure rather than absolute changes in blood pressure or specific values, regx was shown significant in a similar manner. regx is a realistic means of future noninvasive neuromonitoring. dialysis is characterized by markedly increased rates of stroke and cerebral micro-vascular disease, though the mechanisms by which dialysis modalities impact cerebral hemodynamics have not been well studied. this case series compares intra-dialytic cerebral hemodynamics measured by transcranial doppler (tcd) in patients receiving intermittent hemodialysis (ihd) versus peritoneal dialysis (pd). ten outpatient end-stage renal disease (esrd) without stroke were identified. tcd mean flow velocity averaged. six patients administered hemodialysis were followed over minutes, with mean arterial d every minutes. there was no statistically significant difference between dialyses group and no significant change over time. to quantify volatility in patient measurements over time, we calculated the coefficient of variation -sum test. to test if there was a difference in volatility between dialyses groups, we used a wilcoxon rankgroup (p < . ). in this small case series, though cerebral hemodynamics are not significantly different among stable measures are more stable over time for patients on the peritoneal dialyses group. end-stage renal disease (esrd) patients with acute neurologic injury are at risk of altered cerebral hemodynamics during dialysis. here, we present transcranial doppler (tcd) images revealing marked intra-dialytic increased distal vascular resistance and compromised flow velocity in an esrd patient with acute traumatic brain injury. the patient underwent continuous tcd monitoring during hemodialysis to monitor intra-dialytic cerebral hemodynamics. a year-old man with esrd on chronic presented with headaches after a fall. ct head revealed mm right convexity acute subdural hematoma with - mm leftward midline shift and right parietal parenchymal contusion. on arrival to the neuro-icu, the patient was afebrile, hemodynamically stable, and fully oriented with no focal deficits. repeat ct head six hours from initial was stable. the patient was started on his outpatient prescription of dialysis (dialysate na meq/l, blood flow rate ml/min), run without heparin. within first hours of hemodialysis patient developed progressive rightsided headache, which evolved to vomiting, decreased in level of consciousness, and left-sided weakness. he intermittently opened eyes to stimulation but required persistent painful stimulation to answer orientation questions. he had no changes in mean arterial pressure during hemodialysis. his serum bun had decreased from to mg/dl, and his serum sodium remained unchanged. emergent ct head was stable from prior. intra-dialytic tcd waveforms revealed progressively increased distal resistance to flow, measured by pulsatility index (pi) at his bilateral middle cerebral arteries (mca), and compromised mca velocities. this change was dramatic on the right, the same side as his subdural hemorrhage and cerebral contusion. esrd patients with critical neurologic injury are at risk for altered cerebral hemodynamics during dialysis. tcd ultrasonography may be a practical bedside tool to screen for patients at particular risk, and guide medical decision-making regarding dialysis prescription for esrd patients in the neuro-icu. point of care ultrasound (pocus) differs from diagnostic ultrasound in being often performed by clinicians and focused to acquire only relevant images to answer a specific clinical question. most ultrasound modalities have differentiated clinical indications where pocus is appropriate: the use of echocardiography to rule out tamponade in shock is considered pocus while the assessment of diastolic dysfunction in heart failure deserves a diagnostic exam. neuroultrasound has been used in various clinical indications like vasospasm, intracranial stenosis, collateralization, and emboli monitoring. these studies are mostly performed by sonographers as diagnostic studies. with emerging interest in assessing pocus indications, we performed a systematic literature review to identify all clinical indications of neuroultrasound and used a delphi based review by three experts to differentiate clinical indications where neuroultrasound could have point-of-care uses. two authors (lmh, gb) performed a systematic review to identify all reported modalities and clinical indications of neuroultrasound (tcd, duplex, b-mode, carotid, ocular and temporal) in medline, embase, cochrane, and scopus databases. three experts (jgd, ct, as) were surveyed using the delphi method to review each clinical indication and modality on whether it was focused on diagnosis or management and whether the clinical indication was a valid pocus. differences in opinion were settled with a final face-to-face discussion to reach a consensus. the systematic review determined total clinical indications of point of care use of neuroultrasound individualized by disease and modality. in indications it was considered a diagnostic adjunct, in instances it was considered an aide in management, and in instances it was determined to aid in both diagnosis and management decisions. there are many point of care indications of neuroultrasound in neurocritical care. this consensus opinion can guide clinicians to clinical indications where point of care use can aide in bedside diagnosis and management. in a systematic review, we reported current literatures on neuromonitoring methods in left ventricular assist device(lvad) population. we searched five databases (pubmed, embase, cochrane library, web of science, scopus, clinicaltrials.gov) related to lvad and neurological monitoring methods from inception through january . of unique citations, studies ( participants) met the inclusion criteria. the median age was . (interquartile range . - . , . % male). study designs were retrospective observational studies (n= ) and prospective observational studies (n= ). neuromonitoring methods studies included transcranial dopplers(tcd) for emboli monitoring(n= ) or cerebral autoregulation monitoring (n= ), traditional neuroimaging (ct/mri) (n= ), cerebral oximetry(n= ), carotid ultrasound (n= ) and plasma vad, articles studied pulsatile- current evidence on neuromonitoring in lvad is limited and there is no consensus on the indication and effectiveness on use of any neuromonitoring methods. the publications have significant heterogeneity adequate power are warranted to develop an optimal neurological monitoring protocol and prevention strategy. midbrain compression secondary to cerebral edema or hemorrhage results in high mortality and morbidity. quantitative pupillometry holds promise as a bedside indicator of worsening anatomic tissue shifts. because pupil reactivity relies on an intact neural network through the diencephalon and brainstem, compression can lead to changes in pupil size and reactivity. we studied markers of compression and pupillometry within hours of head ct in patients with anterior ischemic stroke (ais) or supratentorial intraparenchymal hemorrhage (iph) causing mass effect. we reviewed scans from patients with unilateral injury from ais (> / of mca territory) or iph (> ml). we assessed midline (mls) and pineal gland shift (pgs), as well as novel measurements of midbrain compression including interpeduncular shift (ips) and the ipsilateral and contralateral cerebral peduncle hemi-distances to the interpeduncular cistern (icphd, ccphd). multilevel modeling was used to analyze radiographic measurements with quantitative pupil metrics including pupil reactivity (dnpi) and size (dsize) differences between eyes. pupil reactivity and size differences were significantly associated with radiographic markers of midbrain noninvasive indicators of brainstem compression. evaluation of optic nerve sheath diameter (onsd) has been widely examined as both a correlate of intracranial pressure (icp), and a potential predictor of outcome after neurological injury. recent studies have evaluated sonographic measurement of onsd, yet clinical limitations to this approach persist. evaluation of onsd measurements via routine brain computed tomography (ct) imaging has been less studied, but offers potential for detection of increased icp in the absence of invasive monitoring. previous studies have employed a cross-sectional approach to onsd measurements via ct scan, primarily among patients with traumatic brain injury (tbi). however, no studies have evaluated serial correlations between ct onsd measurements and icp to evaluate strength of correlations during hospitalization, and across diagnosis types. the purpose of this study was to investigate correlations between onsd via serial ct imaging and icp among adult patients with neurological injury. retrospective cohort study of all adult patients admitted with acute neurological injury requiring icp monitoring and critical care admission. n= . diagnosis type included tbi ( %), aneurysmal subarachnoid hemorrhage ( %), intracranial hemorrhage ( %), cranial mass ( %), and other ( %). there was a strong, positive correlation between right/left onsd across all time points (r= . - , p< . ), suggesting a consistent bilateral response. correlations were strongest between initial inpatient ct scan onsd readings and icp (r= . , p< . ), but decreased over time. patients with increased icp across all diagnosis types experienced higher onsd values upon presentation to the emergency department (ed) and on serial ct scans throughout hospitalization (range . mm- . mm, p< . ). urements as a potential indicator of increased icp in the absence of invasive monitoring. serial ct brain imaging is often performed to evaluate for intracranial changes during hospitalization, and measurement of onsd during this imaging can contribute to decisions regarding more invasive monitoring. monitoring of burst-suppression-pattern (bsp) in electroencephalography (eeg) is relevant to control barbiturate-induced coma. currently, the assessment of bsp is based on continuous observation of the eeg with manual counting of bursts per minute (bpm) by experts, which is prone to inter-rater variability. we evaluated the reliability of a new algorithm for automatic bsp-detection compared to manual assessment in two thiopental-induced burst-suppressed patients. a bipolar -channel eeg-montage was recorded. the montage was bandpass filtered into typical eeg rhythms and segmented into secs -moonen metric, a distance matrix between all epochs in the first hour of data from patient us to cluster this matrix into clusters: burst, suppression and artifact. we labelled the rest of the (test) data from patient and patient by training support vector machine classifier from the labels produced by clustering. the eeg was scored by a neurologist to get ground truth bpm ranges (min, max for intervals of minutes to hour) for both patients. the algorithm provided estimated ranges of bpm for these intervals. the pilot data shows a high correlation of automatic burst counts compared to the manual counting. we found a significant pearson correlation (patient : . , p< . , patient : . , p< . ) and linear regression coefficient (patient : . , p< . , patient : . , p< . ) between estimated and ground truth bpm ranges. the automatic detection of the bursts provides an objective and fast assessment of bsp. the algorithm showed a slightly lower sensitivity due to the missing detection of very short or low bursts. we are ation. ventilated neurocritically ill patients is unknown and explored in this study. a retrospective cohort study was performed on patients admitted to the neurocritical care service between / / and / / , hospital-wide o shut down for maintenance and a switch to olerated with lowest being % owest spo of > % and spo < % amongst the patients in the pre and post-o shutdown groups. -tolerated. with the risk of hyperoxia and its potential negative effects on neuronal injury, a subset of neurocritically whole body hypothermia has been used as a treatment for patients with severe traumatic brain injury (tbi) since many years. invasive brain temperature monitoring is the most commonly practiced for target temperature management in these patients; however, complications are common due to the invasive nature of the procedure. the objective of the current investigation was to evaluate the association between brain temperatures obtained using a non-invasive sensor (accucor) and an intracranial pressure/temperature (icp) catheter during selective brain cooling in patients with tbi. aluated during a selective brain cooling over hours using both a parenchymal icp catheter (raumedic -pt) and the accucor sensor, with a catheter positioned in the nasopharynx. mean temperature values for each participant were obtained along the cooling intervention. outlier values derived from the accucor sensor were detected and removed prior to comparison. the variation in brain temperatures was calculated by mean temperature differences obtained using both measuring devices for each participant. mean brain temperature values were very similar between devices: . °c ( . °c- . °c) for the icp catheter and . °c ( . °c- . °c) for the accucor sensor (p-value: . , % ci: - . to . ). the median temperature difference between the devices was . ºc (minimum: - . °c, maximum: . °c, p-value: . ). our results suggest that there were no differences between brain temperature measurements conducted using the icp catheter and the non-invasive accucor sensor. this conclusion highlights the precision of non-invasive temperature monitoring, a safe alternative to the current invasive practice. monitoring procedures. sepsis-associated encephalopathy (sae) is a multifactorial syndrome, characterized as diffuse brain dysfunction that occurs secondary to infection in the body without overt central nervous system infection. the prognosis for sae is associated with the degree of cerebral damage. we investigated the relationship between the wavelet coherence of cerebral oxyhemoglobin (oxyhb) among different channels and outcomes in patients with sae. consecutive patients with sae were included. moreover, we included normal controls (n= ) for comparison. the cerebral oxyhb data were collected using functional near-infrared spectroscopy (nirsit, obelab inc.). the coherence between sections of prefrontal oxyhb oscillations in five frequency intervals (i, . - hz; ii, . - . hz; iii, . - . hz; iv, . - . hz; and v, . - . hz) were analyzed using wavelet coherence. in addition, we analyzed the coherence of electroencephalography (eeg) signal in three frequency intervals (delta, - hz; theta, - hz; and alpha, - hz). we evaluated the outcomes using glasgow coma scale (gcs) cores at discharge. the patients were categorized into three groups of normal control, good outcome (gcs - ), and poor outcome among the included sae patients (mean age, . years; and male, . %), patients ( . %) had a good outcome. in the poor outcome group, phase coherence was significantly lower compared to good outcome and the normal groups, especially for the myogenic frequency interval iii ( . ± . vs. . ± . vs. . ± . , p < . , respectively). however, the phase coherence of eeg signal was similar in two groups. our results demonstrated that the lower phase coherence of oxyhb in the myogenic signal, which originated from the vascular smooth muscle cells in the brain, was related to the poor outcome in sae patients. this suggests that evaluating cerebral dysfunction using wavelet coherence of oxyhb could be a useful outcome predictor following sae. external ventricular drain (evd) placement is a common procedure in the neurointensive care unit and intracranial hemorrhage (ich) is a recognized complication. in this study we sought to determine the factors associated with ich development after evd placement. retrospective study performed at a tertiary hospital. we identified all patients in whom an evd was placed over a month period. electronic chart review was done to obtain basic demographics, past medical history, use of antiplatelets/anticoagulants, type of catheter placed and presence of intracranial hypertension (ih). computed tomographies were reviewed to identify evd-associated ich. ichs were classified into symptomatic (gcs decline > points, intubation, outcome of death, or new focal continuous variables were analyzed with a proportion of the means test. the sample was comprised of subjects, had evd-associated ich. the median age was years. there was no significant difference in race or gender between patients with ich and those without ich. age, catheter type, history or inpatient use of anti-thrombotics, recent surgery, tpa use, heparin use, history of hypertension, hospital outcome, prior stroke, symptomatic hemorrhages, and icp spikes were analyzed, but only age ( . hemorrhage and . non-hemorrhage, p = . ), history of antithrombotic use ( / hemorrhage and / non-hemorrhage, p = . ) and icp spikes ( / hemorrhage and / non-hemorrhage, p = . ) were significantly associated with ich occurrence. three significant factors were associated with tract hemorrhages; age, history of anti-thrombotic use, and icp spikes. two of these factors have been previously supported by prior studies however, no prior study has correlated icp spikes to evd hemorrhages. additional studies may further validate the association between icp spikes and evd-related tract hemorrhages. targeted temperature management(ttm) aimed at helping to improve neurological outcomes associated with ischemic stroke have been studied continuously. however, it is not well known whether the parameters in ttm initiation, induction, maintenance will affect neurologic prognosis. we restrospectively reviewed medical records of the patients with large hemispheric infarction(lhi) who underwent ttm at snubh neurological intensive care unit from . . . to . . . onset to ttm initiation, induction period, ttm maintenance duration were investigated and dichotomized. neurologic prognosis was determined by the month death and modified rankin scale(mrs). a total of patients were included in the study. longer onset to ttm initiation(> hours) was associated with less month death. shorter ttm induction period(<= hours) was associated with less death rate, more fair outcome(mrs - ). ttm maintenance duration(within days or more) was not statistically correlated with neurologic prognosis. shorter ttm induction period may reduce death in lhi through maximizing icp control effect. the high mortality rate in patients with shorter onset to ttm initiation is likely to be related to the severity of initial symptom(mean nihss vs ). non-pulsatile continuous blood flow can cause endothelial dysfunction and small vasculature injury. the impact of non-physiologic blood flow on cerebral autoregulatory function and brain injury has not been extensively studied. we report a case of posterior reversible encephalopathy syndrome (pres) in a patient supported by a continuous flow pump, venoarterial extracorporeal membrane oxygenation (ecmo) for acute cardiogenic shock secondary to iatrogenic ventricular septal defect (vsd). a year-old male with hypertrophic cardiomyopathy was admitted for elective septal myectomy with an ascending aorta and hemi-arch replacement. the surgery was complicated by an iatrogenic vsd requiring urgent va-ecmo cannulation for cardiogenic shock. on day , ct brain achieved for poor neurological examination revealed extensive bilateral parietal, occipital and cerebellar hypodense lesions consistent with the typical imaging features of pres. a repeat ct brain on day depicted further extension of brain injury to the bilateral frontal lobes. due to worsening neurologic status, the decision was made to place an intracranial pressure monitor and lower the ecmo flow to return to a pulsatile flow state. the patient was closely monitored for improvement with paco levels, serial ct scans, and neurologic examinations. repeat ct scans on pod and depicted improvement in the bilateral cytotoxic edema with paco levels improving to - mmhg at a reduced ecmo flow rate of . - . l/min. his neurologic examination also improved with spontaneous movements noted in all four extremities. although neurologically cleared for heparin loading, he remained too hemodynamically unstable for open surgical repair and his surrogate decision makers decided to withdraw life-sustaining therapy. our case report illustrates the limited knowledge on the consequences of ecmo's impact on cerebral dynamic cerebrovascular autoregulatory changes in real-time that occur with patients with continuous flow pumps. hospital-onset unresponsiveness (hou) may occur in patients hospitalized for non-neurological conditions; while hou tends to be a transient systemic event, it may also indicate underlying neurological problems. quantitative pupillometry provides npi (neurological pupillary index), a quantitative measurement of pupillary light reflexes that have been traditionally assessed via subjective visual impression. we determined the clinical usefulness of npi in predicting the outcomes of patients who have experienced hou. hou was defined as a newly developed altered mental status and cases coded as "unresponsive" in the acdu (alert, confused, drowsy, and unresponsive) scale. we analyzed the demographics, radiological findings, etiology of hou, npi, in-hospital mortality, and -month modified rankin scale (mrs) scores. a total of cases in patients were analyzed, out of which cases ( %) had been assessed with quantitative pupillometry. cerebral herniation syndrome (chs) was found in ( %) cases; higher npi was associated with decreased risk for chs (odds ratio, . ; % confidence interval [ci], . - . ; p= . ), and no other factors were associated with the risk of chs. a total of ( %) cases showed in-hospital mortality. after controlling for clinical covariates and the presence of chs, lower npi was independently associated with increased risk for in-hospital mortality (odds ratio, . ; % ci, . - . ; p= . ). at a cutoff value of . , the specificity and sensitivity of npi for predicting in-hospital mortality were % and %, respectively. multivariate analysis showed an independent association between lower npi and unfavorable clinical outcomes (common odds ratio, . ; % ci, . - . ; p= . ). npi, a quantitative index of pupillary light reflex, was significantly associated with the risk of cerebral herniation and in-hospital mortality in non-neurological patients with hou. measuring pupillary light reflexes through quantitative pupillometry may be useful when responding to hou cases. target temperature management (ttm) improves survival and neurologic outcome and is recommended for cardiac arrest (ca) survivors by international guidelines. shivering is both an anticipated consequence and a major adverse effect of ttm. the bedside shivering assessment scale (bsas) is a simple, validated four-point scale that enables repeated quantification of shivering at the bedside. in this study, we examine the association between time to return of spontaneous circulation (ttrosc) and shivering (defined as bsas > ). data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. baseline characteristics included age, apache iii scores, ttrosc (minutes), time to target temperature (ttt, minutes), and bsas > (percentage of hours bsas > /total number of hours bsas was done). outcome was survival to hospital discharge with good neurologic outcome. group and group included patients with ttrosc below or above the median respectively. all patients received continuous infusions of fentanyl and sedatives (propofol, midazolam, and/or dexmedetomidine) as per our institution's protocol. compared to group (n = ), group (n = ) had similar age ( ± vs ± , p = . ), similar apache iii scores ( ± vs ± , p = . ), longer ttrosc ( ± vs ± , p = . ), similar ttt ( ± vs ± , p = . ), more shivering ( . % vs . %, p = . ), and similar survival with good neurologic outcome ( % vs %, p = . ) respectively. ttrosc was strongly positively correlated with shivering (pearson correlation coefficient, r = . ). in comatose survivors of cardiac arrest who received ttm, longer ttrosc (indirect measure of brain injury) was associated with more shivering. these findings should be further investigated in prospective studies. pupillometry assessment of the pupillary light reflex (plr) is gradually replacing manual plr assessment. this new technology has led to a recent increase in clinical research and subsequent need to validate those results. mcnett et al. recently investigated the association between intracranial pressure (icp) and serial pupillometer values and found that pupillometry readings are different significantly in the setting of increased icp. this is a replication of the mcnett study in a larger multicenter cohort to explore these findings. data from the establishing normative data for pupillometer assessments in neuroscience intensive care (end-panic) registry include over , patients with a neurological condition. subjects with documented icp readings provided , observations (daily mean icp values) which were included in this analysis. statistical analysis (sas v . ) included descriptive statistics and to examine the differences . subject mean age was years, % were female and . % were caucasian. student t-test analysis was used to explore for differences. excepting latency and right eye npi, lower plr values were associated with higher icp (compared to low or normal icp) for all mean pupillometer/plr variables for both left and right eyes (t range [- . to . ]; p-value range [< . to . ]). the findings confirm and extend those of mcnett. patients with increased icp tend to have lower pupillometer readings. automated pupillometer is a non-invasive method that provides prediction of the icp trends which can help neurocritical care professionals in assessing patients with neurological conditions. encephalopathy is a common complication in cirrhotic patients. clinical manifestations are diverse, but few data are available on pupillary abnormalities in such patients. the aim of this study was to evaluate whether automated pupillometry could detect pupillary dysfunction in this patients' population. prospective ongoing study including the assessment of the pupillary changes to light stimulation using automated pupillometry (neurooptics, irvine, usa) in adult cirrhotic patients after icu admission. the degree of encephalopathy was scored by the glasgow coma score (gcs). severity of cirrhosis was assessed by the child-pugh and meld scores. severity of liver encephalopathy was assessed according to standard criteria. different biological variables, including ammonium (nh ), was measured to pupillary assessment. the median values of pupillometry-derived variables were collected for both eyes. -pugh and nh levels were found with any of the pupillometry-derived variables. no differences in pupillometry-derived variables were observed across different degree of liver encephalopathy. automated pupillometry did not show correlations between pupillary abnormalities and the severity of critically ill patients with liver cirrhosis. prognostication in comatose survivors of cardiac arrest (ca) remains challenging. the purpose of this study was to determine if early quantitative analysis of resting eeg can improve prediction of commandfollowing by post-ca day . we prospectively enrolled patients admitted after ca. clinical care was performed according to our institutional protocol, which includes continuous eeg monitoring. -minute resting eeg epochs were clipped daily; clips were excluded if seizures or other confounders were present. epochs from post-ca days - were preprocessed for artifact reduction, then analyzed for three quantitative metrics: power spectral density, permutation entropy, and coherence. we created a predictive model using partial least squares regression analysis to distinguish eeg data as from patients who would or would not recover command-following by post-ca day . cross-validation of results was accomplished with a -times random assignment of % of data as training set and % as testing set. eeg clips were analyzed from patients ( . % female, age . +/- . years, pre-morbid mrs . +/- . and cpc . +/- . ). cardiac arrests occurred out-of-hospital in %, witnessed in . %, and had bystander cpr in . %. mean time to rosc was +/- minutes, . % had a shockable initial ekg rhythm, and . % of patients received therapeutic hypothermia. prior to day , . % regained consciousness and . % had withdrawal of care. using eeg data alone, predictive ability (expressed as average area under the receiver operating characteristics curve) yielded auc . +/comparison, the same model was constructed using clinical features (absence of pupil and corneal reflexes by day ) or laboratory testing (peak nse level). the model combining clinical, laboratory, plus eeg data yielded auc . +/- . , an improvement vs clinical features (auc . +/- . , p< . ) or nse levels (auc . +/- . , p< . ) alone. quantitative eeg analysis may provide adjunctive prognostic information regarding short-term recovery of consciousness. international guideline recommended pupillary light reflex (plr) and/or cortical response (n ) to short-latency somatosensory evoked potentials (sseps) at hours after return to spontaneous circulation as the only strong predictors of unfavorable outcome in comatose patients after cardiac arrest. the aim of this study was to compare this algorithm with a multimodal approach including other prognostic tools. post hoc analysis of an international multicenter (n= ; n= patients) prognostic study on automated pupillometry in comatose post-ca patients. the primary study endpoint was the accuracy of npi in predicting -month unfavorable neurological outcome (uo), defined as cerebral performance category (cpc) of - (severe disability, unresponsive wakefulness or death). patients with findings on plr, sseps, npi and eeg were included; the highest nse was also recorded, whenever available. an npi < on day , a discontinuous eeg background or clinical myoclonus over the first days, bilaterally absence of n calculated as: false positive / favorable outcome. we included patients; ( %) of those had uo. using the approach of guidelines, unfavorable outcome at day was observed in / patients with absent plr and / with absent n ; / ( %) patients with uo were identified. using the multimodal approach, uo was identified in / patients with npi < , in / patients with discontinuous eeg, in / patients with myoclonus and this study suggests that a multimodal approach, including npi, eeg, sseps and nse, could identify a after physicians introduced the idea to declare death based on loss of brain functionality, many countries incorporated brain death into their legal criteria for death. we sought to learn about the global legal perspective on brain death declaration (bdd). we collected legal documents about declaration of death around the world by searching national legislative databases and google. we utilized google translate to convert all documents into english then searched for references to criteria for bdd. in cases where there was conflicting information, we consulted local experts. we located legal documents on death declaration for countries, of which included a reference to brain death. legally stipulated criteria for bdd were identified for / countries. with respect to prerequisites for bdd legal stipulations existed in: / countries on confounders to exclude, / countries on an observation period before bdd, / countries on the minimum temperature for bdd and / countries on the minimum blood pressure for bdd. an assessment for coma was legally required in / countries. the fact that spinal reflexes do not preclude bdd was included in the legal criteria for bdd in / countries. a broad reference to an assessment for brainstem areflexia was legally mandated in / countries. the legal criteria included specific reflexes to test in / countries (pupillary / , corneal / , oculocephalic / , oculovestibular / , gag / , cough / , and other / ). every country legally required an assessment for the inability to breathe spontaneously, but only / described apnea testing in detail. the number of clinical exams required for legal bdd ranged from - . ancillary testing was legally required in / countries. the legally stipulated criteria for bdd differ around the world. standardizing the global legal perspective on bdd would help prevent ) variability in practice and ) false bdds. up to % of patients monitored with pupillometry during therapeutic temperature management (ttm) after cardiac arrest will have sluggish (sl) or non-reactive (nr) pupils. the neuroimaging findings and injury patterns of these patients have not been reported. adult patients treated with ttm after cardiac arrest with available pupillometry data from the neuroptics npi- were studied. discharge outcome was classified as poor (po) if the cerebral performance category score was - , and as good if - . pupil size, percent constriction, and constriction velocity were determined throughout ttm using data from the worst eye at each assessment. the neurological pupil index (npi) was scored from (nr) to (brisk), with values < considered sl. computed tomography (ct) and magnetic resonance (mr) neuroimaging was reviewed by a neuroradiologist blinded to pupillometry and outcome data. poor outcomes occurred in / ( %) patients with nr pupils during ttm, / ( %) patients with sl pupils, and / ( %) with normal (nl) pupil reactivity. pupil size did not predict outcome, but pupillometry data during ttm predicted poor outcome with auc . - . . when nonreactive pupils were first detected, / ( %) were < mm. % of patients had ct imaging, and % had mr imaging a median of (iqr - ) hours after recovery of spontaneous circulation. cerebral edema or herniation were identified in / ( %) nr vs / ( %) sl and / nl patients (p< . ). midbrain injury identified by t sequences was identified in / ( %) nr/sl patients versus / ( %) nl patients (p= . ). midbrain abnormalities were identified more often in patients with nr/sl pupils than edema/herniation ( % vs %, p= . ). a minority of patients with sluggish or non-reactive pupils after cardiac arrest have evidence of cerebral edema or herniation. midbrain injury is a more common mechanism to explain this common neurologic deficit. cardiac arrest (ca) survivors are often comatose and their arousal recovery is dependent on the extent of hypoxic-ischemic injury (hii). long-term neurologic outcomes are variable, difficult to predict, and biased by withdrawal of life-sustaining therapy. somatosensory evoked potentials (ssep) remain the gold standard for predicting arousal potential, but is not broadly available. we hypothesized that early hi-resolution mri may help assess arousal recovery potential as predicted by electrophysiologic outcome. comatose survivors of cardiac arrest admitted to an icu between june and january who underwent ssep and mri were retrospectively identified. d-hii burden in predefined regions. semi-automated region-of-interest (roi) tools in mipav were used to draw borders on dwi around the upper brainstem including the ascending reticular activating system (aras) to assess voxel intensity and derive hii volumes. our outcome of interest was ssep findings classified in two prognostic categories: indeterminate (bilaterally present n s or unilateral presence of n s) and poor prognosis (bilaterally absent n s). we used paired t-tests to compare presence of signal abnormality and rois between patients with sseps predicting poor outcome or indeterminate prognosis. consecutive ca survivors (mean age of . , % female) were included. no significant differences were noted in baseline characteristics between groups though time to rosc was noted to be vs mins for indeterminate and poor outcomes (p = . extent did not predict ssep status. no significant difference was noted in the voxel intensities on adc in the midbrain or pontine tegmentum. quantitative mri measures of hii extent may be superior in predicting arousal potential in comatose survivors of ca compared with manual rating. a quantitative image analysis pipeline is being developed for measuring aras lesion burden and predicting electrophysiologic based outcomes in ca. despite promising preclinical results, the application of intra arrest therapeutic hypothermia (iath) during cardiopulmonary resuscitation have produced controversial results in clinical trials. the aim of this review was to analyze the effects of such therapy on relevant outcomes in patients suffering from out-of-hospital cardiac arrest (ca). the following databases have been searched up to th may for human trials: pubmed (from ), embase (from ), cinahl (from ), the cochrane library (from ) and ovid/medline (from ). the search strategy will use the following terms: "arrest" or "cardiac arrest" or "heart arrest" and "intra arrest" or "during cpr" or "intra cpr" and "hypothermia" or "therapeutic hypothermia" or "cooling". references from identified studies and relevant review articles have also been searched for additional eligible citations. the search has been limited to english publications and has been conducted in accordance with the international liaison committee on resuscitation (ilcor) process of evidence evaluation. a total of six human studies (n= ; treated with iath) including four randomized controlled trial (loe ), one retrospective and one prospective controlled study (loe ) were identified. two studies used trans-nasal evaporative cooling and others intravenous cold fluids. overall rate of return of spontaneous circulation was similar between iath patients and controls ( / ) when compared to control group. no differences were found in the subgroup of shockable vs non-shockable rhythms. different effects on outcomes were observed according to the method used to induce iath when compared to controls. iath was not associated with improved outcomes when compared to standard of care. however, the method used to induce iath may potentially influence the beneficial effects of such intervention. amantadine may improve functional recovery in the subacute state following brain injury. we aimed to characterize eeg signatures in patients with acute brain injury (abi) receiving amantadine that did and those that did not recover consciousness. we studied a consecutive series of patients with acute brain injury patients who were treated with amantadine as a neurostimulant between september and december . all patients were initially comatose and underwent eeg prior to and after the initiation of amantadine. the ability to follow commands was assessed daily based on prior published methodology (claassen et al, annneurol ). eeg features that were assessed included sleep stages, posterior dominant rhythm (pdr), and power spectral density plots. we applied a multivariate regression model using generalized estimating equations (gee) to identify eeg features correlated with recovery of command following. eegs were analyzed by a board certified neurophysiologists. -free eeg clips), patients ( %) recovered consciousness during hospitalization. ich was the most common etiology in ( %) patients, followed by sah in ( %) patients. on average amantadine was given for +/- days. patients ( %) had seizures, only patients ( %) after starting amantadine. in our gee model, age (p= . ), sleep structures (p= . ), pdr (p= . ), and cumulative dose of amantadine (p= . ) were all associated with recovery of command following. spectral features corresponding to higher levels of anterior forebrain corticothalamic integrity correlated with higher levels of consciousness in % of recorded patients after days of amantadine use. the best spectral pattern per patient was seen . days on average prior to recovery of consciousness. eeg may provide a biomarker that indicates subsequent recovery of consciousness in unconscious patients with an acute brain injury that are treated with amantadine. depletion of cerebral glucose (i.e., cerebral glucopenia) occurs commonly and is associated with poor outcome in traumatic brain injury and subarachnoid hemorrhage. however, the incidence of cerebral glucopenia after diffuse hypoxic-ischemic brain injury (hibi) is unknown. we characterized the burden of cerebral glucopenia after hibi and its association with markers of physiological distress and outcome. we retrospectively analyzed cerebral microdialysis data from a cohort of patients with hibi. patients survived sudden cardiac arrest and patient had severe hypoxia after polysubstance overdose. hourly values of cerebral glucose, lactate, pyruvate, and glycerol as well as continuous intracranial pressure (icp), arterial blood pressure (abp) and interstitial brain oxygen (pbto ) were recorded. associations between average glucose/patient-day versus average lactate:pyruvate ratio, glycerol, icp, pbto , and abp were analyzed using linear regression. burden of glucopenia (defined % time with glucose < . mmol/l) was analyzed by patient-day. the relationship between glucopenia burden and discharge outcome was analyzed using the wilcoxon rank sum test. lower cerebral glucose was associated with higher cerebral glycerol (p= . ), higher lpr (p= . ), higher icp (p< . ), and lower pbto (p= . ) levels. there was no association between abp and cerebral glucose (p = . ). glucopenia burden increased progressively over time and peaked by postinjury day . / patients had good outcome (defined as return of consciousness prior to discharge). there was no association between outcome and cerebral glucopenia burden (p = . ). cerebral glucopenia is common after hibi and associates with markers of cellular distress. the burden of cerebral glucopenia progressively increases over several days and appears to peak more than week after injury. although there was no association between outcome and glucopenia burden, the number of patients in this study with good outcome was low. the utility of cerebral glucose monitoring after hibi merits further study. international guideline recommends using bilaterally absence of pupillary light reflex (plr) and/or bilaterally absence of the cortical response (n ) to short-latency somatosensory evoked potentials (sseps) at hours after return to spontaneous circulation to predict unfavorable outcome in comatose patients after cardiac arrest. the aim of this study was to compare this algorithm with a multimodal approach including other prognostic tools. retrospective study of adult (> years) cardiac arrest patients admitted from january to march and who underwent multimodal monitoring. we collected demographic characteristics and cardiac arrest data, together with sseps, the presence of burst-suppression on early eeg, a neurological pupillary index on the automated pupillometry < at after arrest and a neuron-specific enolase (nse) -month unfavorable neurological outcome (uo) with cerebral we included patients; ( %) of those had uo. using the approach of guidelines, unfavorable outcome at day was observed in / patients with absent plr, in / with absent n and / with combined absent pupillary light reflex and n ; / ( %) patients with uo were identified. using the multimodal approach, uo was identified in / patients with npi < and / patients with bs on eeg. among the others, uo was associated with absent n in / patients and with high nse values in / patients. this approach identified / ( %) patients with unfavorable outcome. the area under curve to predict uo for the approach of guidelines was . , which increased to . with the multimodal approach. this study suggests the a multimodal approach, including npi and bs on eeg, sseps and nse, has a higher predictive value for uo than recommended predictive tools. there is a high prevalence of seizures following cardiac arrest (ca), but not well studied among survivors with good neurological recovery. we describe the prevalence of clinical and electrographic seizures, anti-epileptic use, and eeg characteristics of ca survivors with good neurological outcomes. adults with return of spontaneous circulation (rosc) after in-hospital or out-of-hospital ca between / - / were eligible. a consecutive sample of survivors with included. prevalence of seizures and antiepileptic drugs (aed) use within -months after discharge were collected using a questionnaire administered via in-person or phone. a board-certified clinical neurophysiologist reviewed the eeg. of patients surviving to discharge, ( %) with -months follow-up were analyzed. average age was ± years, ( %) were women, ( %) patients had witnessed arrest, ( %) received defibrillation, with an average rosc duration of ± minutes, and a median cpc of at discharge. there were no clinical seizures reported during hospitalization. of available ( %) patients with raw eeg (median duration of days), only ( %) patients had electrographic seizures, ( . %) had continuous background as their best eeg pattern, ( %) with discontinuous background, ( %) with epileptiform discharges, and ( %) patients had burst suppression pattern that recovered later to a normal eeg pattern. none of the patients had any malignant eeg patterns, ( %) exhibited reactivity to a verbal or tactile stimulation and ( %) had the presence of sleep structures and posterior dominant rhythms. surprisingly, ( %) patients were discharged on an aed. clinical seizures and aed use were reported in / ( %) at -months follow up. both short and long-term seizure burden are very low among the cardiac arrest survivors with good neurological recovery. underlying factors related to high utilization of aed before discharge warrants further investigation. objective: early neuro-prognostication in the intensive care unit pediatric patients is essential to enable effective care planning, triaging level of care, and family support. in coma, the reliability of biomarkers such as electroencephalogram (eeg), anatomical neuroimaging to determine potential for consciousness and future functional capacity are less established in children. herein we present two case studies highlighting resting state functional mri (rs-fmri) as a clinically new means defining real-time brain function in the pediatric critically ill population. rs-fmri measures spontaneous low-frequency fluctuations in the blood oxygen dependent (bold) signal to investigate the networks of the brain. a standardized acquisition of data on a tesla mri under light tool melodic. whole brain networks determined by independent component analysis with false discovery rate at p< . to detect major brain networks. cases describe two critically ill children. one, with severe brain injury related to acute necrotic encephalopathy, and the other with diabetic ketoacidosis induced cerebral edema and uncal herniation. both had slow eeg background with sleep features approximately a week after presentation and were comatose by exam on the day of rs-fmri. rs-fmri detected normal brain function in the long-range fronto-parietal network, intact language-area networks, and default mode network. atypical networks were detected in brainstem and deep grey in both children. by hospital discharge, both children were awake and communicative with spontaneous movements. case one remain with tracheostomy with intermittent ventilation, case two had residual left hemiparesis, vision and language intact, mild cognitive deficits. in the cases reviewed, rs-mri may offer an objective measure of functional brain capacity and potential for meaningful recovery with preservation of language and long range connectivity networks in critically ill pediatric patients. provision of positive end-expiratory pressure (peep) through a conventional ventilator during apnea testing for brain death determination removes the need for additional equipment such as a peep valve, allows for use of high peep during apnea in patients with severe hypoxic respiratory failure and facilitates detection of respiratory effort on flow scalars. the advent of ventilators that permit deactivation of the apnea backup setting has made such testing possible. our goal was to examine the feasibility of peep use with conventional mechanical ventilation during apnea testing, with a focus on premature termination and inadvertent external triggering. performed without disconnection from the ventilator (dräger evita® infinity® v ), with deactivation of the apnea backup. this was a convenience sample based on availability of appropriately trained -support and peep - cmh o. apnea was confirmed by absence of chest rise and respiratory effort on the flow scalar. adequacy of respiratory stimulus was established by a co > mmhg and -point co rise from baseline. endpoints included early termination of the apnea test prior to minutes because of patient instability, any oxygen desaturation below % and inadvertent external triggering. inadvertent external triggering required repeat of apnea testing. ten patients underwent apnea testing while connected to the ventilator. apnea testing for at least minutes was successful in all patients. apnea was confirmed in all cases. no patient suffered oxygen desaturation below % or other instability. there was one instance of inadvertent external triggering caused by jostling of tubing, necessitating repeat testing. apnea testing with provision of peep through a conventional ventilator to improve tolerance is feasible. inadvertent external triggering is uncommon but may occur. despite well-defined aan guidelines on brain death declaration, there is marked variability in its practice nationally. this highlights the need for targeted brain death education initiatives. communication with surrogates or families about a brain death diagnosis and its implications is integral to brain death declaration, yet this has not been studied in a simulation setting. we developed a brain death simulation curriculum at our institution addressing knowledge and surrogate communication skill development. as part of this curriculum, multi-disciplinary critical care fellows completed a pre-curriculum multiple choice (mc) knowledge test and survey (likert - scale) evaluating comfort and confidence. a mandatory one-hour neurocritical care attending-led didactic regarding guidelines and technical aspects of brain death examination was conducted. subsequently, each fellow performed an observed brain death examination (simman g mannequin) with feedback followed by a standardized family scenario with delivery of a brain death -simulation survey, mc questions, and provided feedback. statistical analyses used -tail wilcoxon signed rank test (p<. ). thirteen critical care fellows participated (neurology[ ], anesthesia[ ], trauma[ ], pulmonary[ ]). only one fellow had previous formal brain death training with the majority [ %, (n= )] only participating in - brain death declarations. there was significant improvement across all measures: self-rated knowledge ( . to . , pre-simulation to post-simulation, p= . ), knowledge relative to peers ( % to %, p= . ), confidence ( . to . , p= . ) and comfort ( . to , p= . ) with performing a brain death exam, and comfort with family discussion ( . to . , p= . ). test scores improved from % to % after simulation (p= . ). all fellows found the curriculum beneficial (with all aspects wellreceived). critical care fellows may lack experience with brain death declaration. didactics coupled with simulation-based education can improve objective knowledge and comfort with brain death declaration and surrogate communication. there is a growing disparity between availability and demand for neurologic expertise, particularly in smaller community hospitals. telemedicine has helped to bridge this disparity with respect to cerebrovascular disease and is used increasingly to deliver other types of neurologic expertise to patients. while the nihss is widely used in telestroke, other formalized neurologic exams have not been well studied. we seek to determine whether the components of a brain death exam can be reliably performed via telepresence. patients suspected of meeting brain death criteria were enrolled from july to may . standard bedside neurologic exam (bne) performed by the attending neurointensivist in accordance with our institutional protocol was compared with the telepresence neurologic exam (tne) performed by a study neurointensivist blinded to the findings of the bne and a trained bedside assistant. we analyzed the agreement between examiners regarding findings of coma, corneal reflex, pupillary light reflex, oculovestibular reflex, oculocephalic reflex, cough, gag, motor response, and apnea. we enrolled patients over months. proximate causes were intracerebral hemorrhage ( / ), anoxic brain injury, ( / ), and cerebral infarction ( / ). all examination components performed in the bne could be completed by tne. in cases, neither examiner could assess all exam components. in cases spinal cord injury precluded oculocephalic testing. in case refractory hypoxia precluded apnea testing. bne and tne agreed in % of testable components. in cases testing pupillary light reflex was reported as difficult in the tne but not the bne. all telepresence examiners reported high confidence that the exam findings were consistent with brain death. preliminary findings from our pilot study suggest that the use telepresence for brain death examination introduction traumatic brain injury (tbi) is often followed by the loss of con increases each day following the injury, but the contents of consciousness, also known as qualia, do not uniformly return. while there is some information about brain regions supporting arousal, less is known about circuits encoding contents of consciousness. some evidence supports a role for the thalamus in consciousness, but it is controversial whether it supports arousal, or has a more nuanced role in consciousness. to address this question, we combined intracranial recordings in patients recovering consciousness with neuroimaging of thalamocortical circuits. electrophysiology we recorded electrocorticography (ecog) from prefrontal cortex and anterior cingulate cortex, as well as scalp electroencephalography (eeg) from a standard - montage, during singleand parietal cortex based on coherence between the evoked responses in these regions when acc was stimulated. radiology. regions of structural damage were extracted from the post-tbi mri and diffusion tensor imaging (dti) radiographs. tractography using dsi studio™ was performed with seed regions placed in the bilateral mediodorsal nucleus of the thalamus. we found that in patients with injury isolated to the cortex and/or white matter, the cortico-cortical functional connectivity across frontoparietal networks was preserved, and these patients recovered consciousness. however, a patient with thalamic injury failed to recover consciousness, despite an increased level of arousal following injury. the functional connectivity across cortical regions was drastically lower following thalamic injury, even when the cortical damage was minimal. we propose that integration and communication of information across frontoparietal networks, which is required for contents of consciousness, is dependent on thalamic input. thus future efforts have to be focused on restoring this input. brain herniation is a deadly event that requires rapid administration of hyperosmotic agents (hoas) such as . % nacl. a recent retrospective study showed that intraosseous (io) cannulation provides a safe route for rapid administration of hoas compared to central venous catheters (cvc) and peripheral intravenous catheters (piv). prospective study to measure the time-to-treatment for . % nacl or mannitol via io, cvc, or piv. a data collection form ("brain code narrator") was created by nurses and providers to prospectively collect clinical data, hemodynamic measures, and time-to-treatment and administration route for hoas during brain codes. in addition, demographics, diagnosis, serum sodium (na+) and complete blood cell count, as well as immediate and delayed complications, and outcomes were collected. brain code narrator was used to collect data for patients: males with median (iqr) age ( - ) years. diagnosis included intracerebral hemorrhage (n= ), subarachnoid hemorrhage (n= ), and other (n= ). all patients were intubated. most patients were co-treated with induced hyperventilation. . %nacl ( cc) via cvc and io route and mannitol ( gm) via piv were administered during , , and events with median time-to-treatments of ( , ), ( , ) and ( , ) minutes, respectively (p value < . for all comparisons). no adverse events, such as hypotension or tissue injury were noted. preliminary data suggest that during brain herniation, administration of . % nacl via io or cvc is more rapid than iv mannitol. io cannulation for . % nacl may be an alternate route of administration of hoas during brian code. additional data will be provided regarding herniation reversal and long-term hematologic abnormalities. stress hyperglycemia is common in the critically ill and is associated with poor neurological outcomes in cardiac arrest patients. it is unknown whether glycemic dysregulation have different prevalence according to cardiac arrest etiology. we hypothesized that overdose-related cardiac arrest (odca) patients are more vulnerable to hypoglycemic events given the circumstances of arrest. we retrospectively studied cardiac arrest patients treated at two urban hospitals from the multimodal outcome characterization in comatose cardiac arrest (mocha) registry from - . we examined glucose dysregulation (hypoglycemia blood glucose [bg]< mg/dl, hyperglycemia bg> mg/dl) within first h from arrest in odca and non-odca cohorts. statistical analyses included paired/unpaired t-tests, chi-al dysfunction was defined by scores of gos- of the patients, ( . %) were odca. there were no differences in bmi, gender, ethnicity, or therapeutic hypothermia (th) treatment across cohorts, but odca patients were younger ( ± vs ± year-old; p< . ), had lower prevalence of diabetes ( . vs . %; p= . ) and lower hemoglobin a c ( . vs . %; p= . ). mean bg reduction from - h to - h in odca patients was significantly smaller ( . ± . vs . ± . mg/dl; p= . ) despite no difference in mean peak bg. bg nadirs were lower in odca patients ( . ± . vs . ± . mg/dl; p= . ). patients developed glycemic dysregulation: ( %) odca vs ( %) non-odca; odca patients were nearly two times more likely to develop hypoglycemia (rr . [ . - . ]; p= . ) but had no increased risk of hyperglycemia (rr . [ . - . ]). among patients with glycemic dysregulation, odca was associated with higher risk of in-hospital death or neurological dysfunction (or . [ . - . ]; p= . ). despite exhibiting blunted bg reductions to hyperglycemic treatment, odca patients were more susceptible to hypoglycemia in the first h postmanagement strategies should account for cardiac arrest etiology. sedation and neuromuscular blockade (nmb) in patients undergoing targeted temperature management (ttm) after cardiac arrest (ca) are recommended for patient discomfort and management of shivering. this study assessed the association between nmb use and neurological outcome in comatose survivors of ca who received ttm. data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. ttm of °c or °c is chosen based on critical care physician's discretion. baseline characteristics included age, apache iii scores, time to return of spontaneous circulation (ttrosc, minutes), time to target temperature (ttt, minutes), and shockable rhythm (sr, %). outcome was survival with good neurologic outcome. compared to the no nmb group (n = ), the prn nmb group (n = ) and continuous nmb group (n = ) had similar age ( ± and ± vs ± , p = . , . ),similar apache iii scores ( ± and ± vs ± , p = . , . ), comparable ttrosc ( ± and ± vs ± , p = . , . ), longer ttt ( ± and ± vs ± , p = . , . ), comparable percentage of sr ( % and % vs %, p = . , . ), and similar proportion of patients with tt of vs ( % and vs %, p = . , . ) respectively. survival with good neurologic outcome was achieved in % in no nmb group vs % in prn nmb group (p = . ) and % in continuous nmb group (p = . ) in the present study, in comatose survivors of cardiac arrest who received ttm, use of nmb had no effect on neurologic outcome. the apnea test is an essential examination for the determination of brain death. however, hypotension, hypoxemia, and other complications during the apnea test can affect the stability of brain-dead patients, as well as organ function for recipients. therefore, it is necessary to establish standard guidelines for apnea testing. the modified apnea test (mat) comprises delivery of % oxygen through the endotracheal tube connected to manual resuscitator (ambu® bag) with the positive end-expiratory pressure (peep) valve after disconnection of -nine instances of the conventional apnea test (cat) were performed in brain-dead patients; instances of the mat were performed in brain-dead patients. the mean duration of the apnea test was . ± . minutes in the cat group and . ± . minutes in the mat group. there were no significant changes in paco , pao , or ph between the cat and mat groups (p = . , . , and . , respectively). in overweight patients (body mass index prevented dramatic reductions in pao and sao (p < . for both). in the patients who had hypoxic brain injury due to hanging, differences in pao and sao in the mat group were significantly smaller than in the cat group (p < . ). although mat, which was invented to maintain peep, was not efficient for all brain-dead patients, it could be helpful in selected patient groups, such as overweight patients or those who had hypoxic injury due to hanging. clinicians should consider this reliable short-term apnea test. coma is a serious complication that currently has no good biological markers. the hypothalamus plays an important function in consciousness circuity. orexin a/b, a neuropeptide produced in the hypothalamus has an excitatory effect on multiple target areas in the brain. previous orexin studies ry (tbi), stroke and comatose states. the goals of our study: ( ) the utility of orexin as a marker of coma recovery, ( ) the correlation between orexin and recovery at and days, ( ) correlation of orexin and glasgow coma score/score (gcs) over time, a prospective, irb approved study with a target n= with a diagnosis of coma due to stroke, including hemorrhagic, and tbi, treated in the neuro critical care unit at stony brook university ho collected from an external ventricular drain (evd) and corresponding blood serum samples on days , , and . there was no modification to the clinical treatment of individual patients. dictive of whether patients recovered consciousness vs deteriorated. logistic regression showed the relative risk of recovery vs. deterioration: , ( %ci - . ± . , . ± . , respective p-values= . e- , . epredictive of initial coma severity (gcs), with a correlation coefficient, r = . . correlation between - . , - . ). dictive of poor overall not appear as significant as the baseline level in predicting recovery. there has been limited research over the past decade on how race impacts survival from cardiac arrest. it has been suggested that black patients are more likely to have unsuccessful resuscitation and lower rates of survival to discharge, however, it is unclear if this difference is secondary to hospital factors or patient specific factors. more research is needed on racial disparities in post-arrest outcomes at urban medical centers. multimodal outcome characterization in comatose cardiac arrest (mocha) is an irb-approved multicenter observational study. this study sample consists of consecutive cardiac arrest patients treated at two urban hospitals from - . the sample includes both patients who experienced in-hospital and out-of-hospital cardiac arrest. the outcome of interest was in-hospital mortality. associations between race and mortality were evaluated by chi-square and relative risk (rr) with % confidence interval. we included white ( %) and black patients ( % were all found to be at no increased risk for in-hospital mortality relative to other gender and race combinations. there was no difference in location of cardiac arrest (i.e., inhospital vs. out-of- the lack of racial differences in mortality could possibly be explained by the similar rate of out-ofhospital arrests, similar initial non-perfusing rhythms, lower socioeconomic status of all patients, and strong focus of the participating hospitals on addressing racial disparities in the healthcare system. hyperglycemia is associated with poor clinical outcomes in critically ill patients, such as post-cardiac arrest (ca) patients. post-ca prognostication studies have studied clinical examinations, electrophysiology, biochemical changes, and/or neuroimaging, but studies regarding patient blood glucose levels are mostly limited to mortality outcomes. new analysis of glucose trends is needed to guide ca prognostication in order to determine favorable outcomes regarding neurologic functioning. this study was conducted using the irb-approved multimodal outcome characterization in comatose cardiac arrest (mocha) registry. the sample included ca patients admitted to a university-affiliated urban hospital from - . case selection was determined by availability of serial glucose measurements over the first hours post-ca and outcome scores at hospital discharge. poor functional outcome was defined as modified rankin scale (mrs) - or glasgow outcome scale extended (gose) - . statistical analysis included chi-square tests, and prognostic value was calculated by sensitivity. there was no significant difference in outcome regarding age, sex, race, or ethnicity. the study sample consisted of % diabetic patients, with no significant difference in outcome. patients with glucose levels > mg/dl at least once during the first hours post-ca were associated with poor functional outc there appears to be a correlation between glucose > mg/dl within the first hours and poor functional outcome. however, it is still difficult to reliably predict poor vs. good functional outcome due glucose management are needed to better understand this relationship. post-cardiac arrest organ injury is associated with high mortality rate after icu admission. despite improvement in the post-cardiac arrest care, temporal changes in patients' severity, intensity of care and neurological outcome remain poorly defined. the aim of this study is to describe how epidemiology of cardiac arrest characteristics, therapies and outcome have changes over years. retrospective study including adult (> years) cardiac arrest patients admitted from january to march after ca to a university hospital. we collected demographic characteristics and cardiac arrest data, together with main therapies and monitoring during icu and hospital mortality. a total of patients (median age [ - ] years; male gender %) were included over the study period. time to rosc was significantly longer in period i and iv when compared to others (p< . ). icu length of stay and lactate levels on admission were also significantly higher in the period iv than others. there was a progressive and significant increase of out-of-hospital ca, non-cardiac origin of arrest and non-shockable initial rhythm from period i to period iv. also, there was a significant increase in the number of patients developing acute kidney injury and hypoxic hepatitis over time, from period i to period iv. despite a more frequent use of coronary angiography and multimodal neurological monitoring, hospital mortality increased (from period i, % to period iv, % -p< decreased (period i, % to period iv, % -p= . ) over time. in this study, severity of anoxic injury and the incidence of post-cardiac arrest organ dysfunction increased over time. this was associated with a higher proportion of patients with poor outcome. pressure reactivity index (prx) based optimal cerebral perfusion pressure(cppopt) is associated with outcome after traumatic brain injury, but is not explored after cardiac arrest. we examined post-arrest patients who underwent invasive intracranial monitoring to explore characteristics of prx and cpp, and whether these were useful predictors of survival. we included all comatose cardiac arrest patients without primary neurological pathology that underwent invasive intracranial monitoring between - at our institution. cpp, mean arterial pressure(map), prx, cppopt, and deltacpp (cpp-cppopt) were calculated. systemic and brain physiologic measures were compared across the primary outcome of survival. in this pilot study we demonstrated the feasibility of acquiring cpp, prx, and cppopt for post-cardiac arrest patients. in this sample, none of the systemic and brain physiologic measures were associated with survival but the approach is limited by the bias towards poor outcomes in patients receiving monitors. interestingly, cppopt obtained from invasive intracranial monitoring generally ranged within physiologic norms. deltacpp for the single patient with good outcome was positive and small, consistent optimizing cerebral perfusion after cardiac arrest improves outcome are warranted. prognostication after cardiac arrest is challenge because of many confounding factors during hypothermia, severity of the brain injury is a key determinant of whether maximal resources, such as the use of extracorporeal membrane oxygenation (ecmo), mechanical circulatory support, or even coronary artery bypass grafting, are advisable or appropriate. therefore, early and accurate prognostication is essential for decision of therapeutic plan including maxima intensive modalities. in this study, we focused not only the prognosis estimation using mri but also initial ct-based prognosis estimation where features captured by modern deep learning (dl) technique were commonly used. we selected total cardiac arrest patients having initial ct at er, and brain mri after hours from cardiac arrest. diffusion weighted image (dwi, b = ), and apparent diffusion coefficient (adc) images calculated. cerebral performance category (cpc) scores were used as the main outcomes of survivors after cardiac arrest. both experienced neurologist and emergency medicine tried to predict the devised two cascaded deep convolutional neural networks (deep cnns). even fully experienced neurologist and emergency physician could not predict the cpc score exactly with the initial ct scan only and even additional diffusion mri (accuracy : %- % with initial ct only - % with additional diffusion mri). by using dl technique, among subjects of train set, subjects had the correct prognosis score ( . % accuracy) and among subjects of test set, subjects had the correct prognosis score ( . % accuracy) with initial ct scans only. with additional diffusion mri, . % accuracy and % accuracy. in visually equivocal initial ct scans, dl was more related to quantification than visual assessment. dl is superior and very useful for accurate prognostication especially with visually equivocal initial ct scan. cardiac arrest (ca) is associated with a high risk of dying and of neurologic impairment in survivors. target temperature management (ttm) improves survival and neurologic outcome and is recommended by international guidelines. this study assessed the association between the initial acute physiology and chronic health evaluation (apache) iii score and neurological outcome in comatose survivors of cardiac arrest who received targeted temperature management (ttm). data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. ttm of °c or °c is chosen based on critical care physician's discretion. baseline characteristics included age, gender, apache iii scores, time to return of spontaneous circulation (ttrosc, minutes), time to target temperature (ttt, minutes), and shockable rhythm (sr, %). outcome included hospital mortality, and good neurologic outcome (defined as discharge to home or rehab). compared to the bad outcome group (n = ), the good outcome group (n = ) had similar age ( in comatose survivors of cardiac arrest who received targeted temperature management, the apache iii score calculated in the immediate post-cardiac arrest period was a poor predictor of neurological outcome. brain dead patients are victims of trauma, entering the health care system through emergency department (ed).in the ed, these patients are received with injuries and de-arranged physiological conditions that depends on time sensitive treatment and have the potential for improvement with proper management. our study tries to find out the predictors at admission that contributes to brain death (bd) so that their timely intervention can prevent bd a retrospective analysis of the data related to severity of injuries, physiological parameters and laboratory investigation including ct scan of the head at the time of ed admission of each patients were assessed once they were diagnosed brain death. logistic regression analysis was employed to determine the independent factor. p value of < . was considered significant. results brain dead patients records at the time of admission were analysed. on univariate analysis we found glasgow coma scale (gcs) < , blunt trauma chest (btc),skeletal injury, intraventricular hemorrhage (ivh),skull fracture,subarachnoid hemorrhage (sah),midline shift (mls),mean blood pressure (mbp)< mmhg,use of ionotropes, hemoglobin (hb)< mg/dl,international normalization ratio(inr)> . ,albumin< mg/dl,sodium level (na)> meq/dl,urea > mg/dl significantly related to bd.on further multivariate analysis ,we found gcs< (or- . ), btc (or- . ), ivh (or- . ), mls (or- . ), mbp < mmhg (or- . ), inr> . (or- . ), albumin < mg/dl (or- . ) and na level > meq/dl(or- . ) at the time of admission are strongly associated with bd. our study tried to find the predictors at the time of admission which may contribute to bd. addressing them may prevent patient from becoming brain dead. biomedical technology in critical care is advancing at a rapid rate, offering the potential to substantially improve performance through improved efficiency and productivity. recent evidence suggests that visual assessment of pupillary size and reactivity has limited interrater reliability and accuracy, hence, we examined the introduction and implementation of an automated pupillometer in an academic neurological icu. we evaluated clinicians' perceptions about the added utility of the pupillometer to the standard visual pupillary exam. -minute bedside education and demonstration of the pupillometer by a 'superuser', we conducted usability testing at the bedside. participants completed the end-user testing methodology, where they completed specified tasks designed to test the pupillometer's features and later completed a questionnaire regarding their ease of use and interpretation of results, comfort and confidence using the pupillometer, and their behavioral intention to use the pupillometer if adopted into the clinical environment to date, participants have completed questionnaires. participants were allowed repeat enrollment in the study. the participant's professional designations include registered nurses, residents and fellows and the majority have practised in the icu for to years. most of the participants are somewhat comfortable ( / ) performing the traditional visual pupillary exam and somewhat confident ( / ) with the results obtained from this exam. twenty-one, out of responses, were very comfortable in using the pupillometer, / were somewhat comfortable, and / were neutral. if this technology is introduced into icu, the majority ( / ) will use this device to conduct pupillary exams, and / would consider changing management based on the pupillometer results. this study outlines a strategy to evaluate usability and implementation of a newly adopted technology into the critical care environment. improved implementation methods and evaluation of implementation processes are necessary for successful adoption of new technology in acute care settings. propofol infusion syndrome (pris) is a rare complication of propofol infusion. it is characterized by metabolic acidosis, rhabdomyolysis, acute renal failure, hyperlipidemia, and rapid cardiac failure. risk factors for developing pris are: propofol infusion > hours, dosing > mg/kg/hr, critical illness, malnutrition, and use of vasopressors. we present a case of pris that developed after propofol infusion was turned off. a year old woman with medically intractable epilepsy and developmental delay, presented with generalized tonic clonic status epilepticus. she was refractory to benzodiazepines, so she was intubated and started on a propofol infusion. at mcg/kg/min of propofol, she was still having generalized clonic tonic seizures. she was transferred to our neurological icu for continuous eeg monitoring. propofol infusion was increased to mcg/kg/min ( mg/kg/hr) to control her seizures. she remained seizure free for hours. propofol was weaned over hours because she became hypotensive and required norepinephrine. when the propofol was turned off, cpk was , lactate was . , and creatinine was . . she received propofol for hours. twelve hours after propofol was stopped, she developed a metabolic acidosis, lactate increased to . , creatinine increased to . , urine output decreased, and cpk increased to > , . she then developed bradycardia with wide complex qrs, which progressed to asystole. she could not be resuscitated and died. our patient developed pris after propofol infusion was off for hours. she had many risk factors for developing pris, including high dose of propofol, critical illness, malnutrition, and use of vasopressors. pris can occur after propofol infusion has been stopped, and should be monitored for after the infusion has been discontinued in patients that are at increased risk. subdural hemorrhage (sdh) is a common cause of morbidity. we sought to study the impact of antithrombotic drugs on nontraumatic sdh. we retrospectively reviewed medical records of , patients admitted at massachusetts general hospital for sdh during to based on a research patient data registry. there were patients without history of head trauma included in the analysis. baseline demographic and clinical characteristic data were collected. the outcomes including gcs, modified rankin scale (mrs), sdh size, sdh expansion, surgical evacuation, mortality rates, length of stay (los), bleeding and thromboembolic complications were compared between two groups. multivariate logistic regression was performed to analyze association between poor outcome (mrs - ) and all potential predictors (age, diabetes, conditional variable regression method was used because of relatively small sample size to avoid overfitting the model. among patients included, ( . %) were on antithrombotic agents, either antiplatelets or anticoagulants, at presentation and ( . %) were not. anticoagulant and antiplatelet agents constitute . % and . % of nontraumatic sdh, respectively. all antithrombotic agents were discontinued on admission. nontraumatic sdh patients who were on antithrombotic agents had longer los ( . ± . , p= . ), higher rate of sdh expansion (or . ; %ci . - . ; p= . ), higher rate of disability at discharge (mrs - ) compared to no antithrombotic group (or . ; %ci . - . ; p< . ). on multivariate logistic regression analysis, antithombotic group had higher rate of poor outcome than no antithrombotic group (or . ; %ci . - . %; p= . ). use of antithrombotic agents prior to admission in nontraumatic sdh patients correlates with longer los, higher sdh expansion and increased disability at discharge. maintaining goal sodium levels in the neurocritical care population can be challenging. historically, at our institution, the supplementation of enteral sodium occurred by addition of table salt to tube feeding formulas by our dietary team. to make this therapy easier to standardize, monitor, and titrate, a new process was developed. continuous % hypertonic sodium chloride solutions are now administered enterally via feeding tubes. this also allows for the charting of the medication and immediate dose titrations. this pre-post analysis includes patients admitted six months prior to the implementation of the new enteral sodium process compared to patients admitted within one year after the new process change. demographic variables, as well as the indication for sodium goals, initial sodium levels, sodium level for -hours post-addition of enteral sodium supplementations, concomitant use of intravenous hypertonic saline, and achievability of goal sodium levels were collected. descriptive analytics were performed to compare groups. a total of patients were included in the analysis: in the pre-implementation group and in the post-implementation group. the most common indication for goal sodium levels in both groups was traumatic brain injury with head bleed; patients ( %) in the pre-implementation group and ( %) in the post-implementation group. ability to maintain serum sodium concentrations (defined as the ability to maintain goal sodium without the need for intravenous hypertonic saline for > h) within goal in the pre-implementation group was successful in % of patients (n= ) compared with % (n= ) in the post-implementation group. the use of continuous enteral % hypertonic sodium chloride solutions to target and maintain goal sodium levels provided similar efficacy compared to the addition of table salt to tube feeding formulas and is safer and easier to monitor and titrate. coagulation factor xa (recombinant), inactivated-xa inhibitor associated life--factor prothrombin complex concentrate (pcc) was utilized off- retrospective, single center, cohort study including adult intracranial hemorrhage patients who received discharge between efficacy (defined by international society on thrombosis and haemostasis criteria), thrombotic events, icu and hospital length of stay, and mortality. andexxa, coagulation factor xa (recombinant), inactivated-zhzo is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or indication. there is no available literature supporting the use of this drug in acute neurosurgical emergencies. we present our experience of patients treated with andexxa who required acute neurosurgical interventions as a life saving measure. patients were identified from may , to may , using an electronic database report identifying those who received andexxa and subsequent chart review at a single center quaternary care academic medical facility. factor xa inhibitor and time of dosing. patient and both had an external ventricular drain placed while in the emergency room. patient suffered from a cerebral hemorrhage with hydrocephalus while patient was found to have a primary ventricular hemorrhage with hydrocephalus. both were treated with four factor prothrombin complex concentrate (pcc) at an outside hospital. there were no bleeding complications during the procedures. two patients had a craniotomy performed. patient was diagnosed with an acute subdural hemorrhage with worsening midline shift despite receiving pcc at the outside hospital. patient four had an acute-chronic subdural hemorrhage with midline shift but did not receive pcc. in both craniotomy cases, there were no bleeding complications. andexxa was used in four patients taking apixaban or rivaroxaban undergoing lifesaving neurosurgical procedures despite no the utilization of acute extracranial and intracranial stents for the treatment of cerebrovascular pathology is increasing. the optimal antiplatelet agent and dose in this population and the utility of platelet function testing is unclear. all patients from january to april who were hospitalized and received ticagrelor to maintain intracranial or carotid stent patency in which platelet function testing (verifynow) was utilized to guide dosing were collected. relevant demographic, clinical, platelet reactivity unit (pru), and ticagrelor administration data was collected and qualitative assessment of pru results was performed. data was collected on patients and the maintenance doses utilized were , , (most frequent) or mg bid and loading doses of mg or mg. a total of patients' doses were titrated in order to achieve the goal pru range ( - ). among patients given a dose of mg % had a pru in the optimal range ( - ) as compared to % among patients given a dose of mg. twice as many patients given a dose of mg as compared to mg ( % vs %) had a pru between - . among the patients whose dose was titrated the average pru prior to dose escalation was , the average pru subsequent to dose escalation was , and the average pru prior to dose decrease was and the range in % of cases and was between - in % of cases. the utilization of platelet function testing to guide dose titration of ticagrelor to a desired pru range is feasible. a major limitation of this study is the lack of patient outcomes related to thrombosis or bleeding. rivaroxaban. the efficacy and safety of andexanet alfa have been evaluated in the annexa- study, which excluded patients receiving prothrombin complex concentrate (pcc) within the days preceding enrollment. however, there have been limited reports of patients receiving both pcc and andexanet alfa for oral factor xa inhibitor-associated major bleeding, without adverse effect. while thrombotic events were observed in % of annexa- patients, potential for additive risk when combining andexanet alfa and pcc is undefined. we describe a patient who received pcc followed by andexanet alfa for an apixaban-associated intracerebral hemorrhage, who subsequently suffered devastating embolic strokes. de-identified patient data were retrospectively collected from the electronic medical record a -year-old male presented with acute left-sided hemiplegia caused by a large right-sided temporal lobe intracerebral hemorrhage. the patient had a history of atrial fibrillation, for which he was anticoagulated on apixaban. the patient initially received intravenous (iv) pcc units/kg for prevention of hematoma expansion. the following day, minimally expanded hemorrhage was observed on repeat imaging concurrent with a measured apixaban level of ng/ml (reference range - ng/ml). as a result, high dose andexanet alfa was administered as an mg iv bolus, followed by an iv infusion of mg/minute for minutes. over the next several days, the patient's neurologic exam supratentorial strokes, likely embolic in origin. unfortunately, the patient did not survive hospitalization. the combination of pcc and andexanet alfa may carry with it substantial thrombotic risk, and cannot be routinely recommended. targeted temperature management (ttm) is used for neurological protection in patients with neurological injury but shivering during ttm can reduce therapeutic effect by increasing oxygen consumption and metabolic rate. cisatracurium used to prevent shivering has a shorter half-life than vecuronium and is not affected by liver and renal function. the objective of this study was to compare the efficacy and safety between two neuromuscular blockers in order to determine the benefit of cisatracurium. we reviewed medical records of adult neurological intensive care unit (ncu) patients who received st, to may st, . the efficacy between the two groups was confirmed by the presence of shivering and the recovery time of motor function. safety was determined by the incidence of bradycardia and hypotension, the duration of antibiotic use and the mortality rate after discontinuation of the neuromuscular blocker in ncu. recovery time of motor function was assessed using 'motor power' and 'glasgow coma scale (gcs)'. a total of patients were included in the study: patients in cisatracurium group and patients in vecuronium group. the incidence of shivering was . % and . % (p = . ) in vecuronium and cisatracurium, respectively. the median recovery time of motor function was . [ . - . ], . [ . - . ] hours (p < . ) based on the motor power score, . [ . - . ] hours and . [ . - . ] hours (p < . ) based on the motor response score of gcs, respectively. the safety was not significantly different between the two groups. recovery time of motor function was significantly shorter in the cisatracurium group than in the vecuronium group and there was no significant difference in the others. this study identified the benefits of cisatracurium in ncu under ttm. amantadine and modafinil are neurostimulants that may improve or accelerate cognitive and functional recovery after a stroke. this systematic review describes amantadine and modafinil administration patterns post-stroke, evaluates their impact on cognitive and functional outcomes, and identifies the incidence of adverse drug effects. an investigator-initiated medline search identified all full-text english-language publications describing the administration of amantadine or modafinil post-stroke from inception through october , . -stroke); intervention (amantadine or modafinil treatment); comparison (not required); outcomes (cognitive or functional recovery). amantadine and modafinil administration practices, cognitive and functional outcomes, and incidence of adverse drug effects were collected according to the preferred reporting items for systematic reviews and meta-analysis protocols (prisma-p) approach. quantitative analysis was not performed due to heterogeneity in the measures of clinical effectiveness. initially, , publications were identified. eight amantadine ( patients) and modafinil ( patients) publications were included. only ( %) amantadine patients and ( %) modafinil patients received treatment during an acute hospitalization. time from stroke to amantadine initiation was ( , . ) days and the initial dose was ( - ) mg/day. time from stroke to modafinil initiation was ( , ) days and the initial dose was ( - ) mg/day. under-responsiveness was the most common indication for neurostimulants (n= / publications; %). thirty-eight unique measures of clinical effectiveness were reported. a positive response in at least one measure of clinical effectiveness was reported in % and % of amantadine and modafinil publications, respectively. visual hallucinations (amantadine) and excitability/agitation (modafinil) were the most common adverse effects. amantadine and modafinil may improve or accelerate cognitive and functional recovery post-stroke, but higher quality data are needed to confirm this conclusion, especially in the acute care setting. levetiracetam is an antiseizure medication that is used in neurocritical care (ncc) patients to prevent or treat seizures. behavioral adverse events (ade) are reported to occur in approximately % of patients taking levetiracetam; however, the incidence of these ades in ncc patients are unknown and may be exacerbated due to their unique cns pathology. the purpose of this study is to identify the incidence of levetiracetam-associated behavioral (lab) ades in ncc patients. adult ncc patients receiving levetiracetam, admitted between november , and october , , and diagnosed with tbi, sah or ich, or cerebral infarction were included in this study. criteria for determination of lab ades included the following: ) diagnosis codes for delirium, agitation, irritability, hostility, violent behavior, insomnia, anxiety, or depression during this hospital admit; ) administration of an antipsychotic; ) positive cam-icu; and/or ) physical restraints. day of lab ade onset was determined by the start date of the antipsychotic or a positive cam-icu. there were patients included in this study; % males, median admit gcs was . the most common neurological injuries were ich ( %) and tbi ( %). lab ades were identified in ( %) patients. these were identified by diagnosis codes in % of patients, with delirium, depression, and agitation being most common; % received an antipsychotic, % had a positive cam-icu, % had restraints ordered, and % had more than one determining factor. lab ades were reported a median of (range - ) days after levetiracetam initiation. patients with tbi had the highest reported incidence of lab ades ( %). almost half ( %) of ncc patients that received levetiracetam experienced a behavioral ade, which was of levetiracetam use in ncc patients. the recommend the use of units/kg of four--pcc) or rting lower dosing strategies of apcc. in , a fixed, lowimplemented at our institution. the objective of this study was to evaluate the efficacy and safety of fixed, low-dose apcc this single-center, retrospective chart review included adult ich patients who received apcc for oral tcome was achievement of ich hemostasis. hemostasis was defined as no progression of hematoma on head ct within hours post-apcc. safety outcomes included in-hospital mortality and incidence of thromboembolic event (vte) within days post-apcc administration or up to the time of discharge, whichever came first. -four patients receiving apcc for reversal of factor xa inhibitor associated ich ( traumatic and spontaneous) were included for analysis. median age was years; % of patients had a past medical history of atrial fibrillation and % were anticoagulated with apixaban. median apcc dose was units ( - units), with a median weight-based dose of units/kg ( - units/kg). hemostasis was achieved in % of all patients with ich ( % in patients with traumatic ich, and % of patients with spontaneous ich). mortality rate was % and vte incidence was %. of hemostasis in the majority of patients and a low incidence of vte. ally ill patients, yet the optimal monitoring method is unknown. the purpose of this study was to describe the correlation between aptt and anti-xa levels in patients receiving prophylactic sq- a retrospective chart review of patients admitted years were included if they received sq--xa level drawn within hours of each other. aptt and anti-xa levels were then compared to determine correlation and descriptive analyses were performed. correlation was defined as normal aptt levels ( . - . seconds) paired with undetectable anti-xa levels (< . iu/ml), sub-therapeutic aptt ( . - . seconds) with sub-therapeutic anti-xa ( . - . seconds), therapeutic aptt ( - seconds) with therapeutic anti-xa ( . - . iu/ml), and supra-therapeutic aptt (> seconds) with supra-therapeutic anti-xa (> . iu/ml) levels. a total of patients and paired levels were analyzed. the median time between paired aptt and anti-xa levels drawn was . hours, and . % ( / ) of levels were drawn within hour of each other. anti-xa levels were drawn at a median of . hours after the sqpaired levels correlated, while . % ( / ) of levels drawn within hour of each other correlated. a spearman's correlation coefficient of . (p= . ) was found between aptt and anti-xa levels drawn within hour of each other. a sub-therapeutic aptt with undetectable anti-xa was demonstrated in . % of levels drawn within hour of each other. the sqanti-xa levels. there was no significant correlation between aptt and anti-xa levels in patients who received sq--sqh monitoring method in the neurocritically ill population. the utilization of acute extracranial and intracranial stents for the treatment of cerebrovascular pathology is increasing. the optimal intravenous antiplatelet agent for short-term bridging of patients who are unable to tolerate or do not respond adequately to oral antiplatelet agents is unclear. cangrelor offers potential advantages over glycoprotein iib/iiia inhibitors because response can be readily measured using platelet function testing (verifynow) and it has superior pharmacokinetics including a rapid on-set of effect and rapid clearance. patients with intracranial or carotid artery stents who were administered cangrelor for bridging purposes when oral antiplatelet agents were not feasible were assessed. relevant demographic, clinical and procedural data as well as cangrelor dosing and platelet function testing data were collected. patients had carotid artery stents. the indications for bridging were acute gi bleeding, inability to tolerate oral medications due to severe nausea/vomiting and two patients had an inadequate response to initial oral ticagrelor dosing based on platelet function testing. the dose of cangrelor utilized for all patients was . mcg/kg/min and all patients were on a cangrelor infusion for less than hours. platelet function testing (verifynow) was utilized to ensure adequate platelet inhibition and all patients demonstrated adequate inhibition on the prescribed dose. no stent thrombosis or bleeding was observed. cangrelor is a reasonable option when patients with intracranial or carotid stents necessitate an intravenous antiplatelet for bridging when oral antiplatelet medications are not feasible. current guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult intensive care unit (icu) patients recommend a multimodal analgesia-first strategy to minimize opioid and sedative requirements and encourage early mobilization. the purpose of this study was to evaluate the success of a stepwise multidisciplinary implementation of an analgesiafirst sedation pathway followed by introduction of an early mobility protocol in a neuroscience icu (nsicu). we retrospectively evaluated mechanically ventilated adult nsicu patients admitted to a single-center academic medical center. three-month time periods were evaluated at baseline (phase i), after implementation of the sedation pathway (phase ii), and after implementation of the early mobility protocol (phase iii). total of patients were evaluated: phase i (n= ), phase ii (n= ), and phase iii (n= ). we observed a progressive decrease in propofol use during each phase (i, ii and iii) (median . mg/day versus . mg/day versus . mg/day, respectively; p= . between phase i and iii) and increased dexmedetomidine utilization ( % versus % versus . % of patients, respectively; p< . ). opioidanalgesia requirements during mechanical ventilation were similar between groups. we observed a quicker time from admission to pt evaluation between phase ii and phase iii (median [iqr] of days [ ] [ ] [ ] [ ] [ ] [ ] versus days [ - ], respectively; p< . ). rehabilitation therapy was provided in . %, %, and . % of patients while admitted to the icu in phase i, ii, and iii, respectively (p= . ) and increased number of pt sessions provided per patient (median of [ - ], [ - ], and [ - ] sessions/patient during each phase, respectively). no adverse events related to early mobility were observed. interdisciplinary coordination and communication is necessary for effective unit-based practice changes as education alone is insufficient. a multidisciplinary approach to goal-directed therapy targeting pain management and light sedation increased opportunity for early mobility. the use of opioids in the neuroscience intensive care unit offset the balance of analgesia and reliability in performing neurological exam. in lieu of the current opioid crisis, we describe our center experience about the use of ketamine as an alternative medication with opioid sparing/lowering effect. retrospective chart review of patients admitted to nsicu with severe brain injury between november to april were performed. patients were separated into two groups of twenty by randomization and matching, each receiving either ketamine or propofol infusion. data collected includes age, gender, diagnosis, comorbidities, duration of ketamine, propofol and morphine equivalent (me) opioid dose. statistical descriptive analysis and independent samples t-test analytical analysis were performed to determine the difference of opioid use between two groups using spss software. the range of ketamine used over the mean period of . (range - ) days was - mcg/kg/min, while that of propofol over the mean period of . (range - ) days was - mcg/kg/min. / ( %) and / ( %) patients in the ketamine and propofol group required opioids respectively. the cumulative and mean morphine equivalent (me) dose for the ketamine group was . mg and . mg respectively, while on propofol, it was . mg and . mg. results of independent t-test analysis showed a significant p-value of . , indicating significant opioid dose reduction with ketamine. it is essential to recognize the effectiveness of ketamine as an opioid sparing/lowering agent with potential analgesic-sedative medication without significant side effects. introduction different indications. however, serious complications such as i -current pulmonary embolism in patients with a contraindication to unknown. this information would be needed to determine if opportunities for improvement exists. with approval from the local investigational review board (irb), during the period of - were identified from the interventional radiology department. only identified patient data was manually extracted via chart review to determine patient characteristics and a total of patients met inclusion criteria. . % were male. the most common neurocritical care diagnosis were intracranial hemorrhage( %), ischemic stroke ( %), central nervous system (cns) neoplasm ( %) and cns trauma ( %). . % of patients had at least venous thromboembolism (vte) was the most common indication ( %) followed by vte with contraindication for ac ( %), primary adjunctive treatment ( %) adjunctive prophylaxis ( %) and secondary adjunctive treatment ( %). in this single center study, to anticoagulation. andexanet alfa was approved in may for reversal of life-threatening hemorrhages for patients on anticoagulation with apixaban and rivaroxaban. since its approval the reversal of direct oral anticoagulant (doac) associated intracranial hemorrhages (ich) has been controversial. the objective of this study was to describe real world utilization of andexanet alfa at a large academic health system. we retrospectively reviewed patients who received andexanet alfa for an ich. patients were included if they received andexanet alfa from its time of approval to formulary through april , . baseline demographics, anticoagulation and reversal information was collected. a neurointensivist reviewed all imaging. intracerebral hematoma expansion was defined as > % increase in hematoma volume. subdural (sd) and subarachnoid hemorrhage (sah) expansion was defined as > % increase in maximal hematoma diameter. thirteen patients received andexanet alfa for ich. nine patients had an intracerebral hematoma, patient had an isolated intraventricular hemorrhage, patients had sd, and patient had a sah. the median age was (iqr - ) and % of patients were male. six patients were receiving a doac for stroke prevention, and a majority of patients ( %) were taking apixaban. the median glasgow coma scale was (iqr - ), and for patients with intracerebral hematomas the median ich score was (iqr - ). there was follow-up imaging available for patients, and patient had hematoma expansion. one patient died and another had interval surgery prior to repeat imaging. no patients had in hospital thromboembolic events up to days. of the patients, % of patients would have met exclusion criteria from the anexxa- trial. in this small sample of patients who received andexanet alfa for ich it appears hemostatic efficacy was achieved in a majority of patients with no thromboembolic events; however, larger trials are needed. lacosamide is a monotherapy or adjunctive therapy used for treatment of partial onset seizure that enhances slow inactivation of sodium channels. uncommonly reported adverse effects include pr interval prolongation, bradycardia, atrioventricular block, and ventricular tachyarrhythmias. an year-old male with history of atrial fibrillation, hypertension and aortic valve replacement on warfarin presented with an acute subdural hematoma after feeling lightheaded and falling. the patient reported having multiple recent syncopal episodes. he received prothrombin complex concentrate and vitamin k for warfarin reversal with an initial inr of . . he was started on levetiracetam and home medications of metoprolol and diltiazem were continued. the next evening, he had focal seizures, was given lorazepam and transferred back to the icu. he received lacosamide mg iv loading dose, and within minutes had a second episode of asystole. his blood pressure remained stable and he did not lose a pulse. he was given atropine x doses with no response therefore transcutaneous pacing was initiated. several minutes later, he became hypotensive and was started on isoproterenol and epinephrine infusions. ekg showed complete heart block. cardiology was consulted and placed a transvenous pacer. vasopressors were eventually weaned off however neuro exam remained poor. about a week later, family made the decision to transition to comfort measures and the patient passed away. lacosamide is an anticonvulsant primarily used for partial complex seizures. only a few cases of third degree atrioventricular block have been reported in the literature. this case of extreme atrioventricular bock with a lacosamide loading dose is not common, but a drug-drug interaction with metoprolol and diltiazem was suspected. prescribing lacosamide with beta-blockers or concomitant medications that prolong the pr interval should be done cautiously due to increased risk of atrioventricular block. tissue plasminogen activator (tpa) is currently the preferred agent for treatment of acute ischemic stroke. in about % of cases, patients will develop life threatening intracranial hemorrhage. currently the aha/asa guidelines and ncs guidelines recommend reversal of intravenous tpa with cryoprecipitate and platelet infusion. both society recommendations are based off low quality evidence and are given weak recommendations.theoretically, the mechanism of action of tranexamic acid (txa) makes it an appealing agent for reversal of tpa ; txa competitively inhibits activation of plasmin countering the mechanism of action of tpa. the purpose of this case report is to report and support usage of txa for reversal of thrombolysis with tpa. this is a patient case report in which an extensive review of the patient chart was conducted to provide an accurate history of events. extensive literature review was compiled to reflect current therapy guidelines and the off-label use of txa for reversal of tpa. year-old male presented to a tertiary care medical center with signs and symptoms of ischemic stroke symptomatic cerebellar hemorrhage. the delay in obtaining cryoprecipitate and platelet transfusion led the medical team to discuss alternative agents for the reversal of tpa. reversal with txa was discussed based on the medication's mechanism of action. txa mg/kg ( mg) was prepared at bedside and administered over minutes. repeat head ct showed no further progression of hemorrhage and there was an improvement in the patient's neurologic condition was noted hemorrhagic transformation following thrombolysis for ischemic stroke is a life threatening emergency. txa is an appealing option for reversal of tpa as it directly counters the mechanism of tpa and can be easily and quickly accessed. this case reports further strengthens and supports its usage. drug level monitoring is essential to optimize valproic acid (vpa) efficacy and minimize toxicity. total serum vpa levels of - mcg/ml are recommended, though free drug is more precisely responsible for vpa's pharmacologic effect. the interpretation of total vpa levels is complicated by the drug's complex protein binding characteristics. the use of free serum vpa levels has garnered interest, though the therapeutic range is not well defined. little is known about the relationship between free vpa levels and toxicity. we present a novel and unambiguous case of hepatotoxicity associated with elevated free vpa levels. de-identified patient data were retrospectively collected from the electronic medical record a -year-old male with a past medical history of refractory epilepsy was hospitalized for generalized tonic-clonic seizures. his prior home antiepileptic drugs (aeds) included carbamazepine and the vpa precursor divalproex. the patient's total and free vpa levels upon admission were . mcg/ml and . mcg/ml (laboratory reference range normal. the patient's home divalproex er dose was increased from mg twice daily to vpa suspension mg twice daily for his low total vpa level. on hospital day (hd) , the patient had a therapeutic total vpa level of . mcg/ml, but an elevated free vpa level of . mcg/ml in the setting concurrent with a free vpa level of . mcg/ml. the patient's vpa was then transitioned to alternative aeds due to hepatotoxicity concerns. the patient's clinical status later improved, and he was discharged probability scale implicated vpa as the probable cause of hepatotoxicity in this patient. measurement of free vpa levels helps guide dosing decisions and may reduce drug-related toxicity. limited case reports of osmotic demyelination syndrome (ods) treated with intravenous immunoglobulin (ivig) with or without plasma exchange (pe) are published, demonstrating variable neurologic recovery. the combination of ivig and pe led to complete neurologic recovery of our ods patient. electronic chart review to collect data for this case report. -year-old male presented with asymptomatic serum sodium of meq/l in the setting of intractable vomiting and decreased oral intake secondary to small bowel obstruction. his sodium was overcorrected by meq/l within first hours. he subsequently developed altered mental status with lethargy and became unresponsive on day with flaccid quadriparesis and minimal motor response to noxious stimuli. mri of brain revealed osmotic demyelination of central pons and bilateral basal ganglia. ivig was initiated on the day when ods was confirmed on mri. his serum sodium normalized. after day course of ivig g/kg, he could intermittently track with eyes but did not recover motor function. plasma exchange was initiated days after ivig. after sessions of pe, he started to move his right upper extremity antigravity and was attempting to verbalize. after sessions of pe, he moved all extremities antigravity, could talk although he had staccato speech and was able to ambulate with assistance. after sessions of pe, he was ambulating independently; his motor strength was +/ throughout. he was cognitively intact. at one month follow up in the clinic, he was neurologically completely intact, except for minimal upper extremity intention tremor. ivig with plasma exchange led to the remarkable neurologic recovery of a patient with ods. a randomized control trial comparing ivig monotherapy versus pe monotherapy versus the combination of ivig and pe is warranted to better clarify the appropriate treatment protocol in ods patients. digoxin is a commonly used drug in the treatment of heart failure patients but with no intrathecal indication. we describe a rare case of accidental intrathecal administration of digoxin during an elective caesarian section that lead to severe neurological deficits. a -year-old hispanic female underwent elective caesarian section with separate attempts at regional spinal anesthesia with bupivacaine due to failure of achieving adequate anesthesia with the first injection. risk management discovered that patient had erroneously received digoxin as the initial injection, confirmed by therapeutic serum levels of digoxin. two hours after delivering a healthy child, the patient's mental status deteriorated and she became unresponsive. she had three witnessed generalized tonic-clonic seizures and was emergently intubated for airway protection and received keppra. twenty-four hours in, patient remained comatose, continuous electroencephalogram revealed no seizures, magnetic resonance imaging (mri) brain showed diffuse, patchy hyperintensities involving bilateral frontotemporal lobes and basal ganglia. mri spine showed extensive cervical and thoracic cord edema. cerebrospinal fluid analysis showed white blood cells and protein count of . she received solumedrol milligram intravenous for doses followed by -day course of intravenous immunoglobulin (ivig). eleven days in, she was extubated. at discharge, she had intact upper extremity strength, intact speech, with no sensation or motor response below t level. mri showed mild thoracic cord edema. at day follow up, she had intact mental status and minimal improvement in motor strength and sensation below t . this is an extremely sad case of severe neurological deficits resulting from a grave medical error. there are only previously reported cases of intrathecal administration of digoxin in literature but the mri findings, duration of symptoms and neurological deficits were far more severe in our patient. neither cases reported use of high dose steroids or ivig either. neurological complications following organ transplantation can be a result of a myriad of infectious, toxic-metabolic, vascular and iatrogenic causes. given the wide range of possibilities, accurate diagnosis can be challenging. we present a case of acute hyperammonemia complicating renal transplantation. a -year-old female with a remote left mca stroke was evaluated for progressively worsening lethargy that started approximately a week after she had undergone deceased donor renal transplantation. her immunosuppression comprised induction with alemtuzumab plus methylprednisolone with long-term mycophenolate mofetil plus tacrolimus, and antibiotic coverage included valganciclovir, trimethoprimsulfamethoxazole and fluconazole. progressive deterioration in the level of consciousness progressing to coma with absent cough, gag reflex, sluggish pupils and no motor response resulted in the patient being intubated. neurological examination did not reveal any focal deficits besides her pre-existing right hemiparesis. pertinent investigations included an mri brain that showed no acute changes, eeg suggestive of triphasic waves and serial lumbar punctures showing elevated pressures in the - cm h o range. level of umol/l. in addition to appropriate pharmacotherapy and dietary protein restriction, the patient underwent continuous venoher mentation to baseline. additional investigations done to determine the etiology of the hyperammonemia showed the patient to be infected with ureaplasma urealyticum which was treated successfully with doxycycline and moxifloxacin. to our knowledge, this is the first report of ureaplasma urealyticum infection resulting in hyperammonemia fo management of hyperammonemia. in the absence of hepatic impairment, alternate etiologies of hyperammonemia should be sought. acute hyperammonemia requires prompt evaluation and treatment to reduce the mortality and morbidity associated with it. prevalence, characteristics, and outcomes related to ventilator associated events (vae) in neurocritically ill patients is unknown, and explored in this study. a retrospective study was conducted to examine prevalence, factors, and outcomes of patients with vae admitted to the neurocritical care service at harborview medical center between january , and december , . chi-square test, analysis of variance was used to compare patients by vae status. amongst neurocritically ill patients, vaes occurred in ( . %) patients. most common vae was ventilator associated condition, vac, ( . %), followed by infection related vac (ivac), ( . %), and possible ventilator associated pneumonia (pvap), ( . %). most common trigger for vae was an increase in positive end-expiratory pressure (peep). age (median [iqr ], male sex ( %), and bmi ( . %) were comparable across groups with and without vaes. patients with vae experienced higher intracranial pressures than those without vae( . mmhg vs. mmhg, p < . ). compared to patients without any vae, patients with any vae spent longer time on mechanical ventilation ( . vs. . days, p < . ), and in the intensive care unit ( . vs. days, p < . ). mortality ( . % vs. . %), median hospital length of stay ( . vs days) and discharge to home ( . % vs. . %) were similar across both groups. ventilator associated events are prevalent amongst the neurocritically ill. they are commonly triggered by changes in peep, and are associated with intracranial hypertension, increase length of mechanical ventilation and intensive care unit stay but may not affect mor associated with vae in subgroups of neurocritically ill patients and their impact on clinical outcomes warrants further examination. synthetic cannabinoids (sc) are a heterogeneous group of compounds initially developed to study the endogenous cannabinoid system. most sc interact with cb and cb receptors with much higher affinity -tetrahydrocannabinol. the popularity of sc is increasing in adolescents and young adults because of the ability to produce a marijuana-like high without being detected on routine drug screens. we hereby present a case of sc related status epilepticus, hypoxic respiratory failure, severe acute kidney injury (aki) and cerebral edema with fatal outcome. -year-old man with suspected sc adulteration of cbd oil presented with headache and status epilepticus. labs showed leukocytosis, triple acidosis, and tetrahydrocannabinol in urine. ct head showed diffuse cerebral edema with sulcal subarachnoid hemorrhage. intracranial pressure was elevated to - mmhg. hospital course was complicated by severe and refractory metabolic acidosis into hospitalization patient suffered cardiac arrest from pulseless ventricular tachycardia secondary to severe acidosis and metabolic derangements. after multiple attempts of resuscitation, care was withdrawn, and patient passed away. in this case, severe refractory metabolic acidosis proved to be fatal. this case highlights the many challenges in managing a critically ill patient with cerebral edema and renal failure with medically refractory metabolic acidosis. sc are undetectable on routine drug screens and exposure is difficult to establish. sc can lead to multi-organ failure and death that may result from cardiovascular events, respiratory depression, pulmonary complications, and aki. a high clinical suspicion is warranted in atrisk patients. exposure to sc may lead to cardiovascular, cerebral and renal complications that respond poorly to devise appropriate therapeutic strategies in managing such patients. benzodiazepines are the standard medication class for treating alcohol withdrawal symptoms (aws). in acute brain injury benzodiazepines may worsen delirium and its central nervous system (cns) depressant effects may decrease level of consciousness and make the neurological-exam unreliable. barbiturates have similar actions to benzodiazepines on gaba receptors and cause less cns depression. we present our center's experience with the use of phenobarbital in patients with aws and acute brain injury. retrospective chart review of twenty patients admitted in neuroscience intensive care unit(nsicu)with acute brain injury and aws was done. treatment protocol consisted of mg/kg ideal body weight(ibw) of phenobarbital loading dose divided into three intramuscular doses three hours apart, followed by a tapering daily oral maintenance dose for total of seven days. alcohol withdrawal symptoms were assessed using the ciwa score for severity. serum phenobarbital levels were drawn five hours after the third intramuscular dose. liver function tests were performed before loading dose and daily for -times the upper limit of normal triggered protocol discontinuation. none of the patients developed alcohol withdrawal seizures, one patient developed severe transaminitis. loading doses of phenobarbital did not cause hypotension. systemic toxicity was absent and phenobarbital serum levels drawn after the loading doses ranged between . - . mcg/ml (normal range - mcg/ml). patients decreased their ciwa score after the loading doses of phenobarbital suggesting improvement of withdrawal symptoms and there was decreased use of adjunctive medications (benzodiazepines) for management of aws. nine patients required adjunctive benzodiazepines and received mg or less of lorazepam. phenobarbital for management of aws was associated with minimal adverse effects and did not lead to systemic toxicity. phenobarbital can be used in patients with acute brain injury without exacerbating delirium and can decrease the need for adjunctive benzodiazepines. aneurysmal subarachnoid hemorrhage (asah) has a case fatality rate of up to % in patient that rebleed. cerebral arterial vasospasm (vsp) after asah is a leading reason for death and disability. nicardipine is used to treat hypertension and angina, and has been investigate for a potential use in the treatment of vsp after asah. intraventricular nicardine was used for treatment of severe asah after traditional methods failed (ie. ir, hypervolemia, permissive hypertension and intravenous inotropes). mg of nicardipine was mixed with preservative free saline by pharmacy to total ml in volume. ml of cerebral spinal flu drawn from the patient external ventricular device (evd). then the nicardipine solution was instilled and the evd was clamped for minutes. patient had transcranial dopplers (tcds) prior to injection and hours after injection and reopening of the evd. patient's vasospam temporized and neuro exam returned to pre spasm baseline. patient survived vasospam window and was transferred to long term care facility. in neuroscience icu (nsicu) maintaining balance between performing reliable neurological exam with adequate analgesia without causing significant sedation is challenging. ketamine has significant neuroprotective and anti-seizure properties. in spite of these unique neuro-friendly pharmacological profile, it's role in nsicu unit is not well defined. we describe our experience about the use of ketamine in neuro-critical care unit. retrospective chart review of patients admitted to nsicu in whom ketamine was used as first line agent for sedation and analgesia in intubated patients with varied brain injury from january to april was performed. safety parameters collected includes blood pressure changes, intracranial pressure changes, heart rate, arrhythmias, excess secretions and apneic spells. pco was monitored and hypercarbia was avoided. effectiveness was measured by requirement of additional sedation-analgesic medications while receiving ketamine. twenty patients with varied brain injury who were on ketamine infusion as first line agent were selected. mean age was . years (range - years) and patients were male. admitting diagnosis was hemorrhagic stroke ( %), ischemic stroke ( %), seizures ( %), carotid stenosis ( %) and tumor mass ( %). mean duration of ketamine infusion was . days (range - days) and dose range was - mcg/kg/min. no icp elevation was noted among the patients where the icp was monitored. none of the patients had uncontrollable elevated blood pressures nor major fluctuation in heart rate or respiratory rate requiring discontinuation of ketamine. ( %) patients had increased secretions without respiratory compromise. opioid use decreased significantly moreover additional sedation was not required while on ketamine infusion. ketamine is a safe and effective sedative-analgesic in neuro-critical care patients while at the same time allow for a reliable neurological examination to perform while on sedation. more research is warranted before it could be considered as the standard of care. oromandibular dystonia (omd) is a movement disorder characterized by involuntary, sustained muscle contractions of varying severity resulting in sustained spasms of craniopharyngeal muscles affecting the jaws, tongue, face, and pharynx that can lead to abnormal jaw opening or closing or tongue protrusion. these disorders are often treated with botulinum for improvement of symptoms. there is minimal literature related to omd treated for botulinum in the neurocritically ill patient population. we conducted a retrospective electronic medical record review from - of all brain-injured patients admitted to our neurocritical care unit who were diagnosed with omd and received botulinum toxin injections. etiology and location of brain injury along with clinical characteristics including resolution of symptoms were recorded. over a -year period, we injected patients with botulinum type a injection ( mouse units or m.u.) into bilateral masseter muscles for severe omd causing tongue biting/maceration and difficulty with oral care, and refractory to antispasmodics and muscle relaxant medications. among the patients, patients were sah, patient with ich/ivh, patient with bilateral brain injury after post pituitary neurosurgical procedure and patient with diffuse bilateral ischemic stroke related to sickle cell disease. all patients tolerated the procedure with no immediate complications. all patients had gradual improvement of omd albeit variable and only out of patients required a nd treatment. in this small series, injection of botulinum toxin for severe omd from brain injury causing tongue injury appears to be safe, tolerable, and efficacious in reducing enteral antispasmodics/muscle relaxants. no short-term or long-term adverse effects were noted and it helped nursing with oral care over time. larger randomized controlled trials should be performed to evaluate the effectiveness and safety of treatment with botulinum in the critically ill neurologic population. the neurosurgical intensive care unit (nsicu), a level trauma center in san antonio, cares for neuro critical patients. the use of central access catheters is essential for hypertonic fluid administration, vasoactive medications, and general critical care. in this unique population the risk of developing deep vein thrombosis (dvt) is higher compared to other patients due to reasons related to neurological injuries. the objective of this research was to determine the incidence and prevalence of dvt between the use of peripherally-inserted central catheters (picc) versus central venous catheters (cvc) in the nsicu. we prospectively evaluated consecutive patients with a cvc or picc in the nsicu from to . data was collected, by a team of apps on: surveillance vs non-surveillance ultrasounds, blood stream infections (clabsi), indwelling time, complications, and icu length of stay. a total of piccs were placed for catheter days, patients were diagnosed with a dvt related to the catheter, rate of . per catheter days. a total of cvcs were placed for catheter days, patients were diagnosed with a dvt related to the cvc, rate of . per catheter days. a total of dvts were diagnosed, one symptomatic patient and remaining dvts were identified during surveillance ultrasound. two complications were encountered during insertion of a cvc and picc which included development of hematoma on insertion of each catheter. the average length of stay for patients with a picc line was . days. the average length of stay for patients with cvc was days. the nsicu surveillance ultrasounds identified more dvts with the use of picc lines versus cvc warranted if surveillance ultrasounds should be routinely performed for nsicu patients. mortality with acute respiratory distress syndrome (ards) is as high as % in patients with subarachnoid hemorrhage (sah). many of the therapeutic modalities of ards carry potential deleterious effects on icp. we are presenting a challenging case of severe ards and sah. single case report. -year-old male who developed a sudden severe headache. emergent workup revealed a large cerebellar hemorrhage, sah with ivh and hydrocephalus secondary to a ruptured arteriovenous malformation (avm). emergent suboccipital decompressive craniectomy followed by external ventricular drain (evd) placement were performed and transferred to our facility for further aggressive care. hospital course was complicated by severe pseudomonas pneumonia with progression to severe ventilation strategies, sedation, paralysis and inhaled nitric oxide (ino) failed to correct hypoxia. on hospital day (hd) he continued to show refractory hypoxia and was placed on roto-prone® bed. continuous intracranial pressure (icp) monitoring was utilized with evd open at cmh o. prone positioning was attempted for hours daily. hypercarbia during prone positioning lead to elevated icp patient showed improvement of hypoxia, with termination of prone positioning and subsequent weaning of paralytics and sedation. he started following commands and was discharged to a long term care facility after avm embolization, placement of a tracheostomy, feeding tube and ventriculoperitoneal shunt. our patient made remarkable recovery from ards in the settings of obstructive hydrocephalus and sah. strict icp monitoring, ongoing ventilator adjustment and careful utilization of kinetic maneuvers for ards, including prone positioning, contributed. proning may be a consideration in patients with sah, obstructive hydrocephalus and ards with ongoing icp monitoring and ventilator adjustment, but larger scale studies are needed to explore its potential. paroxysmal sympathetic hyperactivity (psh) has been associated with worse outcomes following traumatic brain injury, possibly representing both a marker of injury severity and a source of secondary injury. prior studies suggest that psh is under-recognized and its treatment often delayed. the identification of admission risk factors for psh may facilitate earlier recognition, treatment, and targeted prevention. adults with severe tbi admitted to a neurotrauma icu for at least hours and hospitalized for at least days between january and december were retrospectively identified. consecutive psh-tbi patients (n= ) were identified via review of medication administration records as having been treated with propranolol and/or bromocriptine for at least hours. control-tbi patients (n= ) were matched to the psh-tbi cohort for age ( +/- years) and gcs (median ( , ) ). admission head cts were scored using marshall and rotterdam criteria. independent-samples t-tests, chi-squared, and multivariate analyses of variance were performed. age-matched cohorts did not differ by sex, race, bmi, trauma type, trauma mechanism, iss, or triss. icu admission vital signs differed between groups with psh-tbi demonstrating a higher hr (p= . ) and a trend towards higher sbp (p= . ), but no difference in core body temperature. neuroradiographic features associated with psh included significantly higher rotterdam ct score (p= . ), presence of ivh/sah (p= . ), basal cistern compression (p= . ), and trends toward higher marshall ct score (p= . ), presence of epidural hematoma (p= . ), and ct dai (p= . ). a multivariate analysis adjusting for admission gcs and sbp identified rotterdam score (p= . ), presence of ct dai (p= . ), and icu admission hr (p= . ) as independent predictors of psh. admission ct findings along with hr may help predict subsequent development of psh requiring treatment. early identification, treatment, and prevention of psh may mitigate its negative impact on tbi outcomes. hyperchloremia in patients receiving chloride-containing solutions can contribute to metabolic acidosis and acute kidney injury (aki), and has been associated with increased inpatient mortality, length of stay and aki in patients with spontaneous intracranial hemorrhage. whether hyperchloremia is a risk factor for mortality in patients with traumatic brain injury (tbi) is unknown. the purpose of this study is to determine if patients that develop moderate hyperchloremia while receiving continuous hypertonic saline (hts) have a higher risk of inpatient mortality. this was a retrospective chart review of patients admitted between january and september . included patients were over years old, admitted to the trauma service with a diagnosis of tbi, and received continuous % hts for at least hours for the management of cerebral edema. exclusion criteria were baseline end stage renal disease or hemodialysis, transition to comfort measures within hours or inconsistent documentation. the primary objective was inpatient mortality. secondary objectives were aki, hospital and intensive care unit (icu) length of stay. after tbi, mortality was higher in patients who experienced hyperchloremia, while aki and length of stay were similar. although randomized controlled trials (rcts) did not prove benefits of hypothermia for severe traumatic brain injury (tbi), brain ct images have not been evaluated in detail in these studies. we aimed to explore the prognostic value of brain ct findings in bhypo study. bhypo study was a multicenter rct to investigate the effect of therapeutic hypothermia in patients with severe tbi. the protocol included collection of brain ct data on admission and around day . using the ct database, we evaluated following findings: presence of intracranial lesion (acute subdural hematoma: asdh, acute epidural hematoma, cerebral contusion, subarachnoid hemorrhage: sah, or intraventricular hemorrhage: ivh), basal cistern compression, lesion laterality, marshall ct classification, and rotterdam ct score. hematoma thickness and midline shift were also measured. unfavorable outcomes were defined gos of to by glasgow outcome scale (gos) assessed at months. ct data were obtained from patients on admission and patients around day . there were no differences in ct findings between hypothermia group and fever control group. in the initial ct, univariate analysis showed that odds ratio (or) and % confidence interval (ci) for unfavorable outcomes were: shift > hematoma thickness ( . , . - . : p= . ), sah ( . , . - . , p= . ), sah or ivh ( . , . - . , p= . ), absent cistern ( . , . - . ; p= . ), and midline shift > mm ( . , . - . , p= . ). rotterdam score was significantly higher in patients with unfavorable outcome ( . vs. . , p< . ). regarding the day ct, bilateral lesion ( . , . - . , p< . ) and sah or ivh ( . , . - . , p= . ) were significant. no patients with absent cistern survived. patients were appropriately assigned in bhypo study in terms of ct findings. shift > thickness, sah, absent cistern, and rotterdam score were powerful prognosticator in severe tbi patients undergoing targeted temperature management. cerebral edema (ce) following traumatic brain injury (tbi) causes secondary injury and increased mortality. yet, conventional measurements of ce on head computed tomography (ct) inadequately accounts for ce. serial volumetrics may facilitate estimation of total brain volume. the objective of this study was to measure the reliability of this technique and identify a threshold for brain volume (bv) change which could be indicative of ce. a subset of patients (n = ) with intracranial hemorrhage on admission ct were identified from a prospectively enrolled cohort of subjects with trauma sufficient to warrant icu admission. using medical image processing, analysis, and visualization (mipav), two independent raters calculated bv on admission and follow-up head ct scans by measuring the volume of the intracranial vault and the absolute difference (ml^ ) and percent difference between the bv values of the two scans were calculated. intraclass correlation (icc) and pearson's correlations were calculated, and significance set at . . the overall reliability of bv measurements between raters was excellent (initial scan icc . volumetric analysis to estimate bv appears to be a reliable technique across serial head ct scans. bv changes of more than . % may represent a clinically significant threshold and should be further investigated. beneficial effects of therapeutic hypothermia in adults with traumatic brain injuries are controversial. we wanted to study the effect of therapeutic hypothermia (th) on outcomes after severe traumatic brain injury (tbi) in real practice using the nationwide inpatient sample in the united states. the nationwide inpatient sample was used to obtain data on all adults who had been discharged from to with a primary diagnosis of tbi who required mechanical ventilation, intracranial pressure monitoring, or craniotomy/craniectomy. the patients with th were assigned to the th group, and the rest were assigned to the control group. the primary outcome was in-hospital mortality, and the secondary outcomes included mean the length of stay, non-routine hospital discharge, mean hospital charges. only patients ( . %) out of a total of , underwent th. th group was younger ( . versus . years, p <. ),had a lower proportion of females ( . % versus . %, p= . ) and a higher rate of in-hopsital complication of deep venous thrombosis ( . % versus . % p = . ). when controlling for age, gender, comorbidities, in-hospital complications, hospital characteristics and disease severity, th was associated with an increased rate of in-hospital mortality (odds ratio, . ; % confidence interval, . - . ), longer mean length of stay ( . vs. . days; p< . ), and greater mean total hospital cost ($ , vs. $ , ; p< . ). there was no difference between the two groups in terms of non-routine discharge (odds ratio, . ; % confidence interval, . - . ), therapeutic hypothermia was associated with poorer outcomes in patients with severe tbi. our findings disfavor therapeutic hypothermia in severe tbi in routine clinical practice. it warrants further investigation in a prospective, randomized study. a rising incidence of subdural hematomas (sdh) has been attributed in part to increased use of anticoagulants and antiplatelets. anticoagulants also worsen the severity and prognosis of sdhs, but the impact of antiplatelets on prognosis is unclear. we hypothesized that antiplatelets would not affect sdh severity or outcome, while anticoagulants would be associated with more severe features and a worse functional outcome. we systematically identified and collected data on patients presenting with a new diagnosis of sdh in at a level i trauma center. we examined common markers of sdh severity in three cohorts of patients: those not on any antithrombotics, those on antiplatelets alone, and those on anticoagulants. categorical data was compared with chi-squared tests, and continuous data was compared with mann-whitney u tests. multivariable logistic regression was used to assess the impact of antiplatelet use on functional outcome at discharge, with a poor functional outcome defined as a score of - on the modified rankin scale. we identified patients with a new sdh during : ( . %) did not take antithrombotics, ( %) took antiplatelets, and ( . %) took anticoagulants. antiplatelets were not associated with increased sdh volume, thickness, or midline shift; anticoagulants were associated with increased volume (p< . ), thickness (p< . ), and a trend towards increased midline shift (p= . ). antiplatelets were associated with a better admission score on the glasgow coma scale (p< . ). when adjusted for age and gender, antiplatelets did not affect functional outcome (or . , p . , % ci . - . ), while anticoagulants were associated with poorer functional outcome (or . , p . , % ci . - . ). despite its known association with overall sdh incidence, premorbid antiplatelet use was not associated with sdh severity or a worse functional outcome at a level trauma center. the common data elements therapeutic intensity level (cde-til) score, quantifies the intensity of nursing and medical care aimed at preventing intracranial hypertension for patients with severe traumatic brain injury. we validated the cde til in our neurotrauma intensive care unit (nticu) and found the cde-til to be highly reflective of perceived and measured therapeutic burden but noted that the scale had a ceiling effect. specifically when icp was - mmhg and higher, the cde-til did not capture the escalating burden. in an attempt to eliminate that ceiling effect and to incorporate current h til (p-til). under a quality assurance approved protocol, retrospective chart review was performed on adult patients with severe tbi. the til score was derived using both the cde-til and the p-til for each hour nursing shift for the first full days of admission. the relationship between the cde-til and p-til and the icp were investigated. reliability testing of the p-til, including interrater reliability, and validation of the p-til are ongoing. the p-til and the cde-til are highly correlated (r= . ) and the relationship between the scores and the maximum icp are similar at icp less than mmhg. at higher icps however, the slope of p-til increases to . compared to the cde-til slope of . and illustrates a . times stronger correlation between the intensity of care level as measured by p-til and icp. the p-til has greater sensitivity for quantifying the intensity of therapy aimed at controlling icps, most significantly for patients with the highest icps, icps - mmhg and above, making it an ideal scoring system for communicating current nursing and medical needs of individual tbi patients as well as potentially predicting post-intensive care or post-discharge needs. patients are frequently brought into neurologic intensive care units in cervical spine immobilization after sustaining ground level falls or after being "found down." currently there is no consensus regarding cervical spine clearance in these patients as they are unable to participate in neurologic examination. after normal ct scans, mri scans are frequently employed to evaluate for ligamentous injury and radiographic signs of cervical instability. we conducted a retrospective chart review of patients who were admitted to the neurologic intensive care unit between and in cervical collars after ground level falls or after being found down (presumed ground level falls). patients were included in the study if they were obtunded on admission (gcs< ) with neurologic exams consistent with their cranial pathology. all patients underwent a high definition ct cervical spine or cta of the neck and were cleared if there was no radiographic evidence of fracture or instability. between - , eight patients were admitted to the neurologic intensive care unit that met inclusion criteria. average age at presentation was . years. cranial pathology on presentation included intraparenchymal hemorrhage, ischemic stroke, and subdural hemorrhage. all patients underwent a high definition ct cervical spine or cta neck which showed degenerative changes without fractures, subluxations or other evidence of instability such as increased atlantodental interval, or prevertebral soft tissue swelling. average follow up was . days range ( - ). there were no cases of cleared patients that suffered secondary neurologic injury or symptoms of cervical instability during the follow up period. our study illustrates that obtunded patients after ground level falls can safely be cleared of cervical spine precautions after a high definition ct cervical spine fails to demonstrate fractures, subluxations, or other evidence of cervical instability. this protocol limits the costs associated with mri scans and the risks associated with cervical immobilization. the elderly comprise the highest incidence of traumatic brain injury (tbi) hospitalizations and death, yet most tbi studies neglect the geriatric population. previous studies suggest women have better outcomes after tbi but are inconclusive. we examined differences in outcomes between sexes after tbi in the geriatric population. this is an observational study of patients and older admitted with tbi to a level trauma center. clinical variables including medical history, severity of injury (gcs> , gcs - , and gcs< ), mechanism of injury, and ct findings were collected. good clinical outcomes were defined as a gose > and measured at discharge and months. the chianalysis were used where appropriate. subjects were included in the analysis. ( %) women and ( %) men. average age was . (sd . ) with no significant differences between sexes. ( %) were mild, ( %) moderate, and ( %) severe. the most common etiologies were mechanical fall ( %), motor vehicle accident ( %), and syncopal fall ( . %). no differences in severity of injury or mechanism of injury were found. on admission ct, men had more contusions ( %v %;p= . ) and skull fractures( %v %;p, . ) compared to women. older age, and history of atrial fibrillation or congestive heart failure were associated with increased incidence of death. men were more likely to have in-hospital mortality ( %v %; p< . ). in multivariable logistic regression analysis controlling for other factors associated with mortality, men were significantly more likely to have in-hospital death (or- ;p= . ). at months, men were still found to have higher mortality (or- . ;p< . ). however, there were no significant differences in good outcomes between sexes at discharge ( %v %; p= . ) or months ( %v %;p= ). men have significantly higher mortality rates compared to women in the geriatric tbi population. differences are needed. partial brain tissue oxygen tension (pbto ) can be regulated by the fraction of inspired oxygen and the level of oxygen carrying capacity. we performed a systematic review of the literature using pbto directed treatment with red blood cell transfusion (rbct) to analyze clinical and physiological outcomes as well as adverse events following rbct. we performed a systematic review following the prisma guidelines and pre-registered with the prospero database. the following terms were used: [(brain tissue oxygen or brain tissue hypoxia or pbo ) and treatment] or [(brain tissue oxygen) or red blood cell transfusion) or pbo ) or traumatic brain injury) and red blood cell transfusion]. inclusion criteria were studies in which pbto was measured before and after rbct. the tool used for qualitative scoring was the grade score. risk of bias was assessed via rti and robins-i. a total of articles were screened of which four articles were included in the final analysis. the intervention performed was to administer to units of rbc depending on the hemoglobin level and the threshold set in each study. the clinical outcome was not described in any of the studies. there was an increase in pbto in all the studies, but it was primarily significant when pretransfusion pbto was less than mmhg. the grade certainty rating for the included articles was low to moderate. our review shows that a significant increase in pbto is primarily seen when pre-transfusion pbto is less than mmhg. clinical outcome and adverse events were not described in any of the included studies. in view of the known adverse effects of rbct in critically ill patients and the limited available literature we found, transfusion should only be reserved as a later tier measure for pbto correction, and possibly only when pbto is less than mmhg. withdrawal of life-sustaining therapy (wlst) is associated with % of deaths after severe traumatic brain injury (tbi). wlst frequently occurs within the first days of hospitalization, when prognosis is most uncertain. while patient factors play a role in the decision, institutional practice patterns and physician perception of prognosis also contribute, as demonstrated in canadian studies. we hypothesized that the rate and timing of wlst among patients with severe tbi vary across the united states. we conducted a retrospective cohort study of patients with severe tbi admitted in to us trauma centers included in the trauma quality improvement program. severe, isolated tbi was defined by diagnosis code and glasgow coma scale (gcs) score < . patients under , with severe non-head injuries, or with advanced directives were excluded. centers were grouped by us census region (northeast, midwest, west, south). multiple logistic regression for wlst was performed with region, patient demographics, gcs motor score, pupillary reactivity, and midline shift as covariates. regression -hospital mortality. variability may reflect inconsistent institutional practice patterns, regional cultural differences, and the difficulty of prognostication. more reliable and standardized prognostic assessments are needed in this population. introduction: pre-injury use of antiplatelet agents may increase hemorrhage size and hematoma expansion after traumatic brain injury (tbi). however, empiric platelet transfusions may result in significant morbidity and unnecessary expense and may not be justified. we sought to determine whether a thromboelastography (teg) platelet-mapping (pm) algorithm could safely reduce platelet transfusion without clinically relevant hematoma expansion. methods: a prospective standardized teg pm-based treatment algorithm was instituted to guide reversal of antiplatelet medications in tbi patients. the algorithm established reversal thresholds for arachadonic acid inhibition (aa-inhibition > %) and adenosine diphosphate inhibition (adp-inhibition > %). consecutive tbi patients were enrolled and compared to a historical cohort. hematoma volume was calculated by itk-snap. conclusions: a teg-guided antiplatelet reversal algorithm may significantly reduce platelet transfusions without clinically significant hemorrhage expansion. increasing partial oxygen arterial tension is one method to increase the partial brain tissue oxygen (pbto ). however the effects of hyperoxia on clinical outcomes and adverse effects remain elusive. to investigate the effects of normobaric and hyperbaric hyperoxia on pbto in patients with tbi, we performed a literature review following the prisma guidelines and pre-registered with the prospero database. the following search terms were applied: [(brain tissue oxygen or brain tissue hypoxia or pbo ) and treatment] or [(brain tissue oxygen) or brain tissue hypoxia) or pbo ) or traumatic brain injury) and hyperoxia]. prospective trials and observational cohort studies were included in this review. two reviewers assessed the risk of bias of each study using the rti item bank. a total of articles were screened, of which articles were included. only one study investigated the effects of combined hyperbaric/normobaric hyperoxia and another used hyperbaric as a separate intervention; the majority of studies were of normobaric hyperoxia. overall, an increase in pbto was observed with both normobaric and hyperbaric. clinical outcome was mostly missing; one study showed an absolute reduction in mortality and improvement in favorable outcome using glasgow outcome score at months. adverse events were also only scarcely reported; studies showed that hyperoxia did not induce cerebral toxicity by using markers of oxidative stress, and one study showed no evidence of pulmonary oxygen toxicity in either the hyperbaric or normobaric hyperoxia groups. normobaric and hyperbaric hyperoxia consistently induced an increase in pbto . improvement in clinical outcome was reported in some studies but did not reach statistical significance except in one. adverse events were not adequately investigated. larger prospective studies are required to investigate the clinical outcome effects of hyperoxia, its adverse consequences, and its role in the tiered approach towards brain tissue dysoxia. early prognostication, either from clinical and/or radiological information, is an important aspect in the settings of neurocritical care with limited resources. we sought to determine the values of two radiological scoring systems in predicting the outcome of traumatic brain injury (tbi) patients, which are marshall and rotterdam ct scores in indonesia. therefore, a physician can make a better priority to provide high-yield care to all tbi patients. a retrospective cohort was conducted in a national referral hospital from july to december . all tbi patients admitted to the emergency department (ed) and had an initial ct scan were included in this study. their classification of tbi and initial ct scan were reviewed and all patients were followed to see whether the patient died or alive until discharge from the hospital (in-hospital mortality). statistical analyses were conducted to find the predictive values (sensitivity, specificity, cut-off point, relative risk) of both scoring systems. of tbi patients admitted to ed, there were patients had an initial ct scan. most of them were categorized as mild tbi ( . %), then moderate ( . %) and severe tbi ( . %). in-hospital mortality was . %. with cut-off point in marshall and rotterdam ct scores, their sensitivity ( . % vs. . %, respectively) and specificity ( . % vs. . %, respectively) were similar. same things also found in their relative risks, which are . ( % ci . - . ) and . ( % ci . - . ). both marshall and rotterdam ct scores have significant values in predicting the outcome of tbi patients, thus it should be implemented in daily emergency practice to assist a physician in making further clinical decisions. midline shift (mls) in brain is a critical condition. if not diagnosed timely, it could lead to a devastating outcome. computed tomography (ct) scan is the gold standard technique to diagnose mls in neurosurgical patients. the aim of our study was to find out association between transcranial sonography [tcs] and ct scan in assessing midline shift in patients with tbi. in this prospective ongoing study, adult patients ages - years, of either gender, with tbi were included. demographic details were noted. all patients underwent ct scan, followed by tcs. mls on tcs was determined using standard technique. we noted the mls on ct scan and time window between ct scan and tcs was also measured. consciousness was assessed using glasgow coma scale (gcs) and gcs -pupil [gcs-p] scales. descriptive data are given as mean (sd) or number. spearman's correlation test was used to detect relationship between gcs and mls assessed by ct scan and tcs, and also gcs-p. the value of p< . was considered significant. a total of neurosurgical patients were studied. male to female ratio was : . the age was [ . ] years with weight of . [ . ] kg. ten patients had gcs< . the mean value of mls measured by tcs - . , p = . ). the correlation between tcs and ct scan with gcs was in significan respectively. however the value of gcs- in patients with tbi, mls can be successfully assessed using bedside, non-invasive and non-radioactive monitor tcs when compared to a ct scan. there is a good correlation between gcs and gcs -p. early post-tbi seizures are reported to occur within hours and between days - following tbi in . % and . % patients, respectively. early seizure prophylaxis with phenytoin in severe tbi patients is drugs with better safety profile have emerged as potential alternatives. the objective was to describe seizure prophylaxis practices in critically ill tbi patients. we conducted a retrospective observational study of adult trauma icus. we included consecutive adult icu patients with moderate and severe tbi admitted between jan and dec . data were collected using standardized forms. our primary outcome was the incidence of seizure prophylaxis use. we included patients with a moderate ( %) or severe ( %) tbi. the majority were men ( . %) with mean age of . (sd . ) an ( %) and mva ( %). a total of % required invasive icp monitoring. a total of patients ( %) received early seizure prophylaxis, % for moderate and % for severe tbi. phenytoin, levetiracetam or their combination were used in ( %), ( %) and ( %) of cases, respectively. twelve patients ( %) were previously treated for pre-existing epilepsy. a total of ( %) patients experienced a seizure ( at the trauma scene, in er, in icu and on the ward). among the severe tbi patients in icu for days or more, anticonvulsants were continued for the recommended days in % of cases. early seizure prophylaxis is inconsistently used in severe tbi patients in canada. phenytoin still remains the agent most used. despite the current recommendations, % with severe tbi did not receive prophylaxis and % for a shorter period than days. raised icp persistently in severe tbi patients may be detrimental. however, chest physical therapy (cpt) is equally necessary for preventing secondary factors influencing the risk in these patients. this study was intended to observe the impact of short-term rise in icp with manual cpt in severe tbi patients on outcome along with hemodynamics. this was a prospective, observational trial on adult patients, of either sex, aged - years, with severe tbi, on mechanical ventilatory support with continuous icp monitoring, and receiving cpt on regular basis, included in this study. the cpt was applied for minutes' duration and repeated after an interval of hours in between for a total sessions in a day. the measurement measured intracranial pressure, cerebral perfusion pressure, heart rate, mean arterial pressure (from start of the intervention until min after the intervention at min interval each), and gcs after each session of cpt along with final outcome/gos at the time of discharge and months. the rise in median intracranial pressure of . (- . , . ) and median cerebral perfusion pressure of . (- , . ) was significantly higher during intervention and after intervention phase. in contrast, a median heart rate rise of . ( . , . ) and mean arterial pressure rise of . ( . , . ) were comparable. however, in patients with high baseline icp (> mmhg), poor outcome was noted in terms of low gose ( , ), and higher mortality ( . %) at hospital discharge or months after injury. significant increase in icp in severe tbi patients post cpt for minutes at a time (total minutes each day) was not tolerable in this cohort. moreover, we observed significantly low gose in patients with sustained intracranial hypertension. the effect of manual technique of cpt on final (long-term) neurological outcomes remain inconclusive but with favorable respiratory outcome. survivors of moderate and severe traumatic brain injury (mstbi) require substantial care, much of which is provided by friends and family. we sought to describe the experience and unmet needs of survivors and their informal caregivers follow mstbi, particularly related to care transitions. this study was conducted in two intensive care units (icus) at a level trauma center. we conducted qualitative, semi-structured interviews with both patients and informal caregivers of mstbi survivors at hours, one month, three months, and six months post injury. informal caregivers were defined as friends or family who planned to provide care for the patient. patients were years or older with an mstbi, and not expected to imminently die of their injuries. eighteen patient-caregiver dyads were enrolled. one patient died within hours. at hours, caregivers were interviewed; at one-month caregivers were interviewed; at three months caregivers and one survivor were interviewed; and, at six months caregivers and seven survivors were interviewed. three themes were identified in the qualitative analysis of caregiver interviews: caregiver burden, caregiver health related quality of life, and caregiver need for information and support. experiences varied depending on time since injury, discharge disposition, functional neurologic outcome, caregiver access to resources, and likely multiple other additional factors. interviews with survivors were not insightful secondary to post-traumatic amnesia. this study provides new information about the experience of informal caregivers during the six months after their friend or family member survived an mstbi. caregivers reported that needs evolved over time. at three to months, few moderate to severe tbi patients were well enough to be interviewed, and information obtained by survivors was not insightful. interventions to promote caregiving may be a substantial opportunity to improve patient and caregiver-centered outcomes following tbi. vasospasm following traumatic brain injury (tbi) has a high incidence and a detrimental effect on the neurological prognosis. yet, it remains a neglected, poorly understood phenomenon and there are no guidelines for its management. herein we present a case of severe vasospasm following tbi that caused secondary delayed cerebral ischemia (dci). we further appraised the current literature aiming at identifying predictors of vasospasm in tbi. a y/o white woman presented to the hospital after a mechanical fall resulting in mild tbi with associated subarachnoid hemorrhage (sah). glasgow coma scale (gcs) at presentation was , with no neurological deficits. a non-contrast ct head revealed diffuse bilateral fronto, parietal and temporal sah without evidence of aneurysm or vascular malformations on ct angiogram (cta). toxicology screens were negative. at hours from tbi patient developed acute severe headache. a repeated cta showed right internal carotid artery (ica) and middle cerebral artery (mca) vasospasm with no ischemia identified on mri brain. patient was started on nimodipine. on day- patient developed acute left side hemiparesis and neglect with neuroimaging evidence of a complete right mca infarct. hemodynamic augmentation therapy was initiated with partial improvement of deficits. patient subsequently developed hemorrhagic conversion of the right mca infarct. on day- neuroimaging revealed resolution of vasospasm. patient had residual left side neglect and anosognosia. in line with prior literature our patient developed vasospasm in the large intracranial vessels, at hours from the tbi and earlier than in aneurysmal sah. however, differently from previous reports, gcs at presentation was > , age was > and despite vasospasm developing later than hours it was not associated with good outcome. eded to identify accurate predictors of vasospasm following tbi with secondary dci that could improve detection and management of this detrimental phenomenon. therapeutic hypothermia and/or cooling therapy has been hypothesized to have benefits in patients with traumatic brain injury (tbi). several systematic reviews (sr) are being performed to address this question, but their results are inconsistent. the objective of this study was to assess the methodological quality of sr that included randomized clinical trials (rcts) that assessed the effects of therapeutic hypothermia and/or cooling therapy in patients with tbi. a critical appraisal study was performed in order to assess any sr that fulfilled the inclusion criteria. an unrestricted search of the literature was carried out in march at four major electronic databases (medline, embase, lilacs and cochrane library). two independent reviewers selected the studies, extracted the data and appraised the methodological quality of the included sr using the amstar- (a measurement tool to assess systematic reviews) tool. an overall assessment of the confidence in the results was performed using the checklist available in amstar- website (https://amstar.ca/amstar_checklist.php). the confidence of the results may be graded as high, moderate, low or critically low. this grading is based on the adequacy of the sr to the domains of the amstar- . the search strategy retrieved references. after the selection process, sr were included. the sr were published between - and included to rcts. the overall confidence in the results from included sr was graded as critically low in . %, low in . %, moderate in %, high in . %. a high number of sr addressing similar clinical questions were published in a short period of time. the methodological quality was adequate in only few sr. clinical practice guidelines should considered this result when choosing the evidence synthesis to recommend for practice. neurogenic pulmonary edema (npe) is a clinical syndrome characterized by acute onset after central nervous system injury. the aim of this study was to investigate the clinical features of npe in patients with subarachnoid hemorrhage (sah). the authors retrospectively analyzed a total of patients with sah who were treated at our hospital from april to september . of these patients, were included in this study after the application of predefined exclusion criteria. patient demographics, aneurysm size and location, clinical characteristics, and patient outcomes were reviewed and compared between an npe and a non-npe group. sixteen patients ( . %) presented with npe at admission. among them, patients ( . %) recovered from npe immediately, and ventilatory support was withdrawn within days from onset. a univariate analysis showed that patients with npe were of younger age (p= . ), had a higher rate of vertebral (p= . ), and lower systolic blood pressure on admission (p= . revealed significant differences in the frequency of vertebral artery dissection (odds ratio (or) . , % ci . -- . , p= . ) between the groups with and without npe. no significant group differences were found in other factors, including heart rate, neurologic outcomes at discharge. vertebral art factors for npe. however, neurologic outcomes at discharge did not differ between groups, suggesting that poor outcome due to npe could be reduced by appropriate diagnosis and treatment. antibiotic-impregnated catheters (aic) are recommended for the prevention of ventriculostomy-related infections (vri). other antibiotic prophylaxis strategies following external ventricular drain (evd) placement vary widely by institution. the role of systemic antibiotics for this indication remains controversial. we retrospectively reviewed the charts of all patients having an evd placed between january , and december , . after excluding patients who died or were discharged within hours of evd placement or had an evd placed due to suspected meningitis, patients were categorized into the periprocedural (p) or no periprocedural (np) antibiotics group. patients were determined to have a vri if catheter and up to days after catheter removal. mann-whitney u test was used to analyze descriptive data and baseline demographics. chi-squared models were used to analyze the incidence of infection. included in the no periprocedural antibiotics group (age [ - ] years; % male) and were included in the periprocedural antibiotics group (age [ - ] years; % male). the most frequent indications for evd were subarachnoid hemorrhage (sah) [np: n= ( %), p: n= ( ), p< . ], intracranial hemorrhage (ich) [np: n= ( %), p: n= ( %), p= . ), and other, which included colloid cysts and tumors [np: n= ( . %), p: n= ( %), p< . ]. there were infections in the no periprocedural antibiotics group compared to in the periprocedural antibiotics group (p= . ). the most common pathogen was coagulase-negative staphylococci (n= , %). the use of periprocedural systemic antibiotic prophylaxis did not significantly reduce the incidence of vri. periprocedural systemic antibiotics may not be necessary in the setting of antibiotic impregnated catheters to reduce the incidence of infection. cerebral artery vasospasm is a rare complication of craniopharyngioma resection but can have life altering consequences including delayed cerebral ischemia if not quickly recognized and managed appropriately. we present a case of craniopharyngioma resection in a year old male complicated by refractory vasospasm and its management with intraventricular nicardipine. data regarding the operative management, time course, vasospasm and management was accessed retrospectively after patient discharge. a year old male with recurrence of a craniopharyngioma presented with left eye vision loss and was admitted to the neurosciences intensive care unit after transsphenoidal resection. intraoperatively, the tumor was noted to be adhered to the posterior communicating artery and the left anterior cerebral artery. dense invasion into the hypothalamus was noted. this portion was carefully resected to avoid progressive lethargy. computed tomography angiography revealed new mild narrowing of the left anterior and middle cerebral arteries and bilateral posterior cerebral arteries consistent with vasospasm. the patient was treated with a vasospasm bundle including nimodipine, euvolemia, and blood pressure augmentation. over the next twenty days, the patient continued to have a variable amount of vasospasm despite aggressive medical and intra-arterial management. on post-operative day . nicardipine was then infused into the evd once a day for days, resulting in rapid and sustained improvement in vasospasm. the mechanism of vasospasm following skull base tumor resection is unknown. presence of blood in the operative bed, direct surgical injury to the blood vessels, hypothalamic dysfunction and the release of inflammatory chemicals have all been proposed. treatment remains similar to treatment used in sah, utilizing nimodipine, euvolemia, blood pressure augmentation and intra-arterial verapamil. this case demonstrates the effectiveness of intraventricular infusion of nicardipine on refractory vasospasm. to present a rare case of bilateral internal carotid artery (ica) aneurysms presenting as trigeminal neuralgia (tn), with good outcome post surgical treatment. a -year-old woman presented with disabling tn for year, exclusively affecting the right maxillary and mandibular divisions. symptoms did not abate with trial of adequate doses of gabapentin, duloxetine, oxcarbazepine and indomethacin. thin-cut magnetic resonance imaging (mri) brain with and without contrast showed rare contact with wide-necked aneurysms of bilateral petrous-cavernous icas producing prominent mass effect on bilateral adjacent trigeminal nerves. carotid arteriogram redemonstrated ica aneurysms with left measuring . mm x . mm and right measuring . mm x hours post procedure, tn had completely resolved. patient was started on aspirin mg and clopidogrel mg daily and is being tentatively planned for intervention on left aneurysm. on her month follow-up appointment with neurology, she reports no recurrence of tn. in cases of aneurysmal causes of tn, presence of bilateral aneurysms causing mass effect on the trigeminal nerve at its root is a rare occurrence and needs high clinical suspicion. due to the high risk of rupture associated with giant and symptomatic aneurysms, treatment should be expedited and aggressive in order to not only address symptomatic tn but also to avoid the risk of aneurysm rupture in the future. surgical clipping and endovascular coiling with or without stenting has demonstrated remarkable symptom relief in reviewed literature for other types of intracranial aneurysm. moyamoya disease is a chronic cerebrovascular disease characterized by spontaneous and progressive stenosis or occlusion of the internal carotid artery and its branches. revascularization procedures have been shown to improve cerebral hemodynamics and decrease the risk of strokes, but several postoperative complications are known to occur. we present a case with a fairly rare complication with characteristic radiological findings after surgery. a -year-old girl with moyamoya disease underwent left superficial temporal artery (sta)-to-middle cerebral artery (mca) anastomosis with encephalo-duro-myo-synangiosis (edms), and did right sta-mca anastomosis and edms one year after the initial surgery. the procedures were uneventful and the occlusion time was minutes. she recovered from the anesthesia without neurological deficit, and mri on postoperative day (pod) demonstrated no ischemic lesions and patent bypass, although swelling of the temporal muscle attached to the brain surface was noted. on postoperative day , she experienced a transient neurological event (left hemiparesis). magnetic resonance imaging revealed large cortical and subcortical hyperintense lesions in the middle cerebral artery territory on diffusion-weighted imaging and apparent diffusion coefficient imaging. subsequently, the radiographic findings improved within several days with resolution of the symptoms. revascularization surgery for improving a patient's hemodynamics can prevent the development of strokes, but is known to be associated with perioperative cerebral infarction and cerebral hyperperfusion causing transient neurological deterioration, delayed intracerebral hemorrhage, and vasogenic edema.this case is a reminder that hemodynamic complications can develop subacutely in patients who have undergone successful revascularization for moyamoya disease. the radiological features and mechanisms of this rare condition associated with revascularization surgery for moyamoya disease are discussed. vasospasm with delayed cerebral ischemia is a rare but known complication of endoscopic transsphenoidal resection of pituitary adenoma. this complication has rarely been reported in cases of -arterial treatment have been favorable in some cases. electronic medical record review. the patient is a year old male who underwent subtotal resection of pituitary adenoma via an open right fronto-temporal approach. eight days post-resection he developed progressive headache and leftsided weakness which acutely worsened the following day. his nihss on presentation was , consistent with right mca syndrome. ct brain showed mass effect in the right frontal lobe with . mm midline shift. cta showed sluggish flow through right m branch suggestive of vasospasm. he was taken to cerebral angiogram post-op day and received right ica intra-arterial verapamil and right ica and mca angioplasty. he was started on nimodipine following the procedure. his exam improved significantly over the course of - days. he was discharged home on verapamil mg q hours. at three month follow-up his nihss was and his modified rankin scale was . in the case we present, the patient received intra-arterial treatment with verapamil and angioplasty - days after onset of symptoms. despite delayed presentation the patient ultimately achieved a favorable functional status. vasospasm and stroke post-pituitary tumor resection are complications of which patients should be adequately informed, especially when considering the possibility of good functional outcome with intraof this potentially debilitating and life-threatening complication and attention should be paid to utilizing techniques for early detection of vasospasm. neuromonitoring is an essential part of the management of neurocritical patients. many icus in developing countries manage their patients without monitoring icp. intensivists play a vital role in clinical judgments to manage their patients. raised icp are handled either by medical management or surgical procedures like decompressive craniotomy. the study aimed to see the outcome of patients with raised icp and compare medical vs surgical management in these patients without monitoring icp. a retrospective observational study was conducted among patients admitted from january to december in the icu of dhaka medical college hospital, bangladesh. patients who had etiologies of brain code, clinical presentations and or radiological findings consistent with raised icp were included. patents were grouped into neurosurgical and medical management groups. length of icu stays and mortality were observed. student's t-test and chi-square tests were used to see the statistical significance. total of patients was selected. mean age was . ± . years, and . % were male. traumatic brain injury was the most common cause of raised icp ( . %) among selected patients. . % of patients were managed medically, and neurosurgical procedures managed . % of patients. length of icu stay was higher in neurosurgical patients compared to medical management group ( . ± . vs . ± . ; p= . , non-significant). mortality was higher in neurosurgical patients compared to medical management group ( . % vs . %; p= . , non-significant). mortality was also higher in traumatic brain injury patients who underwent neurosurgery compared to medical management ( . % vs %; p= . , non-significant). neurosurgical management didn't show a better outcome in patients with raised icp when monitoring was unavailable in a resource-limited icu. chronic kidney disease (ckd) independently increases the risk of stroke and burden of ischemic small vessel disease (svd). effects of ckd on intracranial hemodynamics remain poorly defined. this study compared svd and a transcranial doppler (tcd)-based marker of intracranial vascular resistance (pulsatility index, pi) in post-stroke patients with and without ckd. within three months of a stroke. anterior and posterior circulation pi (aca, mca, and pca) significantly correlated with mri lesion volume in all patients. ckd strongly correlated with higher distal resistance (median ckd aca pi . in patients with recent stroke, mri svd volume is significantly associated with anterior and posterior circulation pi. significantly higher svd lesion burdens and anterior circulation pis were observed in patients with ckd. ckd is an independent determinant of increased intracranial vascular resistance in both anterior and posterior cerebral circulations. atrial fibrillation is associated with an increased risk of stroke and systemic embolism. we investigated the prevalence of coexisting subdiaphragmatic visceral infarction (sdvi) in patients with acute ischemic stroke due to atrial fibrillation and also evaluated independent factors of acute sdvi. we enrolled a consecutive series of acute ischemic stroke subjects with atrial fibrillation between mra or cta were excluded. all subjects were prospectively examined using abdominal mr imaging at . t and transthoracic echocardiography (tte) within days of onset. a multivariable logistic regression analysis with predefined variable (age and sex) and the potential confounders that were associated with sdvi i the mean age was . ± . years ( % males). onset-to-abdominal image time was . ± . days. among patients, acute coexisting sdvi ( renal and splenic infarctions and superior mesenteric artery occlusion) were found in patients with acute ischemic stroke and atrial fibrillation. twelve patients had a chronic sdvi; renal and splenic infarctions. no hepatic and bladder infarction was shown. severe significantly associated with the coexistence of acute sdvi and acute ischemic stroke attributed to atrial fibrillation in the logistic regression model. (adjusted or, . ; % ci, . - . ; p = . ). there was a significant relationship between the presence of acute sdvi and severe left atrial remodeling in acute ischemic stroke patients attributed to atrial fibrillation. based on these results, we suggest that abdominal mr imaging for evaluating coexisting acute sdvi should be considered in patients with acute ischemic stroke due to atrial fibrillation, especially with left atrial enlargement on tte. patients with large hemispheric infarction are likely to accumulate chloride due to commonly used hypertonic saline for lowering elevated intracranial pressure. however, the effect of chloride burden on clinical outcomes in these patients is not well studied. this study aims to investigate the impact of maximum serum chloride concentration during admission on in-hospital mortality in critically ill patients with large hemispheric infarction. we conducted a retrospective observational study of patients with large hemispheric infarction who were admitted to the neurocritical care unit, between march and june . patients were excluded if they had baseline creatinine clearance less than ml/min, required neurocritical care for less than hours. multivariable logistic regression models were used to evaluate the association of maximum serum chloride concentration during admission with in-hospital mortality. of eligible patients, ( . %) were died in hospital. compared to patients who survive to hospital discharge, those who died in hospital had higher maximum serum chloride level during admission ( . ± . vs . ± . , p< . ). each mmol/l increase in maximum serum chloride concentration was associated with increased risk of in-hospital mortality with an odds ratio of . ( % ci, . - . , p< . ). after adjusting for confounders including acute physiology, age, chronic health evaluation ii (apache ii) score, baseline serum glucose, base deficit, use of mannitol, hypertonic saline, therapeutic hypothermia, and incidence of acute kidney injury, maximum serum chloride level remained an independent risk factor associated with in-hospital mortality (adjusted odds ratio for every mmol/l increment, . ; % ci, . - . , p= . ). higher maximum serum chloride concentration was associated with higher in-hospital mortality in critically ill patients with large hemispheric infarction. these results suggest serum chloride level should be monitored as high chloride burden may cause poor outcomes on those populations. patients with acute ischemic stroke caused by large vessel occlusion may receive both ct-angiogram (cta) and digital subtraction angiogram in the process of evaluation and management of restoring perfusion. neither aha/asa stroke/imaging guidelines address indications for transcranial doppler (tcd) and/or carotid duplex ultrasonography (cus) in early stroke evaluation and most patients do not receive additional cerebrovascular imaging after reperfusion. we investigated the clinical utility of performing tcd/cus after reperfusion in guiding post-acute care stroke management. we reviewed inpatient ischemic strokes admitted to a comprehensive stroke center in . of these had tcd/cus done and had cta done prior to tcd. of these underwent either tissue plasminogen activator or thrombectomy for reperfusion. these cases were reviewed by two experts (kh, qv), who were blinded to each other, to determine if tcd/cus provided any added value after cta affecting patient management. a nominal group process was performed, using a third blinded expert (as) in case of disagreements to reach consensus. the reviewers reported cases where tcd/cus provided incremental value for management. value added by tcd/cus, as noted by experts, included detection of residual/recurrent mobile thrombus requiring anticoagulation, confirmation of reperfusion in a symptomatic patient, distinguishing between carotid stenosis and occlusion by showing string sign on carotid ultrasound, confirming hemodynamic significance of angiographic stenosis helping triage the need for stenting/endarterectomy, and new information on chronicity of carotid stenosis based on collateral flow patterns hence deferring further intervention. our experience shows a significant added value of performing tcd/cus in more than % of stroke cases in our review. the incremental information provided by ultrasound-guided further evaluation and management decisions in most of these patients. axons of the wallerian degeneration slow (wlds) mutant mice survive weeks after traumatic and ischemic nerve injuries. prior characterization of the mutant wlds protein showed that it is a fusion gene product between the non-functional, truncated n amino acids of ube b and full functional sequence of nuclear nmnat , a rate-limiting enzyme in nad+ synthesis. however, the molecular mechanisms by which the mutant wlds protein protects axons from stroke injuries remain unclear. we sought to understand how wlds is able to robustly protect axons from ischemic injuries, and in doing so possibly identify novel therapeutic targets to attenuate axonal loss in stroke. we first sought to understand the temporal and spatial requirements of wlds activity in protecting axons from ischemic injuries. to achieve this, we developed a novel tool to conditionally regulate the expression of wlds protein by modulating its post-translational protein stability. using this powerful technique, we asked how conditionally "turning on" or "turning off" wlds activity affects axonal survival following ischemic insults. moreover, as the only known function of wlds is in catalyzing nad+ synthesis, we designed a high-throughput pharmacological screen for nad+ analogs to evaluate whether the nad+ synthetic pathway mediates wlds axon protection. we found that conditional expression of wlds protein within - hrs after stroke injuries was necessary and sufficient to confer axonal survival, whereas turning off wlds activity post-injury abolished axon protection. this indicates that wlds activity is a local event in the axon, and exerts axonal protection within a critical time window even after the injury has occured. we further observed that exogenous addition of nad+, but not its precursors or immediate metabolites, was sufficient to confer axonal protection, while attenuating nad+ levels abolished wlds axon protection. this suggests that nad+ is a molecular mediator of wlds axon protection in stroke. we showed that wlds activity is a local axonal event, and uncovered a critical window of - hrs poststroke injury in which the course of axon degeneration can be halted or even reversed in mammalian neurons. moreover, we showed that this process is mediated by rising nad+ levels in axonal compartments through a novel nad+ dependent cell signaling cascade. these findings provide powerful insight into the molecular bases of wlds activity, and uncover new therapeutic targets to delay and potentially even reverse axon degeneration in stroke. unruptured intracranial aneurysm (uia) are incidentally found on the computed tomography (ct) or magnetic resonance angiography in about % of patients. because of the risk of intracranial hemorrhage (ich), the presence of uia is contraindication to intravenous thrombolysis for acute stroke. as noncontrast ct (ncct) is mostly used for thrombolytic therapy and uia is difficult to diagnose using a ncct, uia may be found after thrombolysis. among the patients with acute ischemic stroke treated with intravenous thrombolysis for consecutive years in one stroke center, patients diagnosed with uia by ct angiography immediately after thrombolysis, were enrolled. characteristics of uia and clinical outcomes such as ich and modified rankin scale (mrs) score at discharge were analyzed. among patients treated with intravenous thrombolysis, ( . %) patients were diagnosed with uia. ally relevant artery and patients an aneurysm less than mm in diameter. the median value of the initial national institutes of health stroke scale score was (range - ). the median mrs score at discharge was (range - ). there was no patient who had ich or aneurysm rupture during admission. intravenous thrombolysis could be safe and necessary to the patients with hyperacute ischemic stroke and incidental uia. recent studies suggest that variations in the constitution of the gut microbiome contribute to atherosclerotic burden and cardiovascular disease. while many gastrointestinal (gi) diseases are known to cause disruption of the normal gut microbiome in humans, the clinical impact of gi diseases on subsequent vascular disease remains unknown. we conducted an exploratory analysis evaluating the relationship between gi disease and ischemic stroke or acute myocardial infarction (mi). we performed a retrospective cohort study using claims between - from a nationally composite of ischemic stroke or acute mi. stroke and mi were assessed separately as secondary outcomes. in an exploratory manner, we evaluated the association of each gi disorder in the icd- -cm classification with our outcomes. we then categorized individual gi disorders by anatomic location, disease chronicity, and disease mechanism. we used cox proportional hazards models to examine associations with adjustment for demographics and established vascular risk factors. since this was an exploratory, hypothesis-generating study, we report only notable positive associations. among approximately , , beneficiaries, the following gi disorders were associated with an increased risk of subsequent ischemic stroke: gastric ulcer (hr, . , % ci, . - . ), duodenal ulcer ( . , . - . ), gastritis and duodenitis ( . ; . - . ), disorders of function of stomach ( . , . - . ), other disorders of stomach and duodenum ( . ; . - . ), gastrointestinal mucositis ( . ; . - . ), unspecified noninfectious gastroenteritis and colitis ( . ; . - . ) and gastrointestinal hemorrhage ( . ; . - . ). the following categories of gi disorders were associated with an increased risk of ischemic stroke: stomach disorders ( . ; . - . ), stomach and small intestine disorders ( . ; . - . ), ulcerative disorders ( . ; . - . ) and chronic gi disorders ( . ; . - . ). gi disorders were not associated with an increased risk of mi, and some demonstrated a reduced risk. several gi disorders were associated with an increased risk of ischemic stroke, but none were associated with an increased risk of mi to evaluate the relationship between serum neutrophil-to-lymphocyte ratio (nlr) levels and early neurological deterioration (end) in ischemic stroke patients with large-artery atherosclerosis (laa). we evaluated consecutive ischemic stroke patients due to laa between january and december within the first hours of admission. the nlr was calculated by dividing the absolute neutrophil counts by the absolute lymphocyte counts. among the included patients (n = ; male, . %; mean age, years), . % (n = ) had end events. in multivariate analysis, serum nlr level was independently associated with end (adjusted odds ratio, . ; % confidence interval [ . to . ], p = . ). visit time from symptoms onset, and insitu thrombosis and artery-to-artery embolization mechanisms were also found to be significant factors for end events. in the analyses regarding the relationship between serum nlr values and burden of vascular lesions, nlr levels were positively correlated with both the degree of stenotic lesions (p for trend = . ) and numbers of vessel stenosis (p for trend = . ) in a dose-response manner. we also compared the difference of serum nlr levels according to the stroke mechanisms from underlying vascular lesions. then, hypoperfusion and in-situ thrombosis mechanisms showed higher levels of nlr. however, only in-situ thrombosis mechanism had higher nlr values among the end groups compared to non-end groups (p = . ). serum nlr levels were associated with end events in ischemic stroke patients with laa mechanism. since nlr was also closely correlated with the relevant vascular lesions, our results indicated clues for underlying mechanisms of end events. transcranial doppler (tcd) can detect emboli in numerous cerebrovascular settings. although previous studies have suggested that microembolic signals (mes) may predict recurrent stroke, the practical significance of such findings remains unclear. this uncertainty has deterred the widespread use of embolic monitoring among clinicians. in a retrospective fashion, we investigated the real-world applicability of tcd by examining whether the presence of mes portends worsened clinical outcomes. we reviewed the charts of all ischemic stroke patients (n = ) who underwent mes monitoring from january to december . of the stroke subtypes reviewed, % were atheroembolic, % were cardioembolic, % were lacunar, % were dissection, % were hypercoagulable, % were cryptogenic, and % were due to other causes. +/- mes were detected in % of patients. mes were detected at an average of . +/- . db (with a detection threshold > . db). recurrent stroke was seen in % of patients (monitored over . +/- . days). patients with mes were more likely to have recurrent stroke ( % vs. %, p < . ), undergo a revascularization procedure ( % vs. %, p = . ), have a longer length of stay ( vs. days, p = . ), and have a discharge mrs - ( % vs. %, p < . ) compared to those without mes. multivariable logistic regression analysis showed that mes was an independent predictor of recurrent stroke (or . , % ci . - . ) and of poor discharge mrs - (or . , % ci . - . ) despite controlling for antithrombotic treatments and stroke subtypes. in the largest series of patients who underwent embolic monitoring with tcd, mes predicted ischemic stroke recurrence leading to worsened disability and prolonged hospital stays. given that mes can provide important prognostic information, tcd with embolic monitoring may be clinically useful in the workup of ischemic stroke. expanded patient eligibility for mechanical thrombectomy (mer) of acute ischemic stroke (ais) has resulted in a proportional increase of patients who require emergency angioplasty and/or stenting (eas) to achieve recanalization. post-stenting antiplatelet medication management continues to remain a challenge due to lack of immediate effect and rapid reversibility ideal for patients at high risk of stent thrombosis and hemorrhagic complications, especially after intravenous alteplase (tpa). cangrelor is an immediate-acting intravenous p y receptor inhibitor with rapid clearance and restoration of normal platelet within one hour of infusion termination. we describe our preliminary experience with administration of cangrelor in ais patients undergoing mer and requiring eas as rescue therapy. ten patients with ais who received cangrelor after mer were identified. median admission national tpa prior to mer. cangrelor drip was started immediately prior to eas. median duration of cangrelor drip was hours. dual antiplatelet was given a median time of hours before discontinuation of cangrelor. seven patients had repeat imaging at months confirming durable vessel patency and no restenosis. none of the patients experienced clinical deterioration, symptomatic intracranial hemorrhage, or recurrent strokes during the hospital stay. one patient underwent surgical decompression but did not develop any hemorrhagic complications. median mrs at discharge was , and median nihss at discharge was . in our case series, cangrelor was observed to be a safe alternative to oral antiplatelet drugs in the immediate perioperative period among ais patients who underwent mer and required eas, , including patients who received tpa and at high risk for malignant cerebral edema or hemorrhagic transformation who may require emergency surgical decompression. the response of the neonatal brain to hypoxic ischemic injury (hi) is developmentally specific therefore therapies for brain hi cannot be standardized across the ages. while arginases (arg; isoforms arg- /arg- ) are enzymes actively studied for their neuroprotective/neuroregenerative effects in various neurological conditions, in neonatal hi the arg effect remains unknown. to test the hypothesis that arg changes with neurodevelopment and after hi we exposed mice c bl/ (wild-type) to hypoxia-ischemia on postnatal day , as follows: permanent coagulation of left common carotid artery to induce ischemia, a h recovery period and exposure to % oxygen/balance nitrogen at °c for min to induce hypoxia. animals were perfused at h, h, h, h and day with % paraformaldehyde, brains were post-fixed, sectioned on a cryostat ( um) and examined histologically with cresyl violet stain to assess the degree of damage and arg spatiotemporal localization via immunohistochemistry. arg expression was measured by western blot and arg activity spectrophotometrically. arg expression and activity increase during development, however this increase is suppressed by hi. arg- expression increases on day after hi which corresponds to our findings of arg- accumulation at the penumbra site. cortical arg activity remains suppressed after hi, compared to that in the hippocampus, where it increases. spatiotemporally, arg- localizes into myeloid cells in cns. arg- expression increases in microglia as early as h after injury and remains elevated for a prolonged time. arg- is localized in pyramidal neurons of the indusium griseum, fasciola cinerea, neocortex and hippocampus (ca , ca ). arg- -expressing cells are damaged by hi, however they do not undergo spatial changes. microglial arg- strongly responds to hi and may play role in neuroinflammation and neuroprotection, while argand therapeutic potential of the arg-pathway in neonatal hi. sisco: helping stroke patients with thermasuit cooling trial is a phase study in ischemic stroke with rapid induction of hypothermia to within one hour. this patient had induction followed by early malignant edema requiring decompressive hemicraniectomy while c. this is the first report of hemicraniectomy in a therapeutically hypothermic patient. results y/o woman presenting with a left mca syndrome. initial imaging demonstrated left m occlusion. she received iv tissue plasminogen activator (tpa) followed by thrombectomy with tici recanalization within practice guidelines. she was enrolled in sisco trial. she was sedated with propofol, fentanyl, and versed for induction, reaching target temperature of degrees within minutes. she remained on sedation for shivering and temperature was maintained at degrees with the artic sun. imaging hours after stroke demonstrated completed infarct with edema, midline shift, and lateral ventricle effacement. hypertonic saline was initiated, and she underwent emergent decompressive hemicraniectomy. balancing the risk of worsening edema and coagulopathy caused by mild hypothermia, rewarming was initiated at . degrees c per hour. at the time of procedure patient was at . . a successful hemicraniectomy was performed without complications. six months demonstrated improvement with the patient returning home with modified rankin , and cranioplasty performed without complications. during sisco, an emergency decompressive hemicraniectomy for malignant mca syndrome was performed for a cooled patient without complication or increased bleeding. while therapeutic hypothermia has not shown an outcome benefit in previous clinical trials, these trials have had limitations rapidly reaching targeted temperature. this may have blunted the therapeutic effect. using thermasuit, patients are able to reach target temperature significantly faster. additional clinical trials are needed to determine if the therapeutic window for targeted temperature management in ischemic stroke patients improves outcome. iv rt-pa guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. these exclusion criteria may limit thrombolytic therapy to patients who might benefit. the objective of this study is to determine if iv rt-pa is safe and whether it increases neurocritical care resource utilization in this patient population. retrospective analysis of iv rt-pa treated patients receiving oral anticoagulation (warfarin (inr > . )), novel oral anticoagulant (noac), therapeutic heparin, low-molecular weight heparin (lmwh), or with thrombocytopenia (platelets < k). patients were treated using smart criteria (consent obtained for off label rtafter treatment. increased neurocritical care resource utilization was defined as transfer from a primary to comprehensive stroke center solely for additional monitoring after off-label iv rt-pa use. patients were identified. patients received therapeutic warfarin and one had coagulopathy (unclear etiology); mean inr= . (range . - ). received therapeutic iv heparin, full dose ( mg/kg bid) lmwh, and therapeutic noacs. had thrombocytopenia (mean platelet count k). received intra-arterial (ia) rt-pa, and thrombectomy. there were sich ( . %); for all sichs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive ia rt-pa, incorrect time of onset). two developed hematoma at the catheter site with no clinical effect. patient was transferred for the sole purpose of monitoring post off-label iv rt-pa. these data suggest that iv rt-pa can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sich rates were similar to the ninds cohort. the use of iv rt-pa in these patients may increase eligibility for acute stroke therapy, particularly where ia therapy is unavailable. -pa in such patients does not appear to increase neurocritical care resource utilization though further study with a larger population is warranted. although proteinuria has been reported as a predictor of neurological deterioration, poor functional outcome and in-hospital mortality after ischemic stroke, scarce study investigated the relationship between proteinuria and the malignant middle cerebral artery infarction (mmcai). this study aimed to determine whether proteinuria is associated with the development of mmcai. patients with infarction in middle cerebral artery territory were reviewed. on admission, all patients underwent brain computed tomography (ct), the assessment of national institutes of health stroke scale (nihss) and alberta stroke program early ct score (aspects), and laboratory surveys, including urine analysis by using urine dipstick. patients with known intracranial lesions or possible urinary tract infection were excluded. patients with proteinuria were defined if urine dipstick demonstrates reading of + to +, while others were defined as patients without proteinuria. chronic kidney disease (ckd) was defined if either proteinuria or estimated glome identified. mmcai was determined if a progressive conscious disturbance or signs of uncal herniation were recorded with a midline shift > mm on a follow-up brain ct. we screened patients, and -five ( . %) patients developed mmcai, and ( . %) patients had proteinuria. patients with mmcai had a significant higher score of nihss, lower aspects, less likely being dyslipidemia, and more likely having ckd and proteinuria than patients without mmcai did. after adjustment for age, sex, dyslipidemia and aspects, patients with proteinuria (or= . , %ci= . - . , p= . ) and ckd (or = . , %ci = . - . , p= . ) had a signifi ml/min/ . m did not. in conclusion, proteinuria is associated with the development of mmcai. we suggest that proteinuria may be considered as a clinical predictor for the development of mmcai. although tpa has been shown to improve outcome in ischemic stroke across various etiologies, tpa is contraindicated in stroke secondary to septic emboli due to a significantly higher risk of bleeding. the goal of this study is to determine the safety and short-term outcomes of acute ischemic stroke patients who underwent mechanical thrombectomy due to septic emboli from infective endocarditis (ie). in this multi-center retrospective case series, we reached out to thrombectomy centers known to our principal investigator. we have so far collected data from hospitals across the us to look at outcomes after thrombectomy in patients who had an ischemic stroke from infective endocarditis. centers reviewed their database and did not have eligible cases. to date, we have collected a total of cases ( % male; average age ; % had a known history of ivdu). in % the valve implicated was bioprosthetic. % of the occlusions were m , with the remaining being the carotid terminus ( %) and m ( %). microbiology revealed that % were caused by streptococcus, % staphylococcus, % enterococcus, and % were polymicrobial. the average nihss on presentation was . . % had received tpa prior to the thrombectomy (of those, / were known to have ie). the average best nihss after thrombectomy was . (averaged across cases, the other case expired from new cardiomyopathy and multi-organ failure). % had hemorrhagic transformation (of those, / were tpa recipients). thrombectomy may be a safer and promising option in patients with ischemic stroke secondary to infective endocarditis. more data is required to compare the outcome of patients who received thrombectomy alone versus tpa followed by thrombectomy, and data collection is ongoing. therapeutic hypothermia may be an effective therapeutic measure for malignant cerebral infarction alternative to or in combination with decompressive craniectomy. the neuroimaging marker that suggests the favorable clinical course during therapeutic hypothermia is needed to predict the outcome and/or determine best and earliest timing to rewarm the patients. we included cases who received therapeutic hypothermia for malignant middle cerebral infarction in seoul national university bundang hospital between july and may . we measured hounsfield unit of ischemic core in serial computed tomography scans in each patient. the nadir of hounsfield unit of each patient was calculated. the difference of the nadir by the early clinical outcome (the survival at discharge) was analyzed. the mean age was . ± . and the male comprised . % (n= ). three patients underwent early decompressive craniectomy plus therapeutic hypothermia and patients received only therapeutic hypothermia. the mean target temperature was . ± . . a total of patients ( . %) survived at discharge. a total of computed tomography scans were analyzed (about scans per patient). the mean of the nadir hounsfield unit of each patient was . ± . in the deceased patients and . ± . in the survived patients, and the difference was statistically significant (p-value = . ) the nadir of hounsfield unit in the ischemic core was lower in the survived group than the deceased group in malignant ischemic stroke patients who received therapeutic hypothermia. the change in hounsfield unit in serial computed tomography scan may be used to estimate clinical course and optimal timing of rewarming or rescue craniectomy after therapeutic hypothermia. the volumetric analysis using semi-automated planimetry is currently being performed to elucidate this association further. mhz pulsed-wave transcranial doppler (tcd) increases the exposure of an intracranial thrombus to tenecteplase (tnk-tpa) and facilitates early reperfusion. the aim of the present study is to ascertain if tcd along with tnk-tpa could improve functional outcome in patients treated with tnk-tpa after acute ischemic stroke (ais). this is a single center, prospective, interventional study. patients with ais with national institutes of -tpa bolus) within hours of symptom onset, were randomly allocated ( : ) to either mhz pulsed-wave ultrasound for min. (sonothrombolysis)-intervention group or only tnk-tpa group. ultrasound was delivered using a mark head frame, immediately after the bolus of tnk-tpa. the primary outcome was improvement in the modified rankin scale score at days and . the secondary end points were the occurrence of symptomatic intracerebral haemorrhages and death. between january and march , patients were randomly allocated to the sonothrombolysis group and patients received only tnk-tpa. at the end of days, the sonothrombolysis group achieved mrs - in / ( . %) compared to / ( . %) in the tnk-tpa group. the p-value is . . the result is significant at p < . . the rate of sich and mortality were . % in each group. sonothrombolysis of patients treated with tnk-tpa for ais was feasible and safe, with some clinical benefits at days. the recanalization rates and outcome are better than studies done with alteplase. there was no increase in sich or mortality. tnk-tpa should be the preferred drug for thrombolysis in ais. the study should be carried out in multiple centers to see if the results of the present study can be validated. acute ischemic stroke is the second leading cause of death, especially if the patient did not receive the appropriate treatment geared towards a timely recanalization of the occluded vessels, including intravenous tissue plasminogen activator (iv t-pa) or endovascular thrombectomy. little emphasis is given to the augmentation of collateral flow to offset the deleterious effect of ischemia or lessen the progression of the penumbral tissue into infarction. we present our initial experience with such vasoaugmentation strategy in patients with acute ischemic strokes. we present o university. our series included patients with acute ischemic strokes. we excluded patients with a large vessel occlusion. all other patients were included regardless of whether they received iv-tpa or not. all patients had a ct angiogram including collateral imaging and ct perfusion study at baseline. after explaining to the patients or their next-of-kin, we started the patients on a standardized protocol of milrinone ( mcg/kg bolus followed by . mcg/kg/minute). outcome assessment was comparing the initial mrs and that of the mrs at discharge. chi square contingency analysis was used with a set level of significance of p < . . out of the patients, had good collaterals and had poor collaterals. one of those poor collaterals patient had good cross flow from pcom to the affected hemisphere, but still demonstrated poor collateral score. in our cohort, ( %) achieved good neurological outcome of mrs of or below with patients ( %) achieving a discharge mrs of . conclusions collaterals and small infarction core. the presence of cross flow wasn't helpful. the symptomatology of delayed cerebral ischemia (dci) after aneurysmal subarachnoid hemorrhage (asah) is variable and often challenging to detect, particularly in patients with poor-grade asah. we report severe symmetric quadriparesis as a previously unreported symptom of dci. a -yearwas significant for intact brainstem reflexes and withdrawal in extremities. initial treatments included aminocaproic acid and external ventricular drain insertion, followed by intra-aortic balloon pump placement for stress-induced cardiomyopathy. she subsequently underwent coiling of a ruptured left anterior choroidal artery aneurysm. on post-bleed day , she was noted to have new onset of decreased tone and minimal complex posturing to noxious stimulation in all extremities and severe inattention. transcranial doppler and digital subtraction angiography revealed moderate left greater than right middle cerebral artery and bilateral anterior cerebral artery vasospasm and she received balloon angioplasty and intra-arterial nicardipine twice. post intervention, her quadriparesis moderately improved but she continued to have decreased tone and delayed movement initiation. on post-bleed day , brain mri demonstrated infarcts in bilateral medial frontal lobes, bilateral basal ganglia & subinsular cortices. on day of discharge, she was able to spontaneously raise her left arm and legs, but only minimally moved her right arm to noxious stimulation. this case report adds severe symmetric quadriparesis to the myriad of possible clinical symptoms of dci after asah. awareness of this uncommon clinical presentation could lead to timely detection and management of delayed cerebral ischemia after asah and improved clinical outcomes. brain mri to determine infarct size is common in acute stroke management. many patients cannot undergo mri imaging due to instability, or imaging contraindications. a common ct head finding postthrombectomy is contrast extravasation, thought to be secondary to "leakage" of the blood brain barrier due to ischemia. we hypothesized that extravasation volume on post-thrombectomy ct scan correlates with final infarct size. using ct head as a proxy for final infarct size may help guide clinical decision making when mri scan is not possible. we retrospectively examined a prospectively collected, irb approved stroke code database from / / to / / . inclusion criteria included: anterior strokes that underwent thrombectomy, ct scan within hours of thrombectomy with contrast extravasation, a mri within days of the thrombectomy. demographics, diagnosis, imaging findings were extracted via chart review. we used the alberta stroke program early ct score (aspect) score, to approximate the area of contrast extravasation (ct) and area of dwi hyper intensity (mri). each region of extravasation on ct head was deducted from a score of , resulting in the "estimated infarct size (eis)". each region of mri dwi was was calculated. we demonstrated usefulness of aspect scoring for comparing infarct volume between ct extravasation and final dwi infarct size. post-thrombectomy contrast extravasation consistently underestimated final mri infarct volume by %. this relationship, if validated, may be useful to approximate mri stroke volume. dizziness is a vaguely-defined complaint involving the subjective experience of lightheadedness, disequilibrium, and room-spinning sensation. it is a frequently encountered problem in office visits and in the acute care setting, with approximately . million presentations to the emergency department annually. the differential diagnosis is broad, ranging from benign and of peripheral origin, to timesensitive and potentially fatal of central origin, including ischemic or hemorrhagic stroke and ms. it is estimated - % of patients with dizziness receive stroke diagnoses . despite the low percentage, diagnosis of posterior stroke is the one most feared to be missed by clinicians. we hope to establish a clinical scoring system for timely triage of presentation with dizziness. we retrospectively reviewed charts of patients admitted at hahnemann university hospital between and , following irb approved protocol. charts were chosen with primary inpatient admitting diagnosis: cerebral infarction due to thrombosis of basilar artery, dizziness and giddiness, and cerebral infarction due to embolism of post cerebral artery for a total of charts. patient charts were reviewed to identify predisposing factors, data points for each patient. of patients reviewed, were found to have infarctions involving the posterior circulation, . % diagnostic yield for stroke. we collected a total of data points to understand the disease process. predisposing factors identified were chronic kidney disease, diabetes, hypertension, and hyperlipidemia. surprisingly, previous stroke was not found to predispose to posterior fossa strokes. common exam findings on presentation were hemiparesis and hemisensory loss. statistical analysis is currently in process we discuss our results in the context of previous efforts aimed at developing clinical predictors for posterior fossa stroke in patients presenting with dizziness. high hir (hypoperfusion intensity ratio) is known to correlate with core size, infarct growth and worse clinical outcomes. traditionally larger infarcts have been associated with higher rates of malignant cerebral edema and need for decompressive hemicraniectomy. patients with high hir and malignant profile (tmax > s greater than % of penumbra) are associated with increased risk of malignant cerebral edema. as part of an ongoing study, we retrospectively identified all ais patients with lvo who underwent ctp imaging between january to june in our healthcare system within hours from symptom imaging studies (ct or mri) were analyzed. hir was dichotomized based on proportion of greater and less than . into malignant vs favorable profile and correlation for development of malignant cerebral edema and need for hemicraniectomy was analyzed using chi-square test of proportion for nominal variables and wilcoxon ranked sum tests for the (skewed) continuous and ordinal variables. a total of patients with lvo were identified with a median age of (iqr - ), nihss of . patients with high hir suggestive of a malignant profile (n= ), regardless of reperfusion, were associated with increased risk of malignant cerebral edema compared to those with a favorable profile (n= ) (p< . ). patients with malignant hir developed malignant cerebral edema compared to patients with favorable hir (rr= . , or= . ). patient with malignant hir underwent decompressive hemicraniectomy compared to none with favorable hir. higher hir and malignant profile, regardless of reperfusion, is associated with times increased relative risk of development of malignant cerebral edema. these patients benefit from close monitoring and aggressive care for malignant cerebral edema including osmolar therapy and potential surgical intervention. we present the case of a patient with basilar artery dissection with thrombus, who underwent successful mechanical thrombectomy with stenting and was ambulatory at discharge. patient is an -year-old female with past medical history of ehler's danlos disease who presented with left sided weakness after being found down by her family. nihss on arrival was (left sided weakness / ), bp / , glucose . her cta showed a basilar angiography was notable for a basilar dissection with reocclusion, which was treated with enterprise stent placement with tici reperfusion. mri post intervention revealed right pontine infarct, punctate infarcts in cerebellum. her exam at discharge was notable for improvement in her left sided strength, at / . she was subsequently discharged to inpatient rehabilitation. mechanical thrombectomy and stenting of the basilar artery remains a largely experimental procedure, with few guidelines and little data on outcomes. we present a case of a patient with a basilar dissection who at discharge was ambulatory and near baseline. blood viscosity (bv) is the intrinsic resistance of blood to flow and characterizes blood stickiness. several clinical and epidemiologic studies demonstrated an association between bv and the occurrence of major thromboembolic events. though bv appears significantly higher in cases of lacunar or cardioembolic strokes, relationships with demographic and laboratory findings during the acute stage of ischemic stroke are unknown. we investigated the relationship between baseline characteristics and bv within hours of symptom onset in patients with acute ischemic stroke. we enrolled patients aged years or older with documented histories of ischemic stroke or transient ischemic attack within hours of symptom onset. a scanning capillary-tube viscometer (sctv) (hemovister, pharmode inc., seoul, korea) was used to assess the whole blood viscosity (wbv). the mean age was . ± . years and . % were female. of patients, . % had a history of hypertension; %, diabetes; . %, hypercholesterolemia; . %, coronary artery disease; and %, stroke. additionally, . % were current smokers. sixty-one ( . %) patients were taking antithrombotics regularly. multiple linear regression analysis revealed that hematocrit was positively related with increased bv and prior antithrombotic use was related with decreased bv. hematocritadjusted partial correlation demonstrated that prior antithrombotic use was significantly associated with decreased bv. prior antithrombotic use is significantly associated with decreased blood viscosity within hours of symptom onset in patients with acute ischemic stroke. our findings indicate that antithrombotic medications prevent stroke by inhibiting platelet function and by changing the hemorheological profile. ischemic stroke accounts for % of stroke and is the second cause of death in brazil. the decision regarding thrombolytic treatment depends on clinical history, physical examination, and imaging. one challenge is the exclusion of situations called stroke mimics (sm). a total of patients admitted to the stroke unit were prospectively analyzed. they received a full clinical and laboratory evaluation for the diagnosis of stroke and aiming to rule out the sm possibility. the study looked up for stroke etiology, demographical and epidemiological data, stroke-specific scales, sis, the occurrence of seizures and blood pressure lower than mmhg at admission as variables of interest. the prevalence of sm and the use of thrombolytic therapy in this situation was concordant with medical literature. the risk associated with anticoagulation in acute ischemic stroke (ais) is uncertain. anticoagulation is generally not indicated for early secondary stroke prevention, but may be considered in certain conditions. we assessed the use of a weight-based institution-specific heparin nomogram in ais patients. -new haven hospital who received anticoagulation with a continuous heparin infusion in the setting of ais over a -month period. anticoagulation was initiated with an initial infusion rate of units/kg/hr without bolus, with subsequent increases in the infusion rate by unit/kg/hr, based on aptts obtained every six hours until two subsequent aptts were within goal range. we collected indication for anticoagulation, dose at therapeutic aptt, time to target aptt duration of anticoagulation, transition to oral anticoagulant therapy, cerebrovascular/cardiovascular events and major and minor bleeding complications. patients were included in analysis, % of which were male, with a mean age of ± years and an average weight of . ± . kg. indications for ac were: intracardiac thrombus ( %), (sub)occlusive intra-arterial thrombus ( %), arterial dissection ( %), thromboembolic events and hypercoagulability ( %). the median time between diagnosis of stroke and initiation of anticoagulation was hrs mins. the time to goal aptt was ± . hours with a mean infusion rate of units/kg/hr at time of goal aptt. % of patients were transitioned to an oral anticoagulant and % of patients experienced a cerebrovascular event while on heparin infusion. our institution-specific heparin nomogram provides a safe anticoagulation strategy in ais, but with a longer time to reach therapeutic goal aptt range compared to previously published data. a more aggressive titration strategy with consideration of a higher infusion start rate may facilitate reaching the target aptt within a shorter time frame. vertebral artery dissection (vad) is one of the most common identifiable causes of ischemic stroke in young age patients forming intramural hematoma. vad may occur spontaneously or secondarily to trauma, infection, or underlying arteriopathy. we report cases of spontaneous bilateral vad presenting with lateral medullary infarction a -year-old woman transferred to the emergency room with vertigo. days ago, she felt severe headache on the left temporal area. on neurologic examination, ptosis, facial hypesthesia, dysmetria on the left side were noted, and dysarthria, dysphagia, right beating nystagmus were noted also. she had no past medical history and no familial history of stroke or cephalo-cervical trauma. brain mri depicted acute infarction in left lateral medulla and dissecting aneurysm of right va and near occlusion of left va on carotid enhanced mra. disease was normal. she was treated with warfarin. a -year-old man visited to the emergency room with headache on the right occiput. on neurologic examination, ptosis, miosis, facial hypesthesia, dysmetria on the left side and hemibody hypesthesia on the right side were noted. he had no trauma history or risk factors for stroke except hypertension. brain mri depicted acute infarction in right lateral medulla and dissecting aneurysm in the bilateral vertebral arteries on carotid enhanced mra. laboratory tests showed no abnormal findings. all results were normal for young age stroke evaluation. he was treated with warfarin. although unilateral or bilateral vad due to trauma or underlying medical conditions has been reported, spontaneous bilateral vad is rare. it can present with lateral medullary syndrome or nonspecific symptoms such as headache only. physicians should include vad in the differential diagnosis for patients presenting with brainstem neurologic abnormality or headache, especially young patients. cerebrovascular complications (cvcs) occur in - % of patients with infective endocarditis (ie) and manifest as ischemic stroke, meningitis or cerebritis with % occurring during first weeks of treatment. ct or mri brain can diagnose cvcs but are insensitive early on, precluded in critically ill patients and only demonstrate the sequelae. transcranial doppler (tcd) can identify high-intensity transient signals (hits) associated with cerebral microembolization and may have a role in detecting emboli and preventing cvcs in ie. retrospective chart review and literature review. we found patients with strokes caused by ie at our institution from / to / . tcds were obtained on patients, abnormal for cerebrovascular abnormalities. only patients had minute emboli monitoring performed of which one revealed hits. though mri studies have shown microemboli in % of ie patients (duval ann intern med ), we only found studies using hits on tcds as indicators of stroke risk in ie. in a prospective study of patients with left-sided ie, cvcs occurred in % of patients with hits on tcds versus % of patients who did not (p= . ) ( lepur scand j infect dis ). two studies investigated and patients with cardiac sources of embolism and documented occurrence of hits in % and % of subjects, respectively, with highest prevalence of hits in patients with ie (sliwka stroke , georgiadis stroke . detection of hits using tcd emboli monitoring has a potential to be an important tool for identifying cases of ie at highest risk for cvcs, especially in the early stages of antimicrobial therapy. this can aid further research into preventative interventions beyond antibiotics like earlier valvular surgery or vacuum assisted vegetation extraction. therapeutic hypothermia is considered as an effective therapy to reduce cerebral edema and intracranial pressure for malignant middle cerebral artery infarction, which can be used as a life-saving treatment alternative to or combined with decompressive craniectomy. however, malignant hemispheric infarction involving whole anterior, middle and posterior cerebral artery territory has been regarded as untreatable by any measures. a -year-old man who had had right ventriculoperitoneal shunt for hydrocephalus since several years ago presented with global aphasia and right hemiplegia in may . the brain magnetic resonance imaging showed large acute infarction involving whole left hemisphere including anterior, middle and posterior cerebral arterial territory by occlusion of distal internal carotid artery. as his family refused decompressive hemicraniectomy, therapeutic hypothermia using surface-cooling method (arctic sun® ) was initiated with a target temperature of . . the maximal midline shift on brain ct was approximately mm, five days after stroke onset, which led to foramen of monro obstruction and hydrocephalus in the lateral ventricle of the opposite side. since the hydrocephalus was controlled by draining of the cerebrospinal fluid into the ventriculoperitoneal shunt, the right hemisphere was saved and brain edema combined with midline shift gradually improved. the patient finally survived and was discharged. this case may be the first that therapeutic hypothermia successfully treated large hemispheric infarction involving cerebral arteries without decompressive craniectomy. since the mass effect in our case was much larger than that of malignant middle cerebral infarction, we extended the duration of therapeutic hypothermia ( . ) to days, which prevented herniation syndrome. another interesting point is that we could manage contralateral hydrocephalus caused by extensive midline shift, heralding a fatal clinical course in malignant ischemic stroke, using the preexisting ventriculoperitoneal shunt. current aha / asa stroke guidelines list arteriovenous malformation (avm) as a contraindication for intravenous alteplase (iv tpa) in ischemic stroke. while the associated risk of spontaneous intracerebral hemorrhage varies across the differing types of intracranial vasculature malformations, very little data or case reports exist regarding the risk of hemorrhage with intravenous thrombolytics for ischemic stroke in patients with vascular malformations. a -year-old male with history of cirrhosis and known atrial fibrillation (not on anticoagulation) presented with acute onset left facial droop and left hemiplegia, nihss . onset of symptoms were within the . hour window for iv tpa. a ct head demonstrated an aspects score of . iv tpa was thus initiated. cta of the head and neck revealed a right middle cerebral artery occlusion. additionally, there was a subtle tortuosity of blood vessels within the dural surface of the right temporal lobe, suggestive of possible avm. given the stroke severity, tpa was continued and successful recanalization was completed by thrombectomy of the right m occlusion by aspiration, with confirmation of a dural based avm. the patient did well, with no complications from tpa or thrombectomy and was discharged home with an nihss . the decision to administer iv tpa in patients with symptoms of acute ischemic stroke is determined by last known well time and a non-contrasted ct. vessel imaging should not delay administration of iv tpa as incidental findings may arise which may cloud the use of iv tpa in patients who otherwise may benefit from therapy. this case provides further insight that iv tpa in those with intracranial vascular malformations may be given safely with minimally increased risk. the prevalence of stroke mimics (sm) can reach % of presumable stroke, according to some authors. its presentation can predict the diagnosis of sm with a sensitivity and specificity of % and %, respectively. this study aimed to comparatively evaluate these data in a population hospitalized in a stroke unit. the study prospectively analyzed a total of patients admitted according to the suspicion of sm, the definitive diagnosis, etiology, demographic and epidemiological data, specific scales for stroke including features and its sensitivity and specificity in a specific population. a cross-sectional analysis comprised ( . % female) patients, median age . years ( - ). the median nihss was ( -- in . % of patients. twenty-four patients ( . %) presented with initial suspicion of sm, which was confirmed in ( . %). after univariate analysis on were statistically significant (p = . and p = . , respectively). the multivariate logistic regression showed that the absence of facial paralysis (or= . , p= . , % ci= . - . ), seizure convulsion on admission (or= . , p= . , % ci= . - . ) and blood pressure at admission lower than mmhg (or= . , p= . , % ci= . specificity of . % and . % respectively, with an area under the curve of . (se= . , % ci= . -conclusions sensitivity and specificity, probably secondary to selection bias. these data are inferior to the literature but better adapted to this study population. information collected from chart review and direct patient care. a year-presented with pre-syncope, abdominal pain, and malaise. he was febrile and tachycardic, and subsequently admitted for sepsis. shortly thereafter, he experienced transient diaphoresis, expressive aphasia and right-sided weakness. mri brain showed punctate ischemic cerebellar infarcts. there was high suspicion for embolic phenomena from sepsis or he acutely decompensated to complete non-responsiveness during the echocardiogram. ct brain showed diffuse air emboli in cerebral vasculature and subarachnoid air. he was placed in the left lateral decubitus position and managed with high concentration oxygen. additionally, his antimicrobials were broadened to include fungal coverage. thoracic ct revealed free air in the mediastinum between the candidate for surgical repair of his left atrium due to hemodynamic instability. instead, he underwent urgent endoscopic esophageal stent placement. he then developed a stemi, also thought to be due to air embolus, and went into cardiac arrest with return of spontaneous circulation achieved. the following day, he developed renal failure and coded again. autopsy, in addition to massive cerebral edema and cardiac ischemia, demonstrated strep oralis bacteremia, bilateral adrenal infarcts and acute tubular necrosis. is crucial for the ability to coordinate aggressive care. open surgical repair of the left atrium and esophagus offers the best chance of survival, but its use may be limited by severe sepsis and hemodynamic instability. the efficacy of mechanical thrombectomy (mt) for acute ischemic stroke (ais) due to large vessel occlusion (lvo) is well established in the anterior circulation (ac). ais from lvo in the posterior circulation (pc) differs from the ac in myriad ways, including presentation and resistance to hypoxia. we aim to characterize the differences in risk factors and outcomes of mt for ac vs pc stroke. demographic data was collected for cases of ais undergoing mt from january to january with follow-up imaging and documented functional status at discharge. operative reports were reviewed for procedural data including stroke onset to groin puncture time, number of passes of the stent retriever, and onset to recanalization time. radiology reports of postprocedural non-contrast ct images of the head were assessed. during the study period there were eligible patients ( ac and pc). atrial fibrillation ( . % and . %, p= . ) and hyperlipidemia ( . % and . %, p= . ) were more common in ac strokes while family history of stroke was more common in pc strokes ( . % and . %, p= . ). mortality erence in procedural factors or hemorrhagic complications. ac stroke but not pc stroke. our data shows that pc stroke has a higher mortality rate than ac stroke after mt with no difference in procedural factors or hemorrhagic complications. the higher mortality rate in patients with pc stroke is likely inherent to severe disability from basilar artery occlusion rather than recanalization therapy. the data also support worse functional outcome in ac strokes with increasing age and number of passes. calcinosis is a dysregulation of vascular calcium deposition characterized by small vessel calcification and secondary fibrosis. the effect of systemic calcinosis on mineralization within the central nervous system is underreported and poorly understood. a -year old man presented to icu for possible hemorrhagic transformation of a recent left mca stroke. his medical history was notable for atrial fibrillation, end-stage renal disease, calciphylaxis on warfarin, and parathyroidectomy. his post-stroke hospital course was notable for mildly elevated serum phosphorus. the patient started apixaban two weeks post-stroke as anticoagulation for atrial fibrillation, and underwent a routine ct head one day later. the scan showed extensive high-density signal along the cortex of the recently infarcted left mca territory, initially misinterpreted as hemorrhagic transformation. the signal measured at - hounsfield units, higher than expected for acute blood. a dual-energy calcium overlap map post-processing revealed the high-density material was consistent with acute mineralization, possibly potentiated by the patient's previous calciphylaxis. this case illustrates accelerated mineralization as a mimic of acute hemorrhagic transformation. dual-energy ct is useful for differentiating hemorrhagic transformation from mineralization, and may play a special role in patients with renal disease or history of calciphylaxis. this case illustrates accelerated mineralization as a mimic of acute hemorrhagic transformation of stroke in a patient with esrd and history of calciphylaxis. dual-energy ct can differentiate between intraparenchymal hemorrhage and calcification with high accuracy using material decomposition. this imaging technique may have an especial benefit in patients with renal disease or disordered mineralization. accelerated mineralization post-stroke may worsen cerebral vessel compliance and risk of future stroke, and merits further investigation. systemic inflammatory response syndrome (sirs) without infection is a surrogate of a systemic immune response and has been related with poor outcome in several vascular diseases. we investigated associations of sirs with long-term functional outcome and contributing factors after intracerebral hemorrhage (ich). we analyzed consecutive spontaneous ich-patients from our prospective cohort-study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . sirs was defined according to standard criteria: i.e. two or more of the following parameters during hospitalization: body-temperature < °c or > °c, respiratory-rate > per minute, heart-rate > per consisted of the modified rankin-scale(mrs) at three and twelve months investigated by adjusted ordinal shift-analyses. bias and confounding were addressed by propensity score matching and multivariable regression models. of patients with ich . % (n= ) developed sirs during hospitalization. sirs-patients showed more severe ich compared to without; i.e. larger ich-volumes ( . cm³, iqr( . - . ) versus . cm³, iqr( . - . );p< . ), increased intraventricular hemorrhage ( . %,n= / versus . %,n= / ;p< . ), and poorer neurological admission status (nihss , iqr( - ) versus , iqr( - );p< . ). ich severity-adjusted analyses revealed an independent association of sirs with poorer functional outcome after three (or . , % ci( . - . );p= . ) and twelve months (or . , %ci( . - . );p= . ). increased ich-volumes on follow-up-imaging (or . , %ci( . - . );p= . ) and prior liver dysfunction (or . , %ci( . - . );p= . ) were associated with sirs. in ich patients we identified sirs to be predictive of poorer long-term functional outcome over the entire range of mrs-estimates. clinically relevant associations with sirs were documented for prior liver dysfunction and hematoma enlargement. acute major bleeding secondary to trauma is a significant complication of anticoagulated patients. in -threatening in the absence of a specific reversal agent. annexa- was a prospective, single-arm, open-label study evaluating the efficacy and safety of -primary efficacy endpoints were percent change from baseline in antiefficacy over the first hours after treatment, as determined by an independent adjudication committee. safety outcomes (including thrombotic events and death) were evaluated over days. among patients enrolled in the study, ( . %) had a bleed associated with trauma ( intracranial [ich] , non-ich). mean age was . years. eighty-three patients took apixaban, rivaroxaban, enoxaparin, and edoxaban. of the ich patients, ( . %) had bleeding in multiple compartments. the mean hematoma volume in the trauma patients with single-compartment intraparenchymal bleeding was . cc. among efficacy-evaluable ich patients, of ( . %) had excellent or good hemostatic efficacy. the percent reduction in anti-ich patients taking apixaban and rivaroxaban, respectively. the -day rates of thrombotic events and mortality were of ( . %) and of ( . %), respectively. conclusions high rate of excellent or good hemostatic efficacy, with a relatively low occurrence of thrombotic events. these results are comparable to what was observed for annexa- patients with spontaneous bleeding events, and suggest that andexanet alfa could be a safe and effective treatment in the traumatic population. -factor prothrombin complex concentrates -related ich. adult patients ( years or older) admitted to yale--related ich who evaluated at approximately hours after the baseline ct scan. secondary outcomes included mortality and modified rankin score (mrs) at hospital discharge. chi-square test and multivariable logistic regression analysis were used for unadjusted and adjusted analyses, respectively. twenty--related ich were included in the s patients received aa). majority of the patients were anticoagulated for atrial fibrillation (n= , %). group (unadju patients ( %) in aa group (unadjusted p= . ). there was no difference in mrs at discharge, patients - compared to patients ( %) in aa group (unadjusted p= . ). multivariable analyses adjusted for age, sex, race, and baseline mrs confirmed the absence of these associations (all p> . ). in our limited sample size, there was no significant difference in the degree of hemostasis achieved, allvalidate these results are warranted. symptomatic intracranial hemorrhage (sich) following mechanical thrombectomy (mt) for acute ischemic stroke (ais) due to large vessel occlusion (lvo) is a rare but devastating complication. however, it is difficult to differentiate sich from contrast extravasation on early post-procedural computed tomography (ct). we aim to evaluate the rate of sich and whether the presence of hyperdensities (hd) on post-procedural ct predicts functional outcome after mt. demographic data was collected for cases of ais undergoing mt from january to january with available follow-up imaging and documented functional status at discharge. operative reports were reviewed for procedural data and radiology reports of ct head performed immediately, and - hours post-mt were assessed. of the patients studied, ( . %, / ) had hd on immediate postoperative ct and ( . %, / ) were contrast extravasation (ce) due to resolution of hd on ct at patients developed new hd on follow-up ct, resulting in a total of patients ( . %) having ich and ( . %) having sich. in subgroup analysis, cardiac comorbidities were more common in ce patients than ich patients ( . % and . %, p= . ) with no mortality or outcome differences. diabetes mellitus (dm) was more common in sich patients than those with ce and asymptomatic ich ( . % and . %, p= . ). the mortality rate of sich patients was higher ( % vs . %) and the survivors had worse discharge nihss than pat difference in procedural factors or preference for circulation between any groups. our data show that presence of hd on immediate postoperative head ct does not predict mortality and is not related to circulation or procedural factors. sich is more common in patients with dm and associated with higher mortality rate and poor functional outcome. consecutive patients admitted to the health system with tsd -pcc between may and april were analyzed. baseline demographics and outcomes were abstracted through -up ct. tsdh volume was calculated using the abc/ method. descriptive statistics were used to analyze the -pcc and its association with outcomes. -pcc for tsdh were analyzed. the median age was [ to ], -pcc was . units/kg. patients with he had a median dose of . units/kg ( . to . ) versus . units/kg ( . to . ) for patients without he. he was seen in % of patients (rivaroxaban in , apixaban in ). among patients with he, % of patients died or went to a skilled nursing facility vs % in those without he. discharge to home or acute rehab was lower in those with he ( %) versus those without he ( %) doac use was associated with higher rates of hematoma expansion and worse outcomes in patients -pcc. treatments for the reversal of doac related tsdh should be investigated intracerebral hemorrhage (ich) is associated with peripheral immune dysfunction and infection. we aim to evaluate peripheral immune responses to ich and associations with infection and ich outcome. consecutive spontaneous ich patients admitted to a tertiary center ( / - / ) were included. patients with secondary ich and transition to comfort measures within hours were excluded. ich score, discharge modified rankin score (mrs), antibiotics use, acute clinical infections including pneumonia, bacteremia, and urinary tract infection were systematically adjudicated using modified pantheris criteria. peripheral immune dysfunction was characterized by lymphopenia and lower lymphocyte to neutrophil ratio (lnr). continuous variables were compared using student's t or wilcoxon test; univariate associations assessed using pearson's or spearman's correlation depending on distribution. ordinal logistic regression used to evaluate independent effect of lnr on discharge mrs. (jmp pro . ). cohort had mean age years, % female, median ich score [iqr - ] and median discharge mrs of . thirty-nine patients had suspected clinical infection treated with antibiotics, where only met modified pantheris criteria for infection. lower %lymphocyte (p< . ) and lnr (p< . ) on post-ich days - were associated with worse discharge mrs and higher ich scores (p's < . ). lower mean lnr on post-ich days higher mean lnr on post-ich days - (p< . ). lnr on post-ich day is independently associated with mrs (p= . ) after adjusting for ich score and sex. acute post-ich lymphopenia and reduced lnr are associated with ich score, infection and worse discharge outcome. lnr emerged as independent predictor of ich outcomes in preliminary analysis. determine how acute lymphopenia mediates ich infection risk and outcome. prolonged length of stay (los) in the intensive care unit (icu) is associated with significant medical complications and higher costs in patients with spontaneous intracerebral hemorrhage (ich). aim of this study is to assess predictors of prolonged icu los in ich. we conducted a retrospective analysis of ich patients admitted to our institution over a seven-year period. demographics, clinical data, and laboratory studies at presentation were recorded. initial ct scans were reviewed to determine location, hematoma volume, and presence of intraventricular extension. surgical interventions, insertion of an external ventricular drain (evd), and medical complications, including infections and deep vein thrombosis/pulmonary embolism (dvt/pe) were reviewed. los was calculated based on the number of midnights spent in the icu. patients spending less than -hours in the icu were excluded. ichs were analyzed. the mean age was . ± . years and . % were females. prolonged los, defined by using the point of change and cumulative sum methodology analysis after normalization of the sample, was found to be > days. intubation at presentation (p< . ), presence of ivh (p< . ), insertion of evd (p< . ), surgical evacuation (p< . ), chest infections (p< . . ) and dvt/pe (p< . ) were associated with prolonged los, while location of the hemorrhage, hematoma volume, and ich score at presentation were found not to be significant. this is a preliminary analysis to identify predictors of prolonged icu-los in intracranial hemorrhage. chest infections and dvt/pe were associated with prolonged los. surgical intervention, intubation at presentation, and insertion of evd were also independent predictors. these findings suggest that early evd weaning or shunt placement, and potentially early tracheostomy could help in decreasing the icu-los in patients with ich. diffusion weighted imaging (dwi) lesions are found in nearly % of patients with acute spontaneous intracerebral hemorrhage (sich). however, the timing of dwi lesions after sich ictus remains unknown. the purpose of this study is to estimate the timing of new dwi lesions after acute primary sich. by establishing a time frame, potential pathophysiologic mechanisms for dwi lesions can be elucidated. between september , and january , , patients were enrolled in a prospective study examining dwi lesions in acute primary sich. enrolled subjects received a research brain mri after admission blinded to the clinical teams. during the same admission, select patients received a separate brain mri as part of clinical care. subjects with scans were identified from the study cohort, and their imaging evaluated for dwi lesions. when compared to the first mri scan, the presence of a new dwi lesion on the second mri scan was defined as a new dwi event. a kaplan-meier analysis was performed to estimate the time to a new dwi event from the first mri scan. among enrolled subjects, ( . %) had two brain mris. mean age was . years, % were male, and . % were african american. the median ich score was (iqr ). median time from sich onset to first mri was . days (iqr . ). median time from first mri to a new dwi event was . days ( % ci, . to . ). median time between the first and second mri was . days (iqr . ). our data suggest that new dwi lesions occur days after sich ictus. therefore, acute interventions during the first hours after sich admission may not be associated with dwi is needed to elucidate potential mechanisms associated with dwi lesions in sich. intracranial hemorrhage (ich) is a common complication in children on ventricular assist device (vad) support, though bleed severity is highly variable. this study examined factors associated with ich requiring neurosurgical intervention in this at-risk population. children aged month- years old admitted between - with a diagnosis of intraparenchymal hemorrhage (iph) or subdural hemorrhage (sdh) while on vad support were identified retrospectively from an institutional database using icd- and icd- codes, after obtaining irb approval. patients requiring neurosurgical intervention (ns+) were compared with those who did not (ns-) using manniables). in total, children met inclusion criteria. of those, / ( . %) required neurosurgical intervention bleeds occurred in patients ( / ns+, / ns-). ns+ patients were older at bleed (mean . ± . years vs . ± . years, p = . ). all ns+ patients were taking warfarin, versus / ns-patients (p= . ); none of the ns+ patients had supratherapeutic inr. number of antiplatelet agents did not differ between groups ( . ± . ns-vs . ± . ns+, p = . ). patients received a median of ct scans (iqr - ) with no significant difference between surgical and nonsurgical groups (p = . ). among our cohort, older children and those on warfarin were more likely to require neurosurgical neurosurgical treatment, though results should be interpreted cautiously given small numbers. patients received multiple ct scans, though only a minority ultimately required neurosurgical intervention. unnecessary ct scans in this population. elevated intracranial pressure (icp), usually monitored by invasive icp-measurements, is associated with mortality in intracerebral hemorrhage (ich). the non-invasive evaluation of pupillary function using automated pupillometry is increasingly used in critical-care settings. the association of various pupillary parameters assessed by automated pupillometry with icp is unestablished, specifically the sensitivity and specificity during icp-elevation and the performance of sympathetic versus parasympathetic parameters. we enrolled ich patients admitted to our neurocritical-care unit who received invasive icpmeasurement by an external-ventricular-drain (evd). we monitored parameters of pupillary reactivity [i.e. light-reflex latency (lat; s), constriction and re-dilation velocities (cv, dv; mm/s), and percentage change of apertures (per-change; %)] using a portable pupilometer (neuroptics®) as well as corresponding icp values up to every minutes for the duration of hospital stay. receiver operating characteristic (roc) analysis was performed to investigate associations between changes in pupillary reactivity and elevated icp. sensitivity and specificity of sympathetic and parasympathetic pupillary parameters were analyzed to evaluate associations between pupillary reactivity and icp-elevation in patients ( women, mean age . ± . years), without icp-elevation and no midline shift upon neuroimaging, assessments were compared to assessments in patients ( women, . ± . years) during icp-levels > mmhg and corresponding midline shift. roc-analyses revealed a significant negative association of all assessed pupillary parameters with icp-elevation. best discriminative thresholds for icp-elevation were: cv< . mm/s, per-change< %, lat< . s, and dv< . mm/s. the highest sensitivity and specificity (i.e. . % and . %; p< . ) for an association with concomitant icp-levels > mmhg were found for a combination of the parasympathetic parameters cv< . mm/s and per-change< %. our data suggest an association between non-invasively detected changes in pupillary reactivity and elevated icp. parameters of parasympathetic pupillary modulation seem most reliable to indicate icpelevation. spontaneous ich (sich) remains a deadly complication from the use of direct oral anticoagulants -pcc for the reversal of doac -pcc in the prevention of hematoma expansion (he) in doac associated sich across a large health system. consecutive patients who were admit -pcc between may and april were analyzed. baseline demographics and outcomes were abstracted through retrospective chart review. he was defined as volume> % or > . ml between baseline and follow-up ct. sich volume was calculated using the abc/ method and ivh score. descriptive statistics were used -pcc and its association with outcomes. -pcc for sich. the median age was ( - ), % were caucasian and --pcc dose of . units/kg ( . - . ) compared to . units/kg ( . to . ) with he. he was seen in % of patients (rivaroxaban in , apixaban in ). among patients with he, % of patients died or went to a skilled nursing facility vs % in those without he. discharge to home or acute rehab was similar in both groups while rates of mortality and discharge disposition were similar between those with and without he, -pcc. treatments for the reversal of doac related sich should be investigated further. elderly patients with mild traumatic brain injury (mtbi) are frequently admitted to an intensive care unit (icu), which is potentially both harmful and unnecessary. however, little exists to inform early decision making to determine appropriate utilization of icu care. here we sought to elucidate factors available upon admission to identify geriatric patients who could safely be monitored in a non-icu setting. adults + years admitted with isolated mtbi, defined as positive radiologic study and glasgow coma scale (gcs) - , between january -december were identified. primary outcomes were ernight stay, no surgery, no intubation, and discharged home) and glasgow outcome scale (gos). positive outcome was defined as gos - and a total of patients met criteria. of these, underwent emergent neurosurgical intervention., leaving for analysis. most presented with gcs ( . %) and were admitted to icu ( . %). nearly point decrease in gcs during hospital stay. upon discharge, . % were classified gos - . predictors . ), and no home use of anticoagulant/antiplatelet medication (p = . ). presence/type of a single intracranial hemorrhage (ich) was not significantly associated with outcome, but presence of bilateral or multiple lesions independently predicted poor outcome (p = . ). overtriage of patients to an icu is costly, resource intensive, and avoidable. here, we suggest a conservative framework to assist the determination of which patients can be safely observed in non-icu population who present with mtbi. perihematomal edema (phe) is a known predictor of outcome after intraparenchymal hemorrhage (iph), but factors contributing to edema formation are incompletely understood. tissue water uptake measured using hounsfield unit density on ct scan has emerged as a predictor of edema in ischemic stroke. the aim of this study was to examine this association in iph, where the theoretical driver for edema volume is not anoxic cellular injury, but rather exposure of tissue to blood. women's hospital were prospectively enrolled between september and march . phe and hematoma were identified on ct scans performed at admission and an average of . +/- . hours later. hematoma volume, hematoma surface area and phe volume were measured. net water uptake (nwu) was calculated as the percent change in phe hounsfield unit density compared to normal contralateral hemisphere. associations between variables were examined with pearson correlations and regression analyses. hematoma volume and surface area at admission were significantly associated with phe volume on the admission scan (r = . , p < . and r = . , p < . respectively) and at the follow-up time-point (r = . , p < . and r = . , p < . respectively). there was no association between nwu and phe volume at either time-point (r = . , p = . and r = - . , p = . respectively). in multivariable analysis, hematoma volume at admission remained an independent predictor of phe volume on the follow- these results suggest that, unlike in ischemic stroke, phe volume is not related to water content. rather, hematom may suggests new avenues to predict edema formation. the risk of hematoma expansion (he) in patients with recent intracranial hemorrhage (ich) receiving therapeutic anticoagulation (ac) is not known. we aim to characterize complication rates and factors associated with he in these patients. we performed a retrospective cohort study of adult patients at harborview medical center between - , who presented with ich and were therapeutically anticoagulated within weeks after the ich for a venous thromboembolic event (vte). we excluded patients with ich due to hemorrhagic conversion of ischemic stroke, venous sinus thrombosis, or an aneurysm consequently secured. we assessed the rate of he, defined as either radiographically proven expansion requiring cessation of ac, or death due to he. t-tests and chi-squared tests were used to analyze factors associated with he. - ), % were female. we identified % sdh, % iph, and % multicompartment ichs, % due to trauma, % hypertensive, and % other etiologies. anticoagulation was initiated an average of . +/- . days after ich. overall, % developed he, one third of whom died. most patients ( %) experienced no complications, % developed minor extracranial bleeding events with ac subsequently resumed. patients with he were older ( vs. ), had higher gcs ( vs. . ), lower hematoma volume ( % vs. % > cc), larger maximal sdh diameter ( . vs . mm), anticoagulated earlier ( vs. days), and lower maximal ptt ( vs. ), although trends were not statistically significant. there was a marginally significant association between he and the presence of hydrocephalus (p< . ). while ac in patients with acute ich can be safely tolerated, there is a substantial proportion demonstrating he. our analysis was limited by the sample size. larger studies are needed to identify clinical and radiographic features associated with complications. intracerebral hemorrhage (ich) is a disease that is associated with high morbidity and mortality. we examined our center's experience with surgery for ich and clinical outcomes. we prospectively enrolled patients with spontaneous ich from to . patients were divided into two groups based on whether they received surgical or conservative management. surgical interventions included hemicraniectomy and/or hematoma evacuation. multivariable regression analysis was conducted to compare the clinical outcomes after adjusting for potential confounders. adjusted odds ratio (aor) or adjusted mean difference (amd) were reported. we included patients, ( %) had surgery and ( %) did not. of the surgical group, ( %) had hematoma evacuation, ( %) had hemicraniectomy, and ( %) had both. clinical characteristics were comparable in both groups. in the surgical group, nihss and glucose were higher and creatinine was lower compared with the nonoperative group. through multivariable analysis, we identified independent predictors of surgery in ich patients including baseline hematoma volume (aor . , % ci . - . ; p= . ) and enlargement with (aor . , % ci . increase in hematoma volume, there was a % increase in the odds of having surgical intervention. was less likely to have a favorable discharge disposition to home or inpatient rehabilitation ( % vs. %; p= . ). surgery was independently associated with longer icu length of stay (amd . , % ci . ,- . ; p= . ) and hospital length of stay (amd . , % ci . - . ; p= . ) after controlling for potential confounders. in our patient population, baseline hematoma volume and expansion were independent predictors for surgery in ich patients. after controlling for other variables, surgery did not impact ich outcomes and was associated with prolonged icu and hospital length of stay. moyamoya disease (mmd), an intracranial vasculopathy characterized by internal carotid artery hypoplasia, often presents with intracerebral hemorrhage (ich) presumably due to rupture of fragile collateral vessels. although mmd-related ich is generally managed similarly to spontaneous ich, we present a case in which standard management strategies may have led to an unprecedented catastrophic outcome. case report. a previously healthy -year-old female presented to the emergency department with right-sided weakness, dysarthria, and headache. she was intubated for airway protection. a head computed tomography (ct) demonstrated a large left basal ganglia ich. ct angiogram revealed diffuse narrowing of the entire anterior circulation with robust posterior communicating arteries. brain magnetic resonance imaging (mri) revealed prominent collateral vessels and sulcal hyperintensities ("ivy sign") consistent with mmd. given these findings, systolic blood pressure was kept under mmhg for the first hours. the following day, the patient's mental status gradually worsened. workup including repeat head ct, infectious and metabolic panels, as well as electroencephalogram (eeg) were unrevealing except for a decreased end-tidal carbon dioxide (co ). two days after presentation, the patient acutely developed fixed and dilated pupils. eeg concomitantly revealed slowing and attenuation of the background. repeat ct head showed new diffuse cerebral edema with tonsillar herniation. despite hyperosmolar therapy, paralytics, pentobarbital, and cerebrospinal fluid diversion, no improvement was noted. unfortunately, brain mri revealed multifocal brainstem infarcts with superimposed duret hemorrhages. herein, we report diffuse cerebral edema as a complication of mmd-related ich. we hypothesize that disruptions of delicate cerebral autoregulatory mechanisms led to extensive hypoxic-ischemic injury. in the setting of ich, aggressive blood pressure management coupled with relative hypocapnia may have likely caused vasoconstriction of poorly compliant arteries leading to worsened cerebral blood flow and ischemia. therefore, because of its complex pathophysiology, traditional blood pressure and co targets should be revisited in mmd-related ich. it is unknown whether admission systolic blood pressure (sbp) differs among etiologies of intracerebral hemorrhage (ich). such differences may have implications for blood pressure -lowering strategies after ich. we compared admission sbp across ich etiologies among patients in the cornell acute stroke academic registry (caesar), which has enrolled all adults with non-traumatic ich at cornell from through . trained analysts prospectively collected demographics, comorbidities, and admission sbp, defined as the first recorded value in the emergency department or upon transfer from another hospital. ich etiology was adjudicated by a panel of board-certified neurologists using the smash-u criteria. we used anova to compare mean admission sbp among ich etiologies. after verification of model assumptions, multiple linear regression was used to adjust for age, sex, race, and glasgow coma scale (gcs) score. among ich patients in caesar, admission sbp varied significantly across ich etiologies, ranging from mm hg in those with structural vascular lesions to mm hg in those with hypertensive ich (p < . ). the overall difference in admission sbp across etiologies remained significant after adjustment for age, sex, race, and gcs score (p < . by the wald test). the mean admission sbp in hypertensive ich cases was mm hg ( % ci, - mm hg) higher than in ich cases of all other etiologies combined. among patients with a history of hypertension, the mean admission sbp was mm hg ( % ci, - mm hg) higher in hypertensive ich than in ich cases of all other etiologies combined. in a single-center ich registry, admission sbp varied significantly among different ich etiologies. our results suggest that admission sbp is associated with ich etiology rather than simply representing a physiological reaction to the ich itself. incidence of clinical seizures after intracerebral hemorrhage (ich) has been reported to range from . % to %, with the majority occurring at or near onset. in the present study, we investigate incidence of clinical seizures in ich subjects during hospitalization and evaluate whether clinical seizures are associated with poor clinical outcomes at discharge. a retrospective review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. demographics, admission gcs, admission nihss, admission mrs, incidence of clinical seizures and clinical outcome at discharge were recorded. associations between the presence or absence of seizures and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. clinical seizures were identified in subjects ( . %), presenting in a median time of . days post-admission (iqr ). outcome was significantly worse for subjects who experienced a seizure compared to subjects who remained seizure-free, poor outcome (gos< ) was found on . % and . % respectively (or . , ]; p= . ). this increased risk was significant after controlling for gender, ethnicity, admission gcs, admission nihss, admission mrs higher in the seizure group compared to the seizure-free group, . % vs . % respectively (or . , % ci [ . - . ]; p= . ) after adjusting for mortality and severe vegetative state (gos , ) there was no statistical significant difference between both groups (p= . ). our study shows a significant association between clinical seizures and poor clinical outcome at hospital discharge after controlling for admission status and other type of complications; however, the presence of clinical seizures did not influence in-hospital rates of mortality. despite the well-established use of the national institutes of health stroke scale (nihss) score as a severity scale for ischemic stroke patients, it is still unclear which score is best for intracerebral hemorrhage (ich) patients. while some studies have looked at nihss and glasgow coma scale (gcs) as a predictor of mortality and -month mrs, there is a dearth in the literature looking at how they affect longer functional outcomes. in this study, we look at and compare how initial nihss and gcs predict month functional outcomes in ich patients. one-hundred patients who underwent minimally invasive ich evacuation, a standardized patient population, from december to october were retrospectively reviewed. we looked at nihss and gcs as a predictor of functional outcome at -months, defined as modified rankin scale (mrs) - . multivariate regression models were constructed using clinical and statistical inferences to predict mrs. these variables were also correlated with -month mrs in multivariate analyses. of patients, . % (n= ) were female and the average age was . (sd= . ). on admission, the median nihss was . (iqr . - . ) and the median gcs was . (iqr . - . ). multivariate logistical analyses showed that higher nihss predicts worse -month mrs, however gcs does not (p= . and . , respectively). correlation analysis with mrs at -months reveals that for every . point increase in nihss, mrs increased by . in this cohort, the admission nihss predicts -month mrs in ich patients while controlling for significant covariates, while gcs does not appear to. despite its simplicity and generalizability, the gcs lacks critical ich elements that the nihss includes. the usefulness of the nihss as a predictor of ich outcomes has been questioned, since ich patients often have depressed consciousness on presentation, however we demonstrate its utility as a predictor of -month functional outcomes. among patients with intracerebral hemorrhage (ich), it is unclear whether red blood cell (rbc) transfusions impact outcomes. we investigated the association between rbc transfusions and inhospital mortality in patients with ich. we performed a retrospective analysis using the national inpatient sample (nis) database. we used standard diagnosis codes to identify non-traumatic ich hospitalizations from through . our exposure was rbc transfusions during the ich hospitalization and the outcome was hospital mortality. we performed multivariable logistic regression to estimate the association between rbc transfusion and outcomes after adjusting for demographics, charlson comorbidity index (cci), and hospital characteristics. however, given the absence of ich severity and physiologic variable data within nis, we performed additional analyses in a separate, single-center ich cohort, adjusting for admission ich and apache-ii scores. of , non-traumatic ich hospitalizations in the nis, , ( %) patients received rbc transfusions. patients receiving rbc transfusions had more comorbidities than those not receiving rbc transfusions (cci > : % vs %). rbc transfusion was associated with increased odds of hospital mortality (adjusted or . ; % ci . - . ). in a separate cohort of primary ich patients, ( %) patients received rbc transfusions during their hospitalization. rbc transfusion was not associated with hospital mortality after adjusting for ich and apache-ii scores (adjusted or . ; % ci: . - . ). rbc transfusion was associated with increased odds of hospital mortality after ich. however, underlying medical comorbidities, acute physiologic derangements, and ich severity may account for some of these ns on outcomes after ich. deep venous thrombosis (dvt) is a common cause of morbidity and mortality in patients admitted to the neuro-intensive care unit (nicu). the aim of this work is to assess the incidence of dvt in patients diagnosed with intracerebral hemorrhage (ich) and study its demographic characteristics. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission status, incidence of dvt, hospital length of stay (hlos), intensive care unit length of stay (icu-los) and clinical outcome at discharge were recorded. data was analyzed to assess the prevalence dvt in this period. patients with ich were included. dvt was identified in subjects ( . %). median time to dvt from diagnosis was h (iqr ) after the initial symptoms of ich. the mean age of patients with dvt was . (sd . ) and subjects ( . %) were female. . % subjects were of caucasian ethnicity, . % african-american, . % hispanic, . %asian and . % were from other ethnicities. median hlos was days (iqr . ) and icu-los was days (iqr . ). moreover, . % of patients who presented a hospital-acquired dvt had a poor clinical outcome at discharge (gos< ). ich patients admitted to the nic large prospective trials are needed to understand the baseline characteristics of patients at risk of dvt as well as the utility of surveillance and different prophylaxis methods. studies have demonstrated an association between high average systolic blood pressure (sbp), and increased sbp variability with worse clinical outcomes in non-traumatic intracerebral hemorrhage (ich). nevertheless, the optimal blood pressure target remains elusive. we aim at introducing an alternative approach to assess blood pressure in the acute phase of ich, by using the metric of sbp dose, and showing that it provides a more robust association with clinical outcome. we retrospectively evaluated ichs admitted to our institution over a seven-year period. initial ct scans were analyzed to confirm the presence of intraparenchymal blood. blood pressure was recorded at presentation and hourly for the first -hours. mean sbp (msbp) in the first -hours was calculated; sbp dose (dsbp) was calculated via the trapezoidal method from area under the curve (auc), and divided in three groups: no dsbp (no time spent above mmhg), moderate dsbp (auc spent above mmhg), and high dsbp (auc above mmhg). discharge dispositions were used as surrogates of clinical outcome. poor outcome included death, hospice, and long term acute care hospital. -one patients ( . %) had poor outcome. of the patients in the no dsbp group none suffered poor outcome; % of the patients in the moderate dsbp group, and % of patients in the high dsbp group suffered poor mean sbp in predicting patient outcomes (p< . ). high dsbp in the first -hours was associated with worse clinical outcomes, and was a better predictor compared to msbp. blood pressure dose is a promising novel metric that deserves further study in the management of ich. despite lack of ich-specific therapies that improve outcome, current guidelines recommend treatment of ich at tertiary care centers. as such, ich comprises a large proportion of inter-hospital transfers (ihts) to comprehensive stroke centers (cscs) despite studies suggesting lack of mortality benefit and low csc resource utilization. the subset of patients who derive the most benefit from a csc is unclear. here, we create a triage model to identify ich patients who can safely avoid transfer to a csc. a retrospective cohort of patients with spontaneous ich transferred to our csc was used to develop our triage model. patients with early discharge from the neuro-icu without use of any csc resource during hospitalization were identified as low risk, non-utilizers (lr--nu were identified and used to develop a triage model which minimized the likelihood of release of patients requiring csc resource. this model was tested in a replication cohort for accuracy. the development and replication cohorts comprised and patients respectively of whom ( %) and ( %) were lr-nu. initial gcs and baseline ich volume were associated with lr-nu in multivariate analysis. presence of ivh and infra-tentorial location of ich were also included. initial gcs > , ich volume < ml, absence of ivh, and supratentorial location had an auc, specificity, sensitivity, ppv, and npv of . , . %, . %, . %, and . % respectively for identifying lr-nu. in the development cohort and patient in the replication cohort had a neurosurgical intervention. however mostly these were for non-emergent avm interventions. spontaneous ich patients with initial gcs > , ich volume < ml, no ivh, and supratentorial location might safely avoid iht to a csc. validation in a prospective, multicenter cohort is warranted. metastatic cardiac myxomas have many neurologic complications, including intracerebral hemorrhage. cardiac myxomas are rare intracardiac tumors. though most myxomas are benign, the risk of malignant spread to the central nervous system (cns) is well known. we describe a case of multiple recurrent intracerebral hemorrhages (ich) occurring in the setting of a recently treated cardiac myxoma. a -year old woman with a history of resected left atrial myxoma presented with a one-day history of left ear paresthesias. computed tomography (ct) of the head was performed and demonstrated ichs within the right frontal and parietal lobes and left cerebellar hemisphere. she had presented to an outside hospital several weeks earlier with similar symptoms with imaging demonstrating similar definitive evidence of malignancy or infection. conventional angiography was negative for vasculitis. brain biopsy showed no evidence of amyloidosis or glioma. at our institution, magnetic resonance imaging (mri) of the brain with double inversion recovery also revealed no evidence of vasculitis; however, the study was concerning for multiple cavernous malformations. underwent genetic testing. no mutations associated with familial cerebral cavernous malformations syndromes were identified. several months later, she returned to the hospital with recurrent symptoms. head ct and mri re-demonstrated multiple cavernous malformations with surrounding vasogenic edema, which were mildly increased compared with prior studies. given progression of her mri findings, concern for metastatic cardiac myxoma was raised. considering that - % of patients with cardiac myxoma will have some form of neurologic complication, all should receive a comprehensive neurologic evaluation. diagnosis is made with neuroimaging and brain biopsy. primary treatment of cardiac myxoma includes surgical resection. when cns lesions are present, chemotherapy or stereotactic radiosurgery should be considered. an association between spontaneous hyperventilation, severity of disease at presentation, and poor clinical outcomes has been reported in patients with subarachnoid hemorrhage (sah). we evaluated the relationship between early breathing changes and outcomes in patients with intracerebral hemorrhage (ich). consecutive patients with spontaneous ich were enrolled in an observational cohort study conducted between and at a comprehensive stroke center. patient characteristics and functional outcome at discharge were prospectively recorded. arterial blood gas (abg) measurements and mechanical ventilation settings in the first hours of admission were retrospectively collected, when available. hyperventilation was defined as pco < mmhg concurrent with ph > . in spontaneously breathing patients, excluding mechanically ventilated patients not overbreathing the set rate of a control mode. we assessed for an association between early breathing changes, hemorrhage severity and hospital outcomes by univariate and adjusted analyses. early abg data were available for of patients. patients with abg data had more severe hemorrhages than those without (median ich score versus , p< . ). hyperventilation occurred in ( %) of cases. there was no univariate association between hyperventilation and ich score, admission gcs score or initial hematoma volume. lower initial pco was associated with greater risk of in-hospital death (or . per mmhg, %ci [ . , . ], p= . ) after adjustment for ich score, pneumonia and mechanical ventilation requirements. spontaneous hyperventilation is less common after ich than sah ( % vs %, respectively) and not associated with initial disease severity. the association between lower pco and in-hospital mortality after ich, independent of neurologic severity and comorbid respiratory complications, is consistent with findings of greater delayed ischemia and worse outcomes in spontaneously hyperventilating sah patients. these associations may be mediated by a potentially modifiable underlying mechanism such as acute shifts in cerebral hemodynamics due to pco changes. ich or sah patients often undergo interhospital transfers to tertiary centers. acute clinical deterioration diversion is often implemented via external ventricular drains (evd's). the safety and efficacy of leaving the evds clamped or open during inter-hospital transfer is not known. we aimed to implement a pilot during inter-hospital transport for hemorrhagic stroke patient. under the neuroemergencies management and transfers (nemat) program, department of neurosurgery at mount sinai health system, we implemented this protocol in october, . patients with ich or sah requiring evd placement prior to inter-transfer to a specialized center for ich or sah within our health system were enrolled. recommendations for icp management, for post-evd drainage h and cm or lower for ich were included. evd was clamped for transportation and a dose g/kg of mannitol was given just prior to transportation. icp precautions were maintained throughout transportation. ( male, female_ patients who underwent inter-hospital transfers for ich (n= ) and sah (n= ) after placement of evds for raised icp at the transferring hospital were included. all patients required endotracheal intubation for transfer. / patients had an icp less than mmhg on arrival at the receiving hospital. conclusion: protocolized care for ich and sah patients with evds and icp management during interhospital transfers for patients is safe and feasible. such a protocol could an help facilitate potentially rapid and safe life saving inter-hospital transfers for hemorrhagic stroke patients with evds in large urban health system to to hospitals with specialized definitive neurosurgical and neurocritical care. intracerebral hemorrhage (ich) during pregnancy is abound with diagnostic and therapeutic dilemmas and contributes to pregnancy-related mortality. we present a pregnant patient with ich due to moyamoya disease to highlight these issues. case report. a -year-old -week pregnant asian woman presented after developing an acute onset headache followed by loss of consciousness. in the emergency department, she was comatose with bilateral pinpoint pupils and required intubation for airway protection. initial ct head showed predominantly intraventricular hemorrhage (ivh) that emanated from the left thalamus. ct angiogram revealed highgrade stenosis of the left m segment with moyamoya collateralizations. due to hydrocephalus, an external ventricular drain (evd) was placed. the patient required admission to the neurocritical care unit for further monitoring of exam and vitals. continuous fetal monitoring, and ultimately, successful csection on day of hospitalization was performed through collaboration with the obstetrics and gynecology (ob/gyn) team. cerebral angiogram confirmed the diagnosis of unilateral moyamoya disease as the cause of the patient's ivh. the patient was discharged initially to acute rehab and then home with minor cognitive deficits. the work-up and management of ich in pregnant patients can be challenging. moyamoya disease is a non-atherosclerotic cerebral vasculopathy that can be included in the differential diagnosis for ich in pregnant woman. the most common presentation of moyamoya disease in adults is ich, and it's mainly due to the rupture of dilated and fragile vessels in the basal ganglia, and rupture of saccular aneurysms within the moyamoya collaterals. pregnancy might increase the risk of ischemic or hemorrhagic stroke in women with moyamoya, but available data is controversial. cooperation between the neurocritical care and ob/gyn teams can assist in determining the risks and benefits of medications, imaging, and the need and timing for delivery, thus assuring optimal outcomes for the patient and infant. spontaneous intracerebral hemorrhage (ich) is severely disabling, and survivors often require extensive rehabilitation to maximize recovery. recovery for survivors discharged from index hospitalization is variable and incompletely explained by discharge functional capacity. we assessed whether discharge disposition was independently associated with long term recovery potential. patients with acute ich hospitalized at a tertiary care comprehensive stroke center between and were enrolled in a prospective, observational study that recorded demographics, standard severity s was measured by the modified rankin scale (mrs) at discharge and three months. discharge disposition were ordinalized by activity engagement level from highest to lowest as follows: home, ; acute inpatient rehabilitation (air), ; skilled nursing facili ; and long-term acute care hospital (ltach), . ordinal regression was used to assess the prognostic association between discharge disposition and three month functional status by mrs, adjusting for the ich score and mrs at discharge. among patients enrolled, survived and had complete in-hospital data for analysis, and three outcomes at three months (mrs - ; . % and . % respectively), with most either bedbound or dead ( . % and . % respectively). poor outcomes were less common among patients discharged to air ( . %) or home ( . %). the adjusted model found that a better discharge disposition was associated with more favorable three month mrs (odds ratio . , % ci [ . , . ], p= . ). discharge disposition captures prognostically important characteristics in patients with intracerebral hemorrhage beyond traditional case severity and functional status measures. outcomes are poor for a large majority of patients unable to return home or qualify for acute rehabilitation. whether the prognostic characteristics requiring nursing facility care are modifiable by increasing rehabilitation services in those care environments is not known. as a reversal agent for uncontrolled or life-threatening bleeding for patients taking apixaban and rivaroxaban. approval was based on the results of interim analysis of the ongoing annexa- multicenter, prospective, open-label clinical trial. our institution began using the drug in august . we report our clinical experience. we conducted a retrospective observational study of patients admitted to stanford medical center from -associated intracranial hemorrhage. -associated ich. the mean age was (+/- ). patients were male. the mean glasgow coma scale score was . hemorrhage types included intraparenchymal hemorrhage ( patients), subarachnoid hemorrhage ( patients), and subdural hemorrhage ( patients). hemorrhage was associated with head trauma in patients ( %). ten patients ( %) had "excellent" or "good" hemostasis defined by the annexa- criteria. three patients ( %) developed deep venous thrombosis. no patients developed pulmonary embolism or myocardial infarction. -day mortality was % ( patients). we describe a case series of patients who received andexanet alfa for intracerebral hemorrhage at a large medical center. the incidence of intracerebral hemorrhage (ich) is . per , person years. nontraumatic spontaneous ich is usually seen in setting of uncontrolled hypertension or cerebral amyloid angiopathy and commonly occurs in basal ganglia, cerebral cortex, brainstem or cerebellum. spontaneous ich in corpus callosum with intraventricular hemorrhage (ivh) is very rarely seen and reported. we present an unusual case of corpus callosum hemorrhage with ivh associated with a reversible cerebral vasoconstriction pattern (rcvs) on cerebral angiography. the demographic information and clinical reports were obtained from electronic medical records retrospectively. select neuroimaging was obtained from neuroradiology department. year old caucasian male with a past medical history of chronic obstructive pulmonary disease, essential hypertension, and prior ischemic stroke with residual right hemiparesis presented in unresponsive state when he was discovered on bathroom floor. neurological examination on admission showed no verbal response, eyes open, with reactive pupils, and withdrawal to pain in left arm and leg. blood pressure on admission was / mmhg. computer tomography (ct) of head showed large ich in rostrum, genu and trunk of corpus callosum with intraventricular extension and hydrocephalus. he was intubated for respiratory distress and external ventricular drain (evd) was placed. he was also treated with intraventricular alteplase mg injection for total of doses, hours apart. blood pressure was controlled with nicardipine infusion initially, a up ct head showed resolution of ivh over the next several days, however, no significant clinical improvement was seen. patient remained abulic and akinetic. cerebral angiography performed showed right pericallosal artery beading pattern consistent with rcvs. after transition to comfort care, the patient expired on the th day of hospitalization. spontaneous non-traumatic corpus callosum ichs are rare, and while other causes have been reported, this particular etiology is likely due to rcvs. intracerebral hemorrhage (ich) is a leading cause of disability and mortality. infections are a common complication observed in ich and might be associated with worse outcomes. we aim to evaluate the association between infections and clinical outcomes at hospital discharge. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission status, rates of infections including; pneumonia, urinary tract infection (uti), bacteremia and clinical outcome at discharge were recorded. associations between the presence or absence of infections and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. infections occurred in subjects ( . %). uti was the most common infection ( . %) followed by pneumonia ( . %) and bacteremia ( . %). clinical outcome was significantly worse for subjects who experienced any type of infection during hospitalization, compared to non-infected subjects, poor outcome (gos < ) was found on . % and . % respectively (p= . ). this increased risk was significant after controlling for gender, ethnicity, ermore, an unfavorable discharge disposition -infected group, . % and . % respectively (p= . ). our study shows a significant association between infections and poor clinical outcomes at hospital intracerebral hemorrhage (ich) is a subtype of stroke associated with a high morbidity and mortality. low serum calcium levels have been previously associated with larger hematoma volumes, hematoma expansion and worse outcomes; however, the pathophysiological mechanisms are still not well understood. a confounding effect among serum calcium and magnesium levels has been previously considered. in the present study, we investigate whether hypocalcemia is associated with poor clinical outcomes controlling for serum magnesium levels. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. serum calcium and magnesium levels were measured during hospitalization, hypocalcemia and hypomagnesemia were defined as serum levels below . mg/dl and . m/dl respectively. associations between serum calcium level and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. hypocalcemia was identified in subjects ( . %). clinical outcome was significantly worse in the hypocalcemic group compared to the normocalcemic group, poor outcome (gos < ) was found in . % and . % respectively (p= . ). this increased risk was significant after controlling for gender, ethnicity, serum magnesium levels, admission gcs, admission death) was also higher in the hypocalcemic group compared to the normocalcemic group, . % and . % respectively (p= . ). our study shows a significant association between hypocalcemia and a poor clinical outcome after association. treatment of patients with intracerebral hemorrhage (ich) typically requires advanced care at a tertiary medical center. many patients present initially to regional or local emergency departments and require interfacility transportation to a referral center. mission hospital (mh) is a community-based nonacademic -bed tertiary care facility with comprehensive stroke center certification. we serve as the referral center for affiliated mission health hospitals and regional non-affiliated hospitals across counties. these hospitals are distributed throughout a mountainous and rural area with challenging terrain for transportation and limited resources for critical care transport. here, we aim to describe the current transfer paradigm and consistency of care provided during interfacility transport of ich patients prior to implementation of a dedicated ich regional interfacility transfer protocol. retrospective review of the electronic medical record was performed to identify all patients in calendar year admitted to mh with a principal diagnosis of nontraumatic ich who initially presented to another facility prior to transfer to mh. data, including demographics, transport service type, and transport sequential blood pressures, were collected. blood pressures during transport were analyzed to determine whether blood pressure exceeded our guidelines. patients with ich transferred to our referral center were identified. / ( . %) were transported via critical care transport, and / ( . %) were transported by local ems using general adult transport protocols. / ( . %) had uncontrolled hypertension as defined by or more bp readings above our guidelines. of these, / ( . %) were transported via critical care transport and / were transported via local ems. transport records were incomplete in / ( . %). elevated blood pressures during transport of ich patients are common. rural health systems are challenged by lack of critical care transport capabilities. we are currently implementing a dedicated protocol for interfacility transport care of ich patients. infratentorial intracerebral hemorrhage (ich) is associated with worse prognosis than supratentorial ich; however, infratentorial ich is often excluded or underrepresented in major studies of ich. we sought to evaluate the natural history of infratentorial ich stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ich presenting to our institution. using a prospective, single center cohort of patients with spontaneous ich between - , we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ich stratified by cerebellar or brainstem location. infratentorial ich occurred in ( %) of patients in our ich cohort. cerebellar ich occurred in ( %) and brainstem ich occurred in ( %). compared to cerebellar ich, brainstem ich had significantly worse severity of injury scores, including: admission glasgow coma scale (p < . ), ich score (p = . ), and national institute of health stroke scale (nihss) (p = . ). modified rankin scale (mrs) scores at months were significantly better in patients with cerebellar ich compared to brainstem ich (median [ . - . ] versus median [ . - . ], p = . ). patients with cerebellar ich were more likely to be discharged home or to acute rehabilitation (or . , % ci . - . ) but there was no difference in in-hospital mortality (or . , % ci . - . ) or cause of death (p = . ). patients with cerebellar ich who were alive at months had smaller hemorrhages and lower severity of injury on admission. patients with cerebellar ich have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ich. it has been known that patients with intracerebral hemorrhage (ich) have a higher rate of acute renal tality. the factors such as medications for blood pressure control, blood pressure (bp) variations and use of contrast for imaging without history of previous kidney disease. we analyzed the records from hospitalized patients in the icu from to in a single academic center with primary diagnosis of ich and renal failure. a total of were analyzed, patients ( . %) were reported to ( . %) patients did not meet the criteria for renal risk, injury or failure and ( . %) did not have enough data for the study. antihypertensive therapy used within the first hours of admission was a combination of acei, arbs and b-blockers. patients showed a wide variability in blood pressure (max-min within a day) which could not be and use of iodinated contrast, since ct without contrast was the imaging study of choice in all patients. our observations did not show an association in between bp variability, type of antihypertensive therapy or use of iodinated contrast within the first hrs of admission to acute renal failure in ich patients either with or without history of renal disease. a larger study may be required to support this statement. milrinone, a phosphodiesterase inhibitor, has limited data as salvage therapy for cerebral vasospasm (cvs) secondary to aneurysmal subarachnoid hemorrhage (asah). to date, no study has compared patients treated with intravenous milrinone to a control group receiving standard treatment, primarily hemodynamic augmentation. we compared cvs duration in milrinone-treated patients to a control group, and evaluated additional safety and efficacy outcomes. this was a retrospective, single center, case control study. adult patients admitted to spectrum health or inclusion. the primary outcome was duration of cvs recorded on daily transcranial doppler exams. secondary outcomes assessed efficacy and safety. efficacy endpoints included, but were not limited to: incidence of ischemic stroke, interventions to treat cvs, icu/hospital length of stay (los), and in-hospital mortality. safety endpoints included vasopressor/inotrope requirements and incidence of arrhythmias. -treated and control patients. milrinone use was associated with a longer duration of cvs (p = . ), increased use of intraventricular medications for cvs (p= . ), greater vasopressor requirements (p = . ), and longer vasopressor duration (p= . ). there was no difference in arrhythmias or in-hospital mortality. icu los in milrinone versus control groups was . vs. . days (p= . ) and hospital los was . vs. days, respectively (p = . ). there were ischemic strokes in the milrinone group versus in the control group (p= . ). intravenous milrinone was associated with a longer duration of cvs in asah patients, greater vasopressor requirements, and trended towards a higher incidence of ischemic stroke, though not statistically significant. prospective, randomized, controlled trials are needed to further define the risks and benefits of milrinone therapy in asah patients. aneurysmal subarachnoid hemorrhage (asah) patients sustain several physiologic changes, including a rupture. mri is potentially useful for prognostication in asah but has not been well-studied in this patient population. we present our preliminary experience with multimodal mri in the acute period after asah. we hypothesized that changes in nodes of network critical to consciousness differ between patients with good and poor outcomes. thirty-four asah patients and healthy volunteers underwent multimodal mri at t. mri t images were segmented, and aslconsciousness (i.e., salience network, central executive network, default mode network). wilcoxon rankto test odds of modified rankin scale (mrs) - at months. asah patients had a mean age (±sd) of . ± . years, and controls were . ± . years (p< . ). prefrontal cortex - and - ). r age-matched studies with more subjects and additional mri sequences are needed to better determine mri's potential utility in asah prognostication. aneurysmal subarachnoid hemorrhage (sah) classically presents with the "worst headache of the patient's life" which can be very debilitating and persist for weeks. headache is often refractory to standard treatment, including opiates. pain is thought to be derived from meningeal irritation in the subarachnoid space. the sensory fibers in the anterior meninges are innervated by branches from the ophthalmic division of the trigeminal nerve, which is closely associated with the sphenopalatine ganglion (spg). spg blockade with local anesthetic, first described in , has used as a treatment for various types of headache disorder but has not been described in sah-associated headache. treatment approach is either transnasal or transcutaneous injection. this case series describes five patients who received spg blockade for intractable sah-associated headache. patients with acute aneurysmal sah in the neurocritical care unit were offered adjunct spg blockade for headache refractory to standard treatment. patients rated pain on a - numerical scale, both before and minutes after the procedure, which included either transnasal administration of ropivacaine using the tx device (tian medical) or transcutaneous administration of ropivacaine with decadron. ess score on admission (range - )); two ( %) received transnasal blockade and three ( %) received transcutaneous blockade. median pre-treatment pain score was (range their pain within minutes; the fifth reported % reduction of pain. transcutanous spg blockade resulted in complete pain relief in all patients. the effects were transient, and pain typically returned within hours. there were no complications associated with the procedure. repetitive spg blockade is a safe and effective adjunct treatment for sah-associated headache. a larger clinical trial is planned. tranexamic acid is recommended in the first hours after subarachnoid haemorrhage (sah) and before aneurysm treatment to reduce rebleeding. in brazil, patients are frequently submitted to delayed aneurysm occlusion after sah (> hours from ictus). the objective of this study was to evaluate the effects of tranexamic acid on hospital complications and outcome of patients with sah. all consecutive patients admitted with sah between and at a reference center were included. data were collected prospectively during the hospital stay. all sah patients within hours of ictus were considered eligible for tranexamic acid (ta) up to aneurysm occlusion. we analysed groups: no ta, low dose ta and high dose ta. the primary endpoint was mortality at hospital discharge. other outcomes included hospital complications such as rebleeding, delayed cerebral ischemia and adverse events such as deep venous thrombosis dvt) and pulmonary embolism (pe). one hundred forty five patients were included in the study. approximately half ( , %) received ta, with ( %) receiving low dose and ( %) high dose. at baseline, the high-dose ta group had more -dose group ( % vs %). patients in the low-dose group had lower rebleeding rates ( . %; p= . ) than the no-ta and high-dose ta groups. mortality was lower for the no-ta and low-dose ta groups as compared to the high-dose ta patients. moreover, patients that did not receive ta had longer icu and hospital lengths of stay. dvt/pe rates were very low in our cohort and not different between groups. our study showed that patients that received low dose of tranexamic acid had lower rates of rebleeding as compared to those that received no ta and high-dose ta. mortality was also lower in this group when compared to patients that received high-dose ta. aneurysmal subarachnoid hemorrhage (asah) carries high mortality and morbidity. symptomatic vasospasm is an important complication of asah. about thirty percent of patients with severe vasospasm do not respond to conventional management and will go on to develop delayed ischemic strokes. medical management in these patients are limited and require endovascular therapy with intraarterial vasodilators and angioplasty. milrinone has vasodilator properties and inotropic activity which has been used by intravenous and intraarterial routes for symptomatic vasospasm. in this study, we tested the safety and feasibility of intraventricular milrinone (ivm) in patients with severe vasospasm administered through the external ventricular drain (evd). a retrospective review of medical records of patients with subarachnoid hemorrhage who received ivm between - . ivm was given at a dose of . mg in ml sterile saline every hours through an evd that was subsequently clamped for h. patients received ivm for refractory vasospasm. among those, patients had ruptured asah and one patient had ruptured internal carotid artery pseudoaneurysm secondary to pituitary macroadenoma resection. the mean ivm doses were (range - doses). only one patient ( . %) developed ventriculitis days after ivm. there were no elevations of intracranial pressures with intraventricular administration of ivm. in patients with refractory vasospasm from aneurysmal subarachnoid hemorrhage, intraventricular milrinone administration seemed to be relatively safe. prospective trials are needed to further determine the safety and efficacy. rupture of cerebral aneurysm is the most common cause of subarachnoid hemorrhage (sah). hypertension is a particularly important risk factor for growing and rupture of cerebral aneurysm. in clinical practice, the non-adherence to anti-hypertensive medications is the most important cause of uncontrolled blood pressure. the aim of this study is to evaluate the effect of non-adherence to antihypertensive medications on the long-term prognosis of patients with hypertension and ruptured cerebral aneurysm based on the nationwide health claims database in korea. this study is retrospective cohort study using the national health insurance service-national sample cohort (nhis-nsc) in korea. we included non-traumatic sah patients (icd- ; i ) with hypertension who underwent endovascular coil embolization or surgical clipping for ruptured aneurysm. the primary outcome is defined as composites of recurrent stroke, myocardial infarction, all-cause death. adherence to anti-hypertensive medications is measured by calculating the proportion of days covered (pdc) based on the prescription records, which is treated as a time-dependent variable. we performed multivariate time-dependent cox regression analysis with adjustments for sex, age, diabetes mellitus, treatment morality (coil embolization or surgical clipping), and household income. -nsc, we found patients who received coil embolization or surgical clipping for aneurysmal sah. among them, patients with hypertension were included for analysis. during the . years of mean follow-up period, there were patients who had primary outcome. in the multivariate cox regression, poor adherence to antiindependently associated with increased risk of primary outcome (adjusted hr . , % ci . - . , p-value= . ). in this cohort study with real-world data, poor adherence to anti-hypertensive medications is a strong risk factor for worse prognosis in the hypertensive patients who underwent treatments for ruptured aneurysm. there is need for greater attention to adherence to anti-hypertensive medications in the high-risk patients. tcd is routinely used in aneurysmal subarachnoid hemorrhage (sah) for vasospasm surveillance. the value of tcd monitoring in non-aneurysmal sah (nasah) is unclear. in this study we sought to determine the clinical utility of performing tcd monitoring in a cohort of patients with nasah. retrospective case series study performed at a comprehensive stroke center in a university hospital. patients with sah in whom an aneurysm or other vascular lesion was not identified were extracted from a prospective database covering a year period. patients with nasah were categorized into perimesencephalic and diffuse sah based on the ct appearance. baseline demographics and clinical variables were obtained from the database. tcd results were obtained from a tcd database and conventional criteria were used to diagnose sonographic spasm. categorical variables were compared a total of nasah patients were identified; perimesencephalic and diffuse. spasm was identified in / ( %) perimesencephalic nasah patients and / ( %) diffuse nasah patients (p= . ). no differences were observed between groups in age (p= . ), discharge disposition (p= . ), median her score (p= . ) when comparing patients with spasm to those without spasm. similarly the median number of tcds (p= . ) did not differ among patients with and without spasm. the location of nasah did not influence the diagnosis of spasm (p= . ). sonographic spasm occurs in % of nasah patients but no specific clinical variable appears to influence its occurrence. the clinical significance of such finding needs further validation. complications following aneurysmal subarachnoid hemorrhage (asah) may be associated with early fluid status. this study aims to assess the relation of fluid balance and intravascular volume to outcomes including acute kidney injury (aki), delayed cerebral ischemia (dci), and vasospasm (vsp) in asah. consecutive asah patients were retrospectively collected including patient demographics and admission characteristics. intravascular volume on admission was measured by ivc ultrasound. daily fluid balance in the first days of admission were recorded along with changes in bun and cr. outcomes including dci and vsp were collected. spaghetti plots were used to illustrate trajectory patterns. a linear mixed effect model was used the test the trajectory of slopes. an interaction term between time and patient condition was used to test the slope difference between patient conditions. of patients underwent ivc ultrasound assessment of intravascular volume. patients were hypovolemic on admission with ivc collapsibility index > % or distensibility index > %. ivc slopes were found to be different by patient m balance decreased by - . ± ml/hr (p= . ) while it increased . ± . ml/hr (p= . ) in those - . ± . /hr (p= . ) while it increased . ± . /hr (p= . ) in those without dci (interaction p= . ). - . ± . /hr (p< . ) in those without vsp (interaction p< . ). patient hemodynamics on admission as determined by ivc ultrasound does not correlate with development of aki. however, fluid balance in the first days of admission may be associated with outcomes in asah. early prediction of delayed cerebral ischemia (dci) will improve management of subarachnoid hemorrhage (sah) patients. we used mass spectroscopy (ms) to undertake an unbiased interrogation of plasma proteins associated with dci. this is an observational prospective single-center study of patients admitted to a tertiary care center. serum samples from patients were obtained within hours post-admission. we performed analysis in cohorts separately at different times. the first cohort was a retrospective cohort of matched subjects ( no-dci vs dci). the second cohort consisted of matched subjects ( no-dci and dci). in both cohorts subjects were matched across dci status for age, sex and modified fisher scale. we performed t-tests across dci groups in both cohorts to identify proteins with a difference in concentrations between dci groups. we selected proteins with a p-value of < . for difference across dci in both cohorts as potential candidates. and proteins were identified in cohort- and cohort- respectively. we identified potential candidates in cohort- , and potential candidates in cohort- . six proteins were identified in both cohort- and cohort- (p-value cohort- and p-value cohort- ): complement factor h (p= . and p= . ); complement factor i (p= . and p= . ), antithrombin-iii (p= . and p= . ), histidinerich glycoprotein (hrg) (p= . and p= . ), fetuin-b (p= . and p= . ), and hemopexin (p= . and p= . ). all plasma protein levels were lower in the dci group. in our unbiased approach to identifying biomarkers of dci we identified potential candidates. the compliment cascade and antithrombin-iii has previously been identified as important in the pathophysiology of sah. of interest, we also identified hemopexin (part of the cd -heme-hemopexin scavenging system) and hrg which is associated with cerebral vessel contraction as potential -b has not been previously reported in sah. confirmatory testing needs to be performed to validate our findings. glycemic gap (gg), determined by the difference between glucose and the hba c-derived average glucose (adag), predicts poor outcomes in various clinical settings. our main objective was to evaluate various admission factors and outcomes in relation to gg. we retrospectively reviewed prospectively collected data on adult patients with aneurysmal subarachnoid hemorrhage. admission glycemic gap (agg) was defined as adag ( . ×hba c- . ) subtracted from admission glucose (ag). poor composite outcome was defined as death, tracheostomy, gastrostomy, and/or discharge to a nursing facility. spearman method was used for correlation. generalized linear model was used to test the difference in gg between patient categories. mixed effects model was used to test the difference in trajectory slopes in gg. area under the curve (auc) for roc curve was used to estimate prediction accuracy. sas . was used for all data analyses. the overall mean agg was . ± . mg/dl. agg was significantly correlated with ag (r= . , p< . ), gcs (r= - . , p< . ), lactic acid (r= . , p< . ), and procalcitonin (r= . , p< . ) on admission, but not with hba c (r= . , p= . ). there was a nonsignificant trend of higher agg in those with delayed cerebral ischemia ( . ± . vs. . ± . , p= . ). patients with poor composite outcome had both higher ag ( . ± . vs. . ± . , p= . ) and agg ( . ± . vs. . ± . , p< . ), but the difference in agg was more profound. trajectory slope in the first hours for gg did not differ in patients with poor vs. good composite outcome (- . ± . / hr vs. - . ± . / hr, p= . ), nor did it differ for pointof-care glucose testing (- . ± . / hr vs. - . ± . / hr, p= . ). agg had significantly better prediction accuracy than ag in predicting poor composite outcome (auc: . ± . vs. . ± . , p= . ). admission glycemic gap served as a better predictor of poor outcome than admission glucose. additionally, agg was correlated with ag, lactic acid, and procalcitonin, and inversely correlated with gcs. the use of standardized management protocols (smps) has been shown to improve patient outcomes for multiple neurocritical diseases. however, whether smps improve outcomes after subarachnoid hemorrhage (sah) is currently unknown. we aimed to study the effect of smps on -month mortality and neurologic outcomes following sah. a systematic review of randomized control trials (rcts) and observational studies was performed by searching multiple indexing databases from their inception through january . studies were limited -traumatic sah reporting mortality, neurologic outcomes, and delayed cerebral ischemia (dci). data on patient and smp characteristics, outcomes, and methodologic quality was extracted into a data collection form. methodologic quality of observational studies was assessed using the newcastle ottawa scale (nos). a total of , studies were identified; were assessed in full and met the criteria for inclusion. two studies were rcts and were observational. smps were divided into four broad domains: management of acute sah, early brain injury, dci, and general neurocritical care. the most common smp design was control of dci, with studies targeting this domain. overall, studies were of low quality; most described single-centre case series with small patient sizes. observational studies scored between and on the -point nos. dci and neurologic outcomes were defined inconsistently in the literature, leading to significant challenges in their interpretation. given the substantial hetereogeneity in reporting practices between studies, a meta-analysis could not be performed. the effect of smps on sah remains unknown due to major limitations in study design and quality. notable deficiencies relate to heterogeneous definitions of dci and inconsistent application of standardized neurologic assessment scales. our study highlights the need for rigorous rcts to determine whether the use of a protocol impacts outcomes in critically ill patients with sah. elevated serum chloride has been associated with increased inflammatory markers, worsened systemic hypotension, and renal injury. little is known regarding the effects of hyperchloremia on neurological outcomes after subarachnoid hemorrhage (sah). we reviewed prospectively collected data on adult patients who were admitted for spontaneous sah from to . chloride values were examined on days - . hyperchloremia was defined as serum chloride of meq/l or greater. the primary outcome was delayed cerebral ischemia (dci). secondary outcomes included hospital mortality and month modified rankin scores (mrs). chi-square test and two sample t-test were employed to assess dci and month mr analyze hospital mortality. sah patients were included in the analysis, ( %) developed dci and ( %) did not. patients with dci had higher rates of hyperchloremia on day ( % vs. %, p= . ), day ( % vs. %, p= . ), and day ( % vs. %, p< . ) than patients without dci. after controlling for age, hunt and . , p= . ) and day (or . , p= . ) were associated with higher likelihood of experiencing dci. good functional outcome (mrs - ) was seen in of patients ( %) at months. rates of hyperchloremia were significantly lower in the good outcome group at all time points. after multivariate analysis, hyperchloremia on day (or . , p= . ), day (or . , p< . ), day (or . , p= . , and day (or . , p< . ) were independently associated with decreased odds of good functional outcome at months. early hyperchloremia was associated with dci and worse functional outcomes from sah. the impact of chloride load and fluid management strategy on sah outcomes warrants further investigation. headache is the most common complaint of patients presenting with aneurysmal subarachnoid an efficacious adjuvant therapy in the management of sah-induced headache. we performed a retrospective chart review of patients treated for sah in the neurocritical care unit at a eceived steroids. dexamethasone ( mg every hours) is typically administered for - days in patients with headache refractory to acetaminophen and oxycodone. nursing documented numeric ( - ) pain scores were collected every two hours. we used paired t-tests to compare mean, maximum, and minimum daily pain scores on the day before and during steroid administration. we used multivariate analysis to assess for factors associated with steroid responsiveness, defined as an improvement of or more points in mean daily pain score. there were steroid treatment periods among patients ( % female, mean age ± . , median hunt--two ( %) were classified as steroid responsive. mean daily pain scores decreased by . points (p = . ) during steroid administration. responders reported higher pre-treatment pain scores ( . vs . , p = . ) and demonstrated greater decrease in mean pain scores ( . vs -. points, p < . ). there was no decrease in mean pain scores during the two days following therapy. in multivariate analysis, there was a weak signal that patients who underwent surgical clipping were more likely to have steroid responsive headaches (or . , . no other demographic or clinical characteristics were associated with steroid responsiveness. a subset of patients with sah induced headache may have a favorable, transient response to steroids. tterns and influence on opioid requirements. cerebral vessel vasospasm (cvv) is a feared complication following aneurysmal subarachnoid hemorrhage (asah). there has been an association between cvv and delayed cerebral ischemia which accounts for a great deal of morbidity and mortality following asah. though the majority of patients with cvv respond to blood pressure augmentation, many patients go on to develop delayed ischemic neurologic deficits despite aggressive therapy. there is some suggestion in the literature that intraventricular milrinone (ivm) may be useful in the treatment of cvv. retrospective case series of patients with asah that were treated with one or more doses of . mg index (pi) and frequency of intraventricular milrinone dosing was collected. all patients were treated at cleveland clinic in the neurologic intensive care unit between and . paired t-test analysis was patients in our cohort were dosed with ivm between and times. there were no significant differences territory. there was also no effect of ivm on cvv over time. there were no direct complications secondary to ivm in these patients. based on our results, ivm was non-therapeutic for the treatment of cvv in patients with asah. our data be conducted to evaluate the safety and efficacy of this treatment. our retrospective analysis suggests that the use of intraventricular milrinone may be non-therapeutic for the treatment of cvv. clinical and research tool for riskelement by the national institute of neurological disorders and stroke sah working group. there are few data assessing the we distributed a survey to a convenience sample of attending physicians that care for patients with questions regarding the definitions of the scale components (thin vs. thick, intraventricular blood vs no to determine the overall inter-ing. thirty-three respondents ( % neurocritical care fellowship trained, % ucns certified in neurocritical care, . % neurologists, median years (iqr - ) in practice, treating median of patients (iqr - ) with sah annually from institutions) completed the survey. twenty-three ( . %) reported r measurement of thin vs. thick blood, and . % correctly identified that blood in any ventricle is scored - . ) for the ct scans, which is considered poor agreement. agr regarding the definitions of the score components. the national institute of neurological disorders and stroke sah common data elements may require further clarification in order to standardize research in cerebral vasospasm leading to delayed cerebral ischemia (dci) is one of the most significant factors impacting functional outcome following subarachnoid hemorrhage (sah). although vasospasm is prevalent in this population, treatment options are limited. in recent years, several published case series have reported a positive effect of intrathecal (it) nicardipine for the treatment of vasospasm. we now report a single center one year retrospective cohort experience with intrathecal (it) nicardipine for the treatment of cerebral vasospasm following sah. all patients discharged in with a diagnosis of non-traumatic sah, either aneurysmal or idiopathic, were included in the analysis. demographics, risk factors, clinical course, radiological dci and functional outcome were analyzed. during , patients were admitted with aneurysmal (n= ) or idiopathic (n= ) sah. the mean age was . ± . and . % were women. low grade hemorrhage (h&h - ) was found in . %, medium (h&h ) in . % and high grade (h&h - ) in . %. cerebral vasospasm was diagnosed in . % of the patients, and it nicardipine was used in % of these patients (n= ). only . % of the patients required angiography to treat vasospasm. tcd data was available for patients who received it nicardipine. treatment reduced mean velocities in all arteries within one day (reduction of . - . %, p< . ). this effect remained through the treatment, until the vasospasm resolved. one patient suffered from bacterial ventriculitis. the overall rate of radiological dci, as found in a blinded post treatment assessment of patients' imaging, was . %. in this cohort, . % had a favorable functional it nicardipine is a safe and potentially effective treatment for cerebral vasospasm and prevention of the subsequent ischemic changes. we are currently expanding the analysis to prior years, however, future prospective controlled trials are still needed to evaluate the safety and efficacy of this treatment. patients remain at high-risk for vasospasm, delayed cerebral ischemia (dci), and hydrocephalus after diversion is often necessary in ma additional benefit over standard management by facilitating intracranial blood clearance and decreasing rate of vasospasm and dci, albeit with a possible increased risk of shunt dependency in historical studies. in this study, we assessed safety outcomes among patients who underwent this procedure. retrospective review of outcomes in pa cisternal drain placement at a single institution. between drain placement. the median hunt-hess score was , but the study population skewed towards large drain dwell duration was . days. radiographic vasospasm occurred in all but one patient ( . %) and developed meningitis/ventriculitis, none fatal. the mean length of stay in the icu was . days. sixteen patients ( . %) were discharged home, twenty-one to acute rehab ( . %), one to subacute rehab ( . %), and two died ( %). among survivors, shunt-dependency occurred in / ( . %), compared to the . %- . % range reported in prior literature. in the study population, cisternal drains appear to be safe as measured against historical cohorts, with comparable or lower shunt-dependency rates. this suggests the viability of further prospective studies to determine the appropriate population for and role of cisternal drainage in the management of asah. estimates of seizure onset after aneurysmal subarachnoid hemorrhage (asah) vary widely, reported rates range from % to %. moreover, seizures increase mortality and disability in patients with asah regardless of common asah complications such as: rebleeding, delayed cerebral injury and vasospasm. we sought to establish the frequency of seizures in asah patients, along with their impact over prognosis, during hospitalization and upon discharge. a retrospective review of consecutive patients with asah admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission gcs, admission mrs, incidence of clinical seizures and clinical outcome at discharge were recorded. associations between the presence or absence of clinical seizures and outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with asah were included. clinical seizures were identified in subjects ( . %). outcome was significantly worse for subjects who experienced a clinical seizure compared to subjects who remained seizure-free during hospitalization, poor outcome (gos< ) was found on . % and % respectively (or . , ]; p= . ) this increased risk was significant after controlling hospice, death) was more common for the seizure group compared to the seizure-free group, . % vs . % respectively, however this difference did not reach significance (or . , ]; p= . ) our results showed a low frequency of clinical seizures ( . %) after asah, when compared to other series that have identified an increased incidence of seizures through multimodal approaches. as indexed by gos, along with a non-significant trend towards an unfavorable discharge disposition, among patients with seizures. vasospasm and delayed cerebral ischemia (dci) account for % of the morbidity and mortality after aneurysmal subarachnoid hemorrhage (asah). perfusion ct has been shown to be useful in identifying vasospasm, but this technique is less sensitive to microvascular perfusion changes. mr perfusion (mrp) has been increasingly used in the acute ischemic stroke population and avoids ionizing radiation. we hypothesized mrp may predict the presence of vasospasm by providing measures of impaired cerebral perfusion. we performed a retrospective cohort study with consecutive asah patients between december and august . patients who underwent mrp for concern of dci followed by digital subtraction angiography (dsa) within hours were included. quantitative volumetric analysis was performed at several thresholds of cerebral for the presence of a tmax> lesion. exact wilcoxon rank sums test was used to compare perfusion volumes between patients treated endovascularly versus not treated for vasospasm. we identified patients with a total of mri studies meeting inclusion criteria ( patients treated, patients not treated). no tmax> s hypoperfusion lesion was identified in the untreated group, while / ( %) of the treated patients had at least some delay of tmax> s (p= . ). performance of mrp to detect vasospasm was sensitivity . ( %ci . - . ), specificity . ( %ci . - . ), ppv . ( . - . ), npv . ( %ci . requiring treatment for vasospasm. significant perfusion delay by tmax > s is present in patients requiring endovascular vasospasm treatment after asah. these results suggest that mrp may be a useful tool for patient triage for vasospasm therapy, and further studies are indicated for comparison to other screening methods for vasospasm. recent studies have suggested inflammation and immune dysregulation are important pathophysiology in aneurysmal subarachnoid hemorrhage (asah), and neutrophil to lymphocyte ratio (nlr) was considered as significant clinical predictor of unfavorable outcome including delayed cerebral ischemia (dci). we analyzed nlr of asah patients during ttm, and proposed that the changes in nlr may reflect therapeutic effect of ttm in asah. this retrospective single-center study included asah patients from november , to may , , among which patients underwent ttm after surgical procedures, and other patients didn't undergo ttm. target temperatures were . °c to °c and the durations of ttm were to days. we reviewed the changes of nrl of each patient during ttm and identified whether they had dci, and analyzed in-hospital outcome and -month outcome as measured by the modified rankin scale (mrs). there was no statistically significant difference of overall outcome between ttm group and non-ttm group, but ttm group showed slightly lower rate of dci and better functional outcomes. among the patients, patient who developed dci had higher nlr, and the decreasing rate of nlr was higher in ttm group than non-ttm group. higher decreasing rate of nlr in asah patients while undergo ttm may show the therapeutic effect of ttm. monitoring the trend of nlr value may be helpful in predicting the prognosis of asah patient and estimate the efficacy of ttm for individual patient. eventually, nlr may play important role in deciding practice strategy while treating ttm in asah patients. hydrocephalus is generally regarded as a progressive or static process, but there are few reported cases of transient obstruction of the ventricular system. here, the authors present a rare case of spontaneous symptomatic obstructive hydrocephalus that self-resolved. additionally, a brief review of the literature is performed. records of the patient presented were reviewed in a retrospective manner for all relevant information. pubmed was then searched for all relevant articles. here, we discuss the case of a gentleman in his late 's who presented with worsening confusion and lethargy in the setting of spontaneous subarachnoid and intraventricular hemorrhage. pre-hospital medication includes a daily fish oil supplement; he takes no anticoagulation or antiplatelet agents. approximately one year prior to admission, he experienced an episode of spontaneous left temporal intracerebral hemorrhage. this was attributed to amyloid angiopathy, as evidenced by multiple microbleeds observed on susceptibility weighted imaging at that time. the patient's neurocognitive status steadily declined admission, and he eventually became obtunded. in the process of transferring the patient to the intensive care unit for intubation and external ventricular drain placement, he suddenly became more awake and interactive. the patient's clinical symptoms completely resolved within - hours. no surgical intervention was undertaken. repeat head ct demonstrated that blood products seen in the third ventricle on previous imaging had now migrated into the fourth ventricle. lateral ventricular size had decreased from the prior scan. the following morning, his family members commented that the patient was back to his baseline. transient episodes of obstructive hydrocephalus have rarely been reported in the literature, and are generally associated with an inciting event such as trauma or hemorrhagic stroke. it is possible that there is a higher incidence of transient hydrocephalus, but medical/surgical interventions are performed before the condition is permitted to resolve on its own. raised intracranial pressure (icp) can be a dire consequence of extensive neurologic injury. medical management of elevated icp using intermittent doses of . % hypertonic saline (hts) and/or mannitol is relatively safe and effective for treating refractory intracranial hypertension. at our institution, prior to escalating to sedation and paralysis, hts and mannitol are scheduled. in this study, we aim to describe our experience with scheduled . % hts. methods doses of . % hts during acute admission were included in our retrospective evaluation. only patients who received scheduled . % for anticipated or acute elevated icp in the setting of high-grade subarachnoid hemorrhage (sah) were included. the primary outcome was to characterize efficacy of sustained icp control, by measuring frequency of icp > mmhg and need for escalation of icp management. safety outcomes included incidence of hypernatremia (sodium > meq) and metabolic acidosis. seven out of ( %) patients who received intermittent scheduled doses of . % hts were in the setting of highwere greater than mmhg and no patients required escalation of icp management for the duration of therapy. the median number of doses and duration of . % hts therapy were doses and days (iqr . than meq and patients ( %) developed metabolic acidosis in the setting of hyperchloremia. administration of scheduled intermittent . % hts in the setting of high-grade sah is relatively safe and achieves sustained icp control without need for escalation of icp management. comparative studies of scheduled intermittent . % hts vs alternative medical therapies for icp management are warranted. use of contrast-enhanced computed tomography (ct) studies to evaluate neurological disorders have increased due to its non-invasiveness, fast image acquisition, easy accessibility, and minimal complications. one such procedure is ct myelogram that delineates the extent of spinal stenosis and helps in neurosurgical planning. however, it can result in intracranial migration of contrast medium leading to contrast-induced-encephalopathy (cie). we report cases mimicking as subarachnoid hemorrhage after ct myelogram who subsequently developed cie. case : a -year-old man with chronic low back pain (clbp) was evaluated for confusion, headache due to "intracranial bleed". ct showed diffuse cerebral edema and hyperdensity in the subarachnoid space. external ventricular drain (evd) was placed for suspected post-sah hydrocephalus. however, ct and ct angiogram did not show any cerebrovascular malformation. the patient developed severe encephalopathy and left hemiparesis. repeat ct head showed worsening cerebral edema and hours prior to presentation. severe cerebral edema and left hemiparesis necessitated the use of dexamethasone with improvement in clinical symptoms and examination returning to near baseline. case : a -year-old man with clbp was admitted for "sah" and associated cerebral edema with hydrocephalus. the initial presentation was confusion, double vision, and headache. ct showed diffuse cerebral edema with sulcal effacement, loss of basal cisterns and dilated lateral ventricles. ct and ct angiogram did not show a days prior to presentation. evd placed for hydrocephalus was quickly weaned off the improvement of ventriculomegaly. the patient was discharged with complete resolution of symptoms. cie should be suspected in patients with encephalopathy after ct myelogram. non-contrast ct head is to be interpreted in conjunction with clinical history to avoid unnecessary procedures that might further worsen cie. seizures and ictal-interictal continuum (iic) activity may impact recovery from acute brain injury (abi). empiric antiepileptic drug (aed) intensification for electrophysiologic activity of uncertain significance is challenging to evaluate given structural neurologic deficits, variable pharmacodynamics, and potential sedative effects. we analyzed the eeg and electronic medical records to identify electrographic biomarkers predicting clinical response to aed therapy. we ascertained patients undergoing continuous electroencephalography (ceeg) during admission for abi from a prospective big data repository of clinical data including regularly sampled glasgow coma scale (gcs) scores and med -specific spectral power (alpha - hz, theta - hz, and delta . - hz) and graph theoretical metrics of eeg functional connectivity were compared at time intervals before and after aed therapy. patients met inclusion criteria. , aed doses were administered (mean . +/- . unique aeds per patient). initiating the first aed was followed by a . -point average improvement in gcs (p= . x - ); initiating a second or third aed yielded no significant change, and adding a fourth, fifth, or sixth aed was followed by a . -point worsening in gcs (p= . ). improvement in gcs hours after aed administration was heralded by decline in eeg delta power and rise in network density in the hour following treatment. decline in gcs was heralded by an early rise in delta power and decline in network density. patients with the highest tertile of eeg improvement (greatest combination of rising eeg density and declining delta power) had a consistently improving gcs trajectory in the hours following medication administration, whereas those in the lowest tertile had a consistently worsening gcs trajectory. empirically intensifying aed treatment for disorders of consciousness after abi has diminishing benefit after the initial agent. quantitative eeg biomarkers of early treatment response appears to robustly predict clinical response following aed treatment. new-onset refractory status epilepticus (norse) describes patients with no seizure history who develop refractory status epilepticus (se). the majority progress to super refractory status epilepticus (se). we present a single-center case series of super refractory norse patients to highlight unique features of this group. retrospective chart review was performed to identify adults (age> ) admitted to the columbia university neurological icu from / - / who required continuous midazolam infusions for treatment of super refractory norse. outcome was defined as modified rankin score (mrs) at hospital discharge. descriptive statistics were performed using microsoft excel. of the cases, %(n= ) had a prodrome prior to seizures (infectious, psychiatric or both). patient age was bimodally distributed with %(n= ) less than years old and %(n= ) over . the most common comorbidity was an underlying autoimmune/rheumatologic condition ( %,n= ), though most patients had no pre-existing conditions ( %,n= ). the average stess score was (standard deviation . ). the majority ( %,n= ) remained cryptogenic despite extensive testing. etiologies were identified in %(n= ) - with nmda encephalitis and two with cns infections. immunomodulatory treatment included steroids in %(n= , started on average days from seizure onset, range - ), intravenous immunoglobulin in %(n= , day , range - ) and plasmapheresis in %(n= , day , range - ). the average icu and hospital stays were (range - ) and (range - ) days, respectively. on discharge, %(n= ) had a good outcome (mrs - ), %(n= ) had fair outcome (mrs - ), %(n= ) had poor outcome (mrs - ) and %(n= ) died. compared to prior studies of all norse patients, our cohort with super refractory se were younger, had more frequent prodrome, longer icu and hospital stays and fewer identified autoimmune/paraneoplastic antibodies. the mortality rate was similar to prior studies, but among survivors, super refractory patients were less likely to have a good or fair outcome. we aimed to assess the management of refractory status epilepticus (rse) in developing (ding) and developed (dev) economies, as the management of this condition is resource intense and poorly standardized. investigators from continents collected a large cohort study of rse patients treated between / - / . case-report-forms were finalized at the annual ncs meeting. rse was defined as se that failed to respond to a benzodiazepine and at least one non-anesthetic antiepileptic agent, and was managed with midazolam (mdz) or propofol(pro). the united nations world-economic-situation-prospect was used to identify sites as being from dev or ding economies. four from dev ( patients) economies were included. patients from dev economies were slightly sicker (stess score . ± . vs. . ± . , p< . ). management of patients from dev economies more frequently involved prolonged eeg monitoring (continuous % vs. %, p< . ) but mdz ( . ± . vs. . ± . mg/kg/h) and pro ( ± vs. ± mcg/kg/min, p< . ) doses were higher in ding economies. breakthrough seizures were more common in ding ( % vs. %, or . , p= . ), but no difference in vasopressor use ( % vs. %; n.s.) or withdrawal seizures ( % vs. % n.s.) was seen. hospital ( ± vs. ± days, p< . ) and icu stays ( ± vs. ± days, p< . ) were longer for patients in ding economies. modified rankin scale at discharge was associated with higher stess scores (p= . ) but did not differ between ding and dev economies. direct comparisons between rse patients managed in ding and dev economies are challenging as the baseline level of illness differed but this dataset provides unique insights into differences in utilization of technology (i.e., eeg monitoring), medications (duration and dosage of anesthetics), and length of stay in different health care systems. larger follow-up studies need to explore matched cohorts and explore differences between private-public hospital settings. unlike most anesthetics ketamine acts as an nmda antagonist. we examine the efficacy of intravenous ketamine in the treatment of rse in a large series. retrospective case series of status epilepticus patients admitted between and who underwent treatment with ketamine, patients underwent multimodality monitoring (mmm). we compared patients with complete seizure cessation after ketamine with those without using chi-square and sample t-test. mean age was +/- years old, % of patients were female. seizure burden was decreased by % within hours of starting ketamine in patients ( %), with complete cessation in ( %). average rate of ketamine infusion was . +/- . mg/kg/h, with duration of . +/- . days. average dose of midazolam was +/- . mg/kg/h. ketamine was started on average +/- day after midazolam. patients without complete seizure control after initiation of ketamine ( / patients) were more commonly cardiac arrest patients % vs % (p=. ), and had lower stess score +/- vs +/- (p=. ). all other characteristics were not statistically significant between the two groups including; age, gender, ketamine infusion dosages and duration, apache score, and midazolam infusion dosages. patients ( %) were weaned off pressors after initiating ketamine infusion. when compared the mmm values h before and after ketamine initiation, intracranial pressure values ( +/- vs +/- ), cerebral perfusion pressures ( +/- vs +/- ), cerebral blood flow ( +/- vs +/- ), and lactate/pyruvate ratio ( +/- vs +/- ) were relatively stable. pbo values increased from +/- . to +/- . in our cohort ketamine infusion had a meaningful decreased in seizure burden in rse. our preliminary data also suggests that ketamine infusion didn't affect the intracranial pressure. continuous eeg (ceeg) is widely used to detect seizures (sz) in patients with acute brain injury. however, studies examining sz and epileptiform abnormalities (ea) using ceeg in acute ischemic stroke (ais) are limited. therefore, we aimed to describe the prevalence of electrographic patterns (sz and ea) in ais and its association with outcomes at discharge. retrospective chart review identified patients with ais who underwent ceeg between / and / . demographics, comorbidities and other relevant clinical factors including nih stroke scale (nihss) and treatment interventions were abstracted. ceeg closest to admission (median days) was reviewed for background, sz and ea (lateralized and periodic discharges (lpds and gpds) lateralized rhythmic delta activity (lrda) and sporadic epileptiform discharges (seds). computed tomography or magnetic resonance imaging of brain closest to the time of ceeg was analyzed for midline shift, hemorrhagic transformation (ht) and cortical involvement. outcomes measures were mortality and functional outcome in modified rankin scale (mrs) ( - good and > poor outcome) at discharge. of the patients, had sz and had ea ( . % lpd, . % lrda, . % gpds and . % seds). those with cortical involvement had higher rate of ea and sz compared to those with subcortical stroke ( . % vs . %, p= . ). no difference was found in sz and ea prevalence with regards to age, sex, nihss, midline shift or ht. overall mortality was . %. absence of posterior dominant rhythm (pdr) was associated with increased mortality ( . % when pdr absent vs . % when present, p= . ). sz and ea did not affect mortality or mrs at discharge. despite high frequency of ea ( %), the risk of sz in ais was low at . % and their presence did not impact functional outcome or mortality. however, eeg background with absence of pdr was associated with increased mortality. nonconvulsive seizures (ncs) are a common complication in patients admitted to neuroscience intensive care units and are associated with worse outcomes. ncs can only be diagnosed with continuous eeg (ceeg) monitoring. intermittent conventional ceeg review by neurophysiologists typically occurs - times a day, therefore patients may be seizing for extended periods of time before the seizure is detected. our study aims to evaluate the accuracy of a quantitative eeg (qeeg) trend, the automated seizure detector (asd) in detecting patients' first seizure, which could aid in rapid detection of ncs. this retrospective study includes review of ceeg and qeeg data from adult patients admitted to a single institution neuro icu who developed ncs on ceeg monitoring. independent conventional ceeg review without qeeg by two board-certified neurophysiologists determined the first seizure occurrence for each patient (gold standard). this was compared to the seizure detection sensitivity of the p asd (persyst, inc., prescott az), an algorithm with no user-adjustable settings. recordings from ncs patients were used. mean age was . years and % was female. seizures had variable durations and spatial extents. the sensitivity of p asd was . % ( % ci . - . ) and specificity was . % ( % ci . - . ). mean false alarm rate was . /hour (sd . ) in the time elapsed from the start of ceeg recording until first seizure occurrence. overall, p asd accurately detected the first seizure in % of patients, disregarding false positives. overall, median time to clinical seizure detection was . hours (iqr . hours). this analysis shows that the persyst p asd may have clinically useful sensitivity and specificity in critically ill patients admitted to a neuroscience icu. in conjunction with a low false alarm rate, incorporation of qeeg asd may lead to a reduction in time for seizure recognition. the incidence of early seizures (es) in traumatic brain injury (tbi) ranges between - %. however, the incidence of es after a non-severe tbi (nstbi) with traumatic hemorrhage (th) is unknown. moreover, the data about seizure prophylaxis (sp) in this population remains inconclusive. we aim to determine the incidence of es in nstbi and the efficacy of sp. we respectively reviewed all adult patients with nstbi with evidene of a th on presentation from to . patients with history of epilepsy or receiving antiepileptic drugs (aed) were excluded. we collected demographic data, the type, severity and mechanism of injury; the need for neurosurgical intervention (nsi); es; and sp use. a total of patients met our inclusion criteria, . % had mild tbi; mean age of . years (sd . ); . % males; and . % had subdural hematoma (sdh). same level fall was the most common ( . %) patients had an es in the sp group ( clinical) vs of ( . %) in the non-prophylaxis group (all clinical) (p = . ). levitiracetam as sp was used in . %. patients with combined sdh and traumatic subarachnoid hemorrhage or with multicompartment hemorrhage were more likely to have es than sdh alone (p = . and . , respectively). nsi was not a predictor for es in our cohort. the incidence of es in nstbi patients in our cohort falls within the previously reported ragne. however, it appears to be higher compared to reported rates for mild tbi. es were more likely in the sp group, which might indicate a clinical selection bias. prospective studies are required to further determine the predictors of es and the effect of sp on outcomes in nstbi patients. patients with psychogenic non-epileptic attacks (pnea) sometimes receive aggressive treatment leading to intubation. this study aimed to identify patient characteristics that can help differentiate pnea from true status epilepticus (se). we retrospectively identified patients with pnea and se who were intubated and underwent continuous had acute brain injury or progressive brain disease as a cause of status epilepticus were excluded. we compared clinical features, treatments and outcome between patients who were intubated for pnea and those who were intubated for se. of , patients who underwent ceeg monitoring, we identified and patients intubated for pnea and se, respectively. compared with patients intubated for se, intubated pnea patients were more likely to ( ) be < years of age ( % vs %, p< . ), ( ) be female ( % vs %, p< . ), ( ) be white ( % vs %, p< . ), ( ) have a history of a psychiatric disorder ( % vs %, p< . ), ( ) have no history of an intracranial abnormality ( % vs %, p< . ), and ( ) have a maximum systolic blood pressure < mm hg ( % vs %, p< . ). patients with - of these risk factors had a % ( / ) likelihood of having pnea, those with - had a % ( / ) chance of having pnea, and those with - had an % ( / ) chance of having pnea. sensitivity for pnea among those with - risk factors was % and specificity was %. pnea in patients presenting with emergent convulsive symptoms can be predicted with a high degree of certainty based on the presence of specific demographic, past medical, and physiologic risk factors. care should be taken to avoid over-sedation and unnecessary intubation in this at-risk patient population. a recent systematic review indicates that the mortality of status epilepticus (se) is about . % with a non significant downward trend in recent years. mortality has not changed much despite aggressive management. this study investigates trends and predictors of in-hospital mortality due to status epilepticus at national level in united states. we performed a cross-sectional analysis using the nationwide inpatient sample (nis), - , of us adult hospitalizations with status epilepticus. annual rate of in-hospital mortality was calculated using nis weighting. we identified our status epilepticus patient subset from using codes (dx = . ) from the international classification of diseases, th edition. potential factors associated with in-hospital mortality were assessed using logistic regression. of , hospitalized patients with status epilepticus, , ( . %) died during the index hospitalization. across - , . % of se patients died; with a downward but not statistically significant trend in-hospital mortality from . % ( ) to . % ( ) (p = . ). se patients with inhospital mortality were more likely to be women, older, and with a higher proportion of medical comorbidities, in-hospital complications and extreme loss of function as per all patients refined diagnosis al failure, apr drg severity, mechanical ventilation, tracheostomy, sepsis, pulmonary embolism, acute kidney injury and respiratory insufficiency. mortality due to se was lower than previously reported. mortality has had a non-significant downward trend in the years studied. age, female gender, medical complications and poor baseline functional status are important predictors. availability of aggressive treatment has not modified significantly mortality which requires further study. pregabalin (pgb) is an approved adjunctive treatment for focal epilepsy in adults. pgb lacks drug-drug interactions, has a favorable safety profile and can be rapidly titrated-attractive characteristics for its use in the neurocritically ill. however, data remain limited regarding its use in the icu setting. we are sharing our experience with pgb in neurocritically ill patients with refractory seizures. charts of eight adult patients admitted received pgb were reviewed retrospectively. demographics, antiseizure drug (asd) regimen, and h of eeg data pre-and post-pgb were analyzed descriptively. the cohort comprised eight patients ( females) with mean age of . years. mean icu stay was . days. three patients underwent a neurosurgical procedure related to their primary admission diagnosis, an asd prior to first seizure captured on eeg. prior to pgb, patients had failed on average ( - ) other asds trials. pgb was dosed - mg/day in - divided doses, following a load of - mg. pgb lead to a significant reduction on hourly median seizure burden: . to seizure/h and . to . min/h. pgb led to complete seizure cessation in patients within h and in out of within h of administration. pgb allowed for de-escalation of asd regimen in out of patients. pgb was well tolerated with the exception of mild sedation in patients, which did not warrant further intervention/neurodiagnostics. in this critically ill cohort with refractory seizures, pgb successfully aborted seizures in % of patients. include prospective pregabalin treatment protocols. to describe the first known reported case of utilization of electroconvulsive therapy (ect) to treat super refractory status epilepticus (srse) in pregnancy. we present the case of a year old caucasian female at weeks gestation with pmh focal and generalized seizures who was treated for srse successfully with ect after failed pharmacological treatment. the most likely etiology of srse was sudden cessation of medications upon pregnancy. eeg showed types of seizure activity: rhythmic theta waves over right temporal region with evolution and independent generalized seizures. treatment included use of approximately antiepileptics including , propofol, pentobarbital, magnesium, ketamine, topiramate and valproic acid over the course of days in addition to modifying epilepticus remained super refractory with appearance of mixture of sharp waves on weaning off sedation. she underwent ect with right unilateral electrode placement on day with remarkable improvement in eeg pattern and resolution of srse with single session. patient was back to baseline level of awareness at the time of discharge. on follow up in clinic, she had significant improvement in seizure control with normal fetal development and delivery. treatment of status epilepticus in pregnancy is challenging given the unknown effect of prolonged sedation or hypothermia on fetal development. alternative treatments like ect, vns, dbs, ketogenic diet and hypothermia are sporadically used. use of ect is not considered first or even second line treatment in srse, despite its safe profile, especially in pregnancy. this case adds to the available literature on the success of ect for treatment of srse and puts emphasis on the need for a clinical trial regarding use of ect in srse. the importance of neurocritical care (ncc) has been recognized. but no dedicated educational system for it exists in japan. we have established version of an educational ncc hands-on seminar. this study investigated its effects. this study was a prospective, before-after study using questionnaires and examinations. it was a full-day version . the learning concept was to identify the various methods for maintaining cerebral oxygen balance to prevent secondary brain injury. participants attended five skill sessions: intracranial pressure monitoring, trans-cranial color flow image, targeted temperature management, neuro examination, and eeg, and four scenario sessions: post-cardiac arrest syndrome, subarachnoid hemorrhage, traumatic brain injury, and non-traumatic acute weakness. they had examinations before and after the seminar. the primary outcome was the improvement on examination scores after the seminar. secondary outcomes were the degrees of satisfaction with it and confidence of participants in ncc. we evaluated the improvement of the outcome using wilcoxon signed rank test. a p-value of . or less was considered as significant. thirty-nine physicians and one nurse participated in the seminar. we excluded ( . %) participants because their answers were incomplete. we had ( . %) physicians who are in emergency or intensive care medicine, and ( . %) other professionals. their median age group was in their s (iqr: - ) with median intensive care medicine experience of years (iqr: . - . ). the percentage of correct answers, scores in the examination, improved significantly from (iqr: . - . ) to (iqr: . - . ) after the seminar (p< . ). eighteen ( . %) participants were satisfied with it, and the number of professionals who could not feel ncc-confident decreased from ( %) before the seminar to after its completion (p< . ). our seminar successfully improved the physicians' knowledge of ncc, and gave them more confidence in ncc. glutamic acid decarboxylase (gad) is the rate-limiting enzyme to convert glutamate to gammaaminobutyric acid (gaba). autoantibodies targeted against gad have been implicated in a number of syndromes with neurologic manifestations including stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. we highlight an atypical presentation of this rare disorder with several unique features to the neurological intensive care unit. -year-old woman with pmh of dm, remote left insular ischemic stroke, and recent right leg dystonia presented after being found down with rightward eye gaze deviation, gtc shaking, and urinary incontinence. she required midazolam, lorazepam, loading doses of levetiracetam and fosphenytoin, and propofol infusion to achieve clinical seizure control. despite these interventions, eeg showed ncse with left temporal seizures and anterior midline epileptiform discharges. propofol was titrated to burst suppression. she had several other active medical problems including kidney injury, transaminitis, and myoclonus. seizures and myoclonus were greatly improved after the addition of clonazepam; however, she remained encephalopathic. pertinent diagnostic results included ferritin , ng/ml, ldh , units/l, il- r u/ml, b -micr and serum gad ab titer nmol/l. mri brain showed prominent superior frontal lobe cortical edema. bone marrow biopsy demonstrated good cellularity without malignancy. skin biopsies on three random samples were positive for perivascular dermatitis with telangiectasia. she was started on high dose steroids with subsequent progressive mental status improvement. anti-gad ab associated vasculitis is an exceedingly rare occurrence whose diagnosis previously involved brain biopsy. this case is unique given her acute presentation with refractory status epilepticus, systemic involvement, and diagnosis on skin biopsy. while management has involved immunotherapy, specific treatment guidelines do not exist. given her marked response to clonazepam and corticosteroids, we advocate for early initiation of gabaergic medications such as benzodiazepines and use of immunotherapy. epileptic seizures are a serious complication in patients with subdural hemorrhage (sdh), resulting in increased mortality rates. the incidence of new onset seizures in these patients is unclear. we examined the incidence for new onset seizures and status epilepticus (se) in sdh patients. we examined patients diagnosed with sdh and epilepsy between september to december . we included patients with new onset seizures and extracted those who had seizures after sdh evacuation. clinical and radiographic characteristics, and outcomes of those patients were described. we screened patients diagnosed with sdh, traumatic or non-traumatic. underwent a surgical intervention and ( %) patients had a seizure during their hospital stay. among those who had a seizure, patients had prior history of epilepsy, and had a new onset seizure. although sdh patients with history of epilepsy showed higher incidences of seizures than those with no history (p= . ), sdh patients with history of epilepsy mostly did not evolve into se and those who had no history of epilepsy usually did. there was no significant difference in patients developing se when compared to those without se between the sdh thickness, midline shift, temporal lobe involvement or age of blood (acute or chronic). seizure occurrence in patients with sdh is commonly new onset; however, they are infrequent. in addition, sdh patients with no history of epilepsy have a higher tendency to develop se as opposed to patients with history of epilepsy. larger multicenter cohort studies need to be done for evaluation of these findings. sequoia hospital in redwood city, ca implemented the ceribell rapid response eeg system in to expand its access to eeg for in-patient usage. previously, the hospital had no access to after-hours eeg and the majority of their eegs happened in the icu. this quality improvement project was initiated to understand how access to rapid eeg impacted clinical care and financial metrics across at sequoia hospital. data was analyzed for all patients who received either conventional or ceribell eeg from january , including the department where eeg was conducted, time of day of eeg was ordered, time when eeg began, and clinical diagnosis based on the eeg. data was also captured on patient transfer due to lack of eeg. % of eegs were ordered after hours after the introduction of ceribell, compared to nearly no eegs done after hours before ceribell. % of patients with ceribell eegs were diagnosed with seizures. in , of ceribell eegs, eegs occurred in the in-patient unit or ed. in % of patients with a high suspicion of seizure, seizures were ruled out as a result of reading the ceribell eeg. the introduction of ceribell eegs has greatly expanded access to eegs at sequoia hospital. before ceribell was introduced, eegs mostly occurred in the icu and nearly all happened during regular hours. after ceribell was introduced, eeg was also heavily utilized in the ed and the in-patient unit and gave sequoia eeg access during after hours. as a result of this expanded access and earlier application of eegs, patients have been treated more appropriately. tranexamic acid (txa) is an intravenous antifibrinolytic agent that is used routinely for elective surgery. we report a case of inadvertent intrathecal injection of txa resulting in refractory status epilepticus. case report. a -year-old healthy female admitted for bilateral total knee replacement was inadvertently administered mg of txa intrathecally instead of bupivacaine. soon after administration, she intubated, administered levetiracetam, started on a propofol infusion, and transferred to the neurointensive care unit (nicu). she developed persistent spontaneous and stimulus induced generalized myoclonus refractory to propofol. midazolam infusion was added. nchct and cta demonstrated pneumocephalus, but no acute arterial or venous thrombosis or stroke. veeg revealed generalized nonconvulsive seizures occurring once per minute, not correlating with spinal myoclonus . propofol and midazolam infusions were increased to mcg/kg/min and . mg/kg/hr, respectively, to achieve burst suppression, and valproic acid was added. over the following week, the drips were adjusted to suppress seizure activity. by hospital day , she was weaned off all infusions without recurrence of seizures. by hospital day , she was on levetiracetam monotherapy. she was discharged to rehab after a -day hospital course, and was discharged home days after initial presentation. residual deficits at the time of discharge included mild cognitive impairment and gait instability. she remains seizure-free since hospital day on levetiracetam mg bid. we report a case of refractory status epilepticus and spinal myoclonus after accidental intrathecal txa administration. with aggressive management, the patient survived with mild residual deficits. the mechanism by which txa causes status epilepticus and spinal myoclonus is hypothesized to be related to its inhibitory effects on gaba and glycine receptors, respectively. ictal bradycardia (ib) is a serious complication of temporal lobe epilepsy. if left untreated, ib can cause serious injuries related to syncope, complete heart block and death. management of this phenomenon is controversial: should you treat the seizures or the arrhythmia? we describe the management of a patient who presented with multiple syncopal episodes and found to have symptomatic bradycardia in the setting of temporal lobe seizures. a -year-old male with a recently resected brainstem cavernoma presented with episodes of 'spacing out', face tingling and transient periods of amnesia. he was started on topamax and lamictal. several months later, he began having multiple syncopal events (upwards of a day) that eventually brought him the hospital for evaluation. he was found to be bradycardic with a heartrate in the thirties and had sinus pauses lasting up to ten seconds requiring atropine, an isoproterenol infusion and transcutaneous (tc) pacing. he was also found to have another cavernoma in the right temporal lobe. eeg revealed epileptic activity within the right anterior temporal lobe with correlation to his tc pacing and ib events. lamictal was replaced with keppra and the seizure activity was controlled. he had a pacemaker implanted, after which he did not have any further episodes of syncope and no further seizure activity. the cavernoma was resected a few months later, and he did well postoperatively. ib is an uncommon, but serious, complication of temporal lobe epilepsy. the temporal insula plays a role in the parasympathetic activity of the heart which can cause ib. it may be beneficial for patients who present with symptoms characteristic of temporal lobe seizures or repeated falls/drop attacks to have a full cardiac work up to rule out ib in order to determine if a pacemaker is warranted. the ceeg has had rapid growth within neurological monitoring within the icu, however its still disparate resource in the icus of latin america. is important to know the real situation in colombia about the accessibility to ceeg monitoring. an anonimus survey of questions was conducted from october to april . it was answered by intensivists from latin america, europe, asia and usa. (n= ) considering the accessibility to the ceeg, the ceeg clinical indications and the ceeg monitoring extends (hours) in the icu, we can conclude that colombia is aligned with other countries in the world. in the icus of colombia less than half of the intensivists make decisions in ¨real time¨ with the ceeg and have access to the qeeg modality. the most common cause for non-presciption of ceeg was scarce resources (equipment and human resorces support from a neurology service). cefepime is a fourth-generation cephalosporin with broad-spectrum coverage used to treat infections in critically ill patients. neurotoxic effects have been associated with cefepime, including myoclonus, reduced consciousness, and seizures. we report a case of a patient receiving cefepime who developed non-fluent aphasia and non-convulsive status epilepticus (ncse). two seizure drug trials (levetiracetam and fosphenytoin) failed before marked clinical and electrographic improvement with clobazam. other than cessation of the offending agent, there is little known about the management of cephalosporin associated non-convulsive status epilepticus. data was collected from our institution's health record. a -year-old female with a history of diabetes, chronic kidney disease, recent coronary artery bypass grafting, and mitral valve repair presented with pseudomonas aeruginosa cellulitis of the sternotomy site. on day six of cefepime therapy she developed non-fluent aphasia. mri brain and toxic-metabolic work-up was unrevealing. eeg was consistent with non-convulsive status epilepticus. she failed to respond to standard levetiracetam or fosphenytoin therapy. lorazepam was given with marked improvement in her eeg. clobazam was subsequently started resulting in marked improvement in the patient's language and sustained resolution of ictal pattern on eeg. epileptogenic effects of ß lactam antibiotics are thought to be due to competitive antagonism of the gabaa receptor. beside the recommendation of withholding offending agents when safe to do so, there is no guidance in the literature regarding the appropriate antiepileptic drug choices for the treatment of cephalosporin associated ncse. in this case, clobazam, a benzodiazepine, was an effective treatment. given the theorized mechanism gaba antagonism of cefepime, it is possible that benzodiazepines may ch is needed regarding the optimal seizure control for various etiologies of ncse. when treating seizures and ncse, consideration should be given to the possible mechanism of action of the suspected offending agent. hashimoto encephalopathy is a rare disease. clinical manifestations include abnormal behavior or psychosis, seizures, encephalopathy. pathophysiology is not completely known but it has been associated with autoimmune thyroiditis. we report a case of hashimoto encephalopathy with status epilepticus which responded well to steroids and relapsed following steroid taper. -year-old previously healthy woman was admitted with encephalopathy, new-onset seizures, and delusional behavior for past - weeks. mri brain was unremarkable. eeg showed status epilepticus with right fronto-central origin. she was treated with multiple antiepileptic medications including evaluation for infections, autoimmune and paraneoplastic etiologies revealed elevated thyroid peroxidase, antithyroglubulin and mildly elevated gad antibodies. whole body ct showed no malignancy. she was diagnosed with hashimoto encephopathy. she was treated with iv steroids and ivig. her clinical improvement correlated with decrease in thyroglobulin antibody levels from . to . and thyroid peroxidase antibody levels from . to . . she was discharged on oral steroids and admitted again in few weeks with a relapse of behavioral issues and seizures following steroid taper. she was treated with high dose iv steroids, this time followed by rituximab with significant improvement. she was discharged again on oral steroids with very slow taper and close follow up. our patient had hashimoto encephalopathy and had relapse following taper of steroids. hashimoto encephalopathy is rare condition and is often under-diagnosed. anti-thyroglobulin and thyroid peroxidase antibodies should be checked in patients where no other etiology of new onset status epilepticus is identified. along with seizure management, they should be treated with immunomodulators. closer follow up is needed while tapering the steroids as relapse can occur with behavioral issues and seizures and they may benefit from steroid sparing long term immunomodulatory treatment. non-convulsive seizures (ncszs) and non-convulsive status epilepticus (ncse) are common in critically ill patients. both are associated with neurophysiological disturbances, and even mortality if untreated in a timely manner. [ ]continuous electroencephalogram (ceeg) monitoring has been proven to be effective in diagnosing ncszs and ncses, and assessing the efficacy of treatment thus it is a vital investigation. [ ] we conducted a national survey on the availability of ceeg monitoring within neuro critical care units (nccu) in the uk. to ensure accuracy the consultant in charge or st - covering the nccu was contacted by telephone and asked a serious of questions regarding their use of ceeg and reporting. hospitals were identified as having either stand alone or mixed nccu. responses were obtained from of the units contacted. only % of nccus were able to perform ceeg monitoring from am- pm this dropped to % at night. in % of nccus the itu consultant did not feel confident to analayse the ceeg and make treatment decisions based upon in. the inability of % of nccu to perform ceeg is very concerning, as a single eeg may miss episodes of status, and also makes treatment to achieve burst suppression very difficult. in addition, there appears to be a training gap in ability of icu doctors ability to interpret ceeg. commissioning standards may need to be modified to encourage take of this vital monitoring technique. in addition systems such as possibly setting up a central remote analysis site for all ceeg data for england might improve time to diagnosis and treatment whilst still remaining economically. traumatic brain injury (tbi) is the leading cause of disability in children. neuroimaging is essential for the acute evaluation of moderate-severe tbi, although its prognostic utility is unclear. magnetic resonance imaging (mri) allows for detailed characterization of diffuse axonal injury (dai), the hallmark pathology described in non-penetrating tbi. higher dai grade in adults correlates with worse outcome, but this association has not been rigorously tested in children. we hypothesize that acute rotterdam score and dai grade predict short-term functional outcome in children with acute tbi. patients admitted to stanford children's hospital for acute tbi were identified via retrospective chart review based on icd and icd codes for tbi. inclusion criteria were age > mo and < yrs with blunt, closed head trauma and mri brain obtained during hospitalization. exclusion criteria included history of epilepsy, prior tbi, developmental delay, and penetrating or non-accidental trauma. the first head ct and brain mri obtained during hospitalization were used for analysis of rotterdam score and dai grade, respectively. discharge destination (home versus facility) was used as a marker of short-term functional outcome. multiple logistic regression analysis on cohort of children revealed that lower gcs and ventriculostomy were independent predictors for discharge to acute rehabilitation (or . and , respectively) versus discharge home. neuroimaging analysis revealed that more severe dai significantly correlated with discharge to a rehabilitation facility (p= . ), while rotterdam ct score did not correlate with discharge destination (p= . ). our study demonstrates that higher dai grade is associated with worse short-term outcome in pediatric patients understand the short-and long-term prognostic value of acute neuroimaging in pediatric tbi. , niteroi, brazil zika virus has been associated with several neurological complications. we aim to present three cases of zika associated subacute encephalitis, all requiring intensive care. all patients derived from the rio-zikv-gbs study cohort. all were diagnosed with mac-elisa and pcr for case : -year-old man admitted with lower extremities weakness and urinary retention, preceded by -capsular area, extending to the corona radiata and cerebellar peduncles. he was treated with a -day cycle of intravenous immunoglobulin (ivig). he was discharged one year later due to protracted weaning from mechanical ventilation. case : -year-old man admitted with lower extremities weakness, dysphagia, and dysphonia. days before he presented with and middle cerebellar peduncles, extending to pyramidal tracts. he was treated with ivig. he was discharged after acute treatment and, one year later, presented only with ataxic gait. case : year-old woman admitted with disorientation and behavioral impairment. a week before she presented with % mononuclear) with mild protein elevation. mri revealed hyperintense -t levels. she was also treated with ivig. a year later her neurological exam returned to baseline. all patients had similar clinical presentation, starting with atypical measles syndrome, later evolving to a subacute encephalitis. all showed similar radiological findings, resembling the ones observed with japanese encephalitis, another flavivirus. this new entity is likely a result of zikv-mediated autoimmune activation and it is a challenge for neurocritical care units worldwide. there are two described forms of necrotizing encephalopathy: multifocal necrotizing leukoencephalopathy (mnl) and acute necrotizing encephalopathy (ane). mnl is characterized by multiple microscopic foci of white matter necrosis and is sporadic with predilection for the pons in patients with sepsis or immunosuppression. ane is characterized by multiple foci of grey and white matter disease and is either sporadic or familial; it is typically triggered by febrile viral illness in children without evidence of cerebral infection. a case report with review of the clinical, laboratory, radiographic, and pathologic data. a -year-old woman with post-traumatic epilepsy was admitted with acute encephalopathy and respiratory failure secondary to h n and strepotococcal pneumonia. she developed refractory hypoxemia requiring proning and eventually veno-veno extra corporeal membrane oxygenation. her neurological exam declined with no response to painful stimuli and absent corneal reflexes. continuous restricted diffusion lesions of the cerebral white matter, splenium of the corpus callosum, brainstem, cerebellar peduncles, and deep cerebellum. she died after transition to comfort care and autopsy was pursued by family. neuropathologic evaluation revealed microscopic acute and subacute necrotizing lesions throughout the white matter of the cerebrum, pons, and cervical spinal cord. there were similar lesions throughout the thalamus with sparing of other gray matter structures. there was no significant lymphocytic inflammation or meningoencephalitis. this presentation is consistent with mnl, yet the thalamic involvement is more characteristic of ane. however, ane is rare in adults and typically affects both the grey and white matter. our case affected mostly white matter with microscopic lesions in the grey matter of the thalamus. this case is unique in that it has features of both known necrotizing leukoencephalopathies without clear classification. pharmacotherapy after traumatic brain injury (tbi) aims to prevent secondary insults by optimizing brain homeostasis. to better understand the relationships between medication infusions and cerebral dynamics, we investigated their associations with cerebral compliance (cc), autoregulation (ca) and heart-rate variability (hrv). a retrospective analysis of severe tbi patients admitted to the pediatric icu who underwent brain multimodal monitoring was performed. ca, cc and hrv were estimated by using different parameters: ca by using the pressure reactivity index -a pearson correlation coefficient; cc by using the rap indexa correlation between icp and pulse amplitude; hrv by heart-rate root mean square of successive differences. analysis of variance was used to investigate cerebral dynamics differences during narcotic/sedation (dexmedetomidine, fentanyl, propofol), barbiturate (pentobarbital), vasoactive (epinephrine, milrinone, nicardipine, norepinephrine, phenylephrine) and paralytic (vecuronium, rocuronium) medication infusions. children were identified ( female; ages - years). ca values were significantly higher (i.e. larger positive values) in patients who received vasoactive infusions than those who did not (epinephrine ( . ± . ), norephinephrine ( . ± . )). cc values were much larger (closer to ) in patients who received barbiturate and paralytic infusions compared to those who received narcotic/sedation infusions (pentobarbital ( . ± . ), vecuronium/rocuronium ( . ± . ), fentanyl ( . ± . ), dexmedetomidine ( . ± . ), propofol ( . ± . )). hrv displayed significantly larger values in patients who received narcotic/sedation infusions compared to those who received barbiturate infusions (propofol ( . ± . ), dexmedetomidine ( . ± . ), pentobarbital ( . ± . )). these results suggest vasoactive infusions (epinephrine and norepinephrine) are associated with impaired ca, narcotic/sedation infusions (dexmedetomidine and propofol) are associated with improved cc and greater hrv, and barbiturate infusions (pentobarbital) are associated with impaired cc and less hrv after severe tbi. prospective analysis is needed to validate these associations and investigate whether these medications may be contributors or epiphenomena of altered cerebral dynamics. sleep wake disturbances (swd) after pediatric traumatic brain injury (tbi) requiring critical care admission are poorly quantified, but may have important implications for patient recovery. we conducted a systematic review to quantify swd after pediatric tbi requiring critical care, identify interventions for swd, and determine the association between swd and other post-intensive care syndrome (pics) morbidities after tbi. injury requiring neurocritical care published after and reporting a sleep or fatigue outcome. studies focused on concussion or mild tbi without differentiation of intracranial injury requiring critical care hospitalization were excluded. risk of bias was assessed for included studies. a meta-analysis was not performed due to heterogeneity of included studies. search results yielded articles. abstract review yielded articles, and studies were included in the final analysis ( observational, case reports). we found children with tbi had significantly more swd when compared to controls. studies reported over one third of tbi patients have swd, some persisting for years after injury, but often failed to delineate phenotypes of sleep problems. most studies used subjective measures with questionnaires or interview. seven studies used a validated sleep questionnaire. three studies with total patients presented objective data on swd using actigraphy (n= ), polysomnography (n= ), and electroencephalography (n= ). outside of one case report, no studies evaluated interventions for swd following pediatric tbi. swd in children surviving tbi were associated with pics morbidities including reduced quality of life, behavioral problems, and neurocognitive impairment. heterogeneity and risk of bias among studies was high. research is needed to quantify swd, including identifying phenotypes and utilizing objective measures of sleep. evaluation of pharmacological, psychological, and behavioral interventions for swd is warranted given associations between swd and pics. current guidelines for pediatric severe traumatic brain injury (tbi) recommend maintenance of mean intracranial pressure (icp) under mmhg. increasing evidence has suggested that icp waveform characteristics may be important in understanding the impact of pressure on cerebral physiology. our study objective is to investigate strength of association of brain tissue oxygenation with icp waveform characteristics. retrospective analysis was performed on pediatric patients with tbi who underwent multimodality monitoring including measurements of pbto and icp between january , and january , . data were limited to relatively normal values of pbto between and mmhg and icp values between and mmhg. univariate linear regression was performed to assess strength of association between pbto and icp waveform characteristics including, mean icp values, icp pulse amplitude (amp), and minimum and maximum values of the icp waveforms. patients were identified ( female, ages - years [mean . ; interquartile range . - . ]). pbto was negatively associated with all icp characteristics following analysis. the correlation coefficient (r) was stronger with respect to the relationship of pbto to amp (r = - . ) as compared to mean icp (r = - . ), maximal icp (r = - . ) and minimal icp (r = - . ). p-values were < . for all measurements. these data provide preliminary evidence that icp pulse amplitude is associated with pbto . these findings suggest that icp waveform amplitude should receive greater scrutiny in understanding the impact that icp has on pbto after pediatric severe tbi though further research is necessary to confirm this finding. sarcoidosis is a systemic disease characterized by formation of noncaseating granulomas. in - % of cases, sarcoid infiltrates the central nervous system causing a myriad of clinical symptoms and imaging findings. although rare, neurosarcoidosis commonly involves the brainstem, hypothalamic-pituitary axis, leptomeninges, and spinal cord, causing symptoms such as cranial neuropathies, hypopituitarism, aseptic meningitis, and seizures. based on the review of literature, neurogenic shock as a complication of neurosarcoidosis has not been previously reported. a retrospective chart review was performed on the patient's medical records to obtain laboratory results, imaging studies, and treatment modalities. we demonstrate a case of neurosarcoidosis that initially presented with neurogenic shock, seizure-like activities, and anterograde amnesia. a -year-old african american man with neurogenic shock and seizure-like activities was transferred to our neurointensive care unit. initial workup revealed panhypopituitarism, including hypothyroidism and central diabetes insipidus. mri of neuro-axis was significant for diffuse parenchymal and leptomeningeal enhancing lesions of unclear etiology, including the hypothalamic-pituitary axis, bilateral mesial temporal lobes, and cervical spinal cord. he was intubated for airway protection and treated with dopamine infusion for hypotension and bradycardia thought to be a manifestation of neurogenic shock from his extensive cervical spinal cord lesion. despite significant cervical cord involvement, he remained with good strength throughout. he was extubated after a short course of high dose steroids and stabilization of electrolytes and endocrine function however was found to have anterograde amnesia -pet revealed hypermetabolic lymphadenopathy throughout the neck, chest, abdomen, and pelvis without cardiac involvement. he subsequently underwent lymph node biopsy which revealed noncaseating granulomas. neurosarcoidosis is an infiltrative disease process with varied clinical and imaging presentations. although neurogenic shock is classically seen as a complication from spinal cord injuries above the t segment, neurosarcoidosis affecting the cervical spinal cord can also present with neurogenic shock. the primary goal of traumatic brain injury (tbi) management is the prevention of secondary injury achieved by invasive intracranial pressure (icp) monitoring. near infrared spectroscopy (nirs) is a continuous, noninvasive surrogate measure of cerebral blood flow and oxygenation making it a potentially useful adjunct in the management of tbi. we aimed to determine the association between regional oximetry (rso ) and icp in pediatric tbi. the association between rso and icp was estimated retrospectively in pediatric patients with severe tbi. digital record using univariate dynamic structural equations modeling with a % credible interval ( % ci) for the standardized regression coefficients (src). of study patients had documented events. the association between rso and icp varied between patients and event type. no events triggered by changes in rso occurred. a significant positive (src= . , % ci= . - . ; src= . , % ci= . - . respectively). a negative r this was not significant (src=- . , % ci=- . - . ). during times without intracranial hypertension, changes in icp were positively associated with changes in rso , which may be related to changes in cerebral blood flow. our results also suggest that cerebral desaturation may be seen during periods of intracranial hypertension. our data supports the utility of nirs as an adjunct to understanding changes in icp, however further research is needed to determine if these findings are clinically relevant. rapidly progressive (< hours) primary angiitis of the central nervous system (pacns) has rarely been reported in the literature. most cases have resulted in death. here, we describe the neurocritical care course of a patient with rapidly progressive pacns who survives with a good outcome. data was collected prospectively through direct patient care and chart review. a -year-old previously healthy male presented to an emergency room in acute coma. initial head ct showed diffuse cerebral edema and a left thalamic intracerebral hemorrhage. non-contrast brain mri c perivascular enhancement suggestive of cerebral vasculitis. an external ventricular drain was placed for intracranial pressure monitoring and cerebrospinal fluid sampling, which showed a neutrophilic pleocytosis (wbc= , % pmn). brain biopsy on hospital day (hd) # was consistent with a diagnosis of necrotizing pacns. rheumatologic evaluation was negative for systemic inflammatory disease. therapy included methylprednisolone, plasma exchange, and cyclophosphamide. his hospital course was complicated by ventilator-associated pneumonia, thrombocytopenia, cerebral salt-wasting, and malignant intracranial hypertension which was treated with hypertonic therapy, barbiturate coma, and hyperintensities and resolution of perivascular enhancement. he required tracheostomy and percutaneous gastrostomy and was discharged to a ventilator facility on hd # . on discharge, he was awake and texting on his cell phone. at -month follow-up, his modified rankin score was . our case demonstrates that rapid diagnosis, early immunosuppressant therapy, and aggressive neurocritical support in collected on the optimal therapy of the patients with rapidly progressive pacns. , detroit, mi, united states cerebral amyloid angiopathy (caa)-related inflammation, or cerebral amyloid angiitis is an uncommon disease that presents with acute symptoms secondary to a solitary area of vasogenic edema. this series examines patients presenting with acute neurological symptoms and imaging out of proportion to their exam, suggesting this is a common trend in this diagnosis. cases were collected through epic review, using slicer/dicer to select patients with both snomed diagnoses of caa and cns vasculitis, and snomed diagnosis of caa concurrently treated with prednisone - . cases: ( ) year old female with prior diagnosis of caa presents with transient worsening of right arm dexterity and word-finding difficulty. ( ) year old female presented with loss of vision in the right eye lasting for hours ( ) year old female presents with two days of word-finding difficulty and confusion, using her car remote for her television ( ) year old male presenting after being unable to find words and acting out for two days ( ) year old male with prior diagnosis of caa presents with one day of confusion and nonsensical speech.( ) year old male with history of bilateral occipital hemorrhages of cryptogenic etiology presents with two days of new onset dizziness and left hemianopsia. in each case, patient was identified to have a focal area of vasogenic edema on mri that was significant and alarming in comparison to the patient's presenting symptoms. swi mri showed numerous microbleeds elsewhere to the vasogenic edema consistent with caa. considered differentials included herpes encephalitis, melas, cadasil, and cns vasculitis due to lupus, however all patients exhibited a neurological exam less severe than expected of differentials mentioned prior. all patients were administered an oral steroid regimen with taper for an average of weeks and their symptoms resolved on follow up. use of cranial ultrasound (cus) in pediatrics has been limited to neonates or infants and transcranial doppler (tcd) for stroke risk in children with sickle cell disease. we describe a clinical case showing the utility of performing cus/tcds to assess for new intracranial process in a pediatric patient where head ct was difficult to obtain due to high frequ assessment of waveforms on tcd can be a useful bedside tool in assessing progression of cerebral edema in pediatric patients unable to get a head ct. -month child with acute respiratory distress syndrome required veno-venous ecmo and therapeutic anticoagulation complicated by intracranial hemorrhage with intraventricular extension, mm leftwards midline shift, and hydrocephalus. heparin was reversed and evd was placed. since heparin sedation/paralysis. osmotic therapy was guided by elevated icp. days later, the ability to monitor icps became unreliable due to intermittent evd dra repositioning was deferred because of bleeding risk and lack of clarity whether device malfunction or unsafe because of waveforms with robust arterial diastolic flow and venous flow signifying that icp was lower than plaining unreliability of and repeat head ct showed no gross change. cus and tcd can be a useful tool to screen for high icp using midline shift and spectral waveform analysis in pediatric patients where ct may be contraindicated or challenging to obtain. the structure of intensive care has evolved as the field of medicine has created needs for specialized care. large pediatric hospitals frequently have separated cardiac icu from general pediatric icus, however further subdivision is rare, which differs from adult institutions that often have surgical and neuro icus. this subdivision capitalizes on concentration of expertise and collaboration across providers to improve patient outcomes. texas children's hospital recently opened a new pediatric icu tower and subdivided the picu into six specialty units: surgical, neurology/neurosurgery, pulmonary, hematology/oncology, medical and transitional (for patients with complex needs). we sought to retrospectively review similar patients fitting predefined neuro icu criteria both pre and post move to determine if patient outcome measures were different after cohorting patients. we conducted a retrospective review of neuro icu patients before and after our specialty icu model by comparing june-august to june-august . patients were identified using local data from virtual pediatric systems (vps, llc) and outcomes collected from the electronic medical record utilizing automated data query. primary analysis included patient demographics and outcomes including icu length of stay (los), mortality, prism- and pim- risk of mortality scores. early subgroup analysis included patients with icp monitoring devices in both cohort groups. and patients were in the pre and post cohort group respectively, of which had icp monitors in each group. median time to icp measurement was (iqr - ) and minutes (iqr - ) respectively in pre and post groups (p = . ). icu los, mortality, prism- and pim- were not statistically different. we have developed an algorithm to capture the neuro icu population for future study. preliminary investigations will hopefully confirm patients benefit from this model after programmatic maturity is achieved. west nile virus (wnv) is a mosquito transmitted arbovirus that is endemic in the united states. only % with acute infection develop fevers, and only less than % develop neuroinvasive disease. although the presentation of acute flaccid paralysis is not uncommon, it is extremely rare to visualize the destruction radiographically. here we highlight a case of aggressive neuroinvasive disease with radiographic changes. results y/o caucasian male with arthritis on methotrexate and tofacitinib presented with encephalopathy and generalized weakness. initial evaluation included mri and lumbar puncture. initial mri did not demonstrate etiology of symptoms. lumbar puncture was consistent with viral meningitis (wbc , rbc , glucose and protein ). patient was started on broad spectrum coverage. there was no growth on bacterial or fungal cultures. pcr biofire was negative for acute viruses. weakness progressed, and required intubation for neuromuscular respiratory failure. diagnostic evaluation was repeated days later. repeat mri demonstrated changes on dwi and t weighted imaging, following the motor addition to continued acyclovir, plasma exchange was initiated for an attempt at treatment. the patient's mental status improved, and he refused further treatments including tracheostomy. he was extubated and comfort care was provided given his continued neuromuscular respiratory failure. this case demonstrates severe neuroinvasive west nile encephalitis and flaccid paralysis with radiographic findings. being immunocompromised and age increase his risk for rare presentation of aggressive disease. evidence regarding adequate caloric requirements of critically ill patients with acute brain injuries is suggesting potential risk of caloric debt in neurocritically ill patients. the primary objective of this study was to determine whether guideline recommended weight-based dosing provides adequate caloric requirements compared to indirect calorimetry (ic) measurements in this population. this was a single center, retrospective, observational case-crossover study that included adults admitted within days from admission. we compared resting energy expenditure (ree) determined via ic to the lower (bmi< kg/m : kcal/kg and bmi - kg/m : kcal/kg) and higher (bmi< kg/m : kcal/kg and bmi - kg/m : kcal/kg) actual body weight-based dosing guideline recommendations. we hypothesized that guideline recommended lower-weight based nutrition will not match the caloric demand of patients with acute brain injuries. a total of metabolic studies were performed in patients ( % ich, % non-traumatic sah, % ischemic stroke, % tbi, % status epilepticus, % other etiologies). the mean age was + years, mean weighed + kg with a bmi of + kg/m , and had mean baseline gcs of + . on average ic was obtained on day of admission. lower weight-based recommended nutrition did not provide adequate caloric needs as measured by ic adjusted for obesity ( ± vs ± kcal/day, p< . ). however, higher weight-based recommendation matched the caloric demand as measured by ic ( ± vs ± , p= . ) . in this preliminary analysis, higher weight-based dosing for nutrition matched the caloric demand of critically ill patients with acute brain injury. our results need to be confirmed in future larger prospective studies. central venous catheter (cvc) insertion is common in neurocritically ill patents. standard practice is to obtain a chest radiograph (cxr) to evaluate for the presence of complications, such as pneumothorax (ptx) and catheter misplacement. point-of-care ultrasound (us) has been suggested as an alternative methodology to assess for these complications by using a flush test. patients admitted to our neuro icu between / / - / / who required cvc placement were the subject of this quality improvement analysis. cvc's were placed in the internal jugular (ij) or subclavian (sc) vein followed immediately by lung us to assess for ptx. then, apical or subcostal four-chamber view of agitated saline injected through the distal port of the cvc (ie. flush test) was performed to assess for proper placement. we observed the time delay between start of agitated saline instillation and visualization of contrast in the right atrium and ventricle. this was then interpreted as appropriate (contrast present in </= cardiac cycles) or not. twelve patients were included in this analysis. no patients had a ptx on us or cxr. one patient had a misplaced catheter detected by an abnormal flush test after subclavian cvc insertion using the landmark technique. this was further confirmed by us visualization of the cvc terminating in the ipsilateral ij vein. after immediate removal and reinsertion, followed by an appropriate flush test, cxr then confirmed accurate placement. ultrasound evaluation of cvc complications took < minutes in all cases while it took an average of minutes for the cxr to be avai a potential savings of $ . for each cvc inserted by avoiding the cost of a cxr. in conclusion, we demonstrated us post cvc placement to be an accurate, fast, and potentially less expensive method of confirming cvc placement compared to cxr. major professional critical care societies recommend shared decision-making using decision aids (das) to reduce surrogate decisions incongruent with patient values and preferences and decisional conflict. no das currently exist for any decisions in the neurologic intensive care unit (neuroicu), including goalsof-care decisions. using multilevel input from stakeholders, we recently developed a goals-of-care da for critically-ill traumatic brain injury (tbi) patients that meets international da standards. we aimed to adapt this da to intracerebral hemorrhage (ich) and hemispheric acute ischemic stroke (ais) to widen its applicability and fulfill the shared decision-making needs of surrogate decision-makers of stroke patients. we adapted the existing goals-of-care da by replacing the tbi prognostication model with diseasespecific outcome models as recommended by da quality-standards. we selected the validated month ich-model and -month hemicraniectomy trial outcome data for ais because they include validated long-term outcome assessments. next, we performed acceptability and usability testing of both das using validated scales in family members recruited from two academic neuroicu waiting rooms. we successfully modified the das and created new icon-arrays to optimize the display of predicted outcome probabilities and uncertainties, as has been shown in risk communication studies. twenty family members from two centers participated in acceptability and usability testing. median usage time was ± minutes. usability was very good (mean system-usability-scale-score = / ). % of amount, balance and comprehensibility. we developed three goals-of-care das for surrogates of critically ill tbi, ich and ais patients that include disease specific icon-arrays to communicate outcome probabilities meeting international da standards. das is ongoing, in preparation for a future multicenter comparativeeffectiveness trial. our rigorous development process following international da standards may serve as a template for other neuroicu das. neurocritical care patients receiving rate-based enteral nutrition (rben) consistently received less than their full prescription of enteral nutrition (en) volume due to interruptions in feeding. rate-based en does not allow the nurse to increase the rate after interruptions leaving patients at risk for underfeeding (kim et al. , yeh & peev, . low caloric intake over time is associated with a) immunosuppression, b) impaired wound healing, c) muscle wasting, d) increased hospital and intensive care unit (icu) lengths of stay, e) increased costs, and f) increased mortality (barker et al. , elke et increase the likelihood of adult neurocritical care patients receiving the predetermined goal of % or more of the prescribed volume of enteral nutrition over the course of the nccu length of stay through the use of a volume-based en (vben) protocol which allows the rn to increase the tube feeding rate after interruptions occur. a retrospective pre and postimplementation chart review was conducted on patients aged or greater and less than years with a neurological-related injury or disease process who received en for three or more days during their nccu stay. despite no significant differences in characteristics or gastrointestinal complications between the groups, there was a significant increase in the percentage of prescribed en volume delivered over the course of nccu stay of . percentage points in the vben group (m = . , sd = . ) as compared to the rben group (m = . , sd = . ), t( , n = ) = . , p << . , two tailed, unequal variances. vben can be safely implemented in the neurocritical care population and is associated with significant improvement in en volume delivery. pain, agitation, delirium, and machine support in the icu. a--intensive care syndrome (pics), manifest as psychological and physical debilitation that persists beyond discharge. a-neurocritically ill patients is not known. practices aligned with individual elements of the apopulation were deemed beneficial for patients within this cohort. we asked the question, does the implementation of the a- systematic training on a--professional teams was implemented. baseline data, total bundle compliance, and individual element compliance were measured and analyzed using an approach adopted from the published sccm icu liberation campaign. mortality, ventilator hours, delirium, length of stay (los), and cost were compared to baseline against the third month post education to evaluate the impact of a- preliminary analysis suggests that increased compliance with a-whether wholly or in part, resulted in improved value of care, as evidenced by a decrease in mortality from % to %, as well as a reduction in total icu los adjusted by acuity from . days to . days. this translated into a reduction in cost. as additional experience (and data) become available, further analysis is planned to evaluate the impact of a- early results from a systematic implementation of aand pertinent to improving patient outcomes and value of care. many neurologic diseases are incurable, and patients are faced with prognostic uncertainty, progressive decline and early mortality. as a result, acgme requires training in serious illness communication for all neurology residents; however, only % of programs offer formal education. to address this gap at our institution, we created a training program for neurology residents to improve their skills, attitudes, and behaviors regarding serious illness conversations we designed and implemented a -hour training program utilizing the serious illness conversation guide (ariandnelabs.org). the training program is comprised of a didactic session, a simulated patient experience and debriefing. residents were asked to have a goals of care (goc) conversation with family members (actors) of a patient with catastrophic stroke. a faculty facilitator observed each interaction, allowing residents to self-assess, obtain feedback from the actors and peers and then practice specific components of the conversation. residents filled out a survey both prior to and following the simulation and the faculty filled out an evaluation for each of the residents. led out a pre-survey. the majority ( / ) felt that the residency did not adequately prepare them to have goc discussions though more than % of residents reported feeling comfortable and confident performing these discussions. despite this confidence, the observing faculty found / residents require direct supervision and are not ready to have these conversations independently. the residents struggled with conveying prognosis, maintaining silence, and dealing with strong emotions. all residents reported the training was a helpful, rewarding experience and improved their overall abilities to discuss goc, address prognosis, and explore end-oflife issues. this small pilot study demonstrates an innovative model to improve residents' communication skills surrounding effective goc discussions even when they report increased confidence and independence in these difficult conversations. studies of patient outcomes in mechanically ventilated icu patients have discovered associations among sedative drugs, patient characteristics (demographics and illness), burst suppression (brain inactivation), and mortality. however, association does not imply causation. it remains unclear ( ) whether unintentional burst suppression has a causal effect on mortality, ( ) the degree to which drugs directly impact mortality, and ( ) whether drugs impact mortality indirectly by causing burst suppression. patient characteristics are a possible source of confounding. we estimated causal effects of unintentional burst suppression, critical illness severity and the anesthetic sedation on in-hospital mortality in mechanically ventilated icu adult patients. this was a longitudinal study with an observational cohort of adult icu patients. eeg recordings were obtained for each patient and reviewed by clinical neurophysiologists per institutional protocol to determine the presence of burst suppression in each epoch ( - hour segment). the causal effects were estimated using causal statistical inference (pearl's do-calculus). to assess the robustness of our results towards unmeasured confounding, we performed sensitivity analysis using the e-value. % confidence intervals were created using bootstrapping. on average, increased drug exposure causes a % increase in mortality ( % bootstrapped confidence interval -. , . ) and a % increase in burst suppression incidence (. , . ). burst suppression mediates % of the impact of drug exposure on mortality and is associated with a % increase in mortality (. , . ). increased severity of illness causes a % increase in mortality (. , . ), and a % increase in burst suppression burden, measured by the percent of epochs during which patients experienced burst suppression (-. , . ). unintentional burst suppression contributes substantially to in-hospital mortality. however, unintentional burst suppression appears to be affected more by patient characteristics such as severe critical illness than by high exposure to sedative drugs. infectious endocarditis (ie) is a growing health concern, with increasing incidence in the context of the opioid epidemic. we described a large case series of patients with ie at an urban, academic safety-net hospital. clinical data on patients with diagnosis of ie were entered into an endocarditis work group single-center registry. the mission of the multidisciplinary group is to optimize clinical care, especially as it pertains to cardiac surgical management. we reviewed demographic information, history of prior cardiac valve replacement, intravenous drug use (ivdu), blood culture results, and diagnostic studies (ie echocardiogram, brain ct/mr imaging, and conventional angiography). between november and may , consecutive patients (mean . years; aged - years; % male) with ie were admitted to our center. patients had a history of ivdu in % of cases. unique microbes were isolated, most commonly staphylococcus species ( mssa, mrsa, other). polymicrobial infection occurred in patients. on echocardiogram, vegetations were seen on tricuspid ( ), mitral ( ), aortic ( ), and pulmonic ( ) valves. patients had multi-valve involvement. patients underwent brain ct or mri demonstrating-cerebral infarctions ( ), subarachnoid hemorrhage (sah) ( ), intracerebral hemorrhage (ich) ( ), brain abscesses ( ), and mycotic intracranial aneurysms ( ). neurologic complications occurred most frequently in the setting of mitral valve disease ( infarcts, sah, ich) and in those with staphylococcus ( ) and polymicrobial infection ( ). tricuspid valve vegetations were associated with cerebral infarcts and ich. despite frequent association with ivdu, left-sided cardiac valve vegetations were common. mitral valve involvement, staphylococcus species and polymicrobial infections were associated with increased risk for neurologic complications. neurologic complications also occurred in patients with right-sided valvular disease, suggesting a need for increased surveillance in this population. acute neurological conditions such as traumatic brain injury (tbi), cerebrovascular accident (cva), and hypoxic-anoxic injury (hai) can significantly impact a patient's functional status, and life expectancy. older adults may have poorer outcomes, especially those with premorbid conditions. studies have shown a preference for less aggressive care if patients and/or families anticipate a shorter life expectancy, or poor outcome. as such, early delivery of prognostic information and discussion of goals of care (goc) can be crucial for patients prior to transfer to a tertiary care facility. this is a retrospective cohort study of patients aged and older with cva, hai, or tbi who died within hours of charts were reviewed to assess documentation of pre-transfer goc discussions, code status change after transfer, prevalence of palliative care consultation, and other utilization markers. patients met inclusion criteria with . % being male and . % female with median age . . the majority of patients were transferred from an emergency department ( . %). only . % of patients had documented goc discussions prior to transfer. only . % patients of patients underwent surgical intervention. after transfer, . % of patients downgraded their scope of treatment to comfort measures prior to death, with this being even higher in those and older ( . %). palliative care consultation took place in only . % of patients after transfer. while transfer to a tertiary medical center is sometimes necessary, only . % of patients had documented goc discussions and the majority ( . %) downgraded their scope of treatment to comfort measures after transfer suggesting a potential opportunity for earlier goc discussion and possible avoidable hospital transfers. these findings can inform the design of future interventions to improve communication and decision-making regarding goals of care in patients with high mortality neurological conditions. a neurological emergency response team (nert) was implemented at a dedicated neuroscience hospital in an academic medical center in anticipation of higher patient volumes with the extended treatment window for acute ischemic stroke. goals of the nert are to ensure safe and effective care transition into the acute care setting and a standardize approach to neurological emergency. a dedicated clinical team examined the current structure for safe & effective patient triage, monitoring and transition from the interventional neuroradiology (inr) suite to the neurocritical care unit. clinical nurses with over three years' experience in neurocritical care were vetted, trained & scheduled to provide / continuous coverage. after patients were triaged via telemedicine technology, the nert nurse was alerted via automatic text message system and prepared to receive the patient via ambulance to the inr suite. during the assembly of the inr team, the nert nurse assessed and monitored the patient and initiated diagnostic testing. upon completion of intervention, the nert initiated transfer of care to the neurocritical care unit. stroke volume and door to treatment times were evaluated pre-and post-intervention. in , ischemic stroke patients were admitted through the inr suite, with being treated with endovascular intervention. in , ischemic stroke patients were admitted, with patients being treated with endovascular intervention. since the implementation of the nert, average median arrival time to skin puncture for intervention decreased by seven minutes with a % increase patient volume. a dedicated neurological emergency response team is an effective model to support the increase in patient volume for evaluation of acute ischemic stroke intervention. this approach demonstrates the potential for efficient, safe and timely triage, intervention and care transition to the neuro icu for stroke patients. arctic ground squirrels (ags) endure harsh winter environments through hibernation. curiously, ags are resistant to stroke and other ischemic injuries independent of season or metabolic state. the details of physiologic and cell autonomous genetic adaptations underlying this metabolic resilience is largely unknown. the resilient metabolic and mitochondrial phenotype of ags neural cells was examined in vitro after exposing cells to hypoxia, hypothermia, or mitochondrial toxins and assaying for cell survival, mitochondrial morphology, and oxygen consumption rate. a cdna library prepared from ags cells and nucleofected into mouse neural cells exposed to metabolic stressors was used to perform a functional genetic screen. a bio-informatics pipeline identified screened candidates with key amino acid substitutions that may have evolved to optimize stress response function. newly described dcas base editors capable of substituting c->t (and g->a) were used to systematically mutate and explore the role of identified proteins in mediating the ags optimized adaptive stress response. we found that ags neural cells exhibit marked resistance to all metabolic stressors. this is associated with enhanced mitochondrial function and improved morphology. the functional genetic screen identified a network of evolutionarily-conserved ags transcripts imparting cytoprotection. use of dcas base editors on candidates suggested by the bio-informatics pipeline, confirmed the coordinated role of specific components of the oxidative phosphorylation (oxphos) and endoplasmic reticulum (er) stress response systems in imparting mitochondrial and neuroprotection in our in vitro model. we gained key functional insights into how specific amino acid substitutions in the machinery of the oxphos and er stress responses systems alter mitochondrial function to impart cytoprotection to metabolic insults. this detailed dissection of the ags optimized adaptive stress response pathway will serve as an template for the development of new neuroprotective treatments. acute ascending weakness with respiratory failure is a frequent syndrome encountered in the neurocritical care unit (nccu), often related to demyelinating or infectious etiology. however, here we describe a case of acute ascending weakness with encephalopathy, respiratory failure and autonomic instability that was related to confirmed endocrinological etiology. prospectively collected data was retrospectively extracted from the electronic health record in a patient known to our nccu team. a -year-old male with medical history of childhood meningitis was transferred to the nccu after initially presenting to an outside emergency department (ed) with a chief complaint of bilateral lower extremity weakness progressing to paraplegia over hours. six hours into his course in the ed, he developed bilateral upper extremity paresis and respiratory distress. physical exam in this ed was additionally notable for areflexia and a sensory level at t . he was intubated, initiated on ivig and methylprednisolone, and airlifted to our institution. upon arrival, telemetry showed frequent supraventricular tachycardias refractory to standard treatment. labs (including cerebrospinal fluid) were notable only for serum potassium < . meq/l, thyroid stimulating hormone < . uiu/ml, t . uiu/ml ( . -- . ). he was diagnosed with thyrotoxic periodic paralysis. at endocrinology's urging, the patient was given propranolol mg iv every minutes for doses, propylthiouracil and hydrocortisone. in the hours following propranolol, his potassium improved, his paralysis and encephalopathy resolved, and he was ultimately extubated without difficulty < hours after admission. review of symptoms performed after improvement revealed recent symptoms consistent with hyperthyroidism. intensivists should remain aware of the differential diagnoses that can manifest with motor weakness and respiratory failure. in this patient, severely elevated thyroid hormone led to thyrotoxicosis and subsequent profound hypokalemia. acquiring a thorough history and reviewing laboratory abnormalities remain paramount for timely diagnosis. the objective of the study is to determine the prevalence of disability among icu survivors one year after admission, and factors influencing functional outcome. we conducted a population based cohort study in the icus of the mayo clinic, rochester, mn. we enrolled consecutive patients from the mayo clinic study of aging (mcsa) and then admitted to medical or surgical adult icus at mayo clinic, rochester between january , , and december , . patients admitted to the neuroscience icu were excluded. we collected their demographic and clinical variables, length of icu stay, functional and cognitive status (before and after icu admission), comorbidities (components of charlson score), and apache were retrieved from the electronic medical records using multidisciplinary epidemiology and translational research in intensive care (metric) data mart. one-year functional outcome was categorized using the modified ranking scale (mrs) with scores to representing good functional outcome. cases were included and ( . %) patients were alive one year after icu admission. of them, patients had one-year follow-up functional assessment and ( . %) of them had good functional outcome. on multivariable analysis, poor one-year functional outcome (death or disability) was more common among women, older patients, baseline cognitive impairment (mild cognitive impairment or dementia), higher charlson scores, and longer icu stay (all p< . ). after excluding deceased patients, these associations remained unchanged. in addition, ( . %) of patients who had post-icu cognitive evaluation, experienced cognitive decline after the icu admission. approximately two-thirds of survivors maintained or regained good functional status one year after icu hospitalization. older age, female sex, greater comorbidities, abnormal baseline cognition, and longer icu stay were associated with poor functional recovery. shared decision-making using decision aids (da) is recommended by major professional critical care societies for surrogate decision-making in the icu to reduce decisions incongruent with patient values and preferences and decisional conflict. we converted a paper-based goals-of-care da in critically-ill tbi patients to a digital da. we applied eye-tracking-technology in a single-masked randomized study to understand the effects of and optimize the da navigation design to facilitate information processing. we created two digital das: ( )unmodified conversion of the paper-da with horizontal, top-justified static navigation (control) vs. ( )vertical, left-justified navigation with page subsections and page completion checkmarks (experimental), which encourages users to view pages in order. sixteen healthy participants were randomly assigned to the two groups (n= /group, masked to da assignment) and navigated through the das. using t-tests, we compared user disorientation and usability using validated scales, and eye movements (fixation and saccades) recorded with eye-tracking-technology. impact of navigation on usability was assessed with linear regression, adjusting for disorientation(system-usability-score= b + b *disorientation). disorientation was significantly less in the experimental da (mean . vs. . ;p= . ;smaller values indicating increased disorientation) with no difference in usability (mean system-usability-scale scores vs. ;p= . ;scores> indicating good usability[range - ]). regression analysis revealed a significant association between disorientation and usability (p= . ), with disorientation explaining % of the variation in system-usability-scale scores (adjusted r = . ). eye-tracking measurements revealed longer average fixation per page in the experimental da (mean . s vs. . s;p= . ) and a higher ratio of information processing to search per page (fixation-duration over total duration of both fixations and saccades on a page; mean . vs. . ;p= . ). eye-tracking-technology suggested that the experimental navigation design significantly improved the navigation experience resulting in less disorientation and participants spending less time searching and more time processing the information. while there was no difference in subjective usability, we found a significant association between improved navigability and higher usability. high-fidelity simulation has become an important mode of learning in medical education. currently, there is little data regarding the impact of simulation-based learning in neurocritical care training. in may , we presented a poster at the american academy of neurology annual meeting introducing a comprehensive simulation-based curriculum for neurocritical care training at uc san diego (ucsd). in this poster, we aim to present additional preliminary findings regarding trainee comfort levels, interest, and areas of improvement. this is a single-group pre-post study involving current residents of the ucsd department of neurology. simulation sessions consist of interactive, faculty-led, and checklist-based clinical scenarios (ischemic stroke, intracranial hemorrhage, status epilepticus, spinal cord emergencies) followed by debriefing sessions. collected data assesses for self-perceived comfort/confidence levels, future interest, and checklist item completion. between january and july , pgy - neurology residents participated in various simulation sessions on ischemic stroke, intracranial hemorrhage, and status epilepticus. prior to the session, . % of all trainees reported no more than somewhat comfortable in treating neurological emergencies despite having received some type of neurological emergency training through didactic lectures. rtable in treating the specific simulation case in observation of each simulation session pinpointed specific areas of improvement amongst trainees on an individual basis (i.e. time to intubation after benzodiazepine administration in refractory status). preliminary results suggest that simulation-based learning is valuable and applicable in the neurocritical care training process, allowing trainees to feel more comfortable in managing acute neurological deterioration and faculty to directly observe trainee skill in a controlled setting. through this project, we hope to highlight the need for simulation-based education in neurocritical care training by providing evaluative information and generalizable curricular examples. chimeric antigen receptor (car) t cell therapy for refractory/relapsed hematologic malignancy often causes severe neurologic side effects ranging from encephalopathy and aphasia to fulminant cerebral edema and death. the cause of neurotoxicity is poorly understood. we sought to develop a score based on clinical and laboratory parameters to predict which patients would develop cart-associated neurotoxicity. all patients undergoing cart therapy at brigham and women's hospital for relapsed/refractory hematologic malignancy were prospectively studied. patients were assessed daily during their admission for cytokine release syndrome (crs) and neurotoxicity. vital signs, laboratory data, and medication administration records were extracted from the medical record. logistic regression was used to determine which clinical and laboratory features were significant predictors of developing neurotoxicity. patients were included. experienced crs and experienced neurotoxicity. early (within days after cart infusion) fever and elevated serum c-reactive protein (crp), timing of crs onset, crs grade, and treatment with tocilizumab were all significant predictors of neurotoxicity. using roc curves, optimal discriminators were defined and used to derive a score to predict neurotoxicity. one point was assigned for fever, serum crp > . mg/dl, and each dose of tocilizumab administrated, zero to four points for crs grade, and zero to three points for day of crs onset. this score ranged from to for our cohort and had an auc of %; a score >= predicted neurotoxicity with a sensitivity of % and a specificity of %. bootstrap analysis was used to demonstrate robustness. we used regression analysis to develop a score that can prospectively predict which patients are most likely to suffer from neurotoxicity related to cart therapy. this score can be used for triaging and resource allocation during the care of the patients after treatment with cart therapy. when brain herniation is impending, every minute matters; so the efficient and expedient procurement of all components required for external ventricular device (evd) placement is vital to neurological preservation. the neurosurgical residents at the university of rochester medical center often struggled to assemble the appropriate supplies for an evd placement in a timely manner when patients were not yet admitted to the neuro intensive care unit (neuro icu). additionally it was difficult to track equipment use and supply costs. in response, the neuro icu's quality improvement (qi) team designed an evd "go bag" in an effort to improve delays in care, patient experience, and avoidable costs. the multidisciplinary neuro icu qi team collaborated to design a portable bag that contained all equipment necessary for evd placement. two neurosurgery residents performed time trails, in real emergency situations, by measuring the time from decision to place an evd in emergency department (ed) critical care bay, to collecting the equipment from the neuro icu and return to the bedside in the ed. times were compared with and without using the evd "go bag". the evd "go bag" decreased the time to placement of an evd by up to minutes when compared to the traditional method of retrieving all evd equipment from the neuro icu stockroom. time reduction was due to the speed of gathering supplied and the ability for the neuro icu staff to bring the evd "go bag" to the patient's bedside. the evd "go bag" allowed for better tracking of monetary costs and equipment, allowing for appropriate billing and stocking of supplies. a system was developed where the bag was checked and restocked daily by the critical care equipment technicians and the neuro icu charge nurse despite a growing number of prognostication models in neurologic emergencies, prognostic uncertainty remains inevitable and plays a central role during goals-of-care decision-making for incapacitated critically ill patients. we aimed to examine surrogate decision-makers' communication needs and physicians' strategies for communication of prognostic uncertainty during family meetings for critically ill traumatic brain injury (citbi) patients. we qualitatively analyzed semi-structured interviews of surrogates of citbi patients from two level- u.s. trauma-centers and tbi expert physicians from u.s. trauma-centers. open-ended questions about prognostic uncertainty were asked. interview transcripts were analyzed with the investigatortriangulated-inductive-framework-approach in nvivo-software. prognostic uncertainty was identified as the most difficult aspect of decision-making for surrogates by physicians and surrogates alike, although most surrogates had some pre-existing expectation or understanding of it. % of physicians observed that uncertainty is distressing for families, with % employing specific measures to limit uncertainty. over half of physicians described explaining the concept of uncertainty so surrogates understand that physicians can estimate the odds but not predict the future. physicians typically conveyed prognosis using a range of outcomes, and conveying certainty only for prognostic extremes. surrogates found uncertainty around prognosis was lessened when physicians explained all possible treatment options, with support from clinical data. roughly half noted that too much certainty in providing a prognosis, without a range of possible outcomes, led to distrust in the information provided by the physician, increasing decisional conflict. the vast majority of physicians admitted statistical uncertainty in deriving prognosis, particularly for patients with tbi, and cited mistrust of prognostic models when deriving long-term prognosis. most physicians felt that uncertainty around prognosis led to increased incidence of tracheostomy and feeding tube placement. these results provide foundational knowledge for physician-family communication, by identifying important gaps between surrogates' communication needs and physicians' practices about prognostic uncertainty. the rapid rise in social media utilization among both patients and healthcare providers has moved a considerable portion of conversation around health and disease to the digital space. today, roughly nine-in-ten american adults use the internet, with % of internet users participating in social media. the power and reach of social media platforms makes it imperative for clinicians to be aware of the trends in the public narrative around common disease processes. in this study, we analyzed the last . years of postings ("tweets") from a popular social media platform, twitter, to characterize themes and trends in the digital conversation around stroke, the leading cause of long term disability in the us. tweets under the hashtag #stroke, published from january st to april th , were extracted through symplur signals, llc. a total of , #stroke tweets were qualitatively coded and sentiment analysis was performed after selection for relevance among all homographs. accounts owned by stroke-related advocacy groups were found to be the most prolific contributors of #stroke postings, with content mostly around primary stroke prevention (risks and signs). among the most popular associated hashtags, over half of the tweets focused on comorbidities and the challenges of the stroke recovery process (top trending words included #aphasia, #lockedin, #survivor, #depression). our preliminary analysis describes trends in themes and stakeholder participation in the current #stroke online conversation. it also exposes important gaps in the public discourse beyond the setting of academic and research online communities, namely around existence of therapeutic treatments, availability of resources for patients and families navigating the recovery process, and possibility of successful recovery and long term outcomes. such knowledge around the digital stroke narrative may provide valuable context to intensivists and stroke clinicians interacting with patients and families affected by stroke. the field of autoimmune neurology, specifically the autoimmune encephalitides, has expanded since the early 's. increasingly newer antibodies to various parts of the nervous system are being identified in discovered in patients with meningoencephalomyelitis, or some spectrum of these three singular entities. data was reviewed from electronic medical records for this case report. a previously healthy year-old male initially developed a case of aseptic meningitis, progressing to encephalitis and then extensive longitudinal myelitis leading to profound paresis and respiratory failure. an extensive workup was performed, including evaluation for rare infectious and ominant leukocytosis ( /μl and /μl) and elevated protein (> mg/dl). he was treated empirically with antibiotics which were discontinued after negative results and cultures. after therapy with high dose iv steroids he had minimal improvement and pl had improvement in his symptoms. he was started high dose prednisone with plans to slowly taper after return with positive anti- in review of the literature our patient had several characteristics consistent with others who were also antipsychiatric symptoms. many reports state steroids lead to remission and improvement, however in this case our patient did not have substantial recovery until after the initiation of plex. at this time it is hether these antibodies instead represent a marker of other underlying disease from cytotoxic t cell damage to astrocytes. the united council for neurologic subspecialties (ucns) accredits neurocritical care (ncc) subspecialty fellowships and certifies neurointensivists. in , the american board of medical specialties (abms) approved the application for ncc subspecialty certification by american board of psychiatry and neurology (abpn) and the accreditation council for graduate medical education (agme) approved ncc fellowship training in . previous studies have shown significant heterogeneity in ncc fellowship training and procedural competencies and that many programs do not have the necessary resources for a transition to acgme accreditation. in , an online survey of abpn neurology diplomates was utilized to estimate the number of neurologists practicing ncc, their ncc fellowship training experiences, whether their institutions required certification in ncc, their scope of practice, and their interest in pursuing abpn certification in ncc. survey respondents indicated that they practiced ncc. based upon ucns and other data, this is estimated to be at least % of all neurologists practicing ncc. % of ucns-certified ncc respondents identified the primary scope of their practice as academic involving a fellowship program, and % of non-ucns-certified ncc responders identified themselves as private practitioners. nearly % of fellowship trained ncc respondents obtained ucns certification. % of ucns-certified ncc respondents reported that their institutions required ucns certification, whereas % of non-ucnscertified ncc respondents reported no institutional requirements for certification. over % of respondents thought ncc training was relevant to their current clinical practice. most respondents indicated that they planned to take the abpn ncc examination, and > % of respondents reported that abpn certification would most benefit them by improving their colleagues' perceptions about the quality of certification. ncc training and certification is valued by most neurologists practicing ncc, and most believe that abpn ncc certification will advance the recognition of the field of ncc. cerebral edema is a severe complication of acetaminophen-induced acute liver failure (apapprimary objective was to describe the characteristics of patients with cerebral edema in the setting of apap- this analysis is part of a large, retrospective observational study inclusive of apap-year period from a regional transplant center. we used standardized data collection tools and trained defined cerebral edema based on the interpretation of this ct by a blinded radiologist. we performed univariate analysis based on the presence of cerebral edema. of a total of patients, had data on ct brain imaging. the mean age was . ± . years, and patients ( . %) were female. of patients with neuroimaging, ( . %) had evidence of cerebral edema. patients with cerebral edema had higher average ammonia levels on day of hospital admission ( , % ci - vs. , % ci - mcg/dl). patients with cerebral edema also had significantly higher meld scores by -hours ( . , % ci . - . vs. . , % ci . - . ). this significant difference persisted for subsequent hospital days. thirteen patients ( . %) with cerebral edema received intracranial pressure monitoring. mortality within -days was . % (n= ) if cerebral edema was present vs. . % if absent (n= ). the odds of death within -days, if cerebral edema was present, was . ( % ci . - . ). one patient with cerebral edema died awaiting transplant, and received liver transplant. in this study, cerebral edema was present in % of patients hospitalized for apapwith higher mortality. elevated intracranial pressure and cerebral edema are leading predictors of poor outcomes and mortality in patients with head trauma, intracranial hemorrhages, or acute ischemic strokes. while hypertonic saline (hts) is the mainstay of treatment, recent trials in critically ill populations have demonstrated a reduction in kidney related adverse events with the use of balanced crystalloid groups when compared to . % sodium chloride (nacl). the purpose of this study is to assess adverse kidney outcomes and risk of in-hospital mortality associated with hts in a neurocritical care population. a retrospective cohort study was conducted at a large academic medical center on adult patients in the neurosciences icu who received % nacl and/or . % nacl from july , to july , . the primary endpoint was major adverse kidney events (make- ), defined as at least one component of the composite: in-hospital mortality, receipt of new renal-replacement therapy, or persistent renal ays. baseline characteristics, indication for hts, pertinent lab values including changes in serum electrolyte concentrations, total hts volume and associated sodium and chloride milliequivalents, and patient outcomes were collected. statistical analysis was performed using spss software. in the chloride increase > mmol/l group, patients ( . %) experienced the primary outcome of make- , patients ( . %) experienced in-hospital mortality and patients ( . %) experienced aki primary outcome of make- , and patients ( . %) experienced in-hospital mortality (p= . ). the primary outcome occurred more often in the chloride increase > mmol/l group and in-hospital mortality accounted for the majority of the outcome in both groups. this was not statistically significant due to the sample size and unbalanced comparator groups. social media has been shown to be a valuable tool to improve knowledge, attitudes, and skills. it has been theorized that the success of medical education through social media can be contributed to increased learner engagement, real-time feedback, and enhanced collaboration. we hypothesize that social media is underutilized in critical care medicine in comparison to other specialty fields of medicine and surgery. a list of medical specialties as hashtags were run through "hashtagify" software. this software crossreferences up to , data points on instagram and twitter and assigns a "popularity score" for certain topics. the phrase "critical care" was cross-referenced through a database of medical news run by doximity over a month in comparison to other topic tags. in total, articles concerning the topic "critical care" were posted on doximity news over days. in comparison, there were articles posted under "cardiology," under "internal medicine," and under "emergency medicine." with respect to hashtag utilization on social media, critical care was under-represented, with a popularity score of . this was in comparison to other specialties such as neurology ( ), dermatology ( ), emergency medicine ( ), and ophthalmology ( ). within the critical care hashtag, the major influencers were those representing critical care nursing. despite the large amount of news pertaining to critical care on professionally-curated forums such as doximity, there is significant under-representation in social media. within the hashtag, "critical care," the major influencers represented critical care nursing suggesting that critical care physicians are even further underrepresented. this is in line with previous research suggesting the underrepresentation of medical doctors in social media. given that social media has been shown to be a valuable tool in enhancing medical education, we believe that a greater effort should be made to engage critical care physicians on social media outlets. there is a call for increased diversity in national and international annual meeting participation in terms of attendance, committee participation, leadership, awards and speakers. the neurocritical care society annual meeting(ncs-am) speaker qualifications are not specified in the bylaws. the speakership patterns of the ncs-am have not been examined. we described the speakership patterns in ncs across a -year time span ( ) ( ) ( ) and delineated the trends of united states-neurocritical-care-fellowship- longitudinal cohort study. the ncs-am conference program, a readily available online document, for the years - , were reviewed by the study authors. speakers were identified from the conference program. our primary outcome was the trend of speaker characteristics across the -year time span. our secondary outcome was to determine speakership trends among united states-neurocritical-care-fellowshipinstitution of employment at the time of the meeting. a total of speakers were included in this study, of which % were male. majority of the speakers were us-based( %), mid-to late-career ( %) and were physicians ( %). the speakers were ± years from fellowship. in -years, there was an increased trend towards international, non-physician and early-career speakers' trained from johns hopkins university (jhu) ( , %), massachusetts general hospital (mgh) ( , %) and cornell/columbia university ( , %); while the most common sites of employment at the time of the meeting were jhu ( , %), mgh ( , %) and university of pittsburgh medical center ( , %). this is the first study to evaluate speakership trends across a -year period of the ncs-am. diversity has ble institutional bias are unclear and deserves to be studied further to better define speaker selection in the ncs annual meeting. these data may also be utilized to explore opportunities for collaboration and diversity in future ncs-ams. urinary tract infections (utis) are the fourth most common type of healthcare-associated infection, primarily caused by instrumentation of the urinary tract. there is a %- % increased risk of patients acquiring a catheter-associated urinary tract infection (cauti) for each day an indwelling urinary catheter (iuc) remains in place. in critically ill patients, iuc placement is often required for precise urine output measurement. subarachnoid hemorrhage (sah) patients often require iuc's during the cerebral vasospasm period (i.e. post-bleed day, pbd - ) to maintain euvolemia. this places sah patients at increased risk for developing a cauti. in our local neurosciences intensive care unit (nsicu), an infection control team observed higher cauti rates as compared to the hospital and national average necessitating changing our urinary catheter utilization policy. we report change in practice pattern with implementation of new unit policy the intermittent catheterization (ic) algorithm includes clinician review of the patient's total intake and output and current clinical status. retrospective chart review of cauti incidence (rate per catheter days) and device utilization ratio (no. urinary catheter days/ no. patient days) months before and after implementation of the new policy. time periods were compared using appropriate statistical tests pre-and post-intervention the ic algorithm was implemented to reduce iuc utilization rate with aim to reduce cauti rates. the time periods studied were may to april (pre-intervention period) and may to april (post-intervention period). cauti rates decreased from . ± . during the former time-period to . ± . during the latter time period (p= . ). similarly, device utilization ratio decreased from . ± . to . ± . (p< . ). in addition, use of female and male external catheter devices were encouraged leading to increased utilization systemic team based implementation of policies can result in adoption of positive practices and reduce hospital acquired infectious complications. managing neurological emergencies, particularly overnight, is very challenging for neurology trainees at the beginning of their residency. preparation is key to ensure residents have the skills, confidence, and knowledge to manage acute scenarios. we developed a one-week immersive bootcamp to educate new neurology residents about neurological emergencies prior to the start of the academic year. the bootcamp includes the fourteen emergency neurological life support (enls) modules designed by the neurocritical care society, thirteen faculty-created didactics, nine case-based discussions, and four resident-created simulations. the bootcamp teaches residents about the management of acute ischemic stroke, acute non-traumatic weakness, anoxic brain injury, coma and brain death, intracranial hemorrhage, intracranial hypertension, meningitis, neuromuscular emergencies, status epilepticus, spinal cord emergencies, subarachnoid hemorrhage and traumatic brain injury. residents are also taught about communication with families during and after neurologic emergencies in a didactic session on breaking bad news. it is important for all neurology residents to be adept at managing neurological emergencies. however, having these skills is particularly important for residents in a military program, as residents in the military may ultimately be deployed overseas or stationed at facilities with minimal support, responsible for handling all neurological emergencies, regardless of their sub-specialty. enls training and didactics teach residents about the fundamentals of neurological emergencies. case-based discussions provide residents to act out the way they would utilize this knowledge in a risk-free environment that is translatable to acute clinical situations. the combination of enls training, didactics, case-based discussions and simulations into a one-week immersive bootcamp early in residency should, therefore, provide a solid knowledge base about management of neurological emergencies for incoming neurology residents and allow them to consolidate that knowledge leading to safe and effective management of neurological emergencies. trends and predictors of in-hospital mortality for status epilepticus: national inpatient sample study head or heart: ictal bradycardia and temporal lobe epilepsy julia bevilacqua higher dai grade correlates with worse short term outcome in pediatric traumatic brain injury anna janas; scott hamilton; zachary threlkeld; max wintermark post-intensive care syndrome amongst families of icu patients, including post-traumatic stress disorder (ptsd), is highly prevalent after patient discharge but understudied. the psychological model of "attachment theory" describes how people respond when being separated from loved ones; various "attachment styles" have been associated with the development of ptsd in other settings. adults can be "secure" (comfortable depending on others and being alone) or "insecure." the hypothesis of this exploratory study was that insecure family members of neuro icu patients would be more likely to report ptsd six months after patient hospitalization compared to secure family members. eligible participants were family members of neuro icu patients at a single center who already had attachment styles (secure vs. insecure) defined via a standard survey, the relationship questionnaire, during an earlier study in . over - , these subjects were asked by mail to complete the impact of events scale-revised (ies-r) six months following discharge or patient death. participants were considered to have ptsd if ies- / returned a completed ies-r ( . %). ( . %) of these subjects reported a secure attachment style vs. out of ( . %) insecure respondents (p= . ). this small study did not show a significant difference in rates of post-discharge ptsd amongst neuro icu family members with secure vs. insecure attachment styles, however was only powered to discover a large difference between groups and the rate of ptsd in our population was markedly lower than sible association in larger cohorts with an overall higher prevalence of post-discharge ptsd would be insightful. key: cord- -tqzvdssb authors: dubost, clément; pasquier, pierre; kearns, kévin; ficko, cécile; rapp, christophe; wolff, michel; richard, jean-christophe; diehl, jean-luc; le tulzo, yves; mérat, stéphane title: preparation of an intensive care unit in france for the reception of a confirmed case of ebola virus infection() date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: tqzvdssb the current ebola virus disease (evd) outbreak in west africa is a major challenge for the worldwide medical community. on april th , the world health organization (who) declared , infected cases; among them, , have deceased. the epidemic is still ongoing, particularly in sierra leone. it is now clear that northern countries will be implicated in the care of evd patients, both in the field and back at home. because of the severity of evd, a fair amount of patients may require intensive care. it is highly probable that intensive care would be able to significantly reduce the mortality linked with evd. the preparation of a modern intensive care unit (icu) to treat an evd patient in good conditions requires time and specific equipment. the cornerstone of this preparation includes two main goals: treating the patient and protecting healthcare providers. staff training is time consuming and must be performed far in advance of patient arrival. to be efficient, preparation should be planned at a national level with help from public authorities, as was the case in france during the summer of . due to the severity of the disease, the high risk of transmission and scarce knowledge on evd treatment, our propositions are necessarily original and innovative. our review includes four topics: a brief report on the actual outbreak, where to receive and hospitalize the patients, the specific organization of the icu and finally ethical aspects. the ongoing ebola virus disease (evd) outbreak in west africa is due to the zaire ebola virus, an enveloped, non-segmented, negative-stranded rna virus from the filoviridae family [ ] . ebola virus, like margburg virus, is a highly transmissible, category a biothreat pathogen [ ] . in this useful classification, a represents the highest risk and highest priority agents, b the second highest priority and c the third highest priority, including emerging pathogens that could be engineered for mass spread in the future. evd causes fever, headache, gastrointestinal symptoms, diffuse haemorrhage, multiple organ failure and has a high fatality rate. ideally, all the deceased patients should have been treated in an intensive care unit (icu), meaning that at least % of the cases would have been admitted to the icu. preparation of northern countries for evd treatment is based on two transmission models. firstly, certain healthcare workers are involved in non-governmental organizations that help treat infected people [ ] . as health workers, they are exposed to contaminated blood and other body fluids. thus, they are particularly at risk of infection and may develop the disease, either in west africa or back at home. the current ebola virus disease (evd) outbreak in west africa is a major challenge for the worldwide medical community. on april th , the world health organization (who) declared , infected cases; among them, , have deceased. the epidemic is still ongoing, particularly in sierra leone. it is now clear that northern countries will be implicated in the care of evd patients, both in the field and back at home. because of the severity of evd, a fair amount of patients may require intensive care. it is highly probable that intensive care would be able to significantly reduce the mortality linked with evd. the preparation of a modern intensive care unit (icu) to treat an evd patient in good conditions requires time and specific equipment. the cornerstone of this preparation includes two main goals: treating the patient and protecting healthcare providers. staff training is time consuming and must be performed far in advance of patient arrival. to be efficient, preparation should be planned at a national level with help from public authorities, as was the case in france during the summer of . due to the severity of the disease, the high risk of transmission and scarce knowledge on evd treatment, our propositions are necessarily original and innovative. our review includes four topics: a brief report on the actual outbreak, where to receive and hospitalize the patients, the specific organization of the icu and finally ethical aspects. ß socié té française d'anesthé sie et de ré animation (sfar). published by elsevier masson sas. all rights reserved. secondly, direct dissemination has been limited, despite the occurrence of the outbreak in cities with major commercial airports. during the current outbreak, imported cases of ebola have been reported in countries (italy, mali, senegal, spain, the united kingdom and the united states). among the latter, died. but due to the incubation period (from to days), it cannot be excluded that some people coming back from west africa would declare the infection after their arrival in northern countries. because of the severity of evd, a fair amount of patients may require intensive care. as recently shown in two reports, renal failure and rhabdomyolysis were frequent in severe evd cases [ , ] . common icu therapy, including fluid therapy and dialysis, would help decrease mortality rates [ , ] . thus, the preparation of intensive care units in affluent countries is necessary in order to be able to receive a confirmed case of evd with two main goals: (i) to treat the patient and (ii) to protect the healthcare providers. the french government has required that our unit be able and ready to receive evd cases in severe condition. we recently published a picture presenting a dedicated icu room for evd patients [ ] . in this article, we will detail the preparation of the latter. we purposely decided to limit our presentation to confirmed cases of evd in the setting of hospital care. due to the severity of the disease, the high risk of transmission and scarce knowledge on evd treatment, our propositions are necessarily original and innovative. the first confirmed case of the current outbreak was declared in march but it is most probable that the epidemic started in december [ ] . on april th, , the world health organization (who) declared , infected cases, , of whom have deceased ( %) [ ] . the evd epidemic is the largest in history and is affecting multiple countries in west africa. the risk of an outbreak in northern countries seems highly improbable because of the difference in diagnostic and medical facilities and due to the absence of a reservoir. one of the main risks of contamination is contact with an infected patient, repatriated with the disease, be it already declared or not. healthcare workers are particularly at risk of contamination [ ] . to date, no aerosol transmission has been documented, nor transmission following healthy skin exposure. after contamination through human liquids (including saliva, blood, vomit, urine, etc.), the virus spreads in the organism and replicates itself at a high rate [ ] . this leads to virus particles in the blood that can be as high as plaque-forming unit/ml. the risk of transmission is very high, particularly for the medical teams. one of the goals when receiving an infected patient is to guarantee the best level of protection for healthcare providers. the risk of contamination for laboratory personnel is low thanks to laboratory procedures. to date, accidents during laboratory work with ebola virus have been reported: case was fatal, case was symptomatic and survived and in cases there was no evidence that the accident resulted in infection and the patients survived [ ] . thus, one can assume the same level of risk for health team members. as recently seen in spain, despite wearing personal protective equipment (ppe), a nurse was contaminated during the care of an infected patient [ ] . in texas, a delay in evd diagnosis for a case in the emergency department led to the death of a healthcare worker and fear of several secondary cases [ ] . these events underline the importance of hospital organization and the need for informing both public and healthcare workers. the ppes in use in our centre are fluid impermeable. according to our experience, there are only two choices available when hospitalizing a confirmed case of evd: the infectious ward or the icu. during the preparation of the begin military teaching hospital, a dedicated access to both the icu and the infectious disease ward was identified, and a protected way to move a patient from the infectious ward to the icu implemented. the procedures for corridor decontamination must be known and established. to ensure that healthcare workers are efficient in dressing with the ppe, several training sessions should be planned and supervised by experts (fig. ). this implies that the hospital provides wards with a sufficient number of ppes. even when they are considered skilled at putting on or taking off their ppe, healthcare workers must proceed in pairs, in order to verify they are not making any mistakes. particular attention should be paid when undressing, which is the time period most as risk for contamination. our team was taught how to undress correctly in order to avoid contact with the contaminated part of the ppe. once the ppe is off, workers must thoroughly wash their hands with alcohol gel. in the icu, physical barriers must be in place to prevent visitors or unprotected staff from accessing the high-risk area. this highrisk area should be clearly marked out using coloured panels and stickers. three kinds of area can be differentiated within the unit (table ). there are no clear recommendations concerning the organization of the patient's room, but the following conclusions can be drawn from knowledge from biosafety level- (bsl- ) laboratories [ ] : rooms should be maintained under continuous negative pressure with an increasing pressure gradient from the airlock to the patient room. if possible, the room must include a one-way access or keep forward access. if not possible, a dressing room should be provided close to the patient's room and the airlock will be used to get undressed, thus being considered an ''orange'' area ( table ). the negative pressure within the patient's room is not mandatory but it cannot be excluded that severely infected patients with diffuse bleeding might excrete viruses in the air. dealing with the patient's waste is a major problem and must be anticipated. to ensure a safe evacuation of contaminated biological materials, a high number of bins should be available and specific treatment pathways for these wastes established in advance. as stated previously, a choice must be made between the infectious ward and the icu. if the patient presents with one or more organ failure(s), then the choice for icu is straightforward. if there is no organ failure, one must keep in mind the natural evolution of evd. the occurrence of diarrhoea, nausea/vomiting, electrolyte disturbances, neurological impairment or bleeding (even minimal) may indicate a risk for progression towards severe illness and the patient should be addressed to the icu. a key point in the decision between using an infectious ward or an icu depends on how secure the transfer of a patient from ward to icu would be. scientific evidence that might help guide the physician in this unfamiliar decision is currently scarce [ ] . if biological results are available, some of the following should be considered as severity markers: leukopenia, lymphopenia, thrombocytopenia [ ] , massive activation of monocytes/macrophages [ ] , disseminated intravascular coagulation [ ] , elevated liver enzyme or metabolic disturbances [ ] . in west africa, the mortality of the current outbreak is %, meaning that at least % of the patients may require icu care due to severity. due to the high probability of complications, patients repatriated from the field during the first days of evd should be directly oriented to an icu. only patients repatriated after the th day or very early can be oriented to the infectious ward. another point to take into account when making the decision is the difficulty of transferring patients from the infectious ward to icu. importantly, at all times, discussion between infectious specialists and intensivists is essential when dealing with these high-risk patients. there are currently no specific recommendations for icu care of confirmed evd cases. all the following propositions are based on common sense and on our hospital experience. the dedicated team comprises at least two health workers: one nurse and one doctor or two nurses for usual care, if the patient is stable. the staff includes only senior and experienced workers. people suffering from respiratory disease, claustrophobia and pregnant women should be excluded. staff must pay attention to eat, drink and go to the toilets before wearing the ppe. all the patient's care must be done when wearing the full ppe, including goggles and respiratory devices. we found it useful to install a mirror in the airlock just before entering the patient's room, so that everyone can personally check his/her protection (fig. ) . all care provided to the patient must be weighed from a benefit/ risk perspective. due to the high risk of contamination during accidents for health workers, procedures that have not proven their utility should probably be avoided. the following care should be performed: central venous access, arterial catheterization, pleural drain, mechanical ventilation, and continuous renal replacement therapy. ultrasonography is really a cornerstone in the care of evd cases. technical difficulties and risk of contamination render the availability of dedicated us devices and probes mandatory for each evd room. as concerns the risk of blood handling, ecmo and ecls should be avoided and increased haemorrhagic risk in balance with the current scarce evidence of benefit in critical patients [ ] . if the patient will require a lot of blood work, the insertion of an arterial line should be considered in order to decrease the risk associated with needle handling. if the patient is haemodynamically stable and invasive blood pressure monitoring is not required, insertion of a central venous line is the best solution both for fluid administration and blood analyses. finally, a peripheral line should be kept only for stable patients who may not require daily blood analyses. to be able to safely take care of an agitated patient without any venous access, we decided to have a sedative gas ready in the room. the latter can be a nitrous oxide cylinder, or if not available, an anaesthesia workstation for using inhaled anaesthetics. the aforementioned proposition must remain exceptional, bearing in mind the high risk of aspiration and haemodynamic instability. in all other cases where the patient remains still and cooperative, vascular access should be managed as usual, including local anaesthesia and ultrasonographic guidance [ ] . the jugular site should be preferred for its ease, safe access with us guidance, low risk of infection compared to femoral sites and the possibility of external compression in case of bleeding. hygienic precautions must be respected in as much as possible but reaching the usual aseptic conditions may not always be possible. ppes are not sterile. a surgical gown and two pairs of gloves should be worn. the second pair of gloves can be g-vir (hutchinson santé , paris, france) gloves. the latter are sterile surgical gloves incorporating a disinfecting liquid, reducing the transmitted viral load in the event of a blood exposure accident. the argument to propose such gloves is only theoretical as there is currently no proof that they could decrease the risk of transmission for evd. here again, recommendations are based on those drawn from our experience with severe acute respiratory syndrome-associated coronavirus infection. aerial transmission is not the major mode of transmission for evd, unless one considers end-stage disease with diffuse bleeding including alveolar haemorrhage. nevertheless, few situations are associated with a particularly high risk, justifying the use of an ffp mask ( table ) . tracheal intubation is done with full ppe, including goggles and an ffp mask. rapid sequence induction without facial mask ventilation should be preferred and intubation should be anticipated if possible. during invasive ventilation, interventions must be limited to the ones strictly necessary. a closed suction system must be used, that can work for up to days. all the interventions on the respiratory circuit (change of filter, circuit or suction system) are at high risk of viral particle aerosolization, particularly if secretions are blood-tinted. the circuit should be changed only if needed and not systematically. inhalation should be avoided and replaced by intravenous administration each time it is equivalent. non-invasive ventilation (niv) creates a particular risk of aerosols during a patient's plugging and unplugging, as well as if leaks exist around the mask. due to the high risk of failure and the need for tracheal intubation, niv should probably be avoided, at least if the patient with bleeding disorders. in view of the results of the recent florali study, high-flow oxygen through a nasal cannula may be less dangerous in terms of aerosolization and may be considered as an alternative therapy [ ] . bronchial analysis by suctioning leads to high risk of contamination, particularly if alveolar haemorrhage is present. due to the high prevalence of multidrug-resistant bacteria among patients coming from africa [ , ] , bacterial cultures may be very helpful to adapt antibiotics. disinfection of the fiberscope may be problematic. it is proposed to use non-guided suction or disposable fiberscopes. some disposable fiberscopes have an operator channel allowing performance of bronchoalveolar lavage. two devices are currently available: the bronchoflex su (axess vision technology, st pierre des corps, france) and the ambu ascope tm (ambu, dk- ballerup, denmark). the evaluation of the benefit/cost balance must be evaluated for each clinical situation. in the absence of strong evidence, crrt should be limited to validated indications: hypokalaemia, pulmonary oedema, metabolic acidosis. several elements favour the haemofiltration technique over conventional dialysis: no effluent requiring sewer elimination, less intervention required on the circuit once connected, all the materials are disposable, effluent bags can be disposed directly in hermetic bins. anticoagulation using non-fractioned heparin is easier because it requires less blood checks than citrate. connor et al. [ ] reported the use of citrate on one patient but recommendations cannot be drawn from a single patient. the habits and protocols of the unit should be taken into account in the final choice. the use or not of anticoagulation in case of major bleeding with intravascular disseminated coagulation should be discussed individually. apart from the case of severe hyperkalaemia, low outputs are recommended to limit interventions on the circuit (i.e. ml/kg/h). two situations must be individualized: health workers are present in the room with their full ppe. then the cardiac massage should start immediately even if the doctor is not yet in the room; no health worker is present in the room. the staff members must absolutely take the time to dress in their ppe in the changing room before providing life support procedures. this will clearly lead to a loss of chance for the patient but it is not possible to take the risk of starting a cardiac massage without protection. in this case, the risk of contamination would be particularly high. this procedure should be performed as under normal circumstance, without any extra precautions on top of the usual evd precautions. emergent needs for surgery should not occur frequently during the course of evd but can appear, for example, as a consequence of severe sepsis. this leads to a fair amount of problems, particularly if the patient is bleeding. surgery will expose the theatre staff to contamination, transportation of the patient to the theatre can be tricky, protection of the surgeons during the intervention is problematic and the theatre room should be in negative pressure with careful treatment of used air. surgery should probably be limited to a restricted number of ''simple'' interventions but no list can be a priori established. one way of dealing with this problem could be to limit interventions to the ones that can be performed in the patient's room. this is another reason pleading for the installation of an anaesthesia workstation in the icu room. patient examination is limited due to the ppe. inspection and palpation remain possible but auscultation with a traditional stethoscope is not possible because ears are totally covered by the equipment. we implemented an original system using two electronic stethoscopes. the first stethoscope is placed on the body area of interest. a wireless communication is established between the first stethoscope and a computer staying outside the room, in the ''green'' area ( table ). the bluetooth technology used allows a distance up to meters between the stethoscope and the recording computer. the second stethoscope is used by another doctor, to listen to the recorded files on the computer. for instance we performed this exam using a pair of m tm littmann electronic stethoscopes model ( m corporate headquarters, st. paul, mn - , usa). the physical exam done in the room by the doctor is written on a whiteboard, which is placed against the room's window. thus, the exam and all the information collected during the time in the room are written in a second time, in the patient's files in the green area. this procedure keeps the patient's files clean. nowadays, common monitoring in icus systematically includes a central monitor outside the patient's room. all the parameters that cannot be automatically reported (i.e. neurological state, temperature, etc.) could be written using the whiteboard and recorded in the patient's files afterwards. for safety reasons, only a limited number of parameters can be analysed in bsl- . the time needed to obtain results can be long, depending on the distance and the availability of the bsl- automates and staff. this is not acceptable for a patient in a critical state who may require frequent checking of blood results. we implemented a field laboratory, available in each room dedicated for evd cases, allowing analysis of essential parameters ( table ). the device used for biological analyses, the i-stat (abbott, princeton, nj , usa), includes a wireless printer. communication between the i-stat and the printer was feasible through the window, thus printed results were added to the patient's files (fig. ) . to prevent blood exposure, all the analyses are performed under a captair field pyramid glovebox (fig. ) . all the staff members received theoretical and practical learning for use of the devices. for blood group and antibodies, it was decided to perform analyses of abo, d, k and rhesus subgroup using the mdmulticard (medion diagnostics ag, ch- duedingen, switzerland) [ ] . thanks to this, we are able to transfuse patients in their own group and respecting the dell, kell and rhesus phenotypes. we used a point-of-care test for paludism: palutop + optima (alldiag, cs - strasbourg cedex, france), which allow diagnosis of the four plasmodium species. the use of this test is quite easy and a single training episode for the staff has been judged sufficient. we prepared a mobile x-ray system in the room. after utilization, the x-ray digital radiography detector is disinfected and developed outside the room. the x-ray system is dedicated to the evd patient's room only, for his whole length of stay in the icu. we obtained several models of portable ultrasonographers, both for diagnostic purposes and for us-guided procedures like vascular access. for safety reasons, we decided that a disposable sterile cover would always cover us probes. to sum up, the specific room organization includes, on top of classical icu materials: an anaesthesia workstation, x-ray system, portable us, and a field laboratory with a captair pyramid . see figs. and , which present an ideal icu room for evd patients and a picture of a fully equipped room in begin military hospital, respectively. direct communication with the patient is possible when staff members are in the room but it implies that they are protected by the ppe. to allow a more casual communication and permit communication of the patient with his/her family, we planned to use a webcam and a computer in the patient's room. this would allow good communication and helps the family accept the patient's isolation. the care of evd patients should follow the two following prerequisites. first, there is no specific restriction of care due to evd but only specific limitations due to the increased risk of contamination and diffusion of evd. these limitations can include, among others, surgery or care associated with potential table analysis performable under the captair field pyramid glovebox. parameters analysed comments haemorrhagic risk. secondly, all evd care must be performed under a benefit/risk balance. there are currently no validated ethical recommendations about the care of evd cases. the cornerstone of the care of such patients is to respect the general principles of medical ethics and keep in mind that such a patient may require tailored care. on top of the medical discussion between infectious doctors and intensivists, it may be useful to obtain advice from the local ethics committee. the following points should be discussed at a multidisciplinary level in the hospital before receiving a patient. if the patient is deemed unable to survive, the decision not to admit him/her into an icu on the basis of futility can be made. ppes are effective means of protecting staff members. thus, invasive procedures should not be prohibited but strictly limited to the ones necessary. the decision to undergo, or not, a surgical intervention should probably be made with the help of an ethics committee. informing staff members about evd and the risk of transmission is essential. staff training must take place before and during patient care to obtain a safe and positive attitude toward an infected patient. due to the physical constraints linked with the ppe, pregnant women, people suffering from claustrophobia or respiratory disease should not be included in the staff taking care of an evd case. to decrease the risk of errors due to fatigue, the nurse's schedule was modified for -hour shifts. evd teams were dedicated to the care of evd patients only and would return to the common unit only after the evd patient's discharge. as the protocols in the infectious ward and the icu were similar, nursing teams from both wards were pooled. so, in case of a single admission, the nurses from the other ward could be called for help. the practice of critical care should follow national guidelines, especially concerning the limitation of care and do not reanimate orders. for our part, we are following the recommendations of the french icu society [ ] . for obvious reasons, direct communication between an evd case and his/her relatives is not permitted. but communication should be possible, for instance by using a webcam system or at least by phone and viewing through a window. one must keep in mind that malaria is endemic in west africa. on top of evd, the patient could present other infections, particularly bacterial. the risks associated with handling blood may limit the availability of bacterial tests to bsl- tests only. as the sensibility of the malaria test we used is high, the question of malaria can be dealt with in this way. but concerning bacterial infections, the prescription of empirical wide-spectrum antibiotics without formal bacterial identification may be justified, particularly during the first days evd. one must keep in mind the risk of multidrug-resistant bacteria, as recently described in a case of severe evd [ ] . if bacterial infection is suspected, every effort should be made to obtain bacterial cultures. the current evd outbreak in west africa is a major challenge for the worldwide medical community. the epidemic is still ongoing and according to specialists, the number of cases may exceed , by the end of the current year [ ] . it is now clear that northern countries will be implicated in the care of evd patients, both in the field and back at home. in this perspective, it is fundamental that certain identified, specific centres are ready to take care of such patients. the preparation of a modern icu to treat an evd patient in good conditions requires time and specific equipment. staff training also requires time and must be done well prior to receiving the patient. to be efficient, preparation should be planned at a national level with help from public authorities, as was the case in france during the summer of . financial support: intensive care unit, begin military hospital ( , avenue de paris, saint-mande france). the authors declare that they have no competing interest. ebola haemorrhagic fever face to face with ebola -an emergency care center in sierra leone organ failures on admission in patients with ebola virus disease rhabdomyolysis in ebola virus disease. results of an observational study in a treatment center in guinea a case of severe ebola virus infection complicated by gram-negative septicemia doing today's work superbly 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guinea-pigs and monkeys infected with a mouseadapted variant of ebola zaire virus real-time two-dimensional ultrasound guidance for central venous cannulation: a meta-analysis high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure multidrug-resistant acinetobacter baumannii infections in three returning travelers evacuated from algeria, thailand, and turkey after hospitalization in local intensive care units imported enteric fever: case series from the hospital for tropical diseases successful delivery of rrt in ebola virus disease application of a multivariant, caucasian-specific, genotyped donor panel for performance validation of mdmulticard(r) limitation et arrêt des traitements en ré animation adulte. actualisation des recommandations de la socié té de ré animation de langue française who ebola response team. ebola virus disease in west africa -the first months of the epidemic and forward projections organization of the icu room at the begin military hospital with dedicated devices key: cord- -dukccrjb authors: nachega, jean b.; mbala-kingebeni, placide; otshudiema, john; mobula, linda m.; preiser, wolfgang; kallay, oscar; michaels-strasser, susan; breman, joel g.; rimoin, anne w.; nsio, justus; ahuka-mundeke, steve; zumla, alimuddin; muyembe tam-fum, jean-jacques title: responding to the challenge of the dual covid- and ebola epidemics in the democratic republic of congo—priorities for achieving control date: - - journal: am j trop med hyg doi: . /ajtmh. - sha: doc_id: cord_uid: dukccrjb as of june , , the democratic republic of the congo (drc) has reported , covid- cases with deaths. with other african countries, the drc faces the challenge of striking a balance between easing public health lockdown measures to curtail the spread of sars-cov- and minimizing both economic hardships for large sectors of the population and negative impacts on health services for other infectious and noninfectious diseases. the drc recently controlled its tenth ebola virus disease (evd) outbreak, but covid- and a new evd outbreak beginning on june , in the northwest Équateur province have added an additional burden to health services. although the epidemiology and transmission of evd and covid- differ, leveraging the public health infrastructures and experiences from coordinating the evd response to guide the public health response to covid- is critical. building on the drc’s years of experience with previous evd outbreaks, we highlight the drc’s multi-sectoral public health approach to covid- , which includes community-based screening, testing, contact-tracing, risk communication, community engagement, and case management. we also highlight remaining challenges and discuss the way forward for achieving control of both covid- and evd in the drc. the spread of covid- compounds the burden on health services in african countries that have experienced recurrent outbreaks of deadly zoonotic diseases in recent years. as of june , , the who africa region has reported , covid- cases, with , deaths from countries. most african countries are facing difficult decisions as they attempt to balance efforts to limit the spread of sars-cov- , control local outbreaks of other infectious diseases, and lessen economic hardships and food insecurity for large sectors of the population. [ ] [ ] [ ] the democratic republic of the congo (drc) recently experienced its tenth ebola virus disease (evd) outbreak, the second largest globally after the - west african epidemic, which was recently brought under control. the lessons learned, coordination mechanisms developed, and public health infrastructures put in place for evd are guiding the public health response to covid- in the drc, although the two diseases are fundamentally different. building on four decades of experience with evd, we discuss the drc's response to covid- and associated challenges, priorities, and innovations for disease control. early covid- cases in africa were mostly due to air travel of infected individuals from europe. , the democratic republic of the congo confirmed its first case of covid- on march , . two days after returning from france, an adult male with cough and fever tested positive in the capital city of kinshasa. the subsequent early index cases in kinshasa also occurred among young affluent adult travelers from europe. the drc declared a state of emergency that included travel bans on march , and on april , a lockdown of the initial covid- hotspot, gombe, an affluent health zone in kinshasa, and other selected regions of the country, was instituted. since then, the number has increased to , covid- cases, with deaths (case fatality rate of . %) as of june , . to date, the disease has spread to provinces and ( % of total) health zones in the drc (figures and ) . as in other african countries, the travel bans and lockdowns have had negative socioeconomic impacts on the population, most of whom live below the poverty line. a multi-sectoral national committee to organize the covid- response was created following the diagnosis of the first confirmed cases ( figure ) using lessons learned from the tenth evd outbreak. the committee, which includes a presidential task force that liaises with the president's office and a strategic and operational management task force comparable to that of the ebola incident management system, has support from the who, u.s. and africa cdc, world bank, and u.k. department for international development as part of the fourth strategic response plan. the committee's secretariat is made up of five sections with distinct responsibilities (supplemental figure ). similar organizations have been set up for the management of the response in the different provinces under the coordination of each governor and provincial minister of health. the drc government's covid- task response structure was incorporated into existing health system structures for hiv, tuberculosis, malaria, and other noncommunicable diseases. the tenth evd outbreak in the drc was announced by the ministry of health on august , , ten days after the ninth outbreak was declared over. since june , approximately , people in evd-affected health zones have been immunized with the merck rvsv-ebov vaccine and another , in goma with the janssen ad .zebov vaccine. in addition, investigational drugs were provided to nearly all patients confirmed to have evd either through the monitored emergency use of unregistered investigational drugs protocol (allowing patients to receive investigational drugs under compassionate use) or as part of the pamoja tulinde maisha (palm ["together save lives" in kiswahili]) randomized controlled trial. a multi-sectoral response, including standard public health measures (surveillance, contact-tracing, active case finding, infection prevention and control, risk communication, community engagement, and safe burials) coupled with community-based interventions such as cash-for-work and water and sanitation hygiene projects, as well as security, eventually controlled a complex outbreak that lasted almost years. unfortunately, hope held by health officials to declare the outbreak over on april , vanished as a new case was confirmed on april , thereby resetting the countdown clock. this was the first time an ebola outbreak occurred in a conflict zone with an ongoing humanitarian emergency. numerous factors contributed to the -year-long evd outbreak in the eastern drc, including a fragile and fragmented health system, population displacement, movement of contacts, disenfranchisement of the community, mistrust, and ongoing armed conflicts. the drc continues to face the challenge of having back-to-back evd outbreaks with limited funding for existing needs. on june , , the drc government announced an eleventh evd outbreak occurring in the northwestÉquateur province. the drc ministry of health, in close collaboration with who teams who were already on the ground in mbandaka as part of capacity building, deployed additional multidisciplinary rapid response teams from goma and kinshasa to support local teams. according to the who, as of june , , a total of evd cases (nine confirmed and three probable) including nine deaths (case fatality rate %) were reported in three affected health zones (wangata, mbandaka, and bikoro). overall, . % ( / ) of contacts were traced, but none turned out to be a suspected evd case. also, , people, including frontline health professionals and close contacts, were vaccinated using the rvsv-zebov-gp vaccine since the beginning of this outbreak. the inability to act rapidly and diagnose and isolate cases of evd was an important factor in the large-scale progression of the - ebola outbreak in west africa. a range of novel ebola diagnostic tools were trialed and introduced, including automated pcr machines and rapid test kits for point-of-care diagnosis. system-wide support was put in place for safely transporting samples, sourcing reagents, disposal of hazardous materials, and rapid feedback of diagnostic data into public health and clinical decision-making. although the global covid- pandemic presents unique challenges, several lessons from the evd outbreaks are informing the covid- response. first, the ebola standard operating procedures (sops) have been used as a starting point to speed the development and updating of covid- sops. second, ebola contact follow-up approaches have been leveraged for the follow-up of covid- contacts, with the difference that in this case the duration of follow-up is days, compared with days for evd. because persons with covid- may be asymptomatic, contact-tracing includes the collection of respiratory samples on days and from all high-risk contacts of a confirmed case, regardless of symptoms. third, the follow-up of covid- contacts is modeled after our evd experience using contact-tracers and community health workers (chcws) at the peripheral level: health areas, neighborhoods, and villages. fourth, the evd response established mobile laboratories in target provinces. currently, the covid- response is planning to setup such provincial laboratories for point-of-care (poc, e.g., genexpert) covid- testing. finally, based on the critical importance of community engagement and feedback during the ninth and tenth evd outbreaks in the drc, a mechanism to collect feedback from communities was put in place from the beginning of the covid- response. community-based covid- screening, testing, and contact-tracing as of may , , there were , contacts of the , confirmed cases traced, resulting in a daily contact-tracing proportion of % (table ) . among reported confirmed globally, the current gold standard test for the diagnosis of sars-cov- infection is detection of viral rna in a sample from the respiratory tract by rt-pcr. [ ] [ ] [ ] laboratories with skilled staff and the rt-pcr equipment to perform these tests are scarce in the drc (table ); all covid- testing is performed at the national institute of biomedical research in kinshasa, a national referral laboratory. because of sample transport from the provinces, turnaround times are lengthy for samples collected from provinces, causing delays in diagnoses. of note, poc or near-patient solutions would be preferable. , the genexpert platform, already in place for tb testing across africa, is an attractive option, but drawbacks include cost and limited supplies of sars-cov- cartridges. poc viral antigen detection is not yet sufficiently sensitive. serological testing for antiviral antibodies is unavailable in the drc and is unsuitable for diagnosing active covid- cases. treatment of moderate and severe cases of covid- requires hospitalization for supportive care, oxygen, and anticoagulation as per who guidelines. remdesivir, which has been shown to be effective in reducing the length of hospitalization for moderately severe cases, is not yet available in the drc. weak health systems in the drc, with limited intensive care beds, oxygen supply, ventilators, and trained staff, remain a key challenge in the management of covid- , especially as case numbers rise. several hospitals were identified as reference centers for the treatment of covid- as part of the national plan. furthermore, building on an existing innovative tele-mentoring program developed to capacitate nurses and other frontline healthcare workers, a series of in-service covid- training modules covering triage, infection prevention and control, testing, maintenance of essential services, and other topics was developed. at the start of the outbreak, only ventilators were available countrywide and oxygen supplies were limited, and there was minimal technical capacity to provide intensive care. a clinical protocol was developed by the case management commission with support from technical partners. bilateral and multilateral partnerships are scaling-up donations including medical and personal protective equipment to the reference hospitals, and training has been provided to clinical staff to ensure optimal care and prevention of infection of healthcare workers. remaining challenges and priority solutions are listed in table . as the drc decides how best to control the covid- pandemic, it is essential to reflect on lessons learned from past and current evd outbreaks. the drc must adapt the available infrastructure and protocols to covid- while embedding community needs and concerns into its response. the country must also significantly invest in its fragile health systems to ensure equity, stability, and global health security. control of the covid- pandemic in the drc will be possible only with efficient community screening, testing, and contact-tracing as well as behavioral modification, all of which require adequate local and national resources and enough trained and protected personnel. by addressing the challenges, the drc and other countries in africa can limit the impact of the covid- pandemic on the health of its already vulnerable citizens. coronavirus disease (covid- ) situation reports the late arrival of covid- in africa -mitigating pan-continental spread limiting the spread of covid- in africa: one size mitigation strategies do not fill all countries from easing lockdowns to scaling-up community-based covid- screening, testing, and contact tracing in africa -shared approaches, innovations, and challenges to minimize morbidity and mortality world health organization recommendations for the covid- response at the national level based on lessons learned from the ebola virus disease outbreak in the democratic republic of the congo a rendomized trial of ebola virus disease therapeutics the ebola outbreak in the democratic republic of the congo: why there is no 'silver bullet laboratory testing for novel coronavirus ( -ncov) in suspected human cases. interim guidance. who/covid- /laboratory/ laboratory testing strategy recommendations for covid- : interim guidance detection of novel coronavirus ( -ncov) by real-time rt-pcr . foundation for innovative new diagnostics (find), . sars-cov- diagnostics: performance data. available at scientific brief: advice on the use of point-of-care immunodiagnostic tests for covid- severe acute respiratory syndrome coronavirus -specific antibody responses in coronavirus disease patients clinical management of covid- remdesivir compassionate use of remdesivir for patients with severe covid- h n , . covid- in the drc: dr muyembe fears large-scale contamination of healthcare workers. available at this is an open-access article distributed under the terms of the creative commons attribution (cc-by) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. key: cord- -xzs d authors: lau, joseph t.f.; wang, zixin; kim, yoona; gu, jing; wu, anise m.s.; zhou, qianling; hao, chun; cheng, perry; hao, yuantao title: anticipated negative responses by students to possible ebola virus outbreak, guangzhou, china date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: xzs d nan doi: http://dx.doi.org/ . /eid . to the editor: in , a serious ebola virus disease (evd) outbreak occurred in west africa ( ) . in a study on evd-related perceptions, % of us respondents mistakenly believed that evd could be transmitted through airborne droplets from patients' sneezes or coughs ( ) . evdrelated panic was reported in the united states ( ) and the united kingdom ( ) . during november -december , , we conducted a cross-sectional survey of , undergraduate students in guangzhou, china, where the population of immigrants from africa is high (online technical appendix, http://wwwnc.cdc.gov/eid/article/ / / - -techapp .pdf). our aim was to measure students' anticipated negative emotional responses and avoidance activities (dependent variables) to a possible outbreak of evd ( ) . we constructed scales for the dependent and independent variables to assess evd-related perceptions: ) misconceptions/knowledge about transmission modes, ) scenarios of an evd outbreak in guangzhou (chances, severity, control), ) efficacy of preventive measures and self-protection, and ) public stigma toward evd survivors. mlwin . (centre for multilevel modeling, university of bristol, bristol, uk) was used for multilevel regression analyses (online technical appendix). we analyzed data from , ( . %) students who had heard of evd. to the example of - evd cases detected in guangzhou, . % showed > types of anticipated negative emotions (e.g., fear, panic, worry); . % showed > types of anticipated unnecessary avoidance. most ( . %) indicated > misconception regarding transmission mode (e.g., believed it was droplet or waterborne) but knew that direct contact with the corpse of an infected person ( . %) and body fluids ( . %) could lead to infection and perceived evd as fatal ( . %,) and highly infectious ( . %). about half of respondents believed that effective treatment and a vaccine were unavailable ( . % and . %, respectively); . % anticipated evd outbreaks among africans in guangzhou (during the next months). many students perceived severe consequences if a small evd outbreak occurred in guangzhou and believed an outbreak would have a high fatality rate ( . %), evd is highly infectious ( . %), an outbreak would be of long duration ( . %), and the number of infected persons would be high ( . %); . %- . % of respondents lacked confidence in the government's ability to control an outbreak (e.g., ability to provide adequate vaccines, medication, protective gear). half or more of respondents believed that restricting travel by africans to and from africa and avoiding visiting african-inhabited areas were effective means of prevention. about % were confident that they could protect themselves or family members from evd (online technical appendix tables , ). older age, female sex, longer school years, and rural origin were associated with negative emotional responses, avoidance, or both (online technical appendix table ). in multivariate analyses that adjusted for significant background variables, we found positive associations between both dependent variables and the following independent variables: perceived fatality of evd, perceived nonavailability of treatment, misconceptions regarding modes of transmission, perceived severity of a guangzhou outbreak, perceived efficacy of restricting africans' travel, perceived efficacy of avoiding african-inhabited areas, and public stigma toward evd survivors. confidence in governmental control was negatively associated with both dependent variables. some variables were positively associated with emotional response but not avoidance (perceived irreversible harm, perceived chance of outbreak in guangzhou and in other parts in china, perceived self-efficacy for protection); variables (perceived nonavailability of vaccine and knowledge of transmission mode) were positively associated with avoidance measures but not with emotional responses (table) . because evd causes serious physical harm, negative emotional responses and unnecessary avoidance practices were anticipated. such negative community responses might cause individual and societal harm, as witnessed during the epidemic of severe acute respiratory syndrome ( ) . misconceptions concerning transmission modes were prevalent and significantly correlated with both dependent variables. more than % of respondents perceived that the virus was highly infectious, another significant factor. about % of participants believed that an evd outbreak would occur in guangzhou in the next year. among all participants, many anticipated severe outcomes but were not confident that the government was prepared for and could control such an outbreak. the concentration of immigrants from africa in this region might have increased perceived chances of an evd outbreak and thus lead to avoidance of this population. the high percentages of those who believed that restricting africans' travel was effective also might result in discrimination. public stigmatization toward evd survivors, another significant factor, was a prominent attitude ( , ) . fear, misconceptions, and perceived likelihood of evd to cause death may lead to patient stigmatizing, which could hinder case detection and patients' service seeking. the relationship between stigmatization and evd-related perceptions should be investigated. the study's limitations included the inability to assess real responses, inability to generalize findings to all university students and the general public, and the use of scales that had not been validated. also, some students might have given exaggerated responses. in summary, misconceptions and perceptions regarding evd may result in negative community responses in guangzhou. health education is needed to clarify that evd is not airborne or waterborne or highly infectious and that avoidance is not an effective preventive measure. in addition, the government should start developing and publicizing its preparedness plans. ( ) . these resistant strains harbored the tr /l h and tr /y f/t a mutations in the cyp a gene and its promoter region. these novel mechanisms of resistance have been reported both in environmental and clinical samples in europe, asia, and africa, suggesting a broad geographic spread. however, clinical isolates from states in the united states ( ) and a few isolates from latin america ( , ) failed to show any fungicide-driven resistance in a. fumigatus in these continents, even though use of pesticides is a widespread practice in the americas. colombia was ranked fourth in the world in for the use of pesticides, reportedly using . tons/ , ha, % of which were fungicides ( ) . among the fungicides approved by colombia's regulatory agency, the colombian agricultural institute ( ), tebuconazole and difenoconazole are largely used in the flower industry, more specifically in cundinamarca, where % of colombia's flowers are produced. in , we conducted a study for which soil samples from flower fields and greenhouses were collected in the outskirts of bogota, cundinamarca. samples were inoculated on sabouraud agar at °c, and positive samples were screened for azole-resistance on agar supplemented with either itraconazole ( mg/l) or voriconazole ( mg/l). of the resistant aspergillus strains, were selected (up to colonies for each positive culture), identified as a. fumigatus by β-tubulin gene sequencing, and analyzed for cyp a gene alterations ( ) . results showed great diversity in molecular resistance with the presence of tr / y f/t a (n = ), tr /l h (n = ), and tr (n = ) mutations; isolate had a wild-type cyp sequence ( ) . our study highlights the presence of a. fumigatus harboring fungicide-driven alterations in colombia, south america. the results indicate the importance of initiating active agricultural surveillance along with close monitoring of drug resistance in clinical isolates from naive and azole-exposed patients in these countries. clinical management of aspergillus disease can be challenging because of unfavorable clinical outcomes after patients have acquired multi-azole-resistant strains from the environment ( ). additional studies are needed to evaluate the extent to which pesticide use in floriculture and agriculture (e.g., coffee and banana) contributes to azole resistance in colombia. school of public health news. poll: most believe ebola spread by multiple routes response to ebola in the us: misinformation, fear, and new opportunities representations of far-flung illnesses: the case of ebola in britain feeling at home in the "chocolate city": an exploration of place-making practices and structures of belonging amongst psychosocial impact among the public of the severe acute respiratory syndrome epidemic in taiwan emergence of azole resistance in aspergillus fumigatus and spread of a single resistance mechanism passive surveillance for azole-resistant aspergillus fumigatus azole resistance in aspergillus fumigatus isolates from the artemis global surveillance study is primarily due to the tr/l h mutation in the cyp a gene food and agriculture organization of the united nations statistics division. faostat/agri-environmental indicators/ pesticides. rome: the organization registros de venta de plaguicidas químicos de uso agricola-septiembre de first description of azole-resistant aspergillus fumigatus due to tr /y f/t a mutation in france multiple-azole-resistant aspergillus fumigatus osteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery we thank all research assistants and those who participated in the study. key: cord- -vwudbuzz authors: barbiero, victor k. title: ebola: a hyperinflated emergency date: - - journal: glob health sci pract doi: . /ghsp-d- - sha: doc_id: cord_uid: vwudbuzz as with the ebola outbreak, global under- mortality and morbidity should be considered a public health emergency of international concern. t he - ebola virus disease (evd) outbreak in the democratic republic of the congo (drc) was a tragic and significant threat to thousands of people in the drc and west africa in general. as of march , , an estimated , people in the drc have been infected and an estimated , people have died from this terrible virus. since evd was first characterized in , there have been country-specific outbreaks, including the outbreak in the drc. the total estimated evd deaths from to is , . the median number of deaths for all outbreaks is with a range of to , (table ) . , the evd case fatality rate (cfr) can be or reach %, depending on the scope and location of the outbreak (e.g., uganda [ case death], senegal [ case, deaths]). although there are different types of ebola virus, generally speaking, the evd cfr averages about %. the outbreak in guinea, liberia, and sierra leone infected an estimated , people and killed , with a cfr of approximately %. without question, evd is an important and daunting public health issue for africa and potentially for the world. however, evd is an epizootic infection with periodic human exposure and transmission. since its emergence in ; the virus remains an uncomfortable human pathogen. it kills too fast, kills too many, and is not easily transmitted; thus, human outbreaks are limited, and its pandemic potential is moderate to low. it has not yet achieved equilibrium with its human host as it apparently has with its bat host. furthermore, evd's %- % cfr in humans may be considered evolutionarily unsound in many respects for a successful human pathogen. but, the real issue concerning evd is disease sensationalism. this can be characterized as an unfounded perception of a global emergency, not necessarily anchored in the epidemiology, pandemic potential, and total mortality of a pathogen. rather, it appears the classification of a global emergency is based more on the political ramifications, the newsworthiness of the disease de jour, and yes, financial aspects and funding streams of a declared emergency for an emerging and/or reemerging infection. tragically, more than , died of evd in guinea, liberia, and sierra leone. however, it should be recognized that far more individuals (especially children under years old) died since in these countries from preventable and treatable but less exotic infections. should there not be a "moral claim" by the world's children on emergency resources as well? in , the obama administration submitted an emergency funding request, and in , congress authorized an appropriation of approximately us$ . billion in an omnibus emergency bill to combat evd spread, protect america from an evd outbreak, and support the development of an evd vaccine. notably, this appropriation exceeded the total authorization of us$ . billion for all u.s. government assistance for maternal, child, reproductive health, malaria, nutrition, and neglected tropical diseases by us$ million. did evd epidemiology and national/global risk justify the emergency bill investment? perhaps, perhaps not. clearly emerging and reemerging infections are important and need to be handled with interventions that mitigate spread and minimize mortality, coupled with adequate and sustained epidemic preparedness. indeed, a george washington university milken institute of public health, washington, dc, usa. correspondence to victor barbiero (vkb@gwu.edu). extrapolating trends to january , , without additional interventions or changes in community behavior (e.g., notable reductions in unsafe burial practices), the model also estimates that liberia and sierra leone will have approximately , ebola cases ( . million when corrected for underreporting). over the period from to , in the drc alone approximately . million children under years old have died, mostly from preventable and curable childhood diseases (table ) ( figure) . this number dwarfs the , people who have died from evd globally over the same period. furthermore, at the global level, annually, an estimated . million children under years old die from preventable and curable causes worldwide. which qualifies as a more urgent and important global health emergency: global evd or global under- mortality? the term public health emergency of international concern (pheic) is defined in the international health regulations ( ) as: an extraordinary event, which is determined, as provided in these regulations: to constitute a public health risk to other states through the international spread of disease; and to potentially require a coordinated international response. this definition implies a situation that: is serious, unusual or unexpected; carries implications for public health beyond the affected state's national border; and may require immediate international action. the pheic definition accurately describes an epidemiological emergency. however, it falls short on quantifying the impact of the emergency on existing and/or potential morbidity and mortality on a national, regional, or global scale. as noted, the burden of disease for children under years old dramatically exceeds the cumulative global morbidity and mortality from evd. considering measles alone, from january through november , the united nations children's fund reported , measles deaths ( % in children under years old) in the drc, with over , measles cases. , globally, measles surged in and killed about , worldwide, which is about . times the total number of deaths caused by evd in its -year history as a human pathogen. clearly, great success has been achieved over the last years in reducing deaths in children under years old. however, in my view, the "unfinished agenda for child survival," also qualifies as a public health emergency that should be of international concern. it deserves heightened attention by the governments, multilateral and bilateral donors alike, and should not be marginalized. every day, approximately , children under years old die, the equivalent of boeing plane crashes. clearly, global child mortality fits the world health organization's definition of a "grade " emergency and should be categorized as such. we need increased and continuous global investment in child survival and sustainable health system development. the moral claim of the world's children should no longer be ignored. the "unfinished agenda for child survival," also qualifies as a public health emergency that should be of international concern. ebola: a hyperinflated emergency www.ghspjournal.org timeline of global ebola outbreaks, -present. becker's hosp rev ebola in the democratic republic of the congo: health emergency update. world health organization website what is ebola virus disease? centers for disease control and prevention website ebola virus disease global-health-policy/issue-brief/the-u-s-response-to-ebola-statusof-the-fy -emergency-ebola-appropriation global-health-budget-by-program-area estimating the future number of cases in the ebola epidemic-liberia and sierra leone child mortality estimates: country-specific under-five deaths. unicef global databases ihr procedures concerning public health emergencies of international concern (pheic) children under the age of five have died from measles in the democratic republic of congo so far this year. unicef website press-releases/measles-deaths-democratic-republic-congotop- -unicef-rushes-medical-kits-health more than , die from measles as cases surge worldwide. world health organization website the unfinished agenda in child survival world health organization website it's not ebola . . . it's the systems key: cord- - tgtstd authors: ferranti, erin p.; wands, lisamarie; yeager, katherine a.; baker, brenda; higgins, melinda k.; wold, judith lupo; dunbar, sandra b. title: implementation of an educational program for nursing students amidst the ebola virus disease epidemic date: - - journal: nursing outlook doi: . /j.outlook. . . sha: doc_id: cord_uid: tgtstd abstract background the global ebola virus disease (evd) epidemic of / prompted faculty at emory university to develop an educational program for nursing students to increase evd knowledge and confidence and decrease concerns about exposure risk. purpose the purpose of this article is to describe the development, implementation, and evaluation of the evd just-in-time teaching (jitt) educational program. methods informational sessions, online course links, and a targeted, self-directed slide presentation were developed and implemented for the evd educational program. three student surveys administered at different time points were used to evaluate the program and change in students' evd knowledge, confidence in knowledge, and risk concern. discussion implementation of a jitt educational program effectively achieved our goals to increase evd knowledge, decrease fear, and enhance student confidence in the ability to discuss evd risk. these achievements were sustained over time. conclusion jitt methodology is an effective strategy for schools of nursing to respond quickly and comprehensively during an unanticipated infectious disease outbreak. the ebola virus disease (evd) epidemic of / presented atlanta-area health care providers, health care professions schools, and students a unique challenge to quickly prepare for the care of evd-infected aid workers from african countries affected by this disease. the decision to accept these patients resulted in the activation and expansion of the serious communicable diseases unit (scdu) at emory university hospital (feistritzer, hill, vanairsdale, & gentry, ) . intense public interest followed the decision and resulted in tremendous media coverage. between july and september , , > , stories went out on broadcast and > , print stories were written mentioning emory and ebola ("telling the story," ). some of the attention heightened the fear and anxiety associated with caring for individuals in our community because of the highly infectious nature of evd. people spoke out on social media, fearing that our caring for these patients put our larger community at risk. in response to the public outcry, susan grant, the chief nurse for emory healthcare wrote in the washington post, "we can either let our actions be guided by misunderstanding, fear, and self-interest or we can lead by knowledge, science and compassion. we can fear, or we can care." (grant, ) . the emory university nell hodgson woodruff school of nursing (nhwsn) is located on the same campus as emory university hospital and is also adjacent to the centers for disease control and prevention (cdc). both the cdc and emory healthcare are key partners for the clinical and public health education of our student nurses. the treatment of patients with evd at emory university hospital, combined with our cdc colleagues' response to the evd epidemic in africa and the status of atlanta being a major international transportation hub, necessitated a swift response by key public health faculty and administration of the nhwsn to educate our students and fellow faculty colleagues and staff members about evd. evd education needed to include modes of transmission, risk for exposure and transmission, signs and symptoms of infection, therapy, and counseling techniques to allay fear and anxiety associated with living in atlanta and working or training within the health care facilities treating evd-infected patients. it was our goal to increase evd knowledge, decrease fear, and enhance students' confidence in their ability to discuss evd risk with family and friends. just-in-time teaching (jitt) is an online educational approach that can be used to rapidly disseminate important information in an efficient and effective way to address learning needs during a crisis (chotani et al., ) . jitt approaches have been used to quickly disseminate information after large-scale disasters and public health epidemics, such as the global outbreak of severe acute respiratory syndrome (sars) that occurred in the early s (o'connor et al., ; yang et al., ) . providing information expeditiously during complex humanitarian emergencies, such as a disease outbreak, is essential to quelling the fears of nursing students, who may encounter affected patients during clinical rotations, and communities who are uncertain about essential facts and who might be influenced by media coverage that at times dwells on unpleasant details and fuels the public's apprehensions (stirling, harmston, & alsobayel, ; "teaching in a time," ) . to respond to the emergent evd epidemic, we designed a comprehensive and targeted approach to educate our students. the purpose of this article is to describe the development, implementation, and evaluation of this educational effort. early in the fall semester of , we arranged for lunch-and-learn presentations, inviting all community members to learn more about the evd outbreak in africa. we invited colleagues from the cdc to present information about their experiences in sierra leone, one of the evd-affected countries. interested students and faculty attended other educational events at our university's school of public health. specific to information about the evd patients being cared for at emory's scdu, many attended a town hall meeting held jointly with the medical school where attendees heard directly from the scdu team that was caring for the individuals with evd. in addition to the opportunities provided to learn more about evd across our campus, the faculty decided that because our undergraduate nursing students were engaging in clinical training within the health care facility caring for patients with evd, a more comprehensive and targeted approach to educate our students was needed. additional goals for providing education were to increase student knowledge of evd risks and ways to mitigate exposure, decrease fear of evd, and enhance students' confidence in discussing evd with others, including family, friends, and patients. faculty course coordinators of classes addressing professional role content for each cohort of undergraduate students created an ebola information page on their electronic course sites. the ebola information content included links to cdc, emory healthcare, and other atlanta-area health care evd policies and guidelines. in addition, a -slide powerpoint presentation was developed using cdc guidelines and the newly developed emory healthcare ebola preparedness protocols. the presentation, posted on the course sites, included an overview of the evd outbreak, evd facts, modes of transmission, signs and symptoms of early and later stage infection, emory university's evd-specific travel policies, emory healthcare's publically available ebola preparedness protocols, and cdc's published "frequently asked questions" and answers. the presentation was designed for students' self-directed viewing and learning. participants targeted for this educational program were all undergraduate student nurses enrolled in our prelicensure bachelor of science in nursing (bsn) program at nhwsn in fall and spring . inclusion criteria included all enrolled undergraduate students; there were no exclusion criteria. sample size was determined by the size of the enrolled undergraduate student population. this target group consisted of a total of undergraduate students who were % women, % white, % black, % asian, % hispanic, and % multiracial/ethnic or undeclared. consultation with the emory university institutional review board confirmed that this project met exemption criteria. early in december , the project's data manager (b.b.) invited all students in the bsn program to participate in the evd self-directed education program described previously, via e-mail. the data manager did not serve in a faculty capacity to any of the students at the time. the e-mail stated that faculty were interested in students' perceptions about educational information that had already been provided to them about evd and their experiences and level of comfort with discussing evd with others, such as family members. the e-mail invitation described that the new education program included completing a pretest, viewing a powerpoint slideshow, and completing two post-tests (immediately after the training and five weeks later) and that participation was completely voluntary. the pre-and post-tests were identical. students were enrolled in one of three classes, and faculty members teaching those classes agreed to offer a small incentive in the form of bonus points to students who participated in the study. application of the bonus points was determined by the individual faculty member for each course. the invitation e-mail included a link to the pretest, which was hosted on the research electronic data capture (redcap) platform. redcap allowed for tracking participants for comparison on pre-and posttest results by linking student identification numbers that were loaded into the system. time to complete the pretest was estimated to be about min. the pretest link remained active for days after the initial e-mail was sent. the pre-test survey consisted of three demographic questions, one item related to who they may have already provided any evd information to, two questions related to the student's confidence level providing education to others about evd, one item asking if they felt they needed additional evd training, knowledge questions, two questions related to the student's level of concern about their risk to evd, and one question about attendance at recent campus educational programs about evd. a few of the students either did not receive the initial e-mail or did not receive a valid link to the pre-test; these issues were resolved by sending e-mails to these students individually. the survey link was e-mailed again to students who experienced technological difficulties; no duplicate surveys occurred as a feature of the redcap system. three days after the pre-test survey closed, faculty of the students' classes posted the powerpoint slideshow on their online course sites, and participants were directed where to find the slideshow for viewing. participants did not have access to the powerpoint slideshow before completing the pre-test. time to completely view the slideshow was estimated to be about minutes. the powerpoint slideshow was available to view for three days. students who participated in the pretest were invited via e-mail to complete the post-test. the post-test was also hosted on the redcap platform, and survey responses were linked by student identification numbers. the post-test link remained active for three days. after the post-test, students were on an academic break for approximately five weeks. when classes resumed in january , students who had participated in the pre-and post-test surveys were invited to participate in a follow-up post-test. the purpose of this follow-up post-test was to assess the retention of knowledge and any changes in confidence in addressing evd concerns after a major school break. the redcap system linked survey results across the three tests with student identification numbers. the data manager provided student identification numbers to faculty for the purpose of awarding bonus credit. bonus credit was awarded to students who completed all three surveys. statistical analyses were performed using the statistical package for the social sciences, version (spss, chicago, il). statistical significance was set at p <. a priori. data were reviewed for completeness. any skipped or missing items were summarized and reported for items not related to the knowledge test. missing items on the knowledge test portion were treated as incorrect responses. most of the data collected were categorical and ordinal in nature; thus, most items were summarized using percentages and frequencies. age was normally distributed, so the mean and standard deviation were reported. descriptive statistics were compiled for all student characteristics, demographics, knowledge test scores, training needs, comfort, and confidence items. knowledge scores were computed as the percentage correct out of the evd content items. the two concern items and three confidence items were scaled with four response ordinal categories (not at all, somewhat, very, and extremely). the two concern items were averaged together, and the three confidence items were averaged together. reliability was assessed for each of the averaged items using standardized cronbach alpha and the split-half spearmanebrown formula (eisinga, grotenhuis, & pelzer, ) . average concern was significantly right skewed and still ordinal in nature and was dichotomized into subjects who were "not at all" concerned (score ¼ ) vs. those who were somewhat to extremely concerned (scores > ). average confidence was also right skewed and still ordinal in nature and was also dichotomized into subjects who were "not at all" or "somewhat" confident (scores ) and those who were "very" or "extremely" confident (scores > ). multilevel modeling (mlm) instead of repeated measures analysis of variance was used to test for changes over time for the three time points for the continuous knowledge scores because mlm uses all available data and adjusts for missing data over time (hedeker & gibbons, ) . for the dichotomized items for concern, confidence, and needing additional training, generalized multilevel modeling (gzmlm) was used for these binary response variables with logit link function (e.g., logistic regression) to test for changes over time. age was also included as a covariate since older students may have had more confidence or comfort levels. for consistency, age was included in all the mlm/gzmlm models. for all models, pairwise comparisons were made between responses at all three time points using sidak type i error ratee adjusted p values ("ibm spss statistics for windows, version . ," ). pairwise differences between t and t evaluated the initial improvements immediately after training, between t and t evaluated the longer term improvements from baseline, and between t and t evaluated the sustained or retained effects from the training. baseline surveys were completed by ( %) of eligible undergraduate students. the age of students participating in this study ranged from to years with an average age of . (standard deviation ¼ . ) years. the majority were female ( . %) with . % juniors, . % seniors, and . % accelerated undergraduates. when asked who the students had previously provided any information about the ebola outbreak to, the majority (> %) said friends and family, and slightly less than half ( %) said fellow students (table ) . of the who completed the baseline surveys, ( . %) completed the immediate post-test survey and ( . %) completed the final post-test survey. the who did not complete all three surveys were not significantly different from the who completed all three in age, gender, baseline knowledge, concern, confidence, or wanting additional training. initially, the students scored . ( . ) on the knowledge test and improved immediately after training with scores averaging . ( . ) which was significantly higher than baseline ( p < . ; table , figure ). their knowledge scores were well retained by the third time point with average scores of . ( . ) * evd knowledge test scores analyzed using multilevel modeling (mlm). y dichotomous outcomes analyzed using generalized multilevel modeling (gzmlm) with binary responses with logit link functions. the categories indicated by the counts and percents reported were the target category for the binary response logit link gzmlm. z one subject skipped answering the concern items at time . n u r s o u t l o o k ( ) e with no significant loss in knowledge scores from time ( p ¼ . ). at baseline, only half ( . %) were not at all concerned about their risk (averaged from concern as a health care provider and as an atlanta city resident). these two items showed good internal consistency and reliability with a standardized cronbach alpha and split-half spearmanebrown coefficient of . . this percentage of students not at all concerned did increase significantly over time with improvements from baseline to time ( p ¼ . ) with . % not at all concerned by time (table , figure ). when looking at the two individual concern items (concern as a health care provider and concern as a resident), the levels of not at all concerned was consistently lower for risk as a health care provider, but both showed steady increases over all three time points (table ) . at baseline, slightly more than half ( . %) stated they did need additional training about evd, but this decreased significantly over time with significant decreases from time to time ( p ¼ . ) and from time to time ( p ¼ . ) with overall decreases from time to time ( p < . ) down to only . % wanting additional training by time (table , figure ). at baseline, only . % of the students were very or extremely confident in their average ability to discuss evd with family/friends, answer questions about evd transmission, and convey a calm message about the general public risk for evd. these three items showed high internal consistency and reliability with a figure e estimated percentages (means and % confidence intervals) from multilevel models. note: all estimated means and % confidence intervals were adjusted for age as a covariate in the multilevel models. test scores were analyzed using multilevel models (mlms) and the other three outcomes (additional training [% yes], average concern [% not at all], and confidence average [% very or extremely]) were analyzed using generalized multilevel models (gzmlms) with binary responses and logit link functions. p values are provided for each pairwise comparison between the three time points and were adjusted using sidak pairwise error rate correction. standardized cronbach alpha of . . the average confidence increased significantly from baseline to immediate post-test to . % ( p < . ), but this confidence level decreased slightly by the final post-test at time down to . % which was not significantly less than time ( p ¼ . ) and was still significantly higher than baseline ( p < . ; table , figure ). when looking at the individual confidence level items, the lowest confidence levels were for discussing evd with family/ friends and answering questions about evd transmission. the confidence levels for conveying a calm message about the general public's risk for evd were consistently higher across time (table ) . a final detailed summary of the percentage of correct answers to the individual knowledge test items at all three time points is provided in table . reviewing this table shows that the weakest knowledge areas were for knowing how the ebola virus infection is diagnosed (item with baseline knowledge at . %), knowing how long protection lasts for people who recover from ebola (item with baseline knowledge at . %), and knowing whether you can still contact the virus from a person not showing symptoms (item with baseline knowledge at . %). these three items all showed improvement from baseline to immediate post-test at time , but items and showed the poorest retention by the third time point at the final post-test. two additional items with lower levels of knowledge at baseline were item with only . % knowing if supportive care was currently the only treatment available for ebola patients and item with only . % knowing how health care responders returning from other countries should be monitored. however, after training, both of these items showed significant and sustained improvement with knowledge levels above %. the remaining knowledge test items showed reasonable levels of knowledge at baseline above % that improved to % and higher over time. the west african evd epidemic of / that brought ebola-infected patients to the metro-atlanta area and to a hospital in which our student nurses were completing clinical education rotations provided a unique opportunity for the faculty at the nhwsn to prepare our student nurses for a major, fear-provoking public health event and to test the effectiveness of an educational program. there is little study devoted to the response of health professional schools, particularly schools of nursing in the event of an unforeseen infectious disease outbreak such as evd (stirling et al., ) . furthermore, there is little guidance for how to n u r s o u t l o o k ( ) e swiftly and effectively prepare nursing students for such events, both in their roles as patient providers and community educators. the implementation of a jitt educational program effectively achieved our goals to increase evd knowledge, decrease fear, and enhance students' confidence in their ability to discuss evd risk. furthermore, these achievements were sustained over time. this demonstration educational program highlights the effectiveness of self-directed learning, especially in times of a threatening disease outbreak. limitations to this educational program included a substantial decrease in the number of student participants who completed the final survey from the baseline measurement time point. this decrease aligned with the level of course credit or bonus points provided to students, indicating greater student motivation to complete the full program when credit was awarded in meaningful ways to students. giving extra credit points could also be a limitation of the program findings as it may not be representative of students who did not need extra credit (i.e., students with better course grades). the challenge with implementing consistent bonus points was having differing courses over two separate semesters. greater coordination among faculty and throughout the courses might have helped to encourage student participation. the student nurse population at emory university is primarily female, reflecting common gender norms of the nursing profession. this may, however, limit the generalizability of these findings to other more gender-balanced student groups. the jitt methodology and self-directed learning are effective means of increasing knowledge and confidence and decreasing risk concern among student nurses. in this era of globalization, when any communicable illness is "only a plane ride away" and intense media coverage can increase fear and anxiety, jitt is a successful method of delivering evidencebased information to students in a timely manner. schools of nursing must have the tools and resources to respond quickly and comprehensively during an unanticipated infectious disease outbreak to protect their students and staff, to prevent disease, and to be empowered advocates of accurate information in the midst of an epidemic. r e f e r e n c e s just-in-time lectures the reliability of a two-item scale: pearson, cronbach or spearman-brown? care of patients with ebola virus disease i'm the head nurse at emory. this is why we wanted to bring the ebola patients to the u.s. the washington post longitudinal data analysis statistics for windows, version . . armonk risk communication with nurses during infectious disease outbreaks: learning from sars an education programme for nursing college staff and students during a mers-coronavirus outbreak in saudi arabia telling the story chinese disasters and justin-time education key: cord- -alyyju x authors: james, peter bai; wardle, jonathan; steel, amie; adams, jon title: an assessment of ebola-related stigma and its association with informal healthcare utilisation among ebola survivors in sierra leone: a cross-sectional study date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: alyyju x background: we examined the magnitude and correlates of ebola virus disease (evd)-related stigma among evd survivors in sierra leone since their return to their communities. in addition, we determined whether evd-related stigma is a predictor of informal health care use among evd survivors. methods: we conducted a cross-sectional study among evd survivors in five districts across all four geographic regions (western area, northern province, eastern province and southern province) of sierra leone. ebola-related stigma was measured by adapting the validated hiv related stigma for people living with hiv/aids instrument. we also measured traditional and complementary medicine (t&cm) use (as a measure of informal healthcare use). data were analysed using descriptive statistics and regression analysis. results: evd survivors report higher levels of internalised stigma ( . ± . ) compared to total enacted stigma ( . ± . ). social isolation ( . ± . ) was the highest reported enacted stigma subscale. ebola survivors who identified as christians [aor = . , %ci: . – . , p = . ], who perceived their health to be fair/poor [aor = . , %ci: . – . . p = . ] and who reside in the northern region of sierra leone [aor = . , %ci: . – . , p = . ] were more likely to experience internalised stigma. verbal abuse [aor = . , %ci: . – . , p = . ] and healthcare neglect [aor = . , %ci: . – . , p = . ] were independent predictors of t&cm use among evd survivors. conclusion: our findings suggest evd-related stigma (internalised and enacted) is prevalent among evd survivors since their return to their communities. religiosity, perceived health status and region were identified as independent predictors of internalised stigma. verbal abuse and healthcare neglect predict informal healthcare use. evd survivor-centred and community-driven anti-stigma programs are needed to promote evd survivors’ recovery and community re-integration. the - ebola virus disease (evd) outbreak in west africa is considered the largest and unprecedented public health emergency in the history of the disease [ ] . as at the th march , the morbidity and mortality figures due to evd were estimated at , and , respectively [ ] . the west african ebola outbreak also recorded the highest number of survivors, and current estimates put the number of evd survivors at more than , [ ] . many evd survivors are known to be suffering from short and long-term physical symptoms and mental complications as a result of surviving evd [ ] [ ] [ ] . psychosocial consequences of evd survivorship can be traumatic, due to the adverse psychological experiences of individuals with evd had to grapple with during infection, treatment and post-discharge. these adverse experiences includes various forms of psychosocial challenges such as depression, anxiety and grief due to loss of loved ones and stigma [ ] . stigma constitutes negative attitudes and beliefs that discredit an individual or group of individuals leading to prejudice and societal exclusion [ ] . stigma can lead to experiences and feelings of blame, shame, worthlessness, loneliness, isolation, social exclusion and discrimination in accessing social amenities and healthcare services [ , ] . socially undesirable manifestations (prejudice and discrimination) expressed against those with the stigmatizing attributes are known as enacted stigma whereas the feeling of shame, guilt or worthlessness experienced as a result of having the stigmatising attribute is referred to as internalised stigma [ ] . evd-related stigma is largely based on community fear that evd survivors are still contagious [ ] . such fear is profound if evd survivors experience post-ebola sequelae [ , ] or are aware that the ebola virus can be present in certain immune-protective parts of the body after convalescence (for example, the semen, breast milk, ocular (eye) fluid, and spinal column fluid) [ , ] . evd-related stigma has led to evd survivors being mocked by their communities [ , ] , being evicted from their homes by their property owners [ , ] , losing their former jobs [ ] and being divorced by their spouses [ , ] . some evd survivors have been prevented from visiting public places such as public toilets and have experienced difficulty in trading commodities at their local market due to a community reluctance to touch their items or money [ , ] . evd-related stigma has been reported by evd survivors and their communities in dr congo ( %), guinea ( %) and liberia ( %) [ ] [ ] [ ] , and may be more common among female rather than male evd survivors [ ] . other factors, which have been reported as predictors of evd-related stigma, are age, level of education, and having accessed medical care [ ] . liberian research also suggests evd survivors are reported to be more likely to experience stigma compared to their close contacts who were not infected with evd virus [ ] however the degree of evd-related stigma may decline among survivors over time [ , ] . in sierra leone, stigmatisation is reported in approximately one third of evd survivors [ , ] . stigma associated with infectious disease has been linked to poor adherence to conventional treatment and the utilization of informal or non-integrated forms of health care such as traditional and complementary medicine (t&cm) [ , ] . t&cm refers to a number of health systems, products and practices considered to be predominantly outside conventional medical practice and the medical curriculum [ , ] . in sub-saharan africa, an average of % of the general population is estimated to use t&cm products and % consult t&cm practitioners [ ] . the key reasons for t&cm use in africa have been attributed to its low cost, easy accessibility, the alignment between t&cm philosophy and local cultural and religious values, perceived safety and efficacy, and dissatisfaction with conventional medicine [ ] . in sierra leone, t&cm utilisation is common especially among hypertensive, pregnant women, infertile women, and lactating mothers and in the management of malaria and diarrhoea [ ] [ ] [ ] [ ] [ ] [ ] . studies have reported individuals with hiv/aids or mental health diagnoses that experience stigma are more likely to access t&cm services [ , ] . this pattern of use is reportedly due to the users' perception of t&cm as less stigmatizing than conventional medicine, partly justified by the view that these t&cm approaches are deeply rooted in the local cultural and traditional practices [ , ] . among sars survivors, t&cm was reported to be useful in overcoming sars-related stigmas by creating new social support networks and counteracting potential future stigmatization and discrimination [ ] . most studies on stigma among evd survivors have focussed on its magnitude and nature both immediately following and over a number of years after discharge from an ebola treatment centre [ - , - , , , ] . although recent studies have reported the use of informal healthcare services among evd survivors [ , ] , globally, no study to date has reported whether evd-related stigma is associated with t&cm utilisation among evd survivors. in addition, none of the published studies in sierra leone on evd survivors has explored the sociodemographic and health-related factors associated with evdrelated stigma. such associations are important, as they will inform the design and implementation of future antistigma interventions. therefore, we examined the magnitude and the sociodemographic and health related correlates of enacted and internalised stigma among evd survivors in sierra leone since their return to their communities. in addition, our study determined whether enacted and internalised stigma are possible predictors of informal healthcare service utilisation (t&cm use) among evd survivors in sierra leone. we conducted a cross-sectional questionnaire study between january and august among evd survivors across all four geographic regions (western area, northern province, eastern province and southern province) of sierra leone. participants in this study were adult evd survivors aged years and older experiencing post-ebola sequelae. we excluded evd survivors whose physical and psychological health limited them from providing information, such as those survivors with memory loss, hearing loss, high fever and bleeding or those experiencing acute emotional distress. a sample of evd survivors was determined using a sample size formula for cross-sectional studies (n = z pq/ d ). we increased our sample to to make up nonresponses. multistage sampling method was used to recruit participants across the country. data was collected from the four geographic regions of sierra leone (western area, northern province, southern province and eastern province). five districts were purposefully selected to cover all four geographic regions of the country. the location of the five districts in sierra leone are shown in fig. . the five districts are western area urban and western area rural districts (both in the western area), bo district (southern province), kenema district (eastern province) and bombali district (northern province). these five districts were chosen based on the epidemiological profile of the total confirmed ebola cases and because they are host to the highest number of ebola survivors in sierra leone. we randomly sampled the required number of evd survivors in all five districts based on proportional representation using the national list of registered ebola survivors obtained from the sierra leone association of ebola survivors (slaes). survivors who were randomly chosen were invited to participate in the study via telephone. the survey instrument measures evd demographics such age, sex, marital status, educational status, religious affiliation, employment status, financial status, place of residence (urban/rural), geographical region (north, south, east regions and western area) and time (months) since post-discharge. perceived health status was measured using a five-point likert scale that ranged from "excellent" to "poor". evd survivors were asked if they had been diagnosed with any chronic condition prior to being infected with evd virus. the ebola-related stigma instrument was adapted from the hiv-related stigma for people living with hiv/aids (hasi-p). the hasi-p is a validated -item scale that measures stigma among hiv/aids patients in the past months [ ] . this instrument was validated among hiv/aids patients in five african countries: lesotho, malawi, south africa, swaziland and tanzania. it consists of the following subscales and this includes verbal abuse (eight items, α = . ); healthcare neglect (seven items, α = . ); social isolation (five items, α = . ); fear of contagion (six items, α = . ); and workplace stigma (two items, α = . ) all of which measures enacted stigma. the final subscale called negative selfperception (five items, α = . ) measures internalised stigma [ ] . we decided to use hiv/aids related stigma scale (hasi-p) because hiv/aids patients share similar psychosocial challenges with evd survivors in terms of social isolation, fear of contagion and family and community stigma and discrimination [ ] . in addition, there is widespread misinformation about hiv/aids and evd. for instance, evd and hiv/aids only affects certain groups of people in society (the poor for evd and promiscuous adults or homosexuals for hiv/aids) and the unfounded community fear of being infected with the virus through means that have not being scientifically proven [ ] . to adapt to our setting, the hasi-p was reviewed by two experts in sociology and evd as well as piloted among evd survivors. based on their feedback, we decided to remove the two items that measure workplace stigma since the majority of evd survivors did not have any paid job before or after evd. we also removed the statement "at the hospital, i was left in soiled bed" from the healthcare neglect subscale since majority of survivors were not admitted at the clinic/hospital. in addition, the wording of some statements were changed to fit the local evd survivorship context. further, we decided to assess stigma experienced by evd survivors since their discharged from ebola treatment centre instead of the past months, as was the case when the instrument was validated among hiv/aids patients [ ] . the final adapted hasi-p instrument used in our study is attached as an additional file . evd survivors were asked about their health care utilisation, including whether they have used t&cm treatment (products and practitioners) since their discharge from the etc. the common t&cm modalities considered in our study were informed by studies undertaken previously in sierra leone [ - , , - ] and across africa [ ] . we considered t&cm in our study to include biological based therapy (herbal medicine and animal extract), spiritual therapy (prayer/faith healing), alternative medicine systems (chinese herbal medicine, and acupuncture), and physical therapy/body manipulations (massage therapy, traditional bone setting). trained data collectors obtained the relevant information from evd survivors using self-administered or interviewer-administered (for illiterate participants) formats. the university of technology sydney human research ethics committee (uts-hrec-eth - ) and the sierra leone ethics and scientific review committee granted ethical clearance. a participant information sheet, explaining the purpose and scope of the study, as well as the option to opt out, was given or read (illiterate) to evd survivors before seeking their consent to participate. survivors signing or thumb printing the consent form was interpreted as their willingness to participate. survivors who signed or thumbed printed (for illiterate participants) the consent form were then given the questionnaire to fill or to be interviewed(for illiterate participants).three hundred and fifty eight evd survivors consented and completely filled the questionnaire and were included in the data analysis. we collected our data between may and august and it was done either at the regional office of evd survivors or their homes or the village courtyard. we used ibm spss statistics version to perform all analyses. each of the stigma items was assigned a score of to ( = never, = once or twice, = several times and = most of the time). for each participant, we summed the scores and divided by the number of items to get the mean score for each of the factors/subscales. to obtain the overall total stigma mean score, we summed up the mean scores of each of the factors and divided by . stigma was analysed as a binary variable (yes/no). mean stigma score of zero means that none of the items (experiences) in each of the subscales (internalised stigma, verbal abuse, healthcare neglect, fear of contagion and social isolation) occurred since discharged from the etc. a mean stigma score greater than zero indicated that at least one of the items in each of the subscales occurred once or twice or several times or most of the time. as a binary variable, mean score of zero was taken as the absence of stigma and greater than zero was taken present of stigma. we employed chi-square and fischer exact two tailed tests to determine the association between stigma subscales and sociodemographic and health related variables. we conducted a backward stepwise regressions analysis to establish the most parsimonious model that determines the sociodemographic and health related predictors of internal and enacted stigma. we also used backward stepwise regressions analysis to establish the most parsimonious model that predicts whether internal and enacted stigma is an independent predictor of informal healthcare use (t&cm use). to determine the independent association between evd -related stigma and t&cm use, all of the sociodemographic (age, sex, marital status, religious affiliation, employment status residence etc.) and health related (perceived health status, duration(years) since discharged from etc, known chronic disease) variables were taken as potential cofounders and were adjusted for in the regression analysis. probability less than . was as statistically significant for all inferential statistical analyses. out of the survivors invited to participate in the study, of them agreed to take part in the study. however, failed to completely fill the questionnaire. thus, complete data on evd survivors were analysed. table gives a summary of evd survivors' sociodemographic and healthrelated characteristics. more than half (n = , . %) of survivors were within the ages of - years and close to two-thirds (n = , . %) were females. also close to three -fourths (n = , . %) of survivors perceived their health to be fair/poor. based on the calculated mean scores, evd survivors reported higher levels of internalised stigma ( . ± . ) compared to enacted stigma ( . ± . ). among the enacted stigma subscale, social isolation ( . ± . ) and healthcare neglect ( . ± . ) were the highest and least respectively. we categorised stigma scores into (yes /no) as there was little variability in stigma scores. in general, majority of ebola survivors endorsed at least one item exploring internalised stigma (n = , . %) and any of the three subscales measuring enacted stigma (n = , %). verbal abuse (n = , . %) and fear of contagion (n = , . %) were the highest and least reported enacted stigma subscales respectively (see table ). association between stigma and sociodemographic and health related variables among ebola survivors table summarises the comparison of internalized and enacted stigma with sociodemographic and health related variables among ebola survivors. religious affiliation (p = . ) and perceived health status (p = . ) were associated with internalised stigma. none of the sociodemographic and health related variables was associated with table ). no sociodemographic and health related variables predicted total enacted stigma. association between t&cm use and internalised and enacted stigma this is the first nationally representative study to determine the prevalence of stigma, its sociodemographic correlates and association with informal and nonintegrated forms of health care such as t&cm use among evd survivors in sierra leone. one key finding from our study is that evd survivors report high levels of internalised and enacted stigma since discharge from an ebola treatment centre which is in line with findings from a longitudinal liberian study that reported high levels of stigma at baseline but lower levels at subsequent follow-up visits [ , ] . our finding also resonates with similar short term and smaller sample size cross-sectional studies in sierra leone [ , , ] , liberia [ ] , guinea [ ] , and dr congo [ , ] ,which reported that evd survivors experience several forms of internalised and enacted stigma. our result identifies higher occurrence of internalised stigma when compared with the occurrence of total enacted stigma experienced by evd survivors. our result contrasts to findings reported in a liberian longitudinal cohort study that employed a different stigma instrument [ ] but is in line with a south african study that employed the same stigma tool to measure stigma among hiv/aids patients to that employed in our study [ ] . the higher frequency of internalised stigma (negative self-perception) among evd survivors in our study is a cause for concern and warrants further research attention as it can lead to low self-esteem, low self-efficacy, loss of hope for the future and can interfere with life goal achievement [ ] . the findings for evd studies appear to be similar to some other infectious diseases. for example, similar sequelae have been reported among hiv/aids patients in hong kong [ ] and uganda [ ] , in which hiv/ aids patients reported to feel less worthy of themselves, guilt, shame and self-blame for having hiv/aids. the common types of enacted stigma faced by evd survivors in our study were social isolation, verbal abuse and fear of contagion, all of which are congruent with the common forms of stigma reported by evd survivors in the wider literature [ ] . these findings may be applicable to other emerging infectious disease survivors more generally, as similar forms of stigma from the public and healthcare staff have also been reported among sars survivors in hong kong [ ] . social isolation, verbal abuse and fear of contagion can lead to increased levels of psychological distress, delayed access to medical care, low adherence to medical therapy and reduced quality of life as it has also been reported among hiv/aids and mental health patients [ , ] . drawing from lessons learnt from hiv/aids-related stigma, several evd survivor-centred and community-driven strategies have been suggested that could contribute to evd survivors' recovery and community re-integration. these include community long-term psychosocial counselling for evd survivors to enhance their coping skills, community education and social support programs for evd survivors, recruitment and training of trusted opinion leaders that can spread accurate de-stigmatising messages within communities, minimising social isolation and promoting economic empowerment of evd survivors and evd affected communities [ , ] . the mental health impact of surviving ebola is enormous, and previous studies have reported that psychological distress, anxiety and depression are widespread among ebola survivors [ , ] . although the impact of ebola -related stigma on mental illness among ebola survivors is not well understood, stigma induced psychological distress and anxiety have been found to be associated with adverse mental health outcome among hiv/ aids patients [ ] . since hiv/aids and ebola virus disease share similar stigmatizing attributes [ ] , it is possible that ebola -related stigma maybe contributing to the mental health complications among ebola survivors. thus, it likely that stigma reduction strategies will help reduce the mental health burden among evd survivors. evd survivors in our study who identified as christians and reside in the northern region were more likely to experience internalised stigma. the reasons for the high levels of internalised stigma among christians remain unclear. going forward, an in-depth ethnography study would be required to explain the high levels of internalised stigma amongst christians compared to muslims that was observed in our study. our study findings also reveal that evd survivors who perceive their health to be fair/poor are more likely to experience internalised stigma than those who perceive their health to be good. in hiv/aids patients, the link between stigma and perceived poor health status is postulated to be because stigma is known to promote poor adherence to treatment, lowers emotional coping and social support networks and reduces access to and usage of health and social services leading to poor health outcomes [ , ] . the similarity of our findings suggest that similar concerns may be present for evd survivors. further studies are needed to explore the link between internalised stigma and religiosity as well as perceived poor health status among evd survivors in sierra leone. nonetheless, our results have revealed that religiosity, perceived health status and spatial location are potential predictors of internalised stigma among evd survivors and, that healthcare provider and social workers should consider these characteristics as possible risk factors for internalised stigma among evd survivors in sierra leone. further analysis of the enacted stigma subscales revealed verbal abuse was more likely to occur among evd survivors residing in urban locations when compared to those living in rural areas. our finding may be explained by the fact that adherence to local bylaws to prevent stigma and discrimination by the community was more prevalent in rural areas compared to urban areas [ ] . also, previously identified urban-rural community differences in knowledge and perception of, and attitude towards, evd may also explain our finding [ ] . our study also revealed that evd survivors who are unemployed were more likely to be socially isolated by their communities than their counterparts who were employed. such a finding maybe explained given that unemployed evd survivors are likely to be economically and socially dependent on their families and their communities for their wellbeing and, as such are more likely to experience stigma in the form of isolation from their families and communities compared to employed evd survivors [ , ] . evd survivors who experienced healthcare neglect in conventional healthcare settings in our study were more likely to use t&cm. our finding is not surprising given that healthcare neglect (negative attitude of healthcare providers, long waiting time or being the last person to be seen by the doctor) leads to patient's dissatisfaction with conventional healthcare -a key driver for t&cm use in the general and sub-health populations in africa [ ] . thus, it is important for policy makers and health providers to bear in mind that, like other sub-health populations, evd survivors will likely seek informal healthcare options if they feel neglected by the conventional health system. at policy level, laws are needed that allow evd survivors to receive appropriate care in a safe environment without being stigmatised or discriminated. in addition, educational interventions to change the negative attitude towards evd survivors among health providers are required. however, there were also positive attributes identified for t&cm use. the high rate of t&cm use among evd survivors who experienced enacted stigma (healthcare neglect and verbal abuse) maybe related to the notion that t&cm may serve as a stigma reduction strategy. for instance, t&cm has been used by patients to resist the terminal understanding of hiv/aids and believing that hiv/ aids is chronic rather than a terminal illness [ ] . also, hiv/aids patients and sars survivors have used t&cm practices such as yoga and tai chi to create social support groups as people in such settings are less likely to act differently to each other since they share similar health status and experiences [ , ] . drawing from the experiences of hiv/aids patients and sars survivors in using t&cm in managing stigma, it is possible that evd survivors will be using t&cm not only to address their physical health needs but also to as a coping mechanism against the stigma they are experiencing in their communities and at healthcare facilities. as such, there may be a role for integration of some t&cm where appropriateto help improve conventional health options for evd survivors. going forward, welldesigned qualitative research is required to have a deeper understanding of the meanings of t&cm practice in the everyday lives of evd survivors. the following limitations must be considered when interpreting our findings. first, our study may suffer from recall bias as we relied entirely on self-reported data. second, our study employed a cross-sectional design and, therefore we cannot infer causality between independent and outcomes variables. third, we adapted the hiv/aids-related stigma scale (hasi-p) [ ] to measure evd related stigma among evd survivors, as there is no detailed or validated tool exist for evd related stigma. we decided to use hiv/aids related stigma scale (hasi-p) because hiv/aids share similar characteristics with evd in terms of social isolation, fear of contagion and family and community stigma and discrimination [ ] . finally, our findings are only applicable to evd survivors in sierra leone and may not be representative of evd survivors in other neighbouring evd affected countries. nevertheless, the national nature of this survey represents one of the most representative samples of stigma in evd survivors. the majority of evd survivors in sierra leone experience both internalised and enacted ebola-related stigma although internalised stigma was the most common in terms of occurrence. to reduce evd related stigma, and the impacts of such stigma on evd survivors' health and wellbeing, evd outbreak responses should include evd survivor-centred and community-driven interventions that can help contribute to evd survivors' recovery and community re-integration. evd survivors appear drawn to informal and non-integrated care (t&cm) via both push (i.e. dissatisfaction with conventional care) and pull (i.e. empowerment and social commitments from t&cm). future research is needed to have a deeper insight of the meanings of t&cm practice in the everyday lives of evd survivors. supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file . ebolarelated stigma questionnaire. abbreviations etc: ebola treatment centre; evd: ebola virus disease; t&cm: traditional and complementary medicine we want to extend our thanks and appreciation to the ebola survivors who consented to take part in this study. we also want to extend our appreciation to the staff of the sierra leone ebola survivors association and staff of the ebola clinic at military hospital wilberforce freetown as well as all data collectors for their support during data collection.. we also extend our thanks to the faculty health, university of technology sydney to help fund the field work for this study. in addition, we extend our thanks and appreciation to dean and staff of the faculty of pharmaceutical sciences, college of medicine and allied health sciences, university of sierra leone. the authors thank mr. john alimamy kabba for helping in creating the map used in this manuscript. authors' contributions pbj and jw conceived of the study while, pbj, jw, as & ja contributed in designing the study. pbj analysed the data and wrote the initial draft of the manuscript. jw, as and ja supervised the process and contributed to the intellectual content of the manuscript. all authors read and approved the final version of the manuscipt. the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. availability of data and materials due to confidentiality and privacy concerns, and given the sensitivity surrounding stigma and discrimination among ebola survivors, our study did not receive approval from the university of technology sydney human research ethics committee and the sierra leone ethics and scientific review committee to publicly share the raw data. also, ebola survivors consented to participate in the study on the basis that their data would not be shared with anyone except members of the research team (my supervisors and i). the raw data informing the findings of this study are stored privately at the university of technology sydney data storage platform called cloudstor. however, upon reasonable request, the anonymised raw data underlying the findings of this study can be made available through the following persons not applicable. the authors declare that they have no competing interest. exposure patterns driving ebola transmission in west africa: a retrospective observational study ebola situation report who: clinical care for survivors of ebola virus disease. interim guidance neuropsychological longterm sequelae of ebola virus disease survivors -a systematic review sequelae of ebola virus disease: the emergency within the emergency post-ebola 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cross-sectional study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -ys jrgw authors: jecker, nancy s.; dudzinski, denise m.; diekema, douglas s.; tonelli, mark title: ebola virus disease ethics and emergency medical response policy date: - - journal: chest doi: . /chest. - sha: doc_id: cord_uid: ys jrgw caring for patients affected with ebola virus disease (evd) while simultaneously preventing evd transmission represents a central ethical challenge of the evd epidemic. to address this challenge, we propose a model policy for resuscitation and emergent procedure policy of patients with evd and set forth ethical principles that lend support to this policy. the policy and principles we propose bear relevance beyond the evd epidemic, offering guidance for the care of patients with other highly contagious, virulent, and lethal diseases. the policy establishes ( ) a limited code status for patients with confirmed or suspected evd. limited code status means that a code blue will not be called for patients with confirmed or suspected evd at any stage of the disease; however, properly protected providers (those already in full protective equipment) may initiate resuscitative efforts if, in their clinical assessment, these efforts are likely to benefit the patient. the policy also requires that ( ) resuscitation not be attempted for patients with advanced evd, as resuscitation would be medically futile; ( ) providers caring for or having contact with patients with confirmed or suspected evd be properly protected and trained; ( ) the treating team identify and treat in advance likely causes of cardiac and respiratory arrest to minimize the need for emergency response; ( ) patients with evd and their proxies be involved in care discussions; and ( ) care team and provider discretion guide the care of patients with evd. we discuss ethical issues involving medical futility and the duty to avoid harm and propose a utilitarian-based principle of triage to address resource scarcity in the emergency setting. th e ebola virus disease (evd) epidemic is described by the centers for disease control and prevention (cdc) as "the largest in history," aff ecting not only multiple countries in west africa but also locally acquired cases involving health-care workers in the united states. and principles we propose bear relevance beyond the evd epidemic, off ering guidance for the care of patients with other highly contagious, virulent, and lethal diseases. the policy establishes ( ) a limited code status for patients with confi rmed or suspected evd. limited code status means that a code blue will not be called for patients with confi rmed or suspected evd at any stage of the disease; however, properly protected providers (those already in full protective equipment) may initiate resuscitative eff orts if, in their clinical assessment, these eff orts are likely to benefi t the patient. the policy also requires that ( ) resuscitation not be attempted for patients with advanced evd, as resuscitation would be medically futile; ( ) providers caring for or having contact with patients with confi rmed or suspected evd be properly protected and trained; ( ) the treating team identify and treat in advance likely causes of cardiac and respiratory arrest to minimize the need for emergency response; ( ) patients with evd and their proxies be involved in care discussions; and ( ) care team and provider discretion guide the care of patients with evd. we discuss ethical issues involving medical futility and the duty to avoid harm and propose a utilitarian-based principle of triage to address resource scarcity in the emergency setting. with confi rmed or suspected evd will be properly protected and trained, including training in the proper use of ppe. . th e treating team will anticipate, treat, and/or prepare for likely causes of cardiac and respiratory arrest to minimize the need for emergency response. goals of care will be evaluated on an ongoing basis. . patients with evd and their families or proxies will be involved in goals of care discussions throughout hospitalization and will be made aware of limitations of care as they apply. discussion will include notifi cation of the patient's code status and its rationale. although neither consent nor assent of the patient, family, or both is ethically required for limited resuscitation status, patients and families are ethically entitled to full disclosure. . care team discretion will guide general management of patients with evd. responding providers will exercise discretion regarding which medical interventions, including resuscitative eff orts, can be safely and eff ectively delivered to patients with evd. identifi ed ethics consultants will be available on an ongoing basis to members of the health-care team. operationalizing the above policy requires modifying existing protocols. although this could be accomplished by assigning a "do not attempt resuscitation" (dnar) status to all patients with known or suspected evd, we propose instead assigning a "limited resuscitation" status to patients with evd. th e alternative of a standard dnar order carries the following disadvantages: ( ) dnar may be misinterpreted to mean that providers have no obligation to assume reasonable risk when caring for patients with evd. ( ) it is easier to justify limited resuscitation for patients with suspected, but not confi rmed, evd than it is to justify dnar, because limited resuscitation leaves open the possibility of providing certain resuscitative measures. ( ) a limited resuscitation status for patients with evd maintains a patient-centered focus better than a standard dnar status. a dnar order may be understood by some providers to preclude what, in some cases, would be helpful interventions. risk of exposure to evd varies depending on disease stage: ebola virus is usually detectable in the blood at the time of early symptom presentation. it then increases logarithmically and can reach extremely high levels ( - billion rna copies/ml serum). viral levels are highest when the patient is in the most active phase of the disease. evd is shed in bodily fl uids during the acute phase of illness, including saliva, breast milk, stool, and tears. at all disease stages, there is a scientifi c basis for protecting health-care professionals and others against evd exposure by mandating that all personnel coming into contact with patients with evd wear ppe and undergo specialized training to ensure their safety. as mccullough notes (as quoted in altman ), "there are justifi ed limits on the risk to health and life that health-care professionals are expected to take in the care of patients." ebola virus is detectable in the blood only aft er onset of symptoms and may take up to days following onset of symptoms to reach detectable levels. health professionals caring for individuals with suspected evd should take the same precautions they would take in cases of confirmed evd. because of the uncertainty surrounding diagnosis and associated risk, the ethical justifi cation for following the proposed policy is weaker in suspected evd than it is in confi rmed evd. we err on the side of minimizing risk to health professionals during the limited time period in which evd is reasonably suspected but not confi rmed. evd can be reasonably suspected in situations where individuals present with early symptoms of evd and have had exposure to the ebola virus (ie, contact with the blood or bodily fluids of a person with evd, contact with objects contaminated with the blood or bodily fluids of a person with evd, or contact with animals infected with evd). evd has a substantially higher death rate than other epidemic viral infections. thus, there is a need to illuminate the duty to treat in the particular context of evd. faced with a patient in distress, providers' strong tendency is to attempt to rescue the patient. yet, patient advocacy is ethically limited under circumstances where it poses a serious threat to the health or life of others, including health-care professionals. although clinicians should generally put self-regarding interests aside to serve those in need, this obligation is not absolute. th e obligation to assist may be overridden when there is an unacceptably high risk to health-care professionals. we believe the risk to a provider who assists a patient with evd without proper ppe training and use is suffi ciently high and overrides the obligation providers would ordinarily have in less risky situations. most patients with evd in the united states are likely to be admitted before reaching advanced stages of evd (eg, prior to developing refractory sepsis with multiorgan failure although we agree that resuscitation is futile in patients with evd with multisystem failure and uncontrolled bleeding, we do not agree that resuscitative eff orts are futile for "most, if not all" patients with evd. for example, in patients with evd with perfusing rhythms, there is a reasonable likelihood of benefi t from whatever limited resuscitation measures are available by a properly protected health-care professional who is proximal to the patient at the time of arrest. in this respect, we concur with caplan (as quoted in altman ), who cautions that only patients with ebola "in extremis" should be entirely excluded for all resuscitative eff orts. resuscitative measures that can be off ered by a single provider already in the room at time of arrest are necessarily limited. for example, a single provider cannot simultaneously provide bag-mask ventilation and administer other necessary interventions, such as medications. th e ethical duty to off er limited resuscitation attempts is justifi ed on several grounds. first, health professionals agree to assume a standard level of risk of infection as part of entering their profession. , as a consequence, assumption of risk has become part of the ethical practice of medicine and other healing professions. as dwyer and tsai note, by choosing to become doctors, individuals accept some duty to treat…th e issue here is not a peripheral matter left up to individual choice, but a central concern that helps to defi ne the role of doctoring. assumption of risk is evident, for example, in statements of professional organizations, such as the american medical association (ama) and the american nurses' association. th e ama recognizes that under special circumstances, such as urgent medical disasters, the obligation to assume personal risk to care for patients "holds even in the face of greater than usual risks to their own safety, health, or life." th e ama further notes that although health-care facilities should minimize risk (eg, by ensuring "the availability of protective and preventive measures for physicians and others caring for patients with communicable disease") they must also ensure access to appropriate medical care. th e american nurses' association posits an obligation to care for patients whenever the value of such care is greater than any harm the nurse might incur. th is stance is qualifi ed by the requirement that nursing care not present more than minimal risk to the nurse. for example, a nurse's duty to treat a patient with aids may be overridden if the nurse is immunosuppressed, because that nurse's risk exceeds a level considered "minimal." in addition, the historical practice of assuming risk to provide care to patients with communicable diseases lends support to off ering limited attempted resuscitation to patients with evd. recent history, including treatment of patients with hiv, aids, severe acute respiratory syndrome (sars), and hepatitis a, b, and c demonstrate a commitment on the part of health-care professionals to put patients fi rst, even at risk to their own health or life. th us, the burden of proof lies with those who would deny a duty to assume the risk of treating patients with communicable disease. , th e proposed policy prohibits attempting resuscitation in late-stage evd, when the likelihood of medical benefi t is exceedingly poor. under these circumstances, resuscitative eff orts may be withheld from patients with evd on grounds of medical futility. th e logic of this approach is that the mere fact that a patient is imminently dying does not suffi ce to show that there is a duty to attempt rescue. aft er all, if the patient is actively dying, then any attempt to rescue the patient would fail and should not be instituted. if the likelihood or quality of benefi t falls well below a threshold considered minimal, the intervention should not be off ered or continued. th is approach applies to all patients, regardless of diagnosis. for both patients with and patients without evd, the best available evidence shows that cpr and associated resuscitative measures are ineff ective and off er no benefi t in the setting of progressive multiorgan failure in a patient already receiving maximal supportive care. medical futility also justifi es withholding other emergent invasive procedures, such as endotracheal intubation or vascular access, in the context of an arrest or other precipitous decline for patients with end-stage evd. what is unique in the case of patients with evd is that the medical futility of cpr may arise as a direct result of the delay in responding to the patient's emergency medical needs due to the requirement that all providers be properly donned with ppe. with current donning procedures, the time to prepare providers to respond to patient emergencies renders a standard resuscitation response impractical because of the rapid response required to help an acutely decompensated patient. despite limitations on care, we reject the claim by some that "there is no available therapy for ebola, all the more so for patients in extremis." th e standard of care for patients with advanced evd consists primarily of supportive care. volume resuscitation and continued maintenance of intravascular volume status appears to be particularly important. other organ supportive/ replacement therapies, including iv pressers , mechanical ventilation, and replacement therapy have also been used when indicated. when lifesaving measures are futile, providers should avoid suggesting to the patient and family that "nothing" can be done; they should instead assure the patient and family that everything possible will be done to keep the patient as comfortable as possible. in addition to the above distinctions based on disease stage, we note that complicating factors may require case-by-case assessment. when this occurs, the trained and protected treating team should exercise discretion. an appeal to discretion is not ethically grounded in respect for provider autonomy, as some have argued ; instead, it is based on principles of benefi cence and nonmalefi cence. th e treating team must carefully weigh benefi ts (to the patient) and risks (to the team). although appealing to team discretion is ethically supported, it carries the risk that similar cases will be treated diff erently by diff erent health-care teams. we militate against this concern by encouraging daily discussions among all members of an ongoing care team. we also urge team discretion for patients with evd who present with comorbidities, such as pregnancy or concomitant acute illness. such cases require case-by-case medical evaluation and ethics involvement. in general, nonemergent surgical procedures should not be performed in patients with suspected or confi rmed evd. such procedures should be delayed until they can be performed without risk of evd transmission to providers. emergent operative procedures may require a modifi ed standard of care, with operative capabilities being brought to the isolation unit, rather than having the patient brought to the operative suite. under no circumstances should a code blue be called on a patient with evd that would result in untrained providers being marshaled to the bedside. th us, "heroic" staff members who are unprotected or improperly attired should not rush to the room of a patient with evd to perform cpr or other invasive procedures, such as emergent line placement and intubation. th e ethical justification for this approach is the principle of nonmaleficence, or "do no harm." with current ppe procedures, the time to prepare providers to respond to patient emergencies renders many resuscitative measures impractical because of the rapid response required to help an acutely decompensated patient. as a consequence, avoiding harm to providers may result in patients foregoing benefi ts they might otherwise have received. it is worth noting that providers and bioethicists generally apply the principle of nonmalefi cence to patients, not to providers or the broader community. by contrast, a principle of utility applies to all people aff ected by an act or policy. th us, an institutional policy that minimizes harm to staff , as well as patients, is ultimately justifi ed by utilitarian reasoning, rather than by the standard bioethical principle of nonmalefi cence. aside from resuscitative interventions, other treatments that may be medically indicated create potentially highrisk exposure to health-care professionals. th ese include interventions for pregnant women, such as fetal monitoring, cesarean delivery, induction, or surgical repair of lacerations, , - and continuous renal replacement therapy (rrt), among others. only competent providers trained in proper use of ppe and donned should perform these and other procedures for patients with evd. the primary treatment team should exercise judgment regarding the appropriate use of potentially high-risk procedures in response to sudden clinical changes. interventions that carry little chance of benefi tting a patient, and that place members of the care team at signifi cant risk, should not be provided. extracorporeal life support, for example, would fall into this category for patients with evd with advanced enough disease to require it. by contrast, rrt may be medically appropriate in some situations. ethics involvement is encouraged to ensure consistency and fairness in policies and practices. when assessing risk to providers, it is critical to evaluate the scientifi c basis of risk assessment. media coverage of evd in the united states has sometimes focused on "theoretical-but dramatic-possible mutations of the virus rather than consistent, clear, and scientifi cally supported messages regarding what is known about the virus and what us residents could do to protect their health." when fear, rather than science, becomes the primary driver of evd policies, this will likely result in suboptimal care for patients with evd, unnecessary restrictions on civil liberties, or both. state-based proposals for -day quarantines of health-care workers and others returning to the united states from west africa lacked a scientific basis and imposed unnecessary restrictions on individuals. the us department of defense's -day quarantine, which applied to all defense department personnel returning from evdaff ected areas regardless of risk exposure, also lacked a basis in science, according to the director of health and human services, sylvia burwell. when quarantines represent a way to manage fear, not ebola, they do more harm than good. such measures not only place unfair restrictions on individuals, they also may dissuade health care professionals from contributing in the future to fi ghting the epidemic. avoiding this possibility requires carefully reviewing evidence on an ongoing basis. just as it is now ethically untenable and medically unjustifi able to deny life-supporting therapies to patients with human immunodefi ciency virus (hiv) infection,…only a few decades ago, the fear of hiv and the perception that aids was uniformly fatal led to an approach similar to that currently being taken for evd. when restricting individual liberties is necessary to protect the public health, the guiding principle should be a principle of least infringement. th is requires applying the least restrictive measures possible to protect the public's health. given the resource-intensive nature of providing evd care, demand for evd services may exceed the capacity of a western quaternary care hospital to respond if a signifi cant number of patients with evd were treated at a single hospital. when this occurs, a utilitarian framework should be used to maximize medical benefi t to all patients. triage is a common interpretation of a utilitarian framework applied to emergency medical treatment when resources are limited. triage assigns priority to patients with serious injuries who can be improved with relatively simple procedures but who will not improve without aid. diff erent consequentialist assessments might be appropriate in resource-poor areas, such as africa, that are responsible for treating many patients. another criterion that furnishes an ethical basis for allocating scarce resources is the quantity of resources a patient is expected to consume. this criterion is ethically justifi ed on utilitarian grounds as well, because it represents a means to achieving the greatest good for the greatest number of people. th e approach we propose does not base the distribution of limited resources on medical diagnosis or clinical judgment but instead on prioritizing those who are the most critically ill and can benefi t from less-intensive resource investments. for example, if patients with and without evd are similarly endangered, those patients who require less costly and risky interventions should receive resource priority. th is is not because of diagnosis, but because of the utilitarian value of saving the greatest number of lives. following the american college of chest physicians (chest) guidelines, we endorse the same criteria regardless of whether a patient's need arises from evd epidemic or unrelated conditions (eg, a motor vehicle accident). generally speaking, the principle of utility applies to all patients regardless of diagnosis. for example, if a hospital does not have enough staff or technology to provide rrt to all patients, priority should be assigned to patients with the best prognoses and greatest likelihood of benefi t from rrt; among patients with similar prognoses, priority should be assigned to those who require the fewest resources. in practical terms, the result of this approach may mean that a patient with evd would be denied rrt. to summarize, the focus needs to be on likelihood of benefi t, amount of resource consumed, and duration of need (which includes staff time away from any other patient care), rather than on specifi c diagnoses. th e ethical rationale for such an approach is a strictly utilitarian focus on benefi ts and burdens to aff ected parties. one controversial implication of using a utilitarian framework, such as triage, might be that health-care providers merit priority, both in the allocation of scarce life-saving resources and in protection against evd. th is is because they function as multipliers of societal benefi t during and after an evd epidemic. despite this possible implication, our model policy does not directly assign priority to patients with evd on the basis of occupation. instead, we affirm the equal worth and dignity of all patients, which places ethical constraints on the scope of utilitarian analysis. our proposed model policy is based on ethical principles and scientifi c evidence about evd. we appeal fi rst to the ethical principle of benefi cence, emphasizing the patient-centered duty to aid those who are sick. second, we invoke medical futility to argue that when a treatment offers an exceedingly poor likelihood or quality of benefi t, it should not be off ered. th ird, we stress that the obligation to avoid harm requires setting reasonable limits on caring for patients with evd. finally, when demand for resources exceeds an institution's capacity to meet that demand, the utilitarian-based principle of triage should govern the allocation of resources. we urge ongoing ethics discussion of the principles and policies that should govern communicable diseases more broadly. not only will natural disease outbreaks continue to occur, there is also heightened concern that biologic agents might be intentionally released as weapons. th e cdc recommended heightened surveillance for unusual disease occurrence or increased numbers of illnesses following the september terrorist attacks in the united states, identifying the following biologic agents as being of highest concern: anthrax, plague, smallpox, botulism, tularemia, fi loviruses (ebola virus, marburg hemorrhagic fever), and arenaviruses (lassa fever, argentine hemorrhagic fever, and related viruses). in response to the threat of bioterrorism, the us government continues to take precautions against infectious disease outbreaks, such as smallpox, even though the variola virus that causes smallpox disease was eliminated and no naturally occurring cases have been reported since . an emergency response policy is one of several steps necessary to ensure optimal patient care and minimize disease transmission in the face of a communicable disease outbreak. additional guidance addressing nonemergent safety protocols is needed to manage access to experimental therapies, , the use of placebo-controlled clinical trials during public health emergencies, the challenges of obtaining informed consent for collecting and sharing biospecimens in the context of a public health emergency, the safety of individuals who come into contact with deceased patients, and risk distribution among health-care facilities, health-care specialties, and health-care professionals. , middle east respiratory syndrome (mers) surgical protocol for possible or confi rmed ebola cases. american college of surgeons website assessment of the risk of ebola virus transmission from bodily fl uids and fomites ethicist calls cpr too risky in ebola ebola virus disease): diagnosis. centers for disease control and prevention website rethinking rescue medicine clinical presentation and management of severe ebola virus disease responding to ebola: questions about resuscitation american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care duty to treat or right to refuse? developing the duty to treat: hiv, sars, and the next epidemic : physician obligation in disaster preparedness and response american nurses' association, committee on ethics . health professions, codes, and the right to refuse to treat hivinfectious patients : th e use of quarantine and isolation as public health interventions fight or fl ight: the ethics of emergency physician disaster response news in context: ebola and aids comparisons. the hastings center website responding to ebola: health care professionals' obligations to provide care th e fragile web of responsibility: aids and the duty to treat the problem with rescue medicine wrong medicine: doctors, patients, and futile treatment beyond futility to an ethic of care ethical guidance on the use of life-sustaining therapies for patients with ebola in developed countries guidance paper: ebola treatment centre (etc): pregnant and lactating women practice advisory: care of obstetric patients during an ebola virus outbreak . american college of obstetricians and gynecologists website recommendations for breastfeeding/infant feeding in the context of ebola. centers for disease control and prevention website successful delivery of rrt in ebola virus disease president's commission for the study of bioethical issues . ethics and ebola: public health planning and response federal government response to ebola. senate appropriations committee hearing quarantine is being used to manage fear, not ebola. time magazine panic, paranoia, and public health-the aids epidemic's lessons for ebola doing today's work superbly well-treating ebola with current tools triage in medicine, part ii: underlying values and principles overwhelming casualties: medical ethics in a time of terror triage: care of the critically ill and injured during pandemics and disasters: chest consensus statement ethical considerations: care of the critically ill and injured during pandemics and disasters: chest consensus statement ethical resource distribution aft er biological, chemical, or radiological terrorism recognition of illness associated with the intentional release of a biologic agent smallpox disease overview randomised controlled trials for ebola: practical and ethical issues guidance for safe handling of human remains of ebola patients by hospital and mortuaries financial/nonfinancial disclosures: the authors have reported to chest that no potential confl icts of interest exist with any companies/ organizations whose products or services may be discussed in this article . key: cord- -riw xs j authors: van griensven, johan; de weiggheleire, anja; delamou, alexandre; smith, peter g.; edwards, tansy; vandekerckhove, philippe; bah, elhadj ibrahima; colebunders, robert; herve, isola; lazaygues, catherine; haba, nyankoye; lynen, lutgarde title: the use of ebola convalescent plasma to treat ebola virus disease in resource-constrained settings: a perspective from the field date: - - journal: clin infect dis doi: . /cid/civ sha: doc_id: cord_uid: riw xs j the clinical evaluation of convalescent plasma (cp) for the treatment of ebola virus disease (evd) in the current outbreak, predominantly affecting guinea, sierra leone, and liberia, was prioritized by the world health organization in september . in each of these countries, nonrandomized comparative clinical trials were initiated. the ebola-tx trial in conakry, guinea, enrolled patients by july ; no severe adverse reactions were noted. the ebola-cp trial in sierra leone and the evd trial in liberia have included few patients. although no efficacy data are available yet, current field experience supports the safety, acceptability, and feasibility of cp as evd treatment. longer-term follow-up as well as data from nontrial settings and evidence on the scalability of the intervention are required. cp sourced from within the outbreak is the most readily available source of anti-evd antibodies. until the advent of effective antivirals or monoclonal antibodies, cp merits further evaluation. convalescent blood or plasma transfusion has been used in clinical settings for > years [ ] . until the advent of antibiotic therapy, it was widely used for a range of bacterial and viral diseases. a recent meta-analysis suggests that it could have contributed to an absolute reduction in mortality of around % during the influenza epidemic [ ] . at present, hyperimmune globulin, manufactured from convalescent donors' plasma, is still employed as prophylaxis or treatment for certain infectious diseases (eg, measles, diphtheria, polio, hepatitis a and b) [ ] . passive antibody therapy is not a new intervention but a widely tested, safe, and proven prophylactic and therapeutic intervention. over the last years, convalescent plasma (cp) has been explored for the treatment of viral severe acute respiratory infections such as severe acute respiratory syndrome and (avian) influenza. a recent meta-analysis identified studies that indicated, overall, a % reduced risk in the odds of mortality, particularly if cp was administered early after symptom onset [ , ] . cp is currently being considered as treatment for middle east respiratory syndrome [ ] . for hemorrhagic fevers, well-documented, relatively recent experience stems from a randomized controlled trial comparing cp ( single unit of ml) with normal plasma against argentine hemorrhagic fever [ ] . mortality was . % among the patients who received cp compared to . % in the patients treated with normal plasma. of interest, a delayed neurological condition was observed in some patients after cp therapy, occurring several weeks after apparent cure. cp has also been explored against the hemorrhagic disease lassa fever, with conflicting results [ ] [ ] [ ] [ ] . the world health organization (who) guidelines recommend both convalescent whole blood (cwb) and cp for use against ebola virus disease (evd) [ ] . during evd outbreaks, both are local and readily available sources of anti-evd antibodies. blood transfusion is routinely done in all high-transmission countries involved in the current evd outbreak; however, plasma has numerous advantages in these settings. using apheresis, a single donor can give substantially more cp, up to ml/kg every weeks, compared with unit of ml whole blood (approximately ml plasma) every - months for cwb; hence, more patients can be treated. cp can be given intravenously over a much shorter time period ( minutes vs - hours) and hence is less demanding for healthcare teams in ebola treatment centers. the pathogen inactivation step during cp production increases the safety of the intervention. cp transfusion is also safer with fewer transfusion reactions; cp needs to be abo compatible, but there is no need for bedside cross-matching [ ] . additionally, cp can be stored for much longer periods. hyperimmune globulin has advantages compared with cwb and cp, as it is a concentrated and purified product [ ] . however, this product is presently not available against evd, and hence it has not been evaluated in the current ebola outbreak. nevertheless, it represents an interesting longer-term potential therapy, especially if the ongoing studies suggest efficacy of cp. recombinant monoclonal antibodies are currently being evaluated in sierra leone and guinea [ ] , but will not be discussed in detail given this article's focus on convalescent blood products. the successful use of zmapp (an antibody cocktail comprising ebola virus-specific recombinant monoclonal antibodies) for treatment of evd in non-human primate models, even when administration is delayed until days after a supralethal viral challenge, provides proof of concept of antibody-based therapy for evd [ ] . similarly, the use of immunoglobulin fractions from convalescent animals is effective for treating evd in nonhuman primates [ ] . earlier treatment attempts with monoclonal antibodies or immunoglobulins might have failed because antibody concentrations were too low, antibodies had too narrow a spectrum (eg, monoclonal only), or because treatment was not given repeatedly (zmapp is given times [days , , ]). early cwb studies with nonhuman primates failed to demonstrate efficacy when rhesus macaques were transfused immediately after challenge [ ] . there are no animal studies with convalescent plasma against evd. key questions include whether antibody titers are high enough in cp and cwb to be effective, and if single transfusion, as per current who guidelines, is sufficient. the exact kinetics of neutralizing antibodies in convalescent donors and variation between individuals are currently not well described. clinical data are limited. the most important study on cwb in evd reported on individuals treated during the kikwit outbreak in ; survived [ ] . however, this was an uncontrolled small study, with patients enrolled relatively late after onset of symptoms. moreover, several factors beyond an antibody-related effect could have contributed to the improved survival, such as improved hydration or the administration of other blood components such as clotting factors. moreover, a subsequent analysis after adjustment for age, sex, and number of days since onset of symptoms showed no survival benefit of cwb [ ] . one well-documented case occurred in when a laboratory technician survived evd after receiving plasma transfusions combined with interferon injections [ ] . several evd patients (mainly expatriates) have been treated with cwb, cp, or recombinant monoclonal antibodies during the current outbreak [ ] [ ] [ ] [ ] [ ] . however, most of these patients received multiple anti-evd interventions and high-quality supportive care, so it is not possible to assess the efficacy, if any, of passive antibody transfer. in conclusion, whereas the data on zmapp provide proof of concept, clinical data on and experience with convalescent blood products for the treatment of evd are very limited. consequently, who prioritized the need to evaluate cp in clinical trials, with the aim to determine its efficacy, safety, and feasibility. notably, these interventions can be organized by harnessing or increasing existing national capacities quickly within the affected countries, without the complications or limitations associated with shipping commercial products, which are often in limited supply. an overview of clinical trials is provided in table . the ebola-tx trial, in conakry, guinea, is designed to assess the feasibility, safety, and efficacy of cp against evd [ ] . survival at days after transfusion of patients treated with cp plus supportive care will be compared to that of patients receiving supportive care alone, in an open-label phase / , nonrandomized comparative study. all eligible and consenting patients of any age with confirmed evd (including pregnant women) are enrolled; exclusion criteria are limited to contraindications for cp or patients arriving in a close to terminal condition. available abo compatible plasma is given, within hours after diagnosis, on a firstcome, first-served basis. patients for whom there is no available compatible plasma are enrolled as concurrent controls, complemented with historical controls. the first plasma collection started on february , followed by the first cp administration on february . as of july , patients have been recruited. the main analysis is planned when a cohort of cptreated patients have reached day posttransfusion. due to the fluctuating number of new patients and the decline of the outbreak in guinea, it is difficult to estimate when this will happen. the ebola-cp consortium in sierra leone, which emerged out of the ebola-tx initiative, is conducting a parallel study in freetown using a similar protocol, crf, and data management. the first patient was recruited march as a control (no cp given); due to the declining outbreak in sierra leone, as of july , patients have received cp. the evd trial is a phase / pilot study with viral load changes as the primary outcome [ ] . children and pregnant women are excluded. the study started in monrovia in november but subsequently closed due to the decline in caseload. a total of cp-treated patients and controls were included. the ebola medical treatment team in the th regiment hospital freetown, sierra leone, has been administering cwb, as per who guidance, for compassionate use from december to march (http://awoko.org/ / / / sierra-leone-news-convalescent-blood-treatment-started/). a total of patients opted for cwb transfusion with included as controls. none of the ongoing clinical studies have reported findings. designing trials, and recruiting patients, to evaluate cwb and cp has been challenging. only ebola-tx has achieved a relatively high sample size (> cp-treated patients). the design that would provide the best evaluation would be a randomized trial in which one or other intervention would be compared with control patients not receiving the intervention. however, such randomized designs have proved unacceptable in the volatile settings of the current ebola outbreak, and researchers have at the early stages resorted to nonrandomized study designs [ ] . all cp trials were designed to include concurrent control patients. for example, in the ebola-tx trial, controls were to be patients presenting when no abo-compatible plasma was available. however, when the trial started, the supply of cp increased significantly and the number of patients decreased, resulting in sufficient supply of cp to treat nearly all patients. consequently, it will compare the mortality of treated patients with that of historical controls, with the inherent possibility of biased comparisons. key concerns in all trials regarded potential confounding factors including variations in patient characteristics, ebola virulence on presentation, and differences in standards of supportive care over time. for example, the systematic placement of intravenous access lines in patients for cp treatment could encourage more aggressive intravenous hydration during the trial period. how easy it will be to interpret the results of the trials will depend, to a large extent, on the size of the mortality reduction, if any, associated with the intervention. plasma transfusion is considered a relatively safe procedure, particularly if pathogen reduction is done. however, for use as a treatment of evd, there are additional considerations. safe production, storage, and distribution need to be organized in the affected countries. plasmapheresis technology needs to be available or introduced, including quality-assured testing for transfusion-transmissible infections and an effective cold chain, all of which have been major challenges in the currently affected west african countries. although standards for blood group typing are clearly defined in the national guidelines, errors can result from field realities, such as lack of resources, supervision, and poorly incentivized staff. additionally, weak systems of documentation can lead to poor or mistaken identification. the infection control environment of ebola treatment centers brings with it difficult operational challenges, both for care of patients and, in particular, for the implementation of clinical research. short and intermittent patient contact by staff in protective clothing, with potentially confused patients, is the norm. therefore, mistakes are more likely to occur, such as in patient identification, labeling of blood tubes, and request forms during sample collection and packaging. moreover, introducing the procedure for blood group typing into already overloaded evd diagnostic laboratories might engender additional errors. this can potentially increase the risks of adverse reactions due to preanalytical, analytical, or postanalytical errors. these errors could potentially lead to severe reactions if abo-incompatible plasma with high titers of hemolysins were administered. the ability to monitor patients for and to react to severe, acute adverse reactions is clearly limited by the environment of many ebola treatment centers. some (severe) transfusion reactions might erroneously be attributed to evd [ , ] . for instance, respiratory difficulties, often seen during evd, might be due to transfusion-related acute lung injury. patient management options for adverse events may also be limited. it has been suggested for a number of viruses, including ebola, that the transfer of antibodies might enhance pathogenicity, possibly by antibody-enhanced cell entry [ ] . although more recent studies have suggested that this is unlikely to have clinical significance, it still requires special attention and careful evaluation when employing cp, regardless of whether it is for clinical trials or compassionate use [ ] . no severe adverse reactions or safety risks for healthcare staff have been noted in the ebola-tx trial by july . while this suggests that cp can be employed safely for evd treatment, the use of such treatment, if found efficacious, should be evaluated in noncontrolled settings before introducing it as a standard of care in public health facilities. the quality of blood transfusion services in many west african countries is generally poor, and in many countries, plasma production is not routinely performed [ ] . during the evd out-break, effective plasmapheresis teams were assembled relatively quickly, mainly in mobile plasma units or "plasma mobiles" (http://www.gatesfoundation.org/media-center/press-releases/ / /support-to-ebola-affected-countries-announcement), and national blood transfusion teams trained. this was made possible by the substantial funding made available through international research consortia. as the situation dictated an emergency response, the plasmapheresis material introduced for use in the present trials is unlikely to be an optimal choice for the concerned national transfusion centers. a transition to simpler, nonautomated systems might be indicated. furthermore, pathogen reduction is an expensive procedure and unlikely to be a priority for resource-constrained settings, where the prerogative is the provision of safe basic blood banking services. the experience of the present trials, which has identified the need to further improve the overall quality of blood banking centers in all countries, should result in longer-term capacitybuilding projects once the outbreak is contained. the use of convalescent blood products is further complicated by the requirement to carefully and properly manage the engagement of ebola survivors, who are often stigmatized in their communities. in many west african countries there is reticence toward blood collection, donation, and transfusion, based on superstitions and beliefs in the community [ , ] . experience during the - outbreak suggests that if there are appropriate community consultations and discussions, there is a reasonable acceptability among plasma donors, surviving patients, risk with abo incompatibility acceptability in evd context and their family members, at least in the short term. however, a better understanding of plasma donor motivation is required to ascertain whether possible degrees of coercion have occurred. in all high-transmission countries, evd survivors have organized themselves into survivor associations. although this has probably substantially eased donor mobilization, more indepth assessments of their potential role are merited. other key concerns include confidentiality and privacy, especially if members of the survivors association are involved in the recruitment process. additionally, confronting individuals recently recovered from evd with positive serological tests for other infections can have negative consequences. lack of free access to care for infections such as hepatitis b and c further compounds the situation [ ] . hence, longer follow-up and more in-depth anthropological assessments among plasma donors and patients are required to further document the acceptability and feasibility of cp as evd treatment. it has been suggested that involving survivors as donors in a potentially life-saving treatment could support their social reintegration and reduce stigma, but evidence for this is currently lacking. although hopefully there will not be another ebola outbreak on the scale of the present one, it would be possible to stockpile plasma for emergency use. there are currently > ebola survivors in the high-transmission countries. a single donor, donating ml every weeks, could provide sufficient plasma to treat around patients. with regular donors (approximately % of the potential total), a total of treatments would potentially be available. prequalification of donors with high titers of neutralizing antibodies would make the process most efficient. such scaling up of cp would require either decentralized plasma production or safe transport and storage of cp from a central location to more remote areas. blood transfusion regulations recommend that people who received a blood transfusion should not be permitted to donate blood for months after the date of transfusion, mainly related to the risk of pathogen transmission. applying this to evd survivors following cp treatment would seriously reduce the donor pool. however, if cp is shown to have a substantial effect, the benefits of using such patients as donors would probably outweigh potential risks. it should also be confirmed that cp-treated patients develop sufficient level of neutralizing antibodies against the virus, particularly if treated early in the disease course. the logical next step is to produce hyperimmune globulins from the donated plasma, and several initiatives are focusing on this. as purified and concentrated products, hyperimmune globulins are generally considered to be safer and with higher, less variable antibody titers than cp (table ) . they can also be stored for prolonged periods. animal production of hyperimmune globulins is also under exploration (http://www.faben techcom/technologie/technology/). pending the building up of such expertise within africa, production could be outsourced. current field experience supports the use of cp against evd as acceptable, feasible, and safe. efficacy data are pending. in consideration of the study design limitations described in this article, these trials may not yield definitive data on the extent to which such treatment reduces case fatality rates. however, it is expected that they will, at minimum, provide some indication of the utility of cp and the challenges in delivering such treatment, in future trials. additional research on cp, hyperimmune globulins, and monoclonal antibodies in animal and clinical studies is required to identify the optimal treatment regimen and better understand the mechanism of action. long-term studies are also required to document better the feasibility and acceptability of cp donation outside of a research setting, to assess the willingness of survivors to become cp donors and to identify any negative immunological, medical, or psychosocial effects of repeated cp donations. longer followup of cp treated patients is also indicated to detect late adverse events. although hyperimmune globulins and recombinant monoclonal antibodies have several advantages, the use of cp sourced from within an outbreak is arguably the most readily available source of anti-evd antibodies and will always have the advantage that it is likely to be active against the circulating strain. in each new outbreak, available hyperimmune globulins or monoclonal antibodies will first have to be evaluated against the causative strain and possibly followed by the production of a new product, all of which takes time. until the advent of potent, safe, affordable, and effective antivirals, and the development of effective vaccines, the use of convalescent blood products should remain part of the potential response to evd. financial support. the ebola-tx project is funded by the european union's horizon research and innovation program (grant agreement number ). additional funding is provided by the department of economy, science and innovation of the flemish government. potential conflicts of interest. all authors are involved in the ebola-tx trial. all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. passive antibody therapy for infectious diseases meta-analysis: convalescent blood products for spanish influenza pneumonia: a future h n treatment? polyclonal immunoglobulins and hyperimmune globulins in prevention and management of infectious diseases the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis hark back: passive immunotherapy for influenza and other serious infections passive immunotherapy with dromedary immune serum in an 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enhance immunoglobulin supply in developing countries emergency evaluation of convalescent plasma for ebola viral disease (evd) in guinea clinical trial to evaluate the efficacy and safety of convalescent plasma for ebola treatment (evd ). nct randomised controlled trials for ebola: practical and ethical issues acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with ebola virus disease antibody-dependent enhancement of ebola virus infection evidence against an important role for infectivity-enhancing antibodies in ebola virus infections ebola: a call for blood transfusion strategy in sub-saharan africa blood as medicine: social meanings of blood and the success of ebola trials community perception and beliefs about blood draw for clinical research in ghana large-scale convalescent blood and plasma transfusion therapy for ebola virus disease key: cord- - w elfro authors: tambo, ernest; ugwu, emmanuel chidiebere; ngogang, jeane yonkeu title: need of surveillance response systems to combat ebola outbreaks and other emerging infectious diseases in african countries date: - - journal: infect dis poverty doi: . / - - - sha: doc_id: cord_uid: w elfro there is growing concern in sub-saharan africa about the spread of the ebola virus disease (evd), formerly known as ebola haemorrhagic fever, and the public health burden that it ensues. since , there have been , suspected and laboratory confirmed cases of evd and the disease has claimed , cases and fatality in west africa. there are certain requirements that must be met when responding to evd outbreaks and this process could incur certain challenges. for the purposes of this paper, five have been identified: (i) the deficiency in the development and implementation of surveillance response systems against ebola and others infectious disease outbreaks in africa; (ii) the lack of education and knowledge resulting in an evd outbreak triggering panic, anxiety, psychosocial trauma, isolation and dignity impounding, stigmatisation, community ostracism and resistance to associated socio-ecological and public health consequences; (iii) limited financial resources, human technical capacity and weak community and national health system operational plans for prevention and control responses, practices and management; (iv) inadequate leadership and coordination; and (v) the lack of development of new strategies, tools and approaches, such as improved diagnostics and novel therapies including vaccines which can assist in preventing, controlling and containing ebola outbreaks as well as the spread of the disease. hence, there is an urgent need to develop and implement an active early warning alert and surveillance response system for outbreak response and control of emerging infectious diseases. understanding the unending risks of transmission dynamics and resurgence is essential in implementing rapid effective response interventions tailored to specific local settings and contexts. therefore, the following actions are recommended: (i) national and regional inter-sectorial and trans-disciplinary surveillance response systems that include early warnings, as well as critical human resources development, must be quickly adopted by allied ministries and organisations in african countries in epidemic and pandemic responses; (ii) harnessing all stakeholders commitment and advocacy in sustained funding, collaboration, communication and networking including community participation to enhance a coordinated responses, as well as tracking and prompt case management to combat challenges; (iii) more research and development in new drug discovery and vaccines; and (iv) understanding the involvement of global health to promote the establishment of public health surveillance response systems with functions of early warning, as well as monitoring and evaluation in upholding research-action programmes and innovative interventions. please see additional file for translations of the abstract into the six official working languages of the united nations. the growing public health concern and the burden of ebola outbreaks in the absence of an effective drug and vaccine for the dreadful and deadly outbreak caused by the ebola virus disease (evd), formerly known as ebola haemorrhagic fever, there is growing concern for its public health burden in sub-saharan africa. since , there have been , suspected and laboratory confirmed cases of evd, including cased on the ongoing disease outbreak has claimed lives in west africa [ ] . this part of the world is persistently confronted with this fatal disease which has an incubation period of two to days (averagely - days). symptoms range from, firstly, fever and fatigue before descending into headaches, vomiting, violent diarrhoea, then multiple organ failure and massive internal bleeding [ , ] . ebola typically begins in remote places and can be distributed via hospitals/ healthcare centers or within the community as it takes several infections before the disease is ascertained. the prevalence, morbidity and case fatality of chronological evd outbreaks showed the persistent resurgence in different regions in sub-saharan africa (see figure ) . ebola outbreaks have a case fatality rate of - %, yet no specific drug or vaccine is available for people and/or animals hosts. as of august , the cumulative number of cases attributed to evd in the four countries stands at including deaths. the distribution and classification of the cases are as follows: guinea, cases ( confirmed, probable, and suspected), including deaths; liberia, cases ( confirmed, probable, and suspected), including deaths; sierra leone, cases ( confirmed, probable, and suspected), including deaths and nigeria, cases ( confirmed, probable, and suspected) including death. between the and july , a total of new cases (laboratoryconfirmed, probable, and suspect cases) of evd, and deaths, were reported from the four countries as follows: guinea, new cases and deaths; liberia, new cases and deaths; sierra leone, new cases and deaths; and nigeria, new case who died [ ]. the outbreak is expected to last longer if proper diagnostic tools and rigorous integrated active surveillance response systems are not rapidly established and instituted [ ] . therefore, the following requirements for rapid, scalable and sustainable responses to evd and other outbreaks across african countries, and globally, have been identified. first, the need to urgently recognise and coordinate outbreak action-responses in affected african countries and in cross-border neighbours, as well as collaboration with those that experienced outbreaks in the past, is vital. overall, ebola virus socio-ecology systems have shown to be linked by direct and indirect transmission through contact with objects from patients. for example, the blood or secretions of an infected person or objects that have been contaminated with infected secretions can reach humans from a variety of hosts/sources: naïve infected populations, infected wildlife, fruit and vegetable bats and the handling of infected fruit bats, monkeys, chimpanzees, gorillas, forest antelopes and porcupines are all possible natural hosts (whether ill or dead or found in the jungle or rainforest) [ , ]. thus, tracking, mapping, reporting and documenting veterinary public health zoonosis surveillance responses, the behaviour and medical history of butchers and poachers, as well as agro-livestock business trading are imperative to be able to establish integrated community-based and national comprehensive early warning and outbreak surveillance response systems. second, understanding the unending transmission dynamics and resurgence is essential to actively identify and map transmission foci and local micro-epidemiological situations, which can lead to implementing prompt, effective response interventions tailored to specific local settings. hence, active early warnings approach under the framework of a surveillance response system both for veterinary and human public health should be established and implemented. this system could include, for example, a ban on bush meat consumption, a ban on public places and markets, a reinforcement of safety and inspection regulations on food and fruit eating bats and examining bat migration as well as other animal-household drivers and risk factors [ , ] . third, instituting electronic-based reporting systems based on advances in information and communication technologies (icts) is crucial as already about % of the west african affected populations use mobile phones (mhealth or ehealth). building a local network (e.g. whatsapp) or crowdsourcing data for targeted active responses, as well as the implementation of a geographical information system (gis), are necessary spatial-temporal mapping and decision-making support systems to contain ebola outbreaks. lessons learnt from other outbreaks including cholera, h n and h n avian influenza, severe acute respiratory syndrome (sars), lassa fever, the middle east respiratory syndrome (mers), dengue pandemic and the human-animal with environmentalclimate interface in africa and elsewhere can assist in setting benchmarks for monitoring epicentre/focal early warning alert, incidence and prevalence as well as effective surveillance response interventions measures [ , ] . meanwhile, modelling factors and trends in different changing transmission scenarios could also yield better tactics, as well as strategic evidence not only for policy support, but also for direction, planning and implementation of national and regional early alert and surveillance response systems to control and prevent sentinel sites [ ] . following from the aforementioned three challenges and requirements to respond to evd outbreaks in africa, the following actions are recommended to combat evd as well as other emerging infectious diseases. ebola was first reported in in sudan and congo and named after the river where it was identified. it was later reported in gabon, central africa. the genus ebolavirus is one of three members of the filoviridae family (filovirus), along with the genus marburgvirus and the genus cuevavirus, and comprises five distinct species, of which zaire ebolavirus, sudan ebolavirus and bundibugyo ebolavirus are mostly associated with the major evd outbreaks in africa. reston ebolavirus and taï forest ebolavirus are mostly reported in the asia-pacific region, especially philippines and the people's republic of china, but no symptoms or deaths in humans from these have been reported to date [ ] . the disease outbreak has persisted over the years across central, east and southern africa. on march , , the first case of an outbreak was identified in guinea, west africa, witnessing a total of cases with fatalities, as it spread beyond the remote rural areas to the capital city of conakry. soon after the outbreak was identified, it appeared across the border in the small nation of liberia on march , . this country was the least hit with cases and fatalities thus far. later, it was also identified in sierra leone in late may , just as it appeared the outbreaks in guinea and liberia were winding down. it has since spread to at least two sierra leone districts with cases claiming at least lives, including deaths of new cases within just four days. similarly, between and july , new cases and deaths were reported from liberia and sierra leone. in guinea, new cases and deaths were reported during the same period and one death in nigeria [ ] (see table ). understanding african cultural and customs practices and how they affect psychosocialbehavioural attitudes towards ebola outbreaks african economic community according to the world bank, . each country consists broadly of two distinct zones: a sahelian zone (north), largely landlocked, and a more humid, forested coastal zone (south), with the literacy rate varying from - % (see figure ). similar to the conception and spread of the hiv/aids pandemic in africa, one of the main obstacles in reducing the distribution of ebola has been the widespread ignorance, lack of knowledge and potential panic over evd, considered to be a 'satanic or bewitched' disease, leading to trepidation, isolation, dignity impounding, stigmatisation and ostracism from associated socio-ecological and public health consequences. recently, local residents of the sadialu village in sierra leone were sheltering those infected with ebola, refusing to go to or escaping from hospitalisation referred as "death sentence", and hiding from the local health centre due to circulating beliefs, myths and rumours that the interventions being administered to patients were actually causing the disease (see figure ). such consequences and misconceptions are proscribed in the international health regulations (ihr), human rights laws, as well as the helsinki and the who declarations. these detail the challenges and opportunities that ebola and other infectious diseases are currently facing, including neglected tropical disease (ntd) prevention, control and management, as well as health system coverage and service delivery bottlenecks. harnessing all stakeholders' collaboration, communication and networking, including communities, is essential for improving and nurturing community participation, informal and formal health education, ownership and empowerment of the programmes, and patient independence and dignity, as well as ensuring human rights for all ages at all levels in order develop a productive and sustainable african continent and achieve the millennium development goals (mdgs) and global health. hence, accelerating the response through provision of minimum essential information on risk communication for behavioural impact, developmental communication and health promotion/education personnel and community, working in multidisciplinary to respond to the disease outbreak, will be very useful for adequate and appropriate national staff and other national resources to the field operational epidemiologists, clinicians, and public health officers in fostering positive behavioural changes while respecting cultural practices, and impact on local contexts and outbreak dynamics, prevention and control interventions and scaling up outbreak containment measures, especially effective contact tracing. unfortunately, several countries in africa, as well as governmental and research institutions, are inadequately equipped in diagnostics, tracking, active reporting, prompt healthcare delivery, and accessible and affordable treatment to combat the ebola infection and other emerging infectious diseases. the development of new tools, strategies and approaches, such as improved diagnostics and novel therapies including vaccines, is needed to prevent, control and contain ebola as well as sars, bird flu, lassa fever, dengue and mers outbreaks. hence, the urgent need to develop and implement early warning alert and active surveillance response systems for emerging infectious diseases and the control and elimination of ntds, as well as early warning and emergency systems, cannot be overemphasised. the prerequisites for fighting and containing the transmission and saving lives include concerted actions to empower communities through mobilisation, communication and participation; formal and informal education; and training of community and environmental health professionals. timely and effective reporting, documentation and communication of incidence and prevalence by all stakeholders including the health ministries, international and local ngos, un agencies, religious leaders, who regional and partners (cdc, msf, unicef, ifrc) continue to work together through the sub-regional ebola outbreak coordination center (seocc), global health institutions and other stakeholders are paramount in early containment response [ ] . who does not recommend any travel or trade restrictions is applied to guinea, liberia, sierra leone or nigeria, based on the current information available. moreover, people who don't have the knowledge should be educated on how to protect themselves. also important is the prompt quarantining of the sick and the dead in line with the african customs and burial traditional, cultural myths and practices, as it is believed in such cultures that corpses are still contagious and customary transmits the disease. there is an urgent necessity to strengthen the primary healthcare system, and develop more sensitive serological and molecular diagnostic tools, as well as innovative methods and approaches to assess vulnerability in agreement with current practices (see figure ). this requires further research and development (r&d), capacity building based on international best practices for containing public outbreaks, the drafting of standard processes and operating procedures, biorisk management as samples from patients and animals are an extreme biohazard risk, thorough adherence to the who global alert and response operations, and outbreak communication guide-lines. moreover, maximizing the advances in genomic, biotechnological and communication technologies provides efficient and improved surveillance tools for early warning system prognostic, monitoring and evaluation control and prevention of outbreaks; these should be based on preventing the source as ascribed in the 'one world-one health' standpoint [ , ] . in addition, intensive efficacy and pharmacovigilance assessment of these interventions including diagnostics, drugs and vaccines against ebola and other emerging infectious diseases including ntds must be carefully re-evaluated, and the cut-offs determined and monitored over time, in addition to enhance cross-border collaboration and strengthen effective coordination across african government and populations [ ] [ ] [ ] . real-time active surveillance response systems, research priorities and innovative mechanisms for outbreaks include the development of tools targeting early active diagnosis especially at the onset and during the low level of transmission; tracking and mapping; monitoring human and host population migration; forecasting outbreaks based on risk factors; assessment of indicators and minimal essential datasets to guide evidence decision making; strategic planning and effective control; and prevention programmes and response packages tailored to local settings [ , ] . experiences and lessons learnt from outbreaks in developed nations could be shared with limited-resource countries so that they can to establish early warning and surveillance response systems [ ] . irrefutably, national and regional inter-sectorial and trans-disciplinary approaches must be adopted and related to ministries and organisations in order to build innovative early warning system surveillance response systems through fostering capacity building and training on outbreaks and emerging infectious disease prevention, control and elimination. it is also imperative to understand global health involvement and governance, establish monitoring and evaluation (m&e) of research for action programmes, as well as increase funding to support efforts of existing and new consortiums and research projects in africa. furthermore, there is need to analyse the socio-economic and cultural factors, the status of prevailing health systems, and the risk factors and determinants of the emergence and spread of outbreaks in africa. reliable and well-organised monitoring, the establishment of giss and appraisals of cost-effectiveness in an integrated national health system (with a care management approach) will eventually improve evidence information for policy-makers [ ] . in turn, they can make decisions and guide implementers of health programmes to achieve beneficial and innovative sustainable global public health interventions, quality healthcare outcomes and economic prosperity. consolidating and harmonizing the technical support at local, country, regional, and international level is required in mobilizing the international community in support of national efforts in epidemic and pandemic prevention and control. hence, developing, scaling up and strengthening all aspects of the outbreak surveillance response system including contact tracking, public information and community mobilization, case management and infection prevention and control, and effective coordination. references . who: ebola virus disease, west africa-update disease outbreak news elimination of tropical disease through surveillance and response surveillance-response systems: the key to elimination of tropical diseases improving the performance of outbreak detection algorithms by classifying the levels of disease incidence prioritizing research for "one health -one world need of surveillance response systems to combat ebola outbreaks and other emerging infectious diseases in african countries no funding body supported this study. additional file : multilingual abstracts in the six official working languages of the united nations. the authors declare that they have no competing interests.authors' contributions et conceived, collected and analysed the data, and drafted the manuscript. et, ecu and jyn provided additional information. all authors read and approved the final manuscript. key: cord- - skgb eu authors: chowell, gerardo; nishiura, hiroshi title: transmission dynamics and control of ebola virus disease (evd): a review date: - - journal: bmc med doi: . /s - - - sha: doc_id: cord_uid: skgb eu the complex and unprecedented ebola epidemic ongoing in west africa has highlighted the need to review the epidemiological characteristics of ebola virus disease (evd) as well as our current understanding of the transmission dynamics and the effect of control interventions against ebola transmission. here we review key epidemiological data from past ebola outbreaks and carry out a comparative review of mathematical models of the spread and control of ebola in the context of past outbreaks and the ongoing epidemic in west africa. we show that mathematical modeling offers useful insights into the risk of a major epidemic of evd and the assessment of the impact of basic public health measures on disease spread. we also discuss the critical need to collect detailed epidemiological data in real-time during the course of an ongoing epidemic, carry out further studies to estimate the effectiveness of interventions during past outbreaks and the ongoing epidemic, and develop large-scale modeling studies to study the spread and control of viral hemorrhagic fevers in the context of the highly heterogeneous economic reality of african countries. background a complex epidemic of zaire ebolavirus (ebov) has been affecting west africa since approximately december , with the first cases likely occurring in southern guinea [ ] . the causative ebola strain is closely related to a strain associated with past ebov outbreaks in central africa [ ] and could have been circulating in west africa for about a decade [ ] . however, the current epidemic was not identified until march [ ] , which facilitated several transmission chains to progress essentially unchecked in the region and to cross porous borders with neighboring sierra leone and liberia and seed a limited outbreak in nigeria via commercial airplane on july [ ] . the world health organization declared the ebola epidemic in west africa a public health emergency of international concern on august [ ] , with exponential dynamics characterizing the growth in the number of new cases in some areas [ ] [ ] [ ] [ ] [ ] . economic and sociocultural factors together with the delay in identifying the outbreak in urban settings have hindered a timely and effective implementation of control efforts in the region [ , ] . remarkably, the current size of the ongoing ebov epidemic far surpasses the total number of cases reported for all previous ebola outbreaks combined. a total of , cases, with , deaths, have been reported to the world health organization as of september . a serious shortage of timely resources in the region is the key factor responsible for the onset and disproportionate scale of the ongoing epidemic in west africa [ ] . in particular, the epidemic is unfolding in a region characterized by limited public health infrastructure including: ( ) a lack of essential supplies to implement infection control measures in health care settings; ( ) scarcity of health care workers and staff to manage a growing case burden and carry out essential contact tracing activities to find new cases quickly so that these can be effectively isolated [ ] ; and ( ) the absence of epidemiological surveillance for the timely identification of case clusters [ , ] . containing the ongoing epidemic poses an unprecedented challenge as the virus has moved from guinea to reach urban areas after crossing the unprotected borders of neighboring liberia and sierra leone. a major coordinated operation on the ground is needed to limit the geographic extension of the epidemic. the causative agent of ebola virus disease (evd) is an rna virus of the family filoviridae and genus ebolavirus. five different ebolavirus strains have been identified, namely zaire ebolavirus (ebov), sudan ebolavirus (sudv), tai forest ebolavirus (tafv), bundibugyo ebolavirus (bdbv) and reston ebolavirus (restv), with fruit bats considered as the most likely reservoir host [ ] . the great majority of past ebola outbreaks in humans have been linked to three ebola strains: ebov, sudv and bdbv [ ] . the ebola virus, ebov, (formerly designated zaire ebolavirus), the deadliest of the five ebolavirus strains, was first identified in in zaire (now the democratic republic of congo) and its name was derived from the ebola river located near the source of the first outbreak. past ebola outbreaks have been reported on average every . years [ ] , with a total of prior outbreaks generating over reported cases [ ] . a recent study has estimated million people distributed in areas of central and west africa to be at risk of ebola [ ] . ebola is characterized by a high case fatality ratio which was nearly % in a past outbreak [ ] . after an incubation period mostly ranging from to days, nonspecific symptoms appear, including sudden onset of fever, weakness, vomiting, diarrhea, headache and a sore throat. a fraction of patients may later develop severe internal and external hemorrhagic manifestations and experience multiple organ failures [ ] . except for restv, all other ebola strains are pathogenic to humans. human outbreaks may stem from direct human exposure to fruit bats or intermediate infected hosts that primarily comprise non-human primates (that is, gorillas, chimpanzees and monkeys). human epidemics subsequently take off by direct human-to-human contact via bodily fluids or indirect contact with contaminated surfaces. hence, stopping ebola transmission should be feasible when the cases are detected early and managed properly, because this virus is not transmitted through the air or water [ ] . nevertheless, ebola has been shown to spread through the air under carefully controlled laboratory conditions [ ] . hence, amplification of human-to-human transmission can result in the presence of suboptimal infection control measures in healthcare settings [ ] [ ] [ ] . unsafe burials that involve direct contact with ebola-infected bodies also pose a major infection risk [ ] . a review of key epidemiological parameters of evd and our current understanding of the transmission dynamics and the effect of basic control interventions against this disease would be useful for guiding and assessing the potential effectiveness of control interventions during ebola outbreaks. specifically, here we review epidemiological data from past ebola outbreaks including the basic reproduction number, the serial interval and the case fatality ratio. subsequently, we carry out a comparative review of mathematical models of the spread and control of ebola in the context of past and the ongoing epidemic in west africa. we show that mathematical modeling offers useful insights into the risk of a major epidemic of evd and the assessment of the impact of basic public health measures on disease spread. we illustrate the effects of demographic characteristics, such as the effective population size, size of spillover event (for example, details of initial conditions), baseline infection control measures in health care settings, and the timing of initiation of control interventions including enhancing the effectiveness of isolating infectious individuals, contact tracing to bring infectious individuals into isolation and social distancing interventions in the community. due to the relatively few past ebola outbreaks, available epidemiological data to infer the natural history parameters of evd remain limited. moreover, past outbreaks have been caused by different virus strains, making it difficult to judge whether a certain observed epidemiological characteristic is unique to the causative strain. here, we extract published evidence and review ebola epidemiological parameters from the literature, integrating estimates of the basic reproduction number, the asymptomatic ratio, the incubation period, the latent period, the symptomatic period, the infectious period, the serial interval and the case fatality ratio. the basic reproduction number, r , is interpreted as the average number of secondary cases caused by a typical infected individual throughout its entire course of infection in a completely susceptible population and in the absence of control interventions [ , ] . in the context of a partially susceptible population owing to prior exposure or vaccination, the (effective) reproduction number, r, quantifies the potential for infectious disease transmission. if r < , transmission chains are not self-sustaining and are unable to generate a major epidemic. by contrast, an epidemic is likely to occur whenever r > . when measured over time t, the effective reproduction number r t , can be helpful to quantify the time-dependent transmission potential and evaluate the effect of control interventions in almost 'real time' [ ] . in summary, r is regarded as a summary measure of the transmissibility of infectious diseases, playing a key role in determining the required control effort (for example, intensity of quarantine and isolation strategies). r could also be useful for guiding the numbers of antivirals and vaccines that would be needed to achieve control whenever these are available. r has been estimated for prior evd outbreaks in central africa using mathematical modeling and epidemiological data for two ebola outbreaks, namely the outbreak in democratic republic of congo and the uganda outbreak, respectively [ , ] . unlike the ongoing epidemic in west africa, past outbreaks in central africa have been confined to relatively rural and isolated areas without spreading to urban sectors which facilitated the effective implementation of control interventions. using a homogenous mixing seir (susceptible-exposed-infectious-removed) model that accounted for a gradual decay in the transmission rate at the start of interventions, chowell et al. [ ] estimated r at . [ ] : while allowing for homogeneous mixing, the study took into account three different transmission settings, that is, transmissions in community, hospital settings and during funerals. r was estimated at . for congo, and . for uganda, , but estimates showed substantial uncertainty. transmission from burials alone accounted for . secondary transmissions in congo while community transmission in uganda accounted for . secondary transmissions. variability in r estimates across studies can be attributed to differences in model structure and underlying assumptions. an assessment of r based on the growth rate of the ebola epidemic in west africa a quick look at the ongoing epidemic in west africa without delving into a too detailed analysis permits us to grasp the level of r for the ongoing ebola outbreak. assuming that the early epidemic data in sierra leone and liberia are sufficient to be characterized by exponential growth dynamics, with growth rate r, the incidence (that is, the number of new cases at calendar time t) is modeled as where k is a constant. as the observed data are cumulative i(t), we integrate the above equation from the starting time of exponential growth t to the latest time t, that is, it should be noted that the cumulative number of cases does not follow a single exponential growth term. assuming that the observed number of cases is poisson distributed, the maximum likelihood estimate for r for liberia is estimated at . ( % confidence interval (ci): . , . ). the growth rate in sierra leone is largely divided into two phases with a greater growth rate in the early phase (which could reflect initial case clusters in hospital settings). hence, r is estimated at . ( % ci: . , . ) and . ( % ci: . , . ) for the early and late phases, respectively (figure a) . assuming that the mean generation time is days (with standard deviation . days) based on contact tracing data from an outbreak in uganda [ ] (see below), r for liberia is estimated at . ( % ci: . , . ). for sierra leone, r is . ( % ci: . , . ) and . ( % ci: . , . ) for the early and late phases, respectively (figure b) . estimates in liberia and the late phase of sierra leone are roughly consistent with those published by chowell et al. [ ] . a comparison of the growth trends for past outbreaks in central africa (congo and uganda ) with the ongoing epidemic in liberia is shown in figure . recent studies have started to shed light on the transmission potential of the ongoing evd epidemic. specifically, three studies have estimated the basic reproduction number of evd in the range of . to . [ , , ] . althaus [ ] employed an seir model with the time-dependency of the reproduction number to capture effects of control interventions, following the model by chowell et al. [ ] ; analyzing the country-specific data independently for each country, the estimates were . for guinea, . for sierra leone and . for liberia [ ] . gomes et al. [ ] explicitly accounted for the risk of international spread, and the basic reproduction number ranged from . to . . more importantly, this study employed a global epidemic model with mobility data, indicating that the short-term risk of international spread to outside africa is small and that the expansion of the ongoing epidemic is more likely to occur in african countries [ ] . moreover, fisman et al. estimated r at . using a two-parameter mathematical model that describes the epidemic growth and control [ ] . real-time estimation of the effective (time-dependent) reproduction number revealed estimates in line with r estimates derived from other studies. for instance, by measuring temporal variations in the epidemic growth rate during periods of epidemic growth, the reproduction number was approximated based on a classic formula of r for the seir model, which provided estimates in the range of . to . [ ] . a different modeling study accounted for both local transmission and transnational spread across severely affected countries using a multivariate renewal process model which allowed the derivation of global and country-specific estimates of the reproduction number [ ] . this study indicated that the effective reproduction number r t from june to august ranged from . to . in sierra leone and liberia. hence, control could be reached by halting over half of the secondary transmissions per primary case whenever the reproduction number is below [ ] . moreover, it is worth noting that the exponential growth in ebola incidence is placing great pressure on healthcare facilities, which could affect time-and spacedependent variations in transmission dynamics and the surveillance system [ ] . the analysis of available data using mathematical modeling should, therefore, carefully assess the quality and consistency of the surveillance system employed to collect epidemiological data. hence, mathematical models should ideally be tied to characteristics of the surveillance system as much as possible to avoid potential bias [ ] . for comparison with other filoviruses, the r for the marburg fever outbreak in angola has been consistently estimated at . using two different statistical modeling approaches [ , ] . for comparison with other infectious diseases transmitted by direct contact, r has been estimated at . for an outbreak of acute hemorrhagic conjunctivitis in mexico [ ] . in contrast, for respiratory infections, the reproduction number has been estimated for the sars outbreaks in in the range . to . based on fitting transmission models to the progression of weekly cases prior to the start of control interventions [ , ] , in the range . to . for seasonal influenza [ ] , . to . for influenza pandemics [ ] [ ] [ ] [ ] [ ] [ ] , for pertussis, for measles [ ] and . to . for meningococcal meningitis [ ] . asymptomatic infection with ebola virus is known to occur in a certain fraction of exposed individuals [ ] . by analyzing the antibody responses among asymptomatic close contacts of symptomatic patients, leroy et al. found that ( . %) developed both immunoblobulin m (igm) and igg responses to ebola antigens. however, the study subjects were only those who experienced close contacts, and an estimate of asymptomatic ratio for the general population was not obtained. the majority of cases developed illness to days after infection. a classical study of the zaire strain [ ] indicated that the mean incubation period, that is, the mean length of time from infection to illness onset, is . days with the % quantile days. reanalyzing the data set of household contacts during the ebola outbreak in the democratic republic of congo in , eichner et al. estimated the mean incubation period at . days (with standard deviation . days) [ ] . the fitted lognormal distribution is redrawn in figure a the relationship between the exponential growth rate and the corresponding reproduction number for evd based on a weibull distributed generation time with shape and scale parameters of . and . , respectively. arrows indicate the uncertainty range ( % confidence interval) of the exponential growth rate estimated from the corresponding epidemic data. months of the ongoing ebola epidemic, a recent study estimated the mean incubation period at . days with no significant variation across the affected west african countries [ ] . the serial interval defined as the time from illness onset in the primary case to illness onset in the secondary case [ ] , has been relatively well observed for evd based on household or contact-tracing studies. a household study during the outbreak in drc indicated that the minimum serial interval was days, while the maximum was days [ ] . findings based on contact tracing data for the outbreak in uganda in were roughly consistent with those derived from household data [ ] : mean (sd) and median (quartiles) estimates for the serial interval were . ( . ) and . ( to ) days, respectively. figure b shows the serial-interval distribution along with a fitted weibull distribution with scale and shape parameters estimated at . ( % ci: . , . ) and . ( % ci: . , . ), respectively. the cramér-von mises goodness-of-fit test did not reveal significant deviations between the observed data and fitted model distribution (w = . , p = . ). this estimate is in good agreement with that derived from data of the first months of the ongoing epidemic in west africa, which has been estimated at . ± (sd = . ) days [ ] . this distribution is key to quantifying the reproduction number using the exponential growth rate of cases during the early stage of an epidemic, because the conversion from the growth rate of cases to the reproduction number requires estimates of the generation time distribution [ ] which is known to be informed by the serial interval and the incubation period [ ] . incidence data for the outbreaks in central africa are shown according to the dates of symptoms onset while the weekly incidence curve for the epidemic in liberia comprises total cases based on the daily epidemic curve estimated in [ ] . other parameters associated with the time course of evd have not been rigorously ascertained. however, according to bayesian model-based estimates from a past ebola outbreak [ ] , the mean latent and infectious periods have been estimated at . and . days, respectively, using a vague prior and . and . days, respectively, for an informative prior. these exponential distributions based on a mathematical modeling study are the only available empirical evidence for these two time periods. the mean length of time from illness onset to death is approximately days [ , ] , but the transmissibility from the deceased from ebola may account for a certain fraction of secondary transmissions [ ] . hence, the infectious period could be longer than the observable time to death if the burial is extended. the case fatality ratio (cfr) is calculated as the proportion of deaths among the total number of evd cases, thereby informing the virulence of the infectious pathogen. evd can be fatal, but it is important to note that the cfr being 'almost %' for evd in general does not rest on any empirical arguments. for the well documented outbreaks of ebola (excluding only isolated cases who are likely to have acquired infection from animal contact), the expected value of cfr has always been below % [ ] , with the range from % to %. the so-called zaire strain is considered to be slightly more fatal than the sudan strain. while the cfr for the sudan strain ranges from % to %, the cfr for the zaire strain ranges from % to %. considering that the corresponding quartile for the zaire strain, as determined by the distribution of outbreak-specific estimates, ranges from . % to . %, the cfr of the ongoing epidemic among cases with definitive recorded clinical outcomes for guinea, liberia and sierra leone has been consistently estimated at . % ( % ci: . to . ), which is in good agreement with estimates from prior outbreaks. nevertheless, it must be noted that earlier studies have not addressed ascertainment bias. it is important to follow up the reasons why the estimated % (as of august which involved an underestimation bias due to time delay from illness onset to death) in realtime has been much lower than the published estimate of . % among a portion of cases. given the potential presence of asymptomatic cases, addressing ascertainment error may be the key to appropriately capture the disease burden for the entire population. table summarizes key epidemiological parameters for evd. the transmission dynamics of ebola outbreaks in confined settings in central africa have been previously described using an seir epidemiological model [ ] with the goal of quantifying the effects of social distancing interventions. in this model, the time-dependent transmission rate parameter β(t) captures the effects of implementing basic public health interventions over time. for instance, once interventions are put in place τ days after the onset of the outbreak, the time-dependent transmission rate could be modeled to shift from a 'free course' baseline value β to a value β , where β < β . more realistically, one can assume that the full effect of interventions is not seen immediately but gradually takes hold in the population, as modeled in [ ] . in these models, the basic reproduction number, r , in a completely susceptible population and in the absence of control interventions is computed as the product of the mean transmission rate during the intervention-free course of the outbreak, β , and the mean infectious period, /γ . hence, r is given by: more detailed epidemiological data and information about the contributions of different settings to transmission could guide the design of more elaborate models that could be helpful to quantify the effects of more specific intervention strategies. legrand et al. [ ] developed a structured transmission model to describe ebola epidemics with contributions to the force of infection from the community, funerals and healthcare settings. the most distinctive feature of this model is that transmission during burial rituals is modeled by accounting for the duration of the burial and the intensity of transmission with infectious bodies. this model is comprised by six epidemiologically relevant states and thirteen parameters. the model was calibrated to data of the ebola outbreaks in the republic of congo in and uganda in by fitting three transmission rate parameters, one for each transmission setting and one parameter to quantify the effectiveness of interventions. the full model can be applied to the west african epidemic particularly for guinea, sierra leone and liberia where burial practices involve the touching of bodies of the deceased [ ] . but this feature is believed to be less influential in transmission in the context of nigeria where a limited outbreak developed. to illustrate the effects of control interventions during ebola outbreaks, here we only account for transmission in the community and in healthcare settings by adjusting baseline transmission rates, diagnostic rates and enhancement of infection-control measures (for example, strict use of protective equipment by healthcare workers and effective isolation of infectious individuals) (see for example, [ , , , , , ] ). in this simpler setting, the population is divided into five categories: susceptible individuals (s); exposed individuals (e); infectious and symptomatic individuals (i); hospitalized individuals (h); and removed individuals after recovery or diseaseinduced death (r). susceptible individuals infected through contact with infectious individuals (secondary cases) enter the latent period at rate β(t) (i + l(t) h) /n(t) where β(t) is the mean human-to-human transmission rate per day, l(t) quantifies the relative transmissibility of hospitalized patients compared to symptomatic patients in the community, and n (t) is the total population size at time t. thus, values of l(t) between and would reflect the effectiveness of hospital isolation measures that decrease ebola transmission probability below that seen in the community, and values above . denote increased transmission in the hospital relative to the community, potentially due to biological and/or epidemiological reasons (for example, exposure to body fluids). symptomatic infectious individuals i are hospitalized at the time-dependent average rate γ a (t) or recover without being hospitalized at the average rate γ i. individuals in the 'removed' class do not contribute to the transmission process. for simplicity, one can assume that the timedependent transmission rate β(t), relatively transmissibility of hospitalized patients, l(t), and the diagnostic rate γ a (t), remain constant values at β , l , and γ a prior to the implementation of comprehensive countermeasures. hence, in this model the basic reproduction number, r , is given by the following expression: in this equation, ( /(γ a + γ i ) is the mean infectious period of community cases, γ a /(γ a + γ i ) is the fraction of symptomatic cases that are hospitalized, and /γ r is the mean infectious period of hospitalized cases. this expression can be decomposed as the sum of the contributions of infectious individuals in the community and the hospital as follows: where r comm = β /(γ a + γ i ) and r hosp = β l ( /γ r )(γ a /(γ a + γ i )). importantly, the above components for the reproduction number underscore the fact that the actual reproduction number could vary across regions as a function of the local capacity public health context (for example, infection control practices and availability of personal protective equipment for health care workers) and any local cultural practices that may influence transmission infectious period . days (mean) [ ] serial interval . days (mean) [ ] generation time . days (mean) [ ] time from illness onset to death days (mean) [ , ] case fatality ratio % to % (sudan) [ ] % to % (zaire) (for example, funeral traditions). consequently, an outbreak may be very unlikely to unfold in developed countries simply as a result of baseline infection control measures in place (that is, r < ) whereas poor countries with extremely weak or absent public health systems may be unable to control an ebola outbreak (that is, r > ). this suggests that local socioeconomic and sociocultural conditions are key determinants of disease spread, particularly in the context of the transmission dynamics of evd. the impact of infection-control measures in health care settings is illustrated in figure for different initial values of baseline r . the combined effect of the effectiveness of isolation measures and the diagnostic rate of symptomatic individuals on r is given in figure . the natural reservoir hosts of the ebola virus have yet to be confirmed [ , ] , but laboratory studies point to fruit bats as the most likely culprit harboring the ebola virus in the natural habitat [ ] [ ] [ ] [ ] . ebola outbreaks among humans have been associated with direct exposure to fruit bats and mortality among other wild animals, which tend to succumb to the infection [ ] [ ] [ ] . epidemiological data support the notion that spillover events of ebola virus from a natural reservoir (that is, fruit bats) or an intermediate host, such as non-human primates, into human populations occur with a certain frequency (for example, [ , ] ), but only a small number of those introductions are ever correctly diagnosed and reported or successfully unfold human-to-human transmission chains that lead to outbreaks. this hinders our understanding of the frequency of spillover events as a function of time (for example, season) and its relationship with variation in climatological or socioeconomic variables. we note that two studies have associated the onset of ebola outbreaks with climatological variables [ , ] . specifically, pinzon et al. reported evidence that ebola outbreaks are correlated with drastic shifts from dry to wet conditions [ ] while a more recent study by ng et al. found lower temperature and higher absolute humidity associated with the onset of evd outbreaks during to [ ] . in the context of the ongoing ebola epidemic in west africa, a recent study suggests that people in sierra leone have been previously exposed to the ebola virus, but those introductions have not sparked major epidemics [ , ] . moreover, the ongoing epidemic may have been triggered by a single spillover event as suggested by limited epidemiological data indicating that chains of transmission of reported cases can be traced back to one or two individuals [ ] . this may be explained by the fact that table . the mean time from symptoms onset to diagnosis (γ a ) is assumed to be three days. the isolation effectiveness is given by *( -l ) where l is the relative infectiousness of infectious individuals in health care settings. baseline values of r are calibrated by adjusting the transmission rate β to achieve a given r . evd, ebola virus disease; r , basic reproduction number. three lines represent results for three baseline values of r : . , . and . . ebola introductions have historically tended to occur in remote, rural areas with sparse population structures characterized by higher disease extinction rates [ , ] . by contrast, the unprecedented size of the ongoing epidemic could have benefited from high population mobility across invisible borders, super spreading events [ ] and secondary transmissions linked to health care settings [ ] . figure illustrates the role of the size of spillover events (for example, the number of infectious cases initially introduced in the population) in triggering ebola epidemics in naive populations by showing that the probability that a major epidemic occurs rapidly increases as a function of the initial number of ebola cases. for instance, single-case introductions go extinct without developing into epidemics more than % of the time while five-case introductions lead to major epidemics more than % of the time. several factors hamper the timely identification of ebola outbreaks in africa. first, only a small number of ebola outbreaks have occurred in east and central africa since the first identified outbreak in relative to the regional burden of other endemic infectious diseases, such as malaria. moreover, some areas at risk of ebola have yet to experience ebola outbreaks, which severely limits community-level knowledge of the disease. for instance, the ongoing epidemic of evob is reportedly the first to occur in west africa [ ] . second, early symptoms of ebola virus disease tend to be nonspecific (for example, many cases are only febrile) [ ] , which increases the likelihood of misdiagnosing ebola with malaria or other locally endemic infectious diseases [ ] . unsuccessful treatment of febrile patients and/or the appearance of more specific symptoms during the course of the disease (for example, hemorrhagic manifestations) could increase the likelihood of an 'astute' public-health worker suspecting ebola or other viral hemorrhagic fever [ ] . third, lack of epidemiological surveillance systems and diagnostic testing in poor countries further exacerbates the delay in detecting outbreaks. consequently, the implementation of public health interventions may not start until case or death clusters start to be detected and investigated in the community by public health authorities. in general, the longer the delay in the implementation of control interventions, the higher the chances that the virus percolates from remote and sparsely populated areas into areas of high population density. the probability of observing major ebola outbreaks is highly sensitive to the timing of initiation of control interventions as illustrated in figure . figure the effects of isolation strategies and diagnostic rate on r . basic reproduction number as a function of the combined effect of the level of isolation effectiveness and the diagnostic rate. epidemiological mean parameter values for evd are shown in table . the mean time from symptoms onset to diagnosis (γ a ) is varied from one to three days. the isolation effectiveness is given by *( -l ) where l is the relative infectiousness of infectious individuals in health care settings. the baseline value of r is set at . . evd, ebola virus disease; r , basic reproduction number. this figure shows that a five-day delay is highly unlikely to result in major ebola outbreaks. by contrast, more significant delays exceeding two weeks are likely to lead to ebola outbreaks ( figure ) . basic infection control measures in health care settings are essential to avoid further spread of the disease to other patients, health care workers and visitors. unfortunately, under-resourced african regions not only suffer from a critically low ratio of health-care workers to total population, but also lack essential personal protective equipment (ppe) (for example, gloves, gowns, face masks) to practice standard infection control measures. they also often lack the infrastructure and local capacity necessary to effectively trace contacts and isolate infectious individuals. consequently, it is not surprising that ebola outbreaks have been amplified in health care settings [ , , , ] including the ongoing epidemic in west africa. indeed, a total of health care workers have developed evd as of september [ ] . fortunately, past experience also indicates that early and drastic enhancement of infection control measures in health care settings can substantially reduce the size and geographic scope of ebola outbreaks [ , ] . for instance, figure shows that the rising trend in infected health care workers during the ebola outbreak in congo rapidly declined following the implementation of control interventions. the combined impact of the rate of diagnosing symptomatic cases and the relative infectiousness of hospitalized cases on the probability of observing major epidemics is illustrated in figure . socio-cultural factors have not only contributed significantly to ebola spread, but have also complicated the implementation of control interventions. specifically, cultural practices involving touching the body of the deceased naturally (and greatly) contribute to the dissemination of the ebola virus [ ] . in particular, the potential for transmission to neighboring and distant areas by exposed funeral attendants could facilitate the development of major epidemics [ , ] . moreover, the lack of prior experience or knowledge of the disease can lead communities to deny its existence and to associate illness with witchcraft or conspiracy theories presumably created by governments to gain control of populations or attract resources from the international community [ , ] . for instance, during the ongoing size of spillover event (initial cases) probability of no major outbreak (%) figure the effects of size of spillover event on the likelihood of observing an outbreak. probability that no major outbreak unfolds as a function of the initial number of infectious cases introduced into the population. epidemiological parameter values for evd are shown in table . the mean time from symptoms onset to diagnosis (γ a ) is set at three days. the isolation effectiveness is set at (that is, l . = ). population size n is set at , . the baseline value of r is set at . . the curve corresponds to the mean of the results obtained from model simulations. evd, ebola virus disease; r , basic reproduction number. epidemic in west africa, a group of individuals looted equipment and potentially contaminated materials in an isolation facility in a quarantined neighborhood [ ] . finally, the stigma carried by ebola survivors and family members of ebola victims could exacerbate disease spread. in particular, uninformed families tend to hide relatives and friends infected with ebola to avoid being shunned by their own communities, which enhances transmission rates [ ] . the problem is compounded by the high case fatality ratio of evd whereby misinformed communities tend to associate case isolation with a death sentence. the ongoing epidemic in west africa offers a unique opportunity to improve our current understanding of the transmission characteristics of evd in humans, including the duration of immunity among ebola survivors and the case fatality ratio in the presence or absence of supportive therapy [ , ] , as well as the effectiveness of various control interventions [ ] . for this purpose, there is a critical need to collect detailed epidemiological data in real-time during the ongoing epidemic through the establishment of efficient epidemiological surveillance systems in the affected areas. in addition, we cannot overemphasize the importance of collecting data relating to population behaviors influencing disease spread and control and how these have changed over time. it would also be important to record the level of adoption of preventive and social distancing measures in the community and adherence to infection control measures in health care settings. detailed data regarding control interventions would also be critical to assess their effectiveness in reducing secondary transmissions including information on the changing numbers of isolation and treatment centers, healthcare workers, intensity of contact tracing activities and awareness campaigns in the community. table . the mean time from symptoms onset to diagnosis (γ a ) is set at three days. the relative infectiousness of hospitalized cases is given by l . population size n is set at , . the baseline value of r is set at . by adjusting the transmission rate. after the start of interventions, the transmission rate is reduced by % and the relative infectiousness of hospitalized individuals is reduced by % (that is, l = , l = . ). the curves shown correspond to the mean of the results obtained from model simulations. evd, ebola virus disease; r , basic reproduction number. there is a scarcity of empirical studies quantifying transmission and the effects of control interventions implemented during past ebola outbreaks [ , ] . further work is also needed to quantify the effects of various interventions put in place during the ongoing epidemic in west africa. specifically, careful mathematical and statistical modeling studies could help ascertain the role of social distancing interventions (for example, school closures and cancellation of mass gathering events), infection control measures in health care settings (for example, isolation and other infection control measures among health care workers) and contact tracing and quarantine efforts [ , , , [ ] [ ] [ ] [ ] [ ] . in addition to individual epidemiological data, the timing of such interventions should be recorded along with the scale and extent of interventions (for example, closure of class rooms or entire schools). intervention studies could reveal, for instance, whether effective infection control mechanisms in hospital settings could suffice to bring an epidemic under control or whether a combination of control strategies would be critical to ensure epidemic control (for example, r < ). while a significant number of computational models have been developed to inform preparedness plans against pandemic influenza [ ] [ ] [ ] , comprehensive modeling studies to examine the spread and control of viral hemorrhagic fevers, including ebola, in the context of the highly heterogeneous economic reality of african countries are yet to be developed. the shortage of modeling efforts could be explained by the fact that large ebola outbreaks affecting large population settings were largely unexpected until now. to start filling this gap, datasets comprising detailed demographic, socio-economic, contact rates and population mobility estimates in the region (for example, commuting networks, air traffic) need to be integrated. given that the disease is highly fatal, dynamic features of contact and mobility should also be closely investigated. modeling studies with local demographic characteristics and human movement could be useful not only to assess the likelihood of major epidemics and carry out sensible projections on epidemic outcomes, but also to guide control efforts in the field, such as the estimation of the number, size and location of isolation facilities, the number of health workers and staff and essential supplies that would be needed to respond to a particular outbreak scenario as well as to quantify the effects of potential quarantine efforts in certain areas, border closures and air travel restrictions. proven treatments or vaccines against ebola are still not available. hence, our current working toolbox available to control the spread of ebola still hinges on supportive medical care to increase the survival of those infected and basic non-pharmaceutical public health measures [ ] to prevent transmission, namely: ) infection control measures including standard precautions in health care settings; ) rapid contact tracing and isolation of infectious individuals; and ) social distancing interventions in the community which may include the dissemination of awareness campaigns to inform the population on how to avoid contracting the disease, quarantining individuals potentially exposed to infectious individuals and restricting the movement of communities exhibiting local transmission to prevent onward transmission. these actions must be conducted in close collaboration with local community leaders to effectively reach the population at large. with the ongoing epidemic in west africa, the development of treatments and vaccines against ebola is accelerating [ , ] . for instance, emergency use of a trickle of doses of an experimental drug with unknown efficacy or safety record in humans has been initiated during the outbreak [ ] . recent experiments in monkeys provide promising evidence that this experimental drug could have a significant impact on mortality burden during ebola outbreaks [ ] . furthermore, a promising bivalent ebola vaccine against the zaire and sudan ebola strains is entering human safety trials in september [ ] with an initial goal of building a stockpile of , doses by november . nevertheless, apart from pharmaceutical effects on the prognosis of infection, we have yet to examine how medication changes the transmission dynamics. hence, careful studies could be useful for assessing the impacts of treatment on contact, transmission and diagnosis as well as on the disease burden [ ] . if an ebola vaccine is developed successfully, one could assess the effectiveness of pre-emptive and reactive treatment and vaccination plans in the context of limited stockpiles. finally, it is worth noting that our efforts to prepare against current and future infectious disease threats should also include potential deliberate attempts to trigger epidemics, which are largely unexpected events figure the effects of size of baseline isolation effectiveness and diagnostic rate on the likelihood of observing an outbreak. probability that no major epidemic unfolds as a function of isolation effectiveness and time from symptoms onset to diagnosis. epidemiological parameter values for evd are shown in table . the mean time from symptoms onset to diagnosis (γ a ) is set at one, two and three days. the relative infectiousness of hospitalized cases (l ) is varied from to . population size n is set at , . the baseline value of r is set at . by adjusting the transmission rate. the curves shown correspond to the mean of the results obtained from model simulations. evd, ebola virus disease; r , basic reproduction number. but could pose high impact on public health and global economic activities. emergence of zaire ebola virus disease in guinea 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cost-based comparison of quarantine strategies for new emerging diseases simulating the sars outbreak in beijing with limited data strategies for mitigating an influenza pandemic seasonal transmission potential and activity peaks of the new influenza a(h n ): a monte carlo likelihood analysis based on human mobility modeling targeted layered containment of an influenza pandemic in the united states ebola -new challenges, new global response and responsibility studying "secret serums" -toward safe, effective ebola treatments reversion of advanced ebola virus disease in nonhuman primates with zmapp ebola vaccines to enter us, uk human safety trials cite this article as: chowell and nishiura: transmission dynamics and control of ebola virus disease (evd): a review the authors declare that they have no competing interests.authors' contributions gc and hn drafted and revised the manuscript. both authors read and approved the final manuscript.submit your next manuscript to biomed central and take full advantage of: key: cord- -tydil d authors: wannier, s. rae; worden, lee; hoff, nicole a.; amezcua, eduardo; selo, bernice; sinai, cyrus; mossoko, mathias; njoloko, bathe; okitolonda-wemakoy, emile; mbala-kingebeni, placide; ahuka-mundeke, steve; muyembe-tamfum, jean jacques; richardson, eugene t.; rutherford, george w.; jones, james h; lietman, thomas m.; rimoin, anne w.; porco, travis c.; kelly, j. daniel title: estimating the impact of violent events on transmission in ebola virus disease outbreak, democratic republic of the congo, – date: - - journal: epidemics doi: . /j.epidem. . sha: doc_id: cord_uid: tydil d introduction: as of april , the current ebola virus disease (evd) outbreak in the democratic republic of the congo (drc) is occurring in a longstanding conflict zone and has become the second largest evd outbreak in history. it is suspected that after violent events occur, evd transmission will increase; however, empirical studies to understand the impact of violence on transmission are lacking. here, we use spatial and temporal trends of evd case counts to compare transmission rates between health zones that have versus have not experienced recent violent events during the outbreak. methods: we collected daily evd case counts from drc ministry of health. a time-varying indicator of recent violence in each health zone was derived from events documented in the who situation reports. we used the wallinga-teunis technique to estimate the reproduction number r for each case by day per zone in the – outbreak. we fit an exponentially decaying curve to estimates of r overall and by health zone, for comparison to past outbreaks. results: as of april , the mean overall r for the entire outbreak was . . we found evidence of an increase in the estimated transmission rates in health zones with recently reported violent events versus those without (p = . ). the average r was estimated as between . and . in regions not affected by recent violent events, and between . and . in zones affected by violent events within the last days, leading to an increase in r between . and . . within zones with recent violent events, the mean estimated quenching rate was lower than for all past outbreaks except the – west african outbreak. conclusion: the difference in the estimated transmission rates between zones affected by recent violent events suggests that violent events are contributing to increased transmission and the ongoing nature of this outbreak. since , of the over reported ebola virus disease (evd) outbreaks have been in the democratic republic of the congo (drc) (world health organization regional office for africa, ; anon, ) . the current - evd outbreak in northeastern drc is, as of april , the second largest evd outbreak in history and the first to occur in a conflict setting (world health organization regional office for africa, ). although its magnitude substantially trails the - evd outbreak in west africa, the current outbreak has surpassed epidemic forecasts, particularly mathematical modelling studies that used historical data from prior outbreaks kelly et al., ; enanoria et al., ; ebola haemorrhagic fever in sudan, ; breman et al., ) . these studies had projected a final outbreak size of up to cases as of february while the current outbreak now has reported cases kelly et al., ) . since the evd outbreak began, there have been reports of violent events that have ranged from destruction of ebola care facilities and injured and murdered healthcare workers to events unrelated to ebola care, linked to elections and local unrest (world health organization regional office for africa, ; christopher dickey, ; branswell, branswell, , a branswell, , b branswell, , c branswell, , d . following many of these violent events, ebola response activities have been disrupted. in some cases, new evd case counts have increased in the district affected following these events, despite intensive public health interventions comprising the deployment of rapid diagnostic tests, novel therapeutics, contact tracing, and ring vaccination using a vaccine approved for emergency use with an estimated . % efficacy (elsherif et al., ; world health organization regional office for africa, ; who, ). there has been a growing sentiment that such events may be contributing to evd transmission, but quantitative analysis is lacking. here, we hypothesized that during the current outbreak to date, there had been higher transmission rates in zones that had recently experienced violent events than in zones that had not experienced such events. furthermore, we also hypothesized that shannon entropy computed with respect to space, a measure of the spatial spread of cases and the uniformity of their distribution across districts in this epidemic, has increased over time. a time series of case counts were collected from situation reports presented by the drc ministry of health and were confirmed using situation reports posted by the world health organization (who) (world health organization regional office for africa, ). evd cases were classified as suspected, probable, or confirmed. suspected cases underwent diagnostic testing and were subsequently classified either as confirmed or not confirmed. cases reported post-mortem were classified as probable based upon their epidemiological history. the symptom onset date and the reporting date of probable, confirmed, and suspected cases were collected from the beginning of the outbreak on may through april . beginning on august , data by health zone were also collected for probable and confirmed cases. as the outbreak has continued, cases were reassigned by the drc ministry of health from their initially reported health zone to the health zone where epidemiological evidence pointed to evd acquisition. symptom onset data were later made available going back to the beginning of the outbreak. given the dynamic nature of violence in the region and the relatively short generation time of evd, we undertook a time-varying, health zone-level analysis of the outbreak comparing transmission in zones that had experienced recent violence to those without recently reported violence. we considered a violent event as one reported within the who situation reports until april (world health organization regional office for africa, ). we assigned each health zone as having been exposed to violent events or not. after a violent event, we considered the following three weeks as the exposure period. we modeled the effect of violent events within the previous week, two weeks, three weeks, four weeks, and five weeks to determine the sensitivity to the time period chosen. we used the wallinga-teunis technique to estimate the number of secondary cases r for each case in the - outbreak (wallinga and teunis, ) . we defined the serial interval as the interval between disease onset in an index case and disease onset in a person infected by that index case. we used both symptom onset and case report data in our analyses given the limitations of each dataset. historical outbreaks used case report data, though case report data in this dataset is subject to case reclassification between zones, reflecting epidemiologic knowledge on the place of transmission rather than place of report, that can show up as transmission. in the current outbreak, case report data were updated nearly daily from the official daily totals reported by the drc ministry of health and revised as needed. thus, while the symptom onset data may be the fundamental definition of the serial interval, these data were not always revised as more accurate information became available. we employed a gamma distribution with a mean of . days and a standard deviation of days for the serial interval distribution. this models a serial interval of evd cases approximately ranging from to days, with mean to days (aylward et al., ; wong et al., ; chowell and nishiura, ) . our application of the wallinga-teunis method assumes there are no missing cases. to compare transmission in the current outbreak to past outbreaks, we applied the same estimation technique to reported cases by date from prior outbreaks (ebola haemorrhagic fever in sudan, ; breman et al., ; baron et al., ; georges et al., ; khan et al., ; cdc, ; anon, ; boumandouki et al., ; world health organization abonnement annuel, ; nkoghe et al., ; rosello et al., ) . we estimated the initial reproduction number r initial and exponential decay (or quenching) rate τ for each outbreak by fitting an exponentially decaying curve r(d) = r initial e −τd to the outbreak's estimates of r by day d. this exponential decay "quenching" parameter approximates the often observed reduction in r over the course of an outbreak that may be due to phenomena such as formal control efforts including case finding and quarantine as well as less formal responses including individual behavioral changes or local depletion of susceptibles. this equation approximates temporal change in transmission rate by a smoothed quenching pattern in which r decreases exponentially over time at a rate defined by the quenching parameter. the estimates r initial and τ obtained by this fit are reported for comparison to historic outbreaks and not used for further modeling. we repeated the wallinga-teunis procedure to estimate the reproduction number r separately for each health zone, creating a time series of estimated reproduction numbers for each zone. when estimating r for each zone, we considered the possibility of transmission between regions. the probability of an inter-zone transmission relative to intra-zone transmission is denoted ω, representing the reduced probability of a case transmitting outside of its health zone as compared to their probability of transmitting within their own health zone. we compared estimates based on values of the inter-zone transmission-mixing parameter ω across its range from (no transmission allowed between regions) to (all cases in all regions transmit equally to all other cases, regardless of region). confidence intervals for the wallinga-teunis estimated r by health zone were simulated using the calculated probabilities for each case i transmitting to case j to probabilistically assign a transmission link for every case, based on simulations (wallinga and teunis, ) . using the distribution of r per day per zone, we then calculated the negativebinomial confidence interval for each day per zone. statistical inference on the resulting estimates of r by day per zone was conducted by regressing estimated r on the presence of a recently reported violent events (bartlett, ; politis, ) . to adjust for autocorrelation, the standard errors of the estimates were estimated using a time-series bootstrap with blocks of days over replications. the shannon entropy of the cumulative number of cases was computed based on all health zones and standard errors were computed from the proportion in each geographic region (from, ) . time series bootstrap based on a fixed length of was used to compute standard errors of the time trend, based on ordinary least squares linear regression of entropy on days since the first case. we conducted all analyses in r (v. . for macintosh, r foundation for statistical computing, vienna, austria). as of april , a total of evd cases had been reported. thus far during the outbreak period, a total of cases have been reported in the seven health zones that have experienced violent events whereas cases have been reported in zones without violent events. the outbreak has been centered in health zones of katwa ( %), beni ( %), mabalako ( %), butembo ( %). butembo and beni are the health zones with the most violent events (fig. ). since the beginning of the outbreak in may , the average reproduction number (mean r estimate ) was . . using case report data, after august , , the average reproduction number was between . and . in the days following a violent event in a district, and between . and . in all other cases (fig. ) . the difference between reproduction numbers with and without violent events was statistically significant and increased as the mixing between zones was assumed increasingly limited (transmission mixing parameter ω decreased). even at very high levels of inter-zone transmission mixing, corresponding to relatively homogenous transmission within and across health zones, (ω = . , p = . ), the difference was still statistically significant (fig. ) . we compared the initial estimated r and the quenching parameters of past outbreak to the current outbreak and its respective health zones (fig. ) . the inter-zone transmission mixing parameter ω was varied over a range from to (fig. ) . the log of the estimated quenching parameter was (− . ) for the current outbreak was closest, though slightly higher, to that estimated for the - outbreak in west africa (− . ). this was paired with a slightly higher estimated r initial = . than for the west african outbreak where r initial = . . the (r initial ) reported here for the west african outbreak is consistent with the previous literature (barbarossa et al., ; lau et al., ) . these numbers are consistent with the long trajectory and continued transmission of the outbreak as a whole, although the trend of observed r in the current outbreak is rather different from the west african outbreak where the mean overall r was only above . early in the outbreak before dropping below . as the outbreak continued, where here it can be seen to fluctuate with three peaks above r estimate = . and below r estimate = . (fig. ) (lau et al., ) . the estimated r initial and quenching parameters clustered around the current outbreak estimates, some more extreme (lower quenching) and other more like smaller outbreaks of the past. each health zone was also estimated. health zones at the center of the outbreak appeared on average to have lower quenching. mabalako, butembo, and katwa, for example, often had weaker quenching than the west african outbreak; however, this was not consistent because beni consistently reported a higher level of quenching from the estimates, indicating the complex geographic distribution of transmission among health zones. in evaluating a probable mixing parameter to use for evaluating the results from this outbreak, we can look at the evidence from the time series of r estimate by health zone and examine their behavior (figure ). both extremes of no mixing (ω = . ) or full mixing (ω = . ) are unrealistic and lead to inconsistent results. when no mixing is allowed (ω = . ) this causes false spikes in r estimate in health zones with low levels of transmission following an increase in transmission in a neighboring health zone as the neighboring cases are unable to account for the spread of transmission to the low transmission zone, and this creates a false apparent spike in their own health zone to compensate for a lack of inter-zone transmission. even low levels of mixing (ω = . ) are enough to remove false spikes in r estimate that we see when no mixing is allowed (ω = . ). when full mixing is allowed (ω = . ) this leads to all health zones having identical r estimate at each time point. this herding behavior is strongly seen still when (ω = . ) at unrealistically high levels. even at a middle level of mixing (ω = . ) it appears that health zones herd too strongly to the health zone driving transmission, as spikes in transmission at days , and cause all health zones reporting cases to spike as well, when it is most probable the increase in transmission is being driven only by a few health zones and the others only responding to the initial change in transmission. although we do not make an effort to formally estimate a probable mixing parameter, it would be reasonable to consider the estimates taken with ω = . to ω = . as these are the probable limits of the range for the mixing parameter in this outbreak. using case report data, at ω = . to ω = . we see a difference in the r estimate by violent events (fig. ) . looking only at ω between . and . , we see an increase in r estimate following violent events of . ( % ci: . , . , p < . ) to . ( % ci: . , . , p < . ). however, when considering the symptom onset data the strength of the effect of recently reported violence was reduced, though still significant overall with violent events leading to an increase in r estimate of . ( % ci: . , . , p = . ) to . ( % ci: . , . , p < . ) (fig. ) . to assess the sensitivity of the lag time chosen after a violent event, we looked at the effect of violent events reported in increments of increasing weeks. looking at the case report data with ω = . , the overall effect size is fairly constant whether we consider a period of days or days, with an increase in r estimate of . ( % ci: . , . , p < . ) and . ( % ci: . , . , p < . ), respectively. when looking at the onset data with ω = . , the strength of the effect of recent violent events is strongest when it is evaluated over a full - days, as r estimate increases from . ( % ci: − . , . , p = . ) to . ( % ci: . , . , p < . ) as the lag increases to days and then becomes relatively stable. wannier et al. page epidemics. author manuscript; available in pmc july . we did not consider event times longer than days apart because many of the affected health zones have events that occur less than one month apart, sometimes occuring as little as one week apart. for these health zones, increasing duration beyond this point does not increase the period of time considered as being impacted by violent events, and thus we lose much of our ability to further distinguish between transmission in zones with recent violent events. fig. shows the estimated shannon entropy over the course of the epidemic. the estimated entropy was . ± . on august , rising to . ± . by april . we find evidence of an increasing trend (p < . , time series bootstrap), showing less concentration of cases over time. some increase in entropy is expected early in an epidemic, as cases begin to appear in new health zones. later in an epidemic, a decrease in entropy could occur if there were an increased concentration of cases in a few of the affected health zones. it is possible that the continued spatial spread of the current outbreak, which is second only to the west african outbreak, is contributing to the difficulty in controlling this outbreak. among health zones situated within the evd outbreak in drc, we found that the evd transmission rate (reproduction number r) was higher following violent events. the outbreak was subcritical (r < . , non-sustaining transmission) in zones without violent events reported by who (world health organization regional office for africa, ), while it was supercritical (with estimated r > . , continued transmission) in zones with reported violent events, suggesting that ongoing violence is likely perpetuating an otherwise declining outbreak. our findings suggest that violent events increased transmission in the weeks following a violent event, and that this effect may be sustained for many more weeks. after the destruction of the ebola care facility in katwa, for example, over one month was needed before ebola virus disease relief efforts were fully resumed. our time series regression found an effect of violent events on estimated r across both symptom onset data and case report data, across all plausible levels of inter-region transmission (fig. ) , and lagged follow-up periods of or more days. the consistency of the effect of recent violent events across data sets strongly supports the idea that violence is indeed contributing to the increased transmission and ongoing nature of this outbreak (richardson and fallah, ; frankfurter et al., ; richardson et al., a richardson et al., , b richardson et al., , a richardson et al., , b . more research is needed to confirm and further understand how the frequency and intensity of events may affect the contributions of violence to evd transmission. there are several limitations in our analysis. cases may have escaped detection and reporting (richardson et al., a (richardson et al., , b . if cases were missing in a biased way that systematically under-reported cases in certain areas or at certain times, there could have been a biased estimate of the effect, though the direction of the bias would be unclear. additionally, if there was heterogeneity in the reporting delays, this could have biased the effect estimates made using the case report data, though this objection would not apply to the symptom onset data. the nature and causes of violent events can be quite different. moreover, such events can affect different numbers of people, can vary in geographic scope as well as the duration of their impact. other non-violent events not considered in this analysis, such as strikes, may also be contributing to ongoing transmission. unmeasured causes or determinants of violence in the region may also drive variation in transmission or reporting in an unmeasured way. the epidemic curve in each health zone describes relatively few cases, making interpretations of specific features of their epidemic curves unwise. our analysis relied on who reporting of violent events, and more accurate quantification of these events may be possible. note that the assumption of exponential decay (quenching) of r initial may not accurately characterize this epidemic; however, this was only used for comparisons to past outbreaks, and the estimates of the effect of violent events are not affected by this. while we have shown that the ongoing violence has likely hampered control and contributed to this becoming the second largest epidemic, our efforts to quantify the role of violence should be interpreted with caution. these considerations also suggest that meaningful interventions must consider the sociopolitical determinants of armed conflict in the drc, including the legacies of colonialism, and other forms of historical and ongoing violence (sweeney, ; nzongola-ntalaja, ; council on foreign relations, ; richardson and fallah, ; frankfurter et al., ; richardson et al., a richardson et al., , b richardson et al., , a richardson et al., , b . on april , the democratic republic of the congo's minister of health addressed the worsening outbreak and indicated that with "the difficult security situation, this epidemic had gone beyond public health" (rdc, ) . while this may have been the first time an evd outbreak occurred in an active conflict zone, it is unlikely to be the last time that violent conflict contributes to the prevention of epidemic decline. as evd surges in drc, a polio outbreak surges in a conflict area of nigeria. ebola virus and other infectious disease outbreaks have the potential to become neglected crises in conflict settings if left unchecked. despite immense security challenges, ebola responders and the people in the affected area work tirelessly under dangerous conditions and deserve great respect, gratitude, and protection for their ongoing work to contain this public health disaster. estimated initial reproduction number r initial and quenching rate τ for current and past outbreaks. r initial and τ were estimated for the current outbreak as an overall summary measure, as well as independently in health zones with over a range of inter-zone transmission mixing parameters ω. epidemics. author manuscript; available in pmc july . wallinga-teunis estimated r per day and violent events by health zone for symptom onset and reporting dates, allowing for mixing between regions. r was estimated over a range of inter-zone transmission mixing parameters ω. violent events are marked using triangles with colors matching the affected district(s). epidemics. author manuscript; available in pmc july . outbreak(s) of ebola haemorrhagic fever outbreaks chronology. ebola virus disease the impact of control strategies and behavioural changes on the elimination of ebola from lofa county transmission dynamics and final epidemic size of ebola virus disease outbreaks with varying interventions ebola virus disease in southern sudan: hospital dissemination and intrafamilial spread on the theoretical specification and sampling properties of autocorrelated timeseries prise en charge des malades et des défunts lors de l'épidémie de fièvre hémorragique due au virus ebola d'octobre à décembre ebola response suffers another setback, as who evacuates some staff after attack s redfield: it could take another year to control ebola in drc ebola response teams scrambling to care for patients after attacks set back efforts ebola response is working, who director-general says, amid criticism and violence on a knife edge': ebola outbreak threatens to escalate as violence rises discovery and description of ebola zaire virus in and relevance to the west african epidemic during - outbreak of ebola hemorrhagic fever -uganda transmission dynamics and control of ebola virus disease (evd): a review what's worse than ebola? fighting it in a war zone violence in the democratic republic of congo, global conflict tracker canadian immunization research network. assessing the safety and immunogenicity of recombinant vesicular stomatitis virus ebola vaccine in healthy adults: a randomized clinical trial evaluating subcriticality during the ebola epidemic in west africa indirect rule redux: the political economy of diamond mining and its relation to the ebola outbreak in kono district confidence intervals for gini's diversity measure and shannon's entropy using adjusted proportions ebola hemorrhagic fever outbreaks in gabon, - : epidemiologic and health control issues anatomy of a hotspot: chain and seroepidemiology of ebola virus transmission projections of ebola outbreak size and duration with and without vaccine use in Équateur the reemergence of ebola hemorrhagic fever, democratic republic of the congo spatial and temporal dynamics of superspreading events in the - west africa ebola epidemic a limited outbreak of ebola haemorrhagic fever in etoumbi the congo from leopold to kabila: a people's history. zed books, london. world health organization abonnement annuel the impact of bootstrap methods on time series analysis ebola doit être vaincu le plus tôt (tshibuyi) the genesis of the ebola outbreak in west africa minimally symptomatic infection in an ebola 'hotspot': a crosssectional serosurvey biosocial approaches to the - ebola pandemic the ebola suspect's dilemma the symbolic violence of outbreak: a mixed methods, quasi-experimental impact evaluation of social protection on ebola survivor well-being drc: conflict and displacement in nord kivu and ituri different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures preliminary results on the efficacy of rvsv-zebov-gp ebola vaccine using the ring vaccination strategy in the control of an ebola outbreak in the democratic republic of the congo: an example of integration of research into epidemic response a systematic review of early modelling studies of ebola virus disease in west africa realtime projections of epidemic transmission and estimation of vaccination impact during an ebola virus disease outbreak in the eastern region of the democratic republic of congo health topics: ebola virus disease. (online; accessed . world health organization regional office for africa we thank the ebola responders for their efforts in the - evd outbreak in north kivu and ituri provinces, democratic republic of congo. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. key: cord- -ajzfnd g authors: herstein, jocelyn j.; biddinger, paul d.; gibbs, shawn g.; le, aurora b.; jelden, katelyn c.; hewlett, angela l.; lowe, john j. title: sustainability of high-level isolation capabilities among us ebola treatment centers date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: ajzfnd g to identify barriers to maintaining and applying capabilities of us high-level isolation units (hlius) used during the ebola virus disease outbreak, during we surveyed hlius. hlius identified sustainability challenges and reported the highly infectious diseases they would treat. hlius expended substantial resources in development but must strategize models of sustainability to maintain readiness. d uring the - west africa ebola virus disease (evd) outbreak, hospitals in the united states were designated by the centers for disease control and prevention as ebola treatment centers (etcs). etcs added national capacity to care for patients with highly infectious diseases (hids); that is, hazardous, easily transmissible, life-threatening illnesses with limited treatment options, such as evd and severe acute respiratory syndrome coronavirus ( ) . etcs were equipped with the clinical care resources, specialized infrastructure, and trained staff to safely manage and treat a person suspected or confirmed to have evd ( ) . after the initial designation, etc in each us department of health and human services region was selected as a regional ebola and other special pathogens treatment center (resptc) capable of managing hids for extended periods ( ) . in , a consensus group of infectious disease experts in europe defined high-level isolation units (hlius) as facilities providing optimal infection containment and procedures specifically designed for hid care and released specifications for such units ( ) . a pilot survey of us hlius described the actions taken to establish high-level isolation capabilities and identified the costs of those efforts ( - ). the survey revealed that of the us hospitals spent a cumulative total of $ . million (nearly $ . million per facility) to stand up their specialized isolation units ( ) . because of the substantial expenses and operational challenges of maintaining readiness, how hlius can continue these efforts has been questioned ( ) . the evd outbreak revealed vulnerabilities within the us healthcare and public health infrastructure to address hids. we aimed to identify barriers to maintenance of recently developed isolation and care capabilities, how those capabilities might be applied to outbreaks other than evd, and further infrastructure and resources hlius would add if additional funding were available. in early , we sent a -question survey to the original designated us hlius, including the resptcs. the survey queried challenges and concerns about the maintenance of capabilities. results were collected through adobe acrobat pro (https://acrobat.adobe.com/us/en/acrobat/acrobatpro.html) and analyzed by using descriptive statistics. the university of nebraska medical center institutional review board declared the study exempt (# - x). thirty-six ( %) hospitals responded. of the that completed the full survey, reported they no longer maintained their hliu capabilities. the that provided qualitative information about their decision to close reported needing hliu resources for other, more pressing areas and cited close proximity to at least other hliu as reasons for closing. nineteen ( %) hospitals reported using their hliu for non-hid patients when not activated; the other ( %) use the unit exclusively for patients with hids or for training (table ) . when the hospitals with adaptive isolation units (i.e., units otherwise used for normal hospital care) are activated, an average of . beds (median , range - ) must be taken offline when caring for patient with an hid and an average of . beds (median . , range - ) for patients. ten ( %) hlius with adaptive units stated preference for a unit dedicated to care for patients with hids; however, when asked the estimated costs of developing a unit for hid patients, estimates ranged from $ million to $ million. perceived benefits of a dedicated unit included minimizing disruption of other patients ( hospitals), a constant state of readiness ( hospitals), and an ability to train in the unit ( hospitals). our initial survey reported that hospitals designated as etcs incurred an average per hospital of $ , , ( ). since that time, ( %) of those original facilities reported receiving some degree of federal reimbursement, and ( %) had not received any reimbursement. a cumulative total of $ , , in federal funding (average $ , , , range $ , -$ , , ) was reported by the ( %) reporting hlius. after we excluded federally funded resptcs and hlius that did not report initial investments in the pilot survey, the remaining hlius reported a gap in reimbursement of $ , , . (mean $ , . per hliu). although hliu reported lacking specific protocols or an ability to care for patients with an hid other than evd, all other hlius ( %) reported being prepared to care for patients with hids other than evd (figure ). our survey also queried hlius about the challenges they experienced and challenges they foresee in maintaining the capabilities and capacity needed for hid care (figure ). sustainability concerns was the most cited challenge in establishing and maintaining a hliu. hlius also detailed facility modifications and/or capabilities they would add if additional hypothetical funding were available ( table ) . developed during the height of the west africa ebola outbreak, most newly established us hlius invested immense resources and effort into preparing for patients with evd. however, no formal network of hlius has been established in the united states, except for the resptcs, and at least former hlius no longer maintain hliu capabilities. moreover, hlius not designated as resptcs reported having spent $ . million more than they have been reimbursed to initially develop hliu capabilities. as a result, these hospitals reported struggling to fund ongoing operations and sustain readiness. although many facilities have created adaptable-use hlius because they lack the capital funds, space, or both to create a dedicated unit, such units have major disadvantages because healthcare workers are unable to train in the unit, existing patients must be relocated when the unit is activated for an hid patient, and multiple additional rooms must be taken off-line for the care of patient with an hid ( ) . thus, more than half of us hlius that routinely care for non-hid patients would build an hid-dedicated unit if funds were available. however, because future funding sources for non-resptcs are unclear, lessons on sustainability might be learned from flexible-use hlius in italy and the netherlands, which offer levels of containment based on a patient's condition and offset costs by routine use ( ) . our study had several limitations. the data were selfreported and not validated by external sources. the current status of hlius that did not participate in the follow-up survey is unknown. a decrease in participation from the initial survey to the follow-up could also be due to the longer, more detailed follow-up and could indicate the lack of attention to this area now that the evd outbreak is over. the study population was based solely on a list published by the centers for disease control and prevention ( ) and does not include data from other hospitals that similarly tried to strengthen their ability to treat hid patients. in conclusion, a network of hospitals capable of treating patients with hids was rapidly constructed in response to the recent evd outbreak. however, without the impending threat of evd or another hid on the immediate horizon, public attention on hid preparedness tends to waver, and governments tend to prioritize and shift funding elsewhere. additional external funding sources remain generally uncertain for us hlius not designated as resptcs; therefore, these hlius must strategize methods and models of sustainability if they are to maintain capabilities and readiness. additional training/drills (e.g., for other diseases, purchase of simulation equipment) broad supplies/equipment (e.g., beds, ventilators, family support technology/equipment) laboratory capability and capacity (e.g., reduced transport of materials, lab hood in unit, purchase of new decontamination equipment) $ , on-site waste disposal expanded and updated patient rooms enhanced laboratory capabilities (e.g., additional laboratory tests, larger lab space) expanded isolation unit (e.g., increase capacity of negative-pressure rooms) $ , , renovated/expanded isolation unit separate, permanent isolation unit expanded training (e.g., increased frequency) *individual hlids self-reported data through an electronically administered survey administered in . hliu, high-level isolation unit. framework for the design and operation of high-level isolation units: consensus of the european network of infectious diseases interim guidance for u.s. hospital preparedness for patients under investigation (puis) or with confirmed ebola virus disease (evd): a framework for a tiered approach us department of health and human services. hhs selects regional ebola treatment center for southwestern initial costs of ebola treatment centers in the united states current capabilities and capacity of ebola treatment centers in the united states us ebola treatment center clinical laboratory support beyond the ebola battle-winning the war against future epidemics european network for highly infectious diseases project members. isolation facilities for highly infectious diseases in europe-a cross-sectional analysis in countries current ebola treatment centers we gratefully acknowledge philip smith for his expertise and insight in developing the follow-up survey.ms. herstein is a phd student at the university of nebraska medical center and a graduate research assistant for the nebraska biocontainment unit and department of environmental, occupational, and agricultural health in the college of public health. her research interests include highly infectious diseases, global high-level isolation units, infectious disease response and preparedness, and infection control training of non-healthcare workers. key: cord- -f w fw q authors: nan title: abstracts presented at the neurocritical care society (ncs) th annual meeting date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: f w fw q nan external ventricular drain (evd) management after subarachnoid hemorrhage (sah) is thought to influence patient outcomes and complications. evidence from single center randomized controlled trials suggest that an early clamp trial is safe and associated with shorter icu stay and fewer evd complications. however, a recent survey revealed that most neuro icu's across the us still adopt a gradual wean and continuously draining evd strategy. therefore, we sought to determine the optimal approach at our institution. we reviewed consecutive patients admitted to our institution from to with nontraumatic sah requiring an evd. in , our neurocritical care unit revised our internal evd management guideline from a gradual wean to an early clamp trial approach. we performed a retrospective multivariate analysis to compare outcomes before and after our guideline change. patients that were gradually weaned after institution of the new guideline were also included in the early clamp trial group. we observed a significant reduction in ventriculoperitoneal shunt (vps) rates after changing to an early clamp trial approach ( % early clamp vs % gradual wean, p= . , or= . on multivariateanalysis). there was no increase in delayed vps placement at months ( . % vs . %, p= . ). an early clamp trial approach was also associated with a shorter mean evd duration ( . vs . days, p< . ), shorter icu length of stay ( . vs . days, p= . ), shorter hospital length of stay ( . vs . days, p< . ), lower rates of non-functioning evd ( % vs %, p= . ), and fewer ventriculostomyassociated infections ( . % vs . %, p= . ). we found no difference in symptomatic vasospasm rates between the groups ( . % vs . %, p= . ). an early clamp trial approach is associated with fewer complications and shorter length of stay compared to a gradual evd wean. prospective multicenter studies are needed to provide further insight into the best strategy. autoimmune encephalitis refers to rare sometimes paraneoplastic conditions in which the immune system attacks the brain, leading to altered function. delayed diagnosis and treatment potentially leads to permanent neurological injury or death. the primary objective of this study was to analyze the admission and discharge modified rankin scale (mrs) assessments among patients diagnosed with autoimmune encephalitis, and to identify any effectiveness of immunosuppressive therapy on a subset of these patients. through retrospective chart review we identified patients that met currently accepted clinical and serological criterion for autoimmune encephalitis. clinical data was obtained on these cases and a modified rankin score mrs was assessed on both hospital admission and discharge or subsequent 'best clinical' visit. assessment of "improvement" from initial therapy was based on any decrease in mrs score and clinical neurological functional improvement in accordance with physician and patient affirmation by the time of discharge. seventy-seven patients met criterion for clinical or serological autoimmune encephalitis. of these patients, had cancer and did not have known cancer. fifty-seven ( %) patients underwent immunosuppressive therapy with corticosteroids, ivig, and/or plasma exchange and patients experienced a decrease in mrs score. improvement from initial treatment was %, %, %, and % for admitting mrs scores or through respectively. the p-values for improvement from initial immune therapy based on an mrs of , , or compared to an mrs of were . , . , and . respectively. immunosuppressive therapies for patients with an initial mrs score of , or may have a higher yield than for those with an mrs of . these therapies are generally reserved for those with an mrs of or greater. further study is needed to assess functional improvement in those with autoimmune mediated encephalitis treated with immunosuppressive therapies. many patient, family and hospital factors have been associated with obtaining consent for organ donation after brain death (bd). we evaluated potential factors that played a role in the consent rate in a large tertiary hospital over a period of . years. we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation. we cross-matched the hospital electronic medical records with the records of the local organ procurement organization to identify this population. patients were included in the registry ( . % african american) and were approached for donation. there was a . % consent rate for organ donation. there was no significant relationship between sex, admission diagnosis, icu (neuro vs. medical vs. surgical), physician specialty (neurology vs. other), time from event to bd declaration or religion and decision to donate. families were more likely to consent to donation if the patient was non-aa ( % vs % for aa, p< . ), was younger ( . vs . , p= . ), had a lower creatinine at the time of death ( . ± . vs . ± . mg/dl, p= . ), and had an apnea test completed ( % vs %, p= . ). in a logistic regression model, only aa race and pao independently predicted refusal of donation (odds, %ci, . , p< . and . , p= . , respectively) . although the majority of bd patients in this large series were aa, their families were times less likely to consent for organ donation than non-aa families. there is an urgent need to explore the reasons for low donation rates in this population. post-anoxic myoclonus is seen in up to % of patients who remain comatose, and historically was felt to be a poor prognostic sign. little distinction has been made in the literature between epileptic (cortical) vs subcortical myoclonus. from consecutive cardiac arrest patients that did not return to baseline (may -may ) we identified % (n= ) patients with clinical myoclonus. basic demographics and characteristics of their arrest were collected and eeg reports were reviewed. raw eeg including video was reviewed by two epilepsy-trained neurologists, whenever available. myoclonus was subcategorized into subcortical and cortical based on the presence of a preceding eeg correlate. jerk-locked eeg back-averaging was performed on two representative patients. the average age of patients with myoclonus was +/- years, and % (n= ) survived to discharge. cortical myoclonus was twice as likely as subcortical myoclonus ( % vs %, respectively). compared with patients without myoclonus, patients with myoclonus were more likely to have longer, more severe arrests. patients with subcortical myoclonus were at risk for electrographic seizures, although at a lower rate than those with cortical myoclonus ( % vs %, respectively). mortality rates did not differ between patients with cortical and subcortical myoclonus ( % vs %). patients with cortical myoclonus were more likely to be discharged in a vegetative state compared to those with subcortical myoclonus ( % vs %, respectively (or . ; %ci . - . ). amongst survivors, good functional outcome at discharge did not differ between cortical vs subcortical myoclonus ( vs %, respectively). jerk-locked eeg back-averaging was useful in distinguishing subcortical from cortical myoclonus. myoclonus is seen in every sixth patient with cardiac arrest. cortical and subcortical myoclonus cannot be distinguished using clinical criteria. both may have good outcomes when managed with targeted temperature management and an aggressive antiepileptic regimen. intoxication by central nervous system (cns) depressant drugs can lead to anoxic brain injury by cardiac or respiratory arrest. we tested the hypothesis whether intoxication by these drugs contributes to mortality in acute anoxic brain injury we utilized healthcare cost and utilization project databases (nationwide inpatient sample and kids' inpatient database) to obtain patients admitted with diagnosis of anoxic brain injury. patients with drug intoxication (opioid, alcohol, sedative/hypnotic drugs) were identified. regression analysis was used to assess relationship between drug intoxication status to in-hospital mortality. the regression model was adjusted for age, gender, chronic medical comorbidities, presence of cardiac arrest and hospital characteristics. we analyzed a total of , patients with anoxic brain injury out of which ( . %) had drug intoxication and % were reported to have cardiac arrest. median age was years and % patients were males. in-hospital mortality was %. among the survivors, % underwent feeding tube placement and % had tracheostomy. drug intoxication was a significant positive predictor of inhospital mortality with adjusted odds ratio . ( . - . ), p= . . cns depressant drug intoxication is associated with higher in-hospital mortality in patients with acute anoxic brain injury. cardiac arrest affects approximately , individuals every year and is the third most common cause of mortality in the us. currently, there is no way of reliably risk stratifying survivors of cardiac arrest. identifying early predictors of outcome is vital for triaging and clinical trial enrollment. we proposed to identify key clinical and laboratory parameters that can reliably predict long-term outcomes among comatose survivors of cardiac arrest. this was a retrospective chart review of comatose survivors of cardiac arrest. we gathered data regarding several clinical (age, pre-arrest mrs, gcs on admission, and hours, presence/absence of shock and respiratory failure) and laboratory parameters (troponins, lactate, creatinine, and alt at admission, and peak values within the first and hours) as well as characteristics of the cardiac arrest (duration, arrest rhythm, location, and bystander cpr). we used a dichotomized gos ( - vs - ) at months as the primary outcome. we performed univariate and multivariable analysis to identify predictors of poor outcome. a total of patients were enrolled. on univariate analysis, higher age, higher pre-arrest mrs, lower gcs at hours, non vf/vt arrest rhythm, in-hospital arrest location, absence of bystander cpr, and shock were statistically significant (p < . ) for poor outcome. in multivariable analysis, only higher prearrest mrs and lower gcs at hours were independent predictors of poor outcome; no bystander cpr demonstrated a trend for being an independent predictor. none of the early laboratory data achieved statistical significance for predicting poor outcome. we identified several clinical predictors of poor outcome in our small cohort of comatose survivors of cardiac arrest. the above variables need to be analyzed among a larger cohort that includes all survivors of cardiac arrest in order to develop an injury severity score that can help risk stratify cardiac arrest survivors. after cardiac arrest, somatosensory evoked potentials (sseps), eeg characteristics, and mri are routinely used to evaluate comatose patients. the relationship between structural hypoxic injury, absent cortical potentials and the generation of background reactivity or epileptogenic potentials is unclear. here we evaluate a consecutive series of patients with cardiac arrest that were studied with sseps and evaluate clinical, eeg, and mri measures to study the dissociation between hypoxia-induced thalamic disconnection and spontaneous cortical activity. in this retrospective cohort study, all comatose patients post-cardiac arrest who received sseps were identified and reports were reviewed. patients were found; one patient with a high cervical cord injury was excluded. we recorded presence of cortical (n ) and subcortical evoked responses (p ), whenever available. based on the closest available eeg (maximum days from ssep recording) we determined reactivity, background characteristics (diffuse suppression or burst-suppression versus all other backgrounds), and presence of generalized periodic discharges (gpds) or seizures. diffusion weighted or t flair abnormalities in the thalamus were evaluated based on available mris. chi-square and fisher's exact test were applied as applicable. of patients with ssep, ( %) had absent n s, and % of those (n= ) had absent p . eeg reactivity was possible, albeit less common, in patients with absent n s ( % vs %, p< . ), but none of the patients with absent p s had a reactive eeg. those with absent n s were more likely to have diffusely suppressed or burst-suppressed background ( % vs %, p= . ) and to have abnormal thalamic signal on mri ( % vs %, p= . ). gpds, stimulus-induced gpds, and seizures were equally common in those with and without n s. the integrity of the somatosensory thalamo-cortical pathway does not appear to be necessary for presence of reactivity or generation of periodic epileptiform discharges. all families of patients who have become brain dead (bd) should be offered the choice of donation. this does not always happen and the factors that lead to approaching them or not are not known. our objective was to evaluate which factors influence the donation coordinators (dc) working for an organ procurement organization approach families after brain death we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation and cross-matched the hospital electronic medical records with the records of the local organ procurement organization. in order to refine neurologic prognosis in cardiac arrest patients we sought to incorporate heart rate variability into a multimodal prediction model. heart rate variability has been shown in animal studies to be preserved in survivors of cardiac arrest. in our preliminary study, we retrospectively analyzed patients admitted to the university of virginia who had undergone a cooling protocol following cardiac arrest. analysis of heart rate variability for each patient was done in the frequency domain using the fast fourier spectral transform with spectral bands at . - . hz for high frequency (hf) and low frequency (lf) power within the frequency band . - . hz. the unit-less lf/hf ratio was considered a measure of balance between sympathetic and parasympathetic tone. over a -year period, a total of patients were cooled. patients ( %) had ceeg, ( %) had routine eegs and ( %) had sseps performed. numerous patients ( , % of all arrests or % of all eegs performed) had malignant patterns, defined as burst suppression, severe suppression, or generalized periodic discharges. of the sseps, had an absent n (none survived to discharge) and had an n that was present ( survived to discharge). patients with absent n s and malignant eegs had lower lf/hf ratios when compared to survivors with present n s ( . vs. . ). the trend towards parasympathetic dominance following a severe neurologic injury and loss of normal sympathetic tone in those patients with absent n s and malignant eegs and may serve as an additional marker of poor prognosis following cardiac arrest. physicians often struggle with the intricacies of brain death determination and communication about end-of-life care. in an effort to remedy this situation, we introduced an educational initiative at our medical school to improve student comprehension and comfort dealing with brain death. beginning in july , students at our medical school were required to attend a -minute brain death didactic and simulation session during their neurology clerkship. students completed a test immediately before and after participating in the initiative. of the students who participated in this educational initiative between july and june , ( %) consented to have their data used for research purposes. students correctly answered a median of % of questions (iqr - %) on the pretest and % of questions (iqr - %) on the posttest (p< . ). comfort with both performing a brain death evaluation and talking to a family about brain death improved significantly after this initiative ( % of students were comfortable performing a brain death evaluation before the initiative and % were comfortable doing so after the initiative, p< . ; % were comfortable talking to a family about brain death before the initiative and % were comfortable doing so after the initiative, p< . ). incorporation of simulation in undergraduate medical education is high-yield. at our medical school, knowledge about brain death and comfort performing a brain death exam or talking to a family about brain death was poor prior to development of this initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. this initiative was clearly a success and can serve as a model for brain death education at other medical schools. early withdrawal of life support (ewls) is a major factor in deaths following hypoxic ischemic injury after cardiac arrest (ca) in patients receiving targeted temperature management (ttm). appropriate timing of prognostication, and subsequent withdrawal of life support is recommended in recent guidelines, but is not always followed in clinical practice. we describe the impact of ewls in a multicenter registry database. using data from the international cardiac arrest registry (intcar), we defined ewls as withdrawal in the first three days of hospitalization. among all patients treated with targeted temperature management, we developed a logistic regression model to predict ewls. we then performed a propensity score and evaluated the incidence of good outcome between deciles of risk for ewls. patients entered into intcar from - from different hospitals were included. mean age was (± ) years, mean cpr duration was (± ) minutes, ( %) had a shockable rhythm, and ( %) received bystander cpr. support was withdrawn in , with ( %) events classified as ewls. ( % of total cohort). among patients with support withdrawal, older age (p= . ), nonshockable rhythm (p= . ), increased ischemic time (p= . ), and shock on admission (p< . ) were associated with ewls. among propensity matched patients grouped into deciles of probability for ewls, survival with good functional outcome occurred in % ( th decile), % ( th), % ( th), % ( th), and % ( th decile). early withdrawal of life support after cardiac arrest occurs frequently, and is associated with age, duration of cpr, a non-shockable rhythm, and shock at the time of admission. a cohort of patients propensity-matched to those with ewls had - % survival with favorable neurologic outcomes. these data support that in most patients receiving ttm, conservative and delayed prognostication after cardiac arrest is appropriate. brain herniation (bh) is a deadly event that requires immediate central venous access for infusion of hyperosmotic agents, especially . % nacl. traditional venous catheters, whether peripheral or central, takes several minutes to place, and requires skill for successful placement, thus delaying critical treatment. intraosseous (io) cannulation has been shown, at least during cardiac arrest, to be a secure and rapid means of central vascular access that requires limited training. however, limited data exists on the use of io in bh for administering . %. the aim of study of this study is to measure changes in serum sodium and bh reversal after administering . % via io. retrospective chart review of patients with acute neurologic injury requiring . % and io placement due to a lack of central access. demographics, diagnosis, gcs, sodium (na+), and pupillary reactivity, and immediate and delayed complications were collected. results patients included: males, age range - yo. diagnosis include intracerebral hemorrhage ( n= ), extra-axial hematoma (n= ) and sah (n= ). gcs ranged to . all patients were intubated. most patients were co-treated with hyperventilation, nabicarb, mannitol, and propofol. io was placed in tibia ( ) or humerus ( ); all placed correctly on first attempt. comparing hr post- . % nacl treatment to pretreatment: na+ level increased in of ; gcs improvement in of ; and returned pupillary reactivity in of . no adverse events reported, such as shock, cardiac arrest, tissue or limb injury. preliminary data suggest that during bh, io cannulation results in safe and timely . % administration in patients with no central access. additional safety data is needed, particularly with regards to the potential for myonecrosis. however, if safe, io cannulation should replace central line placement as the initial route of central venous access during bh. the pupillary light reflex is associated with outcome after cardiac arrest as a dichotomous variable (present/absent) at various time points following resuscitation (rosc). infrared pupillometry provides quantitative measures including pupil diameter (pd), and neurological pupil index (npi) which ranges from (nonreactive) to (brisk) and reflects velocity and degree of pupil constriction in response to a standardized light stimulus. these measures may provide early prognostic information to guide therapy. comatose adult survivors of cardiac arrest treated with targeted temperature management were monitored with the neuroptics npi- pupillometer. outcomes were defined as good (go) if discharge cerebral performance category score was - , and poor (po) if - . data are presented as median (iqr). groups were compared using non-parametric statistical tests. fifty-one patients were enrolled; the median age was ( . - . ), and ( %) were male. initial rhythm was vt/vf in %, asystole in %, and pea in %. outcome was good in ( %) patients. the initial pd did not differ between outcome groups [ . ( - . ) po vs . ( - . ) go]. the initial npi was lower in poor outcome patients [ . ( . - ) vs . ( . - . ) go, p= . ] measured . ( . - . ) hours after rosc. npi dropped below in more poor outcome patients [ ( %) vs ( . %) go, p= . ], and to zero in ( %) poor vs ( %) good outcome patients (p= . ). receiver operator characteristic curves confirmed that initial npi predicted poor outcome better than pupil diameter (auc . vs . , p= . ). a low neurological pupil index predicted poor outcome - hours after resuscitation from cardiac arrest, and dropped to abnormal levels (< ) and to zero (reflecting a non-reactive pupil) more often in patients with poor outcomes. additional research is needed to define potential confounders, optimal timing, and thresholds for different levels of neurological risk with pupillometry. prediction of death in a timely manner after withdrawal of life support (wls) is essential during organ donation after cardiac death (dcd). we aimed to develop a modified version of the recently develop dcd-n score to improve the specificity of prediction and test it in a specific group of patients with catastrophic brain injuries referred for dcd. we analyzed prospectively collected data by our local organ procurement agency on all consecutive adults with severe neurological injury evaluated for dcd across centers in the usa from march to may . we analyzed three variables used in the dcd-n score (corneal reflex, cough reflex and oxygenation index) and substituted the fourth variable for vasopressor support. a total of patients, mean age (sd± ) years were included in the final analysis. anoxic brain injury was the most common cause of death ( %) followed by stroke ( %). in multivariate logistic regression analysis adjusted for age and cause of death, absent corneal reflex (or . , % ci . to . , p = . , points), absent cough reflex (or . , % ci . to . , p = . , point), vasopressor support at high doses (or . , % ci . to . , p < . , points) and o ind ci . to . , p = . , points) were associated with the likelihood of death within minutes of specificity % and auc . . the modified dcd-n score has a greater specificity in predicting death within minutes of wls and is developed specifically from a cohort of patients evaluated for dcd. future prospective studies are needed for further validation of this scoring system. significant number of the patients with anoxic brain injury have poor neurological recovery. this created a significant anxiety in families who often request early prognostication. this study was conducted to evaluate possible ultra-early prediction of good neurological recovery in patients undergoing hypothermic protocol for anoxic brain injury retrospective chart review of the patients with anoxic brain injury was conducted. all patient underwent standard evaluation and management in the early stages of icu care, including initiating of hypothermic protocol with intravenous cooling device. all patients underwent evaluations with eeg and ssep within first day after admission during hypothermia phase and mri brain after re-warming. total of charts were reviewed. patient had normal ssep and normal mri. all patients had good neurological recovery, except for one patient who died secondary to severe cardiac failure eeg did not have any predictive value for the good neurological outcome when it was done during hypothermic protocol. normal ssep may a reliable predictor for good neurological recovery. apnea test is the essential component to confirm brain death by stimulation of respiratory center in brainstem. guidelines recommend that apnea testing should meet the criteria of disconnection from mechanical ventilator, and oxygen supplying by catheter. however, during the apnea test under this technique, disconnection from ventilator may induce hypoxia due to abrupt decruitment of alveoli and pulmonary barotrauma such as pneumothorax. there are some studies that suggest continuous positive airway pressure can be effective for patients with hemodynamically instability and respiratory impairment. we suggest a novel method of apnea test by using ambu bag with positive end-expiratory pressure (peep) valve to avoid abrupt change of peep during the apnea test. apnea testing was performed by using ambu bag with peep valve to adult brain death patients. ambu bag was not bagging during the testing and just connected to endotracheal tube with l/min of % oxygen. peep valve was applied the same peep of previous mechanical ventilator. on the apnea testing, vital signs and ekg were monitored. arterial blood gas analysis were measured and minutes after disconnection from mechanical ventilator. there were no significant differences in mean pao between before and after apnea test ( ± and ± , p= . ). mean arterial blood pressure were ± mmhg and ± mmhg before and after the test, respectively. during the intervention and following observation, arrhythmia or pulmonary complications had not occurred. we suggest a novel method of apnea testing which is a simple and easy technique by using ambu bag with peep valve to minimize decruitment of alveoli. this method shows vital signs and respiratory oxygenation of the patients remained stable during the test. declaration of brain death based on clinical exam has been plagued with challenges. as a result, ancillary testing such as nuclear scintigraphy cerebral blood flow (cbf) studies have been recommended. we present a case in which the apnea test could not be completed due to hemodynamic instability and where the nuclear scintigraphy cbf study resulted in a false declaration of brain death. a y/o male was admitted with bilateral hearing loss and confusion. on day two, the patient developed blurred vision, and an mri confirmed bilateral cerebellar and pontine infarctions. by day four, he had developed diffuse cerebral edema in the cerebellum, brainstem, and bilateral occipital lobes, and we proceeded with the clinical exam for brain death. all cranial reflexes were absent; however the apnea exam could not be completed due to blood pressure instability. a nuclear scintigraphy cbf study revealed the complete absence of radiotracer activity, and the patient was pronounced dead. two hours later, the patient regained a gag reflex. on the following day, the clinical exam, with the exception of apnea testing, was again consistent with brain death. a cerebral angiogram was performed and demonstrated normal blood flow to the anterior circulation. the patient was ultimately pronounced dead on day eight after two separate complete clinical brain death exams, including apnea testing, were performed. cerebral angiography showed essentially normal blood flow where nuclear scintigraphy showed no blood flow. nuclear scintigraphy cbf studies are commonly recommended when apnea testing cannot be completed. given the dramatic differences in the results observed between these modalities, a reevaluation of this practice should be considered. patients' perceptions of recovery moderate outcomes, however studies exploring the specific cognitive, functional, and psychological domains associated with subjective perceptions of recovery at hospital discharge after cardiac arrest (ca) are lacking. this is a prospective, observational cohort of patients admitted to columbia university medical center after ca, and survived to hospital discharge between / - / . patients with sufficient mental status to perform a neuropsychological exam and a questionnaire at discharge were included. subjective perceptions of recovery were assessed via responses to the forced-choice dichotomized question, "do you feel that you have made a complete recovery from the arrest?"objective outcome measures of recovery included: repeatable battery for neuropsychological status (rbans), modified lawton physical self-maintenance scale (l-adl), barthel index (bi), cerebral performance category scale (cpc), center for epidemiological studies-depression scale (ces-d), and post traumatic stress disorder-checklist (ptsd-c). chi-square, wilcoxon-rank sum, and logistic regression were used to compare the respondents, and determine factors associated with subjective perceptions of recovery. patients were included with mean age of ± years; % were men and % were white. % responded not having made a complete recovery. no significant differences were found between respondents in terms of demographics, charlson comorbidity index, arrest-related variables, rbans, l-adl, bi, pre-or post-arrest cpc scores. those responding that they had not made a full recovery had higher rates of ptsd-c ( % vs %, p< . ), and depression ( % vs %, p= . ). moreover, everyone that screened for ptsd (n= ) reported not having made a complete recovery. patients with higher ptsd scores were more likely to report not having made a complete recovery (or . ; p< . ) after adjusting for age, gender and depression scores. presence of post traumatic stress disorder symptomatology at discharge, and not neurocognitive or functional status, is highly associated with post-cardiac arrest patients' subjective perceptions of recovery. early eeg background reactivity is a strong predictor of neurological recovery after hypoxic-ischemic brain injury despite hypothermia and sedation. unfortunately, expert interrater-agreement on visual scoring of eeg background reactivity ranges from - %. recent studies indicate that machine-learning approaches using quantitative eeg (qeeg) might yield equivalent or superior performance to current eeg reactivity assessment practices, however its ability to predict outcomes has not been tested. we hypothesized that a qeeg reactivity method can predict long-term functional outcome in hypoxic ischemic brain injury. we retrospectively reviewed clinical and eeg data of cardiac arrest patients managed with hypothermia at two university hospitals. eeg reactivity was tested daily using a structured exam consisting of auditory, tactile, and visual stimulation. our quantitative eeg method evaluated changes in eeg spectra, entropy, and frequency features during seconds before and after each stimulation-step ( qeeg features used). only the first eeg reactivity assessment for each subject was used in the final analysis. good outcome was defined as cerebral performance category of - at six months. a penalized multinomial logistic regression was utilized for feature selection and a random-forest classifier was employed in the training and validation sets. model performance evaluation metric was the area under roc curve (auc). outcome and eeg data was available for a total subjects, and cases were excluded due to presence of burst-suppression, periodic epileptiform discharges, or eeg artifact. forty-seven subjects were included in the final analysis. mean age was . (standard deviation . ) years and . % had good outcome. the combination of four features provided best outcome prediction performance with an auc of . (kolmogorov-smirnov test, skewness, two-group test, and renyi entropy). early qeeg reactivity is predictive of good outcome at six months. a quantitative approach to eeg reactivity analysis might facilitate accurate and individualized prognostication in hypoxic-ischemic brain injury. hypoxic-ischemic brain injury is the leading cause of morbidity and mortality following cardiac arrest, and the ability to predict neurologic recovery in comatose cardiac arrest survivors is limited. functional mri measures brain network connectivity and resting-state network connectivity can be measured in comatose patients. the default mode network (dmn) is one resting state network that has been correlated with consciousness. we hypothesized the degree of connectivity in the dmn and other resting-state networks would correlate with consciousness recovery in post-cardiac arrest coma. consecutive patients with hypoxic-ischemic coma were enrolled. functional mri was obtained on all patients on post-arrest day - on an inpatient tesla mri. the connectivity in multiple resting-state networks was analyzed using pearson's correlations between component maps for each subject and previously defined standard network maps. connectivity in the default mode network and in additional resting-state networks was correlated with outcome. good outcome was defined as consciousness recovery at any point in the acute hospitalization. patients were included in this study. the mean age was ± years ( - ) and were male. patients survived with good outcome. the primary arrest rhythm and the duration of cardiac arrest did not differ between groups (primary rhythm as vt/vf: % vs %, good vs poor, p= . ; cardiac arrest duration: . ± . minutes vs . ± . minutes, good vs poor, p= . ). patients with good outcome had significantly higher mean network connectivity ( . ± . vs . ± . , good vs poor, p= . ). dmn connectivity showed a trend towards significance ( . ± . vs . ± . , good vs poor, p= . ). in comatose patients following cardiac arrest higher fmri measured resting state connectivity correlated with consciousness recovery. functional connectivity may be developed as a prognostic biomarker. sedative and analgesic infusions and neuromuscular blockade agents (nmba) are commonly used for comfort, suppression of shivering, and reduction of metabolic activity during targeted temperature management (ttm) after cardiac arrest. the optimal sedation and analgesia regimens are unknown. we sought to describe variability in sedation and shivering management practices at us and european cardiac arrest receiving centers. international cardiac arrest registry (intcar) centers were surveyed regarding sedation protocols for ttm after cardiac arrest. the survey was administered via redcap with a response rate of %. ten united states and european centers completed the survey. shivering is measured at ( %) of centers and recorded at ( %) centers. ten centers use nmb to control shivering prophylactically, centers use nmb only if shivering occurs, and centers increase opioids or sedatives when shivering occurs, but do not use nmb. the most common sedative was propofol ( / centers), followed by midazolam ( / ) and the most common analgesic was fentanyl ( / ) followed by remifentanyl ( / ). , , and centers report having a sedation target of light, moderate, or deep respectively. a sedation scale is used at ( %) centers, targeted to patient comfort at ( %) centers. daily sedation lightening is protocolized when rewarming starts at ( %) centers, when normothermia is reached at ( %) and not specified in the remainder of groups. of patients who awaken, centers report that they expect this to occur at ( centers), ( centers) and ( centers) hours respectively. among cardiac arrest receiving centers internationally, there is significant variability in ttm sedation and shivering management strategy. our hospital policy allows an optional sbd (with an apnea and a cerebral blood flow test) or a dbd (with an apnea test). we have evaluated the adoption of and reason for performing a single brain death exam (sbd) vs two (dual) brain death exams (dbd) and their impact on organ function and consent for organ donation. we evaluated our hospital's bd registry between january and june regarding sbd or dbd. we also cross-matched our electronic medical records with the records of the local organ procurement organization. of bd declarations, ( %) were sbd and ( %) dbd. during the st five years, % of all bd exams were sbd and during the second %. patients with sbd were older ( . ± . for sbd vs . ± . years for dbd, p= . ), had a primary neurologic diagnosis ( % vs %, p< . ) and were admitted to the neuro-icu ( % vs %, p< . ). during the nd exam, . % patients were on equal or higher dose of pressors. sbd patients had lower k+, bun, creatinine and heart rate, but higher peak na+ and apnea pao (for all p< . ), although apnea ph and paco were similar. the time between injury to bd pronouncement was shorter in sbd by . hours. there was no difference in consent rate between sbd and dbd ( % vs %, p= . ). at our institution, bd declaration was more often done by dbd exams, although the primary diagnosis and the unit of admission influenced the decision. an increased adoption of sbd exams was noted after the aan bd guidelines, supporting sbd exam, were published. although the number of exams did not affect rate of consent for donation, surrogate markers indicated better function of organs after sbd, while dbd patients stayed in the icus over a day longer. there are no data supporting better numbers or function of organs in donors after brain death (bd), if there is a shorter waiting period (as expected with single brain death exam [sbd] ) from the time that bd is declared to the time the patient arrives at the operating room (or). our goal was to find if the number of brain death exams, either sbd or dual (dbd), had any impact on the number of organs recovered and transplanted we evaluated our hospital's bd registry between january and june regarding sbd or dbd and cross-matched our electronic medical records with the records of the local organ procurement organization out of bd declarations, led to consent, of which ( . %) after sbd and ( . %) after dbd. there was a trend for longer consent to or time for dbd ( . ± . hours vs . ± . for sbd, p= . ). there was no difference in the number of organs recovered or transplanted based on the number of exams ( . ± . vs . ± . organs/patient recovered and . ± . vs . ± . transplanted for sbd vs dbd, respectively, p> . ). there was a trend for more lungs to be transplanted after sbd exam ( % vs %, p= . ), but this was not found with kidneys, heart, liver, pancreas or intestines. in multiple logistic regression models, adjusting for variables pertinent to each individual organ function (for example, bun or creatinine level for kidneys, blood gases for lungs etc), the number of exams was not an independent predictor for successful transplantation conclusions sbd exam led to similar numbers of organs transplanted compared to dbd exam in this single center registry analysis. more rapid brain death declaration, as with sbd, is not a factor that influences organ transplantation the glasgow coma scale (gcs) is a standardized and commonly used way of assessing important aspects of neurological condition for critically ill patients. while it is a validated tool for prognostication, it is unclear whether serial measurements add value to this prognosis. we used a large set of serially collected gcs measurements to assess the impact of gcs score on the trajectory of neurological recovery as well as factors affecting score variance. gcs total and subscores ( , time points from , patients) recorded hourly by registered nurses in the neurosurgical intensive care unit (nsicu) between january, and may, were analyzed retrospectively. k-means clustering provided groups with similar progression characteristics during nsicu stay. k-means clustering provided groups with similar progression characteristics during nsicu stay. descriptive features for each cluster were binned into histograms and evaluated for similarity using and kruskal-wallis tests. linear correlations of the sub-scores were very high (eye-verbal: . , eye-motor: . , verbal-motor: . ), while compositional variance was low for aggregate scores. hour-to-hour variance in gcs correlates to significant nsicu activities such as nursing shift changes. among patients with similar minimum gcs scores during their stay, those that recovered were significantly less likely to have deteriorated in the hospital ( , p<< . ). for patients with a minimum gcs<= , those that arrived at their minimum score (i.e., did not deteriorate in nsicu) were . % more likely to recover than those who deteriorated in-hospital (kw, p<< . ) . patients that experienced recovery show significantly greater improvement as early as hours after their minimum score (kw, p<< . ). the gcs is unnecessarily complex for most nsicu patients and can be represented by fewer variables. serial gcs measurements do provide value for prognosis and may be able to distinguish patients with potential to recover early in their hospital course. stroke is a major cause of death and disability, and common admission to neurological intensive care units. preferences for cardiopulmonary resuscitation (cpr) are often discussed, but there is limited understanding of cpr outcomes among stroke patients. systematic review and meta-analysis of published literature from to among stroke patients undergoing in-hospital cpr. preferred reporting items for systematic reviews and meta-analysis, metaanalysis of observational studies in epidemiology, and utstein guidelines were used to construct standardized reporting templates. detailed searches of pubmed and cochrane libraries were supplemented with hand-searched bibliographies. primary data from studies meeting inclusion criteria at two levels were extracted, i) survival to hospital discharge after cpr, and stroke as a primary admitting diagnosis, and the less restrictive, ii) survival to hospital discharge after cpr with stroke listed as a comorbidity, were meta-analyzed to generate weighted, pooled estimates of survival to hospital discharge. of articles screened, there were articles ( %) that underwent full review. three articles met primary inclusion criteria, specifically identifying patients with stroke as a primary admitting diagnosis. twenty additional articles met secondary inclusion criteria, listing stroke as a comorbidity. there was an % ( % confidence interval (ci) . , . ) rate of survival to hospital discharge rate from a combined sample of patients that received in-hospital cpr. among the more heterogenous population of inpatients with stroke listed as a comorbidity, there was % ( % ci . , . ) rate of survival to hospital discharge. adherence to utstein reporting guidelines was poor, and neurological outcomes were measured in ( %) of studies. survival to hospital discharge among stroke patients is lower relative to general hospital populations. these preliminary findings highlight the need for improving the quality of evidence to inform patient and provider discussions of cpr among stroke patients. there is often a tendency to treat patients with traumatic brain injury (tbi) and a glasgow coma scale (gcs) score of on presentation less aggressively because of low expectations for a good outcome. based on the crash trial database, a prognosis calculator has been developed for the prediction of outcome in tbi patients. our aim was to investigate whether the crash calculator can be used for prognostication in patients with tbi and gcs of on presentation. we performed a retrospective review of patients with tbi and a gcs score of from / to / . the crash calculator has been validated to estimate mortality at days and death and severe disability at six months (glasgow outcome scale-gos - ). the calculator uses country of origin (usa in our dataset), age, gcs, pupils reactivity to light, presence of major extracranial injury, and findings on ct scan of brain (petechial hemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated hematoma). the individual prognosis for mortality at days and unfavourable outcome at months was calculated and compared with the actual outcomes. a total of patients were included. a tend toward underestimation of the risk of mortality at days was found (estimated mortality was % compared to actual mortality of %; difference of %, p = . ). however, the estimation of outcome at months was accurate (estimated gos - was . % compared to actual of . %, p = . ). the crash prognosis calculator underestimated the risk of mortality, but accurately predicted unfavourable month outcome in patients with tbi and gcs of on presentation. pending larger studies to validate our findings, we believe that crash calculator can only support -not replace -clinical judgment. there are no nationally enforced standards regarding brain death. few data exist on how brain death is determined across the u.s. we used claims data from - from a nationally representative % sample of medicare defined as icd- -cm code . . the primary outcomes were evaluation by a neurologist or neurosurgeon, defined as a physician evaluation-and-management claim associated with the medicare provider specialty codes for neurology or neurosurgery, during the dates of the hospitalization. cpt codes were used to ascertain ancillary testing: brain radionuclide imaging, transcranial doppler ultrasound, or electroencephalography for brain death determination. exact binomial confidence intervals (cis) were used to report proportions. we identified patients with a brain death diagnosis. common associated neurological diagnoses were stroke ( patients; . %), cardiac arrest ( ; . %), and traumatic brain injury (tbi) ( ; . %). head ct or brain mri was performed in . %; this was true of . % of cases of stroke or tbi versus . % of cardiac arrests. neurologists were involved in the care of patients ( . %; % ci, . - . %). they were more commonly involved in the care of stroke ( . %) or cardiac arrest ( . %) than tbi ( . %) or other conditions ( . %). neurosurgeons were involved in cases ( . %; % ci, . - . %), mostly after tbi or stroke. two hundred patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon. twenty-nine patients ( . %; % ci, . - . %) underwent any ancillary testing. two hundred and nine patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon or underwent ancillary testing. in a nationally representative cohort of elderly patients, one-third of patients with a brain death diagnosis were not evaluated by a neurologist or neurosurgeon or by using ancillary tests. traumatic brain injury (tbi) is a major cause of death and disability in the us. recent advances in d illustration ( di) can precisely quantify intracranial pathology on computed tomography (ct). the current standard of measurement, abc/ , demonstrates variability in precision with bleed phenotype. the aim of this project is to assess accuracy automated di and compare it to standard abc/ measurements. baseline ct scans collected during the protectiii multicenter clinical trial (n= ) were retrospectively reviewed by a central neuroradiologist. subdural and epidural hematomas were identified (n ). the radiologist calculated abc/ score using osirix (mac) and radiant (pc) workstations. in a blinded fashion, research assistants concurrently generated di using the following methods: dicom data were resampled to . mm thickness slices and symmetrized using image analysis software (aquarius terarecon inc, ) . lesions were then compiled into single volumetric regions of interest ( d slicer v . , ) . hemorrhages were divided into two groups for analysis: group . volume of hemorrhage bland-altman analysis. this study was irb approved. there is a significant difference between the results of the di and abc/ methods. in group . the estimated relative bias between the two measurements (after transformation) is . (sd . ; pvalue . ; % ci . , . ). in group , the relative bias is - . , sd . , pvalue < . , % ci (- . , - . ). the di method calculates detailed surface area measurements in large and small volume hemorrhages, while abc/ averages cross-sectional area. the abc/ estimates vary by bleed phenotype and offer less topographical precision than di. this is particularly true in extra-axial hemorrhages, which are numerous studies have shown a significant association between hypotension and poor outcome in patients with head injuries. prior investigations have demonstrated that generation of negative intrathoracic pressure (itp) in ventilated patients with brain injury improves mean arterial pressure (map) and lowers intracranial pressure (icp). we hypothesized that augmentation of negative itp by breathing through an impedance threshold device (itd) with cmh o of inspiratory resistance would improve mean arterial pressure in a porcine model of intracranial hypertension. six spontaneously breathing female pigs ( . ± . kg), anesthetized with propofol, were subjected to focal brain injury through inflation of an french foley catheter placed in the epidural space. once a stable injury was obtained, baseline data were collected for minutes followed by minutes of itd use. results are reported as mean ± sd. the itp without the itd during inspiration was - . ± . mmhg, compared to - . ± . mmhg with the itd, p< . . following brain injury, map (mmhg) was significantly higher during itd use ( ± vs. ± ; p< . ). cerebral perfusion pressure (mmhg) was also significantly higher during itd use ( ± vs. ± ; p< . ). icp (mmhg) was not significantly different between groups ( . ± . vs. . ± . ; p= . ) although end tidal carbon dioxide levels (mmhg) were significantly higher during itd use ( ± vs. ± ; p< . ) presumably due to lower respiratory rates during itd use ( ± vs. ± ; p= . ). contralateral cerebral blood flow (ml/ gm/min) was similar between groups ( ± vs. ± ). in this porcine model of intracranial hypertension, spontaneous respirations through an itd significantly improved map and cpp. this approach could be utilized to prevent hypotensive episodes in the setting of brain injury. the impact of applying nanotechnology and biomedical engineering to improve the management of patients with spinal cord injuries (sci) is still not accurately described, nor understood. a systematic review of the literature was conducted, according to prisma criteria, to identify publications revolving around "sci+nanotechnology" and "sci+biomedical engineering" indexed on pubmed in the period - . furthermore, the database of clinicaltrials.gov was searched to highlight the stage of translation of this research into clinical practice through randomized clinical trials (rct). finally the uspto database was interrogated to identify the number of pertinent patents filed in northamerica in the same timeframe. the literature on bioengineering and nanotechnology contributions to sci is exponentially growing, with almost % of articles published between and . its quality and the interest of the scientific community are high, as confirmed by the average impact factor ( . ) and the average number of citations ( ) of articles published in the last two years. this field still represents a niche of sci research: the articles reviewed represent only . % of all articles on sci published in the same decade. this trend is confirmed on clinicaltrials.gov: out of rct on sci only few focus on the application of those technologies, furthermore out of articles spurring from the rct identified were published after , and % after . interestingly, with patents registered by the uspto, the interest in the commercial application of this research seems vivid. currently, the most promising areas of research are: nanofabrication/nanoscaffolding for structural repair, nanodrugs for regeneration, and design of neural interfaces for functional therapies. this review showed that both universities and independent research institutions (mostly from usa, china and european union) are driving this research race; the figures provided above suggest its potential to become a successful example of translational medicine. there are no neuroprotective and neuroregenerative treatments available for traumatic brain injury (tbi). clinical trials investigating potential treatments such as therapeutic hypothermia and progesterone have failed. pre-clinical studies indicate there may be a role of stem-cells in promoting neuroprotection/neuroregeneration in-vivo in animal models of tbi. we aim to provide a pre-clinical literature review into stem-cells as a potential therapeutic option in tbi-animal models. a literature search was conducted on pubmed and google scholar using the terms "traumatic brain injury", "stem-cell", "preclinical", and "animal studies". studies were included if there was an in-vivo animal model of tbi with either intravenous or intra-cortical stem-cell transplantation, along-with a control group, and investigated either motor or behavioral outcomes, or a combination. twenty-seven studies (n= animals) satisfied the criteria. / ( . %) animals were investigated for outcomes. studies harvested stem-cells from human-source, whereas harvested stem-cells from animal-source. bone-marrow stromal-cells (bmsc) were used in studies, neural stemcells (nsc) in , and miscellaneous in . / ( . %) animals received any stem-cell transplantation, whereas were controls. of animals receiving stem-cell transplantation ( ), ( . %) showed significantly better outcomes relative to control animals in each individual study, with exception of one study. amongst transplanted animals, functional outcomes did not differ significantly when grouped by stem-cell type (p= . ), transplantation route (p= . ), and source (p= . ). animals were followedup until week (n= studies), weeks (n= ), weeks (n= ), or > -weeks (n= ). this pre-clinical data demonstrates that stem-cell transplantation may have treatment potential in tbi as shown by improvement in functional outcome in as many as three-quarters of all animals that were treated with stem-cells. this data provides a foundation for the design of clinical translational studies. age of trauma patients including those with asdh is increasing as stated by national trauma registers. we were especially interested if age > years significantly influences outcome compared to younger patients and if other factors like initial gcs have an influence too. methods midline shift, if asdh was surgically removed, additional contusions, comorbidities and intake of anticoagulants. outcome was analyzed using the glasgow outcome scale (gos) at hospital discharge (gos ) and if possible months after discharge (gos ). uni-and multivariate analysis (cox regression model) was performed using the sigma stat softwar . . adverse outcome p= . . in addition, all patients > years with an initial gcs died whereas only % of younger patients with initial gcs died (p< . ). this was the only significant result in the multivariate analysis the monovariate analysis of our data showed a significantly higher risk for adverse outcome after asdh whe it should be considered if it is reasonable to transfer them from local hospitals to a specialized neurosurgical clinic, especially in times of limited resources. reported incidence of pulmonary edema in isolated head injury varies from - %. lung sonography is a potentially useful non invasive technique to detect extravascular lung water(evlw). this study aimed to identify the presence of evlw using lung ultrasound (b lines > per lung field) in chead injured patients admitted to icu . secondary objectives were to compare diagnostic accuracy and time to identification of evlw using chest x ray versus lung ultrasound. association of evlw with duration of mechanical ventilation (mv)and icu stay were observed after ethical clearance (iec no. int/iec/ / ), patients with head injury requiring mv and critical care were enrolled in the study. daily routine chest x ray and bedside lung ultrasound were done from the day of icu admission until the patient was on mechanical ventilator support. four inter costal spaces (ics) were scanned in semi recumbent position; third and sixth ics on either side of sternum till mid clavicular line. evlw was reprted as > b lines per lung field scan sonographically. details of mv and icu management were noted . evidence of evlw at the time of admission using sonography and cxr was recorded in and patients respectively. during icu stay . % patients showed evlw using lung usg (vs patients on cxr). mean delay in detection of evlw on cxr after detection on ultrasound was . ± . days. patients with low gcs, s. albumin, pao /fio ratio and greater apache ii and saps ii had significantly higher incidence of evlw. duration of weaning, mechanical ventilation and icu stay was significantly longer in patients with presence of evlw (p < . ) conclusions: lung ultrasound appears promising in detecting evlw earlier than chest x ray and may aid to minimize the duration of mechanical ventilation, weaning and icu stay . antiepileptic drugs (aeds) are recommended by guidelines for prophylaxis of early post-traumatic seizures (pts) associated with traumatic brain injury (tbi). there has been an increased use of both phenytoin and levetiracetam for this indication. the purpose of this study is to determine the incremental cost-effectiveness of phenytoin compared with levetiracetam for early pts prophylaxis in tbi patients. a cost-effectiveness study was conducted comparing phenytoin and levetiracetam for early pts prophylaxis during the days post-tbi. patients were included if they were years or older, received a study drug, and had a diagnosis of tbi. patients were excluded if they had a history of epilepsy, did not sustain a recent tbi, were initiated on both study drugs concurrently, or were switched to pentobarbital for elevated intracranial pressure. data was collected via retrospective chart review using electronic medical records and publically reported costs. effectiveness was measured as having a successful seizure prophylaxis regimen (sspr), which was defined as ) no clinical or electrographic seizure, ) no discontinuation of study aed, ) no cross-over of study aed to different aed, or ) no addition of aed during the days of therapy. the costs included costs of the study drugs, phenytoin level, and eeg. the data was used to calculate the primary endpoint, the incremental cost for the incremental change in sspr or the incremental cost effectiveness ratio (icer). the phenytoin regimen (n= ) cost $ . and had an sspr of . %. the levetiracetam regimen (n= ) cost $ . and had an sspr of . %. the icer was $ for each % increase in sspr with levetiracetam. the sspr of phenytoin and levetiracetam were similar. because patients who received phenytoin may differ from those who received levetiracetam, further analysis is needed prior to drawing any conclusions about the cost-effectiveness of levetiracetam relative to phenytoin. augmented renal clearance (arc) has been reported in up % of critically ill tbi patients and may impact therapeutic drug concentrations. improved predictors of arc are needed. serum cysc, a validated marker of glomerular filtration, has not been examined as a marker for arc in critically ill tbi patients. this pilot study tested the hypothesis that serum cysc concentrations are lower than reference values following tbi. adult tbi patients enrolled in the ukccts-unctracs prospective study of arc effects on drug clearance, were eligible. cysc serum concentrations (elisa -r & d cysc) were measured daily for up to days and compared to reference values. descriptive statistics and student t-test for continuous measures (patient vs. reference lower range cysc) were calculated. the first ten patients [ m/ f, mean age= . years ( - y/o), median gcs= (iqr - )] provided a total of serum cysc for analysis. each patient provided at least samples (range - ) for up to seven days. measured serum cysc concentrations were below the reference range in of samples. the overall mean cysc concentration was . + . mg/l vs expected mean of . + . . (ns) measured values fell below the lower reference range in patients ( m/ f) for the first study days (mean = . + . vs . + . p< . ). the mean difference between measured concentration and reference value was . + . mg/l. after days, four patients ( m/ f) remained below reference values with a mean difference of . + . mg/dl. preliminary results show cysc was not consistently below reference ranges in all tbi subjects. a subset of subjects showed significantly lower cysc within seven days of injury. the relationship between cysc and arc needs to be further examined as analysis continues. functional connectivity of the default mode network (dmn) is believed to be necessary for recovery of consciousness after coma. however, dmn connectivity has not been comprehensively studied in patients with acute severe tbi. we hypothesized that dmn connectivity in patients with acute severe tbi is associated with level of consciousness. we prospectively enrolled patients admitted to the intensive care unit for acute severe tbi and performed resting-state functional mri (rs-fmri) as soon as safely possible. dmn functional connectivity was assessed by rs-fmri analysis of the blood-oxygen level dependent (bold) signal using a seed-based approach. pearson's correlation coefficients were calculated between the mean bold time series within dmn nodes and all other regions in the brain. level of consciousness was assessed at the time of the scan using the coma recovery scale-revised (crs-r). two-sample t-tests were performed to identify brain regions with connectivity differences between conscious and unconscious subjects. we then tested for associations between level of consciousness and dmn connectivity within these regions. we enrolled patients ( male, mean+/-sd age +/- years) and matched controls ( male, age +/- years). rs-fmri was performed . +/- . days post-injury. at the time of rs-fmri, patients' levels of consciousness were coma (n= ), vegetative state (vs; n= ), minimally conscious state (mcs; n= ), and post-traumatic confusional state (ptcs; n= ). connectivity within the medial prefrontal cortex and posterior cingulate was selectively reduced in unconscious patients (coma and vs) compared to conscious patients (mcs and ptcs; false discovery rate-corrected p < . ). when these regions were further interrogated, connectivity correlated with crs-conclusions dmn functional connectivity correlates with level of consciousness after acute severe tbi. traumatic brain injury (tbi) is a substantial source of death, disability, and healthcare utilization. many older tbi patients present to community hospitals and are transferred to trauma centers for further care; however, little is known about the provision of care and patient outcomes at the final receiving hospital. we described trauma center care among geriatric transfer patients with tbi. we conducted a secondary analysis on a sub-cohort from a prospective multi-center study focusing on ambulance and emergency department (ed) care of injured older adults transported via ambulance. the current analysis focused on tbi patients transferred to the region's level i trauma center from another hospital. transfer paperwork from the originating hospital was reviewed and we conducted a detailed medical record abstraction, including computed tomography (ct) findings, procedures, length of stay (los), and ed disposition. data were collected on transfer patients. thirty had confirmed abnormalities on head ct ( . %). the mean age was years (range: - ), % female, and the most frequent mechanism of injury was falls ( %). average los was . days (range: - , median los . ), with patients staying one day or less. ct findings included subdural hematoma ( %), subarachnoid hemorrhage ( %), and intraparenchymal hemorrhage ( . %). five patients required neurosurgical intervention ( %), eight required icu admission ( %), two were discharged from the ed ( %), and two transitioned to inpatient hospice ( %). tbi is a frequent cause of transfers to trauma centers. in our sample, admission occurred in the majority of patients, but neurosurgical intervention was less common. however, for appropriately selected patients, strategies such as telemedicine may reduce transfers thus saving resources and improving continuity of care for patients and their families. this is an area in which future research is warranted. the prospects and timing of decannulation may affect surrogate decision making regarding tracheostomy for traumatic brain injury (tbi) patients, yet predictors of decannulation are unknown. methods tracheostomy admitted to an affiliated acute rehabilitation hospital between january and december . patients who had life-sustaining measures withdrawn were excluded. admission data, including injury characteristics and presence of lung injury on initial chest x-ray, and inpatient complications were compared. patients were followed throughout rehab and to the point of decannulation. patients lost to follow up were eliminated from analysis. time of decannulation was verified by inpatient physician notes. a cox proportional hazards model was created to determine factors associated with the time to decannulation and reported as hazard ratios (hr). there were tbi patients admitted to the icu during study period and ( % men, mean yearsold, median gcs ) underwent tracheostomy after ± days of intubation, of which were followed throughout rehabilitation. overall cannulation time was ( - ) days. ( %) patients had their trach removed prior to discharge from rehab after ( - ) days of cannulation. in a cox proportional model adjusting for sex, reintubation, aspiration pneumonitis, and presence of lung injury on admission chest x-ray; a higher hospital discharge gcs was associated with a shorter time to decannulation (hr, . ; % ci, . - . ; p =. ) while patients who required inpatient dialysis had a longer time to decannulation (hr: . ; % ci, . - . ; p = . ). the majority of tbi patients that require tracheostomy will be decannulated prior to discharge from rehab. longer durations of tracheostomy cannulatio hospital discharge and those that receive inpatient dialysis. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. poor outcome was defined via stratified dichotomy of the gos-e. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with outcome. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ) . parameters significant at alpha . are reported. prolonged duration of transgression was associated with poor outcome when: glucose> mg/dl (p= . ); hgb mg/dl (p= . ) and inversely associated with map mg/dl (p= . ) or and was inversely associated with map< mmhg (p= . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple significant associations between physiologic transgressions and patient outcome were found. the data suggest that reducing physiologic transgressions is important to minimizing patient morbidity after tbi. the measurement and management of intracranial pressure (icp) is a key component in the care of severe head injury. extracranial ventricular drains (evd) have remained the standard due to the ability to lower icp with the drainage of cerebrospinal fluid (csf). placement of an evd is a more invasive procedure than intraparenchymal icp monitors (ipm) and it is unclear if the use of an evd improves outcomes. we hypothesized that early placement of an evd, in adult patients with severe head injury, would not affect outcomes. utilizing data from the citicoline brain injury treatment (cobrit) trial, a prospective multicenter study, we identified patients who met the inclusion criteria; ) placement of an icp monitoring device, ) glasgow coma score (gcs) less than , ) evd placement prior to arrival or within hours of arrival at the study institution. primary outcome was glasgow outcome score-extended (gose) at days post injury. secondary outcomes included neuropsychological evaluations at days post injury, mortality, and length of icu stay. logistic regression with forward-stepwise predictor adjustment and propensity score adjustment was performed to assess the independent association between evd placement and outcomes. patients who received an evd prior to or within hours of arrival at the study institution had worse gose at days ( . ± . vs . ± . , p= . ), higher in hospital mortality ( % vs %, p = . ), and did worse on out of neuropsychological measures at days. there was no difference in icu length of stay ( . ± . vs . ± . , p= . ). early placement of evds in severe adult head injury is independently associated with worse outcomes and higher in hospital mortality. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with mortality. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ). parameters significant at alpha . are reported. mortality was . % and . % in the full and ticp cohorts. prolonged duration of transgression was associated with increased mortality for: hgb . (p mg/dl (p mg/dl (p= . ), and sbp . (p . (p= . ). covariates inversely related to mortality included single occurrence of map mmhg (p< . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple associations between physiologic transgressions and mortality were observed. the data suggest that maintaining physiologic measures within gdt guidelines may be important in preventing deaths. current outcome models in moderate-severe traumatic brain injury (mstbi) include only admission characteristics. yet, mstbi patients commonly have prolonged intensive-care-unit(icu)-stays with high risks to develop icu complications, lending to the hypothesis that these may be additionally associated with outcomes. the objective of this study was to examine the incidence rates of pre-specified medical and neurological icu complications, and their impact on post-traumatic in-hospital mortality and month functional outcomes. we analyzed mstbi patients consecutively enrolled in the prospective observational optimismstudy at a level- trauma center between / - / . poor outcome was defined as glasgow outcome scale - . multivariable logistic regression was employed to adjust for admission characteristics and icu-length-of-stay. the mean age was ± years, % were men, and median motor glasgow-coma-scale and injury-severity-scores were (iqr ; ) and (iqr ; ), respectively. the three most common medical and neurological icu complications were: hyperglycemia ( %), systemic inflammatory response syndrome ( %) and fever ( %); intracranial pressure crisis (icp; [ % of n= with icp-monitor]), brain edema requiring osmotherapy ( %), herniation ( %). multivariable models were adjusted for age, marshall-ct-classification, motor glasgow-coma-scale, pre-admission hypotension, icu-length-of-stay and injury-severity-score. after adjustment, in-hospital mortality was significantly associated with in-icu-cardiacarrest (or ; %ci . - . recent studies suggest benefits for early tracheostomy in patients with traumatic brain injury (tbi), yet data regarding who will require tracheostomy is lacking. ad lifesustaining measures withdrawn were excluded. admission and inpatient variables were compared. multivariable logistic regression analyses were used to assess admission and inpatient factors associated with receiving a tracheostomy and to develop models predictive of tracheostomy. there were patients ( % men, mean years-old, median gcs ) meeting study criteria with tracheostomy performed in ( %). admission predictors of tracheostomy included gcs, marshall score, injury mechanism, pao /fio ratio, and number of quadrants on chest x-ray with consolidation. inpatient factors associated with tracheostomy included the requirement for an external ventricular drain (evd), number of operations, pneumothorax, inpatient dialysis, aspiration, reintubation, and the presence of hospital acquired infections. multiple logistic regression analysis demonstrated that the development of hospital acquired infection (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ; p < . ), number of operations (aor, . ; % ci, . - . ; p < . ), pneumothorax (aor, . ; % ci, . - . ; p = . ), reintubation (aor, . ; % ci, . - . ; < . ), penetrating tbi (aor, . ; % ci, . - . ; p= . ) and placement of evd (aor, . ; % ci, . - . ; < . ) were independently associated with patients undergoing tracheostomy. a model of inpatient variables only was more strongly associated with tracheostomy than one with admission variables only (roc auc . vs. . , p< . ) and did not benefit from addition of admission variables (roc auc . vs . , p= . ). potentially modifiable inpatient factors have a stronger association with tracheostomy than do admission characteristics. existing traumatic brain injury (tbi) guidelines are designed primarily for the evaluation and management of tbi in tertiary care centers with advanced neuroscience capabilities. military special operations medical providers, however, are often required to treat and sustain patients in austere environments with limited resources for up to hours. tbi management guidelines directed specifically toward the care of these patients are needed. a review of recent operational experiences involving tbi and a survey of military special operations medics prompted a multidisciplinary expert panel to develop draft clinical practice guidelines/recommendations for prolonged field management of tbi. the panel conducted an in-depth review of literature on tbi and related topics and adapted existing and emerging therapies to address the unique challenges encountered in prolonged field care. tbi management while optimal management of pbto is not fully established. the objective of this -coeur arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). probes were localized in normal appearing white matter. we used a was calculated. a total of data sets were collected from patients (mean age . ± . , median gcs , mortality range from to ). mean pao for the group as a whole was mmhg (± ) and mean cpp was mmhg (± ). mean duration of pbto monitoring was . days (± . ). taking into account all determinants of pbto and using a protocolized approach to correct pbto , the mmhg for a few days. high pao values are possibly required due to the fact that oxygen delivery to the brain is rate-limited by diffusion and impaired by oedema or microvascular ischemia. it should be noted that pulse oximetry is not sensitive to detect pao below this level. traumatic brain injury (tbi) and stroke are extremely common causes of acute brain injury (abi), which cause long term disability and permanent neurological impairment. coma and stupor are common manifestations of abi, due to interruptions of the ascending reticular activating system (aras). neuro stimulants can improve functioning of the aras. despite decades of research there is a paucity of prospective high-level evidence utilizing neuro stimulants to help with earlier awakening from coma and stupor in abi. we reviewed the literature using the grade level of evidence (loe) methodology. we performed a preliminary literature search of the national library of medicine (nlm) using search terms abi and stimulants. within the literature we searched for timing of stimulant use among abi studies and included all forms of abi such as tbi, stroke, and anoxic injury. we retrieved total results, of which we excluded since they did not meet grade high loe criteria or were "n of " studies or aggregates. only high loe randomized studies or meta-analyses were found. among these various stimulants were investigated including methamphetamines such as methylphenidate and lisdexamfetamine, caffeine, armodafinil, galantamine, and amantadine. methylphenidate had randomized trials and a meta-analysis in subacute tbi but reported only attention as a main outcome. we were unable to draw broad-level recommendations about optimal timing, best stimulant, and patient centered outcomes from this data. there is insufficient data to recommend optimal stimulant, timing, and dosing among heterogeneous abi disease models. we propose conducting future homogenous abi neuro stimulant trials in for safety, tolerability, dose-finding, optimal timing, and outcomes based efficacy. neuro stimulants could play a role in earlier awakening and extubation in abi which could improve outcomes similar to sedation/vacation bundles in icu's currently if studied adequately. tbi remains the leading cause of death and disability in young adults in the us and europe. thus far, pharmacological and non-pharmacological intervention studies did not confirm benefits on functional outcomes. the inducible enzyme nitric oxide synthase (inos) is upregulated in response to brain injury, causing excessive production of no, a key driver of secondary injury after tbi. the antipterin vas is a structural analogue of the endogenous nos cofactor and a potent in-vivo selective inhibitor of inos. a randomized, placebo-controlled phase study examined dose levels of vas in patients with acute moderate or severe tbi. cerebral microdialysis showed pharmacologically relevant drug concentrations close to the injury and a tendency for vas to increase the arginine/citrulline ratio, an indirect marker of nos inhibition (stover et al., j neurotrauma ). vas conferred a significant benefit on the extended glasgow outcome scale interview (egos-i) at and months after injury. no changes in systemic blood pressure or partial brain oxygen pressure were noted. a recent pharmacokinetics and pharmacodynamics study further corroborated the selective inos inhibition by vas . the confirmatory nostra phase trial (eudract no. - - ; clinicaltrials.gov identifier nct ) was initiated in . adult patients with a nonrequiring intracranial pressure monitoring, are randomized : to vas or placebo, administered in addition to standard of care, as intravenous continuous infusion for hours, starting between and hours post tbi. the primary efficacy endpoint is egos-i at months post injury. additional endpoints include the daily therapy intensity level and tbi-specific quality of life measures. continuous safety monitoring is performed by an independent committee. nostra iii, the only ongoing registration study in acute moderate and severe tbi, is sponsored by vasopharm gmbh, and plans to recruit patients by q . a glasgow coma scale (gcs) score of on presentation in patients with traumatic brain injury (tbi) portends a poor prognosis. consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. we performed a retrospective review of patients with tbi and a gcs score of . demographics, apache iv scores , pupillary reactivity to light, intracranial pressure (icp), icp burden (the number of days with an icp spike > mm hg as a percentage of the total number of days monitored), and outcome (mortality and glasgow outcome scale-gos at months, with good outcome defined as gos of - ). patients were divided into groups: group (gos = - ) and group (gos = - ). a total of patients were included. the overall mortality rate was . %. at -month, patients ( . %) achieved a gos - . compared to group (n = ), group (n = ) had higher average apache iv score ( ± vs ± , p = . ), more patients with bilateral fixed pupils ( % vs %, p = . ), and higher icp burden ( ± vs ± , p = . ). gos score - was achieved in % of patients presenting with bilateral reactive pupils versus . % of patients presenting with bilateral fixed pupils (p = . ). . % of patients with tbi and a gcs of at presentation achieved a good outcome at months. apache iv scores, icp burden, and pupillary reactivity were significant predictors of outcome. we believe that patients with severe tbi who present with a gcs of should still be treated aggressively initially since a good outcome can be obtained in a significant proportion of patients. elevated circulating catecholamine levels are independently associated with functional outcome and mortality after isolated traumatic brain injury (tbi). we assessed the ability of peripheral catecholamine levels to improve the prognostic performance of the crash and impact-tbi models. prospective, observational, multicenter cohort study, conducted at three level trauma centers in canada and usa. epinephrine (epi) and norepinephrine (ne) concentrations were measured in the peripheral blood at admission (baseline), , and h after trauma. outcome was assessed at months and dichotomized into favorable [extended glasgow outcome scale (go -tbi models, which identified core prognostic markers of severe tbi. the baseline model (m ) included age, gcs and pupillary size/reactivity. the model (m ) included m + hypoxia, hypotension and marshall ct classification. model and included m + epi levels, and m + ne levels, respectively. the risk models performance was assessed by comparing receiver operating characteristic (roc) curves, and by the use of integrated discrimination improvement (idi) index. m had significantly higher roc and idi than the baseline model (m ), to predict mortality. m had a roc = . ( . - . , p = . ) and idi = . (p = . ). the prediction of mortality was not improved by including ne [m = roc = . ( . - . , p = . ) and idi = . (p= . )]. the integrated discrimination improvement index indicated the prediction of unfavourable outcome by the baseline model was improved by including epi (idi = . , p= . ), and ne (idi = . , p= . ) in the models. catecholamine levels improved risk models performance to predict mortality and unfavorable outcome after traumatic brain injury. following traumatic brain injury (tbi), depression is common and may influence recovery. small trials demonstrated that various drugs are beneficial in managing depression following tbi, but no large, definitive study has been conducted. we performed a meta-analysis to estimate the potential benefit of anti-depressant medications following tbi. multiple databases were searched using the terms "anti-depressant tbi," and "depression treatment tbi" to find prospective pharmacologic treatment studies of depression following tbi. studies were excluded if they did not measure depression as an outcome. effect sizes for anti-depressant medications in post-tbi patients were calculated for within-subjects designs that examined change from baseline after receiving medical treatment and treatment-placebo designs that examined the differences between anti-depressants and placebo groups. a random effects model was used for both analyses. of titles screened, studies were included, with total patients. medications evaluated included selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants. pooled estimates showed significant reduction in depression scores for individuals after pharmacotherapy (mean change [mc] - . , % confidence interval [ci]: - . to - . ) and significant difference in reduction of depression scores between medications and placebo in the pooled estimate (standardized mean difference of four trials [smd] - . , % ci: - . to - . ); however only one of the four treatment-placebo studies found medications significantly reduce depression scores more than placebo. this meta-analysis found a significant benefit of pharmacotherapy for treatment of depression in patients with tbi. however, there was a high degree of bias and heterogeneity regarding tbi severity, time since injury, depression severity, and demographics. larger prospective studies on the impact of anti-depressants on post-tbi depression are warranted to better understand treatment effects and the relationship of post-tbi depression and outcome more broadly. pleural effusion (pe) has been reported in % of medical icu. there is little published data on the prevalence and clinical significance of pe in mechanically ventilated patients with traumatic brain injury. head injury patients admitted to icu for mechanical ventilation (mv) within - hours and gcs > were assessed for eligibility. presence of pe was assessed by serial cxr on daily basis and volume of effusion was estimated and recorded. in case there was no evidence of pe on cxr, a bedside sonography in semi recumbent position was done within h of icu admission. pleural fluid volume was estimated based on -point classifications on sonography. details of mechanical ventilation and icu management were recorded. successful weaning was defined as ability to breath spontaneously for h. primary aim was to observe prevalence of pe in mv head injured patients. as secondary measure; impact of pe on duration of mv, weaning and length of icu stay were compared. study enrolled patients. three baseline cxr showed pe. total of ( %) patients developed pe in icu. patients had evidence of pe on both cxr and usg. patients had only sonographic evidence of pe, which were not detected on cxr. significantly more minimal effusions were detected on sonography ( / , p= . ). duration of mechanical ventilation and duration of icu stay were significantly more in patients with pe. (p= . , mann whitney rank sum test) there was no significance difference in duration of weaning in patients with and without effusion ( . ± . , . ± . , p= . ). chest ultrasonography increased the detection rate of pleural fluid. patients with pe had longer duration of mechanical ventilation. early detection may be associated with shorter period of mechanical ventilation and icu stay spine surgery can trigger a systemic inflammatory response syndrome and lead to hypotension requiring vasopressors. as sepsis is a major differential diagnosis in the post-operative period, the objective of this study is to understand the prevalence of a true systemic infection in this setting. retrospective review of all consecutive adults with post-operative shock requiring vasopressors following spine surgery in an academic tertiary medical center. a total of patients, median age years (iqr - ), were included in the final analysis. comorbidities included a median bmi of (iqr - ), coronary artery disease ( %) and diabetes mellitus ( %). median estimated blood loss was cc (iqr to cc). circulatory volume was adequately replaced in a total of % patients within hours post-op. all patients received crystalloids, and an additional % received multiple (> ) units of prbcs transfusion. adequate urine output was confirmed in ( %) of the patients. the maximum median rate and duration of each vasopressor infusion was as follows: phenylephrine mcg/min (iqr - , n = ), hours (iqr - ), norepinephrine mcg/min (iqr - , n = ), hours (iqr - ), epinephrine mcg/min (iqr - , n = ), hours (iqr - ) and vasopressin . units/min, hours ( - , n = ). of the patients, ( %) met at least sirs criteria. infection was confirmed in a total of patients; positive respiratory or blood cultures in ( %) patients and positive urinalysis or urine culture in ( %). two patients ( %) were diagnosed with myocardial infarction. no patients had pulmonary embolism. our study suggests that the risk of infection and sepsis in patients with persistent shock following spine surgery is small but not negligible. larger multicenter studies are needed to confirm our findings and to identify the predictive factors. ischemic and hyperemic injuries may occur unnoticed after severe traumatic brain injury (tbi) and contribute to additional brain damage. maintaining an adequate cerebral perfusion is considered crucial in preventing such injuries, as deviations from autoregulation-guided optimal cerebral perfusion pressure (cppopt) are associated with greater mortality and disability. this makes reliable estimation of cppopt an interesting diagnostic and treatment tool for monitoring. cppopt is defined as the cerebral perfusion pressure (cpp) at which the pressure reactivity index (prx) is minimal. the leading method for estimating cppopt automatically, by aries et al. ( ) , fits a parabola to pairs of prx and cpp data. the method uses preset heuristics to reject the fit as unreliable, namely when the parabola is too "shallow" or does not cover a certain cpp range. as a result, the cppopt estimates could be generated only about - % of the time. moreover, the manually set heuristics potentially restrict the generality of the model. here, we propose an alternative method based on bayesian inference. treating prx at each time as a function of cpp corrupted by noise serves as a "forward model" that can be inverted to yield, for a given data set, a temporally evolving posterior probability distribution over cppopt. the mean of this distribution is a bayesian estimate of cppopt; we find that these estimates are generally consistent with those obtained from the classic method. importantly, the width of the distribution at a given time serves as a metric of uncertainty about cppopt estimation. we find that this uncertainty tends to be large at time points where the classic method with preset heuristics rejects the fitted parabola. our method makes manually setting rejection criteria unnecessary. bayesian estimation of cppopt holds promise as a tool for providing additional decision support in the care of individual tbi patients. quantitative parameters derived from continuous eeg (ceeg) have been useful to understand evolution of traumatic brain injury (tbi) and the impact on regional networks. these parameters are often interrogated at a global level rather than region-specific. the regional evaluation of quantitative eeg parameters may provide an objective assessment of regional network function, and be of predictive value for prognostication continuous eeg was performed in patients with tbi, and mri imaging was obtained during acute and chronic time points post injury (within days and months, respectively). the extended glasgow outcome scale (gose) assessed clinical recovery at months, with good recovery defined as gose score - and poor as gose score - . volumetric measurements of selected brain regions, both cortical and subcortical, were obtained at acute and chronic time points. quantitative parameters derived from ceeg, such as percent alpha variability (pav) and hemispheric symmetry, were calculated continuously and anatomically (frontal, temporal, occipital) through the acute hospitalization course. we hypothesized that persistent regional variation in alpha power post injury would lead to brain regionspecific atrophy and may predict outcome at months acute pav within the first hours post injury was poor in patients with poor outcome. in addition, patients with poor outcome had significantly more atrophy in the thalamus, hippocampus, and temporal and occipital lobes. asymmetry of the hemisphere pav values correlated with both brain atrophy and clinical outcome regional asymmetry of pav within the first hours post injury correlates with chronic brain atrophy and clinical outcome after tbi after moderate and severe traumatic brain injuries (tbis), individuals are often admitted to an intensive care unit (icu), and later require intensive rehabilitation. many neuro-icus engage therapists and physiatrists for rehabilitation and therapy during a patient's icu admission. however, the optimal timing, intensity, and components of rehabilitation needed while in the icu are not known and practice patterns are highly variable. the goal of this study is to describe the rehabilitation practices to identify whether there is consensus on best practices. an electronic survey asking participants to describe tbi rehabilitation practices in their icu was distributed via redcap through the neurocritical care society (ncs) and american congress of rehabilitation medicine (acrm) websites. potential respondents were first asked if they cared for patients with tbi in the icu, and if they answered "yes," they were invited to complete the survey. two email reminders were sent to each group for completion. after weeks, the data were extracted and analysis completed. there were respondents who reported that they cared for patients with tbi in the icu ( attending physicians, advanced care practitioners, therapists, nurses, fellows, and other). of these, % recommended early rehabilitative care. the most common reasons to wait for the initiation of physical therapy and occupational therapy were normalization of intracranial pressure (icp) ( % and % respectively) and hemodynamic stability ( % and % respectively). speech therapy was typically recommended after extubation ( %) and normalization of icp ( %). the majority of clinicians caring for patients with tbi in the icu support early rehabilitation efforts, typically after a patient is extubated, intracranial pressure has normalized and the patient is hemodynamically stable. prospective studies evaluating the merits of these self-reported rehabilitation initiation criteria are warranted. high-dose methylprednisolone (hdmp) has been studied as a potential therapeutic option for acute sci, with mixed results regarding efficacy and consistent suggestion of complications. we conducted a retrospective cohort study of acute sci patients extracted from the medical information mart for intensive care iii (mimic-iii) database to evaluate the hypothesis that steroid-related adverse drug events (ades) occur less often than in published clinical trials using hdmp. three groups of patients coded for acute sci were identified from mimic-iii from june to october : hdmp recipients per nascis ii/iii protocols (hdmp, n = ), patients who received some steroids but not per nascis ii/iii protocols (non-hdmp, n = ), and patients who did not receive steroids (no steroids, n = ) . demographics and data on complications of steroid therapy were extracted. one-way anova or student's t test were used to evaluate continuous variables; chi-squared or fisher's exact test were used for nominal or categorical variables. there were no differences in steroid-related ades between the three groups. there were higher average blood glucose readings in recipients of any steroids compared with the no steroids group, and more variation in blood glucose readings in hdmp recipients compared with the other two groups. there was a higher icu los and ventilator time in the hdmp group compared with the other two groups. compared with three other trials examining similar use of hdmp in acute sci, there were higher rates of pneumonias overall, though lower rates of urinary tract infections, skin & soft tissue infections, pressure ulcers, and superficial thromboemboli/thrombophlebitis. the results of this study are consistent with previous works related to the potential for harm regarding the use of hdmp or any steroids in acute sci. changes in selected adverse event profiles may be due to standardization of icu supportive care over time. cervical spinal immobilization and clearance protocols are important steps in the minimization of secondary spinal cord injury. patients with primary neurologic diseases are frequently found down and placed in rigid cervical collars despite sustaining minimal-to-no cervical injury. in these patients, neurologic dysfunction can complicate and delay cervical clearance. decreasing time spent in cervical spinal immobilization could improve patient care by allowing greater access to / range-of-motion of the neck, increasing patient comfort, and decreasing skin breakdown. through retrospective chart review over a -month period, we collected the following: the rationale behind each mri, any mri evidence of cervical instability, the result of any ct imaging, and the basic mechanism of any trauma. for patients that were simply found down, any evidence of trauma either by history or physical exam was recorded. during the study period, there were instances where an mri of the cervical spine was performed. of those mris, ( %), were performed for cervical spinal clearance. sixty-one ( %) of mris were ordered without any ct imaging first. of the patients with a normal ct, six ( . %) were found to have mri evidence of cervical instability. notably, of the patients who were found down, there was only one instance where the mri demonstrated instability. that patient had extensive facial injuries suggestive of an unwitnessed fall. in the patients that were found down with no history or evidence on physical exam of trauma, there was no mri instability. for patients that are found down without any history or evidence on physical exam of trauma, a ct of the cervical spine is likely sufficient for cervical spinal clearance. acute subdural hematoma (asdh) represents a major clinical entity in severe traumatic brain (stbi), approximately % are accompanied by various extents of asdh. stbi has been reported to cause cerebral circulatory disturbances at an acute stage and had the worst circulatory disturbance among stbi. in this study, we focused on the cerebral circulation of asdh, evaluated the absolute left-right difference between cerebral hemispheres and compared the cerebral circulation between the favorable outcome group and the unfavorable group. we retrospectively reviewed patients with asdh. they were admitted to our hospital from to . in these patients, we simultaneously performed xenon-computed tomography (xe-ct) and perfusion ct to evaluate the cerebral circulation on post-injury days - . we measured cbf using xe-ct and mean transit time using perfusion ct and calculated the cerebral blood volume (cbv). a significant absolute difference in cerebral circulation between the hemispheres among different types of tbi was observed in mtt. there was no significant difference in these parameters between left-right hemispheres with asdh among the favorable outcome group and unfavorable group. although there was no significant difference in age, gcs at the onset of treatment, cbf and cbv, there was significant difference only in mtt between the favorable outcome group and unfavorable group. the circulatory disturbance in patients with asdh occurs diffusely despite the focal injury. additionally, in unfavorable patients, the circulatory disturbance is worse than in favorable patients. because asdh suffered ischemia more than other types of stbi, we had to perform not only removal of the occupying lesions, but also neurointensive care, including whole-body management and hypothermia therapy for the ischemic brain after surgery. we have to adopt a treatment strategy appropriate to the pathophysiology of the different tbi types. kcentra is -factor prothrombin complex concentrate that is fda approved for reversal of warfarin. there is limited research describing the use of kcentra for coagulopathy in the setting of traumatic intracranial hemorrhage. here, we show the largest ever retrospective review for the use of kcentra in the setting of traumatic intracranial hemorrhage. retrospective chart review was performed from - for patients with intracranial hemorrhage who presented to the r adams cowley shock trauma center. patients who received kcentra were identified. basic clinical information was obtained including cardiac/stroke history, blood pressure, glasgow coma score, medication history, and categorization of hemorrhage. pre and post inr level was assessed. hemorrhagic expansion was assessed with ct scan up to up to hours. disposition and thromboembolic events were recorded. forty-four patients were identified as receiving kcentra in the setting of traumatic intracranial hemorrhage. pre and post kcentra dosing inr was found to be significantly different (p< . ) across the two groups assessed (warfarin and tbi/noac coagulopathy). seventeen patients ( . %) had hemorrhagic expansion as determined on ct scan. disposition (home vs rehab vs death) was found to have three significant variables: history of stroke, hemorrhagic expansion, and admission glasgow coma score. eight patients ( . %) were found to have thromboembolic events. here, we show the largest retrospective review describing the clinical use of kcentra for coagulopathy reversal in the setting of intracranial hemorrhage. overall, kcentra is shown to be a safe and effective drug for the reversal inr. importantly, our reported hemorrhagic rate of . % is lower than established rates reported in the literature for warfarin/coagulopathic patients with intracerebral hemorrhage ( - %). the prognostic importance of hemorrhagic expansion was highlighted in the disposition analysis which showed that zero patients were discharge home if there was recorded expansion. despite the impact of post-traumatic amnesia (pta) duration on long-term functional outcome after traumatic brain injury (tbi), radiologic predictors of pta duration are lacking. we hypothesized that the number of traumatic microbleeds (tmbs) detected by gradient recalled echo (gre) magnetic resonance imaging (mri) in neuroanatomic regions that mediate memory correlates more strongly with pta duration than does the number of global tmbs. using a prospective outcome database of patients treated for mild-to-severe tbi at an inpatient rehabilitation hospital, we retrospectively identified patients who underwent acute mri with gre. pta duration was determined by the galveston orientation and amnesia test, orientation log or chart review. a rater blinded to pta duration identified tmbs on the gre datasets globally and in neuroanatomic regions that mediate memory, including the hippocampus, fornix, corpus callosum, thalamus, and the temporal lobe. associations between global and regional tmbs (in the mentioned locations) and pta duration were tested using spearman rank correlation coefficients. the cohort was comprised of % ( hippocampus and corpus callosum tmbs are associated with pta duration, and thus may have greater utility for predicting functional outcomes than global tmb number. validation of these findings in larger prospective studies is indicated. using a large two-center cohort of penetrating traumatic brain injury (ptbi) patients, we previously developed the survival after acute civilian penetrating brain injuries (spin) score, a logistic regressionbased parsimonious risk stratification scale for estimating survival after civilian ptbi. the objective of the present study was to externally validate the spin-score. our multicenter validation cohort comprised ptbi patients retrospectively identified from three u.s. level- trauma center registries. the spin score variables (motor gcs [mgcs], sex, pupillary reactivity, self-inflicted ptbi, transfer status, injury severity score [iss] and inr) were collected from the trauma registries supplemented by chart review. using the spin-score multivariable logistic regression model from the original study, receiver-operating-characteristic area-under-the-curve (roc-auc) analysis and hosmer-lemeshow goodness-of-fit testing was performed. the mean age was ± years, and patients were predominantly male ( %), with % white and % black. in-hospital mortality was %, and -month mortality of discharge survivors was . in this multicenter external validation study, the full spin-model predicts in-hospital survival after ptbi with excellent discrimination and calibration. after removing inr from the model, discrimination remained excellent, but model calibration diminished. the full spin-score may provide important information to guide families and physicians after civilian ptbi. limited data has described alterations in vancomycin pharmacokinetic (pk) parameters in traumatic brain injury (tbi) patients that have resulted in sub-therapeutic concentrations. the primary objective of this study is to evaluate the pk parameters of vancomycin in tbi patients to determine if using the common clinical practice of capping creatinine clearance (crcl) to ml/min in determining dosing impacts achievement of therapeutic concentrations. this was a single-center, retrospective study of patients at least years of age with tbi who received vancomycin and one reported steady-state vancomycin serum level from april to december . predicted pk parameters based on population data using actual and capped creatinine clearance (crcl) at ml/min were compared with calculated pk parameters based on serum trough concentrations at steady state. the difference was assessed using a two-sample wilcoxon rank-sum test where p < . was considered statistically significant. when using actual crcl [median ml/min patients with tbi experienced crcl that were greater than predicted. based on the results of this study, actual crcl is more accurate at predicting vancomycin pk than the common practice of capping crcl at ml/min. therefore, actual crcl should be used when determining vancomycin dosing regimens in patients with tbi to achieve desired therapeutic concentrations. neurocritical care is traditionally provided within institutions in urban centers while access in rural communities has been limited. transport to urban centers is not always favorable for a variety of reasons including critical patient condition, family wishes, weather, and geography. our hypothesis is that tele-neurocritical (tele-ncc) can extend access to this service with meaningful impact on icu outcomes. a tele-ncc pilot study was initiated within intermountain healthcare. starting / / , the study included all ischemic stroke patients admitted to the icu of one primary stroke center in utah. tele-ncc consultations were provided by ncc physicians at our flagship hospital located three hundred miles from the spoke site. tele-ncc consultations occurred via an existing telehealth platform developed inhouse. primary outcomes for this pilot study were icu and hospital lengths of stay (los). secondary outcomes include stroke complication rates and results on a provider satisfaction questionnaire. to date, tele-ncc consultations have been performed with median hospital los = days (iqr . - . ) and icu los = . days (iqr - ). in the months prior to the pilot, there were admissions to the icu for ischemic stroke with median los = days (iqr . - . ) and icu los = . (iqr - . ). for this small sample size, the p-values for comparison of hospital and icu lengths of stay before and after tele-ncc are . and . respectively. tele-ncc care can have significant impact on icu outcomes by expanding access to critical support from neurocritical care specialists. tele-ncc expands access to not only consultation on critical neurological emergencies, but also on when to de-escalate from the icu or in end of life discussions with which general icu teams may not be comfortable. these impacts could be measured as important decreases in hospital and icu los. hospital readmissions increase health care costs, increase patient exposure to nosocomial disease, and imply patients were not stable for discharge. because readmissions are a target for hospitals and payers, several centers have developed predictive readmission scores in order to identify high-risk patients. we contend that these general readmission scores are not suitable for neurocritically ill patients and that specific predictive score must be developed to identify high-risk patients. we conducted a retrospective chart review of consecutive patients admitted to our neuroscience critical care unit. we recorded the readmission scores, reason for admission, length of stay,and if they were readmitted. we then compared the median readmission scores between the two groups. after removing patients without readmission scores or died at the end of the original admission,we analyzed the records of patients. patients were more likely to be readmitted if they were initially emergently hospitalized or had malignancy. readmitted patients had a longer original hospital length of stay. we found no difference median readmission score between those who were readmitted, and those who were not. most readmitted patients ( . %) had an original "low-risk" readmission score. we found that our center's score was poor in predicting readmission for neurocritical care patients and that several components of the score do not apply to our patient population. we propose that to accurately predict readmission,centers should create their own unique readmission scores for more homogeneous admission populations. clinical evaluation of the level of consciousness in non-communicative patients can be very challenging. in this study, we aimed to evaluate the nurses and nursing assistants' (nas) perception of the consciousness on patients suffering from disorder of consciousness (doc). through their activities, nurses and nas have an extended observation time of patient's behavior, and make repeated implicit assessments of patients' clinical state of consciousness. we hypothesized that even in the absence of a structured and explicit evaluation of consciousness (in contrast for instance with the coma recovery scale revised -crs-r), nursing expertise could be a valuable measure to improve assessment of state of consciousness in doc patients. this was a prospective observational single-center study. our primary objective was to correlate the nurses and na's assessment of doc-patients' consciousness quantified through an analogic visual scale (the "doc-feeling score") with the results of the standard methods (including crs-r, fmri, electrophysiology). the secondary objective was to identify elements which correlate with this assessment and/or with the expert's diagnosis (such as visual pursuit, patient's participation to nursing, motor responses to verbal command or adapted reactions to painful care). . linear regression reveals a good correlation between the "doc-feeling score" and the crs-r gold standard (r = . , p-value < . , figure ). global assessment of the level of consciousness by all the caregivers interacting with the patient using the "doc-feeling score" is reliable and can improve assessment of state of consciousness in doc patients. investigating causes of deterioration in neurological patients is important to anticipate these complications and improve outcomes. this is a prospective observational study performed at an academic tertiary care trauma, stroke and neurorehabilitation center. data was collected over a year from rapid response system activations (rrsa). in one year, our center had admissions. rrsa were performed on patients. most common admission diagnosis was ischemic stroke ( %). most common rrsa organ system involvement was respiratory system (n= , . %). the only predictors of death or new limitation of care in those patients who had rrsa were age ( years vs years, p < . ) and history of cancer ( %) vs ( %) p= . . . % (n= ) of rrsa happened during day shift and . % (n= ) during night shift. . % (n= ) of rrsa happened around shift change and were more likely to result in an unplanned icu admission. . % (n= ) of rrsa happened within hours of admission and were more likely to result in unplanned icu admissions. the most common reasons for in hospital decompensation in neurological inpatients are nonneurological. most common organ system involvement responsible for rrsa is respiratory system. the only predictors of death or new limitation of care were history of cancer and age and older. rrsa activations were more frequent during day shift. however, there was no different in the outcomes we evaluated between day and night shifts. rrsa happening around shift change wew more likely to result in unplanned icu admission. rrsa within hours of admission showed an increased risk of unplanned icu admission when compared to rrsa happening after hours of admission. neurocritical care is a growing field with an increasing number of dedicated neuroscience intensive care units. in this dynamic context, it is unclear which types of physicians provide neurocritical care across the united states. we performed a retrospective cohort study using claims data from a nationally representative % within analyzed critical care procedures . the primary outcome was physician specialty, defined by medicare provider specialty codes. in a sensitivity analysis, we excluded claims for services on the day of admission and claims associated with a diagnosis of cardiac arrest, since these activities may often occur outside of neuroscience intensive care units. we identified between and , neurologists were responsible for approximately one-quarter of neurocritical care services among a nationally representative cohort of elderly patients. critically-ill patients on mechanical ventilation (mv) cannot verbally communicate. research suggests several phenomena occur in patients during mv because of impaired communication including anxiety, loss of control, loneliness, and compromised interaction (schou and egerod, ) . for neurocritical care patients, this can be especially profound when coupled with cognitive and motor/sensory deficits. currently, the blom® speaking valve (sv) is the only approved product available that allows phonation in ventilator-dependent patients with tracheostomy. sv trials are known to facilitate vent-weaning. the current standard of care (passy-muir speaking valve, minute trials), is contra-indicated in patients who cannot tolerate cuff deflation. as such, the blom® sv was evaluated for clinical and quality efficacy. we retrospectively evaluated clinical outcomes associated with blom® sv on mv during a trial in a neuroicu of a large tertiary center between / / and / / . baseline demographics, diagnoses, physiologic, sedation, delirium, mobility and swallowing parameters, length of stay, ventilator modes and settings, ventilator days, work of breathing and presence of pneumonia were abstracted along with patient, family and interdisciplinary staff satisfaction survey results. patients were recommended for blom® tracheostomy. patients received sv trials. of the trials were performed, % ( ) were optimal/completed ( + minutes); % ( ) were suboptimal/completed trials ( - minutes); % ( ) unable to complete. satisfaction results from patients/families were positive compared to the interdisciplinary team survey results. remaining parameters currently in analysis with results pending, to be completed by end of august, . impaired communication during mv is suboptimal for neurocritical care patients. our clinical experiences with blom® sv showed positive and negative outcomes. positive benefits were enhanced patient/family engagement and family satisfaction. unanticipated obstacles included significant increase in patient fatigue during sv trials, often delaying ventilator weaning. further study is needed to determine efficacy in this population. patients with clinical signs of cerebral herniation require immediate intervention known as a "brain code". in our neurosciences critical care unit (nccu), a rapid response program is in place to ensure the safety of . % hypertonic saline's use (high risk medication) and to expedite its delivery to the bedside given the emergent need for this medication when ordered. our institution, however, is lacking a more holistic and structured approach to cerebral herniation syndrome that include components of tiers zero to three emergency neurological life support elevated icp or herniation protocol. the neurocritical care communication council consists of bedside staff nurses, nursing leadership, advanced practice providers (nurse practitioners and clinical nurse specialist), pharmacists, respiratory therapists and physicians. the council identified processes during neurological brain codes that could be improved as a result of using a bedside debriefing tool. the unit leadership council of the nccu reviewed literature on hospital debriefing tools and referenced this organizations current resuscitation debriefing tool. from these sources, a brain code debriefing form was constructed. a clinical tool was developed with the expectation of standardizing the brain code process in this nccu. the brain code debriefing form will be piloted to determine unit and system wide value. pre-and postimplementation data will be collected to discover areas of improvement for optimized patient care. through the development of this debriefing tool, it was ascertained that a clinical practice guideline for impending cerebral herniation would be beneficial to further guide and direct evidence-based care. thus, a preliminary algorithm for identification and emergency treatment is in process. the americas medical center is a -bed tertiary hospital complex, located in the city of rio de janeiro. the center was elected by the international and the brazilian olympic committees as the referral hospital for the olympic family (of), comprised of athletes and their crews, support and technical personnel, credentialed media and credentialed governmental representatives from the participating countries. the neurology and neurocritical care teams were selected to head a comprehensive program of acute emergency neurology, including a -bed neurocritical care unit (nicu), and - emergency neurology service. we hereby describe our experience during the olympic games in rio de janeiro, brazil results neurological assessments were conducted in patients from the of, of these involving athletes from countries. the most common reason among athletes were traumatic brain injuries (tbi), with politraumas (all involving cycling), mild tbi ( of boxing, of field hockey, of rowing and of cycling) and moderate tbi (cycling and water polo). three patients were admitted to the nicu: ischemic strokes and politraumas with tbi. motor vehicle accidents with associated tbi involving the of were surprisingly frequent, with assessments, none requiring admissions. finally, ct scans of head, ct scans of the cervical spine and mri scans ( brain and spine mri) were performed to assess the patients. of note, cases of seizures, functional deficits, multiple sclerosis flare and psychiatric complaints were observed affecting the of. not only that multiple sports-related injuries were observed, cases of diverse acute neurological issues were reported involving members of the of. olympic games are complex events mobilizing thousands of people, and a comprehensive and detailed plan for neurological emergencies is of extreme importance the term "handoff" has been defined as the "transfer and acceptance of responsibility for patient care that is achieved through effective communication, passing patient-specific information from one caregiver or team of caregivers to another to ensure the continuity and safety of the patient's care" (patterson and wears, ) . the joint commission reported that two-thirds of sentinel events occur at the time of patient handoff, which led to a national patient safety goal, requiring standardized process for handoffs (the joint commission on accreditation of healthcare organizations, ) . to support this npsg, a nccu specific handoff tool and timeout process were created to support the transition from or to nccu. nccu postoperative handoffs were identified as an area to enhance staff satisfaction and patient safety. baseline data to evaluate the frequency of neurosurgery report was performed in may . using a qualtrics survey in june , staff satisfaction with current ns or report was obtained from nccu rns, nps, and fellows evaluating whether they felt they received: accurate medical history, accurate information about performed procedure, sufficient handoff for patient care, specific patient goals, recent pharmacological intervention, anticipated concerns regarding diagnosis/procedure, estimated blood loss, blood/fluid intake, airway concerns, complications and overall satisfaction with handoff. a taskforce of rns, nps, neurointensivists, and neurosurgeons was established, ending with the creation of a handoff tool and timeout process. the new tool and process were initiated and two months later, a repeat survey was sent to evaluate staff satisfaction and perceived effectiveness of the new process and handoff tool. currently being tabulated at time of submission. using standardized, open communication techniques including handoff tools and a timeout throughout the perioperative period is crucial to positive outcomes and can improve perioperative care in the nccu patient and increase satisfaction and collaboration of all team member during or handoff. in the age of the healthcare reform and rising costs, it is important for strategic service lines to explore cost saving and care efficiency strategies. beginning in september , physician and administrative leadership within the duke neurosciences intensive care unit (neuroicu) began investigating per patient cost to explore opportunities to decrease direct cost to the neuroicu, cost to the patient, and reduce redundancy of care. with assistance from health system finance, the team assessed the following data points within each cost group and compared these values to that of our peers within the us news and world report top honor roll: · number of units · direct cost per unit · total direct cost our performance according to our peers in the following cost areas was: .pharmacy-ranked th out of .laboratories-ranked th out of .radiology-ranked th out of .cardiovascular-ranked th out of . based on these performance metrics, neuroscience administrative and medical leadership developed a project grid of prospective initiatives and identified the following for each cost area: ·stakeholder-led teams inclusive of providers, nursing, and administration ·duration or impact of each initiative: short, medium, or long ·activity phases based on duration the stakeholder-led groups would propose and validate projects based on scope and duration. at each group's meeting, members reviewed charge level financial data by activity code for the group's respective cost area to develop applicable initiatives. multiple initiatives are currently underway including those within the cost areas of pharmacy, laboratories, and radiology. included among these initiatives is a change in routine resistant organism screening and cervical spine clearance. other initiatives will be target intravenous anti-hypertensive treatment and laboratory frequency. the total cost savings from these initiatives can only be estimated at this point but will likely be in excess of $ , for the calendar year. it is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. we examined the association between dedicated neurocritical care units and mortality, and the effects of standardized management protocols for severe traumatic brain injury. we surveyed trauma medical directors from centers participating in the american college of surgeons trauma quality improvement program (tqip) to obtain information about icu structure and processes of care. survey data were then linked to the tqip registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care (ncc) units, the presence of standardized management protocols and mortality. we performed three sensitivity analyses reclassifying ncc units by restricting to closed units, under ucns director leadership, and exclusion of neurotrauma units. data was analyzed from , adult patients with isolated severe traumatic brain injury admitted to tqip centers between to . fifty icus were dedicated neurocritical care units, whereas were general icus. rates of standardized management protocols were similar comparing dedicated neurocritical care units and general icus. care in a dedicated neurocritical care unit was not associated with improved risk-adjusted in-hospital survival (or . ; ( % ci . - . ; p= . ). the results from the model were robust in our sensitivity analyses. the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (or . ; % ci . - . ; p= . ). compared to dedicated ncc models, standardized management protocols for severe traumatic brain injured patients are low-cost process-targeted intervention strategies that may improve clinical outcomes. understanding the differences in processes of care within the context of icu structure is necessary to better understand mortality differences observed between centers, and may help in the design of future trials for severe tbi patients. complex multidisciplinary care of patients in the neurocritical care unit requires reliable and effective communication to minimize medical errors. we implemented a structured rounding process that incorporates ahrq-endorsed team strategies and tools to enhance performance and patient safety (team stepps) to improve interprofessional collaboration between team members. we convened a project team of physicians, advanced practice providers (apps), nurses, respiratory therapists, and pharmacists in a -bed nicu. we defined structured rounding processes and implemented team stepps strategies to promote closed-loop communication between team members during daily rounds. the assessment of interprofessional team collaboration scale (aitcs-ii) was administered to team members at baseline and months post-intervention. impact on overall team collaboration and subscale domains of team partnership, cooperation and coordination was assessed. the possible range of the overall collaboration score is to ; higher scores indicate better collaboration. the survey was completed by ( %) staff at baseline, and ( %) staff post-intervention. overall team collaboration scores improved significantly pre and post-intervention ( . ± vs . ± , p < . ), as did subdomain scores of team partnership ( . ± . vs . ± . , p < . ), collaboration ( . ± . vs . ± . ), and coordination ( . ± . vs . ± . ., p < . ). perceived shared understanding of patient daily goals between nurses and providers (physicians/apps) increased from % to % (chi-square . ; p < . ). % of staff reported that the intervention shortened or did not affect the duration of rounds. of those who reported longer duration of rounds, % responded that the intervention was worthwhile. interprofessional team collaboration can be enhanced by structured rounding and communication workflows. by promoting closed-loop communication during daily rounds, shared understanding of patient daily goals between team members is increased, and may optimize quality and safety of patient care. advanced practice providers (apps) are increasingly utilized to provide clinical care within neurocritical care units (nsicu) . despite the complex issues in this patient population, the specific educational and orientation needs of these providers have not been established. to meet the demands for rapidly and effectively training apps to provide advanced neurocritical care (ncc), a structured educational curriculum was developed and integrated within the standard orientation and on-boarding process for newly-hired app within our nsicu. this curriculum was designed with measurable learning goals, objective assessments of goal achievement, and opportunities for additional education and remediation at multiple steps within the program. the curriculum has three phases with distinct goals and assessments. phase i covers basic triage and resuscitation issues for the acutely-decompensating patient. phase ii covers general critical care principles in significantly greater depth. phase iii provides detailed experience and exposure to specific ncc issues. each phase incorporates relevant reading assignments with a tailored study guide, as well as a multiple-choice question post-test to demonstrate knowledge acquisition. phases ii and iii also include an oral exam incorporating hypothetical patient scenarios to allow the app to demonstrate comprehension and application of the goals for each phase. each phase lasts approximately to weeks with the expectation that the entire orientation curriculum will be completed within six months of employment. in addition to the educational curriculum, phases i and ii include working alongside a more senior app preceptor and providing bedside care for a progressively increasing number of patients. apps not meeting minimum established standards on any aspect of the curriculum are provided additional remediation and instruction by the preceptor and ncc faculty based on an individualized learning plan. a standardized educational curriculum provides a structured learning environment for new apps in the field of neurocritical care. reimbursement changes from the centers for medicare and medicaid services and value based purchasing systems have made quality improvement linked to clinical outcomes more crucial than ever. in one neuroscience icu, providers and nurses collaborate to address key infection parameters that impact patient outcomes. quality metric data in one neuroscience icu was collected over a period of fiscal years. outcome measures, consisting of glycemic and temperature control, and ventilator weaning strategies, were obtained after certain parameters were enforced over two years and then compared to the initial year. the urinary catheter utilization has decreased by over %, with catheter associated urinary tract infections decreased by % in years (p-value < . ). central line utilization decreased by %, with a % decrease in central line associated blood stream infections in years (p-value . ). new ventilator weaning strategies were put into place utilizing adaptive support ventilation mode, which decreased total ventilator days by days/year . successful weaning and extubations resulted in no recorded ventilator-associated pneumonia in the last years. this neuroscience icu maintains glucose below mg/dl more than % of the time. regarding temperature control data, a normothermia protocol was implemented that utilizes aggressive temperature control coupled with bromocriptine administration. as a result, % of patients had a temperature less than °c. all of the quality initiatives that have been implemented have improved the observed/expected mortality ratio by . %. this study shows that by optimizing infection control, temperature management, glycemic control and ventilation strategies, there is an overall positive impact on the patient's morbidity and mortality. as evidenced by these results, this institution is now a top performer when compared in a national clinical database. this presentation will share the pragmatic strategies to create a culture of quality improvement in any neurocritical care unit or patient care organization. health care records are not accessible universally at point of care delivery. in developing countries like thailand a large proportion of health care records are still paper based. patients may not able to convey relevant information about their own medical problems and medications during patient-physician encounters or in the event of emergency. our purpose was to create a simple platform for recording relevant basic healthcare information through a system that can be securely accessed even in countries like thailand. our vision is to improve healthcare communications and leverage social media in thailand and other developing countries, particularly for patients with lower levels of education or socioeconomic status. we created a cloud-based personal healthcare information platform 'meid' that uses a qr code scanned from wristbands and other products like stickers to access patient information. conventional methods require a treating team to request medical records from a patients' prior hospital visits including visits at different medical facilities. time lost during this process can potentially cause delay in treatment decisions. we also aim to improve health literacy in thailand. application name 'meidth' is available in both apple store and google play. we launched meid in thailand in april of . we have more than , active users and have sold more than wristbands. the meid thailand facebook page has received , likes. there are at least two patients that have already benefited from this product: one of these patients received intravenous tissue plasminogen and had a good outcome. timely access to his past medical history and medications via meid was a key in this case. our cloud based personal healthcare information platform using qr codes from wristbands and stickers can help increase health literacy, decrease times to appropriate treatment, improve patient safety and decrease healthcare costs. clinical pharmacists have become an integral part of multidisciplinary medical teams. expanding the role of pharmacists in the neurocritical care units has the potential to positively impact the quality of patient care and provide costs savings. this study examines these potential benefits at one neurocritical care unit. we reviewed patient medication profiles and had formal rounds with a pharmacist four times per week. for the purposes of this study, the focus was on minimization of a select number of high expense drugs. nine months of baseline data was compared to three months of post intervention data. interventions were performed at the time of rounding, which involved timely conversion to enteral formulas, changes to alternative medications or discontinuation of medications. we then performed a cost-benefit analysis to assess the net amount of money saved by reducing inappropriate pharmacy drug use following the interventions. average cost of nicardipine was $ , pre-intervention, compared to $ , post-intervention (pvalue . ). the cost of iv levetiracetam usage on average was $ , pre-intervention and $ , post-intervention (p-value . ), while the cost of iv dexmedetomidine was $ pre-intervention compared to $ post-intervention (p-value . ). average expense per month was reduced by approximately $ , per month compared to the average expense per month from the previous months (p-value . ). appropriate use of stress ulcer prophylaxis was also positively impacted; patient days/month on famotidine was reduced by approximately % from baseline, patient days (pre-intervention) vs days post-intervention. pharmacist interventions within a neurocritical care unit are known to be beneficial clinically for patients, however this study also shows that their interventions offer substantial cost benefits and should justify creating collaborations between pharmacists and neurointensivists. multi-disciplinary rounds have been shown to improve patient outcomes. the objective of this study is to observe the effect on patient care, team dynamic, and nursing satisfaction before and after the implementation of a nursing-led rounding model in the neurological icu. prior to the implementation of the nursing-led rounds quality initiative, nurses in the neurointensive care unit (nicu) were asked to answer a brief survey on basic demographics and perceptions of team dynamics and satisfaction in the nicu. a multidisciplinary systems-based rounding sheet inclusive of the abcdef bundle and previous nicu checklist was created and revised with extensive bedside and senior nursing educator input. while rounding, nurses presented and clinicians were to in real-time come up with an assessment and plan and relay these to the nurse and other team members. any questions, educational pearls or concerns by the clinician team or the bedside nurse were encouraged during these rounds. nurses completed a month post-implementation survey. of the full-time nicu nurses ( %) responded to both the pre-implementation and postimplementation surveys. a bimodal distribution of nursing experience was noted with % new nurses (< year) and % experienced nurses ( years+). more than half of the nurses ( %) reported doing both night and day shifts as opposed to being exclusive to only day or night. there was an increase in the nursing perceptions of participation during rounds as well as education during rounds. nurses felt significantly more involved with patient decision making and felt that they were able to give input into the patients care. the implementation of a nursing-led rounding structure may be beneficial to communication, education and overall patient care. as the project continues, we hope to further examine common icu objective measures as well as other subjective measures such as patient satisfaction scores and communication perceptions. with increased elective and non-elective volume, directing the flow of admissions has become essential to the efficient operation of inpatient strategic service lines. this is especially true in the neurosciences where widespread acute ischemic stroke intervention has placed an especially high demand on comprehensive stroke centers. as a result, an important collaboration was formed at duke between the health system, transfer center and neurosciences to create an algorithm-driven multi-hospital triage and pre-hospital care system called phast (pre-hospital acute services team). in this abstract, we present the formation and current state of this service. this effort was formally begun in the spring of with an initial focus on centralizing the admission process into the duke neurosciences intensive care unit (neuroicu) by an icu physician. after some initial success, it was clear that the service line would benefit from a more formalized process. as a result, a successful multidisciplinary collaboration with a core group of physicians and administrators was formed to develop algorithms and to overcome multiple administrative and legal hurdles. over a period of months, multiple algorithms were developed to systematize neuroscience admissions including acute ischemic stroke and vascular and non-vascular neuroscience emergencies. in an effort to decrease door-to-intervention times as well as effectively mitigate the impact of limited bed-space availability, this system now serves hospitals including with acute neurointerventional services and the rd with a burgeoning neurohospitalist program and incorporated rehabilitation services. in addition to systematizing the transfer and admission process, quality assurance, improvement, and educational processes are in a place. the current state of phast is that of a young but maturing and now essential service for duke neurosciences. extubation involves removal of an endotracheal tube (ett) and is a common intensive care unit (icu) procedure. extubation failure occurs in - % of icu patients and can be difficult to predict accurately. we hypothesized that a multivariate re-intubation scale calculation (risc) model could predict extubation failure better than a single variable like rapid shallow breathing index (rsbi). after irb approval, we conducted a retrospective review of data on mechanically ventilated icu patients above years of age who were not receiving mechanical ventilation through a tracheostomy tube from january , , through december , at mayo clinic rochester. various data points were gathered on these patients via electronic medical records search, and reintubations within hours of extubation were identified. univariate and multivariate logistic regression models were used to predict reintubation after extubation and construct a risc estimate. we included a total of patients which were randomly divided into a derivation set (n= ) and validation set (n= ). in the derivation set, patients had a mean age of ± years, and % were men. three hundred and ninety three extubation failures occurred within hours. predictors of extubation failure included underweight status, gcs score>= , mean airway pressure at minute= ml and total mechanical ventilation days>= in the final multivariable model. risc score was calculated using the validation set and ranged from to . logistic model result shows that, as risc increased by , the odds of having extubation failure was . fold higher (c-index= . ). roc analysis shows that the best cut off for risc was >= vs. < , which demonstrated a sensitivity of . , specificity of . and auc= . . the current risc model warrants further exploration in a prospective study to help critical care providers to decide when extubation can be done more safely. this report presents results of the nd nationwide survey concerning neurocritical care units (ncus) in china. this is an observational cross-sectional survey and close-ended self-reported questions were used. the questionnaire was sent to different provinces (autonomous regions and municipalities) across china from october st, to january st, . basic information, equipment and device information, and staffing and organization information were investigated. in total, questionnaires from ncus at hospitals in regions were received. most of the hospitals with ncus were large-scale (average hospital beds: ), teaching ( . %), and tertiary hospitals ( . %). the average number of ncu beds was , occupying . % of the total number of beds in their department. most of the equipment and devices ( / ) were available in over % of the ncus. however, some devices were centralized by hospital and operated with assistance from other departments. a total of full-time doctors and full-time nurses were employed at the ncus. a few of the ncus achieved a doctor-to-bed ratio of . : ( . %) and a nurse-to-bed ratio of : ( . %). and respiratory therapists, clinical dieticians, clinical pharmacists, and physiotherapists were present in . %, . %, . % and . % of the ncus. the number of ncus increased, the availability of ncu equipment became more sufficient, and the staffing of ncus improved. however, we should pay attention to the management of specialized ncu equipment, the shortage of ncu staff, and the need of ncu training. automated devices collecting quantitative measurements of pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the effect of ambient light conditions on pupil metrics. to address this issue, we we tested the range of pupil reactivity in healthy volunteers in both light and dark conditions. we measured quantitative pupil size and reactivity in seven healthy volunteers with the neuroptics- pupillometer in both bright and dark ambient lighting conditions. bright conditions were created by overhead led lighting in a room with ample natural light. dark conditions consisted of a windowless room with no overhead light source. the primary outcome was the neurologic pupil index (npi), a composite metric ranging from - in which > is considered normal. secondary outcomes included resting and constricted pupil size, change in pupil size, constriction velocity, dilation velocity and latency. results were analyzed with multi-level linear regression to account for both inter and intra-subject variability. seven subjects underwent ten pupil-readings in bright and dark conditions, yielding total measurements. mean resting pupil sizes were . v. [ . - . ], p< . ). all additional secondary outcomes except latency were also significantly different between conditions. we found that ambient light levels impact pupil parameters in healthy subjects. however, changes in npi are small and more consistent in varying lighting conditions than other metrics. further testing of patients with poor pupil reactivity is necessary to determine if ambient light conditions could influence clinical assessment in the critically ill. practitioners should standardize lighting conditions to maximize the reliability of their measurements. neural stem cells (nscs) are known to have anti-inflammatory effect in strokes in previous studies. however, the mechanism of anti-inflammatory effect in direct co-culture with nscs in hemorrhagic stroke remains unclear. the aim of this study was to investigate whether direct co-culture with nscs modulates hemolysate-induced inflammation in raw . cells. we stimulated raw . cells with hemolysate to induce hemorrhagic inflammation in vitro. hemolysate-activated raw . cells were co-cultured with hb .f directly for hours. following direct co-culture, the production of cycloxygenase- (cox- ), interleukin-signal regulated kinase (erk) were assessed by western blotting, and tumor necrosis factor (tnfevaluated by enzyme-linked immunosorbent assay (elisa). hemolysate generates an activation of inflammatory response in raw . cells. direct co-culture with hb .f significantly suppressed the phosphorylation of erk / in hemolysate-activated raw . cells. the expression of inflammatory mediators such as cox- , il-by direct co-culture with hb . f cell. in addition, the expression of cox- , il-attenuated by erk inhibitor (u ). our results demonstrated that direct co-culture with hb .f cells reduced the inflammatory responses in hemolysate-activated inflammation via suppressing erk / pathway. this suggests that nscs treatment can suppress the inflammatory response in hemorrhagic stroke. no pharmacological intervention improves outcomes after primary intracerebral hemorrhage (ich). we developed a novel therapeutic approach based on known biological function of endogenous apolipoprotein e (apoe). apoe is a key mediator of neuroinflammatory responses and modifies recovery from a variety of acute and chronic brain injuries. unfortunately, intact apoe holoprotein does not cross the blood brain barrier (bbb) and cannot be administered as a neurotherapeutic. we created apoemimetic peptides that cross the bbb and down-regulate neuroinflammatory responses in vitro and in vivo. cn- , our lead candidate, is a -amino acid apoe-mimetic peptide derived from apoe's receptorregion. cn- retains anti-inflammatory and neuroprotective effects of intact apoe, was well-tolerated in preclinical studies, readily crosses the bbb, and demonstrates excellent pharmacokinetic, safety, and tolerability profiles in phase studies. this is a multicenter, open-label phase a trial of cn- in patients with acute primary supratentorial ich. a total of participants between the ages and years across study centers, with a confirmed radiographic diagnosis of spontaneous, primary supratentorial ich. patients will be evaluated for eligibility within hours of symptom onset. eligible participants will receive cn- intravenously over --minute infusion every hours up to day maximum. participants will be monitored daily throughout the treatment phase and receive standard-of-care treatment for the duration of the study. primary: to assess safety of cn- administration in primary ich. secondary: to evaluate effects of cn- administration on --day mortality and functional outcomes. exploratory: to investigate feasibility of radiographic surrogates of clinical outcomes using perihematomal edema measurements on serial brain ct and mri, and investigate feasibility of serial biochemical markers of neuroinflammation as surrogate measure of perihematomal edema and clinical outcome. cn- represents a first-in-class agent now entering phase clinical trials in patients with acute ich. novel oral anticoagulant (noac) associated intracranial hemorrhage is a life-threatening condition for which activated prothrombin complex concentrate factor eight inhibitor bypassing activity (feiba) may be used for reversal. few studies report its use in spontaneous or traumatic intracranial hemorrhage. our institutional protocol is reversal with feiba units/kg and escalating doses as needed. the safety and efficacy of this protocol was assessed. we performed a retrospective review of adult patients presenting to a level trauma center between - with spontaneous or traumatic intracranial hemorrhage while on a noac . we evaluated the medication they presented on, indication for anticoagulation, location and size of the hemorrhage, presentation gcs, dosage of feiba recieved, change in size of hemorrhage on serial imaging as well as time between serial images, complications from reversal, and need for blood product transfusion. we identified patients with an acute intracranial hemorrhage while on noacs. patients underwent a baseline head ct documenting acute intracranial blood, were reversed with feiba ( u/kg), and underwent repeat imaging hours later per protocol. ten ( %, / ) patients had no increase in hematoma volume on repeat imaging. two underwent neurosurgical procedures (aneurysm coiling, sub-occipital craniectomy) without intra-operative bleeding complications. five ( % / ) patients had clinically insignificant increase in size of hemorrhage. of those, one underwent a subsequent neurosurgical procedure, which was already anticipated. two ( %, / ) patients had clinically significant hematoma enlargement. of those, one underwent urgent craniectomy (indicated based on initial presentation) and one required a ventriculostomy for hydrocephalus. two patients had no repeat imaging. adjusted dose feiba ( units/kg) may be an effective alternative to standard dose ( unit/kg) for reversal of noacs in acute intracranial hemorrhage. our experience showed clinically significant hematoma expansion in % of patients and no increase in unplanned neurosurgical procedures after reversal with feiba. here we sought to determine if there is an association between recanalization success and rate of hemorrhagic transformation amongst patients who have undergone intra-arterial thrombectomy for ischemic stroke secondary to anterior circulation large vessel occlusion (lvo), many treated at extended time from last seen well (lsw) after mri assessment. stroke patients with anterior circulation lvo treated with thrombectomy between april, to june, were studied. group-wise comparisons were made between patients with post thrombectomy hemorrhage (as confirmed by a single, blinded neuro-radiologist reviewer) and patients without hemorrhage. failed or incomplete recanalization was defined as mtici < b. symptomatic intracranial hemorrhage (sich) was defined as validated hemorrhagic conversion or parenchymal hematoma plus point decrease in nihsss. pertinent baseline characteristics were recorded and analyzed. sich was more prevalent amongst patients with tici< b recanalization (or . [ ci . - . ]). interestingly there was a low rate of sich amongst patients with tici= recanalization ( / [ . %]). although many patients were treated at advanced time lsw no excess rate of sich was observed. baseline characteristics including age, presentation nihss, and presentation aspects were similar among the two groups. rates of sich are low after successful mri seleted thrombectomy regardless ot time lsw. patients with poor recanalization show increased rates of sich in keeping with past literature. our data suggest that thrombectomy after mri selection may be safe and effective for patients at extended time lsw of tor patients with unknown lsw. cta spot sign is associated with hematoma growth, a common complication of intracerebral hemorrhage (ich) that portends worse outcomes. magnesium and calcium are cofactors in the clotting cascade and for platelet aggregation. we tested the hypothesis that magnesium and calcium levels are associated with the presence of the cta spot sign. patients with spontaneous ich presenting to northwestern memorial hospital were identified from a prospective observational registry. inclusion criteria included cta obtained within hours of symptoms onset and admission magnesium and calcium levels. cta spot sign (active contrast extravasation on ct angiography) was identified by a board-certified neurointensivist or neuroradiologist. variables suggesting association with spot sign at p< . were assessed for inclusion in a logistic regression model, and a parsimonious predictive model for ct spot sign was developed using backward stepwise variable selection. patients (age ± . years, % male, median ich score [iqr - ]) were included. seventeen ( . %) patients with cta spot sign were identified. admission magnesium was . +/- . and calcium was . +/- . . lower magnesium (or . , % ci . - . , p . ), lower calcium (or . , % ci . - . , p . ), and higher ich score (or . , % ci . - . , p . ) were independently associated with ct spot sign. magnesium and calcium level on admission are associated with the presence of a cta spot sign in patients with ich. magnesium and calcium supplementation may be attractive therapeutic targets for preventing harm from hematoma growth. cerebellar intraparenchymal hemorrhage (iph) is a rare and likely underreported complication of subdural hematoma (sdh) evacuation. we present two cases of post-operative iph and review the literature. case . an -year-old man underwent craniotomy for evacuation of a chronic right frontoparietal sdh. post-op ct showed pneumocephalus. the patient was extubated and clinically improved. three days post-operatively, he became lethargic and a ct brain revealed a cc right cerebellar iph. he was unable to safely swallow, declined a feeding tube and died under hospice care nine days later. case . a year-old man underwent craniotomy for evacuation for a left convexity sdh. routine post-op ct revealed an incidental left cerebellar iph. he returned to baseline one month later. only four such cases have been reported in the literature ( - ). two cases led to death within one week and two recovered, one with significant deficits. five more occurred following burr hole drainage of sdh and two others following drainage of subdural hygromas ( , - ). the incidence of cerebellar iph following supratentorial craniotomy has been reported in up to . % of cases with significant morbidity or mortality ( ). it occurs irrespective of age, pre-existing coagulopathy or arteriovenous malformations. size of insult and amount of csf loss do not correlate to iph, despite the fact that cerebral blood flow imaging shows over-drainage of cerebrospinal fluid (csf), causes intracranial hypotension and subsequent damage to dural veins ( , ). iph also occurs independently of operating room position, even though having the head turned is thought to compress venous drainage in the neck and cause congestion ( ). cerebellar vasculature may be more sensitive to changes in intracranial pressure, though why this does not lead to complications more routinely is not clear. cerebellar iph should be considered in cases of neurological decline after sdh evacuation. intracerebral hemorrhage (ich) location predicts outcome, but most studies have examined differences between deep, lobar, and infratentorial locations. this study aims to characterize specific deep ich locations in a diverse cohort. the ethnic/racial variations of intracerebral hemorrhage (erich) study is a multi-center, prospective, u.s.-based study. subjects with supratentorial deep ich, known ich volume, and three-month follow-up data were included. logistic regression was used to evaluate the association between location and poor outcome (mrs > ). receiver operating curve (roc) analysis was performed to identify ich volumes specific for poor outcome by location. thalamic, putaminal, and caudate ichs were included. median ich volume was largest in putamen ( ml), followed by thalamus ( ml) and caudate ( ml, p<. ). intraventricular hemorrhage (ivh) was most prevalent in caudate ( %), followed by thalamus ( %) and putamen ( %, p < . ). subjects with thalamic ich were older ( vs vs years, p < . ) and more likely hypertensive ( % vs % vs %, p= . ) than those with putaminal and caudate ich, respectively. compared to thalamic, putaminal ich had more ich expansion ( % vs %, p < . ) and surgery ( % vs % p = . ) but fewer external ventricular drains ( % vs %, p < . ). thalamic location predicted poor outcome (or . , % ci . - . ) at days after adjustment for age, sex, premorbid disability, ich volume, ich expansion, ivh, and admission gcs. roc analysis identified ml for thalamic and ml for putaminal ich without ivh as having % specificity for poor outcome. there are significant differences in characteristics and outcomes within deep ich. specificity estimates for the identified ich volume thresholds require external validation. these findings may have implications for prognostication and clinical trial design. racial differences in outcome after intracerebral hemorrhage (ich) among asians, native hawaiians and other pacific islanders (nhopi) have been inadequately studied since these racial groups have been historically aggregated into a single racial category. a multiracial prospective cohort study of ich patients was conducted from to at a tertiary center in honolulu, hi to assess racial disparities in come after ich. favorable outcome was defined as month modified rankin scale (mrs) score £ . patients with no available -month functional outcome, race other than asians and nhopi, and baseline mrs > were excluded. multivariable analyses using logistic regression were performed to assess the impact of race on favorable outcome after adjusting for the ich score, early do-not-resuscitate (dnr) order and dementia/cognitive impairment. a total of patients ( asians, nhopi) were studied. overall, ( . %) achieved favorable outcome at months. nhopi were younger than asians ( . ± . vs. . ± . years respectively, p< . ), and had higher prevalence of diabetes ( . % vs. . % respectively, p= . ), obesity ( . % vs. . respectively, p< . ), and lower prevalence of early dnr order ( . % vs. . % respectively, p= . ) and advance directive presence ( . % vs. . % respectively, p= . ). nhopi race was a predictor of favorable outcome in the unadjusted model (or . , % ci: . , . ) and after adjusting for the ich score (or . , % ci: . , . ) but not in the final model (or . , % ci: . , . ) . in the final model, the ich score remained as the only independent negative predictor of outcome (or . , % ci: . , . per point). nhopi are more likely to achieve favorable functional outcome after ich compared to asians even after controlling for ich severity. however, this association was attenuated after adjusting for dnr status and baseline cognitive factors. intracerebral hemorrhage (ich) patients often require continuous antihypertensive infusions. we sought to identify clinical and care process predictors of anti-hypertensive infusion duration, and tested whether infusion duration independently predicts intensive care unit length of stay (icu los) after adjusting for validated measures of ich illness severity. we identified spontaneous ich patients admitted / - / to a tertiary center, excluding those transitioned to comfort care within hours. we abstracted demographic and clinical variables from the medical record. we calculated the total duration each patient received continuous infusion of an antihypertensive medication. we categorized glasgow coma scale score as - ; - ; or < . two reviewers independently classified ich location and etiology. we determined univariate associations of clinical variables to anti-hypertensive infusion and performed regression analysis to determine the effect of continuous infusion on icu los. we identified spontaneous ich patients and excluded for early comfort care. in the remaining , mean age was [ - ] years, % were female, median ich score was [ - ], and % had lobar hemorrhages. continuous infusion included nicardipine, clevidipine, labetalol and diltiazem. a total of ( %) patients received anti-hypertensive infusions, mean hours. mean time to enteral antihypertensive administration medication was . hours, and mean icu length of stay was . days [ . - . ]. predictors of longer antihypertensive infusion duration were male gender (p= . ), non-lobar ich (p= . ), non-caucasian race (p< . ), younger age (p< . ), higher initial systolic (p= . ) and diastolic bp (p= . ), worse gcs category (p< . ), and longer time to first enteral medication (p< . ). anti-hypertensive infusion duration independently predicted icu los (p< . ) after adjusting for age, race, gcs category, time to enteral antihypertensives, and ich score. worse gcs category, younger age, non-lobar ich location, and race are significant independent predictors continuous iv antihypertensive infusion duration, which is significantly associated with longer icu stay. patients with sich have a high risk of vte. pharmacological prophylaxis such as unfractionated heparin(ufh) has been demonstrated to reduce vte. however, published datasets exclude patients with recent ich out of concern for hematoma enlargement. aha/asa guidelines recommend ufh - days after hematoma stabilization while the eso has no recommendations on timing of ufh. there are few data for patients who received ufh before hours. our institutional practice is to begin ufh following sich after hours of clinical and radiographic stability. we examine the impact of this practice on risk of hematoma expansion. we performed a retrospective cohort analysis of sich patients admitted in - to a single us university hospital. demographic and clinical characteristics were abstracted. ich was measured via d volumetrics for an admission ct, a hour follow-up, and a follow-up prior to discharge. percent hematoma growth between -hour ct and discharge ct was calculated. risk factors for expansion > %, including early heparin use, were analyzed via oneway t-test and chi-squared tests. results sich patients analyzed had a median ich score of (iqr - ) and median admission gcs of (iqr - ). %( / ) patients received early ufh. %( / ) suffered hematoma expansion > %. overall mean hematoma growth was higher with early ufh (ufh hr - %,p= . ). in multivariate analysis, ich score, gcs and initial hematoma size did not predict > % hematoma expansion. early vte prophylaxis at hours from sich had a statistically significant increase in hematoma size, but this increase is clinically insignificant. in this cohort, early ufh did not increase risk of significant hematoma expansion. further prospective trials are warranted, given the high risk of vte in this population. antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sich) may increase the risk of hemorrhage expansion and mortality. current guidelines recommend consideration of a single dose of desmopressin in sich associated with cyclooxygenase- inhibitors or adenosine diphosphate receptor inhibitors. this study sought to compare outcomes in patients that received desmopressin for antiplatelet reversal in the setting of sich to similar patients that did not receive desmopressin. this retrospective chart review of the electronic medical record included adult patients admitted for sich that were on antiplatelet agents at the time of diagnosis. patients that received desmopressin were compared to similar patients that did not receive desmopressin. exclusion criteria included traumatic brain injury, active coagulopathy and thrombocytopenia. the primary outcome was the incidence of hematoma expansion. additional outcomes included average increase in hematoma volume, in-hospital mortality and functional outcome at hospital discharge. overall, patients ( received desmopressin, did not receive desmopressin) were included for analysis. incidence of hematoma expansion was not different between groups ( % with desmopressin vs % without desmopressin, p= . ). average largest increase in hematoma volume on follow-up imaging from baseline was not different ( . ± . ml with desmopressin vs . ± . ml without desmopressin, p= . . in-hospital mortality was significantly higher in the desmopressin group ( % vs % without desmopressin, p= . ) as well as the incidence of a modified rankin score of - at discharge ( % vs % without desmopressin, p= . ). administration of desmopressin for antiplatelet reversal in sich does not appear to reduce the incidence of hematoma expansion. further studies assessing temporal relation of desmopressin administration and hematoma expansion are needed to confirm the results of this single-center retrospective study. clinical outcome after intracerebral hemorrhage (ich) remains poor. definitive phase- trials in ich have failed to demonstrate improved outcomes with intensive systolic blood pressure (bp) lowering.we sought to determine whether other bp parameters-diastolic bp, pulse pressure (pp), and mean arterial pressure (map)-showed an association with clinical outcome in ich. we retrospectively analyzed a prospective cohort of patients with spontaneous ich and documented demographic characteristics, stroke severity, and neuroimaging parameters. consecutive hourlybp recordings allowed for computation of systolic bp, diastolic bp, pp, and map. threshold bp values that transitioned patients from survival to death were determined from roc curves. using inhospital mortality as outcome, bp parameters were evaluated with multivariable logistic regression analysis. patients who died during hospitalization had higher mean pp compared to survivors ( . ± . mmhg vs. . ± . mmhg; p= . ). the following admission variables were associated with significantly higher in-hospital mortality (p < . ): poorer admission clinical condition, intraventricular hemorrhage, and increased admission normalized hematoma volume. roc analysis showed that mean pp dichotomized at . mmhg, provided a transition point that maximized sensitivity and specific for mortality. the association of this increased dichotomized pp with higher in-hospital mortality was maintained in multivariable logistic regression analysis (or . ; %ci . - . ; p < . ) adjusting for potential confounders. widened pp may be an independent predictor for higher mortality in ich. this association requires further study. a national confidential enquiry into patient outcome and death (ncepod) report concerning management of aneurysmal subarachnoid haemorrhages in the uk suggested up to half of patients received suboptimal consideration for organ donation. as demand for organs continues to increase, so does the need to pursue all potential sources of donor organs. subarachnoid haemorrhages have an estimated mortality of % and can potentially provide younger donor organs with less chronic pathology. this is a comprehensive picture of donation rates within a tertiary centre. retrospective data regarding all deceased patients on the neuro-intensive care unit during with aneurysmal subarachnoid haemorrhage as the cause of death was obtained from the nhs blood and transfusion team. the local audit committee provided ethical approval. data regarding organ donation was extracted and compared to national data, then analysed using fisher's exact test. referral rates were %. this is greater than the national average of . % (p= . ), yet only . % of referred patients proceeded to organ donation. consent was withheld in . % of potential donors. nationally . % of donors are lost due to non-consent (p= . ). . % of consented patients were unable to donate organs, similar to national figures (p= . ). referral rates within this centre are excellent; consent remains the main obstacle. consent rates can be improved using a long contact model where specialist nurses in organ donation establish relationships with relatives prior to any discussion of donation. the ideal discussion is a pre-planned collaboration involving a senior doctor and a specialist nurse. early brain stem testing may facilitate earlier acceptance of death by relatives whilst reducing the duration of the multi-systemic effects of the associated hyperresponsive cascade on donor organs. neurosurgeons should be encouraged to suggest organ donation when declining referrals. further work is needed to assess the barriers to instituting these measures and inspiring change. spontaneous brainstem hemorrhage has been historically associated with high mortality. however, updated data on the frequency and outcome of spontaneous brainstem hemorrhage is scarce vis-a-vis advances in neuro-critical care. the purpose of this study was to investigate the frequency and outcome of spontaneous brainstem hemorrhage. records of consecutive intracerebral hemorrhage (ich) patients presenting to an urban academic medical center from january though december were reviewed. cases with brainstem hematomas were isolated for analysis. data on demographics and outcomes were collected and analyzed. sub-group analysis was also done to look at outcomes based on location of hemorrhage in the brainstem. of consecutive spontaneous ich patients, ( . %) presented with brainstem hemorrhage; ( . %) were pontine, ( . %) mesencephalic, and ( . %) were located in both the pons and the midbrain. the average age was . years and ( . %) were men. median glasgow coma scale on presentation was . . thirty-day mortality rate was . %, with in-hospital deaths and deaths post discharge. two and patients were discharged home or a rehabilitation facility, respectively. in subgroup analysis, thirty-day mortality for midbrain, pons and combined pons/midbrain hemorrhage was %, % and %, respectively. spontaneous brainstem hemorrhage remains an uncommon but highly fatal clinical entity. more than one-half die within days. only a minority are discharged to rehabilitation or home. in sub-group analysis, location of brainstem hemorrhage was shown to influence outcome, with % mortality in case of combined pons/midbrain hemorrhage, and more than % mortality with pontine hemorrhage. midbrain hemorrhage was associated with good outcome with % survival. patients with intracerebral hemorrhage (ich) frequently present with hypertension. it is unclear whether this is due to preexisting hypertension (prhtn) causing the bleed, an effect of the bleed, or both. we retrospectively analyzed a single-institution cohort of ich patients presenting between and . data included home antihypertensive use; asbp; tte, and ekg and imaging results; and nicardipine administration. the primary objective was to assess the relationship between prhtn and asbp, while the secondary objectives were to assess the relationship between prhtn, imaging and acute antihypertensive requirements. ich patients met inclusion criteria. in our assessment for prhtn, we found that % of patients were on antihypertensives, % had lvh on ekg, and % had lvh on tte. there was a significant relationship between lvh on tte and lvh on ekg (p< . ), but not between home antihypertensive use and presence of lvh using either modality. asbp was higher for all patients with markers of phtn, but this was only significant for patients with lvh on tte ( mmhg, iqr - vs. mmhg, iqr - , p < . ) and patients with lvh on ekg ( mm hg, iqr - vs. mm hg, iqr - , p< . ). all patients with markers of prhtn were more likely to require nicardipine, but this was only significant for patients with lvh on tte ( % vs. %, p= . ) and patients with lvh on ekg ( % vs. %, p= . ). all patients with markers of prhtn were more likely to have deep bleeds (p= . for patients with lvh on ekg vs. those without lvh on ekg). there was no relationship between any markers of prhtn and the presence of a spot sign. in patients with ich, prhtn is related to higher asbp, deep bleed location, and increased acute antihypertensive requirements. all spontaneous intracerebral hemorrhage (sich) patients, including those with low severity are uniformly admitted to the intensive care unit (icu) at our institution. many may not benefit from this high-intensity observation and leave the icu within hours without experiencing any complications. identifying low-risk characteristics could aid in triaging such patients to stroke units instead. retrospective data collection of all sich patients admitted to our institution from june , -june , included ich score, need for surgical interventions, medical complications, and icu/hospital los. we analyzed variables predicting short (< hour) icu los among low severity (ls-ich) patients (defined as those with ich score - ). ( %) of sich patients had ich scores of - , of which just under half ( ) had icu los hr. they also spent significantly fewer days in hospital ( vs . , p< . ). we could not identify a clear ich score cutoff that was sensitive enough to predict short icu los. however, requirement for antihypertensive infusion and early clinical deterioration correlated strongly with longer icu los p< . . there appears to be a subset of mild ich patients (ich score - ) who do not require icu observation. a risk assessment score incorporating gcs and ich volume may be able to delineate this low-risk population who could instead be admitted to a stroke unit, with the potential for significant cost saving and hospital efficiency. obesity has been linked with relative longevity in several disease conditions. this relationship has been termed the "obesity paradox." in this study we sought to evaluate the impact of obesity on short-term outcomes in patients with intracerebral hemorrhage (ich). patients admitted with a diagnosis of ich were selected from the - nationwide inpatient sample (nis) database, using icd- codes. patients with ich were dichotomized based on the presence of obesity as a coexisting diagnosis based on icd- codes and diagnosis related groups. the primary outcome measure was in-hospital mortality. length of stay and total charges were also examined as resource utilization measures. of obesity is a major health care burden as evidenced by higher resources utilization. counterintuitively, obesity appears to be associated with lower in-hospital mortality in ich patients. one possible physiological basis for this could be that the higher ldl levels on presentation result in a lower likelihood of hematoma expansion. recent short-term outcome analysis indicates association of spontaneous intraventricular hemorrhage (ivh) related hydrocephalus with incontinence and gait dysfunction. we explore the association of hydrocephalus scores, intraventricular alteplase and clinical variables with these outcomes at long term follow up in survivors from the clear iii trial. clear iii, a randomized, multi-center, double-blinded, placebo-controlled trial was conducted to determine if pragmatically employed external ventricular drainage (evd) plus intraventricular alteplase improved outcome, in comparison to evd plus saline in patients with ivh causing obstructive hydrocephalus. we assessed hydrocephalus scores on survivors at diagnosis, days and . incontinence and dysmobility were defined using -month barthel index subscores (< for bladder and < for mobility, respectively). outcome measures were predictors of incontinence and gait dysmobility at year after ich. this prospective observational study analyzed consecutive ich-patients (n= ) treated at the neurological and neurosurgical departments of the university-hospital erlangen, germany over a month inclusion period ( / - / ). we analyzed the influence of patient characteristics, inhospital measures and functional status on treatment recommendations and on oac initiation during -month follow-up. clear treatment recommendations by attending stroke physicians seem necessary to ensure oac initiation after ich. oac showed beneficial associations; however data here suggests the presence of an indication bias introduced by treatment recommendations and outpatient care during follow-up. therefore, observed association with age and functional status might affect unadjusted analyses. although recently, non-vitamin k antagonist oral anticoagulants (noacs) therapy in patients with non valvular atrial fibrillation have half the incidence of intracerebral hemorrhage (ich) compared to warfarin. however, it would be still controversial subject that outcome of noac-associated ich (nich) might be worse or better than warfarin-associated ich (wich). in this study, we investigated clinical outcome and radiological finding of ich between two different anticoagulation treatments. retrospective review of medical records was performed for , patients who admitted with ich from to in seoul national university bundang hospital. clinical characteristics, functional outcome, location and volume of ich, and all-cause mortality within days were analyzed. among those patients, patients with wich and patients with nich were included. lesion location was common in supratentorial deep area ( . %, . %), lobar area ( . %, . %) and brainstem and cerebellum ( . %, . %) in the nich and wich group, respectively. no significant difference found in initial nihss ( . vs ), discharge nihss ( . vs ), mrs ( to ) at discharge ( . % vs . %), mrs ( to ) at discharge ( . % vs . ), mrs ( to ) at days ( . % vs . ) and mrs ( to ) at days ( . % vs . ) in nich and wich group. we did not find any difference between nich and wich for allcause mortality at discharge ( % vs %), days ( . % vs %), and year ( % vs %). median baseline ich volume was not significant difference in two groups ( . vs . ). in our study, functional outcome, mortality, and baseline ich volume were similar following nich and wich. because of low statistical power due to small sample size in our study, further studies with prospective larger patient cohorts will need to be conducted. novel oral anticoagulants (noac) are increasingly used as an alternative to vitamin-k antagonists (vka) such as warfarin for anticoagulation and have shown lower rates of intracranial hemorrhage in several randomized clinical trials. it has been suggested that noac-iphs might be particularly dangerous, yet the literature regarding hematoma characteristics and outcomes between noac-iphs and vka-iphs is inconclusive. given the lack of standardized reversal strategies and lack of information on outcomes following noac-associated iph, the aim of this meta-analysis was to compare ) mortality; ) hematoma volume, and ) risk of hematoma expansion in patients who developed an iph on noacs versus vka. a meta-analysis of the literature through december was conducted using pubmed, embase and cochrane databases in accordance with prisma guidelines. pooled risk ratios (rr) were calculated for mortality and hematoma expansion and pooled mean difference (md) was calculated for hematoma volume (ml) using random-effect (re) and fixed-effect (fe) models. noac-iph was not associated with increased mortality (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) and hematoma expansion (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) compared to vka-iph. the hematoma volume of noac-iph was smaller than vka-iph (re: md: - . ml; %-ci: - . ; - . , fe: md: - . ml; %-ci: - . ; - . ; studies), but with considerable heterogeneity that could not be alleviated (i = . %, p-heterogeneity . ). noac-iph was not associated with increased mortality or hematoma expansion compared to vka-iph and may be associated with a smaller hematoma volume. controversy exists regarding blood pressure (bp) reduction and perihematomal ischemia (phi). we investigated the association of acute bp reduction and presence of qualitative and quantitative phi in a large prospective cohort of intracerebral hemorrhage (ich). consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. the association of clinical, radiographic factors and bp at baseline and hours with qualitative perihematomal and/or remote ischemia (i.e. dwi bright adc dark) and quantitative ce on adc were determined. patients ( % female) with mean age ± , and nihss (iqr , ) were included. mri time was . hours (iqr , ). % had lobar ich. ich volume was cc (iqr , ). % had perihematomal ( %) or remote ischemia ( %). % of patients had areas of perihematomal adc cc) was associated with higher absolute ( ± mm hg, p= . ) and relative ( % ± % vs % ± %, p= . ) map reduction, younger age (p= . ), h/o tia/stroke (p= . ) and larger ich volumes ( vs cc) (p< . ). in multivariate analysis, map reduction was not significantly associated with ce whereas ich volume was (p= . ). perihematomal and remote ischemia is frequently seen after ich, but the severity of phi is small and of unclear significance. bp reduction may be associated with phi but this was not an independent predictor. introduction: patients with left ventricular assist devices (lvads) receive anticoagulation and antiplatelet therapy to prevent pump thrombosis. consequently, neurological events including intracranial hemorrhage (ich) are one of the most feared causes of morbidity and mortality in these patients. there is little evidence to guide initiation of anticoagulation after such ich events. methods: this is a retrospective, single academic center analysis of lvad patients from - . the electronic medical record was reviewed after irb approval for the physiologic, laboratory, and radiographic data of these patients as well as survival or cause of death by days or by discharge. results: during the analysis, patients were reviewed, of which ( . %) had intracranial hemorrhage. one patient was excluded from analysis after care was transitioned to hospice, thus follow-up scans were not obtained. the remaining patients were receiving both aspirin ( - mg daily) and warfarin ( - mg daily) with an inr of . - . (mean= . ) at the time of ich. aspirin ( - mg daily) was resumed within - (mean= . ) days post ich. warfarin was resumed - (mean= . ) days post ich at - mg (mean= mg) with goal inr ( . - )-( - ) depending on device. there was death due to withdrawal of life support in setting of multiple comorbidities, though follow-up scan days post warfarin resumption revealed no evidence of rebleed. the remaining patients showed no evidence of rebleed on ct scans at months post warfarin resumption and were subsequently discharged to rehab facilities or home with modified rankin scores - (mean= . ). conclusion: in this review of lvad patients, about % suffered ich, and of those survivors aspirin was safely resumed within days and warfarin was safely resumed as early as days post-event. further studies are needed in order to establish safe practice guidelines and risk factors to prevent ich. intracerebral hemorrhage (ich) remains a devastating form of stroke, and perihematomal edema worsen outcomes after ich. recent studies have demonstrated the safety of minimally invasive surgery (mis) for hematoma removal, but the efficacy of mis in the treatment of ich is controversial. this study aimed to evaluate the effect of mis compared with medical treatment for basal ganglia ich. we retrospectively analyzed the clinical outcomes of prospectively collected data from two stroke centers. the treatment strategies of the two stroke centers for basal ganglia ich are different; one stroke center underwent mis and the other stroke center medically treated according to the current guidelines. we hypothesized that mis could reduce perihematomal edema and improve functional outcomes compared to medical treatment. primary outcome of this study was a modified rankin scale (mrs) at months after ich occurrence. a total of patients with basal ganglia ich were treated with different treatment strategies; patients underwent mis and patients received medical treatment. no statistically significant differences were found in age, sex, hematoma volume, and glasgow coma scale scores between the groups. a better functional recovery (mrs < ) at months was found in the medical treatment group than the mis group ( . % vs . %, p < . ). no significant differences were observed between groups in terms of mortality. our findings suggest that the best medical treatment improves functional recovery after basal ganglia ich compared to mis. these results are contrary to other studies of ich, and further randomized trials are required. perihematomal edema (phe) after intracerebral hemorrhage (ich) is thought to be predominantly vasogenic. the presence and extent of cytotoxic edema (ce) is controversial. we investigated phe diffusivity (phed) and factors associated with ce. consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. clinical and radiographic factors associated with ce were determined. cytotoxic edema is detected in the perihematomal area, early after ich and is associated with younger age, larger ich and prior h/o tia/stroke. its clinical significance needs to be studied further. hemorrhagic stroke carries a high mortality rate and determining prognostic factors during initial presentation can aid redirecting intensive care unit (icu) management. we described the physiological profile and clinical outcomes of hemorrhagic stroke patients in a colombian icu. we retrospectively reviewed all hemorrhagic stroke patients admitted to our icu from - . clinical characteristics, outcomes, available laboratory values and hourly vital signs from the first hours in the icu were retrieved and analyzed. our primary stroke center admitted patients, ( %) were hemorrhagic. out of these, required icu management, representing % of the total icu admissions during this time frame. intracerebral hemorrhage (ich) was present in patients while subarachnoid hemorrhage (sah) was seen in . the latter had a median fisher score of . for all patients, the most common risk factors were hypertension ( . %), dyslipidemia ( . %) and smoking ( . %). icu mortality was . % ( . % with ich and . % with sah). mean sequential organ failure assessment (sofa) score was significantly greater in patients who died ( . vs. . , p< . ) and mean glasgow coma scale was significantly lower ( . vs. . , p< . ). vasopressors were required in patients ( . %), mechanical ventilation in ( . %), and half of the patients requiring either support therapy died. only patients ( . %) had fever in the first hours and all died. mean coefficient of variation for systolic, diastolic and mean blood pressure was significantly lower in patients who survived. mortality cases were more likely to have hypokalemia and hypomagnesemia than surviving patients ( . % vs. . % and . % vs. %, respectively). icu-admitted hemorrhagic stroke patients have a poor prognosis. sofa and gcs are accurate predictors of mortality. certain electrolyte disturbances, fever and a higher variation of blood pressure during the first hours were associated with a worse outcome. the association between worsening cerebral edema and unfavorable outcome in ich patients has been described in rcts. the objective of this analysis was to compare hospitalized spontaneous ich patients with and without perihematomal edema (phe) expansion and to evaluate relationships between hypertonic saline (hts) use, peak serum na, phe expansion, and short-term outcomes. we conducted a cross-sectional study of consecutive spontaneous ich patients admitted to a single center from / - / . head cts during the first week of admission, use of hts, and phe (using abc/ method) were evaluated. phe expansion of % or more was considered worsening edema. outcomes of interest included time to peak na, poor disposition (not home or inpatient rehabilitation), discharge mrs - , and in-hospital death. of ich patients, % experienced worsening phe. there was no difference in age, race, sex, arrival bp arrival, or vascular risk factors in patients with or without worsening phe. however, for each mm of midline shift (mls) present on initial head ct, odds of phe expansion was decreased by % (or . , %ci . - . , p= . ). mls on initial head ct was the best discriminator of phe expansion (auc . ( %ci . - . ). although hampered by small sample size, our data indicates that finding that ich patients with degree of mls on initial head ct is the best radiographic predictor of had lower odds of phe expansion. those without mls at presentation may be at risk of phe expansion, and counterintuitively may be those most in need of aggressive medical management. may suggest a role for intensive osmotherapy in patients with favorable imaging at presentation. intracerebral hemorrhage (ich) is a devastating stroke with high mortality rates. previous studies have shown a potential role of immune cells as a prognostication method. a high neutrophil to lymphocyte ratio was associated with poor outcomes after ich. we sought to determine whether absolute lymphocyte count(alc) at admission was predictive of outcomes in patients with ich. we performed a retrospective chart review of all patients admitted to our hospital with a diagnosis of ich from january to december .we collected baseline demographic characteristics, medical history, ich scores, differential leucocyte, platelet and total leucocyte(tlc) counts at admission. the functional outcomes after ich were measured using modified rankin scale (mrs) at discharge. mrs of and were considered poor outcomes. statistical analysis was done after grouping lab values into higher and lower groups with respect to the normal reference ranges a total of patients with ich were admitted to our center during the study period. patients were included in the study and the rest were excluded due to lack of differential leucocyte counts at admission. % ( of ) had poor outcomes. univariate analysis using fisher's exact test showed significant association between low alc levels ( . ) were also found to be significantly associated with worse outcomes (p = . , . , . , respectively). however, after multivariate analysis, only low absolute lymphocyte counts retained significant association (p = . ). intracerebral hemorrhage patients with low absolute lymphocyte counts at admission have a higher probability of poor outcomes at discharge. further studies are required to confirm our results. intraventricular hemorrhage (ivh) is a significant predictor of poor outcome after intracerebral hemorrhage (ich), and may differentially predict hydrocephalus and mortality among blacks vs. nonblacks. we aimed to confirm these findings in a separate cohort of spontaneous ich patients with severe ivh. the cleariii-ivh trial was a randomized, multi-center placebo controlled trial examining the effect of intraventricular alteplase versus saline, on outcomes in patients with spontaneous ivh. we retrospectively analyzed data on all patients, including self-reported race/ethnicity, medical comorbidities, presentation characteristics and functional outcomes. represented race/ethnic groups with > subjects per group were ( . %) white/non-hispanic (wnh), ( . %) white/hispanic (wh), ( . %) black/african american/non-hispanic (bnh), and ( . %) asian. bnh were significantly younger than rest of the cohort with median age [interquartile range] [ , ] years, had more hypertension( %, p= . ), and significantly higher rates of antihypertensive medication non-compliance ( . %, p= . ). wnh had more frequent coronary artery disease ( . %, p< . ), use of vitamin k antagonists ( . %, p= . ) and elevated inr on presentation ( . %, p= . ). bnh had significantly more frequent hydrocephalus on presentation ( . %, p= . ), and a higher rate of ventriculoperitoneal shunt placement ( %, p= . ). neither ich nor ivh volume at enrollment, nor ivh remaining at end of treatment differed significantly between race/ethnic groups. however, bnh patients were more likely to have greater than % ivh reduction, a recognized endpoint for better functional outcomes in cleariii ( . % vs. %-wh; . %-wnh; . %-asian; p= . ), and this difference persisted in those who received intraventricular alteplase (p= . ) and after adjustment for diagnostic ivh volume (p= . ). race/ethnicity was not an independent predictor of mortality or poor outcome at or days on multivariable logistic regression. although functional outcomes did not differ significantly among race/ethnic groups, differences in risk factors, hydrocephalus/shunting post ivh and response to thrombolytic therapy warrant further exploration. investigators from the randomized trial of unruptured brain arteriovenous malformations (avm) trial (aruba) reported in that interventions to obliterate unruptured avms resulted in greater morbidity and mortality compared to medical management. we investigated whether patterns of avm treatment changed after aruba's publication. we used inpatient and outpatient claims data from - from a nationally representative % sample of medicare beneficiaries. unruptured brain avms were identified using icd- -cm code . . the date of first avm diagnosis was coded as occurring before or on november , (online publication of aruba) versus after. outcomes were referral to a neurologist or neurosurgeon, and interventional treatment. interventional treatments were identified using cpt codes - , - , , , or - . the likelihood of outcomes after versus before aruba was compared using survival analysis with log-rank tests and cox proportional hazards models adjusted for age, sex, race, and the charlson comorbidity index. we censored patients at diagnosis of intracranial hemorrhage. we identified , patients with a mean . (± . ) years of follow-up after diagnosis of unruptured brain avm. diagnosis was most often by neurologists ( . %), neurosurgeons ( . %), and internal medicine specialists ( . %). after aruba publication, there were no changes in -year cumulative rates of referral to a neurosurgeon ( . % after, . % before; p = . ) or neurologist ( . % after, . % before; p = . ), but there was an increase in avm treatment ( . % after, . % before; p = . ). after adjustment for demographics and comorbidities, there was an increased likelihood of interventional management (hr . ; % ci, . - . ) after aruba's publication. in a nationally representative cohort of elderly patients, we found an increase in interventional avm management after publication of aruba. this is notable given that our data pertain to older patients who are generally seen as less suitable surgical candidates. elderly patients with severe intracerebral hemorrhage (ich) are often projected to have future functional dependence but unclear degree of cognitive recovery. surrogates for such patients frequently weigh multiple concerns when facing the difficult decision of whether to prolong life with tracheostomy and gastrostomy tube insertion versus pursue comfort care. we aimed to characterize distinct groups of surrogates in these situations, based solely on how they prioritize their concerns. subjects recruited from a probability-based us population sample completed an online best-worst survey that presented the above scenario and asked the respondent to prioritize concerns as the patient's surrogate. clusters were identified with latent class analysis after weighting data to match the us census demographic distribution. class solutions were replicated times from random starting seeds, with the solution chosen after factoring in akaike's information criterion. we identified distinct decisional groups among respondents (response rate = . %). all groups reported multiple concerns as important, but group ( . %) was more concerned than any other that the patient was too old to live with disability. group ( . %) focused on ensuring agreement among other family members. group ( . %) was concerned that the patient might suffer if tube feeding and iv fluids were stopped and that the prognosis could be incorrect. group ( . %) had numerous considerations that were comparably important but prioritized paying for long-term care. groups varied in whether they would actually request prolonging care for the patient (group = . %, g = . %, g = . %, g = . %, p< . ). in a multivariate model, religious affiliation and frequency of attending religious services were the only variables independently predicting group membership. we identified distinct profiles of decisional patterns for surrogates of severe ich patients with uncertain prognosis. these data will inform development of strategically tailored decision aids. cerebral venous sinus thrombosis (cvst) represents an important cause of both ischemic and hemorrhagic strokes in young people. while recent guidelines recommend management in a stroke unit, the impact of neurocritical care in this condition has not been studied. we aimed to assess whether the introduction of a neurocritical care program influenced clinical outcomes in cvst patients. we retrospectively reviewed electronic medical records of adult patients admitted to yale new haven hospital's neuroscience icu (nicu) between and with a diagnosis of cvst. demographics, vascular risk factors, comorbidities, length of stay and discharge modified rankin scale (mrs) were collected. patients were excluded for age hours of presentation. we compared two time periods, before (epoch , - ) and after (epoch , - ) the introduction of continuous staffing of cvst cases by neurointensivists in the nicu. univariable and multivariable logistic regression were utilized to model the odds of poor outcome (dichotomized mrs - vs - ). fifty-three patients with cvst met the inclusion criteria during the study period (mean age (+/- ) years, % female). patients were identified for epoch and patients for epoch . overall, patients ( %) had a good (mrs - ) outcome. for epochs and , good outcomes were observed in ( %) and ( %) patients, respectively (p= . ). in both univariable and multivariable regression analysis (adjusted for age and sex), admission during epoch was associated with a significantly reduced odds of a poor outcome (or . , ci . - . ; p = . ) and (or . , ci . - ; p= . ), respectively. in this small, single-center cohort of patients with cvst, most patients experienced a good outcome. the institution of continuous neurointensivist coverage was independently associated with better outcomes. further validation in prospective, multicenter cohort studies is needed. thrombelastography (teg) provides a dynamic assessment of clot formation, strength, and stability. we examined relationships between teg parameters and outcomes from intracerebral hemorrhage (ich). we prospectively enrolled patients with spontaneous ich between to . teg was performed at the time of admission. we divided patients into two groups based on the presence or absence of hematoma expansion (he). clinical characteristics, baseline teg values, and outcomes were compared between the two groups. multivariable regression analysis was conducted to compare the differences of teg components between the two groups after adjusting for potential confounding effects. we included patients, ( %) with he and ( %) without he. patients with he were more often male and had higher rates of aspirin use, lower incidence of intraventricular hemorrhage, and larger baseline hematoma volumes. after controlling for potential confounders, mean r time was independently associated with he ( . ± . vs. . ± . mi significantly higher risk of he with or . ( % ci: . , . ), p=< . . patients with hematoma expansion were more likely to have poor neurological outcome (mrs - ) at discharge ( % vs. %, p= . ) and had higher mortality rates ( % vs. %, p= . ). overall, patients ( %) died in the hospital. following multivariable analysis, patients who died had significantly lower mean delta ( . ± . vs. . ± . mins.; p= . ) and smaller angle ( . ± . vs. . ± . degrees; p= . ) than those who lived. hematoma expansion and mortality from ich are independently associated with slower clot formation on teg. baseline teg identifies significant coagulation disturbances which may predict poor outcome and represent potential targets for therapeutic intervention. intracerebral hemorrhage (ich) patients often present with acute hypertension requiring intravenous and enteral antihypertensive medications. we performed a cohort study to determine clinical predictors of time to enteral antihypertensive medication and its effect on icu length of stay (icu los). we identified consecutive spontaneous ich patients admitted from / to / to a tertiary center, and excluded those transitioned to comfort care (cmo) within hours of admission. we calculated time from hospital admission to first enteral (oral or feeding tube) antihypertensive. we abstracted demographic and clinical variables. two reviewers examined medical records and classified ich location and etiology. we determined univariate and adjusted associations of clinical variables to time to enteral antihypertensive medication and performed regression analysis to determine effect on icu los. we identified patients and excluded for early transition to cmo. endotracheal intubation (p= . ), higher ich score (p< . ), no outpatient antihypertensive use (p= . ), and non-lobar ich location (p= . ) predicted longer time to starting enteral antihypertensive in adjusted analysis. presenting systolic or diastolic bp, time of icu admission (day vs. night), sex, and race were not significant predictors of time to enteral antihypertensive. time to enteral anti-hypertensive is the strongest predictor of icu los (p< . ) after adjustment for age, gcs, ich score, sex, race, and duration of iv antihypertensive infusion. patients with higher ich scores, intubation, no prior antihypertensive use, and non-lobar ich are at risk for increased time to enteral antihypertensive administration. timely enteral antihypertensive administration is an important and potentially modifiable predictor of icu los in acute ich. overall mortality from intracerebral hemorrhage (ich) represents a combination mortality from a potentially fatal disease as well as practice variation around treatment withdrawal of care. early do-not-resuscitate (dnr) rates are independently associated with in-hospital mortality and may serve as a proxy for withholding aggressive care. the american heart association (aha) guidelines recommended that dnr orders should not be applied before hours out of a concern that less aggressive care would lead to a self-fulfilling prophecy and excess mortality. we performed a retrospective analysis of temporal trends among primary ich patients presenting to all nonfederal emergency departments in california from to using data from the office of statewide health planning and development (oshpd). demographic information, clinical covariates (such as mechanical ventilation, craniotomy), and early dnr status within hours were collected and analyzed using segmented regression to evaluate for differences in linear trends from - compared with - . over a use of early dnr orders for ich patients has steadily decreased over the last years, even after adjusting for age and disease severity. the pace of this downward trend did not significantly change around the time when recommendations on early dnr use for ich in aha guidelines were revised in . spontaneous intracerebral hemorrhage (ich) is a common form of stroke that often results in severe morbidity or death. for most ich, there are no proven therapies for acute management. evidence suggests minimally invasive surgical evacuation of ich may result in improved patient outcomes. the enrich clinical trial is designed to determine the efficacy and economic impact of early ich evacuation using minimally invasive, transulcal, parafascicular surgery (mips) compared to standard guideline-based management. in this abstract we present the trial design and rationale at the foundation of the enrich clinical trial. enrich is an adaptive, prospective, multi-center clinical trial designed to enroll up to patients with acute ich. patients are block-randomized based on hemorrhage location (lobar vs basal ganglia) : to mips or standard management. included patients are - years, gcs - , baseline mrs , presenting within hours from last known well and found to have a spontaneous, cta-negative, supratentorial ich ( - ml). primary efficacy will be determined by demonstrating significant improvement in the mean utility-weighted mrs at days after enrollment. economic effect of mips will be determined by quantifying the cost per quality-adjusted life-years gained at pre-determined time points. the rationale for early intervention is to interrupt the time-dependent ich related pathophysiology caused by mechanical pressures and the pro-inflammatory secondary cascade that leads to worsened cellular injury and edema formation. the planned enrichment strategy acknowledges that hemorrhages in varied locations may have a differential response to mips. study adaptation, in the form of enrichment, may occur if pre-determined futility rules are met for the primary outcome in either of the two locations. enrich is designed to establish the clinical and economic value of early mips in the treatment of ich. enrollment was initiated in december . early seizures (< days) after intracerebral hemorrhage (ich) may be associated with the presence and degree of perihematomal cytotoxic injury. we explored the association between perihematomal diffusivity (phd) and early seizures after ich. consecutive patients from the prospective nih funded dash study (> years, spontaneous ich) were included. all patients had multimodal mri within weeks. perihematomal edema (phe) volume was outlined on t /flair and ich volume on gre; these and adc were coregistered to analyze phd. eeg monitoring was performed for clinical suspicion of seizure. mean adc values of phe and the percentage of phe volume were compared between the seizure and no-seizure groups, with adc values as vasogenic edema. results ( %) of a total of patients had early seizures at a median of day post ich. mean adc in the phe region was higher in the seizure group (mean: +/- vs +/- , p= . ). ich, absolute, and relative phe volumes were not different between groups. the phe of the seizure group had a lower percentage of cytotoxic edema ( % vs %, p= . ) and a higher percentage of vasogenic edema ( % vs %, p was the most predictive of seizure with auc = . , though adc thresholds between - had largely similar auc's. phe volume of > % (of adc > ) identified patients with seizure with sensitivity of . , specificity of . , and remained significant in multivariable analysis. patients with early post-ich seizures have higher mean perihematomal adc and a larger percentage of vasogenic edema in the perihematomal region. vasogenic edema due to bbb breakdown and perihematomal inflammation rather than cytotoxic injury is associated with early post ich seizures. novel neuroprotective treatments hold the promise to improve patient outcomes by broadening time windows of intervention and reducing hypoperfusion and reperfusion injury in the era of mechanical thrombectomy for acute ischemic stroke. hibernating species, such as arctic ground squirrels (ags), demonstrate remarkable resilience to ischemic and reperfusion injuries. bioinformatic analyses of genomes of hibernating species reveals signatures of convergent evolution in genes regulating stability and formation of mitochondrial respirasomes. hypoxia pre-conditioning (hpc) also leads to improved survival upon subsequent exposure to hypoxia, and is associated with increased stabilization of respirasomes. the respirasome is a macromolecule consisting of oligomers of complex i, iii, and iv. cox a l is a key mediator of respirasome stability via interactions with complex i and iii. in this study, we explored the role of cox a l in mediating respirasome stabilization in ags neural stem and progenitor cells (nsc/npcs) as well as mouse nsc/npcs exposed to hpc. respirasome stability was assessed using blue native gel electrophoresis and mitochondrial metabolism assessed by measuring oxygen consumption in vitro (seahorse metabolic analyzer). exposure to mild hypoxia and induction of hif leads to stabilization of respirasomes, upregulation of hif, and modulation of mitochondrial metabolism. interestingly, overexpression of the ags isoform of cox a l, which has amino acid substitutions in residues mediating respirasome stability, recapitulates the effects of hypoxia on respirasome stability and mitochondrial metabolism without altering hif expression. targeting respirasome stability by modulating cox a l is a potentially novel neuroprotective target for treatment of ischemic injuries. testing of these hypotheses in pre-clinical models of stroke is on-going. acute stroke symptoms need timely diagnostics in order to ensure best outcomes. as a non-academic, community-based center located in rural western nc, where we are the regions only comprehensive stroke center, we developed a process to intake stroke patients quickly directly from ct to interventional radiology when applicable. a smooth transition reduces the quantity of time from imaging to interventional suite, ultimately reducing the time it takes to prepare to actively treat a patient. interventional radiology value stream mapping started in june . multidisciplinary team worked in multiple work groups to design and create "code ir stroke now". flow chart created to show multiple moving parts simultaneously, to streamline transition from er (sometimes this includes triage from the region also) to ir. an ir "ready" criteria was made, er and ir checklists, followed by post procedure debrief and treatment plans/order set to standardize care and documentation. first mock code ir was done / / , this was critiqued/perfected. "go live" date: / / . we continue process improvement today. in first three months, patients have gone through this process. average compliance for goal door to puncture < min went from . % to %. door to groin times reduced from minutes to minutes. our performance is minutes quicker than other comprehensive stroke centers ( m avg gwtg database). saved an average of million neurons per patient. total of million neurons saved on average since / / ! door to groin times can be reduced with streamline approach to care. multidisciplinary team approach, including house supervisors, anesthesia, switch-board in addition to the bedside staff and providers can make a smooth transition from the time a large vessel occlusion is identified to getting the patient to the interventional suite. activation of "code ir stroke now" page activates this team / . it is unknown whether antithrombotics for secondary stroke prevention in patients with acute ischemic stroke (ais) due to infective endocarditis (ie) reduce the rate of secondary ais or increase major bleeding. we conducted a multi-center, retrospective cohort study from - of patients with ais secondary to left-sided ie, separated into two groups (antithrombotic vs no antithrombotic). antithrombotics included antiplatelets and/or therapeutic anticoagulation. the primary outcome was a composite of recurrent ais and major bleeding. secondary outcomes included ais and major bleeding individually. a binary logistic regression model adjusted for age and native vs prosthetic valve involvement was used for outcome evaluation. the final analysis included patients ( antithrombotic vs no antithrombotic). median age was years and ( %) patients had prosthetic valve infections. infecting organisms were mostly methicillin sensitive s. aureus ( %) or streptococcus spp. ( %). valve repair/replacement occurred in ( %) patients. aspirin with or without another antithrombotic ( %) was the most common antithrombotic treatment. the primary outcome occurred in . % vs . % of patients with antithrombotics vs no antithrombotics, respectively (or . ; % ci . to . ). ais ( . % vs . %; or . ; % ci . to ) and major bleeding ( . % vs . %; or . ; % ci . to . ) were similar between groups. a subgroup analysis of aspirin monotherapy vs no antithrombotic yielded similar results for the primary outcome ( . % vs . %; or . ; % ci . to . ) and ais ( . % vs . %; or . ; % ci . to . ). major bleeding was increased, however ( . % vs . %; or . ; % ci . to . ; p= . ). antithrombotics after ais secondary to ie were not associated with a decrease in recurrent ais or an increase in major bleeding. aspirin monotherapy was associated with an increase in major bleeding without any reduction in ais. malignant hemispheric stroke (mhs) represents between - % of all hospitalized ischemic stroke in the united states. pooled analysis of european studies has demonstrated that decompressive hemicraniectomy (dchc) for mhs reduces mortality compared with conservative medical management and may also improve functional outcomes. these trials however, excluded patients with major medical comorbidities that might confound clinical outcomes. apache ii and sofa scores are validated icu scoring systems to help characterize disease severity and estimated hospital mortality. this study aims to evaluate apache ii and sofa scores in predicting outcomes for patients undergoing dchc for mhs. this is a single center retrospective analysis of patients who underwent early dchc for mhs between may through january at unc chapel hill. apache ii and sofa scores were calculated for the date of admission or date of first presentation to neurologic care. outcomes included mortality at discharge, mortality at day, and functional outcome at last follow up, up to one year. multivariate analysis included timing of surgery, age, laterality, presence of midline shift, hemorrhage or multiple territory infarction. we identified patients who met inclusion and exclusion criteria. the median age was ( to ), -nine percent of patients received surgery by hospital day . full statistical analysis is pending. our hypothesis is a positive correlation between icu severity scores and mortality. given apache ii and sofa scores capture the effects of acute and chronic disease that would affect patient recovery, we hope to provide a more comprehensive prognostication of outcomes following surgery to help guide physicians and family members of these patients in their decision-making process. we conducted this study to investigate the effects of decompressive craniectomy (dc) combined with hypothermia on mortality and neurological outcomes in patients with large hemispheric infarction. within hours of symptom onset, patients were randomized to one of the following three groups: dc group, dc plus head-surface cooling (dcsc) group and dc plus endovascular hypothermia (dceh) group. we combined the data of the dcsc and dceh group to dch group during analysis. the primary endpoints were mortality and modified rankin scale (mrs) score at months. there were patients in the dc group, patients in the dcsc group and patients in the dceh group. for all patients, the mortality at discharge and after months was . % ( / ) and . % ( / ), respectively. the dch group had lower mortality, but the difference was not statistically significant (at discharge, . % vs. . %, p= . ; months, . % vs. . %, p= . ). after months, patients survived, and . % of the surviving patients had good neurological outcomes (mrs score of - ). the dch group had better neurological outcomes, but this difference was also not statistically significant ( / , . % vs. / , . %; p= . ). the total number of patients experiencing complications in the dc group and the dch group was ( . %) and ( . %), respectively. treatment with hypothermia led to decreased mortality and improved neurological outcomes in lhi patients who received dc. a multi-center rct is needed to confirm these results. destiny ii investigated hemicraniectomy in patients -years and older for the treatment of malignant cerebral edema. we sought to describe the treatment effect of early hemicraniectomy in destiny ii, using number needed to treat to benefit (nntb) and benefit per hundred (bph) treated at and months. as an mrs of is generally undesirable, we also present nntb and bph excluding this outcome. for all possible dichotomizations of the mrs, net nntb was derived by taking the inverse of absolute risk difference, and net bph by multiplying absolute risk difference by . for benefits simultaneously across all disability transitions on the mrs, nntb, and bph, estimates were derived using joint outcome tables: ) algorithmic minimum and maximum and ) four independent experts. the expert data is presented as geometric mean. the algorithmic nntb was . (range . - . ) at -months and . ( . - . ) at -months, while bph was . ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months and . ( . - . ) at -months, and the bph was . ( - ), and . ( - ) respectively. excluding mrs the algorithmic nntb was . (range - . ) at -months and . ( . - . ) at -months, while bph was ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months, and . ( . - . ) at -months, and bph was . ( - ) and . ( - ) respectively. early systematic hemicraniectomy improves outcome (including mrs ) for every - patients treated. excluding patients with mrs , hemicraniectomy improves outcome for every . patients treated. the algorithmic range provides bounds to the data, while the expert geometric mean provides the most accurate point estimate. these data provide a powerful tool to describe the potential treatment outcomes to families during the first day following a malignant middle cerebral artery infarction. background cerebral bypass surgery is performed to restore, or revascularize blood flow to the brain. previous studies have not shown whether emergency surgical reperfusion therapy may be effective in acute ischemic stroke patients with large artery occlusion and hemodynamic deterioration. objective to evaluate the effect of emergency sta-mca bypass surgery on the outcome of hemodynamic compromised patients who had progressive or fluctuating stroke despite best medical treatments. we retrospectively reviewed the clinical and radiological data of consecutive patients treated by both emergency bypass surgery ( cases, . %) and elective bypass surgery ( cases, . %) due to large artery occlusion at a single center. the effect of surgical therapy was measured with the modified rankin scale (mrs) at months. clinical severity was evaluated by the national institutes of health stroke scale (nihss) between pre-and post-operative state. major perioperative complications were defined as any hemorrhagic stroke, myocardial infarction and death. results occlusive sites were the cervical internal carotid artery in ( . %) patients and the middle patients in emergency surgery group and ( . %) patients in elective surgery group. emergency bypass surgery improved nihss (preoperatively, [ - ] ; weeks postoperatively, [ - ]). major perioperative complications in days were happened in three patients ( . %) after emergency bypass surgery, and four patients ( . %) after elective bypass surgery. emergency revascularization surgery may be effective alternative treatment for acute ischemic stroke patients with hemodynamic deterioration refractory to maximal medical treatments without significant complications. larger randomized clinical study is needed to evaluate the effect of emergency revascularization surgery in acute hemodynamic deterioration. multiple studies have reported lower mortality rates in obese patients with various cardiovascular disorders, a phenomenon called as the 'obesity paradox'. such relationship has been largely unreported in patients with neurological pathologies especially stroke. this study reports the effect of obesity on prognosis in patients with ischemic stroke. analysis of national inpatient sample data ( - ) showed a total of , , patients discharged with primary diagnosis of is, icd- code .xx and .xx. patients with obesity were identified using agency of healthcare research and quality (ahrq) criteria. we used binary regression to compare inhospital mortality between obese and non-obese patients with ischemic stroke. from - , , , patients with ischemic stroke were identified of which . % were found to be obese. obese patients with ischemic stroke were more often younger, female, and african american as compared to caucasian. after risk adjustment for demographics, and baseline comorbidities, obese patients with ischemic stroke had lower observed in hospital mortality as compared with non-obese patients with ischemic stroke ( . % vs %, or: . ci= . - . p< . ). from an eleven year nationwide cohort of patients with ischemic strokes, we observed a significant protective effect of obesity and better prognosis including a lower mortality rate. more prospective studies are warranted to further analyze this counter-intuitive trend. very early mobilization of critical care patients improves outcome, length of stay, and patient satisfaction. data for efficacy of very early mobilization for stroke patients have been mixed, and there is limited outcomes data for patients mobilized within hours of receiving intravenous alteplase (iv tpa). the objective of this retrospective observational study was to determine if patients receiving iv tpa who were mobilized earlier were more likely to discharge home. medical records of ischemic stroke patients who received iv tpa between and at two urban facilities were reviewed for mobility protocol activities. patients who received endovascular treatment, were placed on comfort care day zero or one, mobilized after the first hours, and transferred out or left against medical advice were excluded. multinomial regression was used to determine if there were significant differences in patients' discharge status by time first mobilized, adjusting for stroke severity using the national institutes of health stroke scale (nihss), age and gender. of the patients included, . % (n= ) were female, mean age was . (± . ), and the median admit nihss was . [iqr: . , . ]. the median time first mobilized was . hours [iqr: . , . ], . % (n= ) of patients were discharged to home, . % (n= ), a skilled nursing facility (snf), . % (n= ), an inpatient rehab facility (irf), and . % (n= ) hospice or expired. there was suggestive, but inconclusive evidence for a relationship between time first mobilized and discharged to snf versus home (p=. ). for every one hour increase in time mobilized, patients were . ( % ci= . - . ) times more likely to be discharged to snf than home. this study reveals very early mobility is potentially efficacious after iv tpa. longer time to first mobility was associated with discharge to skilled nursing facility, although this was not statistically significant. medical management of cerebral edema after large volume stroke varies greatly across institutions. hypertonic saline has emerged as a common treatment strategy to attempt to reduce edema and theoretically prevent the need for decompressive hemicraniectomy. there is no established protocol for hypertonic saline administration and there have been concerns regarding safety. in a single-center, retrospective analysis we identified patients who received hypertonic saline for malignant edema after an ischemic stroke involving the entire hemisphere or diffuse middle cerebral artery (mca) territory. we compared patients who received continuous infusions of % or % hypertonic saline to those who received continuous infusions with boluses of . %. the primary endpoint was time to goal sodium ( ). secondary endpoints included the need for surgical decompression and adverse events. we included patients who received only continuous infusions of hypertonic saline and patients who received a combination of continuous infusions and bolus doses. we found no significant difference between number of patients who reached goal sodium ( vs respectively, p= . ) or time to goal sodium ( hours vs . hours, p= . ). there was a significant difference in the number of patients who underwent surgical decompression ( vs , p= . ). there was not a significant difference in the rate of acute kidney injury or development of acidosis between groups ( vs. , p= . ). both hypertonic strategies appear to be safe. bolus dosing, on review, was more often instituted during clinical deterioration, accounting for the higher rate of surgical intervention. we feel we can safely be more aggressive earlier in the clinical course to potentially avoid surgical decompression. furthermore, we may need to look more closely at our target sodium, evaluating whether it should be based on the patient's baseline sodium or a universal value. even though recanalization is strongly associated with improved functional outcomes and reduced mortality, clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. in the recent study, endovascular treatment(evt) has been demonstrated to improve functional outcome in patients with acute ischemic stroke (ais) within the time window of onset to or hours. however, beyond usual thrombolysis time window, early neurologic deterioration(end) related with proximal artery occlusion is not uncommon in ais. with this, we report ais case series treated with evt because of end related proximal artery occlusion. from january through march , all patients underwent iat for ais with anterior circulation stroke. among them, twenty-four patients underwent evt due to end. at admission, all twenty-four patients showed near to complete occlusion of a proximal artery and had diffusion-perfusion mismatch. mean age was . initial median initial national institutes of health stroke scale (nihss) was and nihss after end was . all patients had diffusion-perfusion mismatch over %. seven patients treated with iv-tpa before evt. good recanalization (tici b/ ) was achieved in . %. the hemorrhagic complication was seen in the follow-up computed tomography scan in of cases: three were hemorrhagic transformation, another was the subarachnoid hemorrhage. the thromboembolic mortality case. in our report, evt in ais with end achieved safe and successful recanalization. and successful recanalization was associated with good clinical outcome. we think evt could be a useful method in case of end in ais patients with proximal artery near to complete occlusion, even beyond usual to hours time window for evt. jugular bulb venous monitoring can provide information about cerebral hemodynamics and metabolism. we investigated the feasibility and clinical application of jugular bulb venous monitoring in acute ischemic stroke patients at neurocritical care unit. from march to june , we conducted jugular bulb venous monitoring in patients in a tertiary referral hospital. five patients were excluded; without ventilator care and other diseases than stroke. jugular venous catheters were placed in internal jugular vein by ultrasound-guided method. lactate, venous oxygen saturation (sjvo ), and arteriovenous oxygen saturation differnece (avdo ) were monitored every hours. metabolic derangement was defined when lactate level was more than . mmol/l. patients were divided according to presence of clinical deterioration. for long-term prognosis, modified rankin scale - at months were defined as poor outcome. twelve patients ( . %) showed metabolic derangement and they experienced more frequent clinical deteriorations compared to patients without metabolic derangement (n= , . % vs. n= , . %, p= . ). clinical deterioration was noted in patients, and lactate level was significantly higher in the presence of clinical deterioration group ( . ± . vs. . ± . mmol/l, p= . ). adjusting other potential variables (age, baseline stroke severity, sjvo , and avdo ), metabolic derangement was an independent factor associated with clinical deterioration (or . , % ci . - . , p= . ). meanwhile, poor outcome group (n= ) showed no difference on lactate level, but avdo were higher in poor outcome group ( . ± . v. . ± . , p= . ). avdo remained an independent factor for poor outcome after multivariable logistic regression analysis (or . , % ci . - . , p= . ). this study showed that lactate was associated with clinical deterioration during neurocritical care, whereas venous desaturation contributed to long-term prognosis. jugular bulb venous monitoring is a feasible tool in patients with acute ischemic stroke at neurocritical care unit. swift recognition of stroke symptoms, immediate access to testing and timely treatment plays a vital role in functional outcomes (middleton et al., ) . delays can postpone treatment and complicate recovery. delays at this facility included registration, order entry times, and imaging. pi included evaluating and eliminating interruptions, with a goal of reducing the time to treatment. process improvement (pi) utilized an evidence-based algorithm to improve performance metrics and treatment of acute strokes. setting was a suburban, ancc magnet recognized primary stroke center with beds in the ed that experiences , ed visits and , admissions per year. patients included in the acute stroke protocol presented with signs and symptoms of stroke and last known well within hours of symptom onset. participation included ed staff, and staff working in areas impacted by stroke care. code stroke was initiated for patients who fit the criteria. an overhead page was implemented notifying the team throughout the hospital. radiology would prioritize ct and call the ed as soon as ct was ready. in the meantime, ed team continued assessments. with ct resulted, the physician would determine whether the patient was eligible for tpa. the acute stroke protocol included a list of inclusion/exclusion criteria for tpa administration. other treatment requirements included reminders for frequency of vital signs, neuro checks and assessments. implementation began in may and the team began to see a significant decrease in ct times and better compliance of dysphagia screening and nih assessments. ct tat completed within minutes increased from % to %. nih stroke scale completion rose from % to %. compliance with completing dysphasia screening increased from % to %. results stem from a commitment to excellence from the entire team. pi continues to further improve care for stroke patients. induced hypertensive therapy (iht) has used to enhance cerebral perfusion pressure in subarachnoid hemorrhage and stroke, but there is no established indication for iht in ischemic stroke. we report the usage of iht in acute ischemic patients with hemodynamic instability caused by steno-occlusive disease of a main cerebral artery. we reviewed acute ischemic stroke patients with cerebral perfusion deficit due to intracranial and extracranial steno-occlusive disease. iht was applied for early neurological deterioration and maintained until hemodynamic instability was stabilized over hours or neurointervention including angioplasty and extracranial intracranial arterial bypass surgery were performed. patients were analyzed. territories of stroke were of anterior circulation of intracranial vessels, of posterior vessels, and of extracranial vessels. mean duration of ih therapy was . minutes. pre and post nihss score of ih therapy was . and . , respectively. patients ( . %) were showed improvement and patients ( %) were stabilized without further aggravation. patients revealed bradycardia. there was no fatal complication of therapy. patients were performed further treatment include bypass surgery, angioplasty, and stenting after ih therapy. at months follow up, patients showed good outcomes (modified rankin scale , , and ). iht may be safe and effective for the neurologic deterioration or progression of acute ischemic stroke with hemodynamic instability due to severe steno-occlusive disease of major cerebral artery. large randomized trials are needed to confirm this result. most patients with progressive stroke have a poor prognosis. the aim of our study was investigate the factors related with progressive neurologic deficit (pnd) in the patients receiving recanalization therapy for acute ischemic stroke. -month period, were enrolled. blood pressures (bps) at , , and hours after admission and bp variation (bpv) for the first hours were collected. variables associated with pnd were analyzed. among enrolled patients, patients showed pnd. the patients with pnd had higher systolic bps at , , and hours after admission and higher bpv than the others (p < . ). posterior circulation stroke was more prevalent in the patients with pnd (p < . ). in logistic regression analysis, pnd was independently associated with posterior circulation stroke [odds ratio (or) = . , p < . ] and systolic bp at hours after admission (or = . , p = . ). pnd may be associated with elevated systolic bp for the first hours after admission in the patients receiving recanalization therapy for acute ischemic stroke. telestroke has revolutionized stroke care delivery in the modern era. massachusetts general hospital (mgh) uses the most common model, the hub and spoke. the demonstration of superiority of endovascular therapy (et) with intravenous tpa over tpa alone for acute stroke patients with large vessel occlusions prompts a thorough assessment of telestroke's role in the delivery of et, particularly in terms of transferring patients to hubs capable of et. our primary objective was to examine associations between transfer time and clinical outcomes. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct who had nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate the primary predictor, transfer time (defined as the mgh arrival time minus the telestroke consult answered time, n= ). several clinical outcomes were explored by linear and logistic regression to determine association with transfer time. of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and ( %) underwent et at mgh. median transfer time was min, and median aspects decrease was during transfer. longer transfer time was associated with decreased likelihood of undergoing et (p= . ). however, transfer time was not significantly associated with aspects decrease during transfer. for those patients undergoing et, transfer times bore no association to day mrs. this study identifies an association between longer transfer time and decreased likelihood of undergoing et. reasons are varied, and are not clearly related to imaging progression alone. only % of transferred patients underwent et. more efficient spoke triage and transfer may improve the ratio of patients treated with et. these data provide an important perspective during this period of stroke triage evolution. intra-arterial thrombectomy (iat) has been approved for acute treatment of ischemic strokes (is). with the advent of several new devices for iat, this procedure has become more widely utilized with better outcomes. we performed this analysis to evaluate trends and predictors of utilization of iat over an year period. analysis of nationwide inpatient sample data ( to ) showed a total of , patients discharged with a primary diagnosis of is, icd- code .xx, and .xx. iat was ascertained by icd- procedure code . . independent predictors of iat were studied using binary logistic regression. the predictors included in the model were age, sex, race, teaching status, and insurance type. results or . % of is patients received iat. mean age of patients receiving thrombolysis was . years. percentage of is patients receiving iat has consistently increased from . % in to % in . we also observed significant year to year decrease in mortality among patients receiving iat. in , . % of iat patients died as compared to . % in . using binary logistic regression, the statistically significant independent predictors of iat utilization were age (or= . , p= . ), female gender (or= . , p= . ), insurance type as compared to medicare (private insurance or= . p= . , and self-pay or= . p= . ). as compared to caucasians, african americans were less likely to receive treatment (or= . p= . ). also, a teaching hospital was found to be more likely to administer iat as compared to a non-teaching hospital (or = . , p= . ). is patients with younger age, female gender, private insurance and patients admitted to teaching hospitals are more likely and african americans are less likely to receive iat. this study showed that iat utilization has increased significantly since with a steep decline in the in-hospital mortality. this may point to improved iat devices and better patients' selection. telestroke plays an integral role in stroke care. nationally the most common model is the hub and spoke, which is used at our institution. understanding telestroke's role in the transfer of candidate patients for endovascular therapy (et) is critical to minimizing delays. our primary objective was to evaluate predictors of transfer delay. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct with nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate transfer time (the mgh arrival time minus the telestroke consult answered time, n= ). ideal time was calculated using google maps incorporating date/time information for ground transfers and straight line distance at mph for helicopter transfers. ideal time was subtracted from actual time to calculate delay, accounting for distance, mode of transport, weather, and traffic. analysis of covariance was used to explore possible predictors of delay (night vs. day, weekend vs. weekday, tpa delivery at spoke). of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and underwent et. a significant proportion of the variation in delay was explained by the predictors (f= . , p< . ). nocturnal transfer ( - hrs) was associated with significantly longer delay ( . additional minutes relative to daytime transfers, p< . ). weekend vs. weekday transfer and tpa delivery at spoke hospital did not contribute significantly to model variance. our findings highlight the importance of refining protocol approaches. nocturnal transfers were associated with substantial delay relative to daytime transfers. in contrast, delivery of tpa was not associated with delays, underscoring the impact of effective protocols that are in place. metrics and protocols for transfer, especially at night, may have a positive impact on transfer times. the use of anticoagulant therapy in the acute stage of ischemic stroke is controversial. novel oral anticoagulant (noac) is effective in preventing recurrent embolism in patients with non-valvular atrial fibrillation (nvaf), but the risk of hemorrhagic transformation is the major concern for its early use in ischemic stroke. we aimed to study the use of noac in patients with acute ischemic stroke and nvaf. patients with acute ischemic stroke and nvaf, who were admitted to our acute stroke unit from to , were recruited in this single-centre cohort study. the timing of initiation of noac is at the discretion of the treating physician based on the stroke severity and infarct size. nvaf attributed to . % ( / ) of all ischemic stroke cases. the early recurrent embolism rates were . %, . % and . % at one week, two weeks and one month respectively. noacs were prescribed in patients. noacs were initiated within one week in patients ( . %). the median time to noac initiation were five days (iqr . - . ), nine days (iqr . - . ) and days (iqr . - . ) for patients with no/small-sized infarct, moderate-sized infarct, and large-sized infarct respectively. at one month, two patients had recurrent ischemic stroke despite treated with noac. only one patient, who had a large-sized infarct, developed symptomatic hemorrhagic transformation. early use of noac in ischemic stroke appears to be safe. further large prospective studies are required to evaluate the risk and benefit of noac use in acute ischemic stroke. osmotherapy (hypertonic saline or mannitol) is the mainstay of available therapy to counter cerebral edema that can develop after large hemispheric infarction. in a post-hoc analysis of the games-rp trial, we hypothesized that patients with large infarction, treated with intravenous glyburide, might require less osmotherapy than placebo treated patients. games-rp was a multi-center prospective, double blind, randomized, placebo controlled study which enrolled patients with large anterior circulation infarction. patients were randomized to iv glyburide administration (biib ; n= ) or placebo (n= ) with target time from symptom onset to drug infusion decompressive craniectomy (dc), or both. total bolus osmotherapy dosing was quantified by an "osmolar load" (volume in l * osmolarity in mosm/l). of the subjects, the percentage of patients who received bolus osmotherapy did not differ between the glyburide and placebo treated subjects ( % v. %; p= . ). there was no difference in mean total osmolar load received (mosm) or hours from drug bolus to osmotherapy administration. overall, subjects received osmotherapy. the baseline dwi lesion volume (ml) was significantly larger in the osmotherapy treated group ( . ± . v. . ± . ; p= . ). the presence of adjudicated malignant edema on imaging was more common in the osmotherapy group ( % v. %, p= . ), as was dc ( % v. %; p< . ). among patients with adjudicated clinical neurologic deterioration from edema, % (n= ) did not receive osmotherapy. treatment with iv glyburide was not associated with less osmotherapy, possibly due to a ceiling effect resulting from the large infarct volumes. however, osmotherapy use was associated with larger infarct volumes, malignant edema, and higher incidence of dc. use of osmotherapy did not always follow the appearance of clinical or radiographic malignant edema. acute ischemic stroke patients receiving intravenous alteplase (iv-tpa) are placed on bedrest for hours or longer due to provider fear of worsening stroke symptoms from decreased cerebral perfusion. this is based on medical uncertainty and lack of robust studies, despite american stroke association (asa) recommendations for mobilization when hemodynamically stable. this retrospective observational study evaluates very early mobility in acute ischemic stroke patients post iv-tpa while evaluating for change in nihss. medical records of ischemic stroke patients who received iv-tpa between and at two urban hospitals were reviewed for mobility protocol activities. patients who were given endovascular treatment, placed on comfort care on day zero or one, mobilized after the first hours, transferred out or left against medical advice were excluded from the analysis. multiple linear regression was used to determine if those patients mobilized earlier saw a greater change between nihss at admit and hours post iv-tpa administration, adjusting for age and gender. of the patients included in the final analysis, . % (n= ) were female, mean age was . the multiple linear regression results showed no significant relationship between change in nihss from admit to hours post iv-tpa and earlier mobilization, after adjusting for age and gender (ß= - . change in nihss points per hour; p= . ). this study reveals early mobility does not worsen stroke symptoms or severity based on nihss. this suggests that very early mobility of patients after iv-tpa is safe as recommended by asa. interhospital transfers to a stroke center following iv-tpa administration are increasingly common. however, no studies have evaluated icu needs in these transfer patients and such understanding may have a significant impact on resource utilization. the aim of this study is to compare the frequency, timing, and nature of icu-level needs in post-iv-tpa patients that were transferred versus those who present directly to the admitting hospital. retrospective chart review of consecutive, tpa-treated ischemic stroke patients admitted to the icu at a comprehensive stroke center servicing a large telestroke referral network from / to / was performed. we evaluated patient demographics, stroke characteristics, and icu needs between transfer and non-transfer patients before and after icu admission. results patients were admitted to the icu post-tpa. patients ( . %) were transferred from an outside hospital, of which patients had icu needs ( . %). this frequency of icu needs was no different when compared to the non-transfer patients ( / , . %, p = . ). similar icu needs were observed for each specific icu intervention between transfer and non-transfer patients (iv antihypertensive, vasopressor requirement, iv rate control, respiratory support, ia therapy, icp monitoring, hypertonic therapy, and neurosurgical intervention, all p > association with icu needs (or . in transfer patients, or . in non-transfer; both p < . ). transferring post-iv-tpa patients is not associated with increased icu needs. about one-half of post-tpa patients do not have icu needs, and these patients typically have milder stroke severity. our data supports the safety of transferring post-tpa patients, and to potentially monitor a subgroup of these patients in a non-icu setting. the ability to appropriately triage post-tpa patients may lead to more efficient and cost-effective stroke care. stroke patients requiring decompressive craniectomy remain at high risk of prolonged mechanical ventilation as well as ventilator associated pneumonia (vap). early tracheostomy placement may provide a reduction in the duration of mechanical ventilation however prediction of those who ultimately require a tracheostomy remains a clinical challenge. a preoperative assessment of tracheostomy dependence may help to guide decision making. the authors compare key outcome data after early versus late tracheostomy and develop a preoperative decision-making tool to predict postoperative tracheostomy dependence. a subsequent validation utilizing a decision tree analysis applied prospectively is ongoing and will be presented. we performed a retrospective analysis of prospectively collected registry data and developed a propensity weighted decision tree analysis to predict tracheostomy requirement utilizing factors present prior to surgical decompression. outcomes include probability functions for icu los, hospital los, and mortality based on data for early ( day) tracheostomy. a subsequent validation of the decision tree is being applied prospectively to evaluate its predictive value. a total of surgical decompressions were performed on patients with acute ischemic or spontaneous hemorrhagic stroke between - . forty eight patients ( . %) required a tracheostomy, whereas ( . %) developed vap, and ( %) survived hospitalization. mean icu and hospital los were . and . days respectively. utilizing gcs, sofa score and hydrocephalus presence, our decision tree analysis provided a % sensitivity and % specificity for tracheostomy prediction. early tracheostomy conferred significantly fewer ventilator days (p< . ) and shorter hospital los (p= . ) with similar vap and mortality rates between groups. early tracheostomy shortens duration of mechanical ventilation and length of stay following surgical decompression for stroke, however without a demonstrable impact in mortality or vap rates. a preoperative decision tree awards a practical tool that may provide insight to guide preoperative decision-making with patient families. patients suspected acute stroke are critical in time delay of endovascular or intravenous thrombolytic therapy. prehospital notification from emergency medical services (ems) may shorten the door to recanalization time. the 'brain saver', web-based prehospital notification system could reduce the time interval from symptom onset to recanalization. beginning in march , stroke team consisted of stroke specialized doctors, nurses and radiologists of multi departments received direct alarms via smart phone application from paramedics of ems about transport information of patients with suspected stroke. we compared baseline characteristics and prehospital/ in-hospital delay time in stroke patients treated with intravenous thrombolysis or endovascular treatment for months with and without ems use brain saver protocol. patients ( patients with protocol and patients without protocol) were enrolled in this program. the patients who used brain saver had shorter median onset-to-arrival times ( minutes versus minutes, p < . ) and in in-hospital delay time ( minutes versus minutes, p<. ). prehospital notification by brain saver was associated with shorter median door-to-imaging time ( minutes versus minutes, p<. ), door-to-needle time ( minutes versus minutes, p <. ), door to puncture time ( minutes versus minutes, p < . ) we found that prehospital notification was associated with faster door-to-imaging time, door-to-needle time and door-to-puncture time in patients presenting within hours of symptom onset. close collaboration between stroke team in hospitals and the ems system gives stroke suspected patients an in-time emergency care system. infection is a common complication in the acute phase after ischemic stroke. furthermore, malnutrition is associated with unfavorable outcome in patients with stroke. therefore, we investigated that premorbid undernutrition identified by objective and quantitative method, nutritional risk index (nri) was related to the risk of infection after ischemic stroke. a consecutive patients who were admitted within days after ischemic stroke onset between october and october were included. we assessed initial nutritional status using nri, and nri formula as follows: nri = ( . × serum albumin, g/dl) + { . × present weight (kg)/ideal body weight (kg)}. the patients were categorized into three groups on the basis of nri [no risk (nri > . ), moderate risk (nri . - . ), and severe risk (nri < . )]. we compared the clinical characteristics and nri according to the presence of infection. among the included patients (mean age, . years, male, . %), ( . %) patients experienced infection during hospitalization. the rate of pneumonia was . % (n= ), and the rate of urinary tract infection was . % (n= ) among total infection. the proportion of lower nri patients (moderate risk and severe risk) was significantly greater in the infection group ( . % vs. . % and . % vs. . %, p < . ). moreover, higher nri patients were less likely to be admitted to the intensive care unit ( . % vs. . % vs. . %, p = . ). a multivariate analysis revealed that lower nri groups had a higher risk of infection [odds ratio ( % confidence interval); moderate risk . ( . - . ); severe risk . ( . - . ), p for trend = . ]. our study demonstrated that the lower nris predicted infection complications and severe infections after ischemic stroke. this suggests that assessment of nutrition depletion could be a useful predictor and a modifiable risk factor for infection following stroke. cyp c plays a major role in the metabolism of the clop[idogrel. cyp c generates an active oxidized metabolite of clopidogrel that exerts antipl;atelet activity by inhibiting p y reeceptor. the major alleles of the cyp c gene are * , * , * and * and approximately % of caucasians and % of asians have one or more loss of function alleles in this study, patients with at least two * or * allels were classified as poor metabolizer(pm), those with one * or * allele were classified as intermediate metabolizer(im), and those without a * , * or * alleles were classified as extensive metabolizer. in addition. those with (* /* or * /* ) were classified as unknown metabolizer. stroke patients were enrolled for this trial. the mean age was years, and % were women. % had a history of hypertension, % of dm and % of dyslipidemia. of the participants, % were classifies as em, % as um, % as im, % as pm and % as unknown metabolizer. % had good genotype for clopidogrel metabolism and % had poor genotype. there were no significant diffirences in the demographic and clinical findings between the good and poor genotype groups the prevalence of cyp c polymorphisms is different according to the ethnicity. the racial difference in platelet function may lead to diffrerences in the treatment as well as new targets for antiplatelet therapy the social brain hypothesis is an evolutionary theory proposing that the number of contacts in a primate's social network is proportional to neocortical volume. we tested the hypothesis in a patient population with social network data before and after vascular events. we studied whether social network indices would decrease after stroke, but not after myocardial infarction (mi), as anticipated by the theory. we examined trajectories of the lubben social network scale score (range - , higher values indicating larger network) before and after vascular events in participants from the cardiovascular health study. we used a repeated measures design with linear mixed models to compare the change in social network score before and after events in persons with ischemic stroke and with mi. over a mean of . years of follow-up for stroke and . years for mi, we examined an average of social network scores for each participant. we controlled for socio-demographics, baseline cognitive function, and comorbidities. social network scores declined significantly after stroke (an additional - . points every year, % ci - . , - . , p= . ), but not after mi (- . , % ci - . , . , p= . ) compared to the baseline slope in fully adjusted models. social network score declined more steeply after stroke than after mi, even after adjusting for potential confounders. these findings support the social brain hypothesis but do not address mechanism. shrinkage of the social networks may be a specific target for interventions to optimize recovery in vascular diseases, particularly stroke. emergency neurological life support (enls) protocols are an essential component to assessment and management of patients within the first hours of the neurological emergency. with increasing focus on emergent endovascular treatment for large vessel occlusion (lvo) in acute ischemic stroke our institution incorporated stroke van assessment as part of the enls acute stroke initial assessment protocol. stroke van screening tool was taught to all nurses in the emergency department (ed) who triage stroke. all patients who presented to the ed with suspected stroke had a van assessment completed prior to ed physician evaluation and ct imaging. patients with weakness in addition to visual changes, aphasia, or neglect were considered van + and triaged immediately to ct angiogram head/neck with immediate notification to the neurointerventionalist. a sample of patients presenting to the ed as a stroke alert over an month time period were utilized. using the stroke van assessment tool was found to improve time to identification of lvo by reducing time from arrival to cta for van positive patients from minutes pre-intervention (n= ) to minutes post-intervention (n= ). this was a significant decrease in time to identification of patients presenting with lvo (p< . ), improving time to endovascular treatment. incorporating stroke van as part of the acute stroke assessment protocol improved identification of patients presenting with lvo, decreased time to cta imaging and improved time to endovascular treatment which is well documented with improved neurological prognosis. time is essential in neurological emergencies. the van assessment is quick and easy to perform, requires no scoring or calculations, and is the only lvo screening tool tested in the ed by ed nurse and physicians. we suggest incorporating stroke van to the enls acute stroke protocol as a way to improve identification of lvo and improve time to endovascular treatment. elevated blood pressure (bp) is known to be related to hemorrhagic transformation (ht) after ischemic stroke. however, the effect of bp variation on the ht remains unclear, especially in patients with successful recanalization after mechanical thrombectomy. therefore, we investigated the relationship between bp and ht after mechanical thrombectomy following ischemic stroke. a consecutive patients with acute ischemic stroke and successful recanalization (tici b or tici ) were included for the analysis between january and november . the information on bp was obtained over the first hours using various parameters including mean, maximum (max), minimum (cv), and successive variations (sv) for systolic, diastolic bp, and mean bp. we defined major ht as a parenchymal hematoma type (ph ). among the included patients (age, . ; and male, . %), patients ( . %) developed major ht over the first hours after successful recanalization. systolic bp max-min was significantly increased in patients with major ht compared to those without major ht ( . mmhg vs. . mmhg, p = . ) while other bp parameters were not. in addition, systolic bp max-min was significantly associated with symptomatic ht (n= , . %, p = . ). after adjusting for confounders, systolic bp max-min was independently associated with major ht (odds ratio, . ; % confidence interval, . - . ). our results demonstrated that absolute change of systemic bp over the first hours was associated with major and symptomatic ht after successful mechanical thrombectomy after acute ischemic stroke. this suggests that maintaining stable systolic bp is an important factor in possibly preventing major ht after successful recanalization. the benefits of intravenous tissue-plasminogen activator in acute ischemic stroke are highly timedependent. however, there are so many cross-departmental tasks to eligible patent that many stroke centers have difficulty achieving the guideline recommended -hour door-to-needle (dtn) time. we have developed web based visual task management system called "task calc. stroke" (tcs) by using information and communication technology. herein, we performed a trial installation and preliminary evaluation of tcs. the application software of tcs was designed to run on the google cloud platform. tcs alerts the relevant hospital staff to the patient's arrival condition and time, and displayed tasks to be performed and its treatment status by changing color in real time on networked wall-mounted smart devices in the several relevant departments. we started a trial installation of tcs during the daytime from august . we compared lead times before (august to july ) and after (august to july ) trial installation of tcs. trial installation of tcs in our hospital showed successful information sharing. a total of patients included (pre: , post: ) . after the installation, significant reductions occurred in the median time from door to complete blood count time [ . vs. . min, p < . ] and a trend toward a reduction from door to needle time [ . vs. . min, p = . ]. tcs may be useful tool to reduce the lead times of acute stroke patients. tcs is a new approach that has the potential to promote efficiency for acute stroke care. prior history of intracranial hemorrhage (ich) has been considered a contraindication to administration of intravenous recombinant tissue plasminogen activator in acute ischemic stroke, per the original activase fda label and aha/asa guidelines. however, limited data are available on the risks of lysis in patients with prior ich. we performed a cross-sectional study of adult patients who received thrombolysis, using administrative claims data on admissions to acute care hospitals in california between - . diagnosis codes were used to identify patients who received thrombolysis, and to ascertain ( ) a prior diagnosis of ich, including intraparenchymal hemorrhage (iph), subarachnoid hemorrhage (sah), subdural hematoma (sdh), or epidural hematoma (edh); and ( ) relevant comorbidities, including hypertension, smoking, diabetes, heart failure, atrial fibrillation, renal disease, malignancy, and demographic data. we used univariable and multivariable logistic regression to model the odds of in-hospital mortality as a function of prior ich, after adjusting for potential confounders. , patients received thrombolysis during the study period (mean age [sd ], female count , [ %]). of these, patients ( . %) had a documented diagnosis of prior ich on admission. inhospital mortality was % overall, . % for patients without prior ich, and . % for patients with prior ich. in multivariable analysis, all prior ich subtypes remained independently associated with in-hospital mortality, including iph (or . , ci . - . , p < e- ); sah (or . , ci . - . , p < e- ); and sdh (or . , ci . - . , p= . ). only patients had edh and testing was not possible. . % of patients who received thrombolysis during the study period had prior diagnosis of ich. prior ich was found to be significantly associated with in-hospital mortality regardless of ich subtype. we evaluated the association between early neurological improvement (eni) after ert and time spent from symptom onset to recanalization, according to the degree of collateral circulation measured using multiphase cta. patients with anterior circulation occlusion who underwent ert based on a non-contrast brain ct and multiphase cta were evaluated. collateral status was evaluated using a pial arterial filling score, which was developed into a six-point scale. eni was defined as equal to more than %, or as an -point decrement in nihss from baseline. neurological statuses at day and at day (or discharge) were determined by a certified neurologist using nihss. the collateral circulation degree measured by multiphase cta was inversely correlated with baseline stroke severity (p= . ). the proportion of eni at day was significantly lower in patients with poor collateral status (score ~ ) according to the time from symptom onset to recanalization ( - , . %; - , . %; > , . %; p= . ). however, the proportion was similar in patients with a good - , . %; - , . %; - , . %; > , . %; p= . , day or discharge; - , . %; - , . %; - , . %; > , . %; p= . ). collateral status was the best predictor for eni after ert. eni was achieved in only ( . %) patients with poor collateral status, and their time from symptom onset to recanalization was more than minutes. the time window for ert might differ according to baseline collateral status measured by multiphase cta. the current time window for ert within hours from symptom onset to groin puncture could be atrial fibrillation (af) is the most common cardiac arrhythmia among adults. despite of the proven advantage in primary and secondary stroke prevention in patients with af, antithrombotic therapy has been reported to be still underused in many countries. however, there is a little data about the incidence of af and any changing pattern of antithrombotic therapy among patients with af over the past decade in korea. data source for this study were obtained from the nationwide sample cohort comprising , , individuals ( % of entire population in korea) which were established by nationwide health insurance system. during a -year follow-up period, there was , developed af ( . %). the incidence of patients with af remained relatively constant during study period ( . % in vs . % in ). the proportion of patients with antithrombotic therapy increased from . % in to . % in significantly (p for trends < . ). however, the proportion of patients with antiplatelet agents was higher than with oral anticoagulation. af steadily increased over recent years in korea. however, only . % of af patients were receiving antithrombotic therapy. our study demonstrated that there was huge gap between the clinical practice and treatment guideline in antithrombotic medication for af patients in korea over the past decade. ohiohealth (oh) possesses one of the nation's largest neuroscience programs and is the leading volume provider of stroke care in ohio. oh is comprised of hospital-based sites, primary stroke centers, comprehensive stroke center, and a virtual health (vh) stroke network that serves hospitals throughout the state. in august , stroke services at ohiohealth were restructured to enable dedicated clinical time for vh providers, require expertise, training, and quality review participation for stroke responders, streamline activation algorithms to limit hand-offs, and eliminate identified barriers to vh consultation. a month interim analysis was planned to assess the impact of these changes (termed "stroke . "). comparative analyses were performed between the first months of stroke . and the similar time period of the year prior to restructuring. pre-defined metrics included consultation volume, vh response time, iv-tpa time to treatment, research enrollment volume, endovascular referral rate and time to treatment, ischemic stroke (is) observed : expected (o:e) mortality data, and patient retention rate at associate vh sites. during the first months of stroke . , encounters were seen (historical ) with a mean activation to vh log in of . minutes. both volume of patients treated with iv-tpa ( vs. , p< . ) and mean treatment times ( vs. minutes; p< . ) were significantly reduced. mean time to endovascular intervention was less during stroke . ( vs. minutes, p < . ). system-wide o: e mortality was reduced after restructuring ( . vs. . , p< . ), accounting for additional lives saved. acute stroke research enrollment doubled ( vs. ) during this same period. transfer rates to vh hub were unchanged ( vs. %, p = . ). strategic changes in staffing, expertise, vh structure, and access can have profound and positive changes on a well-functioning stroke system. strokes due to cns fungal infections (scfi) are often misdiagnosed. retrospective study of electronically-extracted records in patients with strokes & positive fungal studies, from cerebrospinal fluid (csf) or brain biopsy. other stroke etiologies were excluded. thirteen patients had scfi by a priori exclusion & inclusion criteria. nine were males. mean age was + years. symptoms were mild [nihss ( , . ) (median and iqr)]. focal deficits & headaches (both . %) were common. seventy-percent were immuno-compromised (medications, malignancy, transplant recipients). clinical course was indolent in . %. seventy-percent had poor outcome ( -ltac, -snf, -dead). ninety-two percent had csf pleocytosis (range: - ) while % had csf glucose less than mg/dl (range: - ). seventy-five percent had lymphocytic predominance. seven strokes were from yeasts ( -cryptococcus, -coccidiomycosis, -histoplasma, -candida) and from molds ( -zygomycetes, -aspergillus). sixty-two percent had posterior circulation involvement ( . % yeast vs % molds). there was lepto-meningeal enhancement in % of yeast vs. % of molds infections (p= . ). the basal ganglia (bg) was involved in % of intravenous-drug users (ivdu) vs. % of non-ivdu (p= . ). one had abnormal cns vessel imaging directly attributed to the ischemic lesions. in this series, patients were young, immunocompromised or ivdu. stroke sizes & clinical deficits were modest with no angiographic evidence of vasculitis. majority had csf pleocytosis & hypoglycorrhachia. posterior circulation involvement was typical. lepto-meningeal meningitis was only seen in yeast infections. the bg was spared in non-ivdu but common in ivdu. mechanism of stroke in yeast infections is probably from meningitis & secondary involvement of small perforating branches. mechanism in mold infections in immuno-competent ivdu is probably direct angio-invasiveness in small vessels of the bg. outcomes are poor in spite of therapy. scfi should be considered in selected cases of cryptogenic (recurrent or progressive) strokes with clinical, csf and mri features described. life-threatening bleeding requires prompt reversal of factor xa (fxa) inhibitors. their anticoagulant effects can be reversed with the antidote andexanet alfa. the efficacy of andexanet to reverse bleeding in an apixaban anticoagulated porcine trauma model was investigated. after ethical approval, male pigs (n= ) were given apixaban for days ( mg daily); the sham group (n= ) received placebo. standardized polytrauma by blunt liver injury and bilateral femur fractures were inflicted. minutes post-trauma, animals were randomized (n= per group) to a single andexanet bolus ( , mg), a bolus ( , mg) + infusion ( , mg over hours) regimen, or vehicle (control). blood loss (bl) and hemodynamics were monitored over hours or until death and analyzed by anova (mean±sem). apixaban anti-fxa levels were ± ng/ml with no differences between anticoagulated groups prior to injury. bl in the sham animals was ± ml minutes after injury (total bl ± ml at "x" hours; % survival). anticoagulation with apixaban significantly increased bl minutes after injury ( ± ml; p< . ). controls exhibited a total bl of , ± ml with % mortality (mean survival time = minutes). treatment with a bolus or bolus+infusion of andexanet was associated with a significant reduction in bl versus sham (p< . ) and % survival. two hours after injury, apixaban anti-fxa levels in bolus animals were ± ng/ml, whereas the bolus+infusion regimen resulted in levels of ± ng/ml (p< . ). hemodynamic parameters (e.g., cardiac output) and markers of shock (e.g., lactate) recovered to pre-trauma levels in andexanet-treated groups. clinically and macroscopically, no adverse events were observed. in this study, andexanet effectively and safely reversed apixaban anticoagulation and reduced bl induced by severe trauma under anticoagulation. the bolus alone had a similar impact on survival and bl as the bolus+infusion regimen in this lethal porcine model. current guidelines for management of pain, agitation, and delirium in mechanically ventilated patients in the intensive care unit (icu) recommend an analgesia-first approach to sedation management. however, these guidelines are derived from non-neurologic patient populations leaving uncertainty in their generalization to this population. the purpose of this study was to evaluate implementation of an analgesia-first sedation clinical pathway in the neuroscience icu. a single-center cohort study was performed within the neuroscience icu including patients mechanically ventilated for greater than hours over a time period of three months before and after clinical pathway implementation. providers were educated on the pathway with emphasis on frequent assessment of richmond agitation-sedation scales (rass), critical care pain observation tool (cpot), and confusion assessment method-icu (cam-icu) scores and systematic de-escalation of sedatives through adequate pain and delirium management. outcome measures included frequency and magnitude of rass, cpot, and cam-icu scores, analgesic and sedative medication prescription/administration per day of mechanical ventilation (mv). a total of patients met inclusion criteria ( pre-pathway and post-pathway). there was no statistically significant difference in the median frequency of rass ( . vs. . ) and cpot ( . vs. . ) assessments per day of mv or in median rass (- vs. - ) and cpot ( vs. ) scores. mean acetaminophen usage increased from . % to % (p< . ) post-pathway implementation. there was no statistically significant difference in mean opioid or propofol usage, however a trend toward increased morphine and decreased propofol usage was observed post-pathway. analgesia-first sedation pathway implementation trended towards increased opioid analgesic and decreased sedative use, however only increased acetaminophen usage was significant. this highlights challenges in changing unit-based practices and future directions include focus on the frequency and reliability of pain, agitation and delirium assessment. interdisciplinary coordination and communication remains necessary for effective unit-based practice changes. andexanet alfa (andexanet), a modified, recombinant human factor xa (fxa) molecule, binds and sequesters fxa inhibitors. in a phase study of apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, andexanet rapidly reversed pharmacodynamic markers of anticoagulation. here, the ability of andexanet to reverse the anticoagulant activity of betrixaban was investigated. in a randomized, double-blind, phase study in healthy subjects, andexanet (n= ) or placebo (n= ) was administered intravenously following mg po qd betrixaban to steady state ( days). in cohort (andexanet bolus only), subjects (n= ) received a -mg andexanet bolus hours after the last betrixaban dose (day ) or placebo (n= ). in cohort (andexanet bolus plus -hour infusion), subjects (n= ) received a mg andexanet bolus hours after the last betrixaban dose, followed by a -hour infusion of andexanet ( mg/min) or placebo (n= ). endpoints included safety and pharmacodynamic markers of anticoagulation reversal. following treatment with betrixaban in cohort , andexanet rapidly decreased anti-fxa activity from . ± . to . ± . ng/ml, while the anti-fxa levels following placebo were largely unchanged ( . ± . to . ± . ng/ml). unbound betrixaban plasma concentration decreased from . ± . to . ± . ng/ml with andexanet, but remained constant following placebo administration ( . ± . to . ± . ng/ml). similar results were observed in cohort following andexanet bolus ( minutes after bolus), and the effects were maintained during the -hour infusion of andexanet. for cohort , thrombin generation was restored in / ( %) and / ( . %) of andexanet-administered and placebo subjects, respectively. for cohort , thrombin generation was restored in / ( . %) of andexanet subjects versus / ( . %) of placebo subjects. andexanet was well tolerated; there were no thrombotic events or serious/severe adverse events. andexanet was well tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. these and other studies indicate that andexanet could be a universal antidote for fxa inhibitors. andexanet alfa (anxa), a recombinant human fxa molecule, reverses the anticoagulant activity of fxa inhibitors. in studies of healthy volunteers, anxa showed dose-dependent reversal of direct and indirect fxa inhibitors in tissue factor (tf)-initiated thrombin generation (tg). we compared rivaroxabaninduced inhibition of tg initiated via the extrinsic pathway (tf) versus intrinsic pathway (non-tf). tf-initiated tg was measured using a calibrated automated thrombogram (cat) and ppp-reagent. non-tf-initiated tg was measured using cat and actin fs. anti-fxa activity was measured using an anti-fxa chromogenic assay. pooled plasma was spiked with rivaroxaban or rivaroxaban+anxa; tg, anti-fxa activity, and clot formation were measured. for low tf-initiated clot formation, thromboelastography profiles were measured. anxa alone had minimal effect on endogenous thrombin potential (etp). anxa fully reversed rivaroxaban-induced anticoagulation in the actin fs assay, independent of anxa-tfpi interaction. modulation of tf activity was assessed by correlating etp versus anti-fxa activity with rivaroxaban or rivaroxaban+anxa. rivaroxaban dose-dependently inhibited tf-initiated tg as anti-fxa activity increased. at similar anti-fxa levels, rivaroxaban+anxa had higher etp than rivaroxaban alone, but not in the actin fs assay. clot formation was studied in plasma using thromboelastography without rivaroxaban. anxa did not affect thromboelastography parameters, with/without recombinant tissue plasminogen activator (rtpa). when low tf initiated clot formation without rtpa, anxa reduced the thromboelastography-r parameter, but not maximum amplitude. the fibrin clot was lysed at low rtpa, resulting in well-segregated coagulation and fibrinolysis. with the optimal rtpa, fibrin clots formed at each tf concentration were compensated by the fibrinolytic activity of rtpa. without a fxa inhibitor, anxa had minimal effect on tf or actin fs-initiated tg with no direct effect on rtpa function. anxa dose-dependently and completely reversed rivaroxaban-induced inhibition of tg initiated by intrinsic or extrinsic pathways, but had different effects on etp due to the anxa-tfpi interaction. there is a growing body of evidence relating poor outcomes to off-hour management. studies investigating the effect of overnight extubation (oe) have produced mixed results, and limited data is available for brain-injured patients. there may also be tendency to limit oe due to decreased staffing levels at night. we sought to determine the safety of oe and risk factor profiles associated with extubation failure (ef) in this cohort. we conducted a retrospective review of mechanically ventilated patients admitted to a single-center in-house database. exclusion criteria included limitations in care, tracheostomy placement, selfextubation, and death prior to extubation. the primary outcome was ef defined as non-elective endotracheal intubation within hours. ef rates were compared between daytime ( am - : pm) and overnight ( pm - : am) extubation cohorts. in-hospital mortality served as a secondary outcome. amongst identified patients, ( . %) underwent daytime extubation (de) and ( . %) oe. ef was indifferent between de and oe ( . % and . % respectively; p= . ). however, multivariable adjustment for clinical severity indicators suggests higher ef for oe (or: . , ci: . - . ; p= . ). compared to de, oe was more likely performed in elective post-operative patients ( . % vs . %; p= . ) with lower apache-ii scores (median vs ; p= . ), and shorter durations of mv (median . vs . days; < . ). higher apache-ii score, longer duration of mv, and admission diagnoses of acute vascular injury or neuromuscular disease were associated with ef. there was no difference in mortality (p= . ). in our cohort, oe was not associated with increased ef or mortality. our results suggest that oe can be performed safely if standard extubation criteria are met in low-risk patients. these data provide a basis for subsequent more robust studies. case series have reported reversible left ventricular dysfunction, also known as stress cardiomyopathy or takotsubo cardiomyopathy, in the setting of acute neurological diseases such as subarachnoid hemorrhage. the nature of the association between various neurological diseases and takotsubo remains incompletely understood. we performed a cross-sectional study of all adults in the national inpatient sample, a nationally representative sample of u.s. hospitalizations, from - . our exposures of interest were primary diagnoses of acute neurological disease, defined by icd- -cm diagnosis codes. our outcome was a diagnosis of takotsubo cardiomyopathy. binary logistic regression models were used to examine the associations between our prespecified neurological diagnoses and takotsubo cardiomyopathy after adjustment for demographics. we identified , , adults with a primary acute neurological diagnosis and , , patients admitted to the hospital without a primary acute neurological diagnosis. among neurological diagnoses, subarachnoid hemorrhage (odds ratio [or], . ; %ci, , status epilepticus (or, . ; % ci, . - . ), transient global amnesia (or, . ; % ci, . - . ), and meningoencephalitis (or, . ; % ci, . - . ) were most strongly associated with takotsubo cardiomyopathy. weaker associations were present for ischemic stroke (or, . ; % ci, . - . ) and migraine headache (or, . ; % ci, . - . ). intracerebral hemorrhage and guillaine-barre syndrome were not significantly associated with takotsubo cardiomyopathy. in our multivariable model, female sex was significantly associated with takotsubo (or, . ; % ci, . - . ). we found associations with takotsubo cardiomyopathy for several acute neurological diseases besides subarachnoid hemorrhage. gram-negative meningoventriculitis (gnmv) causes significant morbidity and mortality. in addition to intravenous antibiotics, intra-thecal (it) or intraventricular (iv) antibiotics may be used to treat central nervous system (cns) gram-negative infections, including multi-drug resistant gnmv. there are limited studies on the effect of direct cns administration on cerebrospinal fluid (csf) cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it or iv antibiotics for gnmv since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gnmv during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: gentamicin ( ), colistimethate sodium ( ), amikacin ( ), and tobramycin ( ). the most common pathogens were p. aeruginosa ( ), k. pneumoniae ( ), enterobacter sp. ( ) and e. coli ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p<. ) between the first and last dose of iv/it antibiotics. twenty-five ( . %) patients survived to discharge, ( . %) were confirmed alive at months. patients who survived to discharge went to rehabilitation ( ), home ( ), long-term acute-care ( ) and skilled nursing facility ( ). it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gnmv. it and iv administration may provide additional benefit to systemic therapy. gram-positive organisms are the most common cause of meningo-ventriculitis. systemic antimicrobial therapy may fail to achieve adequate cerebrospinal fluid (csf) concentrations, particularly against organisms with higher minimum inhibitory concentrations, such as mrsa and vre. direct intraventricular (iv) or intra-thecal (it) administration may be beneficial as they can facilitate high csf levels at the site of infection. there are limited studies on the effect of direct central nervous system (cns) administration of antibiotics on csf cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it/iv antibiotics for grampositive meningo-ventriculitis since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gram-positive meningoventriculitis during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: vancomycin ( ) and daptomycin ( ). the most common pathogens were staphylococcus sp. ( ), enterococcus sp ( ), and streptococcus sp ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p=. ) between the first and last dose of iv/it antibiotics. twenty-nine ( . %) patients survived to discharge, ( . %) were confirmed alive at months. it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gram-positive meningo-ventriculitis. it and iv administration may provide additional benefit to systemic therapy. use of prothrombin complex concentrate (pcc) for urgent reversal of anticoagulant associated coagulopathy is increasing, and at the university of illinois hospital (uih), an anti-thrombotic reversal guideline was developed in may in order to assist licensed practitioners in choosing the appropriate reversal agent, optimal dosing, and improve timely administration pcc. the current study examined the safety and efficacy of pcc used for the urgent reversal of anticoagulant associated coagulopathy before and after the development of the anti-thrombotic reversal guideline. this was a retrospective chart review of adult patients who received pcc as the only hemostatic agent at the uih from jan to april . the primary endpoint was hemostasis and secondary endpoints included thromboembolic events and time to pcc administration. there were and patients who received pcc before and after the anti-thrombotic reversal guideline, respectively. frequent cause of coagulopathy was warfarin ( % and %, respectively), and frequent indication for pcc was acute intracranial hemorrhage ( % and %, respectively). -factor pcc was more frequently used before the guideline and -factor pcc was more frequently used after the guideline. in patients presenting with warfarin induced major bleeding, target inr < . was achieved in % and % of these patients before and after the guideline, respectively. clinical assessment of bleeding cessation from direct oral anticoagulant (doac) therapy was difficult to assess. thromboembolic event was observed in % and % of the patients, respectively. median time to pcc administration from its initial order was minutes and minutes, respectively. hemostasis was similarly observed in the warfarin group before and after the development of reversal guideline, but more thromboembolic events were observed before the reversal guideline. in order to further reduce the pcc administration time, a change in workflow has been made to administer pcc in timely manner. dexmedetomidine, a selective alpha- adrenoreceptor agonist inhibiting sympathetic neuronal activity, is a mild sedation agent. two recent case reports showed reduced norepinephrine (ne) requirement in septic shock with clonidine, a less selective alpha- agonist. increased vasopressor responsiveness (vr) was also observed with dexmedetomidine in cardiovascular surgical settings. sympatholytic effects of the alpha- agonists reverse vascular desensitization due to high levels of sympathetic activity in sepsis. depletion of intra-neuronal catecholamines with reserpine has shown to increase vr. in septic sheep infused with escherichia coli, clonidine reduced renal sympathetic tone and restored vr. additionally, alpha- agonists have shown to decrease pro-inflammatory cytokines and reduce mortality, improve capillary perfusion deficit, and lower arterial lactate in animal sepsis models. a prospective trial in human septic shock is in the pipeline. we report decreases in vasopressor requirement with initiation of dexmedetomidine in two patients with brain injury. a -year-old woman presented with a high-grade subarachnoid hemorrhage and concomitant reverse takatsubo cardiomyopathy. her clinical course was complicated by septic shock secondary to aspiration pneumonia at admission. when dexmedetomidine was started after hours of ne infusion, a steady decrease in ne dosage was observed until its discontinuation. increased vr was also observed in a year-old man being treated for new onset refractory status epilepticus. on hospital day , the patient continued to have stimulus-induced seizures on ketamine, midazolam and pentobarbital infusions and required ne to maintain an adequate mean arterial pressure. when dexmedetomidine was added, a decrease in ne infusion was observed within an hour and continued for six hours until the patient no longer required vasopressor therapy. these findings are consistent with aforementioned reports of restored vr by alpha- agonists in septic shock, and warrant further investigation of possible beneficial effects of attenuated hyperadrenergic state conferred by alpha- agonists in various neurocritical care settings. decreasing the amount of time a patient remains intubated has been shown to reduce multiple negative outcomes. by extubating these patients earlier, risk of infection, prolonged immobility, and delirium are reduced. in early , this nsicu was chosen to participate in the society of critical care medicine's icu liberation collaborative. the collaborative was focused on implementation of the abcdef bundle or icu liberation. the successful implementation of the bundle led to a decrease in the amount of time neurocritically ill patients were intubated. the bundle elements began to be rolled out in june (end of st quarter). included in the bundle's roll out was the creation of a respiratory clinical specialist role to help the interprofessional team with the respiratory components of the bundle. this role was a full time respiratory care practitioner who was dedicated to the nsicu and helped to ensure standards were being met. additionally, as a part of the bundle's implementation, a spontaneous awakening trial and spontaneous breathing trial algorithm was developed and initiated. this algorithm relied on interprofessional collaboration between nursing and respiratory therapy with communication to the provider and was rolled out in september (end of rd quarter). ventilator o/e for : st quarter- . , nd quarter- . , rd quarter- . , th quarter- . ventilator o/e for : st quarter- . , nd quarter- . the bulk of the research conducted that proved the benefits of the bundle elements has been completed in medical and/surgical patient populations. the neurocritical care patient population is very specialized and has several nuances that may impact the way the various elements need to be implemented. through this process, we have found that the techniques suggested within each element can positively impact the neurocritical care patient population. the cognitive reserve hypothesis refers to inter-individual differences in the ability of patients to cope with brain pathology. cognitive reserve can be measured by surrogate markers such as education and occupation and has shown to be an important predictor of outcomes in alzheimer disease, multiple sclerosis and traumatic brain injury. in this prospective longitudinal cohort study we determined whether cognitive reserve measured as number of years of education and employment status predicted -month functional outcome of ncc patients. demographic and clinical data, including number of years of education and occupational status, were collected. at three months after discharge, glasgow outcome scales (gos) were collected via telephone from patients or surrogate respondents. gos scores were categorized into 'good' or 'poor' outcome (gos - ). from march to july , / patients with -month follow-up data were included. mean age was ± years, ( %) were male, with stroke as the predominant admitting diagnosis.the two groups with good vs poor outcomes did not differ in age, gender or race in univariate analysis although employment status was statistically different in the two groups. in multivariate logistic regression neither employment nor education was a significant predictor of good vs poor outcome (p = . , p = . ). prognostication in neurocritical care patients is difficult. the effect of cognitive reserve needs to be studied further. our current sample size is small and as enrollment continues, we will determine the relationship between cognitive reserve and -month functional outcome. fever commonly occurs in patients with spontaneous intracerebral hemorrhage (sich). however, it is non-infectious in the majority of cases. blood cultures (bcx) are often obtained as part of a fever workup, yet their utility may be limited and false-positive results may potentially compromise patient care. we hypothesized blood cultures in the first hours would more likely be false-positive. we performed a retrospective chart review of patients admitted to a tertiary medical center with a diagnosis of spontaneous intracerebral hemorrhage. patients with secondary causes of ich as well as institution of comfort measures only were excluded. data obtained included demographics, clinical parameters of ich and blood culture results. blood culture results and charts were reviewed for adjudication of false-positive and true-positive cultures. of included patients with sich, patients ( %) had blood cultures obtained. cultures were positive, of which were classified as false-positive and as true positive. false positive results were more common in the first days ( vs. ), while true positive results were more common after the first hours ( vs. ) (p= . ). early blood cultures in patients with sich are more commonly non-infectious. in line with prior published data, our results demonstrate the high cost and limited yield for blood cultures within the first hours. predictive energy expenditure (pee) equations are commonly used in lieu of indirect calorimetry (ic) due to cost and limited resources; however, these equations may not be as accurate as ic in estimating resting energy expenditure (ree) in critically ill patients. the purpose of this study is to compare pee and measured energy expenditure (mee) in critically ill adults with acute brain injury. this was a retrospective review of adult patients admitted with acute brain injury between may st, and april st, who had ic performed. three predictive equations (pe), harris benedict (hbe), penn state university, and mifflin st jeor (msj), were used in comparison to ic results. subgroup analyses included a modified aspen weight-based equation, stratifying patients based on bmi and type of acute brain injury. patients met inclusion criteria. comparing the pee estimated by the three predictive equations to the mee from ic found no significant difference. high degrees of interpatient variability were discovered in each anova analysis, with standard deviations ranging from - %. despite no difference found among pee and mee, pearson's correlations indicated weak associations when hbe, penn state, and msj were individually compared to mee (r-values = . , . , and . , respectively). in patients with a bmi < kg/m , a significant difference was found (p-value= . ) with pee underestimating the ree. additionally, in aneurysmal subarachnoid hemorrhage a significant difference was observed between pee and mee( p-value= . ). the results of this study highlight the importance of using ic whenever feasible due to the interpatient variability of the ree of critically ill patients with acute brain injury. although predicative equations appear to have similar estimations as ic, interpatient variability warrants more accurate measurement with ic to optimize nutrition in patients with acute brain injury. introduction -factor prothrombin complex concentrate (pcc) should be administered as soon as possible for reversal of anticoagulation in the setting of life-threatening bleeding or urgent procedures. limited information is available on the safety, efficacy, and time to administration of pcc when administered at high infusion rates. on march , grady health system implemented a rapid pcc administration strategy while attempting to reduce times from order entry to administration as a quality improvement initiative. this irb-approved, retrospective evaluation includes pcc administrations days pre-and post-protocol implementation. after protocol implementation, pcc doses were prepared in up to four, -ml syringes, dependent on the ordered dose. each syringe was administered over minutes, not exceeding a rate of iu/minute. the primary objective of this study is to evaluate the safety of a rapid administration strategy for pcc. secondary objectives include turn-around times and effectiveness of inr reversal in patients previously on warfarin. results unique pcc administrations were identified: administrations in the pre-cohort and in the postimplementation cohort. most pcc administrations were in the setting of spontaneous or traumatic intracranial hemorrhage. there were no infusion-related adverse events documented with the exception of a possible pcc infiltration post-implementation which resolved with supportive care only. the median order entry to administration time was higher in the post-implementation group ( vs. minutes). administrations in the pre-cohort and administrations in the post-cohort were for warfarin reversal. a greater percent of patients previously on warfarin reversed to an inr < . in the post-cohort compared to the pre-cohort, . % vs . %, respectively. this retrospective evaluation suggests that rapid intravenous push administration of -factor pcc is safe and effective. time to administration was longer after implementation of rapid pcc administration and may have been due to operational limitations. icu readmission is defined as a return to the icu during the same hospital admission. there are multiple studies related to medical and general surgical recidivism, however there is limited data on icu readmissions following spine surgery. the aim of this study was to evaluate factors associated with icu readmissions following spine surgery. patients requiring icu admission following spine surgery from june to june were studied. variables included age, gender, icu and hospital disposition, icu and hospital length of stay, bmi, comorbidities, surgical location, number of previous surgeries and vertebra manipulated, estimated blood loss, post op blood transfusions, and cause of readmission. a : matched control group based on age, bmi and location of surgery was identified. thirty-two patients required readmission following spine surgery during the study period. there was a higher prevalence of preoperative atrial fibrillation in the readmission group ( % vs. %, p= . ). ebl ( vs ml, p= . ) and lowest maps ( vs . mmhg, p= . ) were not significantly different in the two groups. we found a higher mortality rate ( % vs %, p= . ), longer icu ( . vs . hours, p= . ) and hospital los ( . vs . days, p= . ) in the readmission group. respiratory distress ( %) was the most common reason for readmission followed by cardiovascular instability ( %). discharge rates to inpatient rehabilitation and nursing facilities were similar for both groups; however % of the control group went directly home as opposed to % of the readmission group. complex spine patients who experience icu recidivism have a longer hospital stay and incidence of death within years of their index procedure. they are less likely to be discharged home. preoperative a-fib correlates with increased incidence of readmission to icu post-operatively. further studies are needed looking at post operative fluid and pain management. to demonstrate the feasibility of exenatide infusion for hyperglycemia following acute brain injury. adult patients with acute brain injury and having two blood glucose concentrations > mg/dl and was administered within hours of admission and continued per protocol for a maximum duration of hours. the primary endpoint was feasibility (< % of subjects experiencing severe hypoglycemia (< - mg/dl). descriptive endpoints were also collected. data is presented as medians [interquartile range] or percentages. a total of eight patients received exenatide (age . years [ . , . ], . % male, . % caucasian, . % history of diabetes, a c . % [ . , . ]). admitting diagnoses were intracerebral hemorrhage (n= ), acute ischemic stroke (n= ), subarachnoid hemorrhage (n= ), and subdural hematoma (n= ). glascow coma score was . [ . , . ] and sequential organ failure assessment was . [ . , . ]. based upon predefined criteria, feasibility was met with % of subjects experiencing severe hypoglycemia, . % achieving the blood glucose goal, and % experiencing nausea requiring discontinuation. blood glucose was controlled during the -hour exenatide infusion ( intravenous exenatide infusion is feasible for the treatment of hyperglycemia following acute brain injury. extubation failure remains a common complication in critical care patients, and is associated with increased intensive care unit and hospital length of stays, hospital costs, morbidity and mortality. the most common cause of reintubation is laryngeal edema, often identified by the presence of a high pitched inspiratory whistling sound known as post-extubation stridor (pes). providers in the neurocritical care unit (nccu) at a large urban academic medical center noted higher than normal rates of pes. to reduce the rates of pes and reintubation without delaying extubation, a clinical pathway was created by an interdisciplinary team. the purpose of the pathway was to aid in the identification of patients expected to develop pes and guide prophylactic treatment. prior to project implementation, all providers in the nccu completed hands on training with practice in completing the pathway in the form of a checklist. during the week implementation phase, checklists were completed on all intubated patients daily during rounds. during the week trial, there were a total of ventilator days. there were completed checklists, yielding an . % compliance rate for utilization of the clinical pathway. of the patients who were extubated during the trial, had a checklist completed, generating . % compliance on the day of extubation. a chi-square analysis was performed to evaluate outcomes following all non-palliative extubations during the week pre-implementation (n = ) and post-implementation (n = ) periods. implementation of the pathway was associated with a statistically significant reduction in rates of pes ( , n = ) = . , p< . , reintubation ( , n = ) = . , p< . and reintubation due to pes, ( , n = ) = . , p< . . the clinical pathway implemented in our nccu was safe and effective in reducing rates of pes, reintubation and reintubation due to pes. agency for healthcare research and quality (ahrq) identified postoperative deep vein thrombosis (dvt) or pulmonary embolism (pe), also commonly referred to as venous thromboembolism (vte), as one of the complications acquired in the hospital and thus developed a mechanism to report its rate using administrative data. postoperative vte rate reduction became top priority for the university of illinois (uih) due to its high yearly rate, especially among patients in the neurosciences intensive care unit (nsicu). therefore, a quality improvement team in the nsicu implemented vte bundle and analyzed its effect on the vte rate. the vte bundle was initiated on all neurosurgery and neurology patients admitted to the nsicu since march . vte bundle included lower extremity doppler ultrasound within hours of admission, vte education provided to patient or family member within hours of admission, and daily surveillance on proper use of mechanical sleeves and the mechanical device, low-dose heparin initiation and maintenance therapy, and documentation of activity status. the nursing staff were encouraged to follow the early mobilization protocol. mean vte rate was . per cases approximately -year before and . per cases approximately -year after the implementation of vte bundle. the rate of compliance was high on all aspects of vte bundle, especially on correct placement of ipc sleeve > %; functioning ipc device > %; low-dose heparin > %; documentation of activity status > %. no adverse effects were noted (i.e., skin breakdown, major bleeding) during the study period. this was the first time in years at uih, the postoperative vte rate was reduced among nsicu patients based on the ahrq reports. the reduction may partly be attributed to the implementation of vte bundle; however further evaluation need to be performed to determine the effect size of vte bundle. increasing evidence suggests that large volume infusions of . % sodium chloride (nacl) for resuscitation are associated with hyperchloremic metabolic acidosis and renal vasoconstriction leading to an increased risk of acute kidney injury (aki). in patients with neurologic injury, hypertonic ( . % or %) nacl or sodium acetate (naacetate) may be required for therapeutic hypernatremia, treatment of cerebral salt wasting or elevated intracranial pressure. the primary aim of this study was to determine the incidence of aki in neurologically injured patients receiving intravenous hypertonic nacl and in those who were switched to hypertonic naacetate based on provider preference. this single-center, retrospective study compared patients that received only hypertonic nacl to patients that were switched to naacetate. data was collected to assess renal function, hyperchloremia, and metabolic acidosis. a total of patients were screened and of those were included. the patients who were switched from nacl to naacetate (n= ) had a greater incidence of aki ( % vs. %, p< . ) and hyperchloremia ( % vs. %, p = . ) compared to patients who received only nacl (n= ). the incidence of metabolic acidosis was increased but not statistically significant ( % vs. %, p = . ). on average, hypertonic nacl was switched to hypertonic naacetate on day of treatment with a mean chloride of . meq/l at the time of the switch. there was no statistical difference in the administration of nephrotoxic antibiotics, mannitol, vasopressors, or contrast dye between the two groups. the receiver operating characteristic (roc) analysis demonstrated that if a patient received greater than meq of chloride over days they were more likely to develop aki (sensitivity %, specificity %, p= . , auc . ). neurologically injured patients receiving hypertonic sodium therapy requiring a switch to hypertonic naacetate had an increased incidence of hyperchloremia and aki. in-hospital complications following acute neurological injury has been a topic of extensive research to help reduce the morbidity and mortality among the patients. however, the incidence and prevalence of in-hospital infections following an acute neurological injury at the national level has never been studied. the aim of our study is to determine the frequency and prevalence of in-hospital complications among different patient groups admitted following acute neurological injury. we identified patients with primary diagnosis of ischemic stroke (is), subarachnoid stroke (sah), intracerebral hemorrhage (ich), status epilepticus (se), meningitis, encephalitis and traumatic brain injury (tbi) from nationwide inpatient database ( - ) through using the respective icd- codes. common in-hospital complications among the above-mentioned diagnoses through using their respective icd- codes patients with primary diagnoses of is (n= ), sah (n= ), ich (n= ), se (n= ), meningitis (n= ), encephalitis (n= ), tbi (n= ) were identified. in-hospital events such as myocardial infarction (mi), sepsis, pneumonia, deep venous thrombosis (dvt), pulmonary embolism (pe), urinary tract infections (uti), and gi bleed were identified and compared among different patient groups. patients with se were noted to experience higher systemic complications, mi ( . %), sepsis ( . %), pneumonia ( . %), dvt ( . %), uti ( . %), gi bleed ( . %). patients admitted with meningitis had a higher incidence of sepsis ( . %), pneumonia ( . %), dvt ( . %), pe ( . %) and uti ( . %) compared to the other groups. uti was the most common in-hospital complication observed. based on our analysis, we report a higher incidence of urinary tract infections among all patients admitted following acute neurological injuries. patients with primary diagnosis of status epilepticus experienced more systemic complications compared to the other diagnoses. macroglossia is a phenomenon that has been documented in association with prolonged neurosurgical procedures, brainstem injury, phenobarbital administration, and venous/lymphatic congestion of the tongue. however, exact causation of this condition in the neurocritical care population remains unclear. patients with macroglossia face significant risk for airway compromise. no interdisciplinary patient safety and management protocol exists. patients admitted to two neuro icu's within a single health system between - were reviewed. twenty-five patients with macroglossia were identified. an interdisciplinary patient management protocol was created, instituting airway safety standards, oral care directives, and interventions to promote symptom resolution. early consultation to oral and maxillofacial surgery and consideration of early tracheostomy was recommended. seventeen patients ( %) were women. age ranged from - years. the majority ( / ) of patients were african american. primary diagnoses included status epilepticus ( / ) and stroke ( sah, ais, ich). nineteen patients received antiepileptic medications before diagnosis. average gcs at symptom onset was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and at time of discharge was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . median symptom onset was hospital day [ - ]. twenty patients ( %) required tracheostomy. nine ( %) experienced symptom resolution by hospital discharge. two patients received botulinum toxin injection; both experienced symptom resolution. lingual massage was performed in two patients; in both patients, tongue swelling resolved. tongue lacerations occurred in / patients ( %), although most were observed following macroglossia onset, ruling out trauma as an inciting event. chlorhexidine oral rinse was discontinued for all except five patients due to concern for angioedema. endotracheal tube was dislodged in two patients, complicating reintubation, although successful. no trend in pre-existing allergies or antibiotic regimen was apparent. macroglossia is a relatively uncommon but high-risk condition in the neuro icu that warrants further study. care of patients with macroglossia should be standardized in order to ensure airway safety. an interdisciplinary approach is recommended. one of the biggest challenges of magnetic resonance imaging (mri) examination is the acquisition of high-quality diagnostic images, as it requires the neurological intensive care unit (nicu) patients to keep still for a significant time. in situations with poor patient cooperation, unplanned sedation is inevitable, which can lead to complications such as desaturation and hypotension. we investigated the incidence and factors related to complicated mri examinations (mri-c) in patients admitted to the nicu. we designed a retrospective study to review the data of patients who had an attempt to undergo brain mri during stay in the nicu between july and august . the mri-c group was defined when a patient met one of following criteria: ) required sedation for mri examination due to irritability mmhg or required inotropic agents, ) developed cardiac or respiratory arrest. of patients, ( . %) developed mri-c. the most common cause of mri-c was unexpected irritability at the mri room. among patients with mri-c, ( . %) patients required unplanned sedation; , desaturation; , hypotension; none, cardiac or respiratory arrest. higher apache ii scores (p = . ) and lower gcs scores (p = . ) on admission and use of sedative agents during critical care in the nicu were associated with mri-c (p < . ). in addition, patients with mri-c had longer mri scan time than those without mri-c (p = . ). many of neuro-critically ill patients undergo unsafe mri scans. our findings suggest that severity of illness and use of sedative agents during management in the nicu were factors related to mri-c. introduction: fulminant hepatic encephalopathy (fhe) with diffuse cerebral edema has dismal prognosis if transplantation is not performed. novel therapeutic interventions may change this outcome. we reviewed all cases with fhe admitted to our hospital since . in , we developed a multidisciplinary management protocol, mandating transfer of patients entering grade from other icus to the neurosciences-icu (nicu) for intracranial pressure (icp) management. multiple interventions were utilized including coagulopathy reversal with factor vii and prothrombin complex concentrate (pcc, kcentra), icp device placement, osmotherapy, aggressive ammonia lowering regimen with lactulose and rifaximin, early renal replacement therapy, mild hypothermia for refractory icp, in conjunction with liver transplantation candidacy investigation. results: twenty-four patients ( women, mean age of all patients years) were admitted; seven were managed in the micu/sicu and in the nicu. the etiology of fhe was acetaminophen toxicity in % of patients. the model for end-stage liver disease (meld) admission scores and liver enzymes between the micu/sicu and the nicu were not different (mann-whitney test). although the nicu admission ammonia level was higher than the micu/sicu ( . vs . , p = . ), the lowest achieved ammonia was lower in the nicu ( . vs . , p = . , mann-whitney). patients received icp monitoring (all in the nicu plus in the sicu) and the highest icp recorded was mm hg. the preand post-coagulation reversal inr were . and . , p= . , wilcoxon test). seven patients in the nicu received hypothermic treatment. mortality in the micu/sicu was . % ( / ) and in the nicu . % ( / ), p = . (chi square test). conclusion: a multidisciplinary approach centered around anti-cerebral edema protocol-driven management based on novel interventions may improve the outcome of patients with fhe. catheter-associated urinary tract infections (cauti) are among the most common health-care associated infections (hcais), (gould, ) . neurological patients in the critical care setting are particularly at risk for cauti due to cognitive, motor, and sensory deficits. in the neuro intensive care unit, despite following recommended cauti reduction bundle guidelines, cauti rates continued to rise over the last five years with rates reaching . per catheter days. in january of , the unit implemented a cauti taskforce to perform a literature review of best practices and subsequent : peer training and education targeting cauti reduction. in an analysis of organisms causing the infections, e. coli and enterococcus bacteria accounted for more than % of cautis on the unit. the taskforce (comprised of staff nurses) focused on fecal management, proper cleaning technique, and proper indications of indwelling urinary catheter necessity. using training videos, indwelling urinary catheter care checklists, and real-time feedback on technique, the taskforce performed : training with bedside staff over four weeks. to ensure undivided attention, the taskforce worked in pairs enabling one trainer to teach and observe the staff member receiving training while the second trainer provided the necessary clinical duties for the trainee's patients. after implementation, the cauti rate decreased to . for january-march and . for april-june , lowering total cauti events to for fy compared to for fy . implementing a : training program focused on fecal management, cleaning techniques, and appropriately timed catheter removal can reduce cauti rates in the neuro critical care setting. brain aneurysms can be treated with coil embolization or flow-diverting devices. thromboembolism is a major complication of aneurysmal coil embolization, with an incidence as high as % . new flowdiverting devices have been designed to have a mesh with high coverage area and high flexibility to facilitate the redirection of blood flow. these features can induce blood stagnation and thrombosis. to reduce the risk of thrombosis, the common but unproven practice of dual antiplatelet therapy with aspirin and clopidogrel has been implemented from the cardiac literature. despite some favorable outcomes, clopidogrel, "non-responsiveness" has been reported to be present in as low as % to as high as % making this agent not optimal. this will leave practitioners with other oral p y alternatives such as prasugrel and ticagrelor that have not been studied widely in this setting. it is therefore likely that controversy exists among practitioners regarding the use of optimal antiplatelet agents in neurointerventional procedures. we hypothesized that practices in regards with the use of oral antiplatelets in neurointerventional procedures are likely heterogeneous and different from state to state. by using an electronic survey, we would like to identify different practices surrounding the use of oral anti-platelets in neuro-endovascular centers in the united states. an electronic survey will be distributed via the web using survey monkey (seattle, wa). the survey will be posted on the neuro-critical care society (ncs) web page. all practicing neuro icu or stroke physicians, pharmacists, physician assistants, or nurse practitioners are eligible to respond to this survey. this survey is approved by the johns hopkins hospital irb and the ncs research committee. centers have completed the survey at this point. the results will be analyzed after the closing date of survey ( / / ). to be completed myasthenia gravis (mg) crisis and guillain-barre syndrome (gbs) are immune mediated diseases that may require mechanical ventilation as part of their management if severe. comparative analysis of outcomes in terms of length of stay, disability, and mortality between these two disease entities at national level is not reported mechanically ventilated patients with primary diagnosis of guillain-barre syndrome and myasthenia gravis were identified from the nationwide in-patient sample (nis) database for the years to mechanically ventilated mg patients (n= , mean= +/- . years) were older compared to gbs patients (n= , mean= . +/- . years, p= . ). medical co-morbidities were significantly higher in mg patients (diabetes mellitus, congestive heart failure, coagulopathy, chronic lung disease and dyslipidemia) whereas significantly higher nicotine dependence and alcohol abuse were noted in gbs. significantly higher in hospital complications of pneumonia and urinary tract infection were noted in gbs. disease severity measured by apdrg severity index and rate of treatment with intravenous immunoglobulin and plasma exchange was comparable. length of stay ( . ± . days , p < . ); hospital charges ( $ . ± . vs . ± . p = . ) ; moderate to severe disability ( . % vs . % p < . ) were significantly higher for gbs patient compared to mg. inhospital mortality was comparable ( . % gbs vs . % mg, p = . ). in multivariate analysis after adjusting for confounders including treatment, myasthenia gravis patients had significantly less disability (or . ( % ci . - . ) and shorter length of stay (or . , % ci . - . ). mechanically ventilated gbs patients have higher in-hospital complications, length-of-stay, and disability compared to mg. this may reflect a delay in diagnosis of gbs at admission and poor response to immunotherapy in certain gbs variants. betrixaban is an inhibitor of factor xa (fxa) for prophylaxis of venous thromboembolism (vte) in at-risk patients hospitalized for acute medical illness. a phase trial (apex) compared extended-duration anticoagulation with betrixaban to enoxaparin in acute medically ill patients; the effect of patient characteristics on population pharmacokinetics and exposure-response relationships is analyzed here. patients received betrixaban ( - days; n= , ) or enoxaparin ( ± days; n= , ). the primary efficacy and safety endpoints were composite occurrence of vte events and incidence of major bleeding, respectively. betrixaban dose was mg po qd ( mg po qd for patients with severe renal insufficiency/requiring concomitant p-glycoprotein inhibitor). pharmacokinetic samples were collected - hours or - hours after the most recent dose of study medication. patient characteristics included age, sex, race, region, body weight, crcl category, and specific p-glycoprotein inhibitor. , pharmacokinetic samples were analyzed. at mg, the projected concentration was . ng/ml at hours post-dose and . ng/ml at hours post-dose, showing a stable daily concentration. coadministration of p-glycoprotein inhibitors on the day of sampling more than doubled betrixaban concentration to ~ ng/ml at hours post-dose. at mg, the projected concentration was . ng/ml at hours post-dose, indicating a greater-than-dose-proportional exposure relationship. patient age, sex, weight, crcl category, p-glycoprotein inhibitors, and region were significant covariates affecting betrixaban pharmacokinetics. the exposure-response relationship for the primary efficacy endpoint was not significant, but the relationship between betrixaban concentration and major/clinically relevant nonmajor bleeding was significant in multivariate testing (p= . ). the betrixaban pharmacokinetic profile exhibited stable serum concentrations with qd dosing. several covariates had a %- % effect on betrixaban concentration, but no effect on efficacy/safety. betrixaban dose should be adjusted to mg for patients taking amiodarone or clarithromycin, but not other p-glycoprotein inhibitors. andexanet alfa is being investigated for reversal of anticoagulation by factor xa (fxa) inhibitors. a pharmacokinetic/pharmacodynamics model, developed in healthy subjects, predicted the andexanet regimen required to reverse anticoagulation by fxa inhibitors. the current analysis validated the pharmacokinetic/pharmacodynamic model using interim data from the annexa- study in patients with acute major bleeding. in annexa- , an ongoing prospective, open-label study, bleeding anticoagulated patients received iv andexanet bolus ( or mg) followed by -minute infusion ( or mg/min). anti-fxa activity was measured before andexanet administration (baseline), at end of bolus (eob), at end of infusion, and at , , and hours after infusion. the relationship between baseline anti-fxa activity and reversal in healthy subjects was derived from the pharmacokinetic/pharmacodynamic model and used to predict percent reversal for patients with acute major bleeding. from the first interim analysis of annexa- , patients (apixaban, n= ; rivaroxaban, n= ) had plasma levels available for model qualification, although did not meet criteria for inclusion into safety and did not meet criteria for efficacy analysis. the mean observed percent reversal of anti-fxa activity for rivaroxaban and apixaban was well predicted by the healthy subject pharmacokinetic/pharmacodynamic model; the point estimates fell within the % confidence intervals of predicted values. the percent reversal at eob for rivaroxaban and apixaban were . [ . - . ] and . [ . - . ], compared with . and . predicted by the model. the predicted reversal closely fit the observed confidence intervals through the first hours for rivaroxaban and apixaban, and extended through all evaluated time points for rivaroxaban and slightly outside of post- -hour time points for apixaban, possibly due to higher baseline anti-fxa activity levels for apixaban. the pharmacokinetic/pharmacodynamic model in healthy subjects closely predicted the extent of reversal of anti-fxa activity for apixaban and rivaroxaban in patients with major bleeding. risk factors and methods to predict extubation failure are well established for patients in medical icus and surgical icus. literature on patients who fail extubations in neurological icus is limited. the intention of this study was to collect descriptive information from patients with neurological injuries who failed liberation from mechanical ventilation. retrospective review of all patients with acute neurological injury who were admitted to our neuro icu and who required reintubation within hours of discontinuation of mechanical ventilation between january -february . we identified patients intubated primarily due to neurological pathology who required reintubation within hours after initial extubation over a -year study period. the majority of reintubated patients (n= ; . %,) had a positive fluid balance prior to failed extubation. twenty-six of the reintubated patients had a concurrent underlying chronic cardiac and/or pulmonary disease. five patients were placed on noninvasive ventilation post extubation. low glascow coma scale and absence of basic brainstem functions (gag and cough reflexes) was only minimally predictive of extubation failure. most of our reintubated patients did not have significant supratentorial midline shift nor an insult to the posterior circulation or dominant hemisphere. in patients with primary brain injury who required reintubation, a positive fluid balance prior to extubation may confer a lower rate of successful extubation. lesion location and supratentorial midline shift may not be tightly associated with extubation success. overall, our reintubation rate is quite low. early tracheostomy may play a small but significant role in the low rate of reintubation. further studies may be useful in creating a scoring system to identify the likelihood of extubation success in patients with neurological injury. surgical prophylaxis guidelines for evd insertion recommend peri-procedural antibiotics rather than prolonged antibiotic administration for the duration of evd placement. several small studies have shown that prolonged systemic antibiotic use does not reduce the incidence of catheter related ventriculitis. prolonged use is also associated with a higher rate of multi-drug resistant (mdr) infections. this study aims to show that prolonged antibiotic administration following evd insertion is potentially harmful. this is a single center, retrospective, chart review. all patients admitted to our hospital who had an evd placed from january to march were identified. patients with preceding infections, incomplete data or uncertain infection diagnosis were excluded. sixty-nine patients were analyzed. documented variables included demographics, comorbidities, indications for evd, duration of antibiotic therapy, infections and organisms' sensitivities. eight patients ( %) did not receive any antibiotic therapy; the rest received cefazolin following evd insertion. infections occurred in of ( %) patients; of ( %) were mdr bacteria. ventriculitis occurred in ( %) patients, and of these were resistant to cefazolin (mdr). ventriculitis was not associated with the use or duration of antibiotic therapy. graphical analysis showed that the probability of any infection decreased during the first days of antibiotic prophylaxis. after days, the longer patients remained on prophylactic cefazolin, the higher the probability of infection (spearman rank correlati patients who received antibiotics for > days were . times as likely to develop mdr infections ( % ci, . to . ; p= . ). cefazolin may prevent infections for the first days after evd insertion. however, prolonged administration increased the risk of mdr bacterial infections. a randomized study comparing periprocedural ( hrs) antibiotic use is needed to resolve this controversy. each year more than , deaths are associated with urinary tract infections. eighty percent of all utis are associated with an indwelling catheter. neuroscience intensive care (neuro-icu) units have the highest rates of catheter associated urinary tract infections. catheter associated urinary tract infection (cauti) increases morbidity rates, length of stay, and costs among hospitalized patients. at an urban academic medical center, our neuro-icu had the highest cauti cases among our icus. the purpose of this project was to reduce our cauti cases by %. this quality improvement project used several strategies: ( ) formed a multidisciplinary cauti task force that included nurses, physicians, infection control, management and supply chain personnel; ( ) developed an action plan to update standard of practice by conducting a review of the literature and pilot testing new products; and, ( ) educated staff using huddles, a bedside guide, and email blasts with cauti facts starting in august . additionally, cauti prevention was discussed during patient handoffs among nurses and physicians. data were collected for all neuro-icu patients from fiscal year (fy) - . cauti cases are determined by utilizing cdc's national healthcare safety network. analysis included evaluation of trends across time. we reduced our number of cauti cases from in fy to in fy . as of the beginning of fy , we have not had a cauti for days. a comprehensive approach with a strong commitment by clinicians is critical for sustaining a reduction in cauti. we reduced our cases and exceeded our goal. our efforts to provide evidence-based care are ongoing as we continue to monitor the research and upcoming supplies aimed at making hospitalacquired cauti a never event. isophane insulin (nph) is a commonly prescribed basal insulin to manage hyperglycemia in critically ill patients on continuous tube feeding due to its intermediate duration of action. however, the incidence of hypoglycemia may be higher given the duration of nph can last between - hours and because of the potential for unexpected interruption in feeding. using scheduled regular insulin (ri) instead of nph may reduce this risk given its shorter duration of action. it may also improve glycemic control due to more frequent titration. this was a single-center, retrospective, observational, cohort study from december to may . patients on continuous tube feeding who were prescribed scheduled ri were compared to those prescribed nph. all patients continued to receive an insulin sliding scale. choice of agent was determined by the bedside team. the primary endpoint was incidence of hypoglycemia while secondary endpoint assessed efficacy. in our patient population, a higher incidence of hypoglycemia was seen in those that received nph. hypertonic saline bolus (hsb) is a proven intervention for neurological emergencies arising from cerebral edema and increased intracranial pressure. safety of hsb administered via central venous catheters is well established. however, infusion of hsb through peripheral intravenous access raises concern for complications related to caustic nature of the solution. we aim to assess the safety of peripherally administered boluses of hypertonic saline ( % sodium chloride) at a regional level trauma and comprehensive stroke center. we performed retrospective chart review of patients who received hsbs from january , to january , as part of a quality improvement project. we identified instances of hsb administration. the cases were individually reviewed for iv gauge, location of the iv, whether central access was present at the time of administration, documentation of iv removal, and volume of boluses. patients were excluded if there was concurrent central venous access catheter present at the time of hsb administration or unrelated death within hours after administration of hsb. adverse events were defined as line infiltration, erythema, or swelling at the site of hsb administration. charts were excluded from the study because of presumed administration of hsb through central venous access, not peripheral iv. two patients had adverse events ( . %). none of the patients progressed toward limb threatening complications. the majority of patients ( / ) did not experience erythema or infiltration of the iv. hsb administered through peripheral intravenous access does not pose significant risk of severe complications and may be safely used in emergency situations in the absence of central line access. routine screening of high risk asymptomatic trauma or surgical patients for venous thromboembolism(vte) is controversial. studies suggest against screening while others recognize that some patients at high risk may benefit. the purpose of this pilot study is to evaluate the outcome of routine screening in patients who underwent neuro-surgical interventions. all adult patients admitted to a neuro-intensive care unit with a primary diagnosis of brain injury requiring surgical interventions were included. data from april-june, were retrospectively collected on all subjects who had either spine or cranial surgery. data collected include: incidence of vte, number of times duplex ultrasonography and computed tomography of the chest was performed. on july st, prospective data collection began by screening for presence of deep vein thrombosis(dvt) on day , and from admission or surgery day. all patients received pharmacologic and mechanical vte prophylaxis within - hours post-operatively. a total of (pre-pilot, n= and post-pilot, n= ) subjects were included in the study. in the pre-pilot group, the ages ranged from - and most were male. majority, / ( %) had either craniotomy/craniectomy while / ( %) had spine surgery. about / ( %) were admitted with primary diagnosis of traumatic brain injury. of the subjects, had duplex screening for dvt and had screening for pulmonary embolism(pe). the incidence of vte was confirmed in / ( %); (dvt- % and pe- %). median hospital length of stay was (iqr - ) days. / ( %) were discharged home and / ( %) death rate was attributed to pe. in the post-pilot group, one incidence of pe was identified on day post surgery screening. the rest of the results are still pending. in this preliminary report, post surgical patients have a higher incidence of vte. routine screening might benefit to lower the incidence of mortality caused by pe. epsilon aminocaproic acid (eaca) is an antifibrinolytic agent that crosses the blood-brain barrier and has shown benefit in decreasing bleeding in patients acutely. its use in intracranial hemorrhage has uncertain benefit. we aimed to describe the administration and impact of eaca in a single-center neurosciences intensive care unit (neuroicu) over one year. we performed a single-center retrospective study of neuroicu patients undergoing intravenous eaca administration over a one-year time period. inclusion criteria included eaca administration over hours for a diagnosis of acute traumatic hematoma. the dose and duration of eaca infusion was collected. we additionally collected and compared pre-administration and post-administration prolonged thromboplastin time (ptt) hematology assays and neuroimaging. clinical outcomes were reviewed for survival at hospital discharge. over a -month period (april -may ), patients each received a -hour infusion of eaca. the most common indication for eaca was to prevent worsening of intracranial hemorrhage in patients in traumatic coma (gcs < ). % of patients underwent neurosurgical management. ptt assay values showed a significant difference before and after eaca administration. (ptt . +/-sd vs. . +/-sd; student's t test p< . , n= ). stability of the intracranial hematoma burden was evident following eaca in % of patients. % of patients who received eaca survived to discharge. patients receiving eaca showed a significant reduction in ptt assay values hours after completing their dose. ct neuroimaging demonstrated stable intracranial hemorrhage burden in most patients receiving eaca despite a high prevalence of acute operative neurosurgical management. however, only a modest number of patients receiving eaca survived to discharge. these results suggest that eaca may acutely reverse hematologic abnormalities and enable emergent neurosurgical management in patients with severe, acute traumatic hemorrhage, despite a limited role in affecting survival outcomes in these patients. prognostication is difficult for patients admitted to a neurocritical care unit (nccu). can serum biomarkers obtained as part of routine admission lab work help predict outcomes among patients in this prospective cohort study, the following biomarkers were measured at admission: c-reactive protein (crp), arterial lactate, neuron specific enolase (nse), lactate dehydrogenase (ldh), albumin, and brain natriuretic peptide (bnp). we collected information about demographics, comorbidities, hospital procedures and complications and -day mortality. we compared these serological biomarkers in patients who were alive versus those who had died at days. a total of patients were enrolled over months from june to september , of which whom ( . %) died within days of admission. there were no statistically significant differences in age or gender between the two groups. the -day mortality group had a higher mean charlson comorbidity index (cci) ( . vs . , p= . ) as well as mean nse ( . vs . ug/l, p= . ) and bnp levels ( . vs . pg/ml, p= . ). mean crp, lactate, and ldh were also higher in the -day mortality group ( . vs . mg/l, . vs . mmol/l, and . vs . u/l) while mean albumin was lower ( . vs . g/dl), although these differences were not statistically significant (p< . ). cci and serological biomarkers may have utility in predicting -day mortality among patients admitted to the nccu. as we continue enrollment, we plan to develop a predictive model for -day mortality on admission for patients admitted to the nccu using serological biomarkers, cci and admission characteristics. among hospitalized acutely ill medical patients, the risk for venous thromboembolism (vte) is high. the goal was to examine vte prophylaxis of at-risk patients and vte risk during hospitalization and in the outpatient continuum of care. acutely ill medical patients were identified from the marketscan commercial and medicare databases from / / to / / . inclusion criteria were hospitalization for heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases; months of continuous insurance coverage prior to (baseline period) and after (follow-up period) the index hospitalization. outcomes included the proportions of patients receiving inpatient and/or outpatient vte prophylaxis, and the risk for vte events. years, and . % were female. patients were hospitalized for infectious diseases ( . %), respiratory diseases ( . %), cancer ( . %), heart failure ( . %), ischemic stroke ( . %), and rheumatic diseases ( . %). mean hospital length of stay was . days. in total, . % (n= , ) of patients did not receive any vte prophylaxis, and . % (n= , ) received both inpatient and outpatient vte prophylaxis. during hospitalization, . % (n= , ) received vte prophylaxis (enoxaparin, . %; warfarin, . %; enoxaparin and warfarin, . %; a direct oral anticoagulant (doac), ~ %). following discharge, . % (n= , ) received outpatient vte prophylaxis (warfarin, . %; doac, . %; enoxaparin, . %; enoxaparin and warfarin, . %). among the entire study population, the vte event risk remained elevated up to - days after hospital admission. among hospitalized acutely ill medical patients, the risk for vte was present in both the inpatient and outpatient settings, with significant vte risk extending into the post-hospitalization period. only a small portion of at-risk patients ( . %) received vte prophylaxis in both the inpatient and outpatient continuum of care, suggesting an unmet medical need for vte prophylaxis in the post-hospitalization. brain edema is a good research target in various forms of neurologic injury. a real time measurement of brain edema is possible using thermal conductivity methods. however, this technique might be hard to apply in small rodents, which are commonly used as experimental brain edema models. we developed a new approach method for applying thermal conductivity methods in rodent brain edema model. a -week-old spraque-dawley rats were used for brain edema model. qflow probe was inserted through a suboccipital burr hole, located mm left from the midline, then was advanced anteriorly mm from the occipital bone margin until probe place assistance value indicates valid values (ranging from to . ). probe was fixated using adhesive glues and tagging suture. in vivo brain water content was continuously calculated using thermal conductivity values. for validation, calculated brain edema was compared with standard methods (dry/wet brain weight ratio) in water intoxication models (intraperitoneal injection of distilled water, % of body weight) and drying effect of mannitol was validated in streptokinase induced intracerebral hemorrhage (ich) models. calculated brain water content was . ± . % in thermal conductivity method and . ± . % using dry/wet weight ratio methods (p= . ). in water intoxication model, brain water content started to increase minutes after injection and reached up to . ± . % at hours post injection. on wet/dry weight method, edema was measured as . ± . % (p= . ). in ich model, brain water content started to drop minutes after administration of mannitol ( . mg/kg) and drifted back hours after injection of mannitol. thermal conductivity method in assessing brain edema is applicable in rodents using suboccipital approach through burr hole. this method may better reflect dynamic changes of brain edema. in patients with critical brain injury, alterations of brain physiology with dialysis initiation are poorly understood. from a consecutive series of brain-injured patients undergoing invasive multimodality monitoring between and , patients that underwent continuous veno-venous hemodialysis (cvvh-d) and patients that underwent intermittent hemodialysis (ihd) were identified. changes in mean arterial pressure (map), intracranial pressure (icp), and brain tissue oxygenation (pbto ), and microdialysis lactate-pyruvate ratio (lpr) were compared six hours prior to and twelve hours following dialysis initiation. high-resolution data was collected every seconds, with the exception of lpr collected hourly. data were normalized to patient maximum values, analyzed by fitted segmented regression, and checked for slope change-points by davies' test. values prior to dialysis initiation were averaged as a baseline for comparison. median values for patients undergoing cvvh-d were map +/- . , icp . +/- . , pbto . +/- . mmhg (n= ), and lpr . +/- . (n= ). normalized median values for patients undergoing ihd were map +/- . , icp +/- . . for the cvvh patient segmented regressions with normalized data, there was no change in map (slope . ) during the twelve hours. however, we found a change-point in icp at . hours (ci . - . , slope change . to . ) and pbto at . hours , slope change . to - . ). lpr increased through cvvh (slope . +/- . ). median values for patients undergoing ihd were map +/- . , icp +/- . . there was no identified change-points in map or icp in ihd patients, further parameters were limited by small sample size. initiation of cvvh in patients with neurologic multimodality monitoring showed change-points in icp and pbto in setting of stable map, with slight decrease in icp and pbto . initiation of hd in showed no change-points in icp. data on the cerebral effects of antihypertensive agents are limited but potentially important in patients requiring blood pressure reduction in neurological emergencies. our objective was to measure the effect of rapid-acting antihypertensive agents on cerebral blood flow (cbf) in patients with acute hypertension we conducted a prospective, quasi-experimental study of patients with a sbp > mmhg and planned rapid-acting antihypertensive treatment in the emergency department. patients < years or pregnant were excluded. non-invasive hemodynamic and transcranial doppler measurements of the middle cerebral artery mean flow velocity (mfv) were obtained prior to and post treatment. analysis included descriptive statistics and generalized linear modeling to test the effect of four categories of antihypertensive agents on mfv. categories included clonidine, iv labetalol, iv hydralazine and combination therapy. we enrolled patients ( % female) with a mean age of ± years. eight ( %) patients received clonidine, ( %) iv labetalol, ( %) iv hydralazine and ( %) combined therapy. the mean baseline sbp was ± mmhg and mfv ± cm/sec. the mean percentage fall in sbp by medication was: clonidine - ± %, labetalol - ± %, hydralazine - ± %, and combination - ± %. the overall change in mfv was - ± %, and by medication was: clonidine - % ( %ci - to - %), labetalol - % ( %ci - to - %), hydralazine + % ( %ci - to + %), and combination - % ( %ci - to - %). adjusting for baseline bp, hydralazine caused less change in mfv compared to other medications (difference between means + %, %ci - to + %, p= . ). in this study with modest bp reductions, rapid-acting antihypertensive medications had comparable effects on cerebral blood flow. these results hint that cerebral blood flow may be more stable with hydralazine administration, but further testing of hydralazine and infusions such as nicardipine is required. studies exploring correlations between non-invasive (oscillometric) blood pressure (nibp) and intraarterial blood pressure (abp) have excluded neurocritically ill patients with continuous infusion of vasoactive medications. compared to abp, nibp monitors generally tend to over-read at low values and under-read at high values. this study examines the relationship between simultaneously measured nibp and abp recordings in these patients. following informed consent, prospective observation of patients (n= ) admitted to a neurosciences icu, with simultaneous abp and nibp monitoring and continuous vasopressor (n= ) or antihypertensive (n= ) infusion. paired nibp/abp observations along with covariate and demographic data were abstracted via chart audit. analysis was performed using sas v . . , paired nibp/abp observations from subjects ( % male, % white, mean age years) receiving vasopressors (n= ) or antihypertensive agents (n= ). t-tests show significant difference between paired readings: ([sbp: m= vs mmhg respectively; p<. ], [dbp: m= vs mmhg respectively, p<. ], [map: m= vs m= mmhg respectively, p<. ]). the paired differences for specific medications were tabulated, with - % of the differences < mmhg, and - % of the values with < mmhg difference. bland-altman plots for map, sbp, and dbp demonstrate good intermethod agreement between paired measures (excluding outliers) and demonstrated marked nibp-abp sbp differences at higher blood pressures. pearson correlation coefficients for paired measurements show strong positive correlation for map (+ . ), sbp (+ . ), and dbp (+ . ). despite a statistically significant difference between nibp and abp readings for patients on vasoactive medications, there may be no clinical significance. the relatively positive and linear correlation between paired values guide providers towards not being forced to use one over the other. the final manuscript will aim to detail whether there is a clinical significance in particular vasoactive medications. pathological activity in continuous electroencephalogram (ceeg) data of icu patients is conventionally categorized into a small number of named rhythmic and periodic patterns. we aimed to develop a valid method to automatically discover a small number of homogeneous pattern clusters, to facilitate efficient interactive labeling by ceeg experts. we extracted time and frequency domain features from + hour ceeg recordings from different icu patients. after removing artifacts, we applied principal component analysis ( % variance retained), then separated the data into clusters (k-means). from each cluster we took random samples plus the most central one, rendering samples in total. three expert electroencephalographers independently categorized all samples into one of standard pattern categories (seizures, gpds, lpds, lrda, grda, burst suppression, other). we compared two methods for labeling clusters: ( ) "labor intensive labeling" (lil): assign the most frequent of expert-provided labels; ( ) "labor efficient labeling " (lel): assign the most frequent of the expert labels for the central sample. we compared interrater agreement (ira) among experts vs. between each expert and consensus labels using lil vs. lel. finally, we used laplacian eigenmaps (le) to visualize the data. this research suggests that large ceeg datasets can be automatically clustered into a small number of patterns described by standard icu eeg pattern labels. we demonstrated efficient cluster labeling by inspecting only the central-most representative of each cluster. furthermore, le visualizations support the hypothesis of an interictal-ictal continuum. real time measurement of cerebral oxyhemoglobin (oxyhb) and deoxyhemoglobin (deoxyhb) using near infrared spectroscopy (nirs) may help us better understand the status of cerebral oxygenation and possibly cerebral blood flow (cbf) in patients with acute brain injury. we developed multichannel functional nirs (fnirs) system and evaluated its role in patients with acute brain injury. a channel fnirs system (nirsittm) was used for measuring cerebral oxyhb and deoxyhb in patients with brain injury. measurement protocols were as follows; baseline measurement for minutes with activation stimuli (nipple pinching for seconds). patients groups were categorized as follows; ) global cerebral ischemia with profound cerebral injury (n= ), ) large ischemic stroke or decrease in cbf in the frontal lobe due to severe stenosis in the middle cerebral artery (mca) or internal carotid artery (ica) (n= ), ) high grade subarachnoid hemorrhage with a risk of vasospasm (n= ), control groups did not have either cerebral lesion or cbf abnormality (n= ). global ischemia with good functional outcome group had better oxyhb level (rso ) compared to those with poor outcome ( . % vs. . %, respectively, p = . ). patients with poor perfusion in the mca territory had low oxyhb level compared to mirror lead in the contralateral hemisphere. oxyhb level in patients with decreased vasomotor reactivity on diamox spect had improved after carotid stenting. three patients who underwent superficial temporal artery-middle cerebral artery bypass surgery had transient hyperperfusion syndrome. oxyhb and total hb were elevated in the affected area. patients with sah and vasospasm had blunted oscillation pattern of oxyhb compared to those without vasospasm. bedside multichannel measurement of oxyhb and deoxyhb using fnirs might be useful in understanding hemodynamic changes occurring in patients with acute brain damage at the real time. multimodality monitoring (mmm), brain tissue oxygenation (pbto ) and microdialysis (md) in sah may be important to the treatment of delayed cerebral ischemia (dci). our hypothesis was that concordance between pbto and md occurs in the tissue bed displaying angiographic vasospasm. this retrospective observational study includes patients with sah. the extent of angiographic vasospasm for each vessel was graded on angiography by the on call neuro-interventionalist and quantified as (no spasm) to (severe spasm). pbto and md probes were placed in the frontal lobe white matter. the severity of vasospasm was estimated by the weighted average of ( x aca + x mca + x ica) / . cases with score of or more were considered to have clinically relevant vasospasm. using a within-subjects design, epochs of baseline mmm were compared with during spasm using daily mean for pbto , lpr, glucose, icp and cpp. given the limited number of observations the simplifying assumption was made that the observations from all epochs are independent. the measurements from all patients were divided in the two groups with and without spasm and were compared using a twotailed non-paired student t-test. sixteen sets of baseline and vasospasm epochs were evaluated for pbto and for md. compared with baseline values, the average pbto was significantly lower ( . vs . mmhg, p= . ), lpr was non-significantly higher ( . vs . , p= . ), and glucose was similar ( . vs . mmol/l, p= . ) during vasospasm epochs. there was no difference in icp ( . vs . mmhg, p= . ). these differences were unaffected by induced hypertension, when cpp was augmented for treatment of dci ( . vs . mmhg, p= . ). mmm during angiographic vasospasm after sah suggests discordant changes in brain oxygenation and metabolism. these data suggests that dci may be related to metabolic factors other than tissue oxygenation. multimodal monitoring including brain tissue oxygenation (pbto ) is increasingly used for the management of acute tbi patients. the optimal management of pbto is not fully established. increasing fio is efficacious to correct pbto but may mask other oxygen delivery mechanisms which may be deficient. the objective of this study was to explore the clinical utility of a pbto /pao ratio to detect overtreatment by fio . retrospective cohort stud were collected simultaneously whenever an arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). causes of cerebral hypoxia (pbto < mmhg) were noted. pbto /pao ratio < . was considered abnormal and plotted over time for each patient individually. data sets were collected from patients (mean age . ± . , median gcs , mortality %). . % of the time and associated with a mean pao of mmhg. measures within the low pbto -low ratio category had significantly lower cpp ( vs mmhg), higher pao ( vs mmhg) than patients with normal pbto or normal ratio respectively. various causes of hypoxic pbto were reported when the ratio was abnormal: hypocapnia, low cpp, low cardiac index, long equilibration time... four patterns of evolution of the ratio over time were identified and associated with different mortality rate: . %, . %, . % and %. conclusions associated with increased pao and decreased cpp. this suggests clinicians often used fio to compensate for deficient cerebral oxygen delivery. indeed, various causes of hypoxia besides low pao were identified and corrected. pattern of temporal evolution of the ratio seems to correlate with mortality. pupillary light response (plr) evaluates cranial nerves ii, iii, and midbrain function. bedside quantitative infrared pupillometry provides reproducible assessment of the plr, reported as the neurological pupillary index (npi). increased intracranial pressure results in decreases in npi. intracranial hypotension (ih) can also cause brainstem distortion. we therefore hypothesized that similar changes in npi could be seen with ih. here, we describe sequential changes in npi in ih before and after treatment. we identified four patients monitored with pupillometry for clinical care during ih diagnosis and treatment. ih was diagnosed with a compatible history, exam, and characteristic neuroimaging findings. patients' npi at baseline, during symptomatic ih, and after treatment were compared using related samples friedman's two-way anova and wilcoxon signed ranks tests. two patients were male; causes of ih were csf leak following lumbar instrumentation (n= ) and basilar skull fracture (n= ). mean baseline npi was normal (defined as > ) and declined in one or both eyes concurrent with clinical deterioration in the - hours preceding definitive diagnosis. all patients underwent treatment for csf leak with epidural blood patch or fracture repair, with return of npi > within hours of treatment. the baseline, symptomatic and post treatment npi's differed significantly ( . ± . vs . ± . vs . ± . , mean +/-sd, pre-treatment vs nadir vs post-treatment, p= . ). both baseline and post treatment npi's differed from the npi nadir (p= . ) but there was no difference between baseline and post-treatment npi (p = . ). impairment of the plr, as measured by npi, occurred during symptomatic ih and resolved after treatment. because management of intracranial hyper-and hypotension differ markedly, our results emphasize the importance of evaluating the clinical context before attributing pupillary/npi changes to increased icp. automated pupillometry provides a non-invasive, bedside tool for monitoring progression and treatment of intracranial hypotension the correlation of optic nerve sheath diameter (onsd) as seen on ultrasonography (us) and directly measured intracranial pressure (icp) has been well described. nevertheless, differences in ethnicity and type of icp monitor used are obstacles to the interpretation. therefore, we investigated the direct correlation between onsd and ventricular icp and defined an optimal cut-off point for identifying increased icp (iicp) in korean adults with brain lesions. this prospective study included patients who required an external ventricular drainage (evd) catheter for icp control. iicp was defined as an opening pressure over mmhg. onsd was measured using a mhz us probe before the procedure. linear regression analysis and receiver operator characteristic (roc) curve were used to assess the association between onsd and icp. optimal cut-off value for identifying iicp was defined. a total of patients who underwent onsd measurement with simultaneous evd catheter placement were enrolled in this study. thirty-two patients ( . %) were found to have iicp. onsd in patients with iicp ( . ± . mm) was significantly higher than in those without iicp ( . ± . mm) (p . mm disclosed a sensitivity of . % and a specificity of . % for identifying iicp. onsd as seen on bedside us correlated well with directly measured icp in korean adults with brain lesions. the optimal cut-off point of onsd for detecting iicp was . mm. impaired cerebral autoregulation following neurological insult has been established as a strong predictor of clinical outcome. hypothermia may offer autoregulatory protection in these patients, although the effect of body temperature on autoregulatory status is unclear. retrospective analysis of data from an ongoing prospective study to evaluate multimodal monitoring using near infrared spectroscopy (nirs) for bedside measurement of autoregulation. ninety-one comatose patients (gcs < ) were continuously monitored for up to three days. nirs derived cerebral oximetry index (cox) was used as a marker of autoregulation. cox was calculated as a moving, linear correlation coefficient between regional cerebral oxygenation saturation and map. autoregulation improves as cox values approach , and is impaired as values approach . patients were grouped by trend in temperature seen over the monitoring period: no change (< oc temperature change, n= ), increase (n= ), decrease (n= ), increase followed by decrease (n= ), decrease followed by increase (n= ), and fluctuating (n= ). we performed multivariable logistic regression analysis to assess the association between temperature and outcomes. the association between hourly temperature and cox was assessed using mixed random effects models with random intercept. in patients showing a sustained increase or decrease in temperature, a linear relationship between temperature and cox was seen; for every oc increase or decrease in temperature, cox changed by . ± . (p< . ) and - . ± . (p= . ), respectively, after adjusting for pco , haemoglobin, map and temperature probe location. mean temperature changes over the monitoring period for these groups were . ± . oc and - . ± . oc, respectively. cox did not change significantly in other groups. there was no significant difference in mortality or poor outcome (mrs - ) at discharge and , , or months between patients in each group. in acute coma patients in the neurocritical care unit, increasing body temperature is associated with worsening cerebral autoregulation as measured by cox. the historical tradition of examining the pupillary light reflex (plr) required the examiner to score the size and reactivity of the pupil. a change in the plr from brisk to sluggish or fixed may be a marker of a pathological process and a need for intervention. the plr has been difficult to quantify and has poor inter-rater reliability. handheld pupillometry provides several novel measures, such as the neurological pupillary index™ (npi) and constriction velocity (cv) that may be more quantifiable than the plr. the purpose of this analysis is to examine the relationship between cv and npi in neurologically injured patients. the end-panic registry is a prospective registry of pupillometer values and variables associated with intracranial dynamics (e.g., icp). this analysis from adult (over years) patients from hospitals includes , pupillometer readings; left eye ( , ), and right eye ( , ). subjects had a mean age of . yrs and . % were male. the primary admission diagnosis included neoplasm ( ), ischemic stroke ( ), sah ( ), ich ( ), tbi ( ), and other ( ). the left eye mean/s.d. cv ( . / . ) npi ( . / . ) and size ( . / . ) were similar to the right eye cv ( . / . ) npi ( . / . ) and size ( . / . ); statistically significant difference related to large sample size. the correlation between left eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). the correlation between right eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). constriction velocity is highly dependent on size of the pupil. further studies need to be undertaken to determine the sensitivity and specificity of abnormal npi and cv in detecting pathological processes such as midline shift or rd nerve compression that effect pupillary reactivity. cerebral injury is increasingly described in adult recipients of extracorporeal membrane oxygenation (ecmo) therapy. we describe the association between regional brain tissue oxygenation (rso ) measured by near infrared spectroscopy (nirs), survival, and cerebral injury on neuroimaging. a single-center retrospective chart review was conducted of adult patients who underwent veno-arterial (va) ecmo from april to october . all patients had received nirs monitoring during ecmo therapy. baseline demographics, in-hospital complications, and mortality were recorded. desaturations of rso , defined as decline > % below baseline or absolute value < , were recorded and analyzed. desaturation burden was calculated by area under the curve analysis and measured by rso *seconds. eighteen va ecmo patients ( females) underwent nirs monitoring during the study period. eleven patients experienced desaturations, while did not. patients with desaturations tended to be younger ( . vs. . years old), more likely female ( vs. ), had lower ejection fraction ( . % vs. . %) and experienced liver dysfunction ( patients vs. ). patients with desaturations were more likely to have abnormalities on ct scan ( vs. ). eleven of the patients survived to discharge. survivors tended to be younger ( . vs. . years old) and had lower initial ecmo sweep ( . vs. . ). survivors had lower baseline rso values at the beginning of nirs monitoring (right - vs. , left - vs. ), fewer desaturation events ( vs. ), lower desaturation burden, and spent less overall time desaturating ( : vs. : hours). desaturation on nirs may be correlated with cerebral injury in the adult va ecmo population and may have utility in triggering clinical investigation or determining prognosis. further studies in larger patient populations are needed to determine its reliability and accuracy. pressure reactivity index (prx) is the most validated index to measure cerebrovascular reactivity in patients after traumatic brain injury. the aim of this study is to identify the natural history of cerebral autoregulation measured by prx in various forms of brain injury to monitor restoration or not of cerebral vasomotor reactivity in the acute phase. retrospective analysis of data from ongoing prospective study to evaluate multimodal monitoring using prx for the measurement of cerebral autoregulation at the bedside. thirty comatose patients (glasgow coma scal used as a marker of autoregulation. prx was calculated as a moving, linear correlation coefficient between icp and map. impaired cerebral autoregulation has been pre standard maximal medical therapy was implemented to treat elevated icp, cerebral edema, etc. patients with withdrawal of care in the first hours or brain death on neurological exam were excluded. thirty comatose patients from acute brain injuries ( intracerebral hemorrhage, tbi, aneurysmal subarachnoid hemorrhage, intraventricular hemorrhage, hypoxic ischemic encephalopathy) were studied. the average prx upon starting neuromonitoring using prx was . ± . (impaired), whereas the average prx at the end of day of neuromonitoring was ± . (restored). one third of the patients had icp crisis during monitoring. the average opening icp= . , average highest recorded icp= . . impaired cerebral autoregulation has been implicated as a predictor of clinical outcome. aggressive medical therapy instituted by the neurocritical care team (icp and cerebral edema management, blood pressure control, etc.) may result in restoration of cerebral vasomotor reactivity measured by prx by intensive care day - . restoration of cerebral vascular reactivity may be a necessary but not sufficient for favorable outcome. elevated intracranial pressure (icp) is an important cause of death following acute liver failure (alf). while invasive icp monitoring (iicpm) remains the gold standard, the presence of coagulopathy increases the risk of bleeding in alf. measurement of optic nerve sheath diameter (onsd) using optic nerve ultrasound (onus) may accurately detect elevated icp. our goal was to study the ability of onus to detect sustained intracranial hypertension following alf, and to predict death and therapeutic intensity level (til), a quantitative measure of the intensity of treatment required to control icp. consecutive patients with alf admitted to our institution in a -year period underwent onus. blinded measurement of onsd was performed from deidentified onus videos. patients underwent iicpm on the basis of an institutional protocol for selection of appropriate candidates, coagulopathy reversal and insertion of an intraparenchymal monitor. the til-basic for management of icp during the icu stay was recorded. the ability of highest onsd to predict concurrent icp> mmhg at the time of measurement, sustained icp elevation > mmhg at any time and til-basic> was assessed in patients who underwent iicpm, while prediction of death was assessed in all patients. receiver operating characteristic (roc) curves were constructed for the outcomes of interest. thirty-nine patients with alf were admitted during the study period, / ( %) underwent onus, / ( %) underwent iicpm and ( %) died. of patients who underwent iicpm, ( %) developed sustained icp elevation and ( %) had a til-basic> . the roc area under the curve (auc) of onsd for prediction of concurrent icp> mmhg was . ( % confidence-interval . - . , p= . for null hypothesis of auc= . ), sustained icp elevation at any time was . ( . - . ,p= . ), death was . ( . - . ,p= . ) and til> was . ( . - . ,p= . ). in patients with alf, onsd measurement performed poorly for detection of icp elevation, and was a poor predictor of til and death. limited literature exists regarding the neurochemical and physiologic events that occur as brain death develops. using intracranial multi-modality monitoring, we identify physiological changes that signal the onset of brain death. we measured intracranial pressure (icp), brain partial oxygen tension (pbto ), cerebral blood flow (cbf), and biochemical correlates of cerebral metabolism in patients with diffuse hypoxic ischemic brain injury after cardiac arrest during the development of brain death. monitoring probes were inserted into cerebral white matter through a burr hole using a ct compatible multi-lumen bolt. brain tissue energy-related metabolites (lactate, pyruvate, glutamate, glucose, glycerol) were measured using a bedside microdialysis analyzer. pbto and temperature were measured via a licox catheter. cerebral perfusion was measured with a hemedex bowman perfusion monitor. brain death was confirmed in accordance with institutional guidelines. a characteristic pattern of physiologic and neurochemical findings emerged as brain death occurred. absolute loss of cerebral autoregulation, with a near perfect correlation between icp and map was followed by equalization of map and icp resulting in progressive drop in cpp to zero, followed by a progressive decline in pbto that became unresponsive to a % fio challenge. cerebral perfusion decreased in tandem with pbto . lactate/pyruvate ratio (lpr), glutamate, and glycerol all increased precipitously, with lpr consistently > . brain temperature decreased despite maintenance of a normal core temperature. finally, intracranial compliance, while initially very low (evidenced by marked increase in the p component of the icp waveform), appeared to paradoxically re-normalize as the recording continued. continuous neuromonitoring reveals a characteristic pattern of cerebrovascular physiologic changes that accompany brain death. these changes are consistent with a progressive cessation of cerebral perfusion caused by diffuse cerebral edema. although not currently a part of the formal brain death determination process, such monitoring could be helpful to identify when brain death has truly occurred. automated devices that collect objective quantitative data on pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the normative range of pupillary reactivity in the critically ill, and the relationship between reactivity and traditional monitoring metrics. to determine pupil characteristics in this population, we prospectively collected quantitative pupillometry data in patients admitted to the neuro icu with an expected stay of at least hours. trained nursing staff measured pupillary reactivity with the neuroptics- pupillometer device every -hours. measurements included the neurologic pupil index, (npi) a composite metric ranging from - in which > is considered normal, resting and constricted pupil size, constriction velocity, dilation velocity and latency. these recordings were compared with averaged intracranial pressure (icp) and glasgow coma scale (gcs) assessments within the same hour. we used univariate and spearman's rank tests to explore associations between pupil characteristics and clinical variables, followed by multi-level linear regression to account for intra-and inter-subject variability. one-hundred patients underwent paired observations. fifty-five patients had at least one recorded episode of anisocoria, had low npis in more than % of recordings, and had normal pupil reactivity. average and minimum npi was correlated with average and minimum recorded hourly glasgow coma score (gcs) (p values < . ). increased asymmetry in both pupil size (p= . ) and dilation velocity (p= . ) was associated with increased intracranial pressure (icp). anisocoria was associated with hyperosmolar therapy (p= . ). the presence of low npis in more than % of total pupil measurements was associated with death at discharge (p= . ). the range of pupillary metrics varies among critically ill neurologic patients and correlates with gcs and icp. further study is needed to establish whether change in pupil metrics predict specific clinical events. near infrared spectroscopy (nirs) provides a non-invasive measurement of regional cerebral oxygen saturation (rso ) that may be able to detect seizure activity. in this study, we explored the hypothesis that rso is lower ipsilateral to seizures or epileptiform activity compared to the contralateral side in comatose patients. five patients ( men and women; mean age ) underwent continuous electroencephalography (ceeg) monitoring and nirs recording. ceeg data were classified as baseline, epileptiform activity or seizure, slowing, or burst suppression at hourly intervals over the course of the recoding period (mean duration . hours, range to hours). three patients had idiopathic status epilepticus, two had intracranial hemorrhage, and one had a temporal meningioma. the relationship between rso and epileptiform discharges was explored using scatterplots. the association was assessed using mixed random effects models with a random intercept. an independent within-subject residual structure was used. there were measurements with ceeg and nirs from patients. one patient was excluded as the nirs sensors were potentially reversed. epileptiform activity or seizures were observed in a median of % of the measurements (iqr - %). rso was significantly lower on the side ipsilateral to seizures - . , p < . ) after adjusting for map. all patients only had partial seizures with no generalization. partial seizures and/or epileptiform discharges were not associated with impaired autoregulation. we found a significant lower cerebral oxygen saturation ipsilateral to seizures and/or epileptiform activity. the association was observed in patients with various etiologies of coma, and with either convulsive and non-convulsive seizures. decreases of regional cerebral oxygen saturation at the bedside may alert the clinician of ipsilateral seizures. elevated intracranial pressure (icp) and cerebral edema are common causes of mortality in neurocritical-care patients. key monitoring techniques for icp-elevation include neuroimaging and invasive icp-measurement. examination of the pupils is routinely performed to determine disturbances within cerebral physiology but shows high inter-rater variability. portable infrared pupillometry is increasingly used for accurate measurements. the benefit of these technique remains to be established in patients with elevated icp. aim of this study was identify pupillary parameters associated with icpcrisis in neurocritical-care patients. we prospectively enrolled critically-ill patients (subarachnoid hemorrhage/intracerebral hemorrhage/stroke/bacterial meningitis) admitted to our neurointensive care unit( / - / ) who required placement of external ventricular drains. we recorded serial pupillometer readings [i.e. maximum/minimum apertures(mm), constriction/dilation velocities(mm/sec.), latency period(sec.)] and corresponding icp values every hours after admission. neurological pupil index(npi), an algorithm that compares above mentioned pupillary parameters to a normative model of pupil reaction to light, grades pupil-function on a scale of (nonreactive) to (normal). receiver operating characteristic(roc) curve analysis was performed to investigate associations between pupillary parameters and presence of icpcrisis(icp> mmhg). in our data suggest a relationship between non-invasively detected changes in npi, cv or mcv and icpcrisis. yet, clinical benefit of these parameters is subject to future studies. lung injury is frequently observed in patients with severe, acute brain injury. while these patients often require mechanical ventilation, a lung protective ventilation strategy has not been extensively studied. this may be due, in part, to concerns that elevated positive end-expiratory pressure (peep) could adversely affect intracranial pressure (icp) or cerebral perfusion pressure (cpp). we were interested in exploring this relationship as a first step towards understanding whether mechanical ventilation resulted in a transmission of pressure to the brain. ) and received both mechanical ventilation and icp monitoring were enrolled in this pilot study. an esophageal balloon was inserted to measure their transpulmonary pressure (ptp). fluid responsiveness was assessed prior to the intervention. subjects underwent a step-wise increase in peep (increments of five) from to cmh o. airway pressure, ptp and icp were measured at each peep interval. of the planned twenty, three patients have been enrolled to date. primary diagnoses included aneurysmal subarachnoid hemorrhage and intraparenchymal hemorrhage with a median gcs of . patients were ventilated using either volume control or pressure support ventilation; median fio was . . two patients were on vasopressors and the same two patients were determined to be fluid responsive. at baseline (peep ), mean icp, cpp, and ptp were mmhg, mmhg, and - . cmh o, respectively. when peep was increased to cmh o, the average change from baseline in icp and cpp was - . % and - . %, respectively. when increased to cmh o the change from baseline in icp and cpp was . % and . %. during the intervention icp did not exceed mmhg, nor did any patient experience hypotension. preliminary data suggests that intrathoracic pressure is not directly transmitted to the intracranial compartment. continued enrollment is needed to confirm these findings. neurocritical care after severe traumatic brain injury (stbi) is focused on detecting and preventing secondary brain injuries. in addition to intracranial pressure (icp), measures of brain tissue oxygen (pbto ), regional cerebral blood flow (rcbf), and electrocorticography (deeg) may provide critical clinical data. few studies have assessed the safety of such an approach and the reliability of data that is gathered. we describe here the placement, complications, and reliability of multimodality monitoring (mmm) data from a novel, single burr hole approach using a four-lumen bolt at our institution. we included consecutive adult stbi patients admitted to the neuroscience intensive care unit at the university of cincinnati from april to march who underwent mmm as part of standard clinical management per institutional protocol. data was obtained regarding device placement and complications. all data was visually inspected for errors and gaps in data. patients were included. the mean age was +/- and % were men. bolts were placed a median of . (iqr . - . ) hours from injury. no clinically significant complications occurred, although . % had minor complications (e.g. small tract hemorrhage or pneumocephalus). suboptimal placement of probes was noted in %. we monitored patients a median . (iqr . - . ) hours. icp data was the most reliable, with data available . % of the total monitoring time and only . % error time. pbto and deeg data were reliable for > % of total monitoring time with < % error time. rcbf provided data for % of total monitoring time and had . % error time. mmm in stbi may be carried out via a single burr hole without significant clinical complications and reliably yields continuous data to facilitate clinical decision making. this supports the feasibility of our approach as an alternative to icp monitoring alone. intracranial hemorrhage patients with non-compliant ventricles may have high intracranial pressure (icp) despite normal ventricle size. we aimed to assess the incidence of elevated icp among those with no radiographic evidence of intracranial hypertension. prospectively enrolled primary intracranial hemorrhage patients (sah, sdh and iph) admitted to two tertiary-care centers between / - / were retrospectively reviewed. among patients with external ventricular drainage (evd), admission head ct (hct) scans within h prior to evd placement were reviewed for evidence of elevated intracranial pressure (icp) including: ventricle size (bicaudate index, temporal horn size), basal cistern effacement, midline shift and global cerebral edema. when all of these features were absent, patients were classified as having normal-icp hct. the incidence of elevated icp (> mmhg) at the time of evd placement and during hospital stay were recorded. of intracranial hemorrhage patients enrolled, ( %) had evd. / ( %) had a normal-icp hct. of these, / ( %) had elevated opening pressure at the time of evd placement, and / ( %) had elevated icp during their hospital stay. among normal-icp hct patients with icp> mmhg, % had sah, and the median gcs and hunt-hess scores were (range - ) and (range - ). the positive and negative predictive values of normal-re % %, respectively (auc . , p= . ) the only radiographic feature that was associated with elevated icp was global cerebral edema (or . , % ci . - . , p< . ). approximately half of intracranial hemorrhage patients without radiographic features of elevated icp had icp> mmhg at the time of evd placement and additional patients had elevated icp during their hospital stay. radiographic findings should not be relied upon to exclude the possibility of elevated icp. the measurement of intracranial pressure (icp) is a cornerstone of intensive care management following severe traumatic brain injury (stbi). it has been only recently that the time integral of icp has been quantified in relation to outcome; the time integral of brain tissue oxygen (pbto ) has not been studied. we gathered time-locked intracranial monitoring data on s tbi patients at the university of cincinnati over years. clinical management of all patients followed national standards. raumedic pto probe was used to measure icp and pbto ; accuracy was verified by visual inspection with automated data cleaning. normalized data was mapped based on correlation with glasgow outcome scale scores at - months. we studied patients aged +/- years (mean+/-sd); % were male. initial post-resuscitation glasgow coma scale score was median (interquartile range: . - ). / underwent craniectomy prior to monitoring. among those with good (gos - ) and poor (gos - ) outcome, the average icp was . +/- . mmhg and . +/- . mmhg (p= . ); the average pbto was . +/- . mmhg and . +/- . mmhg (both n.s.). the correlation with outcome was dependent on both icp and time: an icp > mmhg for > minutes was associated with poor outcome, whereas an icp < mmhg was associated with poor outcome only after hours. in contrast, the pbto level, but not the duration, correlated with poor outcome in those without craniectomy at a pbto < mmhg, and particularly below mmhg. pbto burden was less reliable in those following craniectomy. we replicated the effects of icp/time in a cohort of patients with severe tbi, both with and without craniectomy and subsequently demonstrated the burden of brain tissue hypoxia in those without craniectomy. the time integral of multimodality monitoring data may provide more accurate measures of secondary insult burden with implications for clinical care and prognosis. neurologists who work in neurocritical care (ncc) as neurointensivists may have critical care (cc) charges rejected for payment unless they are classified per centers for medicare services (cms) taxonomy codes in their systems as critical care providers. the neurocritical care society and cms created a new ncc code a x to fix this issue. we polled the aan ccen section members for awareness of this problem. we conducted a six question google forms survey using the aan ccen synapse community website to assess knowledge of the ncc taxonomy code: we received anonymous responses by the time we closed the poll on / / . question (q ) and (answers, a ): are you a neurology or neurosurgery back grounded intensivist who does neurocritical care at your hospital? y/n (yes/no). a : % reported being neurologists. q : were you aware of the new cms neurocritical care taxonomy code a x ? y/n a : % were aware of the taxonomy code. q : are you aware why the ncc taxonomy code was created? y/n a : % of respondents were unaware why this code was created. q : what is your primary department for revenue collection? a : % reported neurology, % neurosurgery, % critical care, and % blend. q : are you aware that medicare can reject critical care charges ( and ) can be rejected unless you are listed as a cms 'critical care provider' or as a neurocritical care provider? a : % reported rejected charges at their centers. q : are you aware of rejection of critical care charges happening at your own institution due to this misclassification? y/n a : % of respondents reported rejected charges at their center. although limited in sample size, this survey revealed almost half of the respondents were unaware of the ncc code. we believe a larger study is warranted. arterial subdural hemorrhage (sdh) is a rare but potentially devastating neurologic entity. it has been associated with ruptured aneurysms. we report a case-series of five patients with arterial sdh and their outcomes. a retrospective chart review of our institute's vascular database was conducted using a pre-defined search strategy including the terms "aneurysm", "arterio-venous malformation", "subdural hemorrhage", and "dural arterio-venous fistula" (dural-avf). amongst patients in the database, five cases were identified with ages ranging from to (four females). four had sdh due to aneurysm (two internal-carotid, one middle-cerebral, and one posteriorcerebral artery; one had parieto-occipital dural av-fistula. no patient had preceding head-trauma or anticoagulation. of aneurysmal patients, one had no sah. on admission ct-head imaging, the mean-sdh size was . mm (sd . ; range . - mm), and mean midline-shift (mls) was . mm (sd . ; range - mm). the mean ratio between sdh-size and mls was . (sd . ). in a historic cohort of acute subdural hemorrhage of non-arterial etiology ; the mean size of sdh was . mm and the mean mls was . mm. ratio of mls: sdh size was . . in our series, three patients with aneurysms had decompressive-craniectomy, one had mini-craniotomy for sdh evacuation; the patient with dural-avf had coiling and mini-craniotomy for sdh evacuation. four patients had died during hospitalization, whereas patient with dural-avf recovered to baseline functional-status at -month follow-up. arterial sdh is a rare entity and may present without subarachnoid hemorrhage and any preceding head-trauma. the degree of midline-shift is usually out of proportion to sdh size. there should be a low threshold to obtain vessel imaging in cases of sdh with no clear trauma history. mls: sdh ratio may be a useful screening tool for possibility of arterial sdh especially in absence of trauma and may reflect rate of bleeding. neurostimulant medications (amantadine and modafinil) are sometimes prescribed after acute nontraumatic brain injury to facilitate wakening and rehabilitation participation; the safety and effectiveness of this practice is unknown. following a retrospective evaluation of our experiences, we characterized anticipated challenges to designing a prospective randomized trial of neurostimulant medications to promote rehabilitation participation after acute non-traumatic brain injury. retrospective chart review of patients over with subarachnoid hemorrhage (n= ), intracerebral hemorrhage (n= ) and ischemic stroke (n= ) who received neurostimulant medications over a period of months. data regarding clinical course and potential confounders to assessing response were collected. continuous data are reported as median and interquartile range. neurostimulant medications were initiated in patients at a median of ( - ) days after hospital admission, for hypersomnolence ( %), not following commands ( %), lack of eye opening ( %), and/or low gcs ( %). thirty-nine ( %) patients were receiving sedatives or opioids at the time of neurostimulant(s) initiation. twenty-two ( %) patients received newly prescribed sedatives or opioids after neurostimulant(s) initiation. potentially sedating antiepileptic medications were prescribed to ( %) of patients. twenty-two ( %) patients were intubated at the time of neurostimulant initiation confounding the gcs-v. potentially confounding clinical factors included hydrocephalus ( %), vasospasm ( %), and seizures ( %). twenty-eight ( %) of patients had temporary cerebrospinal fluid diversion in place at the time of neurostimulant initiation. initiation and titration of neurostimulant medications after acute non-traumatic brain injury was common, but timing and indications varied widely. confounders to assessing effectiveness included concomitant sedating medications, variable pathophysiology related to the type and location of the stroke, and clinical factors like seizures, vasospasm, and hydrocephalus. these confounders are likely to make prospective evaluation of neurostimulant medication effectiveness difficult in the period of initial therapy following acute non-traumatic brain injury. brain small vessel disease can cause cognitive impairment via ischemic or hemorrhagic mechanisms. current imaging modalities, specifically magnetic resonance imaging allow for easier detection of different intracranial pathological processes including cerebral microhemorrhages (cms). research demonstrated that the number and location of cms correlate with the type of cognitive impairment (memory, processing speed, executive function, and motor speed). a retrospective analysis of patients (age to ) seen at our neurology outpatient clinic from to who were identified by linguamatics software to have "microhemorrhage" in their radiology mri report. additional information included age, sex, cognitive examination, presence of cardiovascular risk factors, mri, and the number and location of cms. cognitive function was determined by mini mental state examination (mmse) score and diagnosis by a cognitive neurologist. patients were grouped by presence of cm or greater ( to ) and regression was used to determine a relationship with mmse and vascular risk factors. the number of microhemorrhages per patient were ( patients), ( patients), ( patients), ( patients), ( patients), ( patients) and ( patients). vascular risk factors included hypertension ( patients), diabetes mellitus ( patients) and smoking history ( patients). regression analyses indicated that the presence of more than cm correctly predicted mmse lower than at % (p= . ). age was the only factor that influences this finding and increased this prediction to %. this study provides novel evidence that the presence of multiple cms on brain images predicts the presence of cognitive impairment. this study raises the need for more investigations. point-of-care ultrasound is a valuable tool in critical care, allowing timely and frequent beside assessment of clinical questions. neurocritical care has long utilized transcranial doppler but is still early in the adoption of other critical care ultrasounds. this study looked at the comfort level and competency of the participants at the point-of-care ultrasound workshop at the neurocritical care society annual meeting. the workshop comprised of didactics and hands-on small group practice using live models. topics covered included ultrasound physics, lung, cardiac, optic nerve sheath ultrasounds, as well as case studies in neurocritical care. participants were asked to complete an anonymous pre-and postworkshop assessment on a volunteer basis. a total pre-workshop and post-workshop assessments were completed. the mean age of the participants was . ± . years. there were ( . %) attending physicians, ( . %) advance practice practitioners, ( . %) fellows, ( . %) residents, and ( . %) research scientist. participants had limited ultrasound experience prior to the workshop, with ( . %) reported none, ( . %) reported < year, and ( . %) reported to years. on a - scale on comfort using ultrasound with being very uncomfortable and being very comfortable, participants reported a median score of (iqr - ) pre-workshop with an improvement to (iqr - ) post-workshop. for matched pre-and post-tests, all participants had an improvement in their ultrasound knowledge. while the majority of the participants at this workshop had prior ultrasound experience, many are still uncomfortable with their ultrasound competency. the format of didactics and hands-on small group practice improved the comfort level as well as overall ultrasound knowledge of these participants. additional opportunities for point-of-care ultrasound training should be considered in neurocritical care fellowships and meetings. event related potentials (erps) allow assessment of cognitive processing in unconscious brain-injured patients. here we explored the diagnostic and prognostic value of erps obtained shortly after brain injury. we prospectively collected a comprehensive erp paradigm labeled "local global paradigm" from a consecutive series of unconscious patients with acute brain injury. this auditory paradigm allows the assessment of: ) cortical responses, ) unconscious cognitive processing, ) unconscious focusing of attention, and ) conscious processing of sounds. levels of consciousness assessed with the coma recovery scale-revised (crs-r) at the time of recording were correlated with the presence/absence of each erps component and functional connectivity/complexity measures. we tested the prognostic value of each measure for recovery of consciousness prior to discharge. we analyzed recordings from patients (median recordings per patients [iqr , ]). recordings were made [iqr . , . ] days after brain injury and all patients were unconscious at the time of the initial recording. underlying etiologies included ich(n= ), sah(n= ), tbi( ) and other (n= ). there were trends for higher crs-r scores in patients with preserved erp components. crs-r scores correlated with the functional connectivity indexed (rho= . ; p= . ) but not with complexity measures. five ( %) patients regained consciousness (within to days from brain injury). one of these patients had to be excluded due to poor quality recording. all the ( %) remaining patients had the three type of non-conscious responses preserved on at least one recording in comparison to only ( %) among patient who did not recover consciousness (fischer p-value = . ). similarly, connectivity was greater in patients who regained consciousness ( . vs . ; p= . ) but the complexity was similar. simple bedside erp responses indexing cognitive processing during the local global paradigm obtained shortly after brain injury correlate with the level of consciousness but, more importantly, the probability to recover consciousness. over a decade ago, the institute of medicine introduced family-centered care (fcc) as a vital aspect of quality health care by strongly recommending that family members of intensive care unit (icu) patients be actively involved in decision-making. while there are many resources to help icu staff conduct meetings and provide information to families, the latest society of critical care medicine guidelines for fcc recommend the implementation of communication and decision support tools for family members to use. electronic decision support tools such as my icu guide have been effective in pilot studies at allowing family members to customize information delivery and communicate their preferences to icu staff. we sought to integrate a decision support and communication tool for families into an electronic patient portal. we developed an electronic patient and family engagement checklist for the neurointensive care unit (nicu) using doctella (patient doctor technologies, sunnyvale, ca), an existing patient engagement application. checklist components included: identifying a spokesperson, developing an advance directive, understanding diagnosis and prognosis, access to helpful resources, and a family meeting guide and planner. we presented the checklist to our hospital's patient and family engagement steering committee for the icus and received useful feedback. the checklist will also be vetted by the hospital's patient and family advisory council. usability testing will also be conducted. a family engagement checklist using an electronic patient portal is a novel strategy to enhance communication in the nicu. further validation of the tool is needed. applying painful stimuli to brain injured patients is a time-honored practice assumed to provide valuable clinical information for diagnosis, prognosis, and potential guidance for therapeutic interventions. however, there is limited literature that has evaluated and discussed the benefits and potential adverse effects related to repeated painful stimulation during bedside neurological examinations. though providers intend to do no harm, the practice of repetitive painful stimulation can unintentionally damage patient's skin, muscle, and bone, as well as inflict emotional duress. in conjunction with basic ethical principles used to justify painful stimulation during patient examinations, we propose a revisiting of the practice of routine repetitive painful stimulation in neurologic bedside assessments. . discuss the current literature regarding the use of painful stimulation and its beneficial and damaging effects, . describe alternative strategies for neurologic assessments, . propose guidelines to optimize accurate neurologic assessments while avoiding unnecessary repeated painful stimulation, . propose the development of a graded methodology for delivering painful stimulation when necessary for neurologic assessments. a summary of the literature will be outlined and discussed focusing on the ethical considerations and justification for the use of painful stimulation in the neurologic patient and the perception of pain in coma and minimally unconscious patients, . alternative strategies will be presented to minimize bodily and emotional injury, . a proposed outline with a companion flow diagram "easing the pain guidelines" implemented in a tertiary care neurocritical care unit will be presented. there has been little attention paid to the burden of painful stimulation inflicted on patients in the neurocritical care unit. the guiding principle of nonmaleficence (do no harm) morally obligates clinicians to evaluate current practice standards using repetitive painful stimulation in routine neurologic assessments. implementing standardized guidelines will limit unintended harm to patients without compromising accurate neurologic assessments. plasmapheresis is utilized in anti-n-methyl-d-aspartate receptor (nmdar) encephalitis to remove autoantibodies. antiepileptic drugs (aed), such as valproate, are often used to control seizures which may complicate anti-nmdar encephalitis. it is important to prevent rapid reductions of aed levels to ensure proper seizure management in this setting. we obtained total and free (active drug, unbound to plasma proteins) valproate levels intermittently throughout two -day courses of daily plasmapheresis. during the first course, trough levels were obtained. during the second course, levels were obtained before, during, and after plasmapheresis. the patient was a year old female, weighing kg. albumin was . g/dl. her valproate regimen ranged from mg to mg every hours ( to mg/kg/day), given intravenously or enterally. prior to the first plasmapheresis, valproate dose was mg every hours, resulting in a total level of mcg/ml (reference range: - mcg/ml). free valproate was mcg/ml (reference range: - mcg/ml); free fraction was % (reference range: - %). four days later, prior to the th plasmapheresis, the total valproate level was . mcg/ml. two days after the th plasmapheresis the total level was unchanged at mcg/ml; free valproate was mcg/ml and free fraction was %. during the second course of plasmapheresis, valproate total levels, free levels, and free fractions were mcg/ml, mcg/ml, and % before, mcg/ml, mcg/ml, and % during (valproate dose given upon initiation of plasmapheresis), and mcg/ml, mcg/ml, and % after plasmapheresis, respectively. valproate serum levels were not markedly influenced by plasmapheresis. free valproate levels and the free fraction were highly elevated throughout the patient's hospital course, however. future studies should evaluate critically ill patients' clinical response and toxicity correlations as the free fraction of valproate appears to be elevated in this setting. the purpose of this study is to assess knowledge retention of emergency neurological life support (enls) after participation in the course via a prospective observational study. study subjects seeking enls certification consented for study participation (enls-vs) from the ncs website then took a closed-book, multiple-choice question pre-test within hours of enls course participation. after completion of the enls course, participants took the same closed-book, multiplechoice question test (post-test). these tests consisted of novel questions from material presented in the course. questions were not repeated from the enls certification exams. thirty participants enrolled in the study with completing both the pre-test and immediate post-test. all participants' scores improved on the post-test as compared to the pre-test. the mean percent correct on the pre-test was . % with a median of . % (range . - . %). of the participants who have completed both pre-and immediate post-test, the mean pre-test score was . % with a median of . % (range . %- . %). the mean post-test score was . % with a median of . % (range . %- . %). the improvement of scores was statistically significant on the post-test compared to the pre-test ( . % vs. . % %, p< . ). all participants in the emergency neurological life support course showed improved test scores immediately after participation in the standard enls course. this study will assess knowledge retention at -months following training, and is actively enrolling new participants. augmented renal clearance (arc, defined as a creatinine clearance of > ml/min) has been demonstrated in neurocritical care disease states such as traumatic brain injury, intracranial hemorrhage, and subarachnoid hemorrhage. arc may result in increased elimination of renallyeliminated medications, thereby reducing drug exposure with standard doses. the overall prevalence of arc is not well described. the purpose of this study was to estimate the overall prevalence of arc in a neurocritical care population. this was a retrospective cohort study of adults > years of age admitted to the intensive care unit on the neurosurgery service. demographic and pertinent laboratory data were collected for patients admitted from january , thru december , . an arctic score was calculated for each patient ( or greater suggests arc). parametric data was compared using one-sample student's t-test, nominal data was compared using fisher's exact test (alpha = . ). statistical analysis was conducted using ibm spss version . present in a total of . % of patients. a broad spectrum of neurocritical care diagnoses was present. the mean age in years was significantly lower in patients with arc [ . ( sd)] than without arc [ ( sd), p = . ], as was the serum creatinine [with arc . mg/dl ( . sd) vs without arc mg/dl ( . sd), p < . ]. mean hospital length of stay was greater in patients with arc than without [ . ( sd) vs . ( sd), p < . ]. arc occurs commonly in neurocritical care patients and likely merits proactive screening or direct measurement of creatinine clearance in select patients. pharmacokinetic studies of commonly used renally-eliminated medications may be needed to establish population parameters in the neurocritical care population. education surveys demonstrate gaps in resident neurocritical care education and training. we assessed junior residents' baseline knowledge of neurologic emergencies, procedural competency, knowledge of available resources, and the impact of pre-rotation orientations. junior residents (neurosurgery pgy s and neurology pgy s) who had not previously rotated in the neuroicu were surveyed. a three-part survey was administered: part i, knowledge of icu structure and personnel; part ii, procedural competency; part iii, comfort with common neurocritical care emergencies. the survey was comprised of selection responses. after the survey but prior to starting the rotation, each resident was oriented to the unit by a neuroicu attending and nursing director. this orientation reviewed rotation goals, icu structure, personnel and rounding expectations. a survey was repeated to evaluate the orientation. of residents who had not rotated in the icu, ( . %) responded. none of the residents understood their specific role within the icu team. % did not understand the role of the resource nurse and were unaware of where to find procedure equipment. % of residents were not comfortable placing an a-line; % were not comfortable performing a lumbar puncture. over half of respondents said they "didn't know and could not easily find" the indications for hemicraniectomy after malignant mca ischemia, the indications for icp monitoring, or the initial workup of autoimmune encephalitis. residents responded to post orientation surveys. % felt the orientation was helpful in explaining the roles of team members. % felt it was at least "somewhat helpful" in understanding the role of the resource nurse. % felt the orientation was "helpful" and % felt it was "somewhat helpful" in identifying the goals of the rotation. these baseline measures underscore the importance of structured interventions, both before and during the neuroicu rotation, to improve junior resident comfort and preparedness in managing neurologic emergencies. physician-staffed helicopter emergency medical services (hems) are a well-established component of prehospital care in japan. however, there has been no report on hems and neurocritical care patients. we studied characteristics of neurocritical care patients who were transported by hems. we retrospectively evaluated neurocritical care patients who were brought to our emergency and critical care medical center (eccmc) by hems between january, and march, . we excluded patients in whom the outcome was unknown, those who were transported to other hospitals or between facilities. of the most important role of hems is rapid transportation of a flight medical team to the scene to provide immediate, lifesaving medical treatment. we found that half of patients admitted to our hospital by hems were neurocritical care patients. as proposed in the enls of neurocritical care society, hems is considered useful to allow neuro-emergency patients to receive the best care in the first hour. optic nerve sheath diameter (onsd) measurement using ocular ultrasound has been shown to accurately detect elevated intracranial pressure (icp), but does require specialized training. variations in the optimal onsd threshold for detection of elevated icp in the literature limits clinical utility, and may reflect heterogeneity in manual measurement techniques. our objective was to develop, and validate against expert measurement, an image-analysis algorithm for onsd measurement to facilitate standardization and ease of use of this technique. consecutive patients with acute brain injury admitted to the neurointensive care unit underwent ocular ultrasound with a multipurpose point-of-care ultrasound machine. a -second video was recorded from each eye in the axial plane and downloaded in dicom format. the onsd measurement algorithm was as follows. an average of images was calculated using non-overlapped segments of the image sequence. a line integral was performed to estimate the border of the region of interest (roi), the globe. the roi orientation and globe point of the segmented region were established, then a point mm posterior to the globe point identified. the onsd was measured at this point. manual onsd measurement was performed separately from the dicom videos by an expert blinded to the algorithm measurement. an intraclass coefficient (icc) was calculated for absolute agreement between highest onsd measured by the algorithm and expert manual measurement. a total of patients with acute brain injury underwent ocular ultrasound. the icc for absolute agreement between algorithm (median . , interquartile range . - . ) and manual expert (median . , . - . ) highest onsd measurement was . ( % confidence interval . - . ). an algorithm for automated measurement of onsd was developed and demonstrated good inter-rater agreement with expert measurement, although further refinement is required. automated measurement may help standardize and simplify a promising noninvasive bedside tool for the detection of elevated icp. after transition to electronic health record (ehr), transition to inpatient hospice required a separate encounter to account for change in insurance payer in our neuroicu. this negatively affected completed transitions and hence patient-centered care. the focus of this quality improvement project was to define the new process, improve outcomes, and identify further opportunities. the quality improvement method "plan-do-study-act" was employed for this work within a -bed neuro-icu at a large academic medical center. we assessed the current state (not enabling transition to inpatient hospice) and the desired state (enrollment in hospice during inpatient stay). a new process was created using an ehr discharge navigator, coordinating all relevant stakeholder groups (patient/caregiver, nurse, pharmacist, bed control, physician,). in addition, standard methodology for unit-based education, in-service, just-in-time training, and booster education was employed to identify process, outcome, and improvement opportunities. after rollout of the new discharge navigator, % of all patient-facing staff successfully completed the inpatient hospice training. process improvements lead to increase in palliative care consults by % ( to annually) and inpatient hospice discharges up to % ( to annually). furthermore, there was a statistically significant improvement in the vizient mortality index r = . , f( , ) = . , p < . and length of stay index r = . , f( , ) = . , p < . within the study population and period. ability to transfer patients to inpatient hospice is often limited and complicated. this study shows how employing standard quality improvement as well as education and implementation methods can result in improved process and outcome measures with sustainable success. opportunities remain in further analyzing and optimizing 'time to palliative care consult', 'time to admission to hospice and withdrawal of artificial support'. arnp and pa's are a rapidly growing part of the critical care workforce. proper selection among a pool of app candidates for the job is necessary to ensure the "right fit" and optimize patient safety. conventional interview techniques may not be adequate when selecting critical care app's. we hypothesized that use of a simulation center could be used to help select app candidates based on their critical thinking skills in conjunction with contemporary interviewing skills. from to , we performed conventional interviews for app's to staff critical care and neurocritical care patients. in we changed to an interview process consisting of the conventional interaction with the interviewee followed by simulation. after narrowing down the initial candidate pool, each was taken to the simulation center where they participated in a simulation of a decompensating patient. proctors were able to view the simulation in a separate room and direct the simulation mannequin. during this time proctors were able to evaluate the interviewee's patient interaction, assessment and interventions. an evaluation tool was to grade app candidates for their decision making skills, communication and thought. from to , we screened candidates before selecting for interviews and finally of those for simulation. over this timeframe, our center hired app's. comparing the ratio of screen applicants to employment was . and ratio of interviewed to hired candidates was . . these ratios show the competitive process and potential use of simulation in selecting apps. compared to the time period of applicants prior to simulation to after, retention went from to %, and disciplinary action for practice deficiencies went from % to %. the use of simulation based interviews for critical care app's in our institution improved retention and decreased the number of disciplinary actions compared to conventional interview methods. the contraindications for lumbar puncture (lp) in the setting of cerebral mass effect remain debatable. limited retrospective data advocate its potential safety. yet, high-quality guidelines specifically addressing this topic are not available. specific patient populations (post-instrumentation & immunosuppressed) may benefit from csf studies. we reviewed consecutive patients who underwent lp and cerebral imaging a week before or after lp from - . all individuals with evidence of brain herniation, a component of midline shift, or mass effect were included. all subjects received a low volume lp ( - cc of csf). there were patients with radiological increased icp. midline shift (average = mm) was present in patients. we also observed herniation: uncal (n= ), subfalcine (n= ), and a combination of both (n= ) , ventricular effacement (n= ) and cisternal compression with partial occlusion: quadrigeminal cistern (n= ), cerebellar-pontine-angle cistern (n= ), ambient cistern (n= ), crural cistern (n= ), prepontine cistern (n= ), suprasellar cistern (n= ), basal cistern (n= ), suprachiasmatic cistern (n= ), cisterna magna (n= ), interpeduncular cistern (n= ), medullary cistern (n= ). all patients tolerated the lp without complications. most survived a week after the procedure (n= , %). notably, four individuals deteriorated for reasons unrelated to the lp and expired within a week because of withdrawal of care. as brain compliance cannot yet be accurately determined radiologically, we believe anatomical involvement should drive decision-making regarding lp safety. our data suggest that a low volume lp ( - cc) might be safe in individuals with subfalcine herniation, midline mass effect < mm at foramen of monro level, and partial cisternal effacement. we believe that while lps might be safer in patients with supratentorial mass effect, individuals with posterior fossa involvement may tolerate it as well. these promising findings need further verification in larger sample populations. the importance of neurocritical care has recently been recognized in japan. however, to date, there has been no neurocritical care training program. we developed the neurocritical care hands-on seminar as a proposed training module, and here we report the satisfaction of participants. we prepared a post-course questionnaire about participants' degree of satisfaction. the main concept of our seminar was "how to maintain cerebral oxygen demand and supply balance." beginning with a short lecture about this concept, participants joined four hands-on scenarios: post-cardiac arrest syndrome (pcas), subarachnoid hemorrhage (sah), traumatic brain injury (tbi), and states epilepticus (se). in the pcas scenario, participants learned how to trouble shoot regarding targeted temperature management, especially in regard to the management of shivering. in the sah scenario, they learned about perioperative management, including delayed cerebral ischemia. in the tbi scenario, starting with actual insertion of an intracranial pressure (icp) monitor in the simulator, they learned about icp management through a scenario-based simulation. in the se scenario, they learned about se management, with actual continuous electroencephalogram monitoring. this seminar was held twice in . most participants were middle-aged intensivists; % were in their twenties ( / ), . % were in their thirties ( / ), . % were in their forties ( / ), and . % were in their fifties ( / ). most of the participating physicians were specialists in emergency or intensive care medicine ( . %; / ); nurses ( . %; / ) and a clinical engineer ( . %: / ) also participated. most participants ( . %; / ) were satisfied with the seminar, and almost all ( . %; / ) improved their self-confidence in the ability to carry out clinical practice in neurocritical care. we received positive, satisfied reactions from the japanese intensivists who participated in our seminar. for further improvement, we need to collect objective data to assess the utility of our neurocritical care hands-on seminar. lumbar puncture in the presence of mass effect? ciro ramos-estebanez uhcmc, case western reserve university/neurology, cleveland, ohio, usa introduction ) we propose an international consortium that would prospectively confirm the safety of low volume lumbar puncture (lp) in the presence of mass effect in selected scenarios. ) welcome peers and advisors to join the effort. lp may be clinically necessary in the presence of cerebral mass effect. while empirical antibiotic therapy is generally successful, specific groups such as post-instrumentation patients and immunosuppressed individuals may benefit from cerebrospinal fluid (csf) studies. in the absence of high-quality clinical recommendations, uncontrolled retrospective literature suggests that a small volume lp ( - cc) might be without complications in specific situations. nevertheless, the ethical principle of non-maleficence and the liability risk prevent clinicians from performing lps. in this scenario, an extended length of stay, poor outcomes, or a higher cost of care are legitimate concerns. synthesize an external peer reviewed methodology to maintain rigour and transparency. . seek appraisal, approval and endorsement of national and international quality improvement committees. . generate and assimilate the most current clinical evidence through: a. systematic review and meta-analysis. b. prospective randomized controlled clinical trial. . construct a protocol to inform decision making amongst healthcare and non-healthcare personnel. . dissemination and implementation. . schedule updates and/or revision. centers across the globe (north america = , south america= , europe= , and asia= ) have agreed to establish an lp consortium so far. retrospective analyses suggest low-volume lp's relative safety in the presence of increased icp. thereby, an expert consortium trusted with prospective verification would potentially benefit specific patient populations. patient centered decision making in the nccu requires family members understanding of their loved one's preferences and values as well as the complexities of their medical condition and treatments. family-centered care (fcc) is essential so that family members are actively involved in decision-making. stakeholders have reported their preference to receive prognostic information in smaller packets and recapitulated in different venues including rounds, bedside and care conferences. we examine implementation of a multimodal communication strategy on clinician utilization, family engagement and satisfaction in the nccu. an interdisciplinary team convened to develop a plan implementing a multimodal communication strategy. pre-implementation survey of clinicians (mds, nps, rns, etc.) and patient families was completed to determine the level of family engagement already in place in the nccu. four interventions were implemented: family communication boards were installed in patient rooms; family engagement pamphlets developed; a script and schedule for family care rounds was developed; nursing and provider staff were educated on inviting families to participate in patient care team rounds. family involvement on patient care rounds and family conferences was compared before and after the implementation of the best practice initiatives. additionally, pre and post implementation patient satisfaction survey results were also compared to evaluate the project's success. pre-implementation data was collected from october -november . sixty-one clinician surveys and forty family surveys found that family more consistently participated on daily rounds. baseline and postimplementation surveys demonstrated families feeling supported during the decision-making process. the implementation of a multimodal communication framework to achieve consistent family engagement and communication has led to an appreciable change in utilization by clinicians. its use is supported by consistent positive family attitudes towards communication and availability of information in the nccu. neurocritical care society undertook initiatives to integrate social media in member engagement activities and initiated a twitter journal club (#ncstjc) in with the first journal club conducted in february . articles were chosen by a subgroup of the communications committee in consultation with dr. eelco wijdicks, chief editor, neurocritical care journal. these articles were chosen based on their overall importance and the interest bound to generate amongst the journal club attendees. the journal club occurs bimonthy over an hour and is unique in the participation of the authors. the journal club is registered with healthcare hashtag project. each article chosen for #ncstjc is made available free to download weeks before and after the scheduled date for the journal club courts springer. analytics data on usage on article discussed in #ncstjc was obtained from sean beppler, editor, clinical medicine. between feb and apr , sessions were held with data available from . the ncc articles discussed had higher than average altmetric scores (measuring social media activity). these articles represented % of all ncc articles discussed on twitter since feb but . % of all tweets. total usage (number of times an article html page is accessed, or a pdf is downloaded ) was , ( mean , n= ) representing . % usage of all neurocritical care articles, a total of citations and downloads ( mean ) . the upper bound of the audience as assessed by the publisher was total of , for all articles (mean , per article) twitter is becoming an emerging platform for dissemination of information in medical education and academic activities. while the exact impact of the initiative on member engagement or outreach in enhancing journal impact or citations is hard to determine, we saw trends in enhanced engagement. neurostimulant medications have been studied in patients with traumatic brain injury, but few studies describe their use in patients with acute non-traumatic brain injury. our objective was to describe neurostimulant medication prescribing patterns, clinical response, and potential adverse effects in this patient population. retrospective database review of patients with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage who received amantadine or modafinil from december through june . neurostimulant selection, dosing regimen, and indication were recorded. patients were classified as responders if they met two of the following three criteria within days of neurostimulant initiation: ) increase in average daily gcs of greater than points, ) neurological improvement documented in provider progress notes, or ) increased participation in rehabilitation therapies documented in physical or occupational therapist progress notes. safety data included need for a new anxiolytic or sleep aid or seizure. continuous data are reported as median with interquartile range. eighty-eight patients received neurostimulants: intracerebral hemorrhage (n= ), ischemic stroke (n= ), subarachnoid hemorrhage (n= ). median age was ( - ) years and ( %) were male. amantadine (n= ), modafinil (n= ), or both (n= ) were initiated a median of ( - ) days after hospital admission. the median initial daily dose of amantadine and modafinil were mg and mg, respectively. reasons for initiation included somnolence ( %), not following commands ( %), lack of eye opening ( %), and low gcs ( %). forty ( %) patients were responders, occurring at a median of ( - ) days after neurostimulant initiation. twenty-three ( %) patients required new prescription of an anxiolytic or sleep aid. four ( %) patients developed seizure. neurostimulant medications may increase wakefulness and participation in rehabilitation therapies in patients with acute non-traumatic brain injury, with tolerable adverse effects. the role of neurostimulants in this population should be defined in prospective studies. difficulty in obtaining peripheral intravenous (piv) access often necessitates central venous access placement in many critically ill patients. central line placement exposes patients to potential complications such as pneumothorax, hemorrhage, catheter-related infection or deep venous thrombosis. ultrasound-guided piv placement has become common practice in emergency departments, but there is no systematic program to train and support routine use of ultrasound-guided piv access in icus. we have developed a systematic program to train and support icu nurses in becoming experts and clinical leaders in ultrasound-guided piv placement. we hypothesize that implementation of this program will increase nurse confidence and chances of successful piv placement subsequently decrease central line-related complications in -bed neurocritical care icus. we have developed a video didactic training program for the neurocritical care nursing staff. the program discusses use and maintenance of the ultrasound machine and guided-technique for piv placement including the short-and long-axis approaches. the training video is followed by a hands-on simulation session using mannequins. standardized-surveys are administered to nurses before training and then at and months post training. we are prospectively collecting data on nurse comfort level with ultrasound-guided piv placement, total iv attempts, patient central line associated bacteremia (clab) rates and total number of patient central line days. we will compare this data for months pre-and post program implementation. comparisons will be made using t-test and chi-square analyses or non-parametric equivalents depending on data distribution. central-line related complications are an important clinical problem in all icus. we have developed and implemented a systematic training program to support nursing-led ultrasound-guided piv placement. we will determine if this program reduces the overall number of central lines placed, duration of indwelling central lines, and clab rates in a neurocritical care, and subsequently expand to additional icus and beyond. ultrasound measurement of optic nerve sheath diameter (onsd) is a sensitive and specific non-invasive ultrasonographers. despite clinical applications in the icu, er and outpatient settings, neurology residents lack experience and training. the aim of our project was to provide neurology residents with foundational skills in ocular ultrasound and onsd measurement. we designed a two-part workshop for neurology residents covering ultrasound basics, measurement of onsd, and ultrasound appearance of papilledema. workshop was a minute lecture and demonstration followed by minutes of hands-on practice. two weeks later, workshop included additional minutes of practice to consolidate learning. the practical portions were facilitated by emergency medicine attendings and residents with experience in performing ocular ultrasounds. neurology residents tracked the number of practice ultrasounds performed. they also completed anonymous pre-and posttests to assess their knowledge of ocular ultrasound and their comfort level and likelihood to perform future procedures using a -point likert scale. prior to the workshop, the majority ( / ) of neurology trainees had never performed an ocular ultrasound. one ( / ) was able to answer two basic questions about the procedure correctly, which increased to % on the posttest (n= ). trainees performed an average of ultrasounds total during the workshops. resident self-assessment of comfort performing the procedure increased from a median of "very uncomfortable" to "moderately comfortable" on the -point likert scale (p= . ). resident likelihood to perform the procedure in the future increased from a median of "very unlikely" to "moderately likely" on the -point likert scale (p= . ). this session successfully increased basic knowledge, comfort, and likelihood to perform ocular ultrasound among neurology residents. future directions include follow-up to gauge magnitude of practice changes and accuracy of procedural skills. reaching patients by telephone is a common method of assessing functional outcome, cognitive function, and quality of life after hospital discharge. however, when patients do not answer the phone, missing data creates bias and warrants strategies to increase follow-up rates. we hypothesized that we would have less follow up with patients discharged to long-term care facilities and sought to examine other potential sources of lost data. between / and / , we identified all patients admitted to the university of cincinnati neuroscience intensive care unit (nsicu). we excluded those with recurrent admissions, boarders, and those admitted < hours or for uncomplicated post-op care. telephone follow-up was attempted for each patient. univariate analysis was used to identify associations with patients who did not answer the phone. critically-ill patients were included. average age was . +/- . and % were men. the average hospital length-of-stay was . +/- . days. major diagnoses were: ischemic stroke ( %), intracerebral hemorrhage ( %), traumatic brain injury ( %), seizures/status epilepticus ( %) and subarachnoid hemorrhage ( %). ( %) died in the hospital; ( %) died by follow-up. survivors were assessed . +/- . days following admission. calls were answered, were not. there were no associations between rate of answered calls and age, gender, race, hospital length-of-stay, diagnosis, or hospital disposition. there were no differences in between morning vs. afternoon calls. only the number of attempts differed: the probability of an answered call was % on the first attempt but declined to % by the third attempt (or . ; p< . ). our outcome assessment strategy captured data on % of neurocritically ill patients. those who answer the phone are most likely to answer with the first call; the probability of a patient answering after a second phone call may not justify resources needed to continue calling these patients. posterior reversible encephalopathy syndrome (pres) typically presents with vasogenic edema on neuroimaging. a subset of patient, however, can have "atypical findings" including restricted diffusion and intracranial hemorrhage. these atypical findings all suggest acute vascular injury, and may mark a distinct pathophysiological subtype of pres. however, it is unknown whether atypical imaging findings are associated with differences in precipitating factors or outcome. patients with evidence of restricted diffusion, frank hematoma, microhemorrhage, or subarachnoid hemorrhage were classified as having atypical imaging findings. the demographics, risk factors, clinical outcomes, and degree of vasogenic edema for patients with typical (n = ) vs atypical pres findings of vascular injury (n = ) were analyzed. patients with atypical pres had a longer hospital stay ( . vs . days; p = . ) and were less likely to be discharged home ( . % vs . %; p = . ). severity of vasogenic edema (graded using a standardized radiologic scale) was also higher in patients with atypical imaging findings (severe edema: . % vs . %; p = . ). restricted diffusion and hemorrhage are features of acute vascular injury that may mark a unique pathophysiological subtype of pres. pres patients with these atypical imaging features had longer hospital stays, greater degree of vasogenic edema, and were less likely to be discharged home. this may be due to the fact that bleeding and infarction lead to irreversible brain injury, prolonging hospital stay and contributing to overall disability. in , deaths occurred in the neuro-oncologic critical care unit (nccu). the impact of this event is significant for patients, families, and the staff that care for them. brain and spinal pathology can be incredibly debilitating causing a rapid and impromptu decline of the patient's status. in order to better support patients, family, and staff throughout the dying process, the nccu staff created formalized endof-life care interventions. these interventions include educational pieces and supportive approaches to aid all involved through the dying process. several interventions were created to help transition the family members during the dying process. these include the creation of: dnr-cc closet, homemade blankets, condolence cards, hygiene bags, educational packets, word clouds, and aromatherapies and massage items. once the patient's code status is changed to comfort care, a blanket is given to the patient. family members are provided with a bag of toiletries for those that remain at bedside. education on the dying process are given to family members. multidisciplinary resources are provided, such as religious support focused on patient/family beliefs, palliative care for symptom management, and dietary provision of light snacks to the family. education for the physicians, nurse practitioners, nurses, and patient care associates was provided for those who wished to attend to further understand this end of life care program. a item tool was created to collect before and after data on staff satisfaction and comfort with the end of life process. results from this process are currently in process. creating specific end-of-life care interventions for the nccu have enabled staff to better care for patients and families. through the creation of the interventions and utilization of the dnr-cc closet, this unit has been able to better provide comprehensive education and supportive pieces to patients and family members during such a difficult time. delirium is a neuropsychiatric syndrome, characterized by disturbance in awareness, with reduced ability to sustain attention, impaired cognition, perception, tends to fluctuate in severity during the day; in critical care is associated with longer stay and increase mortality. this study aimed to determine the incidence, prevalence, predictors, risk factors and outcomes of delirium in critically ill adult. a historical cohort study was conducted in adult patients hospitalized in a polyvalent icu from january until december . delirium was diagnosed using cam-icu. a bivariate and multivariable risk were analyzed and presented as odds ratio (or) and % confidence interval (ci). a total of patients were enroll. delirium developed in patients.the incidence was . %. three independent predictors for delirium were identified, sedation (or ( % ci, p < , ); alcohol dependence (or , ; %ci, p < , ) and glasgow coma scale < (or , ; % ci, p < , ). delirious patients had a significantly apache ii ( ( - ) vs ( - ), p < . ), higher sofa, ( ( - ) vs ( - ), p< . ) and higher saps iii ( ( - ) vs ( - ), p< . ). other risk factors were hyperlactatemia ( p< . ), and hypotension (map< mmhg),(p< . ). patients required prolonged mechanical ventilation, p< . ), and prolonged icu-hospital stay. the incidence of delirium in the period from january to december , was . % in a polyvalent intensive care unit. exposure to sedative medications, alcohol dependence, and decrease glasgow coma scale minor are independent predictors for the development of delirium. similarly, the icu stay was longer in the group that developed delirium; however, mortality was not affected by the presence of this condition. it has been previously reported that the course of hsv- in the cns is significantly more benign that hsv- , and that it rarely causes encephalitis or significant morbidity in immunocompetent adults. the aim of our study was to investigate the claim that hsv- cns infections are typically benign, and to assess for predictors of poor outcome in those patients who do suffer significant morbidity from hsv- cns infections. restrospective chart reviews were completed on patients with a positive hsv pcr at our institution from july until july . patients with a hsv pcr positive for hsv- were selected in our analysis. multiple clinical variables were evaluated in these patients and we assessed outcome in the patient population, dichotomizing outcome into two categories at the time of discharge: good outcome defined as home or inpatient rehabilitation versus those with poor outcome defined as death, hospice, or placement in a long term acute care facility. patients with hsv- positive pcrs were identified. their charts were evaluated for demographics, laboratory values (serum and csf), imaging results, and outcome. there were patients with poor outcomes. it was noted that they were all female, their mean age was . (vs . in the good outcome group) and two of the three were immunocompromised ( % vs % in the good outcome group). statistical analysis was performed however due to the small sample size no statistical significance was found. however, age, sex, clinical presentation consistent with encephalitis and immune status seemed to have a trend towards poor outcome in this pilot study. future study with larger sample size is warrented to further assess this trend, as hsv- may not be as benign as previously reported. there is a high prevalence of non-traumatic illness in patients presenting to emergency departments as trauma team activations (tta). we sought to determine the prevalence of neurologic emergencies within a population of patients receiving a tta. this was a retrospective review of prospectively-collected registry data capturing all ttas in a highvolume, urban, academic level i trauma center. records from june through june were reviewed to identify patients found to have a diagnosis of ischemic stroke, intracerebral hemorrhage (ich), subarachnoid hemorrhage (sah) or status epilepticus. further demographic, clinical, and outcomes data was then abstracted from the electronic medical record. a proportion of abstracted charts were reviewed by an independent reviewer to ensure data quality. there were , trauma activations in the registry during the study period. patients ( . %) were found to have a nontraumatic neurologic emergency and were included in the analysis. of these patients, there were ischemic stroke ( %), ich ( %), sah ( %), and status epilepticus ( %) patients. the mean age was , and patients ( %) were male. the mean gcs on presentation was . about half of these patients ( %) were intubated in the emergency department. all patients received a head ct scan. patients ( %) received intravenous thrombolysis. neurologic emergencies such as ischemic stroke, ich, sah or status epilepticus were common diagnoses in this population of trauma activation patients. clinicians caring for patients in these settings must maintain a high index of suspicion for non-traumatic illnesses, and act quickly to mobilize appropriate resources when a diagnosis is made to avoid delays in care. further research is needed to examine ways to improve both time to diagnosis and quality of care in this patient population. formalized communication strategies decrease post-traumatic stress disorder (ptsd) symptoms in caregivers in the intensive care unit (icu). in one study, only % of family meetings met all shared decision-making criteria. however, much of the research has focused on family meetings, ignoring less formalized communication. the decision maker (patient or caregiver) was interviewed for all patients admitted to the medical (micu), neurosciences (nsicu), surgical (sicu), and cardiothoracic icu (cticu) for greater than hours. subjects who stated significant decisions had been made were asked to report on aspects of shared decision making on a -point scale. they identified the lead provider, who was subsequently approached to complete the same questionnaire. overall, eligible decision makers were identified, ( %) in the micu, ( %) in the nsicu, ( %) in the sicu, and ( %) in the cticu. of these, ( %) were unable to be contacted, ( %) had insufficient english, and ( %) reported no decisions made, with ( %) enrolled. nineteen ( %) provider interviews were completed. topics most reported covered "well" or "thoroughly" by caregivers were assessment of understanding ( , %) and the nature of the decision ( , %), while those least covered were need for input from others ( , %) and the context of the decision ( , %). topics reported most covered by providers were the nature of the decision ( , %) and opinions about the treatment decision ( , %), while those least covered were patient's values and preferences ( , %) and their preferred role in decision making ( , %). eighteen ( %) caregivers and ( %) providers described all topics covered "well" or "thoroughly." these results demonstrate differences in perception of shared decision making by decision makers and providers. further qualitative investigation is underway to elucidate the nature of these inconsistencies. organ donation is a life-saving medical intervention. the effect of race, insurance and economic status on organ donation and recipients has not been studied at a national level. in our study, we analyzed nationwide in-patient (nis) database of years - to select donors and recipients. baseline demographics (i.e., age, gender, race), insurance status and socio-economic status was compared between two groups. we identified donors (n= ) and recipients (n= ) from - . recipients were significantly older (mean age ± sd, . ± . vs . ± . , p< . ). donors had higher ( . % vs . %, p< . ) proportion of women compared to recipients. both groups had a higher proportion of whites compared to other races ( % and . % respectively). insured patients were largely represented in both groups with private insurance predominating in donors ( %) and medicare in recipients ( . %). interestingly, self pay represented . % of donors but only . % of recipients. race, insurance and socioeconomic status seem to be evenly similarly represented in donors and recipients. interestingly self pay insurance has a higher distribution among donors than recipients. central line-associated bloodstream infections (clabsis) are a common health care associated infection accounting for , infections annually in the intensive care and acute care areas (cdc, ). according to the center for disease control, clabsis result in thousands of deaths yearly and upwards of billions of health care dollars spent on preventable hospital acquired infections. intensive care patients, especially the neurocritical care population, have an increased need for centrally placed catheters related to inadequacy of peripheral access, need for caustic iv medications, and fluid resuscitation. our neuroicu's goal was to decrease utilization and subsequently reduce number of clabsis. in february , we initiated a patient-centered quality improvement effort with this goal in mind. the neuroicu clinical nurse leaders conducted rounds daily to evaluate the necessity and management of central lines. the neurocritical care team and clinical nurse leaders collaborated in exploring alternatives if central lines were present. in addition to daily rounding, clabsi bundles based on cdc guidelines for clabsi prevention were initiated. our neuroicu developed checklist "buster cards" in september of , prompting staff to the bundle interventions. the intent of the cards was to enhance nurse to nurse dialogue of bundle elements. the cards were evaluated monthly for trends in care. from august -june , there was a % reduction in neuroicu utilization of central lines. in addition, the mean number of clabsis per month decreased from . to . . trending of unit buster cards did not show care variances during this time period. implementing daily clinical nurse leader rounds with enhanced team communication significantly reduced the neuroicu's utilization of central lines and thereby decreased the rate of clabsis. percutaneous dilatational tracheostomy (pdt) is one of the most commonly performed procedures on critically ill patients. many studies showed the safety and feasibility of pdt, but there is limited data of pdt in neurocritical care units. we have described our experience of pdt performed by neurointensivist. pdts were performed by neurointensivists at bedside using the griggs guide wire dilating forceps technique. to confirm a secure puncture site, pdt was done under fiberoptic bronchoscopic guidance. from september to may , procedural data were prospectively collected. the patients' demographic and clinical characteristics were retrospectively reviewed. we analyzed immediate complications of pdt as the primary outcome. pdts were performed for patients; the mean age was . years, ( . %) were male, and mean acute physiology and chronic health evaluation ii score was . ± . . overall, the procedural success rate was % and the mean procedural time was . ± . min. periprocedural complications occurred in patients; had minor bleeding and had tracheal ring fracture. there were no serious periprocedural complications of pdt. from our experience, pdt performed by neurointensivist was safe and feasible and was implemented without serious complications. the neurocritical care unit (nccu) is a fast paced setting with a multitude of providers and team members requiring optimal communication. it is also a high cost/high utilization environment, dictating the need for patients to be moved thru appropriate levels of care efficiently. all of this must be accomplished while providing support and opportunity for collaboration and decision making on the part of the patient/ family unit. there is great discussion in the case management world about the benefits of a unit based verses service based case management model. we looked at outcomes following the implementation of a unit based case manager in the nccu. a dedicated case manager (cm) was implemented in the nccu to maximize assessment, advocacy, communication, education, identification of resources, and facilitation of services. processes to support maximal contributions were created.interventions included use of a discharge planning worksheet, implementation of a morning huddle, and space for the case manager to be physically available on the unit. los of patients discharged from nccu decreased from . to . . alos for patients that passed thru the nccu during their hospitalization decreased from . days to . . there was a % increase in discharges from nccu from to . average time from admission to cm assessment decreased from hours to . hours. progress notes indicating intervention and/or communication of the plan increased from to . staff questionnaire indicated increased awareness of los and dc plan needs. in this midwestern, academic medical center, integrating a dedicated, unit based cm resulted in improved los, increased discharges and improved staff awareness of dc plans. high throughput genotyping technologies and large collaborative consortia have revolutionized the field of medical genetics. open data access is the final barrier to be overcome to capitalize fully on the opportunities currently available in stroke genetics research. the international stroke genetics consortium (isgc) has created the cerebrovascular disease knowledge portal (cdkp), a comprehensive web-based resource to explore and freely access genetic data related to cerebrovascular diseases. funded by the nih, the cdkp has been jointly developed by the isgc and the american heart association (aha) institute for precision cardiovascular medicine. the cdkp seeks to democratize access to genomic data and potentiate stroke genomics research by providing open access to genetic, phenotypic and imaging data on stroke. within the cdkp, data are aggregated, integrated, and harmonized according to a pre-specified standardized pipeline. any institution or investigator working with stroke genomic data is welcome to deposit their data or use available data. the cdkp houses two types of data, each meeting different regulatory and analytical needs: summary level data and individual level data. the cdkp offers three main features: ( ) a web-based graphical user interphase that allows the exploration of stroke genomics information through a wide menu of integrated tools for analysis and data visualization; ( ) a repository of full sets of genome-wide summary statistics produced by published landmark studies in the field, available with a single mouse click ; and ( ) a repository of individual level data, accessible through a secure cloud working space provided by the aha platform for precision medicine. the cdkp can be accessed at www.cerebrovascularportal.org. the cdkp advances the isgc's goal of liberal data sharing in stroke genomics and other areas of cardiovascular research that may benefit from genomic analyses. in the future, phenotypic datasets can be added to further enrich sharing of non-genetic data as well. hyperosmolar therapy using hypertonic saline is common in patients admitted to the neurocritical care unit (nccu) for the management of different type of cytogenic cerebral edema or increased intracranial pressure (icp). vancomycin is commonly prescribed in nccu as empiric antimicrobial therapy. the purpose of the study is to evaluate the effects of hypertonic saline therapy on the pharmacokinetic parameters of vancomycin in critically ill patients with generalized or compartmental icp. this was a retrospective, observational study of adult patient consecutively admitted in the nccu between february and february who received hypertonic saline ( % sodium chloride) and vancomycin dosing protocol managed by the pharmacist. patients with serum creatinine > . mg/dl were excluded from the study. the estimation of vancomycin trough levels was done by using published pharmacokinetic equations and then compared to the measured trough levels with the paired t test. the study protocol was approved by our institutional review board. of forty-four patients who met the inclusion criteria, twenty-one patients ( . %) were diagnosed with intracerebral hemorrhage, nine ( . %) ischemic stroke, seven ( . %) subarachnoid hemorrhage, four ( %) subdural hemorrhage, two with brain tumors, and one patient with chiari malformation. the mean dosing regimen was . ± . mg/kg every ( - ) h. the mean measured trough level was lower than the predicted trough level ( ± . vs. . ± . mcg/ml; p < . ). the mean serum sodium level was ± meq/l and the mean serum osmolality was ± mosm/kg. critically ill patients with cerebral edema or high icp who were treated with hypertonic saline achieved a subtherapeutic vancomycin level that may lead to lower through level and possibly poor clinical response. further research is warranted to evaluate the clinical response of vancomycin in this patient population. unnecessary telestroke activations are costly to emergency departments (ed), telestroke providers, and patients. therefore it is important that ed nurses are well trained to effectively recognize stroke symptoms, and decrease the rate of false-positive stroke code activations. the nursing-driven acute stroke care (nas-care) study aims to determine if implementing a standardized ed stroke program decreases door-to-needle times in emergency departments utilizing telemedicine. the nas-care intervention consists of ed nursing education including mock codes, nihss certification, and implementation of a standardized flow sheet. in this interim analysis from the first (of ) nas-care study hospitals, we examined ed admission and discharge diagnoses at each site for months of blinded baseline data collection ("control") and months after standardized training ("intervention"). false-positive encounters were defined as stroke code activations for which the patient diagnosis on leaving the ed was not stroke. although hospitals trended toward a reduction in false-positive stroke code activations after implementation of the standardized stroke education, mock stroke codes, and flow sheet, none of the values were statistically significant. further research is needed to determine whether intensive ed nursing education can improve telestroke resource utilization. pharmacist-driven intravenous (iv) to oral (po) conversion protocols result in greater compliance, improved cost-savings, and better patient outcomes related to length of stay, re-admission, and duration of intravenous therapy. this study aims to determine the cost-savings and patient impacts of such a conversion protocol for anti-epileptic drugs (aeds) including lacosamide, levetiracetam, phenytoin, and valproic acid. a retrospective, observational phase was conducted to determine usual practice patterns concerning conversion to oral therapy between / / and / / . the conversion protocol was approved in december and implemented in january . a second retrospective phase observed conversion practices beginning / / and ending / / . length of intravenous and oral therapy, date eligible for conversion, and date of conversion were recorded. hospital acquisition costs were utilized for medication expenditure calculations. this information was used to determine financial impact of the protocol and is presented as descriptive endpoints. adverse drug events were collected via an institutional incident reporting system. a total of encounters were identified, resulting in encounters in the pre-cohort and postcohort encounters. looking at the pre and post cohorts respectively, both cohorts had similar median lengths of stay ( days vs. days), -day readmission rates ( . % vs . %), and rates of conversion from oral back to intravenous therapy ( . % vs . %). the median length of intravenous therapy was days prior to protocol implementation and decreased to days in the post-cohort. the average cost per day of aed therapy was $ . in the pre-cohort but decreased to $ . in the post-cohort. median missed opportunity costs, defined as the cost savings if conversion occurred at the earliest possible date, also decreased between the cohorts from $ . to $ . . pharmacist involvement in aed conversion had a positive financial impact without compromising patient care. the national institute of neurological disorders and stroke (ninds) established the nih strokenet to facilitate the rapid initiation and efficient implementation of multi-center exploratory and confirmatory clinical trials focused on promising interventions in stroke prevention, treatment, and recovery. strokenet was initiated in the fall , and involves over hospitals across the us. the network is anchored by regional coordinating centers (rccs), along with the national coordinating center (ncc) at the university of cincinnati and national data management center (ndmc) at the medical university of south carolina, as well as active participation by the ninds. one of the primary goals of the strokenet is to serve as the primary infrastructure for conducting stroke clinical trials and pipeline for new potential treatments. to maximize the impact of nih strokenet, it is important for the larger community of stroke researchers and clinicians, including the neurocritical care specialists, to know its structure and the process and timeline by which stroke trials are developed and implemented. since the inception of the network, * proposal concepts have been submitted to the strokenet and are in different development stages. among those evaluated to obtain ninds permission to submit a grant application, have submitted and are in the process. every application has been prepared and submitted for peer review within months of the ninds permission. two* funded strokenet trials are now underway with brisk enrollment rates, and another is awaiting study initiation. (*as of abstract submission date) the nih strokenet has become a stable infrastructure and offers several distinct advantages to developing competitive clinical trial proposals, including scientific input from the strokenet working groups, comprehensive feasibility assessments (including site enthusiasm and patient availability), assistance with grant budgeting, and other requirements for grant submission that are likely to help refine and improve the application. the modified early warning score (mews) is a physiological scoring system, validated in adult medicalsought to determine the value of mews to identify clinical deterioration or occurrence of sepsis in neuroicu patients. we retrospectively reviewed all patients admitted to the neurological intermediate care unit (imc) or neuroicu of a large tertiary care center from / presentation/during admission. baseline characteristics, diagnoses, physiologic parameters, infections, treatment with antibiotics, neurological worsening and mortality were abstracted from the electronic medical record. outcomes were defined as escalation of care and discovery of a new infection or sepsis. of p were male. % were intubated, and in-hospital mortality was % (versus % for all admissions). ( %) were already treated with antibiotics for a known infec diagnosed in %. in reaction to the elevated mews score, antibiotics were added or broadened in %, and level of care was escalated in . % from imc to icu. in . %, there was neurological worsening, most frequently associated with increasing cerebral edema ( %) and midline shift/herniation ( %). the mews score is not a valuable screening tool in the neuroicu population. it preferentially was triggered in known high acuity patients with ongoing or present infections with no change of management in the majority of patients. while associated with high mortality, its ability to indicate new infections or sepsis was poor. in out of patients, the mews score was associated with neurological worsening known at that time of the score. other screening tools should be explored for early warning in the neuroicu. introduction: it is challenging to maintain neurosciences critical care nursing expertise in an environment of a rapidly expanding knowledge, changing evidence-based practices and technological advancements. to address the needs for neuroscience nursing expertise in a mixed critical care unit, our institution developed a core group of nurses, known as "neuro champions", who have additional training and expertise in neurocritical care. methods: nursing participation was voluntary and recruitment was via unit-wide announcements. the goal was to improve patient care by developing a core group of nurses who serve as resources and educators for all things neurosciences related. to develop content expertise, the nurses initially completed a set curriculum including: neuro anatomy and pathophysiology, cerebral hemodynamics and multimodal monitoring, pupillometry, eeg interpretation, temperature management, evds, and quality indicators. bi-monthly meetings continued ongoing education, with content including clinical case studies and review of processes and protocols. additionally, beds staffed by neuro champions were designated as critical neurological care unit ("cncu") beds to co-localize the highest acuity neurosciences patients. the neuro champions are responsible for educating and sharing neuro related practices with the entire icu nursing staff. results: as a result of the implementation of the neuro champion role, our icu has benefited from: ) dedicated co-localized beds for the highest acuity neuro patients; ) increased number of enls certified nurses; ) improved collaboration between the medical team and nurses; ) promoting care uniformity to maintain comprehensive stroke center certification; ) integration of multimodal monitoring advancements, all of which supports advances in patient care and research. conclusions: the neuro champion role has provided a platform for neurosciences-specific nursing expertise in a mixed critical care unit and has facilitated education dissemination to the entire staff via a core group of nurses. this expanded knowledge has improved the care of the neurologically critically ill patients. the rate of cerebrovascular complications in patients treated with extracorporeal membrane oxygenation (ecmo) is about %. transcranial doppler (tcd) can be used to noninvasively monitor cerebral blood flow velocities (cbfvs) in patients undergoing ecmo. the aim of this study is to describe tcd-cbfv patterns in patients undergoing venovenous (vv) and venoarterial (va) ecmo. a neuro-surveillance protocol among ecmo patients was initiated as part of a quality improvement project at our institution. daily neurological exam, daily tcd, brain-ct on days one and three and -hr continuous eeg were performed in all patients undergoing vv and va-ecmo. demographics, clinical and imaging data were collected for the duration of ecmo support. cbfvs, lindegaard ratios (lr), pulsatility index (pi) and resistance index (ri) on tcd were collected. total of patients were included in the study [ female ( %); caucasians ( %)]. mean age was years. ( %) patients received va-ecmo; ( %) vv-ecmo; ( . %) received both va and vv-ecmo. median days on ecmo was days. median number of tcd studies performed was (mean, . we observed an overall pattern of low-normal flow cbfvs and reduced pulsatility in patients on va-ecmo. nurse practitioner (np) and physician assistant (pa) roles continue to expand in the critical care setting. single and multisite studies have examined various aspects of app practice, but none have focused on role implementation within the neurologic critical care unit (nccu). the purpose of this study was to obtain foundational knowledge about how nccu apps are implementing the role nationally this was a voluntary, cross-sectional, descriptive study of nurse practitioners (np) and physician assistant (pa) practicing in the us. apps were invited to participate in this voluntary, item survey. distribution occurred initially through email inquiry via multidisciplinary, professional organization listservs (ncs, aacn, aann) followed by snowball effect circulation. enrollment occurred from march to june . data was collected in redcap and analyzed using spss with descriptive statistics for demographic, institutional, practice, role characteristics of the sample and for each survey data element app participants completed the survey: % np, % pa, % other. the majority of respondents were master's prepared ( . %) acute care trained, ( . %) and hospital employed ( . %). participants were either early in their career ( . % - years as app) or experienced ( . % > years). % work in a direct care role with % providing total care for their patients with an average daily caseload of . + . patients. % of providers believed - patients was a reasonable caseload for total care. in addition to the nccu, % of participants care for patients in step-down or emergency department ( %) with % routinely bilingl for their work. this study is the first to provide information regarding how ncc apps are implementing the role in the united states. this study provides benchmarking data which may guide future research with this population as well as serve as a template for evaluation of other app specialty roles. despite advances in treatment, the median survival for high grade gliomas (hgg) remains poor. there is a growing body of research showing that palliative care improves quality of life and survival in patients with advanced malignancies. we sought to examine our own practices in the neurologic intensive care unit (nicu) regarding palliative care consultation in this population. we hypothesized that the incidence of palliative care consultation is low and associated with a clarification of patient's wishes, measured by a change in code status. we conducted a retrospective cohort review of patients with previously diagnosed hgg admitted to the nicu from - with a length of stay (los) greater than hours. the primary outcome was the incidence of patients with an advanced directive or inpatient palliative care consult (pcc). secondary outcomes included intensive care unit los, change in code status and location of death. patients were identified with hgg. the mean age was . years ( - years), % were male, % were white. zero patients were admitted with an advanced directive on admission. pcc was obtained in patients ( %). pcc was associated with increased nicu stay ( hrs vs hrs p= . ), a change in code status to do not resuscitate ( % vs % p= . ), and an increased likelihood to not die in the hospital ( % vs % p= . ). at our large academic tertiary care facility intensivists underutilize palliative care services for hgg patients. patients with fatal brain tumors are not having end of life discussions prior to admission, indicating a need for early palliative care intervention. patients are six times more likely to change their code status and there is a trend towards dying outside of the hospital if they receive a palliative care consult. hypertonic saline (hts), a hyperosmolar solution, is typically administered using a central venous catheter (cvc) due to concerns of extravasation, but a cvc is rarely readily available. in emergent situations, intraosseous (io) access is used when peripheral intravenous access is not available. existing literature does not address the administration of hypertonic saline using io access for adult patients with brain injury. the administration of hts is often delayed due to the time taken to obtain a central venous access. insertion of an io needle is typically much faster than a cvc. we report the safety and tolerability of hts using io route. a prospective pilot study on the safety and tolerability of % hts via io is currently underway. data on local complications at the site of injection, pain during insertion and during infusion, and serial serum sodium levels were collected. additionally, we report a case of successful administration of . % hts using the io route. preliminary data demonstrated that % hts was well-tolerated, with no reports of severe pain, infections, extravasation, soft tissue injury or local infectious complications in our sample of patients with brain injury. indications for use of hypertonic saline included patients with cerebral edema and mass effect from intracerebral hemorrhage. an appropriate rise of serum sodium levels by approximately mmol/l/hr in was observed. in the case where ml of . % hts, no local complications were observed and serum sodium levels rose appropriately. administration of hts using io route appears to be safe and feasible. utilizing io access for urgent administration of hts may reduce the lag time to administration of the initial bolus, reduce the need for emergent placement or eliminate the placement of cvc in certain cases. optic nerve sheath diameter (onsd) measurement is an emerging bedside tool to assess intracranial pressure (icp) non-invasively in brain injury patients. multiple studies demonstrate onsd width from . mm to . mm correspond to an external ventricular device (evd)-measured icp > mmhg. we sought to create a low cost, -d constructed, re-usable osnd teaching model to train neurology, neurosurgery, and critical care advanced practice providers and physicians. we searched the national library of medicine using terms "optic nerve sheath diameter ultrasound" with combinations of "simulation" and "model." the literature was used in conjunction with a human non-contrast head ct head model to make an eye ball model which was then tested in our simulation center and compared to a live human model. we identified articles, of which were associated with models and two with simulation. one gelatin model was reported, upon which we based our initial design. we could not validate the visual findings of this model. however, following construction of multiple beta models, the design most representative of human eye anatomy was a globe made of ballistics gel with either a mm, mm or mm -d printed "optic nerve" attached to a platform composed of ballistics gel and psyllium powder with a hollowed out core for ultrasound gel the globe rests upon. this model was taught to learners at a continuing medical education event prior to teaching osnd on a live human model. a -d printed skull from ct head data is being created to incorporate this model. a simple -d ballistic onsd model allows learners to learn proper hand placement, basic landmarks, onsd measurement, and practice proper pressure on human eyes. this model can be replicated and utilized in a sustainable fashion given that the globe and platform are composed of ballistics gel. pressure measurements using pressure guide wires is an invaluable diagnostic tool in the management of many endovascular revascularization therapies. its role is well established in coronary artery disease management such as use of fractional flow reserve (ffr) as a standard diagnostic tool to determine need for stenting, angioplasty or bypass. renal fractional flow reserve remains an integral physiologic parameter used in endovascular revascularization therapy of renal artery stenosis. despite the wide spread use of pressure wires in endovascular therapies, its application in the management of cerebral venous diseases remains vastly unexplored. we sought to evaluate the safety and applicability of pressure guide wires in several cerebral venous diseases. patients undergoing diagnostic angiography for possible venous outflow obstruction had pressures measured by pressure guide wires (volcano verrata® or prestige primewire®) across the following vessels: superior sagittal sinus, torcula, right and left transverse sinus, right and left sigmoid sinus, and right and left internal jugular vein. venous pressures were also collected from patients undergoing venous thrombectomy, stenting, or an arteriovenous malformation embolization (avm). five patients who underwent diagnostic angiography for pseudotumor cerebri showed no major variability in their pressures across the cerebral venous architecture which was confirmed by lack of stenosis or thrombi on intravascular ultrasound (ivus). four patients had a pressure difference above which was suggestive of a stenosis and later confirmed by ivus. patients undergoing pressure measurements that had evidence of stenosis or thrombosis by ivus showed improvement in pressure gradients post stenting or thrombectomy. no variability in pressure gradients were noted in a patient that underwent avm embolization. pressure measurements using pressure guide wires can improve diagnostic accuracy and guide management of several diseases of the cerebral venous system. further studies are necessary to understand the applicability of this approach in the management of venous disease. monitoring metrics is imperative for quality assurance and ongoing improvement in a developing clinical unit. a new neurocritical care unit (nccu), specializing in the treatment of critically ill, neurologicallyinjured patients opened in july . this study examined quality metrics that correlate with the development and growth of a neurocritical care program. data from patients with principle diagnoses of ischemic stroke (isc), subarachnoid (sah) or intracerebral (ich) hemorrhage, seizure, or brain tumor, admitted to nccu in and were used in the analyses. quality metrics included overall and individual complication rates per , patient days of pneumonia, venous thromboembolism, pulmonary embolism, sepsis, septic shock, pulmonary edema, gastrointestinal bleeding, and catheter associated urinary tract infection, as well as hospital mortality and length of stay (los). chi-squared and mann-whitney tests and poisson regression were used to compare metrics between and . patient volumes increased by . % ( to ) from to . the overall complication rate declined significantly from . to . per , patient days (p= . ). the highest complication rate in and was pneumonia ( . and . per , patient days, respectively). the proportion of patients who expired decreased from . % (n= ) in to . % (n= ) in , though not significantly (p= . ). there were no significant differences in los among patients with isc, brain tumor or seizure. however, those with sah or ich had significantly shorter stays in (median [interquartile range] = . [ . , . ]) versus ( . [ . , . ]) (p= . ). data suggest that over the initial -year period, complication rates among patients in the nccu improved. los did increase for hemorrhage patients; however, this may be related to greater severity of illness in the patient population over time. further analyses will be conducted to account for severity and other factors. delirium is a frequently seen but underestimated problem in critical care settings. delirium screening is considered time consuming, which is one of the factors leading to under diagnosis. the cam-icu screening tool for delirium has been validated in medical and surgical icus. among neurological patients, it has been validated in stroke patients but not in general neurocritical care population. this study was designed to validate cam-icu flow sheet in neurointensive care unit. a prospective cohort study was conducted in a bed neurointensive care unit of a university hospital. patients meeting the inclusion criteria (all nicu patients) and exclusion criteria (comatosed, aphasic, psychotic, prior diagnosis of neurocognitive disease, persistently vegetative state, sedated) were screened for delirium by ( ) a nurse practitioner using confusion assessment method (cam-icu) and ( ) a physician reference rator using delirium screening criteria in diagnostic and statistical manual of mental disorders- . assessments were done daily monday through friday for the icu stay. paired assessments were done less than hours apart. the study enrolled patients ( male, female). daily assessments were done. mean age of the patients was . and mean sap score was . admitting diagnoses were ich ( ), sah ( ), ischemic stroke ( ), tumor ( ), spinal surgery( ), neurological infections( ), seizures( ),elective angiograms( ), hydrocephalus( ), transverse myelitis( ) and av dural fistula( ). using dsm- criteria, the reference rator identified delirium in out of ( %) patients during the icu stay. out of assessments were positive for delirium according to dsm- and according to cam-icu. cam-icu flow sheet had sensitivity of . % ( %ci . % - . %) and specificity of . % ( %ci . %- . %). cam-icu has high sensitivity and specificity for diagnosing delirium in critically ill neurological population. it is a valid tool for diagnosing delirium. a value stream mapping event (vsm) for general neurology inpatients, revealed multiple barriers related to videofluoroscopy swallow studies. there was a high volume of patients requiring instrumental swallow assessments, a limited number of radiology appointments, and transportation delays that were delaying feeding plans, discharge recommendations and goals of care discussions. an operations engineer involved in the vsm event started the process by collecting observational data regariing timing. after meeting with the chief operating officer, director of patient transport, director of radiology, speech pathology manager, neuro intensive care unit manager and the operations engineer, a pilot program was agreed upon. the results for the three week pilot program were successful, and resulted in a permanent change in procedure. the pilot data showed a decrease in test time by minutes, a decrease in transport delays by minutes, and a decrease in length of stay by . days. the number of patients waiting for the study dropped from . to . per week. by annualizing this data, the change has created new available bed days, additional patient encounters and an incremental annual contribution margin of $ , . with the appointment time consistent, the nurse is able to plan patient care around the study, and ensure the patient is prepared and not delayed for the study. it has also allowed, if deemed safe for the patient to swallow, medications to be changed from the intravenous route to the oral route earlier, and earlier determination of safe feeding and diet restrictions. we previously reported outcome for children with refractory and super-refractory status epilepticus in a cohort of patients. mortality was %. % of survivors required new tracheostomy and/or gastrostomy tubes. the majority of surviving patients experienced some degree of disability at discharge as determined by the pediatric cerebral performance category scale (pcpc). here, we aimed to identify patient factors in this cohort that were associated with a decline in functional neurologic outcome at discharge. retrospective chart review of children age - years who received pentobarbital infusion for status epilepticus in the pediatric intensive care unit of a large tertiary children's hospital from - . outcome was defined using pcpc at admission and discharge. potential factors associated with outcome were evaluated using fisher's exact test and wilcoxon rank sum test. children were included. pcpc score at admission (p= . ), etiology of status epilepticus (p= . ), new tracheostomy (p= . ), and new gastrostomy tube (p= . ) were all significantly associated with children were more likely to have normal baseline neurologic function and more likely to have febrile encephalitis, stroke/trauma, or hypoxic ischemic encephalopathy as the etiology of status epilepticus. duration of pentobarbital infusion (median = days vs. days) (p= . ) and duration of hospital admission (median = . months vs. . months) (p= . ) were both longer in patients who had an admission pcpc score, etiology of status epilepticus, new tracheostomy and gastrostomy tube as well as longer duration of pentobarbital infusion and longer hospital stay were significantly associated with a decline in functional neurologic outcome at hospital discharge in children with refractory and superrefractory status epilepticus. status epilepticus (se) is the most common pediatric neurological, and super-refractory se is a lifethreatening form of se that continues or recurs for more than hours despite multiple therapeutic interventions. this population-based study investigated pediatric se and srse admissions in germany. pediatric (age - years) admissions between - were identified in the arvato health analytics database. se, epilepsy, and febrile seizure cases were identified using a modification of a previouslypublished algorithm based on icd- diagnosis codes (g , g , and r ) and coding for ventilator and intensive care unit use. based on primary diagnosis, prior epilepsy status, and ventilation se was subclassified as non-refractory, refractory (rse), and super-refractory (srse). inpatient mortality, costs, length-of-stay (los), and discharge disposition were assessed overall and for rse and srse. the algorithm identified , seizure-related admissions and classified % as se, of which . % were rse and . % were srse. the rse frequency was highest among ages - . the incidence of cases classified as srse peaked among newborns (age< year), decreasing between ages - years. cases classified as se accounted for . % of total costs associated with seizure-related hospitalizations. srse exhibited the highest per case cost (mean € , ), amounting to . % of all se costs, and these costs correlated with the highest los (median . days). srse was associated with greater mortality ( . %) cases classified as srse accounted for . % of all pediatric seizure-related costs, despite representing only . % of admissions. srse was associated with the highest los and mortality rate. these results highlight the burden of illness associated with srse and suggest that optimization of srse management has the potential to improve outcomes and reduce costs. despite its more routine use and the recognition that mri provides superior detection of traumatic brain injuries, there has been little written about how mri might affect the acute management of trauma patients. we sought to describe mri findings in a cohort of children admitted to the picu with tbi and to extend comparisons between ct and mri in acute trauma. a secondary aim was to quantify in what ways mri findings influenced clinical management in this cohort. we retrospectively identified patients admitted to the picu with an acute head injury between september and may who underwent head mri within the first hrs. we compared mri with ct findings, using the nih common data elements definitions of injury type. we determined by chart review the indication for mri and if there was documentation that mri led to a change in management, defined as either an escalation or a de-escalation of care. seven patients had mri only, and mri identified additional lesions in of the patients who had first undergone head ct. of these, patients had new intra-parenchymal lesions, had new extra-axial lesions, and had both a new intra-parenchymal and a new extra-parenchymal lesion identified. the most frequent new lesions were contusions and traumatic or diffuse axonal injury. acute management was influenced by mri in a majority of patients, leading to an escalation of medical or surgical management in nearly one third and a de-escalation of care in half. early mri may have a beneficial role in the acute management of pediatric traumatic brain injury. mri frequently identified clinically important lesions not appreciated on ct, and findings influenced management decisions. future studies will assess whether early mri improves patient outcomes or provides cost/benefit by reducing length of stay. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. we identified patients who received dh, of whom underwent reconstructive cranioplasty at our institution. the post-cranioplasty complication rate was %, which was due in part to hemorrhage, infectious complications, or csf compartment disturbances. patients receiving early cranioplasty developed an increased rate of hemorrhagic complication ( % vs %; p = . ), increased median hospital length of stay (los) ( vs days; p = . ) and increased median icu los ( vs days; p = . ). of the patients who received dh surgery related to malignant cerebral edema from an acute ischemic stroke, total complication rates trended down for early compared to late cranioplasty surgery ( % vs %; p = . ). patients receiving dh surgery for any cause who underwent early reconstructive cranioplasty, experienced higher rates of hemorrhagic complications and increased hospital and icu los. however, among those patients receiving dh surgery for the specific indication of malignant cerebral edema from acute ischemic stroke, significant differences did not exist between the early and late cranioplasty groups. the total complication rates in these patients trended lower in the early group. another important and mainly unpublished finding is that a majority of dh patients are lost to surgical follow up and may therefore impact the complication rate of this not so benign surgery. postoperative antibiotics (pa) are often administered to patients after instrumented spinal surgery until all drains are removed to prevent surgical site infections (ssi). this practice is discouraged by numerous medical society guidelines, so our institutional neurosurgery quality improvement committee decided to discontinue use of pa for this population. we retrospectively reviewed data for patients who had instrumented spinal surgery at our institution for seven months before and after this policy change and compared the frequency of ssi and development of antibiotic related complications in patients who received pa to those who did not (non-pa). we identified pa patients and non-pa patients. discontinuation of pa did not result in an increase in frequency of ssi ( % of pa patients vs. . % of non-pa patients, p= . ). growth of resistant bacteria was not significantly reduced in the non-pa period in comparison to the pa period ( % vs. %, p= ). the cost of antibiotics for pa patients was $ , . , whereas the cost of antibiotics for the non-pa patients was $ . on a per patient basis, the cost associated with antibiotics and resistant infections was significantly greater for patients who received pa than for those who did not (median of $ . with iqr $ . -$ . vs. median of $ with iqr $ -$ ; p< . ). after discontinuing pa for patients who had instrumented spinal procedures, we did not observe an increase in the frequency of ssi. we did, however, note that there was a non-significant decrease in the frequency of growth of resistant organisms. these findings suggest that patients in this population do not need pa, and complications can be reduced if pa are withheld. the development of flow-diverting stents has allowed for new treatment options for giant vertebrobasilar aneurysms. however, the expertise required to perform these procedures safely and concerns about complications continue to limit their use. we sought to identify common complications of this treatment that can be anticipated by neurointensivists, to optimize management in the postoperative period. we retrospectively reviewed our hospital database of treated aneurysms to identify those with giant vertebrobasilar aneurysms. medical and neurological complications were recorded. six patients ( male, female) underwent treatment of giant vertebrobasilar aneurysms with pipeline embolization devices. five received adjunctive coiling. frequently reported pre-procedure symptoms were dysphagia (n= ), diplopia (n= ), dysarthria (n= ), facial weakness (n= ), hemiparesis (n= ), gaze palsy (n= ), and nystagmus (n= ). five patients ambulated normally. due to concerns about necessary procedures after stenting when on antiplatelet therapy, three patients received prophylactic ventriculoperitoneal shunts, two underwent gastrostomy, and two underwent tracheostomy. angiography confirmed successful aneurysm embolization in all patients. postoperatively, all patients developed new or worsened symptoms attributed to brainstem edema, including hemiparesis (n= ), facial weakness (n= ), dysphagia (n= ), diplopia (n= ), nystagmus (n= ), gaze palsy (n= ), and dysarthria (n= ). neurological symptoms were treated with steroids, with most symptoms subsiding by discharge. five patients had medical complications, including pneumonia (n= ), respiratory failure (n= ), gastrointestinal bleeding (n= ), arrhythmia (n= ), urinary tract infection (n= ), and myocardial infarction (n= ). two patients were re-intubated, three underwent gastrostomy, and one underwent tracheostomy. functional status at -months was available for five patients. three achieved modified rankin scale scores between - , one regressed to a , and one died. the treatment of giant vertebrobasilar aneurysms presents significant challenges. practitioners should anticipate temporary postoperative neurological worsening and various medical complications. prophylactic shunt placement, gastrostomy, and/or tracheostomy should be considered in patients anticipated to likely need these procedures after treatment. ventriculostomy-related infection (vri) remains a major complication of external ventricular drain (evd) placement. historically, prophylactic antimicrobials are utilized to decrease the incidence of vri after evd placement. recent guidelines for the insertion and management of evds recommend a single preoperative dose prior to evd insertion and urges against the use of duration antibiotic prophylaxis. prior to the publication of this guideline, we hypothesized that significant variations existed among institutions with respect to antibiotic prophylaxis practices in this setting. the purpose of this practice survey was to determine trends in antimicrobial prophylactic strategies utilized by various healthcare institutions for evd placement prior to publication of the neurocritical care society (ncs) evidence-based guidelines for the insertion and management of evds. a seven-question practice survey on antimicrobial prophylaxis for evd placement was distributed to active pharmacist members of the ncs by email and open for response from / / to / / . the following information was collected: antimicrobial prophylaxis regimen utilized, pharmacologic class, utilization of impregnated catheters, and institution guidance. survey results were analyzed for trends in antimicrobial prophylaxis in the setting of evd placement. respondents ( / , % response rate) from institutions completed a seven-question evd management survey. most institutions initiate a single dose of antibiotics prior to evd insertion ( / , %). periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by respondents ( / , %). of respondents who do not continue antimicrobial prophylaxis for the duration of evd placement, % ( / ) utilize antimicrobial-impregnated catheters to reduce incidence of vri. the importance of antimicrobial prophylaxis to prevent infectious complications associated with evd placement is widely accepted. prophylactic strategies vary between institutions. periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by survey respondents. antimicrobial-impregnated catheters are commonly utilized in institutions using periprocedural antimicrobial prophylaxis. the postoperative course seen in critically ill neurosurgical patients is known to vary depending on the timing of the surgical procedure. this study seeks to compare the clinical characteristics, complications, and outcomes between elective or urgent surgery patients admitted to the intensive care unit (icu). retrospective review of a two-year neurosurgical patients' cohort. the pre and postoperative conditions and outcomes were compared between elective (group a) and emergency (group b) surgery patients. a total of patients were evaluated, in group a and in group b. the most common diagnosis was intracranial tumor. the mean american society of anesthesiology (asa) score was significantly higher in group b than in group a ( . vs. . , p< . ). mean sequential organ failure assessment (sofa) score on admission was higher in group b ( . vs. . , p< . ). these patients were more likely to require mechanical ventilation (or . , p< . ) and vasopressors (or . , p< . ) . group b had a higher probability of rebleeding (or . , p< . ), intracranial hypertension (or . , p< . ), hydrocephalus (or . , p< . ), and reintervention (or . , p= . ). post-operative nausea and vomiting were less likely in group b ( . % vs. . % and vs. . %, respectively). mean hospital and icu los were shorter in group a than in group b ( . vs. . and . vs. . , p< . respectively). mortality rate during icu stay was higher in group b ( . % vs. . %; or . , p< . ). the preoperative glasgow coma scale (gcs) in patients who died, was below in only a minority of them ( . % in group b; % in group a). in this cohort of neurosurgical patients, emergency, compared to elective operations, were associated with higher post-operative complications and mortality rates. emergency surgery was associated with a higher severity of illness measured by the sofa and asa scores. intraprocedure rupture (ipr) is a rare but potentially serious complication of endovascular coiling of intracranial aneurysms. potential complications include hemorrhage, ischemic stroke, vasospasm and hydrocephalus which can lead to increased morbidity and mortality. the clinical course for these patients is not well studied and characterized. we performed a retrospective review of prospectively collected data for all unruptured aneurysms treated with endovascular coil embolization between july and march at a large universitybased hospital. out of cases of all unruptured aneurysms coil embolizations, ( . %) patients had ipr. we reviewed baseline data, procedure notes, clinical course, and outcomes at discharge and at , and months. among the ten patients, the location of the aneurysms included: basilar apex, internal carotid artery anterior communicating artery, posterior cerebral artery, and posterior communicating artery aneurysm. patients were monitored in the icu for variable lengths of time and daily transcranial doppler ultrasound detected no significant sonographic vasospasm. the large majority of the patients ( / ) were discharged to home at their baseline functional status assessed by modified rankin scale. one patient was discharged to inpatient rehabilitation for cognitive deficits from ipr of a basilar apex aneurysm. they were subsequently discharged home with supervision. there was a single mortality in a patient receiving retreatment of a proximal ica aneurysm with prior stenting and coil embolization who developed massive subarachnoid hemorrhage with diffuse intraventricular hemorrhage with external ventricular drain placement. the incidence of ipr is very low and potentially serious complications occur rarely in these patients. the location and factors associated with ipr are highly variable and without clear associations. outcomes of such complications are overall favorable. a short observation period in the hospital is likely warranted with a benign clinical course the most likely outcome. the standard treatment of cerebral venous-sinus thrombosis (cvst) is anticoagulation. however some patients clinically deteriorate secondary to mass-effect from infarct or intracerebral-hemorrhage (ich). the role of decompressive-craniectomy (dc) in this patient population is unknown. we elucidate the baseline characteristics of patients treated with dc, and report their outcomes. a retrospective chart review of our institutional database identified patients with cvst who were treated with dc. demographic and clinical data were collected. imaging variables collected from ct-head or mri-brain immediately before dc were intracerebral-hemorrhage volume (ich-v), combined volume of mass-effect from infarct/ich and peri-lesional edema (me-v), midline-shift at level of pinealgland (mds-p), midline-shift at cranial-most portion of corpus-callosum (mds-cc), and herniation-type. favorable outcome was defined as glasgow-outcomes scale of - upon last-known follow-up. a total of patients (females= ) treated with dc were identified with mean-age . (+/- . ), mean glasgow-coma scale (gcs) before surgery (+/- . ), mean-ich-v . ml (+/- . ), mean-me-v . ml (+/- . ), mean-mds-p . mm (+/- . ), and mean-mds-cc . mm (+/- . ). transverse-sinus was most commonly involved (n= ). / patients had any herniation, most commonly cingulate (n= ). meanchange in gcs from admission to before-surgery was - . (+/- . ). ten patients were anticoagulated before surgery. on last-known follow-up, / patients had a favorable outcome. four had died. on chisquare analysis, superior-sagittal sinus thrombosis was associated with unfavorable outcomes (p= . ), and mortality (p= . ). on univariate binary-logistic regression, there was a non-significant trend towards unfavorable outcomes (p= . ) and mortality (p= . ) with every-point decrease in mean-gcs before surgery. the predictive-value of other factors towards outcomes is unknown given limited sample-size. decompressive-craniectomy might improve outcomes even in patients with cvst who have developed coma, cerebral herniation, have failed treatment with anticoagulation, and have large-volume masslesions causing midline-shifts of > mm. a prospective multi-institutional observational-cohort would poster presentations better delineate outcomes in comparison to matched-patients who are not treated with decompressivecraniectomy. meningiomas are often benign and mostly asymptomatic, and the treatment approaches may include open surgical resection, radiosurgery, and/or watchful waiting. reported morbidity and mortality rates for elderly patients undergoing meningioma resection vary widely. we sought to investigate mortality rates for elderly patients undergoing craniotomy for meningioma resection using the nationwide inpatient sample (nis). the nis datasets from to were used to identify patient admissions for meningioma resection based on the icd- -cm code . . age categories were defined as years of age. primary outcomes were in-hospital mortality, poor outcomes (defined as death or discharge to a facility other than home), cost and length of hospitalization. a total of , patients were identified who underwent meningioma resection during - of which . % were elderly (> years). each of the primary outcomes was heavily influenced by the advancing age. in-hospital mortality was higher in the elderly as compared to the younger patients ( . % vs % p< . ), as was the rate of a poor outcome ( . % vs . %, p< . ). elderly patients also had a higher cost ($ vs $ , p= . ) and increased length of hospitalization ( . vs . days, p< . ). in our study, age > was strongly associated with adverse outcomes after meningioma resection. this increased risk should be taken into account when considering surgical intervention in this subgroup. based on this study, closer perioperative monitoring may be warranted in the elderly patient subgroup. treatment with anticoagulation improves outcomes in cerebral venous-sinus thrombosis (cvst). however patients who develop extensive infarcts and/or intracerebral-hemorrhage with mass-effect resulting in comatose-state are at risk of poor outcomes, and may benefit from decompressive craniectomy (dc). we evaluated the role of dc in the management of malignant cvst and its impact on outcomes. literature-search was conducted on pubmed and google-scholar using terms "craniectomy", and "cerebral venous-sinus thrombosis". we included studies that described any number of patients with cvst who underwent dc after clinical deterioration and reported their outcomes. a similar search strategy identified patients from our institute. outcomes were reported as modified-rankin scale (mrs) or glasgow-outcomes scale (gos) and were classified as favorable (mrs - ; gos - ), or unfavorable (mrs - ; gos - ). a total of patients (females= ; males= ; unknown= ) who underwent dc for malignant-cvst were identified from studies (n= ) and our institute (n= ). age and gcs (before-surgery) were only available from patients, with mean-age . (+/- . ) and mean-gcs . (+/- . ). patients ( . %) had favorable-outcomes, while patients ( . %) died. in the multi-variate binarylogistic regression-model, every point-drop in gcs decreased the odds of favorable-outcomes by . times (p< . ; %ci= . - . ), and survival by . -times (p= . ; %ci= . - . ). thrombosis in internal-jugular vein (ijv) (or= . ; %ci= . - . ; p= . ) and deep-cerebral veins (dcv) (or= . ; %ci= . - . ; p= . ) predicted unfavorable-outcomes. ijv-thrombosis (or= . ; %ci= . - . ; p= . ) and dcv-thrombosis (or= . ; %ci= . - . ; p= . ) also predicted mortality. interestingly, cortical-vein thrombosis was associated with lower odds of unfavorable outcomes (or= . ; %ci= . - . ; p= . ). data regarding anticoagulation and long-term follow-up were not uniformly available. for patients with malignant-cvst, craniectomy could potentially improve outcomes. factors such as gcs before-surgery and cvst location can help predict outcome following dc and aid the decision-making process. a multi-institutional observational cohort should be designed to prospectively evaluate predictors for, timing of, and outcomes after craniectomy in cvst. the external ventricular drain (evd) is commonly used in the neurocritical care unit to help monitor intracranial pressure (icp) with the added advantage of therapeutically treating elevated icp by diverting cerebrospinal fluid (csf). placement of an evd can be complicated by hemorrhage surrounding the catheter insertion tract, which in some cases may prove to be fatal. this retrospective study was designed to look at the rate of tract hemorrhages after evd placement that were performed at our institution as well as associated outcomes. we conducted a retrospective review of all patients who underwent evd placement during a year period using our institutional database. postinsertion computerized tomography (ct) scans of the head were analyzed independently by physicians to identifying tract hemorrhages. data on primary diagnosis, age, sex, length of icu stay and mortality were collected and analyzed. a total of patients were identified as having had an evd placed during their hospital course. patients were excluded as there were no images of evds present in their records. patients were analyzed, of which % were male. mean age was . years. % of patients had a diagnosis of subarachnoid hemorrhage, % with intraparenchymal hemorrhage and % with ischemic stroke. mortality was % among all evd patients. the rate of tract hemorrhages among all patients with evd images was %. asymptomatic tract hemorrhages occurred in patients ( . %) with patient ( . %) dying due to the tract hemorrhage itself. among patients with tract hemorrhages mortality was . %. the rate of tract hemorrhages was noted to be % with the majority being asymptomatic. there was no difference in mortality among patients with evds who developed tract hemorrhages compared to patients with no tract hemorrhages. verapamil is a phenylalkylamine calcium channel blocker that blocks the calcium ion influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells resulting in vascular relaxation and vasodilatation. symptomatic hypotension and/or extreme bradycardia/asystole are often seen with intravenous verapamil administration requiring pharmacologic treatment. in neuroendovascular field verapamil is mainly being used as a vasodilator agent. current lack of pharmacokinetic/pharmacodynamics data of intra-arterial verapamil often makes very challenging to neurointerventionalists during endovascular procedures. the purpose of this study is to observe acute hemodynamic effects of intra-arterial verapamil administration as well as the safety of higher dose of the medication during endovascular treatment. ten patients who underwent endovascular treatment for acute ischemic stroke were evaluated pre and post procedure with vital signs. the dosage of intra-arterial verapamil was documented and tabulated along with the pre and post heart rate and systolic blood pressure. the dose of intra-arterial verapamil varied from to mg in each internal carotid or vertebral artery, total dose per patient per procedure varied from . to . the average dose of intra-arterial verapamil administered was . ± . mg or . ± . mcg/kg that were infused over to minutes. at the baseline before administration of intra-arterial verapamil, the mean systolic blood pressure (sbp) was . ± . mm hg and the mean heart rate (hr) was . ± . bpm. after administration of intraarterial verapamil, sbp decreased by mean of . ± . mm hg but we observed no symptomatic hypotension requiring any pharmacologic treatment. hr changed only by mean of . ± . bpm post intra-arterial verapamil. we observed no acute significant changes in hemodynamic parameters with administration of verapamil in carotid or vertebral arteries. this may represent its safe use during neuro-endovascular therapy. growing evidence suggests inflammation is critical in epileptogenesis. endogenous brain apolipoprotein e protein (apoe) modulates neuroinflammatory responses to injury through downregulation of glial activation and secondary neuronal injury. we created a amino acid peptide (cn- ) mimicking the binding face of apoe. cn- downregulates the inflammatory response in vitro and in vivo and improved histologic and clinical outcomes across several injury models in mice. we hypothesized that downregulation of inflammation by administration of cn- will reduce the development of epilepsy after pilocarpine induced status epilepticus in mice. c bl/ mice were intraperitoneally injected with pilocarpine to induce status epilepticus. following induction of status, animals were randomized to receive two doses of cn- or vehicle at minutes and hours. status was terminated by injection of benzodiazepine at minutes. epidural eeg leads were surgically placed at weeks and continuous video-eeg (cveeg) monitoring was performed for several days in a row at - weeks post status to determine spontaneous seizure development and frequency. at - weeks following induction of status epilepticus, administration of . or . mg/kg cn- reduced the development of epilepsy by approximately % compared to vehicle treated animals. further, cn- treated animals that did develop seizures had significantly fewer seizures than vehicle mice. similar results were seen with daily doses of mg/kg starting at minutes. importantly, cn- is not an anticonvulsant as cveeg monitoring during status induction clearly demonstrated that seizures were not stopped or reduced by injection of cn- . these results are consistent with the hypothesis that inflammation plays an important role in the development of epilepsy after injury and demonstrates treatments that target inflammation, like cn- , can prevent and/or reduce the development of epilepsy. this represents the first therapy to prevent the development of epilepsy that has entered into clinical trials. to determine the speed of brain entrance of the antiepileptic drugs (aeds) brivaracetam (brv) and levetiracetam (lev) after single intravenous dosing in humans. brv and lev both bind to synaptic vesicle protein a (sv a), but brv has more rapid brain entry than lev in mice and monkeys [ ] . sv a can be quantified in the living human brain using pet imaging with [ c]ucb-j[ ]. pet scans (n= ) were performed with [ c]ucb-j administered by a bolus-infusion protocol in healthy volunteers (n= ). therapeutic dosages of brv ( mg, n= ; mg, n= ; or mg, n= ) or lev ( mg, n= ) were administered as -minute intravenous infusions minutes after the start of the first pet scan. tracer displacement half-times were determined by subtracting the radioligand clearance halftime from the radioligand displacement half-times estimated by exponential fitting of the post-aed drop in distribution volumes (vt). data were also analyzed using an advanced mathematical model that described the relationship between brain [ c]ucb-j pet data and time-varying aed plasma curves to directly estimate brain entrance (k ) of both aeds and [ c]ucb-j, free fraction of [ c]ucb-j in the brain, and vt values. the radioligand clearance half-time was minutes. tracer displacement half-times were . and . minutes for brv mg, and ± minutes for lev mg. lower brv doses had longer half-times, but values were misleading as they assumed % sv a occupancy. the advanced compartment model described well -dose scans. using the advanced model, the brv uptake rate (~ ul/min/cm ) was found to be at least -fold higher than that of lev (~ ul/min/cm ). the results demonstrate that brv enters the human brain faster than lev. the potential therapeutic benefit of this has yet to be determined. while intravenous anesthetic therapy (ivat) represents the gold-standard for treatment of refractory status epilepticus (rse), the optimal depth and duration of therapy is not known. the goal of this retrospective observational study was to describe the relationship between the depth of burst suppression and the ability to successfully wean ivat during rse treatment. fifty patients were identified with rse who underwent continuous electroencephalography. using persyst, the suppression ratio (sr) was calculated up to hours prior to weaning ivat. the type and duration of ivat was recorded, as well as complications. we compared these variables between successful and unsuccessful weans. the mean sr for all patients was . ± . %, with a mean treatment duration of . ± . hours. there was no difference in treatment duration between successful and unsuccessful weans(p= . ), but sr was significantly lower in successful weans ( . ± . % vs . ± . %, p= . ). the receiver operating curve (roc) for the sensitivity and specificity of the mean sr to predict a successful weaning attempt did not identify a threshold to predict weaning success. the use of pentobarbital was associated with a significantly higher sr when compared to midazolam ( . ± . % vs . ± . %, p < . ). patients failed ivat weaning a mean . ± . hours after initiating the ivat wean, which occurred after a mean decrease in the midazolam infusion rate of ± %. depth of sr was not associated with infection risk (p= . ), but was associated with the need for tracheostomy ( . ± . % versus . ± . %, p= . ). vasopressors were required in . % of patients while on ivat. unsuccessful weaning of ivat was associated with a higher depth of sr, which is likely a marker of disease severity. depth of sedation was not associated with increased risk of infection, but was associated with the need for tracheostomy. vasopressor requirements are common. the primary objective of this study was to determine the sensitivity and specificity of real-time neuro icu nurse interpretation of quantitative eeg (qeeg) trends in the identification of recurrent nonconvulsive electrographic seizures in adult patients admitted to the neuro icu. thirteen adult patients admitted to the neuro icu that had nonconvulsive seizures on continuous eeg (ceeg) monitoring were included in the study. neuro icu nurses consented for their participation and underwent a brief, standardized qeeg training session. a -hour qeeg panel (rhythmicity spectrogram, left/right and amplitude-integrated eeg, left/right) printout containing the marked sentinel seizure(s) was displayed next to the bedside ceeg/qeeg monitor. at one-hour intervals, the nurses logged the number of seizures seen in the past hour based on their qeeg interpretation for the duration of their shift. their answers were compared with the gold standard of neurophysiologist interpretation of seizure occurrence on raw eeg. a total of hours of qeeg data was reviewed for patients. average length of data collection was . hours. for the neuro icu nurses' ability to detect the presence of seizures on real-time qeeg the sensitivity was . % ( % ci, . - . %) and specificity was . % ( % ci, . - . %). the positive predictive value for seizure detection was . % ( % ci, . - . %) and the negative predictive value was . % ( % ci, . - . %). the false-positive rate was . /hr. a simplified panel of qeeg trends can be used by neuro icu nurses to screen for recurrent electrographic seizures in critically ill patients with a reasonable sensitivity, an excellent specificity and a very low false-positive rate. this may facilitate earlier identification of recurrent electrographic seizures by notifying the neurophysiologist who is not present in the icu and not able to perform real-time ceeg interpretation. nonconvulsive status epilepticus (ncse) is an indicator of poor outcomes in neurocritical care settings. however, because of unfamiliarity with continuous electroencephalography monitoring (ceeg), the diagnosis and treatment of ncse remains challenging, and its clinical impact and prognostic factors have not been sufficiently reported in japan. we performed ceeg for adult patients in our neurocritical care unit with coma or unexplained altered mental status from april to september . we reviewed all ceeg records according to the american clinical neurophysiology society's terminology ( version), and diagnosed patients with ncse when the ceeg revealed spatiotemporally evolving or fluctuating periodic or rhythmic discharges and after considering clinical information based on the modified salzburg consensus criteria. patients with ncse were aggressively treated with benzodiazepines, fosphenytoin, and levetiracetam. they were divided into a generalized convulsive status epilepticus (gcse) group and a non-gcse group. we compared mortality and outcomes between the two groups after months using fischer's exact test. outcomes were defined as poor when the glasgow outcome scale score was worse at the -month follow-up than at admission. we excluded cases undergoing supportive care or lacking of follow-up. of cases in the study, cases were diagnosed with ncse, including cases with accompanying gcse and cases without. mortality rates at the -month follow-up were significantly higher in the non-gcse group than the gcse group ( % vs. %, respectively; p = . ). the rate of poor outcomes was significantly higher in the non-gcse group than in the gcse group ( % vs. %, respectively; p = . ). this study suggests that the absence of gcse is associated with increased mortality and poor outcomes among ncse patients. limitations of this study include its retrospective design and small number of ncse patients. further studies are necessary to identify additional prognostic factors. super-refractory status epilepticus (srse) is a life-threatening condition in which status epilepticus recurs or continues for over hours despite first-, second-, and anesthetic third-line agent (tla) medications. no treatments are currently approved for srse. a randomized, double-blind, multi-center, placebo-controlled phase trial evaluated brexanolone (usan; formerly sage- injection), a synaptic and extrasynaptic gabaa receptor positive allosteric modulator as adjunctive therapy for srse (nct ; "status trial"). enrolled subjects underwent a qualifying tla wean after at least hours of seizure-or burstsuppression. srse subjects failing the qualifying wean were randomized : to a blinded infusion of brexanolone or placebo as adjunctive therapy following resumption of one or more tla infusions. subjects were administered the blinded infusion for days, during which attempts were made to wean off tla infusions. clinical standardization guidelines (csgs) facilitated standardization across sites by outlining eeg patterns for which tla weaning should be continued, paused, or discontinued. an on-call clinical standardization team provided real-time support. safety was assessed via adverse events, laboratory testing, vital signs, and ecg parameters. the primary endpoint was defined as successfully super-refractory status epilepticus (srse) is a life-threatening neurological condition characterized by status epilepticus persisting over hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. currently, there is no consensus around treatment protocols for srse. this study aims to describe srse treatment patterns and related outcomes in a us population. we retrospectively identified srse cases in cerner healthfacts®, a large, de-identified, us electronic health record database, using records from - . cases were classified as srse using a modified version of a previously published algorithm using icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . , and . ) , ventilator support, pharmacotherapies. descriptive and univariate statistics were used to evaluate anesthetic treatment, anti-epileptic medications, and the association between glasgow coma score (gcs) and mortality. using our algorithm, srse cases ( patients) were classified. multiple tlas were received in % of cases, and in %, > concurrent tlas were received. the first post-admission tlas were propofol, lorazepam and midazolam, respectively, in %, % and % of cases. median anesthetic duration was . days. mortality was higher in - ( . vs. . days; p< . ). srse patients identified in our analysis underwent variable treatment patterns, reflecting lack of co days of tla treatment. nonconvulsive seizures (ncs) and nonconvulsive status epilepticus (ncse) occur in approximately % of neurologically critically ill patients. the most effective antiepileptic drug (aed) regimen to treat ncs and ncse is unknown. this study was designed to determine the efficacy of add-on clobazam, a unique , -benzodiazepine with favorable pharmacokinetic properties, in the treatment of ncs and ncse. a retrospective chart review was performed on adult patients who were admitted to the neurological intensive care unit between january , and june , , were diagnosed with ncs or ncse by continuous eeg monitoring and received clobazam as add-on therapy. the primary efficacy endpoint was defined as clobazam being the last aed added before ncs/ncse cessation, regardless of latency between dosing and ncs/ncse cessation. of the patients included in this study, ( %) had ncs vs. ( %) with ncse. the most common etiologies were autoimmune (n= ) and cns tumor (n= ), with patients ( %) having pre-existing epilepsy. clobazam was the last aed added before cessation of ncs/ncse in of ( %) subjects. clobazam was chosen as the rd to th line agent. clobazam was started at a median of days from the onset ncs/ncse (range - days). the median total daily dose of clobazam was mg (range - mg). this study suggests that clobazam may be effective at various time points in the treatment of ncs/nsce and may prevent the need for addition of intravenous anesthetic drugs to control seizures. however, a prospective study is warranted to determine efficacy and optimal dosing. continuous electroencephalography monitoring(ceegm) with international - system is essential for detect nonconvulsive status epilepticus (ncse). in japan, both ceegm systems and human resources are lacking, and few facilities are able to conduct such advanced monitoring. the ceegm headset, described in this report, is a novel and easy-to-use technology. we attempted to validate the novel ceegm headset by comparing it with a conventional, international - ceegm system (conventional ceegm). we completed this study at a single center, eight-bed neurocritical care unit, between january and june . the new, ceegm headset features eight electrodes (f, c, t, o), and is capable of simultaneously transmitting eeg data by bluetooth. patients with disturbed consciousness, of unknown etiology, underwent ceegm headset followed by conventional ceegm. we verified the concordance rate of the two systems for detecting eeg morphologies (e.g. periodic discharges, rhythmic delta activity, spikes and waves), and diagnosing ncse. eeg morphologies were appreciated according to "american clinical neurophysiology society's standardized critical care eeg terminology: version" and diagnosis of ncse were done according to modified salzburg consensus criteria. among this period, we enrolled thirty patients. three patients were excluded because of not satisfying protocol. final analyses included verified data from patients. the mean age was years old (range: - ), % were male, mean acute physiology and chronic health evaluation (apache) ii score was (range: - ), and mean full outline of unresponsiveness (four) score was (range: - ). we appreciated concordant eeg morphologies, and ncse, in % ( / ), and % ( / ) of patients, respectively. this easy novel ceegm headset may be useful in settings with limited resources or access to conventional ceegm technology. further study is needed to validate the actual diagnostic ability of this novel headset. the traditional approach to interpreting eeg requires physicians with formal training to visually assess the waveforms. this approach is less practical in critical settings when a trained eeg specialist is not readily available to diagnose subclinical seizures, such as non-convulsive status epilepticus, in patients with altered mental status. we have recently invented an algorithm for sonifying eeg, and in the current study, we explored whether individuals without eeg training can detect ongoing seizures by simply listening to one channel of sonified eeg. we sonified eeg samples ( -second long) that represented various conditions commonly seen in the icu ( seizures; lpd, gpd, or burst suppression, and normal or slowing). medical students and nurses were asked to indicate each audio sample as "seizure" or "non-seizure". we then compared their performance with that of eeg experts [epilepsy attendings with > years of experience (n= ) and epilepsy fellows (n= )] and some of the medical students (n= ) who also diagnosed the same eegs on visual display. non-experts listening to single-channel sonified eegs detected seizures with remarkable sensitivity (students: ± %; nurses: ± %) compared to experts or non-experts reviewing the same eegs on visual display (attendings: %; fellows: ± %; students: ± %). if the eegs contained seizures or seizure-like activity, non-experts listening to sonified eegs rated them as seizures with high specificity (students: ± %; nurses: ± %) compared to experts or non-experts viewing the eegs visually (attendings: ± %; fellows: ± %; students: ± %). our study confirms that individuals without eeg training can detect ongoing seizures or seizure-like rhythmic periodic activity by merely listening to short duration of sonified eeg. while sonification of eeg cannot replace the traditional approaches to eeg interpretation, it provides a meaningful triage tool for fast assessment of patients with suspected subclinical seizures. super-refractory status epilepticus (srse) is a life-threatening form of status epilepticus (se) that continues despite, or recurs after, hours of therapeutic interventions, including continuous intravenous anesthetic third-line agents (tlas). no therapies are approved for srse, leading to substantial variation in both management and determination of treatment response. for the phase trial of brexanolone as adjunctive therapy for srse involving up to international sites, we developed and implemented clinical standardization guidelines (csgs) for real-time support of tla administration, weaning, and outcome assessment under eeg neuromonitoring. a clinical standardization team (cst), including investigators and se experts, developed consensus csgs defining acceptable eeg patterns for continuation, termination, or pausing the weaning of tlas. csg implementation was facilitated by training and cst call centers staffed internationally by physicians with critical care eeg expertise. in cases of disagreement, the local site retained final decision-making authority. a "traffic light" system defined: )"green" tolerated eeg patterns (improving background, seizures within hours, discharges > hz, or discharges - . hz with evolution and no improvement over hours), and )"amber" eeg patterns not meeting the above, for which tla weaning should be paused while optimizing anti-epileptic medications and monitoring for transitions to green/red eeg patterns. the initial cst consultations yielded % csg compliance; % of eegs underwent cst review. few cst consultations lasted > minutes ( %); most lasted < minutes ( %). this phase trial demonstrates the feasibility of applying neuromonitoring csgs for tla weaning in srse patients, to ensure better consistency of clinical care and reliability of the primary outcome measure in clinical trials. csgs were well accepted by investigators and may serve as a framework for future clinical trials or clinical therapies in srse. severe brain trauma is a leading cause of death and disability worldwide. post-traumatic epilepsy (pte) is a chronic complication that occurs in up to % of cases (frey, ; najafi et al., ) . drugs and other interventions to prevent epileptogenesis would likely be most effective early after traumatic brain injury (tbi), but cannot be given indiscriminately. there is a critical need for tools that quantify those at high risk for pte. abnormal neural activity, in the form of ictal-interictal continuum abnormalities(iicas) are increased acute brain injuries, and appear to differentiate patients at risk for secondary brain injury (e.g. kim et al., ) . we hypothesized that iicas acutely following tbi may be a marker of posttraumatic epilepsy risk. we evaluated continuous eeg data from moderate to severe tbi patients who did and did not develop pte, (any seizure - months post-tbi; n= ). seizures < month post-tbi were classified as symptomatic, not pte. conventional - scalp electrode placement was used and eegs were reviewed by standard visual analysis, by the mgh neurophysiology service. daily eeg reports were scored for the presence of iicas and seizures. demographic data including gender, age, tbi severity and type of brain injury were recorded. univariate and multivariate regression analyses were performed to determine which iica and demographic features correlated with pte. gcs (p= . ) and tbi severity (p= . ) were significantly associated with pte, as expected. seizures (p= . ), epileptiform discharges (p= . ), generalized periodic discharges ( . ) and lateralized rhythmic delta activity (p= . ) independently predicted risk for post-traumatic epilepsy. epileptiform discharges, in particular, were more prevalent acutely post-tbi in pte patients. increased iica prevalence is significantly associated with pte and may be a predictive marker for identifying patients who may benefit from anti-epileptogenesis trials. rapidly obtaining eeg signals in the ed and icu for at-risk patients can enhance diagnosis accuracy and speed, while cutting down time until treatment. ceribell inc has developed a portable eeg data recorder and electrode headset with rapid setup (~ min) technology without any eeg technician required to overcome the inaccessibility of eeg in urgent situations when seizures are suspected. the purpose of this study is to evaluate the signal quality and performance of the ceribell system compared to a reputable clinical eeg system. we collected eeg samples in the laboratory and at stanford university medical center. laboratory collections on healthy volunteers included simultaneous collection of eeg using ceribell and nihon kohden systems, and a split-signal that recorded eeg to both data recorders from the same electrodes. in the icu, eeg was recorded with the ceribell system on patients and subsequently with the clinical eeg system. data was filtered and spectral densities, mean frequency (mf), spectral entropy (se), and % spectral edge frequency (sef ) were computed. in the split-signal test, the waveforms consistently appeared similar by visual inspection. the analysis of ceribell data revealed (mf = . hz, se= . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the simultaneous test, the ceribell system produced (mf = . hz, se = . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the clinical setting, the ceribell system showed spectral density distributions comparable with the commercial system. our results indicate that the signal quality of the ceribell system is similar to a commercially available eeg used widely in the clinical setting, while requiring less setup time and allowing more portability. status epilepticus (se) is a life-threatening condition characterized by prolonged seizures without regaining consciousness between seizure events. when se continues or recurs hours or more after treatment with third line anesthetic agents, it is considered super-refractory se (srse). there are few population-based studies on the descriptive epidemiology of srse at a national level. the objective was to estimate the incidence of srse in canada in - . we analyzed standardized national administrative record-level data covering all provinces across canada as provided by the canadian institute for health information. srse episodes were classified from two databases for acute care admissions (discharge abstract database) and emergency visits (national ambulatory care reporting system) over fiscal years ( / to / ). cases were identified as srse using a modification of a previously published algorithm using icd- -ca diagnostic codes for epilepsy (g ), status epilepticus (g ), or convulsions (r ) plus an intensive care unit stay of days or more with mechanical invasive ventilation. using our algorithm, from - , the mean annual number of cases classified as srse was , ( . / , persons per year). the annual incidence was higher in males ( . / , per year) than females ( . / , per year). the highest rates were in the age group - years: . and . per , per year for females and males, respectively. the mean age of srse patients was years (sd= years), with % males. the most common comorbidities for srse included metabolic disturbances ( %), sepsis ( %), toxic withdrawal state ( %), cardiovascular disease ( %), and head trauma ( %). in-hospital mortality for srse was %. this is the first study reporting estimates of srse incidence in canada. these results suggest that srse is associated with a substantial disease burden. interventions that improve patient outcomes and reduce mortality are required. new-onset refractory status epilepticus (norse) is a condition characterized by prolonged pharmacoresistant seizures in a previously healthy individual with no identifiable etiology during initial evaluation. typical magnetic resonance imaging (mri) findings include bilateral limbic and neocortical t -weighted hyperintense lesions. fluorodeoxyglucose (fdg)-positron emission tomography (pet) findings have not been previously reported. this study sought to describe fdg-pet and mri characteristics in patients with norse. methods patients were retrospectively identified amongst a database of autoimmune-mediated encephalitis from - , meeting diagnostic criteria for norse and having undergone mri and pet over the course of their illness. imaging findings were confirmed with a board-certified neuroradiologist. nine patients were autoantibody positive: three n-methyl-d-aspartic acid (nmda) receptor, two glutamic acid decarboxylase (gad), three voltage-gated potassium channel (vgkc)-complex with two having leucine-rich glioma-inactivated protein igg positivity, and one gamma-aminobutyric acid (gaba) b receptor. all patients had identifiable abnormalities on fdg-pet. hypometabolism was most common, with of patients having diffuse, bilateral, or unilateral frontal, parietal, or occipital cortical hypometabolism. nine patients also had bilateral ( ) or unilateral ( ) mesial temporal hypermetabolism. two patients had multifocal hypermetabolism with bilateral or unilateral frontal abnormalities in addition to mesial temporal findings. of the nine patients with fdg-pet hypermetabolism, concurrent mri scans failed to show corresponding t -weighted hyperintense lesions in the mesial temporal and medial frontal regions in two patients. fdg-pet findings in norse include bilateral or unilateral mesial temporal or mesial frontal hypermetabolism with diffuse, bilateral, or focal cortical hypometabolism. hypermetabolism may reflect regions predominantly involved in acute epileptogenesis. fdg-pet may improve sensitivity when compared to mri alone. while seizures are uncommon but reported in primary intraventricular hemorrhage (ivh), little evidence is available on the prevalence of hyperexcitable patterns on long term eeg monitoring. we sought to determine the prevalence of hyperexcitable patterns and seizures in patients with primary ivh who were extracted from a cohort consisting of patients with spontaneous intracerebral hemorrhage (sich) who underwent continuous electroencephalogram (ceeg) monitoring between january and december at yale-new haven hospital. indications for ceeg monitoring included fluctuation of or depressed mental status, abnormal movements and a limited clinical exam. we recorded demographics, radiologic hydrocephalus, duration of eeg recording and eeg findings. hyperexcitable patterns comprised generalized, bilateral independent or lateralized periodic discharges (pds), lateralized rhythmic delta activity (rda), brief potentially ictal rhythmic discharges (b(i)rds), and spike-and-wave discharges (sw). of adults with sich who had ceeg performed, patients had primary ivh. hydrocephalus was present in patients ( %). patients were monitored for a mean duration of . (± . ) hours. patients had hyperexcitable patterns and/or electrographic seizures ( %): electrographic seizures and co-existent hyperexcitable patterns were captured in of patients ( %) and hyperexcitable patterns without seizures in of patients ( %). hyperexcitable patterns included periodic discharges (pds) ( ) (generalized, lateralized and bilateral independent, with and without rhythmicity), rhythmic delta activity (rda) ( ) (both lateralized and generalized, with and without sharps), brief potentially ictal rhythmic discharges(b(i)rds) ( ) and spike-and-wave discharges (sw) ( ). there was no significant difference between patients with and without hydrocephalus and hyperexcitability or electrographic seizures (p= . ). both electrographic seizures and/or patterns of hyperexcitability on eeg are common in our selected cohort of primary ivh patients. this underscores the importance of continuous eeg monitoring in this patient population, since the detection of non-convulsive seizures may offer an opportunity for therapeutic intervention. patients with aneurysmal sah (asah) frequently have ictal-interictal continuum (iic) eeg patterns. while seizure burden can worsen outcomes, less is known about iic burden. we investigated the impact of iic burden and anti-epileptic drug (aed) treatment on asah outcomes. we included patients with asah undergoing continuous eeg (ceeg) from - . patients with nonaneurysmal sah or %, - %, - %, - %, < %. age gender, admission gcs, apache ii score, fisher and hunt and hess (hh) scores, aed dosing and discharge gos were ascertained by chart review. presence of iic patterns in asah independently predicts worse neurologic outcome, although maximum burden does not. although nearly half of these patients receive aed treatment, our data suggest that aed treatment may not influence outcome. prospective studies may further delineate the clinical risks and benefits of aed treatment. refractory status epilepticus (rse) is defined by failure to control epileptic activity after the administration of st and nd line antiepileptic agents. mortality associated with rse has been estimated to be around - % at hospital discharge. we conducted this study to analyze trends in the frequency and management of rse. we conducted a cross-consortium (uhc) database from to . this is a database from academic medical centers and their affiliated hospitals in the united states and consists of a sample of , , patients. data including age, sex, antiepileptics (aed) and length of stay was collected. total mean age was . years and females were . %. there was an increasing trend of using lorazepam as the first line aed ( . % in to . % in ) and a decreasing trend was noted of using midazolam as the first line aed ( . % in aed ( . % in to . % in . leviteracetam was the most common second line aed used throughout all years which was followed by propofol followed by phenytoin/fosphenytoin. mean length of hospital stay was . days. between to , the proportion of hospitalized patients in the united states diagnosed with rse has increased. lorazepam and leviteracetam have been the most common aeds used. mean length of hospital stay has not changed. status epilepticus is associated with high risk of multi-organ dysfunction. ketamine for the treatment of super refractory status epilepticus (srse) has the benefit of a different mechanism and lack of cardiac depression when compared with other anesthetic agents. this study evaluated the improvement in sequential organ failure assessment (sofa) score in patients treated with ketamine for srse. this is a retrospective study of patients with srse from to . the timing and dosage of anesthetic agents used in their treatment were abstracted. sofa scores at admission and for the first days after initiation of ketamine were calculated. the presence of shock prior to initiation of ketamine included septic shock and cardiogenic shock. outcomes including mortality, organ failure, and hospital associated infections (hais) were also recorded. a total of patients were treated with ketamine after failure of seizure control using other anesthetic agents. seventeen ( . %) had an improvement of their sofa score while ( . %) did not. the median sofa score on admission was (iqr - ) for those who had an improvement and (iqr - ) for those who did not (p= . ). cardiac arrest was the etiology of srse for ( . %) patients who improved vs. ( . %) patients who did not (p= . ). patients required to vasopressors for hemodynamic support, with less needed for those who had an improvement (p= . ). there was a higher rate of hais in patient who did not have an improvement of their sofa score (p= . ). there is a subset of patients treated with ketamine for srse who have an improvement in their sofa score, require less vasopressor support, and have a lower rate of hais. further studies are needed to better understand which patient population may most benefit from the use of ketamine for treatment of srse. the ceribell eeg system (ces) is a novel channel eeg device with instant sonification and visual display capability that can be set up quickly without an eeg technician. we hypothesized that by using ces, we can decrease time to eeg acquisition and improve diagnosis and treatment decisions in suspected nonconvulsive seizures (ncs). adult icu patients (gcs < ) who had continuous eeg (ceeg) as part of clinical care were enrolled. once ceeg was ordered, consent was obtained and ces was placed by the treating physician (n= ) who listened to the left/right hemisphere signals for seconds each. suspicion for seizure ( =low, =high) and decision to treat (yes/no/not sure) were rated pre-and post-sonification. three blinded epileptologists compared accuracy of sonification with visual ces eeg. outcomes were difference in time to eeg acquisition, change in suspicion for seizure and decision to treat, and ease of use ( =challenging; =easy). patients (mean age +/- , median gcs of (iqr - . ) were enrolled from : am to : pm. start of eeg acquisition was significantly faster for ces ( minutes (iqr - ) vs minutes (iqr - ) p< . ), median difference minutes (iqr - ). one patient had ncs during sonification and this was accurately identified and treated. low suspicion for seizure ( ) was more likely postsonification ( % vs %, p= . ). treatment decision changed in % after sonification, and this was in the correct direction % of the time. inappropriate decision to treat decreased from % to % (p= . ). negative predictive value was % ( % ci - %). ces was consistently rated easy to use. the ceribell eeg system is easy to use, speeds eeg acquisition, accurately identifies ncs, and enables appropriate treatment decisions. it has the potential to greatly enhance timely diagnosis and treatment of ncs in critically ill patients. the aim of the study was to understand the efficacy of ketamine in refractory status epilepticus and identify the underlying factors affecting the effectiveness of ketamine. moreover, we also studied the rate of complications in patients who underwent continuous midazolam ketamine dual therapy for treatment of refractory status epilepticus. this is retrospective cohort study evaluating the efficacy of ketamine in patient with refractory status epilepticus in total of patients admitted to university of maryland medical center in either neuro intensive care unit /micu during the last five years between ( - ). we established a standardized algorithm for managing refractory status epilepticus. electrographic and clinical control of seizures was classified into four groups: likely response, possible response, permanent response and no response reviewed by a team of epileptologist and neuro intensivist. the effective doses of ketamine to abort rse were studied. complications intensive care unit stay while on therapy were reviewed. of the patients, were male, were female. % of the patients had cardiac arrest as an etiology of seizures. median loading dose was . mg/kg, median maintenance dosage was mg/kg/hr. % of the patients had no response to ketamine. % were responsive to ketamine of which, patients had likely response to ketamine, patients had possible response. . % of the patients had permanent response to ketamine. % patients had hospital acquired infections, % patient had metabolic acidosis, % had ards. this is one of the largest single center study illustrating the efficacy of ketamine in aborting rse. further study should address the difference in incidence of complications in patients with usage of ketamine versus groups alternative therapies. this study also demonstrates the etiology of seizures and its influence on efficacy of ketamine in aborting rse. acute cardiopulmonary complications are frequently observed in convulsive status epilepticus but mechanism is poorly understood. complications include tachy-arrhythmias, myocardial ischemia, takotsubo cardiomyopathy and neurogenic pulmonary edema. herein, we mapped evolution of cardiac dysautonomia as function of sequential electrographic stages of se in four subjects admitted to icu. we hypothesize pathological co-activation of both arms of autonomic system contributes to cardiac complications. heart rate variability (hrv) is considered a proxy for ans tone on heart. we analyzed hrv in time and frequency domain, complexity measure (lempel ziv-lz) during se and mapped changes as function of stages of se as determined by scalp eeg. conventional scalp eeg recording and lead i-ekg (sampled at hz) were analyzed using kubios hrv software . . cardiac vagal index (cvi) and cardiac sympathetic index (csi) were calculated using geometric lorenz-plot method. parasympathetic activity is expressed in rmssd, pnn, cvi, and hf power four adults (range - ; m= ) were admitted to icu following convulsive se. ictal hrv changes initially reflected high sympathetic system activation (high csi) and reduced vagal tone (low hf, rmssd) as reported previously with convulsive seizure. earlier stages of se (stage i and ii) were marked by dual activation of the ans with sympathetic predominance (lower cvi/csi ratio). later stages of se (stage iv and v), demonstrated progressive increase in parasympathetic activity (hf power, rmssd, cvi, cvi/csi ratio). hf power and rmssd at stage v se was three times higher than during discrete seizure. lz complexity measure downtrended with the loss of fluctuations in late stages of se. in one subject se terminated with asystole this case series highlights dynamic changes in sympatho-vagal imbalances with progressive se. dual activation of sympatho-parasympathetic system and loss of complexity measures are associated with increased cardiac complications. therapies directed towards stabilization of cardiac dysautonomia might minimize complications super-refractory status epilepticus (srse) is a life-threatening neurological condition that is characterized by status epilepticus that persists for hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. srse is associated with limited treatment options, and high morbidity and mortality. this study aims to describe and quantify inpatient srse treatment and its associated outcomes in the us. srse cases were classified retrospectively using a modified version of a previously published algorithm applied to a large, de-identified, us electronic health record database (cerner health facts®) covering > hospitals ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . cases were classified utilizing icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . and . ) , ventilator support or with los> days or missing age were excluded. univariate statistics were used to describe mortality, hospital los, icu los, and discharge disposition. our algorithm classified cases as srse ( patients). most cases ( %) were to large ( + beds) and/or teaching hospitals ( %). mean hospital los was . days, and icu los was . days. both los and icu los were significa average mortality rate was . %. mortality rates increased with number of tlas used ( - tla= . %; -rged home ( % with tracheostomy), while % (n= ) were discharged to another facility. treatment of srse requires acute, intensive management in the hospital setting. los and mortality rates were high and increased with increasing use of tlas. while good outcomes remain possible even after srse, additional interventions are needed that enable seizure control, liberation from anesthetic and ventilator management, and improved mortality. refractory status epilepticus (se) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. initially used in childhood epilepsies, ketogenic diet (kd) has also accumulated supporting evidence in the treatment of pediatric se. recently, the implementation of kd in adults with refractory and super-refractory se has been shown to be feasible and effective. we describe our recent experience with a new onset refractory status epilepticus (norse) patient and the unexpected challenge of achieving and maintaining a ketotic target. practical advice, a comprehensive review of offenders jeopardizing ketosis commonly used in the neurocritical care unit and alternatives is provided. a previously healthy -year-old woman was admitted with cryptogenic norse following a febrile illness with a course complicated by prolonged super-refractory se. a comprehensive work-up was notable only for mild cerebral spinal fluid (csf) pleocytosis, elevated non-specific inflammatory serum markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (mri). repeat csf testing was normal and serial mris demonstrated resolution of edema and diffusion restriction with gradually progressive hippocampal and diffuse atrophy. she required an aggressive approach including high anesthetic infusion rates, anti-seizure drug trials (in various combinations), empiric partial bilateral oophorectomy, and immunosuppression. enteral ketogenic formula was started on hospital day , however, sustained beta-hydroxybutyrate levels > mmol/l were only achieved days later following a careful comprehensive adjustment of the care plan. notably, a significant response to kd was only achieved with beta-hydroxybutyrate levels > . mmol/l. there are hidden carbohydrates in commonly administered medications for se, antibiotics, and even electrolyte repletion formulations and solutions used for oral care -all challenging the use of kd in this setting. tailoring comprehensive care and being aware of possible complications of kd are important for the successful implementation and maintenance of ketosis. early seizures are estimated to occur in - % of patients with moderate to severe traumatic brain injury (tbi) (herman , vespa ). continuous eeg (ceeg) is essential for detection of nonconvulsive seizures (claassen ) the university of california davis protocol for tbi includes ceeg on a case by case basis, which we reviewed. a retrospective review of patients admitted to icu for tbi from / / - / / was performed for demographics, icu length of stay (los), and ceeg. patients with ceeg were assessed for demographics, tbi severity, gcs, ceeg indication and findings. patients were identified. twenty-one were monitored on eeg. median age was , % were female. indications for ceeg included seizure prior to admission (n= ), altered mental status (ams) (n= ), ams with paroxysmal events (n= ). seizures were recorded in patients. median duration of ceeg was . , . , and . hours among the groups. those with seizures prior to hospitalization were connected to ceeg earliest (median . hours) but had the longest median icu los ( . hours), followed by ams ( . and . hours) and ams with paroxysmal events ( . and . hours). median gcs was , , and respectively. median los for patients without seizures or interictal epileptiform activity (iea) was . hours, . for those with iea only, and . for those with seizures. median gcs was . , , and among the eeg groupings. our data suggests seizures prior to hospitalization, ceeg recorded seizures, and iea predict longer icu los. associated lower gcs likely indicates more severe injuries. tbi patients with ams may have delay to seizure detection and treatment. our rate of seizure detection is lower than expected. a more consistent protocol for ceeg will likely improve seizure detection. prospective studies are needed to determine if ceeg can predict and influence outcomes. status epilepticus is a serious neurologic emergency. although many studies have been published on incident status epilepticus, there are few data on the risk of recurrent status epilepticus. we performed a retrospective cohort study using administrative claims data to identify all patients hospitalized with status epilepticus in california, new york, and florida between - . our primary outcome was a recurrent hospitalization for status epilepticus. survival statistics were used to calculate the cumulative rate of recurrence at days, year, and years. in subgroup analyses, we compared rates of recurrence according to age, gender, race, and etiology (stroke, traumatic brain injury, acute and chronic central nervous system (cns) infections, brain tumors, dementia, autoimmune cns disease, or unspecified etiology). we identified , patients with status epilepticus. during a mean follow-up of . (± . ) years, , ( . %; % ci, . - . %) developed recurrent status epilepticus. the cumulative rate of recurrence was . % ( % ci, . - . %) at days, . % ( % ci, . - . %) at year, and . % ( % ci, . - . %) at years. the -year cumulative rate of recurrence was . % ( % ci, . - . %) in women versus . % ( % ci, . - . %) in men, . % ( % ci, . - . % ( % ci, . - . %) in patients < , and . % ( % ci, . - . %) in white patients versus . % ( % ci, . %- . %) in non-white patients. the -year cumulative rate of recurrence was highest for status epilepticus associated with autoimmune cns disease ( . %; % ci, . - . %) and chronic cns infection ( . %; % ci, . - . %). approximately in patients with status epilepticus experienced a recurrent episode within years. recurrence was most often seen in younger patients, non-white patients, and patients with underlying autoimmune cns disease or chronic cns infection. super-refractory status epilepticus (srse) is a rare, life-threatening form of status epilepticus (se) refractory to multiple therapies including anesthetic third-line agents (tlas). enrollment in a srse clinical trial is challenging because patients may present urgently before srse is confirmed or may dynamically improve before randomization. pivotal clinical trials in srse require patient selection criteria accurately identifying srse at randomization. in this phase trial of brexanolone as adjunctive therapy for confirmed srse, the enrollment scheme enabled operationally confirming srse prior to randomization during a qualifying wean (qw) under real-time eeg neuromonitoring. informed consent was obtained for all subjects ) admitted in se having failed first-and second-line therapies; ) transferred on tlas in seizure-or burst-suppression; or ) transferred without seizure-or burst-suppression or not receiving tlas. subjects were required to achieve seizure-or burst-suppression for hours through continuous administration of one or more tlas, followed by a post-enrollment qw of tlas. enrolled subjects failing the qw were randomized to concomitant brexanolone or placebo following reinstitution of one or more tlas. subjects not randomized after a successful qw underwent a -week follow-up. the qw protocol and criteria for qw failure were developed and implemented utilizing eeg neuromonitoring to confirm srse after enrollment using the definition of shorvon and colleagues. a qw was performed on over evaluable subjects across international sites to enable enrollment of patients with confirmed srse. subjects with a successful qws who were not randomized provided insight into outcomes associated with se and avoided the randomization of patients who did not meet srse criteria following enrollment. the use of neuromonitoring-guided diagnosis during a structured qw helped confirm srse, facilitating the enrollment of appropriate patients into this phase trial in a rare, critically ill, and dynamic srse patient population. autoantibodies to the kda isoform of gulutamic acid decarboxylase (gad ab), commonly found in t dm patients, have been associated with drug resistant epilepsy. ketosis prone diabetes is a heterogenous syndrome encompassing various forms of beta cell dysfunction culminating in diabetic ketoacidosis. rates of epilepsy in patients with ketosis prone diabetes are not known. we compared the prevalence of epilepsy in patients with ketosis prone diabetes in a multi-ethnic population with the prevalence of epilepsy in the type diabetes population as well as the general population in a metropolitan medical center. our study design is prospective review of retrospectively collected sera of patients admitted for diabetic ketoacidosis (defined as ph < . , bicarb < , with ketonemia or ketonuria) for the presence of gad ab. all these sera were assessed separately for autoantibody presence or absence at dr hampe's lab in washington, seattle. we also reviewed patients medical records for neurological diagnoses. this done in a blinded fashion by two separate reviewers. out of our patients with ketosis prone diabetes, . % also had epilepsy. this is higher than the published rate in type diabetics ( . %) and the general population in the surrounding area (< . %). antibody testing revealed % of patients with ketosis prone diabetes were gad ab positive with a rate of epilepsy of %. a two-tailed t test between the gad ab + group and gad ab -group showed no statistically significant difference in prevalence of epilepsy in these two groups. while prevalence of epilepsy is higher in the ketosis prone diabetes population than the general population of houston, the difference is not related to titers of gad ab, and must be due to some other unknown factor in these patients management of refractory status epilepticus commonly involves the induction of seizure-or burstsuppression using anesthetic agents. however, the duration and endpoints of these therapies are not well defined. specifically, weaning anesthetic agents is complicated by the emergence of eeg patterns on the ictal-interictal continuum (iic), which have uncertain significance, given that iic patterns may worsen cerebral metabolism and oxygenation, have a dissociation between scalp and depth eeg recordings, and indicate a late stage of status epilepticus itself. determining the significance of iic patterns in the unique context of anesthetic weaning is important to prevent the potential for unnecessarily prolonging anesthetic coma. we identified a series of patients who underwent over hours of burst-suppression therapy, multiple weaning attempts, and continued weaning despite the initial emergence of iic patterns. patients who experienced anoxic brain injury were excluded from the series. we report cases of patients who underwent successful weaning despite initial emergence of iic patterns. eeg patterns following anesthetic weaning (including lateralized periodic discharges approaching hz frequency and lateralized rhythmic delta activity) as well as terminal eeg patterns are described in detail. in these patients, continuing weaning of anesthetic agents despite the emergence of iic patterns did not result in relapse to status epilepticus. while the metabolic impact of these patterns on brain activity is uncertain, weaning strategies that treat iic as a surrogate of recurrent status epilepticus risk further prolonging anesthetic management and its known toxicity. we speculate that iic patterns are transitional and may have a context-specific association with status epilepticus relapse, with less risk conferred when these patterns are observed during the weaning of anesthetic agents after prolonged burst-suppression therapy. other electrographic features aside from this clinical context may discriminate the risk of status epilepticus relapse, such as eeg background activity. brivaracetam (brv) is approved as adjunctive therapy for focal (partialyears) with epilepsy. brv is available as oral tablets, oral solution, and an intravenous (iv) formulation. the formulations are interchangeable. this abstract reports the safety and tolerability of iv brv. during clinical development, participants received iv brv. we report pooled safety findings from participants receiving brv - mg doses. the therapeutic range of brv is - mg twice daily. in n , healthy volunteers received iv brv as a -minute infusion or mg/min bolus ( , , , or mg single doses; n= in all groups). in ep (nct ), healthy volunteers received iv brv mg as a single -minute bolus injection or oral tablets. in n (nct ), patients received days of brv oral tablets mg twice daily or placebo, and then . days of iv brv mg twice daily either as a -minute bolus or -minute infusion for nine doses in total. treatment-emergent adverse event (teae) data were pooled. data reported are for iv brv - mg (n= ). most frequent teaes were somnolence . %, dizziness . %, fatigue . %, headache . %, dysgeusia . %, euphoric mood . %, feeling drunk . %, and infusion-site pain . %. infusion-site pain was specific to administration route. most teaes were mild or moderate and occurred mostly in healthy volunteers. iv brv was well tolerated, with an ae profile consistent with oral administration except for routespecific injection-site aes, dysgeusia, euphoric mood and feeling drunk. the interpretation of these data was complicated by the difficulty of pooling disparate studies involving healthy volunteers and epilepsy patients with heterogeneous medical histories and concomitant antiepileptic drug use. further clinical trials or real-world experience are needed to understand potential clinical impact. ucb pharma funded refractory status epilepticus (rse) is a challenging condition that requires multiple antiepileptic drugs (aed) to treat. during rse, the brain is under excessive excitation, which results in an increase in glutamate receptors such as alpha-amino- -hydroxy- -methyl- -isoxazolepropionic acid (ampa) and nmethyl-daspartate (nmda).. perampanel (per), a novel, noncompetitive ampa-receptor antagonist, may have a role in the treatment of rse and there are positive results in different animal models with rse. we identified adults patients over a month period who were treated with per for different forms of rse. one was excluded as the etiology of rse was anoxic brain injury and care was transitioned to comfort only within hours of initiating per. three patients had a definite response to per, which we defined as resolution of ictal patterns on electroencephalogram (eeg) within hours of per without adding a new aed. one had a possible response with significant improvement in eeg findings; however, there was some eeg improvement predating the initiation of per. in observed several treatment factors that may have increased response to per. those who responded had it used earlier in the treatment cascade (sixth or seventh vs. ninth or tenthaed ), higher initial dose ( mg vs mg), and were escalated to maximum dosage within hours. they were also more likely be receiving continuous ketamine and midazolam, suggesting a possible synergy with per. there were no documented adverse effects in any patient prior to discharge. one patient did experience a decline in phenytoin levels, which could be related to per as there are reports of enzyme-inducing properties. we observed efficacy of per in several patients with focal and generalized rse without a significant adverse effect profile. further studies are needed to clarify the dosing, timing and appropriate indications in rse treatment. topiramate is a potent broad-spectrum anti-epileptic drug (aed) with several mechanisms of action including blockage of the inotropic glutamatergic ampa receptor, voltage-gated sodium channels, antagonism of non-nmda glutamate receptors and enhancement of gaba mediated chloride conductance. we hypothesize that topiramate is an effective adjunctive therapy in rse and srse due to multiple mechanisms of action. we performed a retrospective analysis of patients admitted to the intensive care unit with status epilepticus (se) at a tertiary referral center from - . we reviewed demographics, age, seizure type, etiology, prior aed/topiramate exposure, time to response to treatment, eeg reports and neuroimaging results. rse was defined as failure of benzodiazepine and another conventional second line aed to stop se. srse was defined as se that continues or recurs hours after being treated with an anesthetic agent. ( %) were male, ( %) had a history of seizures; mean age of patients with se was . years. of treated patients, ( %) had focal non-convulsive se (ncse), ( %) had myoclonic se, had myoclonic, followed by generalized ncse, ( %) had generalized ncse, and ( %) had focal and generalized nonconvulsive se, prior to administration of topiramate. ( %) patients were treated with aeds, ( %) patients with aeds prior to topiramate. electrographic seizures improved in ( %) patients after receiving topiramate. resolution of electrographic seizures occurred within hours in ( %) patients, hours in ( %) patients, hours in ( %) patients and hours in ( %) patients. our findings suggest that topiramate could be an effective adjunctive treatment in rse and srse. however, prospective studies, including larger number of patients are needed to confirm these findings. patients with refractory status epilepticus (se) require multiple antiepileptic drugs (aeds) to abort seizures, and often barbiturates. there is a paucity of data on how to wean aeds safely once seizures are controlled while minimizing medication side-effects or withdrawal symptoms. a retrospective review of patients admitted to mayo clinic in rochester, minnesota for se between and was performed. patient demographics, se type (focal versus generalized, convulsive, and refractoriness), seizure etiology, aeds in admission and at outpatient follow-up, aed side effects from use and withdrawal, and functional outcomes in terms of modified rankin scale were recorded. of ( . %) patients had refractory se, ( . %) patients had refractory non-convulsive status epilepticus (ncse), ( . %) patients had convulsive se, ( . %) patients had ncse, and ( . %) patients had epilepsia partialis continua. of the patients with outpatient follow-up (ranging to weeks following hospital discharge with . % patients following-up within one month), patients were on an aed regardless of etiology. patients were on a median of aed in both refractory and nonrefractory se at follow-up. ( . %) patients had withdrawal seizures after aeds were weaned ( had a prior stroke, traumatic brain injury, idiopathic, multifactorial). none of the patients completely weaned off a barbiturate had seizure recurrence at follow-up. -month mortality in refractory se was / ( . %) and / ( . %) in non-refractory cases. favorable functional outcome at follow-up was achieved in / ( . %) patients with refractory se versus / ( . %) in non-refractory se. we found a low rate of late seizure recurrence after weaning aeds in refractory and non-refractory se, particularly in the case of barbiturates. spreading depolarizations (sd) are strongly associated with secondary brain injury after aneurysmal subarachnoid hemorrhage (sah). however, studies to understand whether sds play a causal role in secondary injury are hindered by existing sd induction methods which are invasive, cumbersome, and cause primary tissue injury. we developed a method to study the role of sds after experimental sah using commercially available transgenic optogenetic mice which express channelrhodopsin (chr ) in cortical neurons. we used in vivo laser speckle and doppler flowmetry, intrinsic signal imaging, and local field potential (lfp) and extracellular potassium shifts to detect sds. we optogenetically induced sds with light through intact and unaltered skull in multiple regions without causing primary brain injury. we found regional differences in thresholds for optogenetically-induced sds (from lowest to highest threshold): ( ) whisker barrel, ( ) motor, ( ) sensory, and ( ) visual cortex. lower thresholds were associated with higher chr tissue expression. changes in lfp and increased extracellular potassium concentrations at the site of stimulation preceded precipitation of an sd. finally, we induced and detected sds in the setting of sah over several days through chronically implanted glass coverslips non-invasive optogenetic light stimulation can reliably induce sds in the setting of sah. longitudinal optogenetic induction of sds in chr transgenic mice is a potentially useful tool to study the role of sds in the pathogenesis of secondary brain injury after sah. aneurysmal subarachnoid hemorrhage is a devastating neurologic injury with significantly prolonged hospital courses and high morbidity and mortality. when aneurysms are detected, they often require securement either via surgical clipping or endovascular techniques. a subset of intracranial aneurysms, given location, poor surgical approach, and wide neck are amenable to flow diversion which promotes thrombosis through redirecting of blood flow within an aneurysm leading to slow obliteration. approximately % of treated aneurysms with flow diversion do not obliterate after months, but currently there is no validated way to predict treatment failure. computational models of blood flow of flow diverted aneurysms predict a significant difference in the hemodynamic energy loss across aneurysms between cases that resolve and those that do not. energy loss could be estimated clinically during angiography, however, this hypothesis needs to be validated experimentally because computer models often over estimate hemodynamic parameters, poorly predict flow through stents, and may not have the resolution to fully describe intra-aneurysmal blood flow. in this pilot study, four cases of giant fusiform intracranial aneurysms will be selected --two with resolution following flow diversion treatment, and two without resolution. models of each vessel geometry will be fabricated using additive manufacturing techniques. under fluoroscopy, within the model vessel, flow diverting stents will be placed within the aneurysm in the same configuration that was achieved clinically. model blood, containing tracer particles will be pumped through model aneurysms and using particle image velocimetry, energy loss will be calculating within model vessels following treatment. energy loss between aneurysms successfully and unsuccessfully treated with flow diversion will be compared experimentally. hemodynamic energy loss may be a clinically measurable value which could predict treatment failure after flow diversion. additive manufacturing techniques can be used to test patient specific hemodynamics to improve understanding of flow-diversion treatment success or failure. the national institute of neurological disorders and stroke (ninds) and the national library of medicine (nlm) initiated development of unruptured cerebral aneurysms and subarachnoid hemorrhage (sah)specific common data elements (cdes) in as part of a joint project to develop data standards for funded neuroscience clinical research. through the development of these data standards, the ninds and nlm sah joint cde initiative strives to improve sah data collection by increasing efficiency, improving data quality, reducing study start-up time, facilitating data sharing/meta-analyses and helping educate new clinical investigators. the sah cde working group (wg) consisted of international members with varied fields of sahrelated expertise and was divided into domains such as subject characteristics and assessments and exams. the wg developed a set of sah-specific cde recommendations by selecting among, refining and adding to existing field-tested data elements, especially established stroke cdes. wg cde recommendations were drafted into the nih cde repository. following an internal review of recommendations, the sah cdes were vetted during a public review on the ninds website for weeks and later posted on nlm and ninds websites. version . of the sah cdes was available on the ninds cde website in april . these new sah cdes and recommendations include those developed for unruptured intracranial aneurysms and long-term therapies. the website provides uniform names and structures for each data element, as well as guidance documents and template case report forms using the cdes. the ninds encourages the use of cdes by the clinical research community in order to standardize the collection of research data across studies. the ninds cdes are a continually evolving resource, requiring updates as research advancements indicate. these newly developed sah cdes will serve to be a valuable starting point for researchers and facilitate streamlining and sharing data. subarachnoid hemorrhage (sah) represents % of stroke admissions in the us. aneurysmal hemorrhage represents the most dangerous etiology, however - % of sah have negative digital subtraction angiography (dsa). there is variation in practice with regards to repeat diagnostic studies and timing of such studies. it is not uncommon to repeat dsa in - days of the initial assessments. this study aims to describe the costs associated with prolonged icu stay and repeat diagnostic studies this patient cohort. retrospective review of all patients admitted for spontaneous sah between january and april at our single institution. patients with at least one negative initial angiogram for suspected spontaneous sah were included. patients were categorized into diffuse patterns of sah and nondiffuse. cost estimates were based on standard costs as provided by our financial department and cdc estimates for costs of hospital acquired infections. one hundred fifty-four patients were identified with initial negative dsa. second angiograms were performed in % of patients, and potentially positive causal findings in / ( . %). icu los for angiogram negative diffuse sah and non-diffuse were . and . days respectively. other indications for icu stay included vasospasm ( . %), evd placement ( . %), and intubation ( %). the excess cost estimates per patient for angiogram negative diffuse and non-diffuse sah were $ , and $ , respectively. hospital acquired complications were an additional total $ , for the cohort. this is the first study to our knowledge attempting a cost analysis of the diagnosis and management of patients with angiogram negative sah. we had a high frequency of patients requiring icu admission for other indications, which should continue to dictate the level of care. however, there may be a cohort of lower risk patients in which de-escalation would not harm, and be of benefit in the reduction of morbidity and cost. purpose: to evaluate the feasibility and potential role of bedside optical coherence tomography (oct) as a diagnostic protocol in terson's syndrome (ts) in patients with acute subarachnoid hemorrhage (asah). background: % of sah patients become permanently legally blind. the average cost of lifetime support and unpaid taxes for each blind person is approximately $ , . ts presents as ocular bleeding commonly associated with asah. it can be diagnosed by fundoscopy, yet retinal haemorrhages, detachments and macular holes may be undetected. early ts identification is critical since untreated it may lead to legal blindness, limit rehabilitation and impair quality of life. pilot study: sah patients were screened for ts with dilated fundoscopy and then with oct. mood assessments (phq- , hds), quality of life measures (nih-promis) and subjective visual function scales (vfq- ) were performed. there was a . % (n= ) incidence of ts. dilated retinal fundoscopy significantly failed to detect ts (n= , . % missed cases). ivh was significantly more in ts ( . % vs. %). no participants experienced any complications from oct examinations. neither decreased quality of life visual scores nor a depressed mood correlated with objective oct pathological findings at weeks follow-up after discharge. there were no significant mood differences between ts cases and controls. oct is the gold-standard in retinal disease diagnosis. this pilot study showcases its bedside feasibility in asah. in our series, oct was a safe procedure that enhanced ts detection by decreasing false negative/ inconclusive fundoscopic examinations. it allows early diagnosis of macular holes and severe retinal detachments, which require acute surgical therapy to prevent legal blindness. besides, oct aids ruling out potential false positive visual deficits in individuals with a depressed mood at follow up. a comprehensive study is underway to understand the impact oct might exert on blindness prevention and quality of life. fever is common in patients with aneurysmal subarachnoid hemorrhage (asah), and blood cultures are commonly sent to diagnose etiology. several studies have shown a low incidence of positive blood cultures, but no studies have assessed blood cultures in patients with asah. we performed a retrospective analysis of patients admitted with asah between january to december . blood cultures were adjudicated as true positive (tp) or false positive (fp) based on speciation, time to positivity, number of cultures positive, and repeat culture results. tp patients were compared to all other patients. age, gender, hunt hess, modified fisher, aneurysm treatment, incidence of delayed cerebral ischemia (dci), length of stay (los), and neurological outcomes were analyzed. patients with asah were included. blood cultures were sent on ( %). sixteen were positive. eleven were adjudicated tp and fp. thus, . % ( / ) of patients had true bacteremia, and blood culture yield for true infection was . % ( / ). fp rate was . % ( / ). eight tps were gram negative ( %), and all contaminants were staphylococcus non-aureus. median post-bleed day for tp results was . only patients were tp within the first week of admission ( . %). tp patients had higher admission wfns (p=. ) and ivh score (p=. ), but age, gender, aneurysm treatment, and fisher score did not differ. tp patients had longer icu and hospital los and higher incidence of dci ( % vs %, p=. ). mortality did not differ in the two groups either. the yield of blood cultures in asah patients is low. even with a contamination rate under %, % of positive blood cultures are fp. future studies should evaluate factors to identify patients at higher risk of bacteremia to reduce costs and improve care. intra-arterial verapamil therapy reduces cerebral vasospasm after aneurysmal subarachnoid hemorrhage (sah). there is little literature that quantitatively describes its safety, required dosing, or efficacy. as a result, therapeutic outcomes need to be subjectively analyzed by experienced radiologists during the intervention and clinically correlated by cerebral perfusion pressure, intracranial pressures and transcranial dopplers. we present a novel imaging analysis to quantify cerebral perfusion in realtime and apply this technology to patients undergoing therapy for vasospasm. we developed software to evaluate changes in contrast flow dynamics for digital subtraction angiography (dsa) scans performed pre-and post-intra-arterial therapy for vasospasm. performing signal intensity curve deconvolution on a voxel by voxel basis provides quantitative d perfusion parameters including: time to peak, time to drain, area under the curve, root mean transit time, arrival time, tissue concentration, arterial input functions and cerebral blood flow at each voxel. after aligning perfusion studies, our software then displays and automatically creates regions of interests for changes in perfusion to visualize the effects of interventions. our software quantitatively measures perfusion from dsas and can normalize two dsas accounting for differences in volume and speed of contrast administration. two applications of this technology are demonstrated. the first subtracts perfusion from pre-and post intra-arterial interventions quantifying exact changes in perfusion at each voxel. the second compares two dsa studies of the same patient at different dates to contour the territories susceptible to delayed cerebral ischemia. we compare this analysis to mri imaging when applicable demonstrating ischemic changes aligning to the susceptible territories outlined by our analysis. dsa based perfusion is an effective study to quantify the need for and the precise effects of endovascular interventions. quantitative thresholds and analysis based on dsa perfusion may assist with real-time assessment of treatment efficacy for patients undergoing intra-arterial verapamil therapy. we aim to characterize the clinical predictors of ventriculoperitoneal shunt (vps) placement in aneurysmal subarachnoid hemorrhage (asah) patients. there has been no clear consensus as to effective measures of predicting vps placement in these patients. we reviewed the clinical data of patients with aneurysmal subarachnoid hemorrhage (asah) who were treated at our institution between - . we eliminated patients who died or had withdrawal of care during admission. we recorded patient demographics and clinical predictors including admission/discharge glasgow coma scale (gcs), hunt hess score, aneurysm size/location, modified fischer score, modified rankin scale (mrs), intracranial pressure (icp) values during evd clamp trial, and incidence of vasospasm requiring intra-arterial therapy. there were patients included in this study and % of patients required vps (n= / ). vps patients had significantly worse mrs functional scores at discharge ( . vs . ; p= . ), but this began to balance at year ( . vs . ; p= . ). aneurysms were significantly larger in vps patients ( . cm vs . cm; ci: . to . ; p= . ). a greater percentage of vps patients had posterior fossa aneurysms, but this was not found to be statistically significant ( % vs %; p= . ). vps patients had significantly lower gcs scores at admission ( . vs . ; p= . ), and discharge ( . vs . ; p= . ). there was no difference in modified fischer score (p= . ) or hunt hess (p= . ), but both variables were higher in the vps cohort. there was no difference in the frequency of vasospasm in the vps cohort (p= . ), or icp values (p= . ). patients presenting with large aneurysms and poor gcs scores had a significantly higher likelihood of requiring vps during admission. these patients had significantly poorer mrs scores at discharge but not at year. subarachnoid hemorrhage (sah) affects a young population and results in death or disability in the majority of those who experience it. this epidemiology is very different from other forms of stroke. consequently, patients with sah and their families may have different priorities for recovery. involving patient perspectives is encouraged in research and is often accomplished using patient-reported outcome measures (proms). however, whether proms reflect patient and family priorities is unclear given that (a) proms are often developed without their input; and (b) generic proms may not apply to specific conditions. we aimed to systematically review the sah literature that has: a) involved patient, family or caregivers in evaluating existing outcome measures, b) developed novel outcome measures by incorporating their perspectives (including co-development), or c) described outcomes important to patients, families, or caregivers. we searched embase and ovid medline from inception to december , . study eligibility and data extraction was performed independently and in duplicate. for each eligible citation, we abstracted the following: study population, design, type of patient involvement, and outcome measure(s), as applicable. we planned a qualitative summary of all included studies. our search yielded unique citations. only four articles have met our eligibility criteria. in each, patients (n= ) self-report impairments resulting from sah and their impact on their lives (aim c). none involve the evaluation of prom applicability. additionally, we found articles that, although they did not meet our a priori eligibility criteria, discuss collecting proms (n= ), using proms to predict health outcomes (n= ), and comparing prom applicability without patient perspectives (n= ) in sah populations. based on our findings, there is alack of patient, family, or caregiver involvement in selecting or identifying outcomes after sah with direct relevance to them. sah research may be overlooking outcomes that are important to patients. early brain injury (ebi) after aneurysmal subarachnoid hemorrhage (asah) is defined as brain injury occurring within hours of aneurysmal rupture. although ebi is the most significant predictor of outcomes after asah, its underlying pathophysiology is not well understood. we hypothesize that ebi after asah is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes associations between cytokines. methods asah patients were enrolled into a prospective observational study and were assessed for markers of ebi: global cerebral edema (gce), subarachnoid hemorrhage early brain edema score (sebes), and huntassays to determine levels of pro-and anti-inflammatory cytokines. pairwise correlation coefficients between cytokines were represented as networks. cytokines levels and differences in correlation networks were compared between ebi groups. of the patients enrolled in t associated with high grade sebes. correlation network analysis suggests higher systematic inflammation conclusions ebi after sah is associated with increased levels of specific cytokines. peripheral levels of il , il and ession levels of individual cytokines may offer deeper insight into the underlying mechanisms related to ebi. few recent studies have evaluated health resource utilization and patient outcomes in aneurysmal subarachnoid hemorrhage (asah) in the united states. empirical evidence implicates asah as one of the highest cost diseases treated in the hospital. we identified asah patients to determine hospital charge, length of stay (los) and patient disposition associated with care in u.s. hospitals using claims data from the national inpatient sample (nis). patients within the international classification of disease, th revision (icd- ) diagnosis code were identified; a secondary analysis of the nis ( ) was conducted utilizing icd- clinical modification codes excluding patients with traumatic and non-aneurysmal sah. population size, patient outcome, average charge and average los were calculated using subgroups including: aneurysmal clipping or endovascular coiling (n= , ), aneurysmal clipping or coiling with external ventricular drain (evd) (n= , ), use of evd only (n= , ), other surgical procedures (n= ) and medically managed (n= , ). analyses were survey-weighted and adjusted for patient and hospital characteristics. in , asah resulted in an average per patient hospital charge of $ , , an average los of days, an average mortality of % and total, annual hospital charges of $ . billion. the highest average charge per patient ($ , ) and hospital los ( days) were attributed to clipped or coiled patients with evd, and highest mortality ( %) found in medically managed patients. these data support the conclusion that asah is a high cost illness managed in u.s. hospitals, and help raise awareness to the potential economic benefits resulting from developing safer, more effective therapies. additional analyses with updated datasets including lifetime burden of asah (e.g. physician fees, long term medical and care costs, hospital re-admission impact, quality of life, productivity loss, caregiver burden) should be explored to understand the full economic burden of asah and the potential cost effectiveness of new therapies. external ventricular drain (evd) placement is a mainstay of treatment for patients with aneurysmal subarachnoid hemorrhage with hydrocephalus or elevated intracranial pressures, but the optimal strategy for evd management is still unclear. the goal of this study was to compare the impact of evd clamping at three different levels on the duration of drain placement and the intensive care unit (icu) length of stay. we performed a retrospective analysis of patients admitted with aneurysmal subarachnoid hemorrhage to the neurological icu from december to january and included all patients who had an evd placed. patients who died were excluded from the study. patients were divided into three groups: patients whose evd was clamped at mmhg, patients whose evd was clamped at mmhg, and patients whose evd was clamped at mmhg. duration of drain placement in days and icu length of stay in days was compared among the groups using an analysis of variance (anova). outcomes were adjusted for presenting hunt-hess score, modified fisher grade, gender, and age. there were patients who had their evd clamped at mmhg, who had their evd clamped at mmhg, and who had their evd clamped at mmhg. there was no difference in duration of evd placement among the three groups (adjusted p-value . , unadjusted p-value . ) nor in icu length of stay (adjusted p-value . , unadjusted p-value . ). evd clamping at three different levels did not affect drain duration nor length of stay in icu. this study was limited by the small number of patients enrolled. further studies are need to clarify optimal strategies for evd management in the icu. headache is a presenting complaint in majority of patients with asah and is known to persist long after initial icu care. various medications have been used for control of headache with major emphasis on opiate use. history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder. we looked at prevalence of opiate use at discharge and its associated factors. chart review of all patients admitted in a tertiary care center between jan and march was carried out. along with baseline demographic data, information about use of pain scores, csf diversion, use of opiates, average morphine equivalent doses, use of opiates at discharge and destination at discharge was collected. analysis was carried out using microsoft excel. the study was approved by hospital irb. patients were admitted with asah in above period ( % female, average age: yrs). ( % home, % snf) survived to discharge. among survivors, % required csf diversion for hydrocephalus. all people complained of pain on presentation and were prescribed opiates during hospital stay. average oral morphine equivalent doses used was mg per day. ( %) patients were prescribed opiates on discharge. alternative regimens included ( patients: tricyclic antidepressant (tca), opiate + tca, acetaminophen, dexamethasone, tca and opiates). most common prescribed form of opiate was oxycodone. there was no significant association between opiate use/morphine dosing and age, gender, final disposition and csf diversion, opiate prescription at discharge is common in patients with asah. no clinical characteristic seem to predict analgesic need at discharge. little data exists about better alternatives leading to variety of treatment approaches. further controlled trials are needed to decrease opiate use and prevent adverse effects delayed cerebral ischemia (dci) in sah has been associated with vasospasm-dependent and vasospasmindependent phenomena. for more than years isolated hemostasis disorders have been reported in these patients. the objective of this systematic review is to describe the natural history of hemostasis in sah. we systematically reviewed the medline, embase, cochrane and lilacs databases using controlled language and the prisma statement and included studies on spontaneous sah analyzing any hemostasis parameter. we screened titles, of which observational were included. evidence was evaluated following the strobe statement. no meta-analysis was attempted because of the methodological nature and heterogeneity of the studies. hemostasis is profoundly altered during the first hours after bleeding, with several alterations noted including a hypercoagulable state concomitant with increased fibrinolysis activation and reduced clot stability. direct and indirect coagulation markers show a trend towards normalization of hemostasis in the first to days. platelet count decreases with a nadir to days after bleeding and a recovery in the following weeks. a later nadir is associated with dci. platelet aggregability is consistently decreased in the first few days, regaining its normal function around the second week after bleeding. in addition, the persistence of these alterations or the presence of a second peak in pro-coagulatory activity is associated consistently with dci and worse functional outcomes. the hyperacute phase of sah is characterized by a profound activation in hemostasis with reduced clot stability, probably due to an increase in the fibrinolytic pathways. on the second day post-bleeding, a slow trend towards normalization takes place, except in patients evolving towards dci. further research on the pharmacologic manipulation of hemostasis in sah might be warranted to decrease dci and improve outcomes in this population. hypertonic saline(hts) is a treatment for sah-related cerebral edema, administered to improve cerebral perfusion and reduce brain injury. hts a supra-physiological chloride concentration that can contribute to acute kidney injury which can lead to a poor outcome. in a previously published single-center cohort of , l sah patients, . % developed acute kidney injury (aki). hyperchloremia, but not hypernatremia, was correlated with an increased risk to develop aki (o.r. . ). aki was correlated with increased mortality. a secondary analysis of the aforementioned sah patient cohort ( ) ( ) ( ) ( ) ( ) ( ) , was analyzed. trends of acute kidney injury were evaluated in relation to the burden of exposure to intravenous chloride, as well as serum levels of sodium and chloride. the proportion of patients developing aki with a maximal serum chloride concentration of (p , will be randomized into one of two treatment groups: standard hypertonic saline solution (nacl . %) versus a solution of nacl/na-acetate. we hypothesize that by reducing the iv chloride burden(baseline compared to post randomization exposure), the delta serum chloride level will decrease, and will subsequently reduce aki occurrence (acetate trial, clinicaltrials.gov nct ). aki is common in sah patient population, and associated with worse outcomes. serum chloride concentrations are a significant risk factor for the development of aki. a prospective randomized clinical trial now underway examining the relationship between the hypertonic solution composition and serum chloride concentration, and to the development of acute kidney injury in aneurysmal sah. spontaneous spinal subarachnoid hemorrhage (ssah) is a rare but serious condition that can lead to a variety of medical complications. literature to this point primarily includes isolated case reports, and none have looked at hyponatremia as a complication. patients were identified from the electronic medical record database at the mayo clinic in rochester, minnesota. the advanced cohort explorer tool was used, searching from january to december . inclusion criteria were spinal subarachnoid blood products due to hemorrhage into the spinal subarachnoid space not due to ( ) redistribution of blood from intracranial subarachnoid hemorrhage, ( ) trauma, ( ) medical procedures, or ) predominant hematomyelia who experienced symptoms and received treatment at our facility. eight patients (median age years, range - ) were identified as meeting the study criteria. five of these eight patients experienced hyponatremia during hospitalization with a median value of meq/l. all of these patients were treated with free water restriction and one patient briefly received . % sodium chloride solution; in all cases the hyponatremia improved after free water restriction. in all cases the hyponatremia improved with fluid restriction, and there was no documentation of increased urine output, suggesting that it was likely due to siadh. cord compression and hyponatremia were present together in two patients, and in these cases treatment of the hyponatremia was particularly useful to avoid worsening edema. to our knowledge this is the first compilation of cases of spontaneous ssah highlighting hyponatremia as a complication. there is significant morbidity and mortality associated with aneurysmal subarachnoid hemorrhage (sah) and only about % of patients survive and resume their previous lifestyle after - months. many randomized clinical trials (rcts) have been conducted yet no treatment definitively improves outcome from sah. outcome is strongly related to baseline factors, yet imbalances are common in early trials. we developed a technique to identify promising treatments at early phase using a pooled control arm model (ppredicts: kent, shah, mandava neurology ) that compares early studies at their own baselines. we applied this method to sah to develop a multi-dimensional model (ppredicts-sah). models for functional outcome and mortality (dependent variables) were developed based on baseline variables (eg: wfns grade - % and age) using methodology developed for ischemic stroke (mandava, kent, stroke ). the outcome model is a -dimensional surface bounded on either side by +/- . prediction interval surfaces. these prediction interval surfaces incorporate statistical variability to assess whether a treatment differs from expected outcome. treatment arms from rcts and single arm trials, of various treatments of sah were compared against the pooled controlled arm. the best model fit was for good outcome (modified rankin score - equivalents) based on % patients with wfns - and age (r = . ; p< . ). seven trials of known negative drug tirilazad were superimposed on the model and fall within the +/- . prediction interval surfaces confirming futility. three trials were neutral and within the prediction interval surfaces while case series using implanted prolonged release nicardipine and a low dose heparin study were above the +p= . surface showing promise. models were also developed for mortality (r = . , p=. ). outcome models based on percentage of high grade wfns and age were successfully developed. this approach may be useful to prioritize treatments worthy of further study. oral nimodipine is recommended to improve outcome in treatment of aneurysmal subarachnoid hemorrhage (asah). fda approved nimodipine liquid oral solution (nos) in to reduce complications associated with administering nimodipine capsules (nc) to patients with impaired swallow. experience with nos at our center has been complicated by increased liquid bowel movements (lbm) prompting unnecessary testing for infectious diarrhea and exposure to invasive fecal management devices. study approved by local qualtiy improvement review committee. data was collected prospectively in consecutive patients diagnosed with asah during intensive care unit (icu) course. formulations of nimodipine available were generic nc (heritage pharmaceutical) and nos (arbor pharmaceuticals). we examined total icu days exposed to nos, icu days with lbm, infectious diarrhea investigations, and fecal management device use. all statistical tests were performed using minitab. patients were studied from / / to / / ; patients exposed to nos for icu days, icu days with lbm, infectious diarrhea investigations, and required fecal management devices. patients exposed to nc for icu days, icu days with lbm (all cases were also received nos), no infectious diarrhea investigations, and no fecal management device requirements. odds ratio for lbm with exposure to nos was . ( % ci . to . , p < . ). the high incidence of lbm with nos resulted in more infectious diarrhea testing and fecal management device use. uncontrolled diarrhea may increase risk for dehydration and delayed cerebral ischemia, although this is not explored in the current study. nos can mitigate risks associated with needle aspiration of nc, however these issues coupled with higher cost may limit benefit of its use. possible solutions may include compounding nc into a liquid formulation by pharmacists or pharmacy technicians. possible safety and cost benefits require further investigation. headache (ha) management after subarachnoid hemorrhage (sah) is challenging and lacks standardization. we hypothesized that inadequate inpatient ha pain management leads to the development of chronic ha (cha) after sah. prospective, observational study of non-traumatic hunt and hess (hh) grades i-iii sah patients admitted from / to / . after informed consent we recorded demographics, clinical and radiographic features, analgesic and steroid doses, hospital course and inpatient pain scores using numeric rating scale (nrs, - ) before (nrs-pre) and after each analgesic administration over post-bleed days - . a phone survey administered - months after admission evaluated cha burden. inpatient ha control effectiveness was evaluated by percent pain resolution from initial pain score, using nrs-pre. the percentage of administrations yielding full pain resolution was compared between those with and without cha. chi-square and t-tests were used for statistical analyses. patients, % female, mean age . ± . years with hh grade i ( / ), ii ( / ), and iii ( / ) sah were enrolled with lost to follow-up. at follow-up, . % patients ( / ) reported daily ha, . % ( / ) occasional ha, and % ( / ) no ha. full pain resolution after analgesic administration was associated with less cha ( [ . %] vs. [ . %], p= . ). mean daily inpatient opioid dose (morphine equivalents) for patients with and without cha was . mg and . mg, respectively (p= . ). mean nrs-pre were . vs . for patients with vs without cha, respectively (p= . ). inpatient analgesia for sah-related ha is inadequate and may be associated with the development of chronic ha. patients with cha had higher mean inpatient pain score and fewer analgesic administrations resulting in complete pain resolution. inpatient opioid dose per day was higher in cha group, although not statistically significant. additional research is needed to characterize the relationship between inpatient headache management and chronic headache after sah. subarachnoid hemorrhage (sah) remains a significant cause of neurological morbidity and mortality with few interventions to prevent delayed cerebral ischemia. hypocapnia has been associated with worse outcomes in brain injury. sah patients may be particularly susceptible to hypocapnia induced vasoconstriction. this study aims to describe the incidence of iatrogenic and spontaneous hyperventilation in sah patients. a descriptive analysis was performed on a retrospective cohort of adult sah patients admitted to beth israel deaconess medical center icus between and with gcs < who were treated with mechanical ventilation and an extraventricular drain, and had at least one abg. patients on chronic ventilator support were excluded. the lowest paco per icu day was analyzed. patients were included with days with at least one documented paco . mean gcs on admission was . (sd . ). . % of patients survived to hospital discharge. . % of patients were exposed to severe hypocapnia (paco mmhg, those with severe hypocapnia had similar pao and pao /fio ratios, but mildly increased leukocytosis ( . vs . ). . % of paco s < mmhg occurred during spontaneous ventilation or over-breathing. prior studies have shown that hypocapnia causes decreased brain tissue perfusion and is associated with worse outcomes in sah patients. these recent data demonstrate that severe hypocapnia is common in patients with sah severe enough to warrant intubation, and is associated with both iatrogenic and spontaneous hyperventilation. hypocapnia is not primarily compensatory or hypoxia driven, as suggested by mean ph and pao . confirmation of this association and potential future interventions require further study. although delirium is associated with higher rates of hospital complications among critical care patients, limited data exist on risk factors for delirium in aneurysmal subarachnoid hemorrhage (sah). a previous study identified older age, high hunt hess grade, intraventricular hemorrhage (ivh), and hydrocephalus as risk factors for delirium. we sought to identify risk factors for delirium during admission after sah. retrospective review was performed of prospectively collected data for consecutive sah patients enrolled into the university of maryland recovery after cerebral hemorrhage (reach) study. baseline data and clinical complications during each admission, including delirium, were recorded. statistical analysis was performed using univariate and multivariate logistical regression. sah patients from july to january were reviewed. while age was not singly associated with delirium during icu admission, higher hunt hess grade, ivh, hydrocephalus, hospital-acquired infection, elevated troponin, and intubation were significantly associated with delirium on univariate analyses. upon stepwise multivariate logistic regression, ivh (or . , p= . ) and intubation (or . , p= . ) remained significantly associated with delirium. ivh and intubation predicts delirium during icu admission for sah. further analyses are needed to determine if the relationship between ivh and delirium is primarily explained by risk of hydrocephalus, risk of fever, medication exposure, or through independent mechanisms. stroke triage scales are very important in order to expedite acute evaluation, assure quick door to neuroimaging time and decrease door to needle time in patients with ischemic stroke eligible to intravenous thrombolysis. subarachnoid hemorrhage (sah) is associated with a high mortality in the acute phase due to a particular risk of early and devastating re-bleeding. therefore patients with sah also need urgent assessment. the performance of classic triage stroke scales in the identification of patients with sah was not previously evaluated. the objective of our work was to evaluate the performance of the los angeles prehospital stroke screen (lapss) in identifying patients with sah admitted to a tertiary hospital. we evaluated consecutive patients admitted to a tertiary hospital with sah from january to may . at hospital admission, lapss was applied by trained nurse personnel to all noncomatose patients with complaints suggestive of neurological disease. a total of with sah patients were evaluated (mean age . +/- . ), . % females). lapss was applied to patients. lapss was positive in only patients ( . %). patients with a positive lapss had higher nihss stroke score at admission ( , [ , ] versus , p< . ), lower glasgow coma scores ( [ , ] versus , p< . ) and a significant shorter door to neuroimaging time (p< . ). in patients with sah and mild symptoms, lapss was not a sensitive screening tool in our series. hospital and pre hospital services using lapss for triage of patients with stroke should be aware of this limitation and include in triage flowcharts specific questions evaluating sah specific symptoms. spontaneous subarachnoid hemorrhage (sah) is a neurological emergency, which despite current advances in management strategies and advent of institutional protocols, remains with significant rates of mortality due to poorly understood causes. our objectives were to characterize in-hospital mortality by evaluating the primary cause of death and externally validate the hair score, a clinical score that prognosticates mortality. in this retrospective cohort study, we reviewed all sah patients admitted to our neuro-icu between april , and march , . univariate and multivariate logistic regressions were performed to identify predictors of in-hospital mortality, our primary outcome. to validate the hair score, the model's predictors were hunt and hess score at treatment decision, age, intraventricular hemorrhage, and re-bleeding within hours. discrimination was assessed by visualizing the receiver-operating curve and calculating the area under the curve (auc). among sah patients with a median age of years (interquartile range, - ), . % females, inhospital mortality was . % (n= ). of those, ( . %) had a neurological cause for death or withdrawal of care and ( . %) had a cardiac death. median time from sah to death was days. the main causes of death were the primary effects of the initial hemorrhage, re-bleeding and refractory edema. factors significantly associated with in-hospital mortality in the multivariate analysis were age, hunt and hess score, and intra-cerebral hemorrhage. maximum lumen size was also a significant risk factor among aneurysmal sah patients. the hair score had a satisfactory discriminative ability, with an auc of . . our in-hospital mortality is lower than previous reports, attesting to the continuing improvement of our protocolized subarachnoid hemorrhage care. the major causes are the same as previous reports. the hair score showed good discrimination and could be a useful tool for predicting mortality. so far, scientific and therapeutic efforts mainly focused on the prevention of rebleeding and ischemic complications(dci) in patients with subarachnoid hemorrhage(sah). however, data regarding the impact of parenchymatous hemorrhage(ph) on longterm outcome in these patients is limited. all consecutive patients with atraumatic sah admitted to our hospital over a -year-period( - ) were retrospectively analyzed. extent of sah as well as presence, localization and volume of ph were evaluated. functional and health outcome were assessed after months using the modified rankin scale (unfavorable: - ) and the eq- d. propensity-score(ps)-matching was performed to minimize potential bias due to confounding variables between sah-patients with and without ph. of overall patients with atraumatic sah, ( . %) patients had ph on initial imaging. ph-patients had a worse clinical condition on admission (wfns: ph ( - ) vs. Øph ( - );p< . ) and a greater extent of sah (modified fisher: ph ( - ) vs. Øph ( - );p= . ). median ph-volume was . ( . - . )ml with largest volumes in patients with ruptured )ml). after successful ps-matching (parameters: age, wfns, modified fisher and graeb score) patients with ph had worse functional and health outcome after months compared to those without ph (mrs - : ph / ( . %) vs. Øph / ( . %);p= . ; eq- d: ph ( - ) vs. Øph ( - ); p< . ). in multivariate analysis presence of ph was the strongest independent predictor of unfavorable outcome after months followed by the occurrence of dci (risk-ratio( %ci): ph . ( . - . ); p< . ). parenchymatous hemorrhage is frequent and associated with functional and subjective impairments in patients with atraumatic sah. aneurysmal subarachnoid hemorrhage (asah) is associated with early and delayed brain injury. insulin growth factor (igf ) is a potent cellular growth-promoting factor with demonstrated independent neuroprotective actions in stroke and neurologic disease but has not been well characterized after asah. this study sought to examine the relationship between plasma igf levels and outcomes after asah. this cohort of asah patients was . years (sd . ) and female ( %) with a mean hh ( %), wfns ( %) and fisher ( %). initial and peak plasma igf concentrations were measured in plasma samples from a banked biorepository using a commercial sandwich solid-phase elisa kit. delayed neurological deterioration (dnd) and delayed cerebral ischemia (dci) were determined using radiologic and clinical information. igf levels were log transformed due to non-normality. anova, t-tests, pearson correlations and logistic regression analyses were completed using spss and sas. older age was significantly associated with lower initial and peak plasma igf levels (r=. , p<. ; r=. , p<. ). men had higher initial and peak plasma igf levels than women (p<. ; p=. ), and premenopausal women had higher initial and peak plasma igf levels than post-menopausal women (p=. ; p=. ). lower peak plasma igf levels were associated with increased clinical severity by wfns (p=. ) and fisher grade (p=. ) as well as the development of dnd (p=. ; p=. ). lower peak igf levels were associated with the presence of dci (p=. ). controlling for age and fisher grade, log peak plasma igf levels remained significantly associated with the presence of dnd (p=. ; or . ; ci: . -. ) and dci (p=. ; or . ; ci: . - . ). igf levels have not been well characterized after asah. these results suggest lower plasma igf are associated with clinical severity and outcomes after asah and provide impetus for future work to further examine these relationships. induced hypertension (ih) is the mainstay of medical management for delayed cerebral ischemia (dci) after subarachnoid hemorrhage. however, using vasopressors to raise systemic blood pressure well above normal levels may be associated with systemic and neurological complications, of which posterior reversible encephalopathy syndrome (pres) has been increasingly recognized. however, the frequency and risk factors for ih-induced pres have never been systemically evaluated we identified patients treated with ih from sah patients admitted over a three-year period. pres was diagnosed based on clinical suspicion (i.e. unexplained deterioration), confirmed by imaging. we conducted retrospective extraction of data on ih therapy, including baseline and highest target mean arterial pressure (map) and vasopressor dose/duration. we compared those with pres to ihtreated controls and also described the clinical features and sequelae of all pres cases. five sah patients were diagnosed with pres, with median time from initiation of vasopressors to diagnosis of . days (range - days). baseline map did not differ between pres and ih controls, but highest target map was greater ( vs. mm hg, p= . ). magnitude of ih was similarly greater ( vs. mm hg above baseline, p= . ). all cases presented with lethargy, three had new focal deficits, and one had a seizure. one died from cardiac complications but the other four patients had complete resolution with ih discontinuation, without infarction or residual disability. pres was diagnosed in % of patients undergoing ih therapy and was most likely when map was raised well above baseline to levels exceeding the traditional limits of autoregulation ( - mm hg). high clinical suspicion for this reversible disorder appears warranted when aggressive ih targets are maintained for several days or in the presence of unexplained neurological deterioration. other interventions may be preferable for refractory dci when moderate degrees of ih have been attempted. patients with aneurysmal subarachnoid hemorrhage (asah) may receive significant exposure to potentially harmful ionizing radiation exposure (phire) from diagnostic tests and therapeutic procedures during their initial hospitalization. we hypothesized that risk factors to detect excessive phire are present at the time of admission. following irb approval, all patients admitted to our institution with documented asah over a -year period were retrospectively evaluated for inclusion and exclusion criteria. patients were excluded if they died prior to discharge. all study data, including sah-specific and patient-specific risk factors, were obtained from the electronic medical record. the total effective dose of ionizing radiation (tedir) per patient was calculated from previously published radiation exposure data. phire was considered to have occurred if tedir was greater than msv, the annual phire limit for radiation workers. logistic regression models were then fit to the dataset to evaluate clinical variables that significantly the risk of phire in these patients. data were collected from patients ( . % of all asah patients evaluated). the mean tedir in these patients was . msv. forty-two ( . %) of patients met criteria for phire. in multivariate logistic regression modeling, male gender (or= . , ci= . - . ), posterior circulation aneurysms (or= . , ci= . - . ) and ventriculostomy (or= . , ci= . - . ) were significantly associated with an increased risk of phire. in this study, approximately % of asah patients received phire. male gender, posterior circulation aneurysms and ventriculostomy were significantly associated with increased risk of phire. these factors may serve as important predictors of patients who require additional or complex care necessitating repeated diagnostic or therapeutic procedures during their hospitalization. alternative diagnostic or therapeutic modalities should be considered for patients with these risk factors to limit the risk of phire. future research should also evaluate the effect of phire on neurologic outcomes in these patients. it remains unclear whether patients with unruptured intracranial aneurysms (ica) should be treated. vessel wall enhancement (vwe) in high-resolution magnetic resonance vessel wall imaging constitutes a promising marker of aneurysm instability in this population. to find risk factors for aneurysm instability, we sought to identify predictors of vwe in patients with unruptured icas. we conducted a retrospective analysis of prospectively collected data on patients with unruptured ica evaluated by a single provider. all patients were evaluated using a previously validated algorithm to ascertain vwe using high-resolution magnetic resonance vessel wall imaging. two different raters, blinded to the study data, categorized all observed aneurysms as vwe-positive or vwe-negative. kappa statistics were used to evaluate the reproducibility of this approach. univariable and multivariate logistic regression modelling was utilized to identify factors associated with vwe after adjusting for potential confounders. patients with unruptured ica were included in the analysis (mean age [sd ] , female sex [ %]). of these, ( %) were vwe-positive and ( %) were vwe-negative. inter-rater reliability for vwe ascertainment was excellent (kappa . , %ci . , . ). out of ( %) patients presenting with cranial nerve palsy were vwe-positive. in univariable analysis, age (p= . ), headache on presentation (p= . ), and size (p< . , per additional millimeter) were associated with vwe-positive status. in multivariable analysis, headache on presentation (p= . ) and size (p= . ) remained independently associated with vwe. cranial nerve palsy is an established clinical marker of aneurysm instability; consequently, our results confirm the role of vwe as a marker of aneurysm instability. headache on presentation and aneurysm size are independently associated with vwe; these risk factors for aneurysm instability could be used to select patients with unruptured icas that may benefit from vessel wall imaging. prognostication in subarachnoid hemorrhage (sah) patients presenting in coma is crucial for surgical decision making. indications for aggressive aneurysmal treatment are unlikely for those not demonstrating signs of neurological improvement chronologically or after ventricular drainage. early neurological evaluation is, however, challenging in critically ill sah patients requiring anesthesia and intubation for airway protection. in this single-center retrospective study, we applied continuous amplitude-integrated eeg (aeeg) monitoring using a subhairline montage for wfns grade v patients who did not undergo emergency aneurysm treatment. monitoring was initiated soon after admission to the icu. patterns of aeeg findings were classified according to rundgren, et al. as follows: flat (f); suppression-burst (sb); electrographic status epilepticus (ese); and continuous (c). based on the aeeg findings, indications for aneurysm treatment were reevaluated. outcome was assessed at six months using the glasgow outcome scale. twenty-three patients, men and women, aged . ± . years (mean ± sd), were eligible since december . all patients underwent prophylactic intravenous sedation. the population represented % of all grade v patients including those resuscitated after cardiac (n= ) or respiratory (n= ) arrest. the glasgow coma scale scores were (n= ), (n= ), and (n= ), respectively. aneurysms were located in the posterior fossa in patients ( %). aeeg monitoring was initiated . ± . hours median . , . - . hours after arrival. all patients showing early f (n= ) or sb patterns (n= ) died. one patient demonstrated ese remained in a persistent vegetative state. five out of patients with a c pattern underwent aneurysm treatment; clippings and coil embolization. moderate disability was attained in and severe disability in . two patients undergoing conservative therapy died. continuous aeeg provided useful prognostic information for identifying salvageable sah patients undergoing sedation in the early phase. delayed cerebral ischemia (dci) may result in focal neurological deficits and cerebral infarction after subarachnoid hemorrhage. while global cerebral blood flow (cbf) may be variably reduced, dci is more likely related to regional impairments in cbf below critical perfusion thresholds. we applied volumetric methods to assess the proportion of brain exhibiting hypoperfusion (pbh) in those with clinical dci and in the symptomatic hemisphere of those with focal deficits. methods patients with aneurysmal sah underwent o-pet and ct imaging during period of risk for dci (median days after sah, iqr - ). we measured pbh as proportion of voxels with cbf < ml/ g/min, after excluding regions of infarction/hematoma on ct. we compared pbh in patients with vs. without dci at time of pet and, in those with focal deficits, we compared hypoperfusion between affected and unaffected hemispheres. pbh was greater in the ( %) with dci compared to those without dci ( %, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) p= . ) despite higher mean arterial pressure (map) and most being on active hemodynamic therapies. global cbf was also lower in those with dci ( . vs. . ml/ g/min, p= . ) but did not differ between those remaining symptomatic and those whose deficits had resolved. while mean hemispheric cbf was not lower in the affected hemispheres of with lateralizing deficits ( . vs. . ml/ g/min, p= . ), there was greater pbh in the symptomatic hemisphere ( % vs. %, p= . ). sah patients with dci have a greater proportion of brain with hypoperfusion despite active hemodynamic therapy and higher map. there was also larger proportion of the symptomatic hemisphere with hypoperfusion despite no asymmetry of hemispheric cbf. such measurements of hypoperfusion may better reflect the regional pathophysiology of dci than global averaged measures of cbf. further studies should determine whether burden of hypoperfusion correlates with tissue and patient outcomes. patients who survive aneurysmal subarachnoid hemorrhage (asah) are often burdened with lasting cognitive impairment due to a combination of sequelae including neuro-cardiac injury. the impact of neurocardiac injury after asah is poorly understood. this study sought to examine if neurocardiac injury detected by global longitudinal strain (gls) is associated with poor performance in neuropsychological np memory impairment after asah. we studied asah patients at months and at months (sahmii study r nr ) after hemorrhage. speckle tracking gls from apical views were assessed days - from bleed from transthoracic echocardiograms. neuropsychological (np) outcomes covering domains were completed at and months after hemorrhage by trained personnel. memory tests included controlled oral word association (cowa), wechsler memory scale (wms) and rey auditory (r-aud) and complex figure (reyc). anova and kruskal-wallis, pearson and spearman correlations and logistic regression were completed using spss and sas. there were ( %) patients with abnormal gls (defined as >- %) and ( %) in the and months groups respectively. gls groups had similar age, gender and fisher grade. abnormal gls was associated with higher hh at (p=. ) and (p=. ) months. abnormal gls was significantly associated with decreased performance in r-aud memory domains at months (p=. ) and months (p=. ) after asah and even when controlling for age and hh at months (p=. ). gls<- was associated with poor memory performance months after asah in cowa (p=. ) and the wms (p=. ) even after adjusting for age and hh, cowa (p=. ) and wms (. ). neuro-cardiac injury detected by gls was associated with decreased performance in memory domains of np function at and months after asah. while these relationships require further examination, neurocardiac injury may contribute to long term np impairment after asah. delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. we hypothesize that ketamine infusion (k), as compared to traditional sedatives (control), will safely improve the hemodynamic profile in high grade ventilated asah patients retrospective review of asah patients admitted / to / requiring mechanical delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. ventilation > hrs, and without dnr within hrs from admission. we assessed demographics, hemodynamics, pressor, dci at weeks, ventilator and icu los, and mortality. fisher exact, wilcoxon, and paired t-test applied. comparing k (n= ) vs control (n= ), median (q , q ) results for: age ( , ) vs ( , ); hunt and hess ( , ) vs. ( , ); mpm- day estimated mortality . % vs. . %; and gcs ( , ) vs ( , ) . ketamine initiated on day ( , ); icu los ( , ) vs. ( , ); and vent los ( , ) vs. ( , ) . mean (sd +/-) for hours before and after ketamine: map ( ) vs ( ), p . , except where noted. ketamine infusion, as a second line sedative, had no effect on mortality or icp, and improved map. however, there was a nonsignificant increase in dci as well as vent los, without a greater rate of tracheostomy. prospective studies are needed to study the effect on dci and long term outcomes. seizures are a well-known complication of aneurysmal subarachnoid hemorrhage(asah) and occur most commonly in the immediate post-hemorrhagic period. most commonly used antiepileptic drugs (aeds) for seizure prophylaxis in asah include phenytoin and levetiracetam. there is no reliable data available on the safety and efficacy of restricting aed prophylaxis only till the aneurysm is secured. we retrospectively chart reviewed patients admitted to our neurosciences intensive-care-unit with asah during the last two years. seizure incidence was studied in patients treated with phenytoin versus levetiracetam and in patients treated for to days versus those where aed was discontinued immediately after aneurysm was secured. in patients aed prophylaxis was discontinued immediately after the aneurysm was secured, and in patients it was continued for to days. of th phenytoin was used in patients and levetiracetam was used in patients. in patients receiving aed prophylaxis for to days, phenytoin was used in cases and levetiracetam was used in cases. none of these patients had seizures reported during hospitalization or at three month follow-up. stopping the aed prophylaxis immediately after aneurysm coiling is not associated with increased risk of seizures. seizures at presentation in patients with asah are not associated with development of epilepsy at months. both phenytoin and levetiracetam are well tolerated in patients with asah when limited to the immediate post-hemorrhagic period. the main preceding factor of delayed cerebral ischemia (dci) in asah is cerebral vasospasm (cvs). anticipating dci can have major impact on patient outcomes. studies have attempted to predict dci in patients with asah by using various imaging modalities that measure cvs, ranging from transcranial doppler ultrasonography, ctp, and mr perfusion. few compare these imaging modalities to the accepted gold standard of dsa. we propose that mri using asl imaging can be used as a sensitive and specific measure of cvs and can be used as a marker to identify patients with asah who are at risk for developing dci. to support our hypothesis, we compare asl results in patients with documented cvs on dsa who developed dci. patients in the academic years to with the diagnosis of asah were admitted to our nicu. the inclusion criteria for the patient population was the presence of asah confirmed by dsa, diagnosis of dci by a neurointensivist, mri with asl, and a repeated dsa during the hospitalization after dci was suspected. all patients underwent mra with asl on day in an attempt to capture the peak time of cvs. nine patients were included in this study. all cases with perfusion defects on asl sequences had confirmed cvs on dsa except for one. the outlier in our cohort developed dci with asymmetry on asl that was not demonstrated on dsa. to our knowledge, no studies have compared the specificity of asl with dsa in detecting cvs. this study highlights the utility of asl in detecting cvs in patients with asah. our limited data suggests asl can be utilized for detection of dci and cvs with greater confidence than the conventional modalities. we also suggest that asl approaches the utility of dsa in the detection of cvs. blood glucose dysregulation following aneurysmal subarachnoid hemorrhage is associated with serious complications and poor clinical outcome. an influence of hyperglycemia on the occurrence of delayed cerebral ischemia (dci) is assumed, nevertheless the exact mechanism remains unclear. the goal of the present study aims to investigate the influence of systemic blood glucose level on cerebral perfusion measured by dynamic perfusion computed tomography (pct) and outcome. daily serial blood glucose levels and pct data sets of patients treated at our neurointensive care unit after asah were retrospectively analyzed. serial pcts were performed between six hours and days after aneurysm repair. mean average of mean transit times (mtts) was calculated for each perfusion scan. the maximum mean transit time (maxmtt) and outcome assessed with glasgow outcome scale were correlated with defined blood glucose ranges as followed .) > mg/dl (hyperglycemia) .) - mg/dl (elevated glucose level) .) - mg/dl (strict glucose control) and < mg/dl (low glucose level). hyperglycemia (> mg/dl) was associated with prolonged maxmtt (p< . , rs = . ) and was linked to an increased risk of infarction (p < . ) whereas strict glucose control ( - mg/dl) correlated significantly negative with maxmtt (p < . , rs = -. ). strict glucose control was also associated with a lower occurrence of cerebral infarction and good outcome (p < . , rs = . ). in contrast, elevated blood glucose levels ( - mg/dl) and hyperglycemia showed a negative correlation with good outcome (p < . , rs = -. , rs = -. ). the present analysis supports for the first time the assumption that dysregulation of blood glucose balance influences cerebral perfusion and thus may contribute to the occurrence of dci and poor outcome. therefore careful monitoring and prompt treatment of blood glucose levels after asah should be highly valued to avoid cerebral perfusion deficits correlated with poor outcome. the aim of this study was to determine the correlation between transcranial doppler (tcd) velocities and angiographic vasospasm after subarachnoid hemorrhage (sah). methods patients with sah were evaluated with spencer technologies tcd power m mode from - days, following the sah. both the temporal windows were insonnated to determine flow velocities in the middle (mca) and anterior cerebral arteries (aca) and the suboccipital widow was used to determine flow velocities in the vertebral (va) and basilar arteries (ba). the middle cerebral artery/ipsilateral extracranial internal carotid artery velocity ratio (lindegaard ratio) was also correlated with vasospasm ct angiography and conventional cerebral angiography was used to confirm tcd findings suggestive of vasospasm. the sensitivity, specificity, likelihood ratios for positive and negative tcd results, positive there was males and females and with mean age . +- . years. % were aneurysmal sah. delayed ischemic neurological deficits (dind) developed in / patients ( . %). interobserver ue of cm/s were useful (likelihood ratio for negative result = . , likelihood ratio for positive result = . ). lindegaard ratios correlated well with vasospasm. tcd diagnosis of vasospasm was more often present in the mca, followed by aca and basilar arteries. tcd is a good non invasive method to detect vasospasm and predict the occurrence of dind. very high angiographic vasospasm. tcd is also useful to follow up patients with angiographically proved vasospasm. aneurysmal subarachnoid hemorrhage (asah) is a significant cause of morbidity and mortality. the mortality rate approaches %. nearly half of the survivors remain unable to care for themselves . dci occurs in % of these patients . when present, it doubles the risk of poor outcome. -several methods have been used to treat cerebral vasospasm and dci, which is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (sah). milrinone safe and, potentially, effective treatment of dci as reported in low level of evidence literature . however, the efficacy not compared in a randomized way to placebo. we will examine the effectiveness and safety of intra-venous injection of milrinone for the treatment of dci following aneurysmal sub-arachnoid haemorrhage. our intension is to study the outcome of using milrinone as an addition to current therapies such as hypertensive therapy are not effective enough, yet can not be replaced as it is standard of care. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. the study is a pilot trial of a randomized placebo-controlled double blind trial testing the potential beneficial effect of milrinone, a phosphodiesterase inhibitor, on clinical neurological outcome in patients with dci after aneurysmal subarachnoid hemorrhage. the study drug will be given along with the standard therapy when dci occurs. the administration of milrinone increases cerebral blood flow most likely as a result of cerebral vasodilation. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. milirinone promising treatment for delayed cerebral ischemia following aneurysmal sub-arachnoid haemorrhage .particulary by using standardized protocol as a finding suggestive of good prognosis fever in the neurocritical care population is very common and is strongly associated with increased mortality and poor outcome. fever is aggressively treated in the icu due to its deleterious effects. yet despite best efforts with standard antipyretic agents and even with aggressive cooling measures with endovascular cooling catheters some patients may still have refractory fevers. celecoxib, a cyclooxygenase- (cox- ) inhibitor, has been used as an adjunctive antipyretic agent. this is a retrospective analysis to evaluate the effectiveness of celecoxib in lowering temperatures in patients with refractory fevers. this is a retrospective chart review of patients admitted to a neurointensive care unit at a single institution with fevers (> . c) that do not respond to convention treatment with acetaminophen, endovascular cooling catheters and ibuprofen. patients with severe traumatic brain injury, subarachnoid hemorrhages and intracerebral hemorrhages were included. patient temperature recordings were obtained in the period of hours before and hours after administration to the first dose of celecoxib. the mean temperature of the before and after periods were compared and temperature difference was calculated. patient records were included. the average of the mean temperatures in the before periods and after periods were . c (+/-sem . ) and . c (+/-sem . respectively. there was a significant difference on mann-whitney-wilcoxon rank sum test (p< . ). one average there was a drop of . (+/-sem . ) degree celsius of the mean temperature after the start of treatment. in neurocritically ill patients with fevers that are refractory to conventional treatments adding celecoxib, a cox- inhibitor seems to be effective at lowering the core body temperature. further study is warranted to evaluate for adverse effects such as risk of cardiovascular events. achieving and maintaining normothermia (nt) after subarachnoid hemorrhage (sah) or intracerebral hemorrhage (ich) often requires temperature modulating devices (tmd). shivering is a common adverse effect of tmd's that can lead to further costs and complications. we evaluated a new esophageal tmd, the ensoetm (attune medical: chicago, il), to compare nt performance, shiver burden, and cost of shivering interventions with existing tmd's. patients with sah or ich and refractory fever were treated with the ensoetm. patient demographics, temperature data, shiver severity, and amount and costs of medication used for shiver management were prospectively collected. control patients who received other tmds were matched for age, gender, and body surface area (bsa) to ensoetm recipients and similar retrospective data was collected. all patients were mechanically-ventilated. fever burden was calculated as areas of curves of time spent above . or c. demographics, temperature data, and costs of ensoetm recipients were compared to recipients of other tmd's. eight ensoetm recipients and controls between october and november were analyzed. there were no differences between the two groups in demographics or patient characteristics. no difference was found in temperature at initiation (p = . ) and fever burden above °c (p = . ). ensoetm recipients showed a non-significant trend in taking longer to achieve nt than other tmd's (p = . ). ensoetm recipients required fewer shiver interventions than controls (p = . ). ensoetm recipients incurred fewer costs than controls per day (p = . ). the ensoetm achieved and maintained nt in sah and ich patients and was associated with less shivering and lower pharmaceutical costs than other tmd's. further studies in larger populations are needed to determine the ensoetm's efficacy in comparison to other tmd's. targeted temperature management is an important aspect of care in neurologically impaired patients. however, achieving optimum temperature for a specific patient can be challenging; a patient's size, body composition, metabolism, and hypothalamic function contribute to his or her response to a given temperature management modality. the purpose of this study is to evaluate patient response to esophageal temperature management when continuously applied for at least h. deidentified core temperature data for patients (a total of measurements) were obtained from three hospital sites where esophageal temperature management was used for at least h (range - h). indications for active temperature management included: cardiac arrest ( ), refractory fever ( ), subarachnoid hemorrhage ( ), intracranial hemorrhage ( ), and traumatic brain injury ( ). goal temperatures ranged from - °c and initial patient temperatures ranged from - °c. deviation from goal was calculated by subtracting target temperature from actual temperature for each measurement which allowed the calculation of the mean and standard deviation for each time point across all temperature management protocols. across time points, representing an average treatment time of . h, . % of mean deviations from goal were within ± °c and . % were within ± . °c. in interpreting these results, several limitations must be considered. this dataset reflects a wide range of temperature management protocols and clinical scenarios. for example, a larger than average deviation in measurements recorded in the - h period was related to rewarming in cardiac arrest patients who rewarmed slowly. also, the later time points were dominated by sah, ich, and refractory fever patients who often experience more pronounced fever spikes. this analysis indicates that esophageal temperature management is a feasible option for patients who require active temperature management for or more hours. the role of therapeutic temperature management (ttm) in neurocritical care is uncertain. one question that has been inadequately addressed is the diversity of practice across multiple neurocritical care units (nccu) throughout the world. a barrier to understanding this practice variance is a data collection method that would provide adequate understanding of how ttm is implemented in various nccus. the purpose of this pilot study is to test the efficacy of a data collection method that would provide unitlevel data on ttm practice. the design of this study was prospective, observational, and cross-sectional study using quality assurance methodology. the study received institutional review board approval. to reduce the risk of loss of confidentiality and promote privacy, individual patients were not consented. data on temperature management was collected each day for consecutive days. completed data was available for days. mean daily census of patients included the following mean number of patients with sah ( ), ich ( ), ischemic stroke ( ) and other ( ). of those, ttm was provided to at least one patient during of days ( . %). the most common ttm method (tylenol) was used on patient days; surface cooling was used on patient days. ttm was initiated for fever management ( patient days) and normothermia ( patient days). the most common associated complication was hypocalcemia ( ) and hypokalemia ( ). the data collection form was easily and quickly filled completed on a daily basis, but provides limited data. although the form captured a significant number of events surrounding the use of ttm, the primary limitation noted is the inability to link specific events (e.g., hypokalemia) to specific patients or diagnoses. this pilot study demonstrates the efficacy of data capture and provides insight towards refining a prospective observational study to describe ttm practice. brainstem tumors are exceedingly dangerous due to its proximity to the structures responsible for basic human survival in the neurocritical care setting. these lesions may cause autonomic dysregulation. we report on a rare case of a female with a past surgical history of ventriculoperitoneal shunt with a brainstem mass of müllerian type epithelial tissue. methods year old caucasian female presented to our hospital status-post fall after episodes of lightheadedness, as well as, episodes of decreased respirations in her sleep. mri showed a medullary contrast enhancing mass with calcifications measuring . x . x . cm and a small calcified lesion in the right lateral ventricle. suboccipital craniectomy for biopsy and decompression was performed. intraoperatively, the heart rate and blood pressure dropped transiently due to the mass being firmly adhered with calcification to the medulla. the neuropathologist diagnosed the tissue as mullerian type epithelium with estrogen receptors. post-operatively, our patient encountered several instances of cardiac pauses on monitoring that required the need for cardiology to place a permanent pacemaker. the above is a rare case of a calcified heterogeneously contrast enhancing brainstem mass that underwent neurosurgical biopsy. histopathology results indicated müllerian type epithelial tissue which is tissue that gives rise to female reproductive organs. the origin of a brainstem lesion from an embryologically gynecological site could be speculated to have traveled retrograde via the ventriculoperitoneal shunt catheter. patient required postoperative cardiac management and intervention with a pacemaker for encroachment or mechanical conflict of the mass onto the rostral ventrolateral medulla. oncology recommended pet ct scan and further consideration for tamoxifen chemotherapeutic regimen. this case is a reaffirmation of the importance of brain tumor location and tissue diagnosis for the purpose of adjuvant treatment of neurosurgical lesions in the neurocritical care setting. tranexamic acid (txa) has been used off label in cardiovascular and orthopedic surgery, as well as in trauma resuscitation. the use of txa has increased since the publication of crash- ( ) and matters ( ), demonstrating its efficacy in trauma patients to reduce bleeding. there remains concern about the thrombotic risk as well the reduction in the seizure threshold after txa administration. case description: we present a case of a -year-old female admitted to the surgical icu after a motor vehicle accident with multiple traumatic pelvic and extremity fractures and soft tissue injury. she subsequently developed extensive arterial and venous thromboses with bilateral acute ischemic strokes with superimposed posterior reversible encephalopathy syndrome after txa administration. a second case involved a -year-old female who had a fall from standing and given txa in the field by ems. shewas admitted to the neurocritical care unit with status epilepticus and suffered a complicated course with cardiogenic shock due to stress induced cardiomyopathy. discussion: the risk-benefit balance of txa administration is generally considered acceptable in severe bleeding. the cases presented here suggest the neurological risks of txa administration may be poorly understood and demonstrate the need for better patient selection and heightened awareness for early identification and management of complications given the possible severity of neurologic sequelae. conclusion: txa is an anti-plasmin drug that is increasingly used in the areas of trauma and postoperative bleeding. we aim to educate clinicians in the potential neurological complications that can arise with its use. cryptococcus neoformans is normally an opportunistic infection known to cause meningoencephalitis and can present with stroke like symptoms. in imaging, cns vasculitis can be identified, which can lead to cerebral infarcts. when involved, these cerebral vessels are small sized leading to lacunar infarcts. we present a case that involved a large vessel territory leading to patient mortality. initial treatment with glucocorticoids, though beneficial in other meningoencephalitidies, may actually be harmful in fungal cns infections. case: a year old male with a presents with weeks slurred speech and worsening headache. an enhancing lesion on brain mri in left temporal lobe was concerning for vasculitis. patient was treated with glucocorticoids, with a negative rheumatologic workup and discharged home. patient subsequently presented days later with worsening symptoms, with ct imaging showing completed infarcts. blood cultures were positive for cryptococcus neoformans; patient died due to diffuse right mca territory edema and brain herniation syndrome. discussion: it is important to consider cns infection even in immunocompetent patients who present with any of the following: fever, nuchal rigidity, mental status change, and headache. cns vasculitis in association with infection is caused by basilar meningeal exudates. these cause traversing vessels to become inflamed, leading to distal inflammation and subsequent thrombus and infarction. we present a right mca territory infarct , presumed to be based on the aforementioned vasculitic process. when acute infarcts are associated with opportunistic cns infections, they are usually not associated with large vessel infarction. we also examine the adjunctive use of glucocorticoid therapy for treatment of fungal cns infections. this is an infrequent case of cryptococcus neoformans causing a cns infection in an hiv-seronegative patient not on chronic immunosuppressive medications. this case presents a unique complication of cryptococcal infections, a cns vasculitis leading to infarction in a large vessel territory. we describe the baseline characteristics, continuous intravenous midazolam doses, seizure control, hospital course and outcomes in patients who received high dose continuous midazolam infusion for refractory status epilepticus in this retrospective case series study, we evaluated adult patients with refractory status epilepticus treated with high continuous intravenous midazolam doses in an academic neurocritical care unit between august and june . four patients were identified. the maximum midazolam dose for each patient was: withdrawal seizures (occurring within hours of discontinuation of continuous iv midazolam) occurred in patient b. "ultimate continuous iv midazolam failure" (patient requiring change to a different continuous intravenous antiepileptic drug despite maximum optimized dose) was not observed in any of the four patients. hospital complications occurred in patient a and b due to infections. hypotension related to continuous infusion midazolam occurred in patient a. three out of four patients discharged alive to a skilled nursing facility; after a goals of care discussion with the family, the fourth patient had withdrawal of care due to the severity of his brain injury. in this case series, we report the use of high dose continuous iv midazolam for treatment of refractory status epilepticus. there were no midazolam-related deaths. neurologic complications in infective endocarditis (ie) occur up to % and are independent predictors of mortality. infectious intracranial aneurysms known as "mycotic aneurysm" (ma) are rare constituting - %. hemorrhaging rate is %. mortality is % with rupture. ruptured ma poses significant management conundrum due to lack of available solid prospective data guiding the order (cardiac vs neurosurgical) or timing (early vs delayed) of surgery. a y/o male iv drug abuser presented with acute hypoxemic respiratory failure secondary to pneumonia and suspected meningitis. gsc intubated on iv antibiotic. hemodynamic instability prompted tee showing large aortic valve vegetation. blood cultures positive mssa fulfilled criteria for ie. tests showed kidneys infarctions. ct brain showed r mca territory infarct with sah.cta head revealed small ma along the distal r mca m branch confirmed with cerebral angiogram. acute heart failure and arrhythmia led discussion on cardiothoracic surgery for valve replacement. due to ruptured ma, decision to secure it was made prior to cardiac surgery. after failed endovascular intervention, patient underwent surgical clipping. post operative mri brain showed new infarcts suggesting recurrent embolization. due to risk of intracranial bleeding, cardiac surgery was postponed for at least weeks initially then to weeks. patient underwent avr after completed weeks of antimicrobial therapy with st jude mechanical valve and discharged on anticoagulation with a modified rankin scale of . this case reflects on how urgent surgical intervention should take place.safety period between neurological event and cardiac surgery is largely debated because of lack of controlled studies. there has been no consensus on how to approach those cases as paucity of robust evidence. given their rarity the best management modality remains unclear. this case stress the importance of multimodal therapy in achieving good outcome although the timing of surgery remains a matter of debate. we present a patient with vertebral cerebral artery embolism (cae) following blunt trauma. case presentation: a year-old male was admitted with a right vertebral artery dissection and occlusion with intraluminal air, widespread pneumocephalus, bilateral pneumothoraces, a pulmonary laceration, and multiple fractures including ribs, c transverse foramen (with normal alignment), and femur following a motor vehicle collision. his pupils were initially nonreactive, and he experienced one hour of witnessed generalized seizure activity on arrival despite aggressive treatment. management: midazolam infusion, levetiracetam, and fosphenytoin were initiated for seizure control. targeted temperature management to celsius was initiated on arrival out of concern for hypoxic brain injury. computed tomography at hours demonstrated resolution of vertebral and intracerebral air, diffuse edema, and diffuse loss of gray-white matter differentiation, thus a hypertonic saline infusion was initiated. the following day, an mri demonstrated diffusion restriction in the areas adjacent to the air, including c - and diffusely throughout bilateral cerebral hemispheres. prognosis was thought to be poor. however, the following day, the patient awoke. by day four he followed commands. he was discharged to skilled nursing on day . at three months he had only minimal residual right hip weakness. discussion: there are only three case reports of cae following blunt trauma, and only one involving the vertebral artery. air migrates to the arterial circulation due to a positive gradient from low central venous pressure or high airway pressure. pulmonary venous air then embolizes to cerebral vasculature. as little as ml of arterial air emboli can be fatal with the major cause of death being circulatory obstruction and arrest from air trapped in the right ventricular outflow tract. conclusion: this patient developed pneumocephalus and cae due to a pulmonary laceration. as the cerebral air reabsorbed, his seizures resolved and his exam improved. petrous ica aneurysms are extremely rare - and difficult to treat surgically, due to the inherent challenges of microsurgical access to the carotid canal of the petrous bone - . endovascular approaches may also prove challenging, typically as the consequence of therapeutically-unamenable morphology, but occasionally due to size considerations as well. a -year-old male presented with headache and vertigo for the past weeks. the patient was hivpositive with medication noncompliance and denied any history of trauma or head injury. head ct identified a . x . cm heterogeneous soft tissue density lesion in the right petrous bone. ct angiography revealed a . x . x . cm lobulated giant aneurysm of the right petrous ica. mri/mra was performed to rule out thrombosis and showed giant partially thrombosed right petrous ica aneurysm. the decision was made to treat using flow diversion. the patient underwent catheter angiography, confirming a giant x . cm right internal carotid artery petrous segment aneurysm. we proceeded with flow diversion pipeline endovascular device, placement of two pipeline endovascular devices (flex x and x ) successfully. final angiographic runs showed significant stasis within the aneurysm and demonstrated the flow-diverter construct was well placed both proximal and distal to the aneurysm neck with no sign of endovascular leak. the patient was discharged home well. we suggest that flow diversion is an ideal treatment for petrous ica aneurysms, specifically un-ruptured lesions of complex morphology. other options for treating petrous ica aneurysms challenging, not possible, less effective, and/or carry substantial risks. second, several of the disadvantages of pedocclusion of side vessel branches and preclusion of future coil embolization, do not apply to the petrous segment of the ica. lastly, use of ped in petrous ica aneurysms has proven effective in the vast majority of reports. the spot sign is a focus of enhancement within the hematoma on ct angiogram (cta) with unique characteristics. it has a spot-like appearance within the margin of a parenchymal hematoma without connection to an outside vessel. it should measure greater than . mm in diameter in at least one dimension. its contrast density (hounsfield units, hu) is at least double that of the background hematoma. finally, there should be no hyperdensity at the corresponding location on non-contrast ct. it is a strong predictor of hematoma expansion and poor prognosis in intra-parenchymal hemorrhage. the pathogenesis of spot sign remains unclear. some studies showed an association with faster rates of contrast leakage which indicates continued bleeding. a spot sign has not been reported with isolated intraventricular hemorrhage (ivh) before. a case report of a -year-old man with a past medical history of hypertension who got admitted to the er with acute encephalopathy and right-sided weakness. head ct-scan (hct) revealed isolated ivh. cta was notable for a spot sign. it measures . mm in diameter and hu in density (surrounding hematoma measures hu). it lies within the hematoma without connections to any adjacent vessel. a follow-up hct after four hours showed expansion of the ivh. although seems uncommon, looking for a spot sign in isolated ivh can also anticipate expansion of the hemorrhage. a further study is needed to validate this observation and calculate the prevalence of the spot sign in isolated ivh. west nile neuroinvasive disease may present with nonspecific physical exam and imaging findings. to our knowledge, this is the first report of wnnd involving the temporal lobe in adults with neuroimaging suggestive of limbic encephalitis. our patient presented in winter and developed autonomic instability and sensory deficits, which are all rare findings in wnnd. -year-old texan with dm presented with acute confusion and seizure in november. patient complained of headache, fever, diarrhea and lower extremity weakness after a fishing trip. patient was febrile with mosquito bites on his arms. neurological exam was significant for comatose state, absent brainstem and deep tendon reflexes, and flaccid paraparesis. he developed autonomic instability with labile blood pressures. lp revealed wbc/mm (monocyte predominance), rbc/mm , glucose mg/dl, elevated protein of mg/dl, and a positive west nile virus (wnv) igm antibody; gram stain, hcv pcr, and the paraneoplastic and autoimmune panels were negative. eeg showed severe diffuse brain slowing. mri brain had t flair and dwi changes in right hippocampus and posterior limb of internal capsule. emg described severe subacute sensorimotor axonal polyneuropathy without prolonged distal latencies and normal conduction velocities. he received days of ivig without improvement and was terminally extubated. our patient presented with both clinical entities of west nile: wn fever and wnnd (present in less than % of cases). our patient had axonal polyneuropathy with paralysis which is due to inflammatory changes in the white matter tracts affecting spinal sensory pathways. sympathetic ganglia involvement caused the autonomic instability, another very rare manifestation of wnnd. november presentation was due to warmer texas winter. recognize that west nile fever and west nile neuroinvasive disease may present together in winter. recognize that west nile neuroinvasive disease can present with rare temporal lobe neuroimaging, sensory involvement, and autonomic instability. intracerebral hemorrhage (ich) is a common pathology seen in the neurocritical care setting that can be associated with significant morbidity and mortality. the use of sympathomimetic agents containing phenylpropanolamine (ppa) have been associated with ich in the past which lead to the drugs' removal by the fda as an over the counter medication in . we report a case in which ppa was the etiology for a spontaneous ich in a patient who was taking an appetite suppressant. case report and review of the literature we report a case of a year old female with no prior medical history, who presented with sudden onset left sided hemiparesis and hemianesthesia found to be due to a right striatocapsular intraparenchymal hematoma. systolic blood pressures at presentation and throughout the hospital course were normal. extensive work up including multiple ct scans of the head, mri brain, ct angiography, mr angiography and digital subtraction angiography were performed with no evidence of any vessel abnormality. etiology of the ich was attributed to the use of ppa. in young patients with no known comorbidities, ppa use should be considered a primary etiology of ich when no intracranial vessel abnormality can be detected. seizures have been known to cause sudden death, but reports in the literature of only cardiopulmonary failure in cases of sudden unexpected death in epilepsy (sudep). we present the case of a patient who presented post-seizure and developed sudden progressive and fatal cerebral edema within hours after a second seizure. a year old female with a history of down syndrome and epilepsy presented to the emergency department after a prolonged convulsive seizure. she received doses of mg lorazepam and levatiracetam . mg/kg with cessation of seizure activity and return to baseline neurologic status within hours of the initial event. head ct showed lack of sulci throughout the cerebral hemispheres and basilar cistern effacement despite being at her baseline neurologic status. hours after presentation the patient had another seizure, vomited, was intubated and an additional mg/kg of levatiracetam given. hours after presentation, the patient was admitted to the neuroicu with absent brainstem reflexes and repeat head ct with worsened cerebral edema and tonsillar herniation. formal brain death testing was performed approximately hours after the patient's initial presentation. seizures are known to cause a hypermetabolic state in the brain. uncontrolled neuronal firing leads to hyperemia, failure of na+/k+ atp pump, increased levels of neuronal chloride, and inability for cells to maintain homeostasis. in this case, the patient's initial head ct showed cerebral edema, likely from prolonged seizure activity. once the second convulsive seizure occurred, a period of pre-intubation hypoxemia coupled with post-intubation hypotension allowed for progression of cerebral edema in an already compromised brain; similar to what is seen in post-cardiac arrest and traumatic brain injury. this case illustrates the importance of controlling for factors that can contribute to secondary brain injury in seizure patients. posterior reversible encephalopathy syndrome (pres) is a clinico-radiographic syndrome characterized by seizure, headache, encephalopathy and neuroimaging findings of symmetric white matter edema in the posterior cerebral hemispheres. cerebellar and brainstem involvement occurs rarely. here, we report a patient who presented with severe pres complicated by diffuse cerebellar edema and obstructive hydrocephalus requiring decompression with ventriculostomy placement. this is a case report from a tertiary medical center. a -year-old woman with a history of migraine presented to the emergency room with -day history of fever, right upper quadrant abdominal pain, nausea and vomiting. on day two of hospitalization, the patient developed worsening headache, dizziness and lethargy and her blood pressure was elevated to / mmhg. ct of the brain showed cerebellar edema and bilateral occipital lobes with effacement of the fourth ventricles and associated hydrocephalus involving the lateral and third ventricle. mri obtained post-operatively revealed t -weighted/flair diffuse hyperintensities in the parietal, occipital lobes and cerebellum. there was no mass lesion or restricted diffusion in diffusion weighted images (dwi) suggestive of acute infarction. cerebellar edema with compression of the fourth ventricles with hydrocephalus was slightly improved status post interval ventricular drain placement. ventriculostomy was weaned off over the course of seven days. follow up mri showed improvement of the hydrocephalus with decreased in t -weighted hyperintensities in posterior parietal and occipital lobes as well as within the cerebellum. severe cerebellar edema with obstructive hydrocephalus is an exceedingly rare complication of pres; however, prompt recognition and surgical decompression in addition to usual medical management is critical to achieve a favorable outcome. while obstructive hydrocephalus may be successfully treated with medical management and blood pressure reduction, this case emphasizes that clinical evidence of brain herniation should prompt immediate consideration for emergent ventriculostomy placement or surgical decompression to redirect cerebrospinal fluid and reduce intracranial pressure. one of the biggest uses of qeeg is the alpha delta ratio (adr). adr drops of % from baseline are associated with vasospasm (vsp/dind). we describe a case in which subtle qeeg adr change occurred in a poor grade sah patient over a number of days, making it challenging to detect an acute adr drop. this is a case report and literature review. this study also compared hemispheric adr values against the mca values by tcd, dsa, cta and clinical exam. a year old female with hunt hess iii, wfns iv, came in comatose with a ruptured ica aneurysm. over six days, she developed refractory vsp/dind. the patient's adr was gradually declining but their increased icp required propofol sedation, which itself lowers adr. re-analysis over multiple days had to be performed, and that re-analysis showed a gradual adr decline preceding the vsp/dind. when looking at our cases, we found a sensitivity and specificity of ( , %) when using the adr nadir compared to cta/dsa. recent publications have shown the adr method has less than ideal sensitivity and specificity of ( , %). qeeg adr is a useful multimodal monitoring parameter in neuroicu patients with relatively good baseline adr. however, its ability to detect vsp and dind in poor grade sah patients who have adr values that are already low (< . ) is challenging, particularly given the confounders in this population, such as eeg artifact which artificially raise adr values, and sedation (e.g., propofol) which suppress adr values. based on this information, we would suggest neuroicu centers carefully use continuous eeg monitoring for other indications such as nonconvulsive seizures, unless they have sophisticated bedside protocols about sedation vacation (baseline daily adr that is not) and eeg department resources (technicians who can fix eeg electrode artifacts). hypoxic-ischemic brain injury is a severe consequence of global cerebral hypoperfusion following cardiac arrest. brain ct findings may include diffuse sulcal effacement, loss of cisternal spaces, poor differentiation of grey/white matter, and decreased densities in the basal ganglia and watershed territories. the connection between aggressive resuscitation, as seen with in-hospital cardiac arrest, and cerebral edema is unclear. here we present the case of a hemodynamically unstable patient who developed transient reversible cerebral edema believed secondary to aggressive resuscitative efforts and pressor therapies. a year old female with a past medical history significant for diabetes and hypertension presented to the emergency department with headache and non-bilious vomiting. workup revealed isolated ventricular hemorrhage secondary to a ruptured left posterior inferior cerebellar artery (pica) aneurysm and cerebellar arteriovenous malformation, which underwent subsequent embolization. during her early hospital course she remained intubated due to pulmonary factors, but awake and alert with a non-focal neurologic examination. her course was subsequently complicated by a severe metabolic acidosis requiring several doses of bicarbonate boluses and continuous infusion, cvvhd, intravenous crystalloids, hydrocortisone and multiple pressors to maintain stability. over a hour period she received liters of volume while maintaining a mean arterial pressure above mm hg and o saturations above %, without requiring cpr. subsequent progressive encephalopathy developed, with a ct brain revealing diffuse sulcal effacement prompting hyperosmolar therapy. gradually her encephalopathy began to improve, with repeat imaging showing improvement of cerebral edema and return of grey/white matter differentiation. this case highlights a potential etiology of reversible cerebral edema that may confound early prognostication in patients with hemodynamic instability such as multi-organ failure and in-hospital cardiac arrest. further investigations are warranted. langerhans cell histiocytosis (lch) is a rare disease with an incidence of . - . cases per , children under years of age. frequency in adults is unknown. the hypothalamic-pituitary manifestations of lch (commonly diabetes insipidus) and hypernatremia are well known complications. here we present a case where a patient presented with poor mental status and the etiology remained unknown initially despite extensive testing. electronic medical record was reviewed regarding hospital course, sodium trends, and radiology images. this patient is a year old female with history of langerhans' cell histiocytosis with biopsy-confirmed suprasellar metastases (complicated by pan-hypopituitarism) who was transferred to our institution for hypernatremia and hydrocephalus. she had undergone two cycles of chemotherapy, most recently one week prior to presentation, and five rounds of radiation completed three months earlier. her presentation to the community hospital from a nursing facility was with unresponsiveness and she was intubated on arrival. her sodium was at that time; and had been three days prior. sodium was corrected from to over the course of four days with a drop from to within the first ten hours. her mental status improved to the point where she was awake and following commands; however still remained intubated. when she presented to our institution her sodium was and subsequently became unresponsive with a poor neurological exam limited to cranial nerve function only. she was evaluated with eeg monitoring and mri brain; however both were unrevealing for a cause. she had an external ventricular drain placed for concern for hydrocephalus that did not change her exam. one week later repeat mri brain revealed extrapontine myelinolysis. this case highlights the complications associated with intracranial lch and the need for repeat imaging in patients with rapid sodium correction to identify effects of osmotic demyelination. cangrelor is a rapid-acting, intravenous p y platelet receptor inhibitor with a plasma half-life of - minutes and full platelet recovery achieved within one hour after discontinuation. because it is rapidly reversible, cangrelor is commonly used to bridge patients with recent coronary stents to cabg surgery. oral p y inhibitors, such as clopidogrel, have a delayed onset and offset with platelet recovery occurring over - days, making their use challenging perioperatively or in the setting of an acute bleed. safety and efficacy data of cangrelor in noncoronary stents are lacking. we present two patients in whom cangrelor was used to maintain internal carotid artery (ica) stent patency acutely. both patients presented with an ischemic stroke secondary to acute occlusions of the left ica and left middle cerebral artery (mca) and were taken emergently to the neurointerventional suite for carotid artery stenting (cas) and mechanical embolectomy of the mca clot. heparin and eptifibatide were administered intraoperatively. post-procedure dynact demonstrated intracranial hemorrhage complications. dual antiplatelet therapy (dapt) with clopidogrel and aspirin, typically initiated following cas, was deferred given the difficulty of reversing their antiplatelet effect in hemorrhage expansion. instead, cangrelor was initiated to maintain carotid stent patency at . mcg/kg/min in one patient and . mcg/kg/min in the other patient and infused for . and hours, respectively. platelet reactivity was trended with the verifynow® assay and used to adjust cangrelor dosing. serial imaging was obtained to monitor hemorrhage expansion. one patient was transitioned to oral dapt and discharged while the other patient deteriorated neurologically from malignant cerebral edema and expired. cangrelor may be useful following cas complicated by intracranial hemorrhage when the need to maintain stent patency must be balanced with the risk of hemorrhage expansion. further research is warranted to determine its safety and efficacy in noncoronary stents. cerebral amyloid angiopathy (caa) although has been described in the literature, the different categories of this entity and its recognition and subsequent treatment are still elusive. it is important for neuro intensivists to recognize its variable presentation . we describe a single case report and perform a systemic review. caa depending on pathology can be categorized as inflammatory-caa where perivasculitis is seen on biopsy. this causes a non-destructive perivascular inflammatory infiltration and amyloid deposition pattern. on the other hand, amyloid beta related angitis (abra) results in a vasculitis and there is predominantly granulomatous angio-destructive inflammatory mediated disease affecting leptomeningeal and cortical vessels characterized by meningeal lymphocytosis and abundant amyloid-beta deposition within the vessel walls. caa on the other hand results in no inflammation of vessels but rather just deposition of amyloid deposition in the walls of vessels. we report a case of a year old man with an extensive cardiac history, who presented with syncope. initial computed tomography (ct) of head was negative. during admission, he acutely started having trouble answering questions including his name, and was unable to communicate his needs. repeat ct head showed hypodensity in left frontal region which was attributed to a stroke. he than developed complex partial seizures requiring intubation and seizure management. lumbar puncture showed mild pleocytosis. mri brain showed edematous changes of the left subcortical and deep white matter frontal lobe region which on repeat imaging subsequently worsened. biopsy was eventually performed which confirmed inflammatory cerebral amyloid angiopathy. he was treated with steroids and immunosuppression with gradual improvement. month follow up in clinic with continued improvement to independence. recognize the various subtypes of caa in their pathology, presentation and potential treatment. in acute emergency situations, intraosseous vascular access represents an alternative route of vascular access when peripheral vein insertion is difficult. we present the first documented case of intraosseous alteplase (tpa) administration in a patient with acute ischemic stroke symptoms. methods year old male with past medical history of hypertension, end stage renal disease, and diabetes mellitus presented to the hospital with sudden onset expressive aphasia and right sided numbness minutes prior to ed arrival. nihss was and code stroke was activated. patient blood pressure was / . ct head did not show any acute intracranial hemorrhage. it was decided to proceed with thrombolytic therapy. one peripheral venous access was obtained through which nicardipine drip was started to lower the blood pressure however second peripheral venous access was attempted multiple times but was unable to be obtained. tpa is more effective the faster it is administrated, and there was no known contraindications to administering tpa via intraosseous access (io). we report the first known case of successful and safe administration of fibrinolytic therapy through the intraosseous route in a patient with acute ischemic stroke symptoms. intraosseous access has been considered to be more invasive than intravenous (iv) and carries theoretical risk of bleeding however we were able to demonstrate tpa administration through io without any local or systemic complications. the bioavailability of alteplase through io access has not been studied however it is considered to be close to iv infusion in case of morphine and vasopressors. no studies negate or support the use of intraosseous access in stroke patients. contraindications are few and complications are uncommon. the findings of our case report suggest that intraosseous cannulation may be safely used for fibrinolysis in acute ischemic stroke patients with difficult peripheral venous access in in-hospital or out-of-hospital setting. tufts medical center, boston, massachusetts, usa we report a case of a pregnant patient with bilateral ovarian teratomas who presented with treatment refractory nmda receptor encephalitis despite removal of bilateral teratomas, successfully treated with rituximab. case report and discussion of treatment and outcome. year old weeks pregnant female with known ovarian cysts who presented with one week of confusion and subsequent status epilepticus. she was started on empiric treatment with ivig while undergoing workup. nmda receptor antibody was confirmed. left oophorectomy and right ovarian cystectomy were performed, both of which confirmed ovarian teratoma. she was given high dose steroids. her worsening condition prompted consideration of additional agents. plasma exchange and rituximab were initiated and then she was continued on rituximab alone. she improved dramatically over six weeks and delivered at full term via spontaneous vaginal delivery. at one year follow up, the child was healthy and meeting appropriate milestones. we report the use of rituximab for safe and successful treatment of nmda receptor encephalitis in a gravid female. neovascular glaucoma (nvg) is a known complication of carotid endarterectomy in patients with carotid stenosis. there are no previous reports of acute nvg refractory to medical treatment following carotid artery stenting (cas). we report a patient who needed surgical treatment for acute exacerbation of nvg following cas. a -year-old man with hypertension, diabetes, and hypercholesterolemia presented with recurrent transient weakness in his right hand. fifteen days before presentation, he had experienced acute loss of vision on the left side because of central retinal artery occlusion. magnetic resonance imaging of the brain was unremarkable. conventional angiography showed an occlusion of the left proximal internal carotid artery. ophthalmological evaluation before cas showed neovascularization of the iris and a normal intraocular pressure (iop) of mm hg in the left eye. cas was uneventful, but the following morning, the patient developed pain in the left eyeball with an iop of mm hg. anterior chamber paracentesis followed by intraocular injection of bevacizumab, panretinal photocoagulation, and medical treatment failed to reduce the iop below - mm hg. eighteen days following cas, an ahmed glaucoma valve was implanted in the left eye to treat the refractory nvg. iop decreased to mmhg and his ocular pain resolved completely post implantation. although nvg is a rare complication of cas, it should be suspected in patients who develop acute ocular pain following cas. nvg may respond to anterior chamber paracentesis, panretinal photocoagulation, and bevacizumab, but surgical treatment, such as implantation of an ahmed glaucoma valve, should be considered in cases with refractory nvg. background: cerebral amyloid angiopathy is a common cause of spontaneous lobar intracerebral hemorrhage. convexal subarachnoid hemorrhage can be a manifestation of cerebral amyloid angiopathy. whether focal amyloid burden predicts future hemorrhage is unclear. case: an -year-old man presented with transient left arm weakness and paresthesias in the setting of previous cognitive decline. mri showed a convexal subarachnoid hemorrhage of the right central sulcus, as well as susceptibility weighted imaging findings consistent with superficial siderosis. lumbar puncture revealed normal cell count with a mildly elevated protein. he had spontaneous resolution of his symptoms after several hours. one year later he presented with sudden onset confusion and imaging again showed a convexal subarachnoid hemorrhage over the posterior right frontal lobe. susceptibility weighted mri revealed hemosiderin over the right posterior frontal and anterior parietal lobes. an amyloid-pet, obtained one year prior to his first spell as a research participant, demonstrated asymmetric amyloid deposition in the right temporo-parietal region. years after his initial episode he presented again with confusion, headache, and decreased level of alertness. a ct scan demonstrated a right-sided temporo-parietal intracerebral hemorrhage in the area of asymmetric amyloid deposition on pet. his family opted for comfort measures only, and he was discharged to hospice. autopsy revealed severe amyloid angiopathy, as well as alzheimer disease, braak stage vi. discussion: this case illustrates the clinical course of a patient with amyloid angiopathy, including recurrent convexal subarachnoid hemorrhages, and superficial siderosis. of importance, the amyloid pet scan predicted the location of his intracerebral hemorrhage years later. the case of a -year-old man, presenting with a past medical history of migraine headaches, dipola, vertigo, with symptoms later progressing to lethargy and confusion for days. brain mri revealed a peripherally enhancing mass within the left thalamus with central restricted diffusion, which is consistent with a cerebral abscess. case report of congenital heart disease when discovered in adulthood is an interesting entity, especially when it is the source of brain abscesses. detailed history taking, physical examination and appropriate imaging can usually reveal the anomaly. the diagnosis of brain abscess should promote the clinician to consider right to left shunts as a possible predisposing condition for brain abscess management of acute cerebral embolism in patients with implanted ventricular assist devices (vads) is particularly challenging, since chronic anticoagulation often precludes the use of intravenous tissue plasminogen activator (iv-tpa). we describe a vad patient who suffered cerebral embolization, and was successfully treated with thrombectomy, emphasizing the nuances particular to this clinical scenario in the context of limited historical experience. a year-old man with heart failure (ejection fraction %) and heartware ii vad implantation about months prior, was found at the scene of a car accident with expressive aphasia, right homonymous hemianopia, extinction and right hemiplegia, with a national institutes of health stroke scale (nihss) score of . upon arrival, his ct was unremarkable, but cta revealed occlusion of the left middle cerebral artery (m segment). since his inr was . , he underwent emergent thrombectomy with the solitaire device, resulting in complete revascularization (tici = ) minutes from onset, with rapid deficit resolution (nihss = ). the procedural and clinical success was accompanied by lack of evidence of infarction in subsequent ct studies, and a modified rankin score of upon discharge. the removed thrombus displayed early organization, suggesting unexpected firmness, and underscoring the potential importance of mechanical removal rather than chemical lysis in vad patients. our case has attributes that set it apart from those previously reported: ) the use of a hybrid (i.e. retrieval plus aspiration) endovascular retrieval technique, ) the lack of concurrent use of thrombolytic drugs, and ) the rapid, sustained and optimal clinical improvement. the utilization of vads continues to grow, yet the literature regarding endovascular techniques for managing these types of patients remain scarce. however, the increasing availability of centers capable of delivering this type of treatment, suggests that thrombectomy should be strongly considered in vad patients with acute cerebral embolism. extreme cerebral oxygen changes has not been reported via monitoring of partial brain tissue oxygen levels. here we present an asah patient with brain tissue oxygen (pbto ) monitoring, who developed cerebral hypoxia due to cerebral vasospasm, then went on to develop cerebral hyperoxia with associated cerebral infarction. methods yo female with hh fg sah with initial gcs of t underwent coiling of a ruptured basilar tip aneurysm. a pbto monitor was inserted to guide therapy. this patient had multiple episodes of low pbto ( mmhg). this corresponded to infarction on follow up head ct and mri with preservation of local arterial vessels on mra, consistent with diagnosis of dci. in the present case, high pbto is more likely resulted from a combined effect of ) increased cbf from co-administration of ketamine at the time of milrinone infusion; ) decreased cerebral metabolic demands in already infarcted left frontal lobe, resulting in reduced oxygen uptake; ) accelerated reperfusion and thus hyperemia with milrinone. restoration of flow with milrinone may have been too late to reverse the prolonged period of vasospasm induced ischemia, resulting in perfusion of infarcted tissue, or luxury perfusion. clinicians utilizing pbto monitoring for dci management should be cautious of high pbto values, as it may herald cerebral infarction. further studies are needed to better elucidate the mechanism of reperfusion injury and potential treatments. patients with acute brain injury, especially those with intracranial hemorrhages are at a higher risk for hemorrhage while on therapeutic anticoagulation. unfractionated heparin (ufh) is frequently used as it is easily reversible and has a short half-life. activated partial thromboplastin time (aptt) is traditionally used to monitor its effect. several disadvantages with aptt monitoring include inability to reach therapeutic goal, over-or under-dosing and its associated complications. anti-xa level is reported to have better correlation with actual degree of anticoagulation using ufh. retrospective chart review of patients with acute brain injury who required initiation of early therapeutic anticoagulation and monitored with anti-xa level. case - year-old-man with intracerebral hemorrhage (ich) developed lower extremity deep vein thrombosis (dvt) and required therapeutic anticoagulation. patient became therapeutic within six hours of titrating infusion based of anti-xa levels and remained therapeutic. asymptomatic rectal bleeding associated with fecal management system was noted. case - year-old-man with cerebral venous sinus thrombosis presented required therapeutic anticoagulation. ufh infusion was initially monitored using aptt levels which had widely varied lab results, thus monitoring was switched to anti-xa levels which provided a more consistent therapeutic range. however, patient developed thrombocytopenia in the setting of inflammatory bowel disease. therefore, ufh infusion was changed to argatroban infusion. case - year-old-man with lower medullary acute ischemic stroke due vertebral artery dissection required therapeutic anticoagulation to prevent recurrence. patient became therapeutic within hours of titrating based of anti-xa levels. to monitor therapeutic anticoagulation, anti-xa level appears to achieve target anticoagulation level faster and without serial variation as compared to aptt. however, anti-xa level estimation is costlier as compared to aptt and not widely available. by restricting it to special populations like those with acute brain injury might justify its use and underscore cost-effectiveness. neurological admissions presenting to the icu benefit from a dedicated neurocritical care team but many community hospitals lack this subspecialty expertise. with an aging population and a neurointensivist shortage, more patients are transferred to designated neurocritical care units which increases healthcare spending and resource utilization. recognizing this obstacle, we describe the management of a patient in status epilepticus via our novel "eneuro-icu" consult program in which a 'sub-hub' of the northwell health tele-icu was set up at the only hospital out of in our health system that is staffed / by neurointensivists. a -year-old man with history of a left frontal meningioma presented with multiple seizures to a hospital within our healthcare system. he received mg of lorazepam and levetiracitam in the emergency department and was admitted to the icu for further monitoring. there he was witnessed to have recurrence of clinical activity concerning for ongoing seizure. levetiracitam was increased and phenytoin was added. neither immediate neurological consult nor continuous eeg was available, thus an "eneuro-icu" consult was obtained. in this model, the bedside provider contacts the tele-icu that facilitates a conference call with the neurointensivist. av technology was used to provide consultations and follow ups. the neurointensivist determined the patient was rapidly returning to baseline and recommended a head ct, lab studies and continuation of the anti-epileptic drugs. the eicu team monitored the patient overnight. by leveraging the infrastructure in place for management of critically ill patients remotely, an additional level of subspecialty care was offered in a timely manner and allowed the patient to remain at their local facility. based on the success of the initial program we are currently in the process of extending the virtual consult service to various community hospitals' eds/icus to improve outcomes for patients who would benefit from neurocritical care services. hypoglycemic encephalopathy is a potentially life-threatening manifestation of hypoglycemia, it is usually caused by metabolic change, hypoglycemic agents, and malignancy. here, we report a patient with hypoglycemic encephalopathy caused by sleeve gastrectomy a -year-old woman was admitted due to unconsciousness of acute onset. she showed normal corneal and vestibulo-ocular reflex but sluggish pupil light reflex and decerebrated posture by painful stimulation. she has taken severe medications for weight control including orthosiphon powder and hydrochlorothiazide after bariatric surgery. laboratory studies showed significantly low blood glucose level ( mg/dl) with normal liver enzyme and creatinine. there was no evidence of adrenal insufficiency. electroencephalography showed no epileptiform discharge. initial and follow-up brain magnetic resonance imaging revealed diffuse high signal intensity on white matter expanded to cortex, corpus callosum and posterior limb of the left internal capsule, suggesting hypoglycemic encephalopathy. in abdomen-pelvic ct, there is no mass lesion like carcinomas or insulinoma. the clinical diagnosis of hypoglycemic encephalopathy followed by sleeve gastrectomy was made by given history of bariatric surgery and the lack of evidence of hypoglycemic agent overdose, adrenal insufficiency, endogenous hyperinsulinism or malignancy. there are several hypotheses that sleeve gastrectomy can encourage hypertrophy of beta cells, hypersecretion of glucagon-like peptide, glucagon abnormality and increased insulin sensitivity, that may induce hypoglycemia. we suggest that clinicians should consider sleeve gastrectomy itself as a possible cause of profound hypoglycemia pulmonary embolism (pe) is a fatal complication in neurological conditions with plegic extremities. clinical presentations and supportive testing can be variable. we present a case of pe which presented with st segment elevations weeks after spontaneous intracerebral hemorrhage (sich). case report and review of the literature we present a case of a year old female with a history of a recent sich with resultant left hemiplegia who presented with a syncopal episode and chest pain. on physical examination, she was noted to be tachypneic and tachycardic with an unchanged neurological exam. pulmonary embolism can present with a variety of ekg abnormalities including st elevations after sich and the treating physician should be aware of these idiosyncrasies. anticoagulation should be cautiously initiated in such cases. infectious intracranial aneurysms (iia) are rare neurovascular lesions associated with infective endocarditis. we present a case of a large iia which developed within hours of a negative ct angiogram and ruptured despite weeks of appropriate antibiotic treatment. a year-old woman presented with fevers and malaise. her initial workup revealed an aortic valve mass and blood cultures grew out streptococcus. three days after intravenous penicillin therapy was initiated for bacterial endocarditis, she developed a new headache and right hemianopsia. a head ct demonstrated a left occipital lobe stroke with hemorrhagic transformation. further workup with ct angiography revealed a mm outpouching along of the distal branch of the left pca, consistent with an infectious intracranial aneurysm. on repeat imaging, this aneurysm demonstrated growth despite medical treatment, and required coil embolization/occlusion. aortic valve replacement was planned after weeks of antibiotic therapy because of continued severe aortic insufficiency and persistent valve vegetation. on the day of surgery, she developed acute word-finding difficulty followed by a rapid neurologic deterioration resulting in coma. a head ct demonstrated a new left frontal intraparenchymal and subarachnoid hemorrhage associated with the rupture of an mm x mm irregularly shaped aneurysm in the region of the left mca bifurcation, which had been absent on a prior surveillance ct angiography just hours prior. she underwent emergent coil embolization, extraventricular drain placement, and decompressive hemicraniectomy. despite these measures, her exam did not improve. she was transitioned to comfort measures and life-sustaining therapies were withdrawn. the development of iia can occur despite appropriate medical treatment. these aneurysms may rapidly expand and rupture within hours, as shown by our case. even with prior exonerating imaging, clinicians should have a high suspicion for iia development in all infective endocarditis patients. the corneomandibular reflex, also known as wartenburg reflex or von solder phenomenon, is a rare pathological reflex signifying severe supranuclear trigeminal injury. it presents as contralateral jaw deviation to corneal stimulation. etiologies include upper brainstem lesions, large hemispheric lesions with brainstem compression, as well as advanced amyotrophic lateral sclerosis and multiple sclerosis when corticobulbar pathways are affected. this clinical finding is useful in differentiating structural and metabolic causes of coma, as this examination finding would not be present in metabolic phenomena. a middle aged man presents with a hypertensive right thalamic hemorrhage and a four score of e m b r . the patient's cornea was stimulated with a cotton swab. the cornea was tested bilaterally to determine any lateralizing features. recording on video was performed with patient's family written consent as patient was comatose. upon stimulation of the patient's cornea a contralateral jaw jerk was appreciated. this was replicated contralaterally. this case describes a common patient with a rare physical examination finding. there is utility in recognizing this finding as it will aid in determination of the underlying cause of a comatose state. the corneomandibular reflex present at presentation rules out a metabolic cause. a structural cause was validated by imaging studies (shown). the reflex arc was researched and has been independently artistically rendered (shown), which demonstrates the pathway beginning with the afferent limb of the corneal stimulus (v ) which travels to the main trigeminal sensory nucleus via the trigeminal ganglion. severe supranuclear trigeminal lesions will inhibit inhibitory interneurons within the mesencephalic nucleus, leading to activation of the motor nucleus of the trigeminal nerve. this causes activation of the ipsilateral external pterygoid muscle which produces a contralateral jaw jerk. overall this patient fared poorly and expired several days after admission. pneumocephalus is when air enters and is contained inside the intracranial compartment. when intracranial pressure increases causing neurological decline, patients can experience nausea, vomiting, seizures, dizziness, and altered mental status. here we present three cases of postoperative pneumocephalus which resolved quickly with humidified oxygen delivery via high-flow nasal cannula. we follow the cases with a review of the mechanisms and pathophysiology of pneumocephalus and its treatment, as well as future directions in management. case series of patients with post-operative pneumocephalus who were treated with high-flow nasal cannula. case describes a -year-old woman who underwent hemicraniotomy for removal of meningiomas, with focal postoperative neurological signs and mm of midline shift on head ct due to pneumocephalus. case describes a -year-old woman who underwent right anterior temporal lobectomy for seizures, who developed postoperative focal prefrontal lobe signs and mount fuji sign on head ct. case describes a -year-old man with bilateral subdural hematomas, status post bilateral burr hole evacuation. he was excessively somnalent postoperatively with bilateral pneumocephalus. with high-flow nasal cannula, they all returned to clinical, and near radiographic baseline within , , and hours, respectively. recognizing the limitations of a small case series, we believe these cases support use of high-flow nasal cannula when treating patients with symptomatic pneumocephalus. thsee patients showed more rapid clinical and radiographic improvement after implementation of hfnc oxygen therapy than previously described using other methods. high-flow nasal cannula may help washout nitrogen from the lungs, allowing a downward gradient from the nitrogen in the intracranial air bubble out the lungs. in addition, high-flow nasal cannula is more comfortable for the patient, allowing for more consistent treatment. randomized studies are needed to confirm our findings. the neurotoxin produced by clostridium botulinum is the most lethal toxin known by weight. early recognition and treatment of botulism are crucial for full recovery. we present a case of progressive paralysis secondary to botulism toxemia following a gunshot wound (gsw). a -year-old man suffered a gsw to the right lower extremity. he was treated in the emergency department where the wound was irrigated and closed. some bullet fragments could not be retrieved due to close proximity to popliteal vessels and surrounding nerves. he returned ten days later with diplopia and nausea. he denied consumption of canned foods or illicit substances and had no preceding upper respiratory or gastrointestinal illnesses. on examination, he exhibited ptosis and symmetric bilateral motor weakness with diminished deep tendon reflexes. the gsw showed no signs of infection. progressive respiratory insufficiency resulted in intubation and mechanical ventilation. a lumbar puncture revealed normal opening pressures and cerebrospinal fluid analysis was unremarkable. titers for acetylcholine receptor and anti-muscle specific kinase antibodies were negative, as was a tensilon test. blood toxicology analysis showed no evidence of illicit substances or heavy metal poisoning. a high suspicion for wound botulism led to consultation with the regional poison center and cdc. blood and anaerobic wound samples were obtained for toxin bioassay and culture. empiric intravenous penicillin g therapy was started. equine heptavalent antitoxin (h-bat) was obtained and administered on hospital day . serum toxin bioassay tested positive for botulinum neurotoxin type a. the patient required a gastrostomy tube due to persistent dysphagia. after one month of hospitalization, he was discharged home and continues outpatient physical therapy. wound botulism from traumatic injury is exceedingly rare with only one to two cases reported annually. our case is the first reported incidence of wound botulism from a single gunshot wound. hyperammonemic cerebral edema (hce) with brain herniation carries a dismal prognosis historically despite aggressive treatment. however, we report a case where a patient with severe hce and herniation returned to her neurological baseline after aggressive medical management. a -year-old woman became acutely comatose with a blown left pupil and required intubation several days after admission for encephalopathy. head ct demonstrated diffuse cerebral edema with central and bilateral uncal herniation. profound hyperammonemia ( ug/dl) was implicated, though hepatic function was normal. her intracranial hypertension was ultimately controlled using hyperventilation, sedation, and osmotherapy, resulting normalization of her brainstem reflexes and improvement in her coma and imaging. continuous veno-venous hemodialysis (cvvhd) normalized her ammonia and encephalopathy that was initially refractory. multiple porto-hepatic shunts were identified on hepatic ct angiogram as the cause of her hyperammonemia, and were embolized. she was eventually weaned off cvvhd and extubated, without residual neurological deficits. our case demonstrates that, with contemporary management, clinical and radiographic reversal of hce and herniation is possible and prognosis is not uniformly poor. therefore, neurological prognostication in these patients should only be performed after assessing the clinical trajectory following cerebral resuscitation and ammonia reduction. furthermore, our case provides an example of how cvvhd can be used to reduce refractory hyperammonemia quickly until the cause of the hyperammonemia can be ascertained and addressed. finally, this is the first case reported of hce secondary to primary portosystemic shunt in absence of hepatic disorder; vascular imaging of the liver should be considered in the work-up of patients with hyperammonemia. a good neurological prognosis is possible for patients with hce and cerebral herniation with aggressive management that includes reduction of icp and ammonia. ccvhd is a useful adjunct to treat refractory hyperammonemia. a porto-systemic shunt should be considered as an etiology for hyperammonemia. cerebral venous sinus thrombosis (cvst) often presents with intracerebral hemorrhage and seizures. extensive involvement of the cerebral sinuses can lead to comatose state due to cerebral edema and associated intracranial hypertension. if not reversed with early therapeutic anticoagulation, then mechanical thrombectomy and decompressive hemicraniectomy (dhc) may be necessary as life-saving measures. however, etiological diagnosis of associated hypercoagulable state is needed for successful long-term treatment. case report of a patient presenting with cvst requiring anticoagulation, dhc and total colectomy (to treat underlying ulcerative colitis) as treatment with full anticoagulation was associated with lifethreatening hematochezia. twenty-five year old man with one week history of diarrhea presented with left sided weakness. imaging studies confirmed extensive cvst with minimal venous drainage through bilateral cavernous sinuses as well as right hemiparesis secondary to left post cingulate intracranial hemorrhage. patient subsequently developed loss of vision and became encephalopathic, despite initiation of anticoagulation with heparin. hence, mechanical thrombectomy was attempted but was unsuccessful. he also developed consumptive thrombocytopenia for which his anticoagulation was switched to argatroban. progressive neurologic deterioration necessitated dhc. his neurological examination progressively improved upon re-initiation of anticoagulation resulting in restoration of vision and resolution of left hemiparesis. later in the disease course, he developed symptomatic hematochezia associated with his primary disease, ulcerative colitis and required total colectomy. subsequently he was transitioned to oral anticoagulation and transferred to inpatient rehabilitation facility due to deconditioning from prolonged hospitalization. cvst can be life-threatening unless early treatment is initiated. appropriate and timely treatment including etiological diagnosis can lead to favorable patient outcomes. adverse effects of intrathecal non-ionic contrast during myelography are rare but can include seizures and encephalopathy. to our knowledge, cerebral edema has only been reported in the literature in two previous cases. we report a case of malignant cerebral edema following intrathecal administration of non-ionic contrast who developed seizure like activity with radiographic evidence on a head computerized tomography (ct) scan of acute diffuse cerebral edema. an year-old male underwent an elective spinal ct myelogram using mm of isovue m non-ionic contrast to evaluate chronic lumbar pain related to spinal stenosis. no complications were reported intra-procedurally and the patient was discharged home. the patient began to complain of progressive worsening headaches. the following morning he started complaining of nausea/vomiting, lost consciousness with posturing vs seizure like activity. a head ct revealed extensive brain edema and swelling with crowding of the brainstem and herniation ( fig. ). this patient was intubated and given an iv mannitol, . % hypertonic saline followed by an infusion of % hypertonic saline infusion. serial cts revealed complete resolution of his cerebral edema hours after admission ( fig. and ) . the patient's mental status improved, was extubated, and then was discharged home days after admission. while significant adverse effects of non-ionic contrast following spinal myelography are rare, the potential life threatening severity of these incidents warrants further patient education following this routine outpatient procedure. we recommend close neurological monitoring after intrathecal administration of contrast media. patients should be provided with detailed instructions about the potential side effects of non-ionic contrast and how to seek medical attention if symptoms of cerebral edema are noted post procedurally. a large acute traumatic subdural hematoma with brain compression and midline shift is typically considered a neurological emergency necessitation surgery. spontaneous resolution of a large subdural hematoma is considered a rare phenomenon with a few case reported in the literature. to our knowledge, we present the first case of spontaneous resolution of a traumatic acute subdural hematoma with brain compression and midline shift on dual antiplatelet therapy. a year-old patient initially presented after being found down and unresponsive in his home. the patient was on aspirin and clopidigrel. he was found to have altered mental status, wasn't following commands, and had a glascow come scale score of < . the patient's initial head ct revealed a large left acute subdural hematoma (sdh) measuring . cm in diameter. neurosurgery was consulted upon arrival for possible emergent evacuation. the patient's repeat head ct showed a decreased sdh to . cm in diameter. given the rapidly resolving sdh, surgery was postponed. another repeat head ct the following day revealed a decrease in size of the sdh to mm in diameter. several theories have been proposed for the rapid resolution of an acute sdh including csf leaking into the sdh through a tear in the arachnoid membrane with rapid reabsorption, redistribution of the hematoma in the subdural space, and acute fluctuations in icp driving the spontaneous resolution of the sdh. close neurological and repeat imaging may be helpful in managing these patients. as seen in our patient and others, a low density band in the subdural hematoma may indicate csf and be a predictor for spontaneous resolution of an acute sdh. the features of this atypical case offer points of discussion regarding the surgical or non-surgical approach of these patients. early post-hypoxic myoclonus -or myoclonic status epilepticus -develops within hours of the initial anoxic injury and is associated with poor outcomes per current aan practice guidelines. late posthypoxic myoclonus -or lance-adams syndrome -develops > hours after the anoxic injury, consciousness is regained, and is associated with relatively good outcomes. the patient is a yo man with a history of alcohol and cannabis use disorder, bipolar disorder, pnes who presented after attempted hanging for up to minutes. intial rhythm was pea; he had rounds of cpr, received mg epinephrine, and was intubated prior to rosc. myoclonic jerks were noted within hours post arrest. hypothermia protocol was initiated as gcs was t. ct head showed subtle loss of grey-white differentiation. eeg initially showed that his generalized myoclonic jerks correlated with cortical activity. he was started on versed gtt, keppra, vpa with improvement in the frequency of jerks. on post-arrest day , mri brain showed mild cerebellar edema. mri c-spine was negative for significant myelopathy, arguing against myoclonus as a spinal reflex. mentation gradually improved; on post-arrest day he opened his eyes to command. eeg evolved to show gpeds and sirpids and oxc and tpm were added. on post-arrest day a paralytic challenge resolved electrographic spikes, suggesting subcortical origin of myoclonus. he continued to improve cognitively, but despite clonazepam, vpa, home oxc he continues to have severe intention myoclonus. despite the presumed poor prognosis, the patient's family pursued aggressive measures and his mentation gradually improved. early post-hypoxic myoclonus carries a poor prognosis, however, in this case, the patient survived with a good cognitive outcome likely owing to his age and relatively few comorbidities. further studies are needed to differentiate early-onset lance-adams from myoclonic status since prognosis differs greatly. posterior reversible encephalopathy syndrome (pres) can occur from multiple etiologies and often presents with rapid-onset headache, altered consciousness, seizures and/or visual disturbances. vasogenic edema involving predominantly cerebral white matter is a key finding on imaging studies. although seizures are a frequent presenting symptom of pres, refractory status epilepticus (rse) requiring multiple antiepileptic medications is very rare. a case report of a patient presenting with pres and clinical course complicated with rse necessitating use of intravenous anesthesia, ketamine, and newly-available brivaracetam. -year-old woman with history of congestive heart failure, chronic iron deficiency anemia and uncontrolled hypertension was admitted for severe encephalopathy and convulsive status epilepticus (cse) for longer than minutes necessitating propofol and midazolam infusions. her admission systolic blood pressures were in the s, and mri brain revealed bilateral parieto-occipital t /flair hyperintensities consistent with pres. despite adequate control of hypertension following admission, patient remained encephalopathic and continuous electroencephalography (eeg) demonstrated nonconvulsive status epilepticus (ncse). the patient's ncse continued despite use of maintenance antiepileptics (fosphenytoin, lacosamide, levetiracetam) and high-dose infusions of midazolam and propofol. ketamine infusion was started to maximize nmda receptor blocking properties, and burstsuppression pattern on eeg was easily achieved with bolus infusions followed by continuous infusion. addition of brivaracetam was used to replace levetiracetam and allowed patient to remain seizure-free when iv anesthetics were weaned off. patient required prolonged hospitalization with gastrostomy tube placement and tracheostomy, which was later decannulated prior to patient's discharge to home with family. high index of suspicion is necessary to identify patients in ncse with prolonged encephalopathy that have pres. early use of ketamine along with a benzodiazepine may result in rapid achievement of burstsuppression to treat se. brivaracetam may be a useful agent to treat rse. diagnosis of diabetes insipidus(di) includes polyuria, hypernatremia and low urine specific gravity. we present two patients, receiving hyperosmolar therapy for intracranial hypertension (iht), in whom using low urine specific gravity to diagnose di lead to delayed treatment. this is a retrospective case series. criteria used to diagnose di at our institution include polyuria, sodium < mosm/kg and urine to plasma osmolality ratio < . case : -year-old male with subdural hematoma, iht on hyperosmolar therapy, developed polyuria. sodium rose from to meq/l. urine specific gravity was . excluding di. eventually, sodium rose to meq/l. specific gravity remained . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . , consistent with di. vasopressin was initiated, however the patient had already developed lactic acidosis and renal failure due to hypovolemia. case : -year-old female with intracerebral hemorrhage and iht on hyperosmolar therapy, developed polyuria. sodium rose to meq/l, specific gravity remained > . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . consistent with di. vasopressin was initiated. hyperosmolar therapy increases urine osmoles and raises urine specific gravity. this interferes with diagnosis of di which requires low urine specific gravity. while specific gravity measures the weight of particles, osmolality measures particles independent of their weight and thus accurately measures urine tonicity in the presence of heavy particles like mannitol. moreover, urine/plasma osmolality ratio is able to demonstrate relative hyposmolarity of urine when compared to serum assisting with diagnosis of di even when urine specific gravity is elevated. we conclude that urine specific gravity does not reliably detect di in patients receiving hyperosmolar therapy. urine osmolality and urine/plasma osmolality ratio may detect di earlier and prevent dehydration and kidney injury. these findings should be validated prospectively. endovascular intervention in the treatment of cvt(cerebral venous thrombosis) is an alternative strategy when cases deteriorate despite best medical management or develop refractory intracranialhypertension. we present a patient with cvt due to heparin-induced thrombocytopenia(hit), with intraparenchymal hemorrhage(iph) and refractory intracranial-hypertension, who was managed with systemic anticoagulation, continuous intra-sinus infusion of rtpa and mechanical thrombectomy(mt) resulting in excellent outcome. case report: a -year-old woman with left parafalcine meningioma s/p cyberknife was started on subcutaneous heparin for radiation necrosis days prior to admission. she presented to the hospital with new onset headaches and nausea. ct head showed increased edema with mid-line shift around the meningioma, for which steroids were started. within days her headaches worsened and repeat imaging demonstrated right temporal iph. emergent hematoma evacuation was performed. mri brain showed right cerebellar infarct and mra head showed extensive cavernous sinus thromboses, from right internal jugular vein and into sigmoid and transverse venous sinuses. she tested positive for hit and was switched to argatroban drip. patient however continued to deteriorate due to refractory intracranial-hypertension. intra-cavernous rtpa injection and mt was done but the thrombosis was noted to recur on repeat angiogram hrs later. an intra-sinus catheter was left in place for continuous infusion of rtpa at mg/hr. for hrs was done while argatroban drip was continued. the patient's intracranial pressure returned to normal. repeat venogram showed resolution of cvt. patient tolerated the therapies well, without any further hemorrhagic complications. modified rankin score at month follow-up was . this case features successful aggressive endovascular interventions including in-situ rtpa infusion, mt and concomitant systemic anticoagulation for cvt due to hit, complicated by intracranial hemorrhage and refractory intracranial hypertension. the paucity of high quality evidence related to safety, efficacy and modality of endovascular treatment lead to making therapeutic decision on individual basis. acute brain injury may be followed by encephalopathy marked by electroencephalographic features along the ictal-interictal continuum (iic). the use of perfusion imaging to co-localize radiographic features of known malignant eeg patterns may add an important context to guide treatment escalation or de-escalation. this is only the second report in which widely available ct or mr perfusion techniques were favored for this application over more cumbersome metabolic imaging such as pet. retrospective analysis was performed on records for patients admitted to a neurosciences icu, exhibiting encephalopathy, with eeg features on the iic, who underwent perfusion imaging. studies included ct perfusion, mr perfusion, arterial spin labeling, or spect. these studies were obtained for unrelated purposes. escalation or de-escalation of anti-convulsant and sedative medication, hospital course, and patient outcomes were extracted. perfusion imaging data was juxtaposed with eeg patterns along the iic, and patient outcomes are described in narrative form. seven cases were identified. four cases occurred in the context of intraparenchymal hemorrhage, of which one was secondary to meningioma resection. two cases occurred after treatment for subdural hematoma, and one case was related to ischemic stroke. anti-convulsant and sedative management was escalated or de-escalated relative to the presence or absence of radiographic co-localization of hyperperfusion in all but one case. emerging data indicates that some iic eeg patterns may merit aggressive treatment. metabolic signatures of secondary brain injury as measured by cerebro-oximetry or microdialysis have associated these patterns with unfavorable outcomes. we report case studies in which information gleaned from basic perfusion imaging may suffice to distinguish between benign iic patterns and those that should be regarded as near-ictal. the cases hint at novel ways to conceptualize treatment of encephalopathy following acute brain injury and suggest a dimensional shift in thinking towards electroperfusive status epilepticus. sudep has classically been a diagnosis of exclusion. recent studies have shown, however, that similar genes -and even genes within the same family -are associated with sudep and brugada. this suggests that perhaps the cardiac irritability of brugada syndrome exists on a spectrum with epileptic sudden death. a yo man with a history of presumed seizure disorder presented as a transfer from another hospital after being found to have anoxic brain injury following cardiac arrest. he had been shopping with his wife when he was thought to have one of his typical seizures. he was non-responsive for about minutes. on arrival ems found him pulseless. cpr was started en route and continued for minutes in the ed where he was defibrillated three times before achieving rosc. he completed the therapeutic hypothermia protocol. cardiac catheterization was clean. eeg showed diffuse slowing with no epileptiform discharges. imaging showed diffuse anoxic brain injury. after nearly two weeks without clinical improvement he was made comfort care. . of note, previous seizure workup failed to identify epileptiform activity. he was given an aed prescription which he never filled. further chart review showed that he had previously presented to the ed after a "seizure" episode which lasted minutes. his neuroexam was non-focal. ct head was negative. review of his ekg at that time showed type brugada syndrome pattern with an elevated jpoint and t-wave inversions in v and v . his sudden cardiac arrest is most likely a result of symptomatic brugada symptomatic brugada is important to identify early since deaths such as the one discussed above may be prevented by an implanted defibrillator. this case highlights the need for heightened awareness and more effective testing for brugada in the setting of seizure or pseudoseizure. patients with cerebral air embolism (cae) often exhibit more severe symptoms than those typically associated with the number of air emboli and size of infarcts on brain images. however, this discrepancy between symptoms and imaging findings has not been sufficiently explained. we report a case of cae in which disruption of the blood-brain barrier (bbb) and perfusion defects were identified via brain magnetic resonance imaging (mri). a -year old man with a lung mass was admitted to our hospital. percutaneous needle aspiration of the mass was performed in the left lower lobe of the lung. the patient developed sudden confusion and irritability after the procedure. during neurological examination, he could follow only simple commands and exhibited symptoms of left-sided weakness and neglect (medical research council grade ). noncontrast computed tomography (ct) of the brain revealed a few small air emboli in the right frontal subcortical area. multimodal mri of the brain was performed minutes after the onset of symptoms. t -weighted gradient-echo imaging revealed only a few small air emboli in the right frontal area, and diffusion-weighted imaging findings were unremarkable. in contrast, time-to-peak imaging revealed widely distributed perfusion defects in the right hemisphere, while contrast-enhanced t -weighted imaging revealed prominent leptomeningeal enhancement, suggestive of bbb disruption in the right hemisphere. magnetic resonance angiography revealed no steno-occlusive lesions. the patient was treated with % oxygen via a high-flow nasal cannula. his weakness subsided the next day, although his confusion persisted for days. follow-up mri performed five days after the onset of symptoms revealed resolution of the abnormal findings. our findings suggest that disruption of bbb and perfusion defects may develop in patients with cae. extensive impairments of the bbb and perfusion may explain the mismatch between severe neurological symptoms and small air emboli/infarcts. co-existence of cerebral salt wasting and diabetes insipidus is an extremely rare entity that has only been described in adult case series and a paediatric series. due to the complex nature of diagnosing this entity, mistreatment may ensue and lead to high morbidity and mortality rates. we report a case of a patient who was admitted to the neurosurgical intensive care unit after sustaining a subarachnoid haemorrhage secondary to a ruptured anterior communicating artery aneurysm. a -year old lady presented with sudden onset of severe headache and nausea. gcs was (e v m ) with no focal neurological deficits. she underwent endovascular coiling and embolisation of the aneurysm under general anaesthesia and had a left external ventricular drain inserted. in the immediate postoperative period, she was found to be polyuric, with the initial workup suggestive of diabetes insipidus. desmopressin was administered with initial good effect. however, her polyuria recurred and persisted despite desmopressin. the repeat workup revealed the presence of concomitant cerebral saltwasting. she was then treated with fludrocortisone and sodium chloride supplementation. careful monitoring of her serum sodium levels and overall fluid balance allowed close titration of the desmopressin, fludrocortisone and sodium chloride supplementation. she was eventually weaned off treatment and discharged well with normal sodium levels and with no neurological deficits. this case highlights the difficulty encountered in managing concomitant cerebral salt wasting and diabetes insipidus in critically ill neurosurgical patients and the need to for a high index of clinical suspicion, early intervention and close monitoring. levetiracetam is a commonly used antiepileptic drug (aed) used to treat epilepsy. this agent was approved by the fda in , is available in oral and intravenous formulations, and offers advantageous pharmacokinetics, minimal drug interactions, and a favorable side effect profile. the purpose of this case report is to describe a case of severe, asymptomatic rhabdomyolysis exacerbated by levetiracetam administration. the medical record was reviewed and data was collected to describe a case with a pertinent review of the literature. a -year-old african-american male with a history of hypertension presented to the emergency department following a tonic-clonic seizure. baseline labs were drawn and revealed a ck level of , iu/l, negative urine myoglobin and normal renal function. levetiracetam therapy was initiated and no further seizures were noted. the patient's ck continued to trend up throughout his stay despite aggressive fluid resuscitation with a positive myoglobin on hospital day . the ck reached a peak of , iu/l on hospital day . after a literature review and evaluation of his medication list, six casereports were identified linking elevated ck and rhabdomyolysis to levetiracetam administration. at that time levetiracetam was discontinued and the ck rapidly declined to , iu/l on hospital day . the patient never had muscle pain or kidney injury and was discharged on hospital day . this case-report describes rhabdomyolysis associated with levetiracetam administration with a naranjo probability scale score of indicating a probable adverse drug reaction. the adverse effects of generalized pain and neck pain are described in the package insert with an incidence of - %; however, it is not reported that ck levels were monitored. due to the frequent use of this aed and given the rare yet serious adverse effect of rhabdomyolysis, ck levels should be monitored upon initiation. acute toxic leukoencephalopathy (atl) is a potentially reversible disturbance to white matter caused by exposure to toxins. we report the first case of a patient with atl in the setting of a fentanyl overdose and reviewed the literature. a year-old man with a history of opiate abuse was found unconscious, last seen well nine hours prior. he was known to have purchased mg of fentanyl that day. he was intubated and briefly required blood pressure support. he was initially hypoglycemic and suffered fulminant liver damage, acute kidney injury, rhabdomyolysis, and stunned myocardium. comprehensive toxicology screen was positive for cannabis and fentanyl. mri of the brain showed pronounced bilateral restricted diffusion in the high frontoparietal subcortical white matter with radiographic stability five days later. he remained intubated and neurologic exam poor with fluctuating brainstem reflexes and posturing despite improvement in end-organ function. atl has been reported in a -month-old girl and an -year-old man with exposure to transdermal fentanyl, both of whom had favorable outcomes ( , ). one case has been reported following oral oxycodone ingestion ( ). of cases of atl secondary to inhaled heroin, % were fatal ( ). preferential white matter injury has been seen in cases of hypoxic ischemic encephalopathy (hie) ( , ). it was initially thought to be secondary to wallerian degeneration following grey matter damage, but post-mortem pathology has shown direct insult to axons ( ). atl has been reported in one case of hypoglycemic coma ( ) and one case of uremia ( ). it has never been reported in isolated hepatic encephalopathy, secondary to seizure, or with cannabis use alone. based on our review of the literature, the most likely causes of this patient's atl are fentanyl or hie. fentanyl should remain on the differential as a previously unreported cause of atl. autonomic dysregulation is a common complication of acute spinal cord injury (sci). subsequent hypotension may worsen central nervous system injury as well as neurologic and mortality outcomes. to help mitigate this occurrence, consensus guidelines recommend maintaining patients' mean arterial pressure (map) > mmhg within the first seven days based on evidence from limited clinical trials. limited data exists describing the use of midodrine, an alpha- agonist and the previously only available enteral vasopressor, for blood pressure (bp) augmentation in this setting. the use of midodrine is limited by cardiovascular side effects such as bradycardia. droxidopa, a novel enteral precursor of norepinephrine that works independently of the central nervous system, may serve a role in sustaining map in acute sci. we describe a novel case of droxidopa use in a -year old male who sustained a spinal cord contusion secondary to severe stenosis at the fourth cervical vertebrae following a ten-foot fall. droxidopa was used to facilitate vasopressor wean in the setting of neurogenic shock as a complication of acute spinal cord injury. to sustain adequate cns perfusion (map goal > - mmhg) and facilitate patient transfer to a lower level of care, droxidopa mg three times daily was initiated after five days of continuous infusion of intravenous norepinephrine. daily assessments of hemodynamic parameters were performed, including blood pressure, heart rate, map, and an electrocardiogram. successful wean of norepinephrine was achieved within hours of droxidopa initiation, with an average map sustained above mmhg. the patient was transferred to a lower level of care within hours of droxidopa initiation. no cardiovascular side effects were observed. droxidopa was well tolerated and facilitated transition from norepinephrine infusion to an enteral option. droxidopa may be a viable option in stable neurocritical care patients who require vasopressors to sustain adequate cns perfusion. traumatic brain injury is acute and sometimes rapidly aggravated during or after surgical treatment. imaging study is most important and computed tomography (ct) is the golden standard in tbi. however the patient should be transfer to ct room or relatively high cost mobile ct scanner may be used. ultrasound is not expensive and also does not produce radiation exposure. we studied the effectiveness and advantages of intra-operative ultrasound examination in traumatic brain injury patients intra-operative ultrasound was used after decompression of injured brain from june to april . the ultrasound device was the affiniti (philips ultrasound inc, usa) and . mhz transducer was used. the transducer was covered by thin transparent sterilized vinyl with ultrasonic gel with aseptic manner. to protect brain injury by the ultrasonic probe, a saline soaked gauze was applied on the cerebral cortex. the axial images were captured and then stored in pacs system promptly. ultrasound images were compared to postoperative ct scan. there were male and female patients were examined by ultrasound during there surgery. ipsilateral hemisphere, especially cortical layer was slightly distorted to identification. brain stem area was visible in most cases. contralateral hemisphere was seen in unilateral craniotomy and craniectomy cases. in bilateral craniectomy cases, both hemispheres were observed well. parenchymal hemorrhage was also identified and confirmed for removal using ultrasound. in severe brain swelling cases, arachnoid space was seen increased echogenicity. ultrasound image was compared to postoperative ct scan. intra-operative ultrasound is effective in real time inspection of brain during surgery and may helpful detect opposite or parenchymal hemorrhage before closure and leaving operation room. to describe a rare case of a varicella zoster virus (vzv) meningitis with progressive multiple cranial nerve deficits in the absence of cutaneous zoster rash. a young woman with idiopathic thrombocytopenic pupura on steroids presents with horizontal diplopia in the setting of seven days of intractable headache. she had no meningeal signs, fever, leukocytosis or cutaneous rash. within three days into hospitalization, she developed bilateral cn vi, cn iii, right cn v and right cn vii palsies in a progressive fashion. csf analysis revealed cell count of , /mm , a protein of mg/dl and glucose mg/dl. cytology, tuberculosis, bacterial and fungal cultures, ace and hiv testing were negative. vzv-dna was detected in csf in high titers vzv quant: . million. contrasted brain mri revealed mild diffuse leptomeningeal enhancement in the basilar region. she recovered almost all cranial nerve function within days of treatment with acyclovir and high dose steroids. a diagnosis of polyneuritis cranialis with zoster sine herpete (zsh) was made given pcr positive vzv-dna in csf. vzv reactivation with a wide array of neurological deficits can present without rash making diagnosis challenging. zsh should be in the differential for acute cranial nerve deficits as prompt treatment with acyclovir can lead to rapid recovery. stress-induced cardiomyopathy or neurogenic stunned myocardium is a well-documented cardiac complication following aneurysmal subarachnoid hemorrhage (sah). onset is usually immediate, within hours after aneurysm rupture, and is characterized by left ventricular dysfunction with pulmonary edema and elevation in cardiac biomarkers. this can often be mistaken for an acute myocardial infarction or ischemia. the pathogenesis appears to be the result of elevated catecholamine levels following injury leading to myocardial contraction band necrosis and cardiac dysfunction. this syndrome occurs more commonly in patients with severe or "high-grade" sah. we review a case of delayed cardiac dysfunction coinciding with the onset of vasospasm. a -year-old female presented with a h&h , mf sah. she appeared to have lost consciousness prior to arrival and was reporting worst headache of life. she had an evd placed upon arrival with opening pressure at . she underwent endovascular coiling of a ruptured aneurysm of her anterior communicating artery aneurysm. initial echocardiogram demonstrated normal wall motion with ef of %, and minimal troponin i elevation at . ng/ml. on post-bleed day the patient became more somnolent and developed chest pain with an ecg demonstrating st-elevation in all anterolateral leads concerning for acs. she was taken for cardiac catheterization where she had non-obstructive vessels with no vasospasm seen. her ef was reported at - % with apical ballooning present. her repeat echocardiogram also demonstrated a new apical akinesis with ef %, and troponin peaked to ng/ml. her tcds at the time were suggestive of vasospasm with bilateral lr > , but no focal deficit present. it appears that regardless of timeline, stress-induced cardiomyopathy or neurogenic stunned myocardium occurs after sympathetic or catecholamine surge and may occur after the onset of vasospasm in patients with aneurysmal sah. the rapid neurological assessment of critically ill patients with neurologic disease is paramount when determining a course of action. neuromuscular blockade is often used during critical care transport and in the emergency department. unfortunately, this can delay examination and assessment leading to unnecessary testing and procedures. historically, neuromuscular blockade reversal was accomplished using a combination of neostigmine and glycopyrrolate. however, this can lead to incomplete reversal and unwanted side effects from these medications. sugammadex is a cyclodextran injectable compound that has been fda approved in the united states since for rapid reversal of rocuronium induced neuromuscular blockade. sugammadex works by forming a complex with rocuronium and rendering it unable to bind to nicotinic cholinergic receptors at the neuromuscular junction. sugammadex can reverse neuromuscular blockade without the unwanted side effects of cholinesterase inhibitors. this is a case report of the successful use of sugammadex to reverse the effects of neuromuscular blockade in an intracerebral hemorrhage patient. a year old male with a history of atrial fibrillation and a supratherapeutic inr presented via aeromedical ambulance with a ml left frontal intracerebral hermorrhage causing a mm midline shift. he received a mg bolus of rocuronium prior to arrival and had a gcs of upon presenting to the neurosciences icu. a train-of-four revealed / twitches. he was given mg/kg of sugammadex with a return of / twitches within seconds. a more accurate neurological examination was then obtained demonstrating that his brainstem reflexes were intact, he could open his eyes spontaneously and reacted purposefully to painful stimulation. this allowed a non-operative course to be taken. sugammadex can reliably and quickly reverse neuromuscular blockade allowing for the immediate assessment of the neurocritical care patient. it is a useful tool with minimal side effects. piperacillin-tazobactam is commonly deployed as empiric antibiotic therapy. piperacillin-induced hematologic laboratory test abnormalities were rare in pre-marketing studies, and whether these alterations are of clinical significance has been studied little. aberrations in platelet function have not been implicated. in the present case, we discuss a patient presenting with hypertensive intracerebral hemorrhage (ich) who sustained two additional hemorrhages in distinct locations after routine removal of intracranial monitors and an external ventricular drain (evd). these significant bleeding events occurred exclusively during piperacillin-tazobactam therapy and were correlated with new abnormalities in the patient's platelet function assay (pfa) results. a -year old vietnamese male with hypertension presented for treatment of a left basal ganglia ich. epinephrine/collagen and adenosine diphosphate/collagen pfas at the time of evd and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. hospital course was complicated by aspiration pneumonia requiring empiric piperacillin-tazobactam administration. after removal of the quad-lumen bolt and evd on separate days, both follow-up ct scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. repeat pfas were abnormally prolonged, representing a distinct change from baseline. a trend toward normalization of pfas was observed after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter. the present case is unique in that the significant bleeding that occurred was attributable to objectively confirmed platelet dysfunction rather than thrombocytopenia. other possible innate causes of bleeding were less likely as the patient demonstrated normal platelet count, von willebrand multimers, platelet morphology, and clotting factors. this is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed. the life-saving potential of extracorporeal membrane oxygenation (ecmo) has been well recognized since the s. modern advancements of research and technology have allowed ecmo to be accepted as a dependable intervention for patients with severe pulmonary or cardiac failure. however, with increased use, associated complications that detract from the benefit of ecmo are surfacing as well. this case report describes a case of diffuse intracerebral hemorrhage (ich) after prolonged ecmo resulting in cerebral edema, mass effect, and eventual brain herniation. the patient is a previously healthy year old female who presented with fever, chills, and myalgia. when evaluated at urgent care, she was noted to be hypoxic and was sent to an outside hospital where her monospot test was positive. upon arrival, the patient was placed on venovenous ecmo (vv-ecmo) due to severe hypoxia. she was also in acute renal failure requiring continuous renal replacement therapy (crrt). she had an episode of hypotension with bradycardia. subsequently, her pupils were noted to be fixed and dilated. a stat ct head then showed diffuse bilateral hemorrhages at the graywhite junction as well as diffuse edema. labs showed thrombocytopenia likely due to disseminated intravascular coagulation (dic). her exam was consistent with brain death. it has been estimated that up to % of patients who were placed on ecmo as a last resort for respiratory failure have neurological complications including ich. there is no stereotypical pattern of bleeding but diffuse hemorrhage has been seen, which is consistent with the pattern seen in our patient. notably, those with ich have significantly higher rates of mortality. thrombocytopenia, dic, and platelet dysfunction that develop as a result of ecmo are thought to play a role in the development of ich. to present a case report of syndrome of the trepheined (sot) and paradoxical herniation without craniectomy. sot is reported when a constellation of positional neurological symptoms arise following large craniectomy, resolving in a delayed fashion following cranioplasty. paradoxical herniation may occur in extreme cases.the pathophysiology is incompletely understood however proposed mechanisms include compression of underlying brain by the flaccid skin flap due to the gradient between atmospheric and intracranial pressure exacerbated by upright pressure, changes in cerebral blood flow, and csf fluid. a middle aged woman with a history of mood changes eight months preceding admission presents with worsening left hemiplegia over one week. mri revealed a x mm right frontal cystic mass. hyperosmolar therapy and steroids were initiated for midline shift and brainstem compression. her immediate post operative course after tumour excision was uncomplicated. on post-operative day two, she developed uncontrolled hypertension, worsening anisocoria, and decerebrate posturing requiring urgent intubation. head ct revealed uncal and subfalcine herniation despite a large resection cavity. an external ventricular drain was placed and removed due to lack of drainage. within hours of trendelenburg positioning, she improved both clinically and radiographically. she did not undergo an intraoperative csf reduction and no preadmission history (back pain, orthostatic headache, trauma) to support an occult csf leak. she had a recurrence of symptoms on post-operative day eight which also resolved upon lying flat for hours. she was ultimately discharged to acute rehab and tumor pathology returned as glioblastoma (who grade ). this novel case of sot in the absence of craniectomy demonstrates the complex and poorly understood consequences of slow growing massive tumors, csf dynamics and exertional force on static cns structures. this case also illustrates the benefits of a collaborative, multidisciplinary approach to patient care in the neuroicu. to present a lesser known leukoencephalopathy that occurs when patients overdose on inhaled heroin vapor 'chasing the dragon" is a method of inhaled heroin vapor that is different from smoking or snorting heroin. heroin powder is placed on aluminum foil, which is heated by placing a flame underneath. the white powder turns into a reddish-brown gelatinous substance that releases a thick, white smoke, which resembles a dragon's tail. the fumes are "chased" or inhaled through a straw or small tube. currently the us is facing a growing epidemic of heroin use making this leukoencephalopathy more pronounced. a -year-old female with history of drug abuse presented to the emergency department with altered mental status. the boyfriend informed staff that she likely smoked heroin. on arrival, she was drowsy but easily arousable. her brainstem reflexes were intact but she was grossly dysmetric. urine drug screen was positive for opiates only. initial ct of the brain demonstrated extensive loss of gray-white differentiation within the cerebellar hemispheres and bilateral lucency in the globus pallidus and developing hydrocephalus. patient was placed in the neurointensive care unit to monitor and was managed medically with hypertonic therapy to combat her cerebral edema. an mri was done which demonstrated a distinctive pattern of symmetrical white matter t hyperintensities in the cerebellum, hippocampus and internal capsule bilaterally characteristically known as "chasing the dragon" sign. the patient gradually improved with supportive treatment, but continued to have mild ataxia upon discharge. we present a case of leukoencephalopathy that was generally rare to see, but now that heroin use is now at a year high within the us, this phenomenon may become more prominent. heroin inhalation leukoencephalopathy should be suspected in all patients with a history of chasing the dragon when they present with neurological abnormalities. the use of intra-venous (iv) thrombolysis for the treatment of acute ischemic stroke is now the standard of care. this is typically followed by endovascular thrombectomy if patient is eligible does not improve . we present a rare acute ischemic posterior circulation stroke that had progression of the stroke despite receiving both intra-venous thrombolysis and endovascular thrombectomy. case report: a years old african-american gentleman with past history of obesity, sleep apnea and prostatic hyperplasia, presented with acute onset left hemiparesis, with limb ataxia, who then progressed to altered sensorium in the emergency room needing endotracheal intubation. his initial nihss was . he was given iv thrombolysis, with subsequent vascular imaging that showed a top of the basilar clot, that was removed via endovascular intervention. a sister and one of the aunts reported a history of 'clots' when asked about family history. despite initial improvement, the patient deteriorated clinically after about hours from symptom onset, and was found to have extension of stroke into the brainstem, with simultaneous acute loss of brainstem reflexes . the patient was started on palliative withdrawal of care by the family about days from the initial onset of symptoms. his thrombophilia work-up revealed later that he was homozygous for methylenetetrahydrofolate reductase (mthfr) gene mutation, c >t. this case with a poor outcome due to extension of the ischemic stroke despite receiving the standard of care therapy, highlights the need for considering the use of anticoagulation within hours postthrombolysis and thrombectomy in cases with underlying thrombophilia. the current guidelines do not support this aggressive approach. there is a dire need for randomized controlled trial about such cases to provide evidence based care to avoid a repetition of a similar poor outcome. barbiturate therapy has shown benefit in reducing intracranial pressure (icp) in patients who are refractory to other treatment modalities. however, severe adverse drug effects can accompany barbiturate use when used at the high doses required for icp management, such as hypotension, hepatic/renal dysfunction, and infection, among other deleterious consequences. dyskalemia has been reported infrequently in the literature with most of the cases involving patients on thiopental. there remains little guidance for management of this adverse effect. we present a case of severe dyskalemia induced by high-dose pentobarbital therapy and experience with management of this rare but life threatening effect. the patient was a -year-old male with traumatic brain injury and subdural hematomas complicated by refractory icp elevations. after hyperosmolar therapy, sedation, and csf drainage failed to control icp, and he was deemed to not be a candidate for surgical decompression, high-dose pentobarbital was started. after initiation of pentobarbital, his initial potassium of . mmol/l decreased to a nadir of . mmol/l over the next hours despite aggressive repletion with a total of meq of oral and intravenous potassium chloride. upon down-titration and discontinuation of pentobarbital, the serum potassium rapidly rebounded to . mmol/l with st-segment elevations on ekg. pentobarbital was restarted in an attempt to stabilize escalating icps and elevated serum potassium. subsequently a slow taper was utilized to mitigate dyskalemia during barbiturate discontinuation. dyskalemia associated with high-dose barbiturate therapy presents a significant dilemma to practitioners as both severe hypo-and hyperkalemia can be life threatening. published literature provides little guidance on how to safely manage patients who experience this adverse effect. patients receiving barbiturate therapy should have frequent potassium monitoring especially in the initiation and discontinuation phases. potassium repletion should be approached with caution, especially preceding discontinuation of barbiturate therapy. diffuse astrocytoma (formerly known as 'gliomatosis cerebri') may present with seizures or symptomatic raised intra-cranial pressure. this is typically followed by a few months of relatively stable phase (with treatment) and then possible subsequent development of glioblastoma multiforme. we present a rare case of a previously healthy caucasian lady who had new onset seizures, that showed glioblastoma multiforme already present on a background of diffuse astrocytoma. case report: a years old caucasian lady with no significant past medical history was admitted with new onset focal seizures with secondary generalization, needing intubation and propofol for airway protection. brain imaging showed left frontal ring-enhancing mass, with a smaller satellite lesion in the left insular cortex, on a background of diffuse infiltrative lesion involving left fronto-temporal lobe and a smaller area of right parafalcine frontal lobe. biopsy of the left frontal mass revealed it to be glioblastoma multiforme. this is a rare situation when a previously healthy patient presents with new onset seizures and already has glioblastoma multiforme on a background of diffuse astrocytoma (or 'gliomatosis cerebri'). her post operative imaging revealed disease progression with increase in the size of the left insular cortical lesion. she was discharged home with plan for radiotherapy and chemotherapy. diffuse astrocytoma with glioblastoma multiforme within can remain asymptomatic till late in the disease course. diffuse astrocytoma (or 'gliomatosis cerebri') is a rare disease and even more rare is to have this remain asymptomatic till the development of glioblastoma multiforme within. this particular case highlights the need for vigilance about such a possibility, as this aggressive brain tumor carries a grave prognosis, especially when it develops on background of a diffuse astrocytoma. subdural hygromas (sdg) are cerebral spinal fluid collections in the subdural space that may occur following trauma. decompressive craniotomy may increase the risk for acute sdg or other forms of external hydrocephalus along the surgical plane. while these are traditionally benign and resolve spontaneously, they may in rare cases cause clinical deterioration. we report three cases. cases and were alcoholic men aged and , respectively, who suffered severe traumatic brain injury (tbi) following falls while intoxicated. they had early clinical deterioration prompting emergent hemicraniectomy for left-sided sdh with midline shift (mls). case clinically worsened on postoperative day (pod) with posturing, decreased pupillary responses, and new-onset seizures. new bilateral, extensive subdural hygromas were noted, enlarging over serial ct scans up to -cm with progressive mass effect. uncal herniation and downward brainstem displacement occurred by pod despite external ventricular drainage. case deteriorated on pod with fluctuating exam and newonset seizures. imaging revealed new subgaleal fluid collection measuring . -cm and a contralateral sdg. on pod , hemicraniectomy was performed for new mls from enlarging fluid and hemorrhage in extradural component. both died shortly after withdrawal-of-care. case was a year-old man with dural arteriovenous fistula who presented with spontaneous left-sided sdh and underwent left hemicraniectomy. on pod , he had new-onset seizures and new bilateral sdg measuring . -cm on the left and . -cm on the right without mass effect. two days later; the right sdg grew to . -cm causing significant mass effect. he recovered after burr-hole evacuation and temporary subdural drain placement. sdg following sdh evacuation can have a malignant course, causing clinical deterioration without prompt recognition and csf diversion. all patients had large volume sdh and two were alcoholic; larger prospective cohorts are required to identify risk factors. seizures may be an early clinical sign. moyamoya disease is an intracranial vasculopathy that results in stenosis of bilateral internal carotid arteries with subsequent development of extensive collateralization. the diagnostic criteria for moyamoya disease are well established and generally accepted, yet reaching the diagnosis can be challenging in some cases. herein, we present an unusual case of progressive cerebral vasospasm triggered by pituitary apoplexy that led to a delay in the underlying diagnosis of moyamoya disease. case report. a -year-old female with hyperlipidemia presented to the emergency department with a bifrontal headache, right-sided weakness, and dysarthria. ct angiogram showed extensive multifocal narrowing of the bilateral supraclinoid icas, proximal aca/mcas, and posterior circulation. mri brain revealed a left insular stroke as well as a sellar mass with a central hemorrhagic component. mr perfusion demonstrated decreased perfusion in the right hemisphere. lumbar puncture and extensive vasculitic workup was unremarkable. endocrine studies were notable for elevated prolactin with low fsh and lh levels. despite protracted blood pressure augmentation strategies, the patient continued to experience progressive infarcts in the left mca/aca territory. repeat ct angiogram showed progression of vasculopathy, and transcranial doppler studies demonstrated worsening vasospasm of the right mca and left pca arteries. the patient received corticosteroids given concern for apoplexy, and was maintained on aspirin and verapamil. given the aggressive nature of her vasculopathy, the patient underwent conventional angiography two weeks later, which revealed bilateral suzuki grade iii moyamoya. following this diagnosis, she received bilateral sta-mca bypass surgeries. it is important to revisit the differential diagnosis of cerebral vasospasm when the clinical course does not conform to expectations. this case highlights moyamoya as the causative agent in progressive vasculopathy likely masqueraded by pituitary apoplexy and concomitant vasospasm. moyamoya is an important diagnosis to consider in patients with a fulminant vasculopathy refractory to traditional treatment of vasospasm. visualization of intracranial structures by ultrasound in adults is limited by the presence of skull, though ultrasound imaging can occur through temporal windows. point of care ultrasound allows assessment of midline shift, brainstem, and ventricles. doppler allows visualization of cerebral perfusion patterns. patients with a hemicraniectomy have better temporal windows available since a portion of their skull has been removed. in such patients, ultrasound can provide a non-invasive method to serially assess midline shift, intracranial hematomas, and focal ischemia at the bedside. we present images of a cranial ultrasound that shows remarkable anatomical details that correlate well with computed tomography (ct) head. a year-old male presented with right-sided weakness and confusion and was found to have a left parietal intraparenchymal hemorrhage with cerebral edema and left-to-right midline shift on ct head. increase in cerebral edema and expansion of the hematoma caused clinical neurological decline necessitating a left-sided hemicraniectomy with clot evacuation. a cranial ultrasound was performed two days after surgery to assess for progression of cerebral edema and intracranial hemorrhage. a transtemporal approach in axial plane was used to visualize intracranial structures through the craniectomy window. physiological structures like the falx cerebri, lateral ventricles, midbrain, mammillary bodies, choroid plexus, splenium of corpus callosum, thalami, and circle of willis were visualized with incredible anatomical detail. pathology such as intracranial hemorrhage, focal ischemic areas, vasogenic edema as well as encephalomalacia were identified with close correlation to the noncontrast head ct. the patient is currently recovering in the neurocritical care unit with supportive care. cranial ultrasound has potential applications in point of care assessment of intracranial pathology in neurocritical care patients. this application has promising use in directing therapy in patients who are otherwise unstable for transport or are unable to undergo neuroimaging secondary to positioning needed for management of cerebral edema. cerebral mucormycosis is a rare infection caused by fungi found in soil and decaying vegetation. the rhino-orbital-cerebral type is classically associated with aids, diabetes, malignancy and immunosuppression. we observed a series of young immunocompetent patients who presented with a fulminant form of isolated cerebral mucor associated with severe meningoencephalitis, parenchymal necrosis and symptomatic cerebral edema. six patients with histopathological diagnosis of cns mucormycosis admitted to the university of cincinnati neurocritical care unit between and are presented. patient ages ranged from - (median ). none had diabetes or hiv. drug use (intravenous and intranasal) was confirmed in patients. they presented with altered mental status ( ) and focal neurologic deficits ( ). four patients presented with fever and leukocytosis. mri revealed lesions in the basal ganglia ( ) or cerebellum ( ) which were characterized by t hyperintensities with patchy restriction and susceptibility signal. contrast enhancement was present in patients. mass effect ( ) and midline shift ( ) were prominent. mechanical ventilation was required in four patients. all but one patient received amphotericin b. three died from intractable intracranial pressure (icp). one patient eventually gained functional independence, one still requires high level of care, and one was lost to follow-up. csf analysis was negative for mucor in all cases. fulminant cerebral mucormycosis should be considered in every young patient presenting with rapid onset meningo-encephalitis and necrotized cerebral lesions, especially if located in the basal ganglia. history of ivdu should raise further suspicion. these patients should be monitored in intensive care settings as they can rapidly develop malignant cerebral edema and increased icp. antifungal therapy should be initiated upon presentation as it has been shown to improve morbidity and mortality. the incidence of acute ischemic stroke in the immediate post-partum period ranges between - % and is considered a serious cause of morbidity and mortality. pregnant or postpartum women are less likely to receive iv tissue plasminogen activator (tpa) primarily because of pregnancy, ongoing peripartum bleeding and/or recent delivery. the fda classifies tpa as a category c drug and current recommendations consider pregnancy a relative contraindication for receiving tpa. we present two cases of peripartum ischemic strokes with varying ischemic stroke time windows requiring aggressive revascularization therapy (endovascular and pharmacologic). a y g p presented to an outside hospital days post-partum with new onset of facial droop and left upper extremity weakness (nihss ). imaging showed right m cutoff and occlusion of several m branches. the patient was not a candidate for tpa given ongoing vaginal bleeding. the decision was made to proceed with mechanical thrombectomy when her exam worsened to nihss . the thrombectomy was successful with tici c reperfusion. she was discharged home days later with a nihss of zero. a y g p presented days post-partum with new onset of left facial droop and slurred speech (nihss ). imaging showed right m cutoff with reconstitution, but with significant associated penumbra. acute worsening of exam post tpa triggered a push for mechanical thrombectomy achieving a tici recanalization. post procedure the patient's only symptom was decreased sensation in left fingertips. at -day follow up the patient had returned to her baseline with a nihss of zero. endovascular and pharmacologic revascularization therapy should be considered on an individual basis in the peripartum population. current literature is limited to case reports /case series. larger multicenter trials are warranted and anticipated in the near future. while the optimal duration of burst suppression for status epilepticus (se) has not been established, burst suppression poses significant morbidity that may be dependent on the amount of time spent in burst suppression. herein, we report a case of se that resolved after ultra-short burst suppression. case report. a year-old female was admitted to the neuro-intensive care unit after experiencing several brief tonic-clonic seizures characterized by right-sided shaking and left-sided head turn. despite lorazepam and levetiracetam administration, the patient did not return to baseline and was transferred to our unit. on presentation, her workup revealed a leukocytosis and a glucose level > mg/dl. lumbar puncture showed a mild pleocytosis for which broad spectrum antibiotics were initiated. on initial examination, she was unresponsive and was not following commands. electroencephalogram (eeg) demonstrated frequent sharp and slow discharges in the right posterior quadrant with generalization (~ seizures/hour) with minimal improvement following levetiracetam and phenytoin administration. given the refractory nature of seizures, the patient was intubated and treated with general anesthetics. using propofol, burst suppression was achieved (consisting of - s bursts with intermixed suppressions) and was continued for < hours. following weaning, the patient had no further evidence of seizures, and eeg showed lateralized periodic discharges in the right occipital lobe. mri did not demonstrate an occipital focus, but did reveal cortical diffusion restriction in the bilateral posterior hemispheres. the patient was extubated the following morning, and was transferred to the neurology floor two days later. this case provides evidence that in certain situations, relatively brief periods of burst suppression in se can serve as a "reset switch", allowing for resolution of seizures while minimizing toxicities associated with prolonged burst suppression. further studies to determine which patients may benefit from ultrashort burst suppression are warranted. there are two systems of facial control, voluntary and emotional; these are independent up to the level of the facial nucleus. we described a case of a patient who presented with isolated emotional facial palsy after intracerebral hemorrhage (ich). retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital. a year-old woman with history of migraines who presented to the emergency room after a colleague noticed she was not moving the left lower side of her face when she smiled. head ct showed a large right frontal ich involving the medial frontal lobes and anterior thalami. on review of an old mri done, an underlying developmental venous anomaly with an associated cavernoma was seen. her exam was notable for a flattened emotional affect, no facial palsy when asked to activate on command, but a facial droop that occurred in the context of her smiling to jokes and other humor. her nccu course was complicated with significant brain edema requiring osmotherapy up to weeks out from the initial insult with self-limited episodes of brain herniation characterized by extensor posturing, dilated pupils, hypertension, hyperventilation and tachycardia. these were initially dismissed as sympathetic storming vs seizures as she will come out of those to her baseline (awake with mild left sided weakness) many times without therapy. she eventually required a hemicraniectomy two weeks after presentation. conclusions solated emotional facial palsy can be the presenting sign after ich when the hemorrhage involves the contralateral thalamus, of the striato-capsular region or the medial frontal lobes. in this case, transient icp elevations were leading to dilated pupils, tachycardia and hypertension -highlighting that heart rate changes can be variable with elevated icps and that in young patients, brain herniation episodes can be self-resolved with hyperventilation. yo female with no pmh developed fever, headache, and neck pain. she presented to outside hospital day after ct head was negative, patient was discharged. symptoms did not improve and she went to her pcp on day and was instructed to go to the ed. she presented to osh and underwent a lp that was indicative of viral meningitis with wbc cells/mm and protein mg/dl. patient admitted and treated with acyclovir. on day , she developed generalized body aches. on day , she was trying to stand with assistance and she became rigid. parents report a total of seizures and was intubated for airway protection. she underwent another lp on day with an opening pressure of cm h o. csf was sent for paraneoplastic panel. csf analyses and blood cultures were negative. evd placed for icp pressures of - cm h o. history obtained from mother and father who reported the patient had been hiking weeks prior. results mri brain showed meningeal enhancement scattered throughout the supratentorial and infratentorial brain and most compatible with inflammatory sequela of meningitis. patient continued on keppra, high dose steroids, antibiotic, antiviral, antifungal therapy until cultures resulted. additional treatments included ivig therapy followed by plasmapheresis, and finally rituximab. continued workup with brain biopsy showed demyelinating process and possible necrotizing encephalitis. mri four weeks after initial presentation showed white matter demyelination and deep gray nuclei lesions consistent with adem. four score of on admission improved to (e , m , b , r ) weeks after patient presented from osh. diagnosis of adem vs ms variant made based on the above data. case provides information for the clinician diagnosing and treating adem. potential for further studies with treatments described above and their effect on meaningful neurological outcomes. dengue is a flaviviruses transmitted via mosquitos and prevalent in south east asia. neurological complications are rare but can involve encephalitis, myelitis, neuromuscular dysfunction and neuroophthalmological problems. we describe an interesting case of dengue encephalomyelitis. retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital a year-old ship filipino captain with no significant past medical history but an extensive exposure to heavy metals, travel throughout the pacific, who presented with progressively worsening fevers, encephalopathy, urinary retention and tremors. he was transporting iron ore and other metals in a cargo ship from russia through south-east asia through to bermuda. while passing through the pacific, he began to experience malaise, myalgia, and fever. he was treated with amoxicillin but became worse, developing urinary retention, periods of confusion, and word finding difficulties. he was initially hospitalized in bermuda and then transferred to our hospital for further workup. given his rapid deterioration, he was initially in the nccu. his exam was notable for mild expressive aphasia, paratonias, right-sided weakness with hyper-reflexia, and a low amplitude tremor. his csf was notable for lymphocytic pleocytosis, elevated protein, low glucose. mri brain showed flair hyper-intensities in the frontal lobes, and diffusion restrictions in the bilateral basal ganglia and thalami. mri spine showed extensive flair hyper-intensity lesions. an extensive workup evaluated for heavy metal toxicities, autoimmune disorders and infectious workup. csf analysis came back positive for dengue igg and igm, leading to a diagnosis of acute dengue fever and encephalomyelitis. with supportive care in the nccu, he improved considerably over - weeks and was discharged home to the philippines. dengue encephalomyelitis is a rare infection but should be considered in patients living in endemic areas. treatment includes supportive care with fluid resuscitation, neurological monitoring and monitoring for hemorrhage. posterior reversible encephalopathy syndrome (pres) is known to cause altered mental status and leukoencephalopathy in the setting hypertensive emergency. we present a novel case of severely asymmetric pres due to a concurrent right transverse sinus dural arteriovenous fistula (davf). a year-old woman with hypertension, non-compliant on medication, had fatigue and weeks of intermittent left sided weakness when she presented to an outside hospital for evaluation. initially upon arrival her glascow coma scale (gcs) was . her mental status deteriorated over hours, eventually requiring intubation. her peak blood pressure was / . outside ct demonstrated scattered intracerebral hemorrhage (ich) and she was transferred for higher level of care. on admission her gcs was . review of her outside ct was remarkable for extreme right-sided white matter hypodensity, moderate left white matter hypodensity, and small scattered ich. workup including infectious, inflammatory, and neoplastic processes were excluded through serum, csf studies, and mri. conventional angiogram demonstrated a right transverse sinus davf with reflux into cortical veins, which was subsequently embolized. her white matter t -weighted hyperintensities improved on follow-up mri, and her gcs was at the time of discharge. our case highlights the possibility of asymmetric pres due to abnormal venous congestion due to the right-sided davf. venous hypertension likely caused the patient's intermittent left sided symptoms in the weeks prior to admission. few cases of unilateral or asymmetric pres have been reported following induced hypertension for treatment of subarachnoid hemorrhage or in the setting of vascular malformation. to our knowledge, this is the only case of severely asymmetric pres and preceding stroke like symptoms due to a davf. the most common pathology associated with an intraluminal carotid thrombus is underlying atherosclerosis. in rare cases it may be associated to thrombocytosis. currently there are no clear recommendations for the treatment of ischemic stroke associated with thrombocytosis. our case describes the use of plateletpheresis for the acute management of thrombocytosis complicated by an internal carotid artery thrombus resulting in a right mca stroke. a -year-old female with past medical history of menorrhagia who presented complaining of left face, arm and leg weakness with associated shortness of breath. upon arrival her nihss was and the initial head ct was unremarkable. laboratory results revealed a hemoglobin . mg/dl, hematocrit mg/dl, and platelet count of x /ml. she was not a candidate for thrombolytic therapy due to the time window. soon after admission she had acute worsening of symptoms with an nihss of . a cta of the head and neck showed acute ischemic infarction involving the right mca territory with non-occlusive intraluminal thrombus within the right carotid bulb. asa mg and heparin infusion were initiated promptly. after a thorough work-up for thrombocytosis, reactive thrombocytosis secondary to iron deficiency anemia was diagnosed. plateletpheresis as well as oral ferrous sulfate were started. after one plateletpheresis cycle the platelet count stabilized at x /ml. complete thrombus resolution was confirmed on follow-up cta on day of admission without need for surgical revascularization. the role for plateletpheresis is not well established in secondary thrombocytosis. in cases with extreme thrombocytosis immediate surgical thrombectomy may be contraindicated due to high risk of rethrombosis. urgent cytoreduction with correction of the putative mechanism for thromboyctosis should be undertaken for optimal management. plateletpheresis is safe and efficient in reducing the platelet count to decrease the risk of clot progression or further clot formations which could worsen patient outcome. hyperpyrexia is an elevated core body temperature secondary to an elevated hypothalamic set temperature. hyperthermia is an elevated core body temperature beyond the normal hypothalamic set temperature. intracranial hypotension can present with a wide variety of symptoms ranging from orthostatic headache up to coma. it has never been reported to present with fever, namely hyperpyrexia. a case report of a year old female patient with a history of depression, diabetes mellitus, hypertension, and angiogram negative subarachnoid hemorrhage status post ventriculo-peritoneal (vp) shunt placement six years ago who was complaining of worsening headaches and slurred speech for the past three months but acutely decompensated one morning. she suddenly became confused and agitated but became obtunded. initially, she was given haldol. she was found to be febrile (rectal temperature of . f). she was given dantrolene and bromocriptine for suspected malignant neuroleptic syndrome with no effect. creatine phospho-kinase was not elevated. she underwent infectious work up which later came negative. cooling measures like external cooling, peripheral iv cooling, tylenol and nsaids were also not helpful. fever responded to central intravascular cooling but encephalopathy did not. several expert attempts of lp and shunt tapping failed to obtain csf. brain imaging showed bilateral chronic symmetrical hygromas, diffuse pachy-meningeal thickening and enhancement, slit-like ventricles and slumping of the midbrain with closure of the mammillary pontine distance. following shunt setting adjustment, the encephalopathy markedly improved and the fever did not recur after stopping the cooling measures and antimicrobials. intracranial hypotension might present with hyperpyrexia, likely secondary to hypothalamic dysfunction. in our case, hyperpyrexia was reversible as the intracranial hypotension was emergently treated. nevertheless, spontaneous intracranial hypotension might be difficult to diagnose especially if it presented with non-classical symptoms like fever. complex emotions about critical illness can affect families in the icu. rightfully, we put focus on how they are impacted, but we also need to pay attention to how it can affect providers and our decision making. a poignant case from my training was a -year-old girl struggling with lupus. she had now developed lupus cerebritis and had massive intracranial hemorrhages. despite aggressive efforts to manage cerebral edema, she repeatedly herniated brain matter out of old craniotomy scars with incredible force. it was the most horrifying thing i've ever seen. other organs were also failing, with four consulting services working to salvage them unsuccessfully, prompting numerous procedures. this went on for a month. the therapies that we can offer have limits from a physiological standpoint which we must recognize and respect. we struggle with reconciling the interventions we feel compelled to implement versus what is realistic. i remembered the most valuable advice that i once received: "only do something to someone if it does the complexity of the neuro icu is amplified by the nature of intracranial catastrophes and poor recovery (in contrast to pure medical illness). providers cling to what is technically indicated while families cling to hope, but neither is enough and concurrently too much. we lose our autonomy to grieving families telling us to "do everything" losing sight of the bigger picture. we lose our autonomy to one another by pushing onwards, which can unintentionally push each other into the territory of doing more harm than good. something for them". all services began to share this view, thus slowly dialysis, steroids and immunosuppression stopped. eventually, her heart stopped. my experiences have reiterated a simple paradigm: to do no harm. through this, i can empower myself to take control of each situation by first taking control of myself. we report a case of an hiv positive patient who presented with cryptococcus gattii meningitis who then developed acute respiratory distress syndrome (ards) secondary to pneumocystis jirovecii pneumonia (pjp) that required ecmo support. ards in immunocompromised hiv positive patients is associated with extremely high mortality. ecmo can improve oxygenation in patients without increasing alveolar pressure and therefore avoid mechanical lung damage with ventilation. we present a patient with newly diagnosed aids with cryptococcus gattii meningitis and course complicated by pjp that progressed to severe acute respiratory distress syndrome (ards) for which veno-venous ecmo was initiated. patient is a year old male who presented to the emergency department with new onset seizures. lumbar puncture in the ed overflowed the manometer and demonstrated wbc , rbc , protein , glucose , positive yeast gram stain positive for yeast with pcr and ag positive. his cultures later grew out cryptoccoccus gattii. he was admitted to the nsicu and we placed a lumbar drain and an intraparenchymal ipc monitor that demonstrated elevated icps to the - mmh but improved with drainage. the day of admission he acutely desaturated and required emergent endotracheal intubation. chest x-ray demonstrated bilateral infiltrates. bal was positive for pj. five days following presentation and respiratory failure he was started on veno-venous ecmo. two days following initiation of pjp treatment with bactrim his chest x-rays and lung compliance began to improve. he remained on ecmo for a total of days before decannulation. he underwent induction chemotherapy for four weeks for meningitis. this case report demonstrates the use of ecmo in a complicated and critically ill patient with aids, pjp, and cryptoccous gattii meningitis. to our knowledge, few cases of ards secondary to pjp are reported and none are reported with concurrent cryptococcus gattii infection. sympathetic storming occurs during the acute care of patients following severe brain injury. cannabinoid cb receptors (cb r) mediate the effects of delta( )-tetrahydrocannabinol (thc), the psychoactive component in marijuana. expression of cb r is widespread in the central nervous system and includes the hypothalamus, which is thought to mediate the hypothermic inducing effects of cannabinoids. dronabinol is a synthetic analogue of thc we present a novel therapeutic use of cannabinoids in a case of super-refractory sympathetic storming following coccidioidal meningitis and extensive bilateral subcortical stroke a -year-old previously healthy man was transferred from an outside hospital for treatment of meningitis, vasculitis, and hydrocephalus requiring placement of a ventriculostomy. workup subsequently revealed coccidioidal meningitis. during hospitalization the patient had severe vasospasm, elevated intracranial pressure, diabetes insipidus, cerebral salt wasting, and severe sympathetic storming. intermittent storming episodes with high fever persisted for over weeks despite treatment with bromocriptine, dantrolene, tylenol, ibuprofen, phenobarbital, and sinemet. due to its mechanism of action, a trial of dronabinol mg divided twice daily was tried. the storming episodes ceased and within hours the average temperature decreased by about . degree centigrade. temperature over the next several days was better controlled with a substantial reduction in use of anti-pyretics, surface cooling measures, and other storming medications our case highlights a novel therapeutic use of cannabinoids in super-refractory sympathetic storming related to brain injury. dronabinol may be an alternative pharmacotherapy with unique mechanism of action in difficult to control sympathetic storming patients with poor grade subarachnoid hemorrhage(sah) commonly present with significant mental status changes that preclude reliance on neurologic exam for screening for neurologic deterioration. jugular venous oximetry monitoring has been suggested for use in guidance of hyperventilation therapy, barbiturate coma, and vasospasm monitoring. no studies are found in literature validating its use in sah. milrinone has been using for the treatment of vasospasm in sah in an established protocol in the montreal neurological hospital. this study was performed using multiple methods of monitoring, but not jugular bulb oximetry. we report one case with high grade subarachnoid hemorrhage complicated by vasospasm treated with milrinone using jugular bulb monitoring for dose titration. methods years old female presented with thunderclap headache and subsequently became comatose. noncontrast head computer tomography showed posterior fossa subarachnoid blood. she was intubated, external ventricular drain (evd) was placed and she was admitted to neurosurgical intensive care unit (nsicu). angiogram showed left posterior inferior cerebellar artery aneurysm and was successfully coiled. her hospital course was complicated by refractory symptomatic vasospasm. angiogram showed basilar artery vasospasm treated with intra-arterial verapamil. post procedure patient was not able to tolerate norepinephrine due to tachycardia and could not maintain hypertension on phenylephrine. milrinone was then started. jugular bulb catheter was place because the area at risk was not amenable to invasive multimodality monitoring. oximetry was monitored and her milrinone rate was titrated to goal of venous oximetry in the range of - %. on day , angiogram showed no more evidence of vasospasm. her exam was back to her prior poor baseline. subsequently, she was discharged to long term care facility. our case demonstrates the benefit of using jugular venous oximetry monitoring guidance for milrinone dose titration. further, it may be an effective tool is research studying treatments of cerebral vasospasm repetitive transcranial magnetic stimulation (rtms) is increasingly used in treatment of various conditions including depression, chronic pain, and movement disorders. the use of rtms for chronic management of medically refractory epilepsy has grown substantially in the last years. however, little literature exists on use of rtms for acute status epilepticus. the exact antiepileptic mechanism of rtms remains unclear, but may be secondary to inhibition of cortical excitability. we report promising response to rtms in a case of super-refractory focal status epilepticus. the study is a case report. a daily dose of pulses of hz rtms was applied to the left occipital lobe. treatment course was divided into periods of - consecutive days each for a total of days of treatment over days. a -year-old woman with recent hemiarthroplasty complicated by wound infection presented with acute unresponsiveness and right gaze deviation, evolving into fluctuating encephalopathy, word finding difficulty, and right hemineglect. eeg revealed persistent left posterior quadrant lateralized periodic discharges (lpds), at times evolving into electrographic seizures, and positron emission tomography demonstrated a co-localized hypermetabolic focus. mri revealed subtle bilateral occipital t hyperintensity without diffusion restriction, which later resolved; cerebrospinal fluid was noninflammatory. seizures continued despite treatment with multiple aeds, burst suppression, and empiric trial of high dose corticosteroids. the patient demonstrated abrupt electrographic and clinical improvement after rtms initiation. previously unseen brief periods of lpd resolution were observed within minutes after first tms session with further improvement in eeg background correlating with improvement in encephalopathy and clinical findings over subsequent days. given excellent safety profile, rtms may be useful transitional therapy in management of some cases of status epilepticus. durability of efficacy, patient selection, and optimal treatment schedules remain important unresolved questions. further study is required. central pontine myelinolysis (cpm) occurs due to rapid osmotic shifts causing demyelination in white matter, typically due to rapid correction of hyponatremia mostly in setting of alcoholism, malnutrition, and/or liver/renal dysfunction. sequelae may include cranial neuropathies, quadriparesis, seizures, and encephalopathy. no specific treatment exists; literature reports indicate favorable outcomes in only - % of patients. our patient is a year old male with hypertension, tobacco and alcohol abuse, admitted with severe aortic stenosis, complicated by alcohol withdrawal, pneumonia, and acute kidney injury. he was treated with benzodiazepines, broad spectrum antibiotics, and fluid resuscitation. on hospital day (hd) , he had to be intubated for airway protection due to acute confusion and quadriparesis. his blood work was notable for wide fluctuations in serum sodium, from on admission to on hd to on hd . otherwise, laboratory evaluation was remarkable only for mildly elevated ast and serum creatinine. mri brain days after symptom onset (hd ) showed dwi and flair hyperintensities around central pons bilaterally crossing midline. eeg showed severe generalized slowing. diagnosis of cpm was made and intravenous immunoglobulin (ivig) ( . g/kg/day for days) was initiated within days of symptom onset, on hd . after initiation of ivig, patient showed rapid improvement, first noted in the bilateral upper extremities. by hd i.e., days after initiation of ivig, he was able to be successfully extubated; and he had regained - / strength in all extremities. neuropsychology testing at month demonstrated intact cognition. we describe a case of rapid clinical improvement in cpm following treatment with ivig. in addition to ours, about similar cases have been reported, in which beneficial outcomes were demonstrated following prompt initiation of ivig. one proposed theory would be through reduction of myelinotoxic antibodies, thus promoting remyelination. few cases have reported central neuronal hyperventilation (cnh) secondary to infiltrative malignancy or autoimmune disease. the lesion is usually located at the pontine tegmentum and interrupts the fibers between the respiratory centers in the pons and those in the medulla. we report a case of a year old female with multiple comorbidities who was admitted to the neurocritical-care unit after intra-operative rupture of a mm distal basilar aneurysm while being electively coiled. an external ventricular drain (evd) was placed due to early signs of ventriculomegaly. the postoperative exam showed progressive encephalopathy, left > right hemiplegia progressive tachypnea (rate and depth) despite being on assisted mode ventilation leading to severe hypocapnia ( . mmhg) and compensatory renal acidosis (bicarbonate = . mmol/l) to maintain normal ph. attempt to sedate the patient led to severe metabolic acidosis. intraventricular nicardipine was started and the patient ventilator settings were changed to bi-level pressure control. transcranial doppler (tcd) showed markedly improved vasospasms. the patient respiratory rate and, to a lesser extent, the tidal volumes improved after several days. sedation was weaned off successfully. evd was successfully weaned off and removed. tcd and ct angiogram showed severed basilar artery vasospasm while mri done later showed bilateral tegmental midbrain ischemia. one case has reported acute central neuronal hyperventilation following left thalamic bleed while another reported chronic neuronal hyperventilation that was attributed to old bilateral lacunar thalamic strokes by exclusion. our case is the first to report central neuronal hyperventilation following aneurysmal subacrachnoid hemorrhage that got complicated by bilateral tegmental midbrain strokes. while respiratory centers are known to exist in the medulla and the pons, more recent articles have described networks that regulate breathing extending to the midbrain peri-acquiductal grey and possibly the thalami. our unique case supports this hypothesis. serotonergic and atypical antipsychotic drugs are often used in the critically ill in the treatment of posttraumatic depression and anxiety disorders. hyperactive delirium may mask serotonin syndrome, which carries high morbidity and mortality if left untreated. we describe a case of serotonin syndrome in a critically ill patient in the setting of surgical and neurocritical intensive care unit. a -year-old male with remote trauma presented with left upper abdominal pain. a ct-scan of abdomen showed left diaphragmatic hernia. he underwent left thoracotomy and repair of diaphragmatic hernia. his postoperative course was complicated by sepsis, ileus, and aspiration pneumonitis. he was started on sertraline and quetiapine for stress-induced anxiety disorder, depression and agitation. despite increasing doses of sertraline, patient became agitated, tremulous, and confused. physical examination included fever, tachycardia, hypertension, diaphoresis, dilated pupils, hyperactivity, and clonus. initially considered to be due to hyperactive delirium, these manifestations did not improve with haloperidol. neurocritical care was consulted. due to presence of hyperactivity, fever and clonus, serotonin syndrome was strongly suspected. sertraline and quetiapine was discontinued and cyproheptadine added. within -hours his symptoms improved and cyproheptadine was tapered over days. serotonin syndrome, a potentially life-threatening syndrome, is manifested by triad of mental status changes, neuromuscular and autonomic hyperactivity. a multitude of drug combinations can result in serotonin syndrome. serotonin syndrome is a diagnosis of exclusion, based on history and neurological examination in a patient taking serotonergic drug. ht- a receptors are most commonly incriminated along with high levels of norepinephrine.the keys to management include discontinuation of all serotonergic agents, supportive care, and cyproheptadine. cyproheptadine, a potent ht- a antagonist, is effective in ameliorating symptoms. a high suspicion for diagnosis is important for reducing morbidity and mortality associated with this neurologic syndrome in the critically ill. ruptured cerebral mycotic aneurysm as consequence of infective endocarditis (ie): a management qeeg adr in poor grade sah: is it really useful? recognize the various subtypes of cerebral amyloid angiopathy bilal butt baylor college of medicine -hour development of a giant infectious intracranial aneurysm: a case report catherine albin intra-operative ultrasound in traumatic brain injury patients namkyu you syndrome of the trepheined (sot) and paradoxical herniation without craniectomy elysia james spectrum health neurosciences -icu division stephen a. trevick , andrew naidech , leah tatebe patients were included. median age was years. % were female, % smokers, % hypertensive and % diabetic. % had a history of cad or mi and % had hyperlipidemia. in the multivariable analysis, the odds ratio for unfavorable outcome, defined as mrs score of - , was . ( %c.i: . - . ) and . ( %ci: . - . ) for the intermediate-grade(iii) and high-grade(iv and v) hh groups respectively, when compared to the low-grade(i and ii) hh group. age, hypertension and diabetes were found to be negatively associated with mrs, while hyperlipidemia was positively associated. gender, race, smoking and history of cad/mi were not significantly related to mrs. a positive trend for better mrs outcome was observed across years (p= . ). this trend was not related to hh grade on admission, (p= . for interaction between hh grade and year). hh scale on admission is associated with the mrs outcome upon discharge for patients with nontraumatic sah. models predicting the probability of a good mrs outcome could be created based on the hh grade on admission, age, hypertension, diabetes and hyperlipidemia status. the data suggest a trend toward improvement in medical and surgical care for this patient population across years. ciro poor-grade subarachnoid hemorrhage (sah) is associated with high mortality rates. although death rates have decreased in the last three decades, the exact mechanisms of demise are still to be determined in this patient population. a retrospective study of consecutive poor-grade sah patients (world federation of neurosurgical societies grades iv and v) aggressively treated in two academic high-volume centers, one in the netherlands (amc) and one in canada (smh). the primary outcome was in-hospital mortality. the main reasons of death were evaluated. a total of poor-grade sah patients were admitted between and , to amc and to smh. ( %) patients died, and ( %) of those patients died before having the culprit aneurysm treated. the median interval between hospital admission and death was three days (iqr - ).withdrawal of life support was the main reason of death in both centers (total of deaths - %), cardiopulmonary causes, aneurysm rebleeding, refractory intracranial hypertension, and other extracranial causes), represented less than %. extensive review of patients chart for all the data collection including literature search for similar cases if reported before. although rare, there are multiple case reports and series of nkh and clinical findings of hemichorea-hemiballism (hc-hb). there are few case reports of nkh with unilateral signal changes in the caudate and putamen. our patient presented with acute right basal ganglia ich. despite the typical imaging findings of nkh, work-up and management of ich took precedence over control of bg. mri findings were different in our patient given presence of positive gre and dwi/adc in areas other than t hyperintensity, which is known to be associated with nkh. we hypothesize an association between ischemia and hemosiderin deposition with hyperglycemia. the selective vulnerability of unilateral involvement of basal ganglia and caudate is unclear and needs more research. identification of neuroimaging findings in nkh in absence of focal neurological deficits (hc-hb) is important, especially for a first responder. early recognition can prevent icu admission, provide efficient patient care and allocation of resources. although most metabolic diseases affect basal ganglia bilaterally; nkh is associated with specific unilateral neuroimaging findings even in absence of movement disorders or focal neurological deficits. a year old male with a history of seizure disorder due to mesial temporal lobe sclerosis, presented with altered mental status after a lamotrigine overdose. he had consumed . gm of the drug. he was awake and alert at presentation. urine toxicology was negative. initial creatine kinase (ck) was iu/l and peaked at iu/l; his creatinine was . mg/dl. lamotrigine level went from mcg/ml to . mcg/ml after hours. four days after admission it was mcg/ml. a head ct at admission was negative. despite initial alertness, he developed profound encephalopathy with agitation and rigidity, requiring heavy sedation, induced paralysis, and intubation. this in turn lead to hemodynamic instability, which along with persistently elevated lamotrigine levels, prompted initiation of continuous veno-venous hemodia-filtration (cvvhdf) on hospital day . the lamotrigine level declined to . mcg/ml within hours, the encephalopathy and rigidity resolved, and he was extubated. to our knowledge, this is the first reported case of lamotrigine toxicity managed with cvvhdf. overdoses up to g have been reported and can even result in death. while cleared hepatically, the half-life of lamotrigine is approximately twice as long when patients have chronic renal failure. in a small series of patients with renal failure, approximately % of lamotrigine was reported to be removed by hemodialysis. we applied this principal to our patient. our experience suggests that augmenting drug clearance with dialysis may help reduce the time on mechanical ventilation, need for higher doses of sedatives, and improve time to discharge. cvvhdf should be considered a supplemental treatment option for lamotrigine toxicity. traumatic brain injury (tbi) complicated by percutaneous coronary intervention (pci) remains a significant clinical dilemma. dual anti-platelet therapy (dapt) is standard after pci, but may contribute to progression of tbi. novel antiplatelet drugs with ultra-short half-lives, such as the p y -adenosine receptor antagonist, cangrelor, may provide added clinical flexibility in avoiding tbi-associated hematoma progression, particularly in the absence of reversibility options. case report. we report a year-old female who presented to the ed after a syncopal episode with a fall down a flight of stairs. an ekg was obtained demonstrating inferior wall stemi. signs of head trauma included facial and scalp contusions, and bloody otorrhea. initial gcs was . a non-contrast head ct demonstrated tsah and contusions of bilateral frontal lobes and left temporal lobe, and a non-displaced fracture of the left temporal bone. neurosurgery, interventional cardiology and critical care were consulted. the patient developed signs of cardiogenic shock related to stemi and was taken emergently to cath lab. successful revascularization of proximal rca occlusion was achieved. heparin was given per protocol, and aspirin and cangrelor administered post-pci. cath lab was complicated by tonic-clonic seizures requiring intubation. repeat head ct demonstrated blossoming of bifrontal contusions, trace subdural hematoma development and increased tsah conspicuity. dapt infusion was continued, and subsequent imaging was stable, allowing transition to asa and clopidogrel. she survived with only minor disability. newer generation p y inhibitors can be administered intravenously with reliable platelet inhibition similar to older p y receptor inhibitors. with rapid reversibility upon discontinuation, their utilization should be considered any time pci complicates tbi. cerebral air embolism (cae) is a rare but potentially fatal entity with high morbidity and mortality, commonly seen secondary to iatrogenic causes like neurosurgical procedures, vascular surgeries, etc. as also deep sea diving. cae after esophagogastroduodenoscopy (egd) is extremely uncommon. we present a rare case of cae post egd resulting in diffuse cortical infarction. an year old man underwent an elective (egd) for esophageal stricture with biopsy and balloon dilatation. patient did not wake up after procedure. on initial exam, patient was comatose, glasgow coma scale t with decerebrate posturing. computed tomography (ct) revealed multiple foci of cerebral air embolism. ct angiogram of the brain was negative. diffusion weighted imaging and apparent diffusion coefficient imaging sequences in magnetic resonance imaging (mri) showed diffuse, global bi-hemispheric cortical infarction. ct chest showed pneumomediastinum. only cases of cae from egd have been reported in literature prior to this case. received hyperbaric oxygen therapy(hbo). patients had a documented patent foramen ovale (pfo) or some form of arteriovenous (av) shunt. presence of av shunts/ pfo, therapeutic endoscopic procedures providing vascular communication as well as providing pressure gradient are all factors facilitating air embolism associated with egd. hbo therapy has been shown to improve outcomes in cae patients, initiating therapy > hours after insult and early and significant ischemic changes seen on ct/ mri prior to starting therapy were strong predictors of poor outcomes. our patient did not have a documented echocardiogram with a shunt study prior to the egd. cae after egd causing global cerebral bi-hemispheric ischemia as seen in our case is extremely rare. hbo has been shown to improve outcomes. time to treatment > hours and early ct/ mri changes suggest poor outcomes. studies do not recommend benefit of screening for pfo or av shunts prior to every egd. key: cord- -l fyxtva authors: venkat, arvind; wolf, lisa; geiderman, joel m.; asher, shellie l.; marco, catherine a.; mcgreevy, jolion; derse, arthur r.; otten, edward j.; jesus, john e.; kreitzer, natalie p.; escalante, monica; levine, adam c. title: ethical issues in the response to ebola virus disease in us emergency departments: a position paper of the american college of emergency physicians, the emergency nurses association and the society for academic emergency medicine date: - - journal: j emerg nurs doi: . /j.jen. . . sha: doc_id: cord_uid: l fyxtva the outbreak of ebola virus disease (evd) in west africa has presented a significant public health crisis to the international health community and challenged us emergency departments to prepare for patients with a disease of exceeding rarity in developed nations. with the presentation of patients with ebola to us acute care facilities, ethical questions have been raised in both the press and medical literature as to how us emergency departments, emergency physicians, emergency nurses and other stakeholders in the healthcare system should approach the current epidemic and its potential for spread in the domestic environment. to address these concerns, the american college of emergency physicians, the emergency nurses association and the society for academic emergency medicine developed this joint position paper to provide guidance to us emergency physicians, emergency nurses and other stakeholders in the healthcare system on how to approach the ethical dilemmas posed by the outbreak of evd. this paper will address areas of immediate and potential ethical concern to us emergency departments in how they approach preparation for and management of potential patients with evd. the outbreak of ebola virus disease (evd) in west africa has presented a significant public health crisis to the international health community and challenged us emergency departments to prepare for patients with a disease of exceeding rarity in developed nations. with the presentation of patients with ebola to us acute care facilities, ethical questions have been raised in both the press and medical literature as to how us emergency departments, emergency physicians, emergency nurses and other stakeholders in the healthcare system should approach the current epidemic and its potential for spread in the domestic environment. to address these concerns, the american college of emergency physicians, the emergency nurses association and the society for academic emergency medicine developed this joint position paper to provide guidance to us emergency physicians, emergency nurses and other stakeholders in the healthcare system on how to approach the ethical dilemmas posed by the outbreak of evd. this paper will address areas of immediate and potential ethical concern to us emergency departments in how they approach preparation for and management of potential patients with evd. in march , an outbreak of ebola virus disease (evd) was confirmed in the west african nation of guinea with subsequent rapid spread to the neighboring countries of liberia and sierra leone. given the underdeveloped health infrastructures in the primary affected nations and the high transmission and mortality rate of the disease, domestic and international public health agencies called for aid and personnel to be rapidly deployed to the affected nations to treat infected patients and prevent further spread of the ebola outbreak. yet despite significant efforts from the international community, evd continues to represent a significant challenge in the region. as of january , the centers for disease control and prevention (cdc) reports that the total case count stands at , with , deaths and continues to rise. in the united states, the transfer of ebola-infected healthcare workers from the outbreak zone to us hospitals raised public awareness and fear of spread of the disease. this fear was heightened after the initial missed diagnosis in a us emergency department of a patient with evd who later died, the transmission of ebola to nurses who cared for this patient and a subsequent case of an emergency physician who traveled to west africa to care for patients with evd and required hospitalization after returning to the united states. these cases raised significant concerns that us emergency departments and hospitals were not adequately prepared to diagnose and treat patients with evd. in addition, the infection of healthcare personnel created the specter of a more widespread outbreak in the general population due to poor infection control guidelines, inadequate training and management protocols in us medical centers and initially absent mechanisms to identify potentially infected individuals arriving through us ports of entry. a subsequent controversy surrounding a nurse who returned from west africa without symptoms of evd and was held in quarantine highlighted concerns about how personal liberty and public health should be appropriately balanced. in response, both emergency medicine and emergency nursing organizations and federal agencies have issued guidance on the nature of evd, approaches to identification, isolation and treatment of potential patients and standards for use of personal protective equipment (ppe) by healthcare providers. [ ] [ ] [ ] while the number of cases in the united states remains low to date ( total patients, diagnosed in the us and deaths), the outbreak of evd has raised ethical issues relevant to us emergency departments and hospitals, emergency physicians and emergency nurses. issues artic-ulated in the medical literature and by the press include the following: how resources should be used in preparation for the likely rare event of an undiagnosed patient with evd who presents to a us emergency department, whether there should be a different standard for care of ebolainfected patients than for other patients with less contagious and lethal diseases and whether healthcare providers are obligated to place themselves at a significant degree of risk while caring for these patients due to their professional status. to address these concerns, the american college of emergency physicians (acep), the emergency nurses association (ena), and the society for academic emergency medicine (saem) developed this joint position paper to provide guidance to us emergency physicians, emergency nurses and other stakeholders in the healthcare system on how to approach the ethical issues posed by the outbreak of evd. this paper will address areas of immediate and potential ethical concern to us emergency departments in how they approach preparation for and management of potential patients with evd. since the outbreak of evd, numerous articles have been published on the epidemiologic characteristics of this condition and the microbiological details of the causative organism. [ ] [ ] [ ] [ ] however, particular characteristics of evd are worth highlighting to provide the factual basis for addressing the ethical questions raised in this outbreak for us emergency departments. first, it is well recognized that individuals with evd will often have relatively non-specific symptoms, common to many viral infections, in their initial stages of presentation (eg, fever, headache, myalgias). , such non-specific presentations make unrecognized infection with ebola a realistic concern. lack of prompt identification of potential patients by emergency department staff can increase the risk of spread of the disease and mandates a heightened awareness of the risk factors for the disease. second, the pathophysiology of contagion is related to contact with blood or bodily fluids from an infected individual, with rising viremia in the late stages of disease presenting a particular risk for human-to-human transmission. however, even a low level of viral inoculation can lead to evd. this recognized pathway of spread aids in evaluating the risk of transmission from patient to healthcare providers or the general public. at the same time, knowledge of how the ebola virus is transmitted heightens the ethical concerns posed by the potential presentation of highly symptomatic and contagious patient(s) to an emergency department, especially if to a center without specialized experience in the care of evd patients. finally, the lack of specific effective treatment and the high mortality rate posed by evd exacerbates public fears, may create irrational panic relative to the actual risk and lead to unexpected institutional consequences such as the avoidance of the use of healthcare facilities where evd patients are being or have been treated. the emergency department in the united states, and increasingly worldwide, serves as the primary gateway to the acute healthcare system. it is estimated that % of admissions to hospitals in the us are initially assessed and treated in emergency departments. the emergency department is also the only access point in the us acute healthcare system available to patients hours per day- days per week. in the us there is a legal obligation under emtala to provide a medical screening exam for an emergency medical condition and treatment until the emergency medical condition is resolved or stabilized to the extent of that hospital's capability (until appropriate transfer) regardless of insurance status or other socioeconomic factors. , finally, the emergency department is the primary location for the initial evaluation, diagnosis and treatment of the acutely ill undifferentiated patient. these facts together help define the ethical construct of emergency medical practice where access to quality emergency care is a right of all patients in the us. as noted in the acep code of ethics, "emergency physicians shall respond promptly and expertly, without prejudice or partiality, to the need for emergency medical care." the ena code of ethics states that "the emergency nurse works to improve public health and secure access to health care for all." the society for academic emergency medicine, through its mission statement "to lead the advancement of emergency care through education and research, advocacy, and professional development in academic emergency medicine," also supports the ethical mandate for all patients in the united states to have access to quality emergency medical care regardless of disease process, ability to pay or other characteristics. while the above ethical framework emphasizes the critical importance of the availability of emergency care to all, it is clear from both published codes of ethics and the literature on the "duty to treat" that there are rare circumstances in which risk to the individual healthcare provider and institution should be weighed in determining the treatment plan for a patient who poses significant risk to providers or the general public. the acep code of ethics notes the requirement of the adequacy of in-hospital and outpatient resources in the provision of emergency care. the american medical association code of ethics states that "because of their commitment to care for the sick and injured, individual physicians have an obligation to provide urgent medical care during disasters. this ethical obligation holds even in the face of greater than usual risks to their own safety, health or life. the physician workforce, however, is not an unlimited resource; therefore, when participating in disaster responses, physicians should balance immediate benefits to individual patients with ability to care for patients in the future." the american nurses association code of ethics specifically states, "the nurse owes the same duties to self as to others, including the responsibility to preserve integrity and safety." within the larger ethics literature, explorations of whether there is a duty to treat on the part of healthcare providers at risk to themselves also indicates that codes of ethics, historical references and theoretical analysis do not mandate an absolute obligation. rather, particular factors of disease process, availability of resources and training, countervailing responsibilities outside of the professional realm, personal viewpoints on the virtues of courage and resilience as well as relational ethics perspectives and obligations imposed by professional status have guided the evaluations of the obligations of healthcare providers in the face of outbreaks of infectious disease. [ ] [ ] [ ] [ ] for emergency departments, emergency physicians and emergency nurses, there is a need to weigh all of these considerations against the special role played by emergency departments in the us healthcare system and the duties that accompany the professional status of emergency physicians and emergency nurses. with this background, we will present an ethical framework that has potential application for emergency departments, emergency physicians and emergency nurses along with other health system stakeholders in the particular response to evd in the united states. this framework will address questions relevant to us emergency departments and separate consideration of the current situation (few confirmed cases within the united states with a relative abundance of resources to respond) versus potential scenarios (increasing number of potential and confirmed domestic cases of evd in a variety of locations due to spread in the us and widespread number of potential and confirmed domestic cases that would strain existing resources and creates a necessity of disaster triage response) where appropriate. what in the current outbreak of evd, as of january , , there are no extant active cases in the united states. as such, the most immediate issue is how to contain the spread of the disease from its present locus in west africa and end the current epidemic there. with the underdeveloped nature of the health infrastructure in the primary affected nations and the declaration of a public health emergency of international concern by the world health organization, there is widespread recognition that ending the epidemic does and will continue to require the volunteering of healthcare providers to serve in the outbreak zone. under the ethical principle of reciprocity, which calls for acting in a manner that one would want others to act in return, there is an obligation to support emergency physicians and nurses who volunteer to serve in the nations primarily affected by the current ebola epidemic, just as we would welcome support or available expertise in a time of health crisis in the us. yet as a practical matter, support of volunteerism needs to be weighed against the special logistical concerns faced by most emergency departments, where local staffing levels must be maintained to provide safe patient care. an application of the principle of reciprocity in this outbreak would include support of emergency physician and nurse volunteerism in the current outbreak through the covering of shifts and other professional obligations in the volunteer's absence and acceptance by volunteering emergency physicians nurses of any potential risk of contagion on return to the us and the resultant need for monitoring for signs of the disease and possibly prolonged isolation. we would propose that in considering the support of volunteerism by emergency physicians and nurses, the specific background, training and education of the provider is a key decision making factor. education and training are essential components of preparation prior to disaster or disease outbreak response. medical volunteers should be appropriately trained in disease management, including rendering effective supportive care within the resource constraints in the primary outbreak zone, prior to travel to infected areas. they should ensure to the extent possible that malpractice, health and life insurance are in place to cover potential events, likely with the assistance of the non-governmental organization or other agency sponsoring their volunteer efforts. they should be willing to undertake the risks of volunteerism, including infection or threats to individual safety and security. [ ] [ ] [ ] volunteers should be prepared to ensure appropriate infection control practices in their international work and to follow recommended protocols upon return for monitoring for symptoms of evd and the isolation that might result. [ ] [ ] [ ] without this preparation, volunteering emergency physicians and nurses may be a liability rather than a benefit to the resource-poor countries primarily affected by the ebola outbreak and a risk to the domestic population upon their return to the us. it is appropriate for emergency departments and hospitals to query volunteering staff on their willingness to undergo the necessary training to be effective in the primary outbreak zone. with the continuing spread of the disease in west africa, those volunteering emergency physicians and nurses with existing experience in ebola and disaster response should be given priority over those without such training. specific decisions regarding support for volunteer efforts should also include the number of volunteers and impact on ed staffing and potential impact on public health domestically (i.e., will the loss of experienced providers adversely affect the care of patients in the local area served by the emergency department?). if the current outbreak were to spread significantly within the us, the ethical evaluation of the appropriateness of supporting volunteerism overseas would likely change since this could result in the expertise on the management of evd being shifted out of the country rather than being available domestically. this emphasizes the importance of supporting present efforts of containing and ending the current epidemic in west africa, including with the volunteerism of trained emergency physicians and nurses, as the most effective means of preventing the spread of evd to the us and other countries. some emergency departments have supported the volunteerism of emergency physicians in particular through altruistic coverage of shifts to allow staff to travel to the primary outbreak zone. in addition, private foundations have provided grant funding to alleviate the financial burden of volunteerism of emergency department staff in the outbreak zone. while these novel approaches have been largely confined to academic settings, they do suggest that there may be methods for individual centers to address the logistical difficulties that can arise when us emergency department providers volunteer in the primary outbreak zone. the application of these options to individual centers is one that is best judged on a case-by-case basis based on the factors noted above. finally, emergency departments, emergency medicine and nursing professional societies, non-governmental organizations and government agencies can aid volunteer efforts by educating health care providers and the lay public using published evidence on the pathophysiology of ebola and its transmission to alleviate the stigma that returning volunteer staff may experience after their efforts. at the same time, as noted above, volunteering emergency physicians and nurses have an obligation to adhere to monitoring and isolation protocols upon return to the us as a reciprocal ethical obligation for the support their efforts have received. what it is anticipated that patients with a confirmed evd diagnosis will be transferred to these hospitals which will have enough ppe and other treatment requirements (isolation rooms, dedicated equipment and designated physicians, nurses and other necessary health care professionals and staff with proper training under cdc guidelines) to manage patients for at least days, after which governmental agencies would assist in acquiring more supplies and expertise if needed. however, not every state or locality has such a facility, nor is it likely that an undiagnosed patient would necessarily present to one of these centers. therefore, the cdc has provided guidelines for so-called frontline (any emergency department or acute care facility) and ebola assessment hospitals, which can safely isolate, treat and transfer patients with suspected or confirmed evd. to meet these standards, the cdc has called for all emergency departments to have protocols in place for the recognition of potential ebola patients and training for the proper isolation and assessment of these individuals. the hierarchy of treatment facilities for evd codifies the reciprocity-based obligations that hospitals have to each other in the current state of the outbreak. such reciprocity should extend to the sharing of ppe, trained staff and other necessary equipment as needed to care for a suspected or confirmed ebola patient until transfer can be effected to a designated treatment center. hospitals and emergency departments should consider and develop relevant protocols for rapid credentialing of staff and transfer of equipment to allow resources to be brought to bear should there be additional cases in the us. if the current epidemic were to spread significantly in the us, hospitals should consider whether and how they can upgrade their capabilities to meet the needs of rising numbers of patients, presumably with the assistance of government resources. another ethical consideration is the reputational impact upon hospitals caring for ebola patients. as has been reported in the press, hospitals have expressed concern that the potential costs and risks accrued in treating an ebola patient along with the public fear generated by the disease may have an adverse impact on volumes and financial results for medical centers. the facility in dallas that treated a recent case reported that afterward emergency department volumes dropped and still have not returned to their expected level. it is therefore imperative, in the face of a disease such as ebola that has generated such public scrutiny and at times hysteria, for hospitals to be cognizant of their ethical responsibility to support the efforts of designated treatment centers as well as frontline facilities that might encounter ebola patients and potentially be perceived adversely by the public. we affirm that the principle of reciprocity extends beyond physical means of support (equipment, personnel) to reputational support in the setting of an outbreak of evd. such support could, where appropriate, take the form of publicly confirming the safety and quality of other healthcare facilities with ebola patients, educating other facilities on effective policies and procedures in caring for evd patients and avoiding messages that implicitly suggest a competitive advantage from not treating patients with this highly infectious disease. through such support, hospitals ensure that the public is aware and reassured of the unified response the medical system will take towards both the existing epidemic and the potential for worsening if the outbreak spreads from west africa. without such reputational support and cohesion in the healthcare system, should the epidemic worsen, it is conceivable that public doubt and panic may lead to untenable consequences such as facilities avoiding the care of at-risk patients and the public fearing certain hospitals as being sites of contagion rather than medical care. trainees (nursing students, medical students, residents, and fellows) routinely care for patients with infectious diseases in the ed and should understand and use proper measures to protect themselves while caring for patients with potential or confirmed contagious diseases. both the accreditation for graduate medical education program requirements in emergency medicine and guidance on ebola affirm that trainees should know how to recognize, treat and isolate patients with infectious disease in general and ebola specifically. , the model of the clinical practice of emergency medicine goes further by listing within the domain of emergency medicine "understand[ing and apply[ing] the principles of disaster and mass casualty management including preparedness, triage, mitigation, response, and recovery." additional content areas in the model relevant to ebola response include the following: personal protection (equipment and techniques); universal precautions and exposure management; and emerging infections, pandemics and drug resistance. together, these raise the issue of whether the current evd outbreak should be viewed as an opportunity for trainees in emergency medicine and emergency nursing to care for patients during an international infectious disease epidemic. few health care professionals in the united states have experience with the diagnosis and treatment of ebola or the infection control precautions required to safely care for patients with this disease. yet some such individuals may include trainees either with specific backgrounds in infectious diseases or previous experience with the ppe utilized in caring for such patients. historically, the outbreak of an unknown or uncommon infectious disease has led to initial concerns by health providers about risk to self that ultimately give way with time and knowledge to acceptance of an affirmative duty for trainees to learn to treat patients with these conditions. for example, the early fear and stigma surrounding hiv-infected patients in the s gave way to a widely recognized duty to treat these patients and instill the same ethic in trainees. as knowledge of the pathophysiology and epidemiology of evd and its implications for healthcare providers become more widely disseminated, a similar evolution may take place. however, based on the current conditions of the ebola outbreak, it is likely that very few of these professionals will need to be called upon to fulfill this duty. as long as the ebola incidence in the united states remains low, each institution can and should manage its burden of suspected ebola cases with a cadre of nurses and physicians highly trained in ebola treatment and prioritize infection control. the ethical justification to restrict the number of caregivers who come in contact with ebola-infected patients is that, given the limited experience with the disease in the united states, unnecessary exposure to infected patients would increase the risk to providers, other patients and the public. it is prudent to limit the potential chain of infection when possible. because experienced or specially-trained nurses and attending physicians can effectively manage suspected or confirmed ebola cases, trainee involvement is not required and would entail unnecessary risks to trainees and their patients. trainees should, however, be fully prepared in case they find themselves in a position where their duty to treat an individual patient outweighs a duty to the public to limit exposure to the disease. however, if not trained or equipped properly, their duty to reasonably protect their own safety should not be superseded. non-participation of trainees in the care of ebolainfected patients is then an instance of exclusion, rather than exemption. institutions exclude trainees as an infection control strategy; trainees do not opt out. some trainees may object to these policies, as they may feel ethically compelled to care for ebola-infected patients as a function of their professional role and view their exclusion as a restriction of their own moral agency and liberty (to fulfill their commitment to treat the sick). however, this restriction is justified by the greater good of protecting public health. ensuring trainee well-being and availability to care for other ed patients as well as limiting contagion are ethically justifiable reasons to exclude trainees. exclusion of trainees from the care of ebola-infected patients is not simply paternalistic because the primary aim is to protect patients and the public and represents a proportional response relative to the professionalism and moral agency consideration of trainees. at the same time, a blanket exclusion of trainees from the care of ebola patients in the primary outbreak zone may be ethically inappropriate. if the trainee has the relevant experience and is able to meet the other requirements outlined above for volunteerism in the countries most affected by ebola currently, a case-by-case evaluation would seem appropriate for supporting the participation of volunteering trainees in the international response where there is a desperate need for available healthcare providers. such support would have the added benefit of growing the cadre of individuals with the relevant expertise in caring for patients with evd should the current outbreak spread to the us. however, it is worthy of consideration whether academic medical centers can appropriately manage the risk to their trainees in the conditions posed by the outbreak in west africa. there are additional reputational risks should a trainee contract ebola or the public adversely view institutions where a large cadre of providers, including trainees, have traveled to care for patients in the primary affected countries. as such, we affirm the ethical appropriateness of academic medical centers to consider on an individual provider basis whether a trainee should be supported in volunteering to travel to africa rather than endorsing a policy of automatic exclusion or support of providers in this regard. such individualized evaluations should take specific account of the level of training, previous background, experience with ebola and the ppe required to care for patients with this disease, the ability to undergo the necessary preparation for functioning effectively in the primary outbreak zone and the willingness to comply with monitoring and isolation protocols upon return to the us. under the current state of the ebola outbreak, it is anticipated that cases in the us would be scattered and readily managed at designated treatment centers. at the same time, it is recognized that suspected patients may present to frontline emergency departments without specialized expertise in the management of evd, and, as seen in the case of the patient in dallas, this may pose a risk to health care providers, including emergency physicians and emergency nurses. as a result, various health care providers have expressed reluctance to care for patients with ebola. [ ] [ ] [ ] [ ] historically, such provider reluctance has often arisen with the emergence of unknown infectious diseases. a survey of thousands of healthcare workers in new york found that half would hesitate or refuse to report to work during a severe acute respiratory syndrome (sars) outbreak (though % would report to work during a mass casualty situation). most cited concern for family, followed by concern for self, as reasons not to report to work during a sars epidemic. individual conscience then, rather than professional tradition, seems to be the main force that compels nurses and physicians to risk their lives in service of patients. , with this background, it is fair to ask whether there are circumstances under which emergency department providers could opt out of the care of ebola patients. under us law, nurses and physicians have a legal duty to treat patients with whom they have entered into a therapeutic relationship. once undertaken, the duty continues until the patient and professional mutually agree to end the relationship or the care is transferred to another professional. nurses and physicians have special duties in service of the sick, and since this obligation holds even in face of greater than usual risks to one's own safety, healthcare professionals consequently accept greater risks than ordinary, balancing immediate benefits to individual patients with the professional's own health and ability to treat future patients. but there is no consensus on the specific limits of this duty. , emergency nurses and physicians are front line in an outbreak and, implicit in their specialty choice, accept additional risk beyond what is typical for many of their colleagues. as noted above, this is acknowledged in professional codes of ethics and statutory mandates (e.g., emtala). [ ] [ ] [ ] [ ] there are potential additional penalties for those health care professionals who refuse to work or treat patients during a pandemic, including reduction in pay, termination and, in some states that have adopted variations of the model state emergency health powers act (mhehpa), the possibilities of licensure actions, fines or imprisonment. , though the legal foundations of the duty to treat and its consequences are significant, the most compelling ground for these obligations is that health care is a moral enterprise. , "all its efforts converge ultimately on decisions and actions which are presumed to be good for some person in need of help and healing." nurses and physicians have a professional commitment to heal the sick. they are morally accountable to this commitment and are expected to demonstrate the virtues that it entails-such as courage, compassion and fidelity. , this virtue-based ethic is independent of the patient's right to access to healthcare and the contract between the patient and physician. rights-based and contract-based accounts of the duty to treat would allow nurses and physicians to opt out of caring for patients in an epidemic as long as others were willing to take their place. but nurses and physicians who opt out in such cases still fall short of their moral commitment. emergency nurses and physicians, therefore, have a duty to care for ebola-infected patients and, in most instances, accept the associated risks. , but the duty is not unlimited. an "abstract limitless duty" obscures the discussion about reasonable risk acceptance among nurses and physicians. allowing for reasonable and practical limits to the duty to treat-applied equitably to all clinicians-may increase the likelihood that nurses and physicians will live up to their individual obligations during an outbreak. the limit is illustrated by an account of a physician who, during the ebola outbreak in the democratic republic of the congo, "found dying patients in an abandoned hospital, left to care for themselves amid rotting corpses, sometimes in the same bed." a nurse or physician should not be expected to treat patients in a context where the risks are extraordinarily high and the potential benefit to patients extremely low. indeed, the first duty of emergency nurses and physicians in the current ebola outbreak or other emerging infectious disease is to protect themselves in the care of patients, if for no other reason than to ensure their availability to treat subsequent patients. by contrast, care of ebola-infected patients in a us hospital with the proper ppe and training would fall well within the duty to treat. in the current state of the ebola outbreak, establishing cadres of highly trained clinicians at well-resourced institutions may be the best way to deliver uniform care under a duty to treat and limit potential spread of infection in the us. under the above noted virtue and professionalism-based ethical framework, , , , , emergency nurses and physicians may also volunteer in place of colleagues who they see experiencing exceptional moral or emotional distress over caring for ebola-infected patients-for example, as a result of unusually severe consequences for loved ones should they become ill. but as the burden of ebola-infected patients rises, the duty to treat is a responsibility of all emergency nurses and physicians who have the necessary training, skills and experience. while the duty to treat is intrinsic to health care professionals, institutions may also hold emergency nurses and physicians accountable to this standard. however, institutions may not invoke the duty to treat to coerce hospital employees into accepting unnecessarily dangerous conditions: for example, to expect them to deliver care to ebola-infected patients without proper ppe or training. institutional leaders have an ethical responsibility to prepare for outbreaks, ensure that the providers who risk their lives in the service of patients do so with as much protection and support as possible and make available appropriate channels for emergency physicians and nurses to communicate concerns about the adequacy of the training and preparation they receive. preparation includes, but is not limited to, making high quality ppe readily available, ensuring that all relevant staff are educated and trained to use it properly (especially proper donning and doffing) and limiting exposure to only those individuals needed to care for patients and prevent the spread of infection. experience with the sars epidemic in canada suggests that hospital leaders owe even more than merely providing equipment and training to nurses and physicians who fulfill their duty to treat under hazardous conditions. some healthcare workers died from sars, and some spread the disease to their families. healthcare workers have moral obligations to their families, and institutions should make it possible for them to care for patients without abandoning their responsibility to their families or risking their families' lives. institutions should, for example, assist with child care and provide temporary living quarters to reduce the risk of disease transmission to family members and the associated anxiety and moral distress. institutions, as well as public health agencies, may also consider additional acts of reciprocity toward healthcare workers who fulfill their duty to treat, such as insurance to protect them and their families should they become ill or die as a result of caring for ebola-infected patients. ultimately, however emergency nurses and physicians care for the sick primarily out of personal moral obligation; financial incentives alone are not likely to increase the likelihood that they will discharge their duty under epidemic conditions. the protections that institutions and society provide healthcare workers-for themselves and their families-are ethically required. just as emergency nurses and physicians may not generally opt out of caring for the sick, institutions and communities may not opt out of caring for healthcare professionals and their families. in sum, the duty to treat patients with infectious diseases, including ebola, is both a legal responsibility and an ethical obligation of the healthcare professions. the duty should be borne equitably by professionals, who in turn, should be adequately supported by institutions and society as a whole. given the expected low number of us cases, there is a role for institutions to ask healthcare providers to volunteer to serve on treatment teams for suspected ebola patients as a means of limiting training efforts, time and expenditures (eg, credentialing of the ability to perform invasive procedures with ppe), reducing the potential risk of infection and ensuring relevant personnel and expertise are available to provide care. however, such volunteer-based plans do not address the special role of emergency departments where patients may present in an undifferentiated manner and potentially in acute distress, and where alternative providers may simply not be available. for emergency physicians and nurses, who through their choice of profession knowingly accept the above circumstances of patient care, , the current state of the ebola outbreak does not justify opting out of the care of suspected or confirmed ebola patients who may present to the emergency department, but this obligation is contingent upon institutional and governmental resources that provide adequate training and equipment to fulfill this duty. there also needs to be a recognition by healthcare personnel, hospitals and other public health and legal authorities as well as patients that the duty of emergency physicians and nurses to treat must be absolutely contingent on first ensuring personal safety through the proper use of ppe. , should ebola rise in prevalence in the us, contingency planning to meet the duty to treat should move beyond training and equipment to mechanisms to support the weighty obligations of emergency physicians and nurses to protect themselves and their families while caring for affected patients. with the high mortality rate, lack of specific treatment and need for specialized ppe in order to prevent transmission, there have been legitimate questions whether the goals of care should change in patients critically ill with evd. specifically, in the circumstance where a patient requires procedural interventions (central venous access, intubation, dialysis, etc) to provide intensive care level support, is the risk posed to providers too high compared to the low potential of benefit, if any, to a patient whose illness may have progressed to a point where such interventions are unlikely to be successful? furthermore, given the time needed to don ppe-an absolute requirement prior to any procedural intervention on an evd patient-should cardiopulmonary resuscitation during an arrest event be considered futile due to the potential delay in its initiation and again the likely prognosis of the patient? , , since the initial posing of these concerns about the risk versus benefit posed by critical care and resuscitation interventions in patients with evd, case reports have appeared showing that aggressive, intensive care level interventions, including intubation, central venous access, large volume and blood resuscitation and dialysis, can be successful in treating critically ill individuals with this disease and do not pose an automatic risk to providers if ppe is properly used. , while anecdotal and representative more of what is possible in idealized circumstances (specialized care units with previous expertise and training in care of evd patients and a high number of dedicated providers), these cases imply that utilizing the full panoply of critical care resources for this patient population may be appropriate treatment. however, the highly contagious nature of evd and the need for specialized ppe, along with the experience in africa of rapid transmission to family members caring for ill patients, makes it appropriate for hospitals to not allow family presence during such procedures as is allowed in other critical care or resuscitation circumstances. with respect to cardiopulmonary resuscitation, to our knowledge, no published report has indicated the successful or unsuccessful use of cardiopulmonary resuscitation in an arrest event in an ebola patient, though resuscitation success in a us healthcare facility may be similar to other infectious diseases at similar stages, from initial manifestations to overwhelming sepsis. at this time, consideration of do-not-resuscitate status in a late-stage evd patient is best determined on a case-by-case basis, taking into account potential benefit to the patient, any limitations of interventions imposed by the disease and the potential risks to the treatment team. however, the circumstances described for the above patients are not typical of that seen in most emergency departments in the us. while the current state of the outbreak would likely lead to a typical ed encountering a patient early in their evd process, if at all, and being able to isolate such an individual until transfer to a higher level of care, should the number of cases rise due to spread of the disease, it is conceivable that emergency departments could encounter patients in a variety of stages of ebola with the risk-benefit calculation on procedural interventions being highly relevant. unlike the above cases, should the current outbreak spread, emergency departments would encounter patients with fewer resources (less isolation facilities, lower ratios of providers to patient) than those expended in the above reported cases and having to simultaneously care for other patients with a variety of conditions. here there is need to refer to the special role played by emergency physicians and nurses in the healthcare system. the assumptions that accompany the choice of these professional roles (exposure to acutely ill, undifferentiated patients) and the specialized training and skills that emergency physicians and nurses possess impose a higher obligation than other medical professionals to be prepared to treat an acutely ill ebola patient in the emergency department setting. , at the same time, as we note above, the duty to treat is not absolute. there is no obligation for an emergency physician or nurse to implement treatment measures in an acutely ill ebola patient without training in the use of ppe, the availability of such supplies and, at a minimum, simulated experience with performing critical care procedures while utilizing ppe. , , without such minimum standards, the social contract that accompanies the professional standing and obligations of emergency physicians and nurses breaks down. this social contract calls for a rational person to expect an emergency physician or nurse to apply their skills to aid an acutely ill patient but at the same time for those professionals to have the requisite training and equipment to provide such aid in an appropriate manner. all emergency departments and hospitals should therefore consider that protocols for ppe training and isolating suspect patients, as called for in the current interim cdc guidelines, are likely inadequate should the current epidemic spread more prominently to the us. to fulfill the ethical obligations imposed by the duty to treat should the current outbreak become more prevalent domestically, more robust training with ppe and the performance of procedures with such equipment will be necessary for a wider cadre of emergency physicians and nurses to appropriately treat acutely ill ebola patients in intermediate or late stages of the disease while ensuring the maximum feasible protection of the healthcare provider. weighing when such expanded training may be warranted should take into account the continued status of the outbreak, the cost of such preparation and the availability of appropriate resources to be effective. in the unexpected scenario where the number of patients with evd overwhelms existing resources, more traditional disaster triage protocols would be applicable. such protocols attempt to apply resources in a manner to benefit the largest number of patients. in the case of ebola, where the evidence to date is that an overwhelming amount of critical care resources are required to effectively treat a late-stage patient, disaster triage protocols would need to weigh at what point in the treatment spectrum such resource expenditure would become untenable. such protocols, to be ethically appropriate, would need to be transparent, proportionate and accountable to oversight along with having a legal imprimatur to be effective in the emergency department and acute care setting. to avoid such a crisis situation, the devotion of resources now to end the epidemic in the primary outbreak zone in africa is vital. the outbreak of evd in west africa has presented a significant challenge to the health systems of the primary affected nations and, even with a low case count, raised concerns about the preparedness of the us healthcare system to respond to uncommon infectious diseases. in some ways, ebola is a unique test for us emergency departments, emergency physicians, emergency nurses and other stakeholders given its rarity in the us, high mortality rate, high risk of transmission to healthcare staff and non-specific presenting symptoms that can make initial diagnosis more difficult. however, as shown with other unanticipated infectious disease outbreaks (hiv, sars, mers), emergency departments will almost certainly be a key location for patient identification and treatment. the ethical concepts applied in this paper are relevant, especially reciprocity, duty to treat and grounding in the specific facts of the disease process in question, when considering how acute care facilities should prepare for likely future outbreaks of infectious disease. we propose that preparation for future emergency department responses to unanticipated infectious disease outbreaks should include ethical as well as logistical and medical factors. given the multiple stakeholders represented in emergency department practice, the model shown here of multi-disciplinary and organizational consideration of the ethical issues involved would likely have application when considering the approach to future infectious disease challenges. the outbreak of evd in west africa and the presentation of patients to us acute care facilities has raised a series of intertwined logistical and ethical issues of relevance to us emergency departments, emergency physicians and emergency nurses. while the current state of the epidemic has not led to a large number of evd patients presenting to us facilities, consideration of ethical questions that are relevant now and of potential relevance in the future will allow emergency physicians, emergency nurses and other stakeholders to prepare appropriately for the challenges posed by ebola and consider its implications for future epidemic infectious disease events. an emphasis on the principle of reciprocity, the obligations imposed by and underlying assumptions of the duty to treat and the specific characteristics of the disease process will aid in addressing the ethical challenges posed in the current outbreak of evd. er doctor discusses role in ebola patient's initial misdiagnosis, : dallas morning news nurse's discharge leaves one ebola case in u.s., though larger battle continues plenty of hugs as craig spencer, recovered new york ebola patient, goes home. n y times hospitals prepared for the next ebola case? sci am ebola quarantine questioned american college of emergency physicians. healthcare resources for suspected ebola cases emergency nurses association. ena topic brief: ebola virus disease centers for disease control and prevention. ebola (ebola virus disease 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acgme guidance statement on ebola virus infection and resident/fellow training in the united states the model of the clinical practice of emergency medicine aids doctors: voices from the epidemic: an oral history public health ethics: mapping the terrain ebola: when health workers' duty to treat is trumped montana nurses concerned about ebola bellevue staffers call in "sick" after ebola arrives hospital staffers reportedly take sick day rather than treat new york's first ebola patient health care workers' ability and willingness to report to duty during catastrophic disasters for the council on ethical and judicial affairs of the american medical association. physician obligation in disaster preparedness and response ethics and sars: lessons from toronto center for law and the public's health. model state emergency health powers act potential penalties for health care professionals who refuse to work during a pandemic ethics and the moral center of the medical enterprise toward a virtue-based normative ethics for the health professions physicians' duty to participate in pandemic care ebola triage screening and public health: the new "vital sign zero clinical review: sars-lessons in disaster management survey of hospital healthcare personnel response during a potential avian influenza pandemic: will they come to work? responding to ebola: questions about resuscitation a case of severe ebola virus infection complicated by gram-negative septicemia clinical care of two patients with ebola virus disease in the united states the idea of a social contract: the elements of moral philosophy crisis standards of care: a systems framework for catastrophic disaster response the drafting authors wish to thank the acep ebola expert panel and saem global academy of emergency medicine for their critical review of the manuscript during preparation and the leadership of acep, ena and saem for their sponsorship of this effort. key: cord- -gf wy a authors: idowu, abiodun benjamin; okafor, ifeoma peace; oridota, ezekiel sofela; okwor, tochi joy title: ebola virus disease in the eyes of a rural, agrarian community in western nigeria: a mixed method study date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: gf wy a background: ebola virus disease (evd) is a severe hemorrhagic disease caused by ebola virus. several outbreaks have been reported in africa and often originated from remote agrarian communities where there are enormous misconceptions of the disease, refusal of early isolation and quarantine, and unsafe burial rites practices which aggravates the epidemics. it is on this basis that this study was conducted to (assess) the knowledge, perceptions, beliefs and preventive practices against evd in a predominantly agrarian rural community in southwest nigeria. methods: this was a cross-sectional study conducted in igbogila town, yewa north local government area of ogun state, southwest nigeria in the latter part of during the evd outbreak. mixed methods were used for data collection. quantitative data collection was done using a pre-tested interviewer administered questionnaire. four hundred and seven respondents selected by multi-stage sampling technique were interviewed. descriptive and inferential statistics were done, and the level of significance was set at . . qualitative data collection involved four focus group discussions a year after the epidemic was declared over in the country. the discussions were recorded, transcribed and analyzed along major themes. results: all respondents were aware of evd with radio and television being the major sources of information. knowledge of the disease was however very poor with many misconceptions and it was significantly influenced by educational level of respondent. evd survivors will be welcomed back into the community by few residents ( . %) and a much fewer proportion ( . %) will freely entertain a survivor in their house. most would prefer local herbalists over orthodox medical practitioners to care for their loved one in case they contract evd. although respondents knew that burying a victim is dangerous, they opposed cremation. conclusion: there was poor knowledge of evd with a lot of misconceptions. community members were not pro-active about prevention with dire consequences in the event of an outbreak. continuous public education should be done via mass media, traditional institutions and other community-based channels as part of emergency preparedness. ebola virus disease (evd) is a severe hemorrhagic disease caused by ebola virus: a non-segmented, enveloped, negative-strand rna virus [ ] . the first case of evd was identified in , since then, several outbreaks have been reported in africa [ ] . in the last years, an outbreak of evd has been reported at least every years [ , ] . in ; the deadliest, most widespread (affected ten countries), evd outbreak that lasted approximately years occurred making it a global emergency [ ] . current corona virus disease (covid- ) pandemic has again brought to the fore, the need for countries to maintain a high standard of preventive measures and preparation for emergency response for any emerging or reemerging infectious disease. populace needs to be enlightened on evd preventive measures such as maintenance of careful hygiene (washing hands with soap and water or an alcohol-based hand rub), avoiding contact with non-human primates and bats, avoiding contact with infected person's body fluids or infected items, and avoiding funeral or burial rituals that require handling of the body of someone who has died from evd (confirmed or suspected) [ ] . public health response to evd outbreak include: case finding (suspected, probable and confirmed), contact tracing, isolation and early quarantine, treatment of symptomatic cases, and ensuring appropriate burial for the deceased [ ] . however, a closer look at past evd outbreaks revealed that they often originated from rural agrarian communities where there are many misconceptions about the disease, refusal of early isolation and quarantine, and unsafe burial rites practices which aggravate epidemics [ , ] . it is on this basis that this study was conducted to assess the knowledge, perception, beliefs and preventive practices among residents of an agrarian community in ogun state, southwest nigeria. findings will provide useful information to aid future outbreak prevention and control as well as emergency preparedness efforts. this was a descriptive cross-sectional study which employed mixed-method (quantitative and qualitative) approach in data collection. the study setting was igbogila town, ibeshe ward, yewa north local government area of ogun state, southwest nigeria. yewa north is located at the west end of ogun state sharing border with benin republic (a neighboring country). igbogila is predominantly rural and agrarian with many of the residents engaged in agro-forestry related occupations. at the time of the study, the town had one primary healthcare centre, two public secondary schools, five public primary schools, one major market, few churches and mosques. only residents between and years that had been living in the study area for at least months prior to the study participated in this study. quantitative data were collected during the ebola epidemic in nigeria (july -september ). sample size was determined using cochran's formula (n = z p( -p)/ e ) [ ] . the calculation was based on: prevalence of good knowledge (p) of % obtained from a similar study [ ] , standard normal deviate (z) at % confidence being . and % margin of error (e) resulting in a minimum sample size of . this was increased by % ( ) to make up for non-responses and incomplete questionnaires giving a total sample size of . multi-stage sampling was used to select the respondents. in the first stage, one ward (ibeshe) was selected from the eleven wards in yewa north using simple random sampling technique (balloting). in the second stage, one town (igbogila) was selected from the seven towns in ibeshe ward. igbogila comprises nine smaller communities which were all included in the study. respondents were equally allocated to the communities i.e. about respondents were required from each community. the third stage involved the selection of houses following enumeration and systematic sampling of houses. the houses in the communities largely had no numbering system, so, the research team carried out house numbering. in the fourth stage, households were selected from the houses. only one household was selected per house (simple random sampling (balloting) was used to select one when there were more than one household). in the final (fifth) stage, respondents were selected from households. only one respondent that met the inclusion criteria was interviewed per selected household (simple random sampling (balloting) was used to select only one respondent when there were more than one eligible respondent). respondents were interviewed face-to-face using a pre-tested interviewer administered questionnaire adapted from similar studies [ , ] . eight research assistants who were fluent in yoruba, english and 'pidgin' english were trained for data collection. the questionnaire sought information on socio-demographic characteristics, awareness, knowledge, attitude and perception of evd. knowledge was assessed using questions on cause, transmission, symptoms, prevention and cure of evd. perception and attitude to evd were assessed using respondents' agreement or disagreement to a set of likert statements. data were coded, entered and analyzed using epi info™ . statistical package [ ] . descriptive statistics (frequency, mean and standard deviation) and inferential statistics (chi-square test) was used to test association between categorical variables. level of significance was set at %. in the knowledge section, each correct response given by respondents was allotted one point. overall knowledge was assessed using five domains: cause ( point), transmission ( points), symptoms ( points), prevention ( points) and cure ( point). this gives a total maximum score of points converted to percentage. using % cut-off point; respondents with total score < % were graded as 'poor knowledge' while those with > % were graded as 'good knowledge'. attitude was scored using three points likert scale; the maximum obtainable score was and the least was . using the mid-point ( ) as cut-off point, respondents with score < were graded as having "poor attitude" while those with scores > were graded as having "good attitude". for the qualitative aspect, focus group discussions (fgds) were conducted in november , about a year after the epidemic was declared over by who [ ] . the main purpose for the fgds was to explore explanatory models for the disease in rural communities and their preventive practices against an outbreak. according to the who, this is important in any epidemic preparedness and response [ ] . discussants were approached face-toface and selected into one of four groups: higher secondary education students ( discussants), females of reproductive age ( discussants), adult male ( discussants), elderly female ( discussants). fgd participants were selected by purposive sampling as discussants in each group were selected to be of the same gender and about same age as suggested by ritchie and lewis qualitative research framework [ ] . in each group, one of the discussants volunteered his/her home for the discussion. fgds were moderated by the principal researcher with the assistance of one note taker and a time-keeper. each session lasted for about h. discussions were held mainly in local (yoruba) language understood by all the participants and taperecorded in addition to notes. each discussant was assigned a number. at the end of each session, discussants were given light refreshments. the recordings were later translated and transcribed in english. data was saturated in domains of cause, and spread of evd, but, unsaturated in domains of treatment. thematic analysis was done manuallyrecurring themes from the data were identified, emerging patterns noted, and report written based on these identified patterns. for the purpose of presentation, the groups were coded as follows: higher secondary school students (hs), adult males (am), older females (of), and women of reproductive age (rf). participation was voluntary and formal consent was obtained from each participant. respondents were informed of their right to withdraw at any point of the study without prejudice in line with helsinki declaration [ ] . a total of respondents completed their interviews while respondents withdrew their participation, making the response rate to be . %. mean age of respondents was . + . years with slightly more males (n = , . %). almost one-quarter, ( . %) had no formal education and half (n = ) earning less than , naira monthly (less than us dollars) ( table ) . all the respondents were aware of evd. majority, ( . %) heard of it through radio and television, ( . %) got to know from their friends or family members. print media such as newspapers and flyers were not reported as a source of information by the respondents. 'dirty environment' was the most commonly mentioned cause of evd ( . %), only ( . %) knew that a virus is implicated. few ( . , . and . % respectively) knew that eating poorly cooked bush meat or contact with non-human primates or contact with body fluids of infected persons pose risk of evd transmission. a minority knew fever ( . %), vomiting ( %) and headache ( %) as symptoms of evd. (table ) . a third ( . %) knew hand washing and avoidance of contact with non-human primates as preventive measures while only ( . %) knew that avoiding funeral or burial rituals involving contact with victims' corpses is a preventive measure (table ) . neither age nor sex of the respondents significantly influenced their knowledge of evd. however, those respondents with at least secondary education were more likely to have good knowledge of evd (p = . ) ( table ). a majority ( . %) believed that evd really exists and ( . %) perceived it to be very fatal. while ( . %) agreed that it is not curable, ( . %) believed that victims could survive if given prompt medical intervention. almost a quarter, ( . %) saw it as a political ploy that government officials wanted to use to embezzle funds and only about half ( . %) thought that the country was truly ebola free (table ). in respect to their attitude; ( %) reported that they would accept to be quarantined if they were found to have had close contact with a case, ( . %) would support and empathize with a friend or relative who is infected, however, only two-fifths ( %) would buy from a shopkeeper who has recovered from evd and even a lesser proportion ( . %) would welcome a survivor back to the neighbor-hood. only ( . %) would entertain a survivor in their homes. overall, respondents ( %) had a good attitude towards evd ( table ). sociodemographic characteristics of discussants the mean age of the fgd participants was + . years, ( %) were females, ( %) had no formal education while ( %) had tertiary education. the participants were largely farmers ( %), and petty traders ( %). one discussant was a herbalist (table ) . the recurring themes on how ebola disease can be contacted were: eating infected bush meat, unprotected contact with infected persons, and intercourse with multiple sexual partners. "it is gotten by coming in contact with infected animals, animals such as bats and bush meats" -hs ( years old male student). "the disease is catching whoever has sex with prostitutes …" -am ( year old bricklayer). more respondents believed that local herbalists know the cure for ailment. "i will call a herbalist to come and treat the person (a case) at home" -rf ( years old female farmer). "i believe that they are lying by saying there is no cure for the disease … … , if the victim is taken to good traditional healers, the person will be cured" -hs ( year old male student). when asked how best to handle the corpse of a close relative that died of evd, it was evident that the people knew that burying someone with evd is not without any risk. "i will not move close to the corpse. the people who died of the disease are usually burnt but i cannot allow my own dead family member to be burnt. i will just call them at the centre (primary health facility in the area) to come and help me bury the corpse" -hs ( year old male student). while some ( out of the ) of the respondents did not stop eating bush-meat (bats inclusive), many ( out of ) of the respondents stopped eating bush meat. the precautionary measure was however for a while as it was found that these respondents that initially restrained their intake of bush meat had resumed its consumption. "i stopped eating bush meat and bat, but when i later saw that people who ate bush meat did not die, i started eating them back" -am ( year old male farmer). the important theme that emerged on preventive measures for evd was the use of salt water. some respondents bathed with salt water, drank and mandated its use in their family till they experienced related adverse effects. "i bathed with salt water as instructed by my father" -hs ( years old male student). "my six children and myself used salt water to bath for some days but stopped when we started having skin rashes" -of ( year old female trader). their current preventive practices were explored (without prompting). majority of the respondents confessed that they were eating bush meat as before. they were mostly not taking any pro-active preventive measures to prevent evd such as limiting close physical contact or direct contact with bush animals. "i am not doing anything. i am eating bush meat …." -rf ( year old female farmer). "i am not doing anything … … i did not need to bother myself" -of ( year old female). at the outset of the evd outbreak, the nigerian government embarked on widespread health campaign with major attention on mass media. the mass-media platforms successfully raised evd awareness as all the rural dwellers in this study were aware of evd and they indicated that radio and television were their main sources of information. mass-media played similar pivotal role in purveying awareness for residents of urban communities in lagos, nigeria [ ] and for locals at epicenters in sierra leone [ ] . however, the high level of awareness did not translate to better knowledge of the disease. most respondents had poor knowledge riddled with many misconceptions. for instance, most of them either did not know the cause of evd or misconceived the cause to be dirty environment. there are evidences that have implicated bush-meats especially non-human primates e.g. bats in the spread of evd, yet only few ( %) knew that evd is spread by contact with infected non-primate animals [ , ] . the prominent misconception of the cause of evd as revealed in the fgd was the belief that ebola disease is acquired by leading a promiscuous lifestyle. this apparent disparity between biomedical and traditionally perceived etiology could stymie prevention in the event of another outbreak because based on etiological variances, local perception of prevention will conflict with orthodox suggestions [ ] . apart from the misconception of cause of evd, the knowledge of community-based modes of transmission (from infected individual to others, and from infected fomites/objects to man) of evd were also less known among the residents of the agrarian community. this is worrisome because during outbreaks, community-based transmissions are responsible for most secondary cases and thus responsible for perpetuating the spread of infection [ ] . the knowledge of prevention of evd was also found to be inadequate. more than % did not know that; avoiding direct contact with people, frequent hand washing, avoiding contact with non-human primates' body fluids and blood, and avoiding contact with infected items are precautionary measures. when the respondents were asked how they will handle the corpse of a relative that died of evd; it was evident that the people knew that burying someone with evd is not without risk but they opposed cremation -"… i cannot allow my own deceased family member to be burnt". cremation is rejected because it is not culturally acceptable in most parts of west-africa where autochthonous residents strongly believe that deceased soul will haunt living relatives if not given a traditionally acceptable burial [ ] . this has potential to impede effective burial of dead cases and it can aggravate epidemics as evidenced by catastrophic events that followed unsafe burial of cases at the early stages of the outbreak (in sierra leone and liberia) [ , ] . it may be beneficial to gradually institute interventions involving anthropologists and traditional institutions to discuss and relay such messages at the grass root level. exploring the respondent's knowledge of cure of evd, it was found that although some ( . %) knew that there is no cure for the disease, yet, most preferred local herbalists over orthodox medical practitioners to care for their loved one in case he/she contacts evd. being a rural setting, this is not surprising. the rationale behind this preference is the fear of having their relative isolated from them: "… ..once they carry the person (victims) away from you, you will not be allowed to see them again …" the discussants' preference of local herbalist over medical practitioners is another cause for concern as such misconceptions had made people in gulu district, uganda to resort to traditional practices such as 'ryemo gemo' rituals (wild shouting, jumping and running into nile river), 'chani labolo' rituals (slaughtering and littering intestines of several goats on ground) in kotido district of uganda, all in an attempt to 'cure' the disease. such practices only enhanced the spread of the disease and complicated the economic cost of the outbreak [ , ] . this also has implications for other highly infectious diseases such as lassa fever and covid- that require isolation of confirmed positive cases as part of containment. in such situations, similar preference for alternative treatment options may negatively impact control efforts. the factor that was found to significantly influence participants knowledge about evd was their educational status. the agrarian community dwellers with at least secondary education in this study were more likely to have good knowledge of evd compared to those with only primary or no formal education. this highlights the need to increase education coverage in local communities as the level of education of the populace could play an important role in determining the magnitude of spread as modelled by outcomes in two separate outbreaks in sudan [ ] . most respondents indicated stigmatizing attitudes towards evd survivors. a total of % stated that they will not buy any goods from a survivor, many expressed that they will not welcome a survivor back into the community nor allow survivor into their house. these discriminatory statements were similar to the initial problems local residents at ebola epicenters posed during early phases of the outbreak in liberia [ ] . the danger in this is that persons that suspect that they may have evd, and indeed any infectious disease hide it because of fear of stigmatization. this could drive disease outbreaks further. during the outbreak, the preventive method most respondents in this study observed was avoiding bush meat and use of salt water which are largely misconceptions. the use of salt water may have negative health consequences. though the exposure is there with consumption of bush meat, the key thing is close contact and method of handling during preparation of the animals. this was not really a big issue in evd outbreak in nigeria as the cases recorded were invariably linked to the imported case. the natives already exhibited poor knowledge and bush meat is commonly consumed due to their agro-forestry background hence the need for proper education. one year later, majority of the discussants stated that they had resumed bush meat consumption and were no longer taking any recommended precautions to prevent contracting evd. the main reason for this in-action could be linked to their religious belief, that 'god' protects them from 'evil diseases' like evd (table ) . unfortunately, this behavior may have serious consequences in the re-occurrence of evd outbreak in the country. the study was conducted in a setting that can be described as 'high risk' for evd outbreak. data was collected prospectively, and the mixed-method approach yielded more information necessary for understanding community explanatory models of the disease in the context of outbreak preparedness and control. the study did not emphasize on how local beliefs and practices could aid control efforts in such epidemics. more content could have been covered by adapting dunn's framework [ ] and this could be addressed in larger scale studies. the grading system adopted for measuring 'attitude' could have affected the result of the overall attitude (majority had good attitude) as their 'neutrality' was not factored into the grading system. no case of evd was recorded in the study area during the outbreak, nevertheless the limited data provides relevant information useful to researchers and other public health stakeholders in infectious disease prevention and control. the study has shown very poor knowledge of evd with misconceptions. though majority perceived the disease to be severe, some believed it was a ploy of whites against african countries and avenue for government officials to embezzle money. respondents exhibited stigmatizing attitude which may hinder control efforts in disease outbreaks. they were also not pro-active about prevention of possible future outbreak as most had gone back to harmful practices initially abandoned because the outbreak was declared to be over in the country. immunopathology of highly virulent pathogens: insights from ebola virus world health organization. ebola hemorrhagic fever in zaire, -report of an international commission outbreaks chronology: ebola virus disease emergencies preparedness response: ebola virus disease outbreak news overview, control strategies, and lessons learned in cdc response to the - ebola epidemic ebola response: package and approaches in areas of intense transmission of ebola virus. geneva: world health organization ebola viral hemorrhagic disease outbreak in west africa − lessons from uganda the ebola epidemic: a global health emergency sample size determination study on ebola virus disease knowledge, attitudes and practices of nigerians in lagos state 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to undetected spread of ebola virus and impeded rapid containment; one year into the ebola epidemic the impact of traditional and religious practices on the spread of ebola in west africa: time for a strategic shift community perspectives about ebola in bong, lofa and montserrado counties of liberia. results of a qualitative study a time for fear: local, national and international responses to a large evd outbreak in uganda cultural contexts of ebola in northern uganda modelling the role of public health education in ebola virus disease outbreaks in sudan the liberia ministry of health. national knowledge, attitudes and practices study on ebola virus disease social determinants in tropical disease springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors wish to thank the research assistants and participants for their commitment throughout the period of study. special thanks to adebolu olayinka, ogundan olayinka and taiwo toyosi for their assistance with data entry and transcription. authors' contributions abi-was involved in the conception, design, acquisition, analysis, interpretation of data and drafting and revision of the manuscript. ipo-was involved in the conception, design, analysis, interpretation of data, drafting of the manuscript and substantively revised it. eso-was involved in the interpretation of data and substantive revision of the manuscript. tjo-was involved in interpretation of data and substantive revision of the manuscript. all authors read and approved the final manuscript. there were no external funding for this study. the datasets used and/or analyzed during the study are available from the corresponding author on reasonable request. ethical approval was obtained from health research ethics committee of the lagos university teaching hospital (approval number: adm/dcst/hrec/ app/ ). informed consent (in writing) was duly obtained from participants. not applicable. the authors declare that they have no competing interests. key: cord- - x ii authors: gabel speroni, karen title: call to action for a us nurse general: from ebola to corona date: - - journal: j nurs adm doi: . /nna. sha: doc_id: cord_uid: x ii nan strategizing supply chain needs through the covid- pandemic. in , we initiated a national ebola virus disease (evd) survey research study for rns when the st evd patient was hospitalized in the united states. , researchers reported concerns of rns, who identified not only evd challenges but also those that are applicable to new emerging diseases. five years later, a new emerging disease has hit the world with pandemic strength, coronavirus (covid- ). the evdrelated challenges reported by rns from the evd study continue to be those we see with covid- (table ) . these challenges underscore the need for a call to action. the evd study conclusions were that nurses perceived a moderate risk in the provision of evd-related patient care (ie, persons under investigation and confirmed patients). while the potential impact of nurses leaving the field of nursing as a result of evd was small ( . %), knowledge that nurses would consider leaving the workforce prematurely provides guidance for the design of optimal management strategies for evd and other emerging diseases, particularly in a country with a projected nursing workplace shortage. the need and opportunity for safe patient care training extend not only to rns but also to ancillary staff. those responsible for training should consider evd, flu, and unknown emerging diseases. per the qualitative analysis we reported, the ability to provide the most effective care may only be possible when all parties involved understand and follow best practices guided by good evidence and meticulous science. the voices of nurses may influence the discourse on the ethics, politics, and distribution of resources necessary to address evd and other emerging infectious diseases. continued research that seeks to understand nurse perceptions and needs is an initial step in securing a safer workplace for nurses. nurses statements from the evd study continue to be on point for covid- , including "we need a new practice specialty of nursing for emerging diseases and biohazard, etc. they need special education, training, and preparedness and surely should be compensated with hazard pay." "it is a call to action for better preparation for contagious diseases in general." most importantly, one rn stated, "i am concerned that this issue is being politicized in a destructive way when some good could come from it. nurses should be trusted to control infection. where is the surgeon general on this issue? perhaps we need a national nurse." a call to action is needed for nursing to continue to progress and to lead our nation. we are all in this together. a us nurse general can further direct and ensure needed resources are budgeted, allocated, and made available for rns to innovate, research, and gather data to implement evidence-based strategies for safely caring for patients, testing, and vaccinating, not only for covid- but also for the next emerging disease. centers for disease control and prevention. cdc / : saving lives, protecting people, coronavirus (covid- nurses' perceptions on ebola care in the united states, part us nurses' perceptions regarding caring for suspected, probable and confirmed ebola virus disease patients, part key: cord- -ocfjj v authors: blumberg, lucille; regmi, jetri; endricks, tina; mccloskey, brian; petersen, eskild; zumla, alimuddin; barbeschi, maurizio title: hosting of mass gathering sporting events during the – ebola virus outbreak in west africa: experience from three african countries date: - - journal: int j infect dis doi: . /j.ijid. . . sha: doc_id: cord_uid: ocfjj v • mass gatherings at sporting events attract millions of international and national host-country travellers, who may put themselves at risk of acquiring local endemic infectious diseases. • the – ebola virus disease (evd) outbreak in west africa that resulted in over cases and deaths required that countries holding these events put in place public health programmes for enhanced surveillance and specific response plans for any suspected cases of evd. • three major sports events were held in africa during the evd outbreak, attended by athletes from numerous african countries including liberia, sierra leone, and guinea, the three countries most affected by evd: the african youth games (botswana), africa cup of nations (equatorial guinea), and all-africa games (republic of congo). • a large range of infectious diseases other than evd were considered with respect to the differential diagnosis of acute febrile illnesses and for the provision of laboratory diagnostics and treatment options. • the experience from these three mass gathering events during the ebola epidemic illustrates that these events can be held safely provided that countries put measures in place for enhanced surveillance and response systems for communicable diseases. mass gatherings at sporting events, , or religious pilgrimages, , attract millions of international and national hostcountry travellers, who put themselves at risk of acquiring local endemic infectious diseases. [ ] [ ] [ ] over the past five decades, the public health authorities of the host country have focused their attention on the transmission of infectious diseases and their impact on the attendees at the mass gathering, the local population, and the local health system. the appearance and reemergence of several new lethal pathogens of humans with epidemic potential have heightened awareness of the potential of rapid spread at mass gathering events. new zoonotic infectious diseases of humans include nipah virus, hantaviruses, west nile virus, ebola virus, severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome coronavirus (mers-cov), and avian viruses, among others. , the unprecedented ebola virus disease (evd) epidemic in west africa and the ongoing zika virus (zikv) outbreak in south america , were declared public health emergencies of international concern (pheic) by the world health organization (who) in august and february , respectively. yellow fever outbreaks in a number of african countries in / are cause for concern, with infections in unvaccinated travellers to angola posing a risk on return to their countries of residence. , there are a number of challenges for countries hosting major international sporting events during a pheic. , , the - evd outbreak in west africa, which resulted in over cases and deaths, required that countries holding these events put in place public health programmes for enhanced surveillance and specific response plans for any suspected cases of viral haemorrhagic fever (vhf). three major sports events were held in africa during different phases of the ebola virus outbreak, with participation by sportsmen and women and supporters from a broad range of african countries, including liberia, sierra leone, and guinea, the three most affected countries. at the invitation of the host countries, who missions were conducted to the three respective countries to support and advise on specific ebola prevention and response strategies. in this article, the three major sporting events are described, highlighting the activities undertaken to ensure public health security and the outcomes of these mass gatherings with specific reference to evd. the african youth games are held every years. the first games were hosted by morocco in rabat and athletes from countries participated. the second african youth games were held in gaborone, the capital city of botswana, from may to may , ; in retrospect, this was at a time when the ebola virus outbreak had expanded rapidly within the affected region. this event took place at a number of venues in gaborone and drew around athletes aged to years, who took part in a wide range of sporting events including football, swimming, fencing, boxing, cycling, and rugby, as well as their support teams; the participants came from african countries including liberia, sierra leone, and guinea. spectator attendance was mainly from botswana and countries in the region. at the beginning of may the ministry of health of botswana was on high alert and requested that the who provide rapid technical support in strengthening public health capacities under the framework of the international health regulations (ihr) , in the context of the expanding ebola virus outbreak. botswana had never previously managed cases of suspected or confirmed vhf. while no general travel restrictions were applied to athletes from the evd-affected countries, contacts of known cases of evd were not permitted to leave their respective countries. proof of yellow fever vaccination was required as a condition of entry for travellers from yellow fever endemic countries. at the international airport in gaborone, port health staff screened incoming travellers for fever; they were supported by a small team of medical personnel trained for the event. a small medical facility was established at the airport for the isolation of patients. while a strong national surveillance system supported by district outbreak response teams was already in place for epidemic-prone diseases, this was supplemented by a daily surveillance system for specific priority conditions pertinent to the event. both a syndromic approach and laboratory confirmation to identify participants with an acute febrile illness were used. a daily analysis attempted to establish trends. an emergency -h reporting system was established for persons with suspected meningitis or vhf, and for any outbreaks. an isolation facility was established in an existing health centre outside of the major hospitals. extensive staff training was conducted using videos and demonstrations in the use of personal protective equipment (ppe) and infection control practices, as well as simulation exercises. sourcing of adequate supplies of ppe was a challenge. since botswana did not have laboratory capacity for vhf and other specialized testing, arrangements were made for testing to be conducted in the biosafety level (bsl ) laboratory and reference laboratories at the national institute for communicable diseases in south africa, approximately h by road from gaborone. the requisite export permits and transport arrangements were facilitated. the public health and hospital laboratories in gaborone were able to test for malaria and meningitis and common pathogens. training sessions in the recognition and management of a range of communicable diseases were held for medical personnel. the africa cup of nations competition was organized by the confederation of african football and held in equatorial guinea between january and february , . initially scheduled to be hosted by morocco, this major football tournament was moved to equatorial guinea at a late stage after morocco requested postponement due to the ebola virus epidemic in west africa. south africa, egypt, ghana, and sudan all declined to take over as hosts. fifty-one countries competed and qualified for the tournament: south africa, equatorial guinea, congo, mali, algeria, gabon, burkina faso, cameroon, cote d'ivoire, guinea, ghana, zambia, tunisia, senegal, democratic republic of congo, and cape verde. four cities in equatorial guinea hosted the event: the capital city malabo, bata, mongomo, and ebebiyin. in addition to supporting the overall evd preparedness, the main objective of the joint who team was to strengthen the country's readiness to detect and manage evd during the africa cup of nations. equatorial guinea had never previously detected a human case of evd, neither associated with the most recent epidemic in west africa nor during any previous outbreak. nevertheless, the neighbouring country of gabon verified its first evd outbreak in and detected sporadic evd outbreaks in and / , with confirmed cases and deaths reported. with people coming to the country from many african countries, the risk of importing evd existed and required mitigation. a crisis committee to coordinate preparedness and response activities for evd, chaired by the prime minister, was established in december following the declaration of the pheic by the who. overall, no major communicable disease events were reported. the republic of congo hosted the xi edition of the all-africa games. the games were held in stadia throughout the city of brazzaville from september to september , , with participation of athletes from countries, including sierra leone, liberia, and guinea. the ministry of health and population of congo was responsible for the overall coordination and delivery of health services, and worked in close collaboration with other ministries, the organizing committee, and the who, to ensure rapid detection and containment of infectious diseases, especially evd. the republic of congo had previous experience of managing vhf with referral to the reference laboratory in kinshasa, democratic republic of congo, directly across the congo river from brazzaville. health risks to visitors and local communities during the all-africa games were assessed at an early stage, and planning for constant disease surveillance and risk assessment during the event was organized. enhanced surveillance for key notifiable diseases was implemented in all stadia and other important locations like the airport. during the games, the ministry of health participated in daily all-hazard assessment with the national organizing committee and developed and shared daily situation reports. the data gathered from the surveillance units at the sports village during the events showed that of the cases reported from the sports sites during the events, trauma accounted for %, followed by malaria at % and respiratory tract infections at %. no significant threat to public health was detected during the event, with a minimum effect on the surge capacity of the public health services. thus, early planning, risk assessment, and preparedness activities as well cross-sectoral collaboration resulted in successful organization of the event amidst the ongoing evd in west africa. no major public health incidents occurred during the three major sporting events. each of the countries enhanced their surveillance and reporting systems. only a few outbreaks of gastrointestinal and respiratory infections and malaria and a few traumatic injuries were recorded during the period, and importantly, no suspected cases of evd or other vhf occurred. while outbreaks of infectious diseases have been reported during events, mostly from faeco-oral, respiratory, and vectorborne transmission, to date there have been no published incidents of a case of vhf presenting at a mass gathering. [ ] [ ] [ ] even though the risk of introduction of a case of evd would in reality be quite low, the high profile of these sporting events and the major negative effect of even one suspected or confirmed case on the games, necessitated special preparations over and above those needed to monitor and manage the more usual communicable disease risks associated with mass gatherings. persons with early or acute evd are less likely to travel and unlikely to take part in a sporting event. exit screening was introduced after the declaration of evd as a pheic, and transmission requires direct contact with blood and body fluids of infected persons. however, evd was spread to a number of countries through travel, persons are asymptomatic during the incubation period, sexual transmission by survivors is now well documented, and certain contact sports may pose a risk, albeit small, for transmission. with specific reference to evd, the challenges are the nonspecific nature of early illness with its broad differential diagnosis, the infrequent finding of haemorrhage, which could raise the index of suspicion of a vhf, the many other infections presenting with bleeding, delays in laboratory exclusion of vhf in the settings of these three events or the confirmation of alternative diseases, the need to ensure that patients receive adequate treatment for common infectious diseases and importantly for a mass gathering scenario, the potential for panic amongst athletes and the local communities, and the risk of potential disruption to the games. there are many additional resources needed to respond to potential vhf cases, some of which are not readily available, and these require additional funding. given the countries of origin of the participants and spectators, a large range of infectious diseases other than evd needed to be considered with respect to the differential diagnosis of acute febrile illness and the provision of laboratory diagnostics and treatment options. training of health workers and resources needed to be provided, given that these were not necessarily common diseases in the host countries. these conditions included trypanosomiasis, meningococcal disease, crimean-congo haemorrhagic fever (cchf), lassa fever, dengue, arboviral infections, and leptospirosis, as well as the more familiar typhoid, malaria, hepatitis (a, b, and e), hiv, sexually transmitted infections, tuberculosis, and gastrointestinal (viral and bacterial) and respiratory infections, including influenza. the annual influenza season in temperate zones in southern africa typically occurs from late may to august. meningococcaemia or meningococcal meningitis was a particular concern, given the increased risks in young people, particularly those in close contact in hostel-type accommodation, the origin of some of the participants from countries within the african meningitis belt, and possible increased carriage rates. the typically very rapid progression to severe illness over a matter of hours, difficulty in recognition because of nonspecific signs and symptoms, particularly with meningococcaemia, high mortality rates, and occurrence of bleeding with confusion with vhf, was particularly concerning in the setting of a mass gathering. overall, for vaccine preventable diseases, such as measles, meningococcal meningitis, pneumococcal sepsis, influenza, mumps, and hepatitis a, pre-travel vaccination for participants is known to reduce disease incidence at mass gatherings. meningococcal disease at the hajj has rarely been recorded since pre-travel vaccination was enforced. for communicable diseases that do not have vaccines available, a high state of public health alert, with public health teams on standby coupled to educating the attendees and local population, can go a long way in improving their prevention and detection. brazil will be hosting the olympics in rio de janeiro in august , with many thousands of people from all over the world travelling to brazil. the unexplained rapid spread of the mosquito-borne zikv across south and central america adds another viral threat (in addition to dengue, japanese encephalitis, and yellow fever) for the attendees of the olympic games, further challenging preparedness and surveillance efforts. south africa successfully hosted two mass gatherings during the influenza a (h n )pdm virus pheic without any major communicable disease incidents. these were the confederation cup in and the fifa soccer world cup in . while epidemics due to vector-borne transmission pose different challenges to ebola virus and influenza, the same principles of enhancing surveillance and response efforts and reducing all possible risks would apply. the experience garnered during these three mass gathering events during the ebola epidemic illustrates that these events can be held safely even during a pheic provided that countries put measures in place for enhanced surveillance for communicable diseases and are well prepared to respond to any incidents. although additional resources and training will be required, the efforts are worthwhile and form part of the legacy of mass gatherings for the detection and response to future cases or outbreaks of formidable diseases. european football championship finals: planning for a health legacy olympic and paralympic games: public health surveillance and epidemiology hajj: infectious disease surveillance and control global perspectives for prevention of infectious diseases associated with mass gatherings communicable diseases as health risks at mass gatherings other than hajj: what is the evidence? emerging infectious diseases and pandemic potential: status quo and reducing risk of global spread emerging respiratory tract viral infections emerging and re-emerging infectious threats in the st century world health organization. ebola virus diseases outbreak rapid spread of zika virus in the americas-implications for public health preparedness for mass gatherings at the brazil olympic games yellow fever cases in asia: primed for an epidemic why is the yellow fever outbreak in angola a 'threat to the entire world'? public health for mass gatherings mass gatherings and public health: the experience of athens olympic games. who/euro ebola virus disease outbreak, end of ebola transmission in guinea and liberia morbidity and mortality of wild animals in relation to outbreaks of ebola haemorrhagic fever in gabon transmissibility and pathogenicity of ebola virus: a systematic review and meta-analysis of household secondary attack rate and asymptomatic infection assessing the impact of travel restrictions on international spread of the west african ebola epidemic potential impact of sexual transmission on ebola virus epidemiology: sierra leone as a case study we thank the public health authorities of botswana, equatorial guinea, and the republic of congo and their respective who representatives.conflict of interest: the authors have no conflict of interest to declare. key: cord- - or vf authors: ayebare, rodgers; waitt, peter; okello, stephen; kayiira, mubaraka; atim ajok, maureen; nakatudde, irene; bhadelia, nahid; lamorde, mohammed title: leveraging investments in ebola preparedness for covid- in sub-saharan africa date: - - journal: aas open res doi: . /aasopenres. . sha: doc_id: cord_uid: or vf the emergence of sars-cov- in china and transmission to more than territories worldwide, including nine countries in africa, presents a delicate situation for low-resource settings. countries in eastern and central africa have been on high alert since mid- in anticipation of regional spread of the ebola virus from the democratic republic of congo. significant investment has been made to support enhanced surveillance at point of entry and hospitals, infection control practices, clinical case management, and clinical research. with a new threat on the horizon, african countries have an opportunity to leverage the existing capacities for ebola preparedness to brace for the imminent threat. a novel coronavirus (sars-cov- ) rapidly emerged in china and has spread internationally. on jan , , it was declared a public health emergency of international concern (pheic) by the world health organization (who) after exceeding , cases and deaths, with countries reporting cases. the declaration was in part justified by the need to strengthen preparedness in countries with weaker health systems . concerns exist about these countries' capacity to prevent, detect and respond to the covid- outbreak. as of the time of writing, more than african countries with in sub-saharan africa have each reported a case of covid- and other countries are at risk of importation of a covid- case from china. weaknesses in public health systems were a prominent driver of the - ebola virus disease (evd) outbreaks in west africa and similar challenges have fuelled the evd outbreak in the democratic republic of the congo (drc), which is ongoing. we, therefore, questioned whether capacities enhanced for evd could be leveraged to sars-cov- , a biologically distinct virus requiring a broader public health response. coordination structures are essential to ensure emergency and contingency plans are in place, operational structures exist with clear communication channels, and adequate resources are available for impending threats. during the west africa evd outbreak, nigeria, transitioned its emergency coordination centres and public health activities for polio eradication to respond to evd . in the current evd outbreak in drc, the who has provided dedicated preparedness support to enhance national capacities for evd in drc and its nine neighbouring countries. currently, seven out of the countries have met their minimum targets for evd coordination . the declaration of a pheic is a timely intervention to enable african countries to mobilize resources domestically and through international sources to operationalise preparedness plans. utilization of existing structures will be critical for the timely organization of preparedness and response efforts. yields from this resource have been key in establishing sars-cov- testing capacity in over countries on the continent within one month of declaration of a pheic through the africa cdc coordination body. risk communication entailing significant community outreach and education on infection prevention and control as part of the evd response has supported improvements in hand hygiene, social distancing, case identification and reporting. similarly, risk communication is needed for covid- ensure standard precautions are enhanced particularly in the context of respiratory hygiene. to date, the risk communication platforms are being utilized to disseminate infection control measures for covid- and to identify public myths about the novel disease condition, so that targeted communication to demystify public confusion and rumours is delivered. in healthcare settings, careful logistics planning is critical to ensure panic buying of face masks and respirators by the general public does not lead to scarcity in health units. stockpiles of personal protective equipment for evd could in the interim, support some needs for covid- but such decisions should only be made after careful assessment of ongoing risk of importation of evd. unfortunately, these same countries must also plan for scenarios with concurrent outbreaks for covid- and evd and test their systems to ensure resilience against resource limitations and workforce fatigue. surveillance efforts deployed for evd in eastern and central africa could be modified to incorporate current case definitions for covid- . consequently, surveillance in health facilities will be critical, including in private facilities frequented by international travellers and intensive care units that may not have been adequately addressed in evd preparedness efforts. already, expensive screening for evd at land borders neighbouring drc could require an extension to all national borders if covid- cases are reported in surrounding countries. in countries with laboratory detection capacity, testing is currently centralised in a few laboratories that meet the necessary biosecurity requirements. while domestic and international efforts are underway to acquire more testing capacity, sample collection and transportation systems enhanced for evd and international referral diagnostic testing could be utilized to inform public health and clinical management strategies. biological differences between ebola virus and sars-cov- in the mode of transmission and case presentation will limit some benefits of evd preparedness. country scenarios must include plans for exponentially larger patient numbers than for evd. while evd requires close contact, covid- is transmitted mainly through droplets, contact with contaminated hands and potentially through aerosol-forming procedures. facility-based isolation capacity is likely to be exceeded during a large outbreak and self-quarantine at home may be needed for milder cases. cohorting severe cases under investigation will be highly dependent on the availability of appropriate hospital beds, laboratory confirmation capacity and a skilled workforce. hospital-based clinical case management teams that have received training in care for critically ill patients are a resource to leverage to bridge the gap for covid- . in uganda, the existence five teams based at five different hospitals, two of which are in the capital, is an example of a scalable baseline human resource capacity. cardinal features of the training such teams have received include infection prevention and control , outbreak investigation, laboratory, clinical case management. optimised supportive clinical care for evd patients has been recently introduced but will be challenging to scale, even if adapted for covid- . respiratory support in dedicated facilities may rapidly become inadequate and consequently, efforts to detect early and contain imported cases are critical. african countries can engage in research for medical countermeasures (vaccines and experimental drugs). the successful conduct of the palm trial (pamoja tulinde maisha) in the ongoing evd outbreak in drc serves as an example that can be used for therapeutic research for covid- . sub-saharan africa also has vast experience working with some of the investigational products being studied in china; ritonavir-boosted lopinavir has been used in sub-saharan africa as antiretroviral therapy for treatment-experienced patients in sub-saharan africa and most recently, remdesivir was used in the palm trial for evd in drc. with results from the covid- trials set to be made available soon, africa has a unique opportunity to rapidly access life-saving investigational therapeutics that are familiar and potentially readily available. although challenges remain, african countries that have been supported for evd preparedness in ongoing and past evd outbreaks have capacities that can be enhanced for the covid- preparedness and response. no data are associated with this article. this concise, well-expressed open letter addresses the highly relevant topic of commonalities in emergency responses for immunization, evd and covid- and their importance to health system strength and resilience. this reviewer notes anecdotal reports of similar pivoting to covid- by coordination systems for emergency responses to polio in papua new guinea. this letter is timely and well presented. coordination: make specific mention of the under polio rapid response and contract tracing functions emergency responses, as applied first to evd and now to covid- ; consider whether new communication channels such as whatsapp group necessitated by travel restrictions, apply as examples in this analysis. consider whether the option of integrated surveillance for vaccine-preventable-disease syndromes (e.g. measles) and for other public health priorities apply to this analysis, noting the likely decline in essential health service coverage will increase vulnerability to other outbreaks. consider including mention of rapid diagnostics and low-cost sample transfer, which may become available and differ for covid- from evd. infection control: given the dynamic nature of covid- evidence, consider review and update of modes of spread. use of "cohorting..." as verb slightly confusing, consider revision -also seems to repeat idea in preceding sentence. minor grammatical error in sentence "in uganda, the existence ...". consider special mention of oxygen (by concentrator or cylinder supply) as an essential medicine, with or without assisted ventilation, as a distinctive need of covid- at all levels of clinical care (see open letter from stoppneumonia.org). overall, noting over views now, congratulate the authors on this submission. https://stoppneumonia.org/open-letter-to-leaders-of-the-global-coronavirus-response-on-access-to-medical-oxygen/ is the rationale for the open letter provided in sufficient detail? yes are all factual statements correct, and are statements and arguments made adequately supported by citations? yes where applicable, are recommendations and next steps explained clearly for others to follow? partly no competing interests were disclosed. reviewer expertise: global immunization, health services delivery in resource-constrained settings, global child public health. botswana institute for development policy analysis (bidpa), gaborone, botswana the letter is written in clear language and a format accessible for decision makers and clinical practitioners. a few comments to make: while the authors duly note the distinct biological characteristics of sars-cov- from evd, the article could benefit from the acknowledgement that researchers worldwide are still learning the effects of covid- on patients, such as organ failure, apart from respiratory problems. it would be interesting what the implications of that would be on the clinical capabilities of african states to emergency committee regarding the outbreak of novel coronavirus ( -ncov) usa many thanks for asking me to review this very valuable open letter that describes how ebola response and preparedness "assets i see that the letter has already been viewed over times, which i believe attests to its value. the letter is short, beautifully written, clear, and concise. there has been much discussion and debate about both the strengths and challenges that countries in sub-saharan africa (ssa) face in preparing for and responding to covid- . interesting what the implications of that would be on the clinical capabilities of african states to address the challenge.sub-saharan african countries often have financial challenges to effectively implement their health policies and other interventions. the authors could look into what fiscal lessons has africa learnt from evd that they could apply to covid- ?the evd, as the authors state, affects largely two blocks of countries -central and west africa. at that scale it would catch the attention of the african union and trigger their response. this could have been brought on to bear on the collective response of the african countries under the auspices of the au or sub-regional groups and the lessons this carries for their response to covid- . this is a must read for all actors in the health sector in sub-saharan africa. the piece is succinct and proposes pragmatic approaches african countries could explore. where applicable, are recommendations and next steps explained clearly for others to follow? yes no competing interests were disclosed. reviewer expertise: public policy, health governance, governance, decentralisation. the letter states that "african countries can engage in research for medical countermeasures (vaccines and experimental drugs)." i think diagnostics should also be included as a mcm. are all factual statements correct, and are statements and arguments made adequately supported by citations? yes yes where applicable, are recommendations and next steps explained clearly for others to follow? partlyno competing interests were disclosed. competing interests:reviewer expertise: global health and public policy i confirm that i have read this submission and believe that i have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. key: cord- -byyx y authors: ryan, jeffrey r. title: seeds of destruction date: - - journal: biosecurity and bioterrorism doi: . /b - - - - . - sha: doc_id: cord_uid: byyx y this chapter provides the reader with an understanding and appreciation for the scope and importance of biological threats and the opportunity to see where they may be and have become the desire of terrorist groups and the makings of weapons of mass destruction. the history of biological warfare is covered in depth. these major events are important in helping us understand the issues related to using biological substances against an adversary. the difference between biosecurity and biodefense are explained and then related to homeland security and homeland defense, respectively. this chapter also details how expensive these programs are, with nearly $ billion having been spent on civilian biodefense since fiscal year in the united states alone. as discussed herein, there is a significant difference in the reality and the potential of bioterrorism. bioterrorism on a large scale is a low-probability event. bioterrorism on a small scale is a fairly routine occurrence with little potential. biological threats remain very much in the news. recent examples, such as laboratory incidents, the ebola outbreak of , and other emerging threats, are covered in this chapter. the dawning of the st century will be characterized as the age of terrorism. terrorism has affected most of us in one way or another. the shocking images of the september , , attacks remind us of just how dramatic and devastating terrorism can be. in most developed countries, the concept of bioterrorism and many of the words associated with it are widely recognized. in the united states, bioterrorism became a household word in october , when bacillus anthracis (the causative agent of anthrax) spores were introduced into the us postal service system by several letters dropped into a mailbox in trenton, new jersey (see fig. . ). these letters resulted in deaths from pulmonary anthrax and other cases of inhalation and cutaneous anthrax (thompson, ) . in the weeks and months that followed, first responders were called to the scene of thousands of "white powder" incidents that came as a result of numerous hoaxes, mysterious powdery substances, and just plain paranoia (beecher, ) . public health laboratories all over the united states were inundated with samples collected from the scene of these incidents. testing of postal facilities, us senate office buildings, and news-gathering organizations' offices occurred. between october and december the centers for disease control and prevention (cdc) laboratories successfully and accurately tested more than , samples, which amounted to more than million separate bioanalytical tests (cdc, ) . henceforth there has been a national sense of urgency in preparedness and response activities for a potential act of bioterrorism. humankind has been faced with biological threats since we first learned to walk upright. in his thought-provoking book guns, germs and steel, dr. jared diamond points out the epidemiological transitions we have faced since we were hunters and gatherers. more than , years ago the human experience with biological peril was mostly parasitic diseases that only affected individuals. after that, human societies began to herd and domesticate animals. the development of agriculture allowed for population growth and a shift from small tribal bands to a concentration of people into villages. larger groups of people could stand up to smaller elements, thereby enabling them to successfully compete for resources and better defend the ground that they held. agriculture also brought some deadly gifts: animal diseases that also affected man (zoonotic diseases), outbreaks of disease due to massing of people and lack of innate immunity, and a growing reliance on animal protein (diamond, ) . for ages human societies and cultures have been looking for a competitive advantage over their adversaries. advances in weapons of all types and explosives allowed military forces to defeat their enemies overtly on the battlefield and covertly behind the lines. technologies leading to nuclear, biological, and chemical weapons have also been exploited. indeed, each has been used legitimately and illegitimately on different scales to bring about a change in the tactics, the military situation, or the political will to face an enemy in battle. biological agents are no exception to this rule. as such, biowarfare (biological warfare) has a historical aspect to it that must be considered here because advances in the use of biological agents over the last century are one of the main reasons why bioterrorism exists today. when president richard m. nixon said, in november , that "mankind already holds in its hands too many of the seeds of its own destruction," he was signing an executive order putting an end to the united states' offensive capabilities for waging biowarfare. it is arguable that this statement foretold the potential doom we might all face when then state-of-the-art technologies became commonplace techniques in laboratories all over the world today. this chapter accordingly derives its name from the preceding quote and should serve to remind the reader that the seeds we sowed so long ago have now sprouted. the question remains: how shall they be reaped? bioterrorism is the intentional use of microorganisms or toxins derived from living organisms to cause death or disease in humans or the animals and plants on which we depend. biosecurity and biodefense programs exist largely because of the potential devastation that could result from a large-scale act of bioterrorism. civilian biodefense funding (cbf) reached an all-time high after the anthrax attacks of . conversely, the reality of the situation is that these well-intended programs cost taxpayers billions of dollars each year. rapid detection biothreat pathogen tools are available to assist responders with on-site identification of a suspicious substance. in addition, biosecurity and biodefense are "big business" in the private sector. security measures to protect agriculture and certain vulnerable industries from acts of bioterrorism and natural biological threats are also in place. detailed reports published in the journal biosecurity and bioterrorism (schuler, ; lam et al., ; sell and watson, ) show that us government cbf between fiscal year (fy) and fy amounted to more than $ billion. comparing fy to fy , there was an increase in cbf from $ million to $ . billion. the departments of health and human services and homeland security, which together account for approximately % of the fy request, have remained relatively constant in their funding. other agencies, most notably the department of agriculture and the environmental protection agency, have been more variable. these two agencies saw increased budget requests in fy , focusing on programs that protect the nation's food and water supplies. civilian biodefense spending, not including special allocations for project bioshield, reached a consistent level of approximately $ billion from fy to fy (sell and watson, ) . refer to table . for a summary of the cbf budget for fy - . bioshield is a program that was designed to give the united states new medical interventions (eg, vaccines, treatments) for diseases caused by several biothreat pathogens. when bioshield was conceived, it cost us taxpayers a total of $ . billion, which was metered out to the department of health and human services over a -year period. reports surfaced that suggest bioshield funds were being squandered and that few useful products were realized (fonda, ) . however, biothreat pathogen research and product development for unusual or rare diseases is fraught with numerous hurdles. this program will be addressed in chapter biosecurity programs and assets. the us postal service spent more than $ million developing and deploying its biohazard detection system (bds). at the peak of its utilization, the us postal service was spending more than $ million each year to operate and maintain the system. the bds is used only to provide early warning for the presence of a single biothreat pathogen, anthrax. furthermore, the system screens letter mail that comes from sources such as mailboxes and drops, which accounts for approximately % of all letter mail volume (schmid, ) . this model program and the technology it uses will be covered extensively in chapter consequence management and a model program. all of this seems rather incredible when comparing the level of funding given to one of the greatest biological threats of our time, the human immunodeficiency virus (hiv), which causes aids. an estimated . million people are currently living with hiv in the united states, with approximately , new infections occurring each (nih, ) compared with the $ . billion level of funding it receives for biodefense (sell and watson, ) . before delving into the subtleties of biosecurity and biodefense, one should explore the historical aspects of the use of biological agents in warfare and terrorism. the history presented here is not all inclusive. rather, it is a fair assessment of key events and characterizations that can be examined in other more comprehensive documents. pathogens and biological toxins have been used as weapons throughout history. some would argue that biological warfare began when medieval armies used festering corpses to contaminate water supplies. over several centuries this evolved into the development of sophisticated biological munitions for battlefield and covert use. these developments parallel advances in microbiology and include the identification of virulent pathogens suitable for aerosol delivery and large-scale fermentation processes to produce large quantities of pathogens and toxins. however, the history of biological warfare is shrouded by several confounding factors. first, it is difficult to verify alleged or attempted biological attacks. these allegations might have been part of a propaganda campaign, or they may have been due to rumor. regardless, some of the examples we have been given cannot be supported by microbiological or epidemiologic data. in addition, the incidence of naturally occurring endemic or epidemic diseases during that time complicates the picture so that attribution is impossible (christopher et al., ) . more important, our awareness that infectious diseases are caused by microbes does not go back very far in human history. germ theory, or the fact that infectious diseases are related to and caused by microorganisms, emerged after through the independent works of pasteur, lister, and koch (tortora et al., ) . therefore how could the attacking or defending commander know that the festering corpses might cause disease when people at that time thought that epidemics were related to "miasmas," the smell of decomposition, or heavenly "influences"? one need only consider the origin of certain disease names to appreciate this confusion. for instance, malaria gets its name from malaria, or "bad air" (ie, swamp gases; desowitz, ) . it was not until that we learned that the etiologic agents of malaria are protozoans in the genus plasmodium. the name influenza refers to the ancient belief that the disease was caused by a misalignment of the stars because of some unknown supernatural or cosmic influence (latin influentia). it was not until that we learned the flu was caused by the influenza virus (potter, ) . regardless of the lack of awareness of germs at the time, a few of the historic reports about the use of biological weapons in battle are worth noting here: • in the th century bc, assyrians poisoned enemy wells with rye ergot, a fungus. • in the th century bc, scythian archers tipped their arrows with blood, manure, and tissues from decomposing bodies. • in ad , attackers hurled dead horses and other animals by catapult at the castle of thun l'eveque in hainault (northern france). castle defenders reported that "the stink and the air were so abominable…they could not long endure" and negotiated a truce. • in ad at karlstein in bohemia, attacking forces launched the decaying cadavers of men killed in battle over the castle walls. they also stockpiled animal manure in the hope of spreading illness. however, the defense held fast, and the siege was abandoned after months. russian troops may have used the same tactic using the corpses of plague victims against the swedes in . • in ad the spanish contaminated french wine with the blood of lepers. • in the mid- s a polish military general reportedly put saliva from rabid dogs into hollow artillery spheres for use against his enemies. • francisco pizarro reportedly gave smallpox virus-contaminated clothing to south american natives in the th century. • in a letter dated july , , general jeffrey amherst, a british officer, approved the plan to spread smallpox to delaware indians (robertson, ) . amherst suggested the deliberate use of smallpox to "reduce" native american tribes hostile to the british (parkman, ). an outbreak of smallpox at fort pitt resulted in the generation of smallpox-contaminated materials and an opportunity to carry out amherst's plan. on june , , one of amherst's subordinates gave blankets and a handkerchief from the smallpox hospital to the native americans and recorded in his journal, "i hope it will have the desired effect" (sipe, ). • the same tactic was used during the civil war by dr. luke blackburn, the future governor of kentucky. dr. blackburn infected clothing with smallpox and yellow fever virus, which he then sold to union troops. one union officer's obituary stated that he died of smallpox contracted from his infected clothing (guillemin, ) . as previously mentioned, scientists discovered microorganisms and made advances toward understanding that a specific agent causes a specific disease, that some are foodborne or waterborne, that an agent can cycle through more than one species, and that insects and ticks are the vectors of disease. furthermore, medical professionals established that wars, famines, and poverty opened populations to the risk of epidemics. once these links were established, we learned that we could apply control and intervention methods. scientific knowledge about disease transmission coupled with social stability and active public health campaigns aided human survival. it subsequently became possible for advanced populations to protect their citizens from the burden of some of the most insidious infectious diseases, such as plague, cholera, diphtheria, smallpox, influenza, and malaria. these epidemics swept across nations in previous centuries, hitting hardest in crowded urban centers and affecting mostly the poor (guillemin, ) . at the opening of the industrial revolution, public health in cities had improved, water and food sources were monitored by the state, and vaccines and drug therapies were being invented as further protection. with many childhood diseases conquered, more people were living longer, and they were now dying of more "civilized" diseases such as cancer, heart disease, and stroke (diamond, ) . in underdeveloped nations, public health did not develop; hence, epidemics were prevalent and continued to be devastating. the dichotomy between developed and developing nations remains marked by generally good health versus widespread, preventable epidemics (guillemin, ) . as western nations were taking advantage of innovations in public health and medicine to mitigate epidemics, their governments invented biological weapons as a means of achieving advantage in warfare (diamond, ) . the german military has the dubious honor of being the first example of using biological weapons following a state-sponsored program. however, during world war i, they used disease-causing organisms against animals, not people. the goal of their program was to interrupt the flow of supplies to the allied frontlines. to do this they targeted the packhorses and mules shipped from norway, spain, romania, and the united states. in , dr. anton dilger, a german-american physician, developed a microbiology facility in washington, dc. dilger produced large quantities of anthrax and glanders bacteria using seed cultures provided by the imperial german government. at the loading docks, german agents inoculated more than animals that were destined for the allied forces in europe (wheelis, ) . from the german perspective, these attacks violated no international law. in addition, these activities were dwarfed by the atrocities of chemical warfare that was being waged on both sides of the line. to counter the german threat and explore the potential of air warfare the french sought to improve their integration of aerosols and bombs. at the same time as the french were signing the geneva protocol, they were developing a biological warfare program to complement the one they had established for chemical weapons during world war i (rosebury and kabat, ) . after world war i the japanese formed a "special weapons" section within their army. the section was designated unit . the unit's leaders set out to exploit chemical and biological agents. in they expanded their territory into manchuria, which made available "an endless supply of human experiment materials" (prisoners of war) for unit . biological weapon experiments in harbin, manchuria, directed by japanese general shiro ishii, continued until . a post-world war ii autopsy investigation of victims revealed that most were exposed to aerosolized anthrax. more than prisoners and chinese nationals may have died in unit facilities. in the japanese military poisoned soviet water sources with intestinal typhoid bacteria at the former mongolian border. during an infamous biowarfare attack in , the japanese military released millions of plague-infected fleas from airplanes over villages in china and manchuria, resulting in several plague outbreaks in those villages. the japanese program had stockpiled kg of anthrax to be used in specially designed fragmentation bombs. in , shortly before the battle of stalingrad, on the german-soviet front, a large outbreak of tularemia occurred. several thousand soviets and germans contracted the illness. some estimate that more than % of the victims had inhalation tularemia, which is rare and considered to be evidence of an intentional release. it was determined later that the soviets had developed a tularemia weapon the prior year (alibek and handelman, ) . during world war ii the allies had great fear of german and japanese biological weapons programs. their fears were sparked by sketchy reports that the japanese had an ongoing effort, and british intelligence suggested that germany might soon target britain with a bomb packed with biological agents. on the basis of these fears, great britain began its own bioweapons program and urged officials in the united states to create a large-scale biological warfare program. on december , , the us government convened a secret meeting at the national academy of sciences in washington, dc. the meeting was called to respond to great britain's request. army officers had urgent questions for an elite group of scientists. only a few months before, the president of the united states had grappled with the issue of biological weapons. president franklin d. roosevelt stated that "i have been loath to believe that any nation, even our present enemies, would be willing to loose upon mankind such terrible and inhumane weapons." secretary of war, general henry stimson, thought differently: "biological warfare is…dirty business," he wrote to roosevelt, "but…i think we must be prepared." president roosevelt approved the launch of the united states' biological warfare program. for the first time us researchers would be trying to make weapons from the deadliest germs known to science. in spring the united states initiated its bioweapons program at camp detrick (now fort detrick), maryland. the program focused primarily on the use of the agents that cause anthrax, botulism, plague, tularemia, q fever, venezuelan equine encephalitis, and brucellosis. production of these agents occurred at camp detrick, maryland, and other sites in arkansas, colorado, and indiana. the british had made two primary requests of us: ( ) to mass produce anthrax spores so that they could be placed in bomblets and stored for later deployment against the germans in retaliation for any future strike and ( ) the british supplied us with the recipe to make botulinum toxin and wanted to see if we could mass produce it. naturally the entire program was wrapped in a cloak of secrecy. fig. . is a collage of some important facilities built at camp detrick to produce and test bioweapons formulations. the british program focused on the use of b. anthracis (anthrax) spores and their viability and dissemination when delivered with a conventional bomb. gruinard island, off of the coast of scotland, was used as the testing site for formulations. at the time british scientists believed that the testing site was far enough from the coast to not cause any contamination of the mainland. however, in there was an outbreak of anthrax in sheep and cattle on the coast of scotland that faced gruinard. as a result, the british decided to stop the anthrax testing and close down the island site. despite the cessation of experiments, the island remained contaminated for decades until a deliberate and extensive decontamination program rendered the island inhabitable again. the us bioweapons program continued to grow in scope and sophistication. much of this was prompted by fear of a new enemy: the threat of communism, the soviet union, and its allies. experiments to test bioweapons formulations were routinely performed on a small scale with research animals. however, more comprehensive field and laboratory studies were performed with human research volunteers exposed to actual live agents and some situational scenarios using surrogate nonpathogenic bacteria to simulate the release of actual pathogens inside of buildings or aimed at cities. in researchers from detrick visited the pentagon on a secret mission. disguised as maintenance workers, they released noninfectious bacteria into the duct work of the building to assess the vulnerability of people inside large buildings to a bioweapons attack. the pentagon trial was considered to be a success because it revealed that germs could be formulated and released effectively for a small-scale act of sabotage. however, there was considerable doubt that biological weapons could be effective against a target the size of a city. accordingly, several tests were conducted on american cities (miller et al., ) . in the us army admitted that there were intentional releases of noninfectious bacteria in bioweapons experiments (cole, ) . one such trial took place in san francisco in september , when a us navy ship sailed a course adjacent to the golden gate bridge to release a plume of seemingly nonpathogenic bacteria (serratia marcescens). this trial was intended to simulate the dispersion of anthrax spores on a large city. on the basis of results from monitoring equipment at locations around the city, the army determined that san francisco had received enough of a dose for nearly all of the city's , residents to inhale at least of the particles. although the researchers believed that what they were releasing was harmless, one report shows that people reported to area hospitals with severe infections because of the release of this agent, of which was fatal (cole, ) . three years later, bioweapons experts took their secret exercises to st. louis and minneapolis, two cities that resembled potential soviet targets, where sprayers hidden in cars dispersed invisible clouds of harmless bacillus spores. in nonpathogenic bacillus globigii spores were released into the new york subway system using a broken light bulb to demonstrate the ability of a specific formulation to make its way from a central point source to both ends of the system in less than an hour. revelations of these experiments became known in when a senate subcommittee panel heard testimony from pentagon officials (us department of the army, dtic b l, ) . until that point, neither us citizens nor their representatives in washington knew anything about the american germ program. after nearly decades of secret research aimed at producing the ultimate biological weapons and stockpiling them for use against our enemies, president richard nixon surprised the world by signing an executive order that stopped all offensive biological agent and toxin weapon research and ordered all stockpiles of biological agents and munitions from the us program be destroyed. accordingly, on november , , he uttered these historic words in a speech to the nation on …biological warfare-which is commonly called "germ warfare. " this has massive unpredictable and potentially uncontrollable consequences. it may produce global epidemics and profoundly affect the health of future generations. therefore, i have decided that the united states of america will renounce the use of any form of deadly biological weapons that either kill or incapacitate. mankind already carries in its own hands too many of the seeds of its own destruction. subsequently, in the united states and many other countries were signatories to the convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction, commonly called the biological weapons convention. this treaty prohibits the stockpiling of biological agents for offensive military purposes and forbids research into offensive use of biological agents. although the former soviet union was a signatory to the biological weapons convention, its development of biological weapons intensified dramatically after the accord and continued well into the s. in late april , an outbreak of pulmonary anthrax occurred in sverdlovsk (now yekaterinburg) in the former soviet union. soviet officials explained that the outbreak was due to ingestion of infected meat. however, it was later discovered that the cause was from an accidental release of anthrax in aerosol form from the soviet military compound , a soviet bioweapons facility. (this event is examined thoroughly in chapter case studies as a case study to demonstrate the potential of weaponized anthrax.) the robust bioweapons program of the soviet union employed more than , people. building at koltsovo was capable of manufacturing tons of smallpox virus each year. in kirov, the soviets maintained an arsenal of tons of weaponized plague bacterium. by soviet anthrax production capacity reached nearly tons a year. in the later part of the s the russians disassembled their awesome bioweapons production capacity and reportedly destroyed their stocks. as the soviet union dissolved, it appeared that the threat of biowarfare would diminish. however, the age of bioterrorism emerged with the anthrax attacks of . in addition, the us department of state published a report in that affirmed that six countries had active bioweapons programs. table . summarizes some of these events. biodefense programs and initiatives come out of a sense of vulnerability to biowarfare potentials. bioterrorism is deeply founded in what has been gained from active biowarfare programs (miller et al., ) . in the early s the leftist terrorist group, the weather underground, reportedly attempted to blackmail an army officer at fort detrick working in the research institute of infectious diseases (usamriid). the group's goal was to get him to supply organisms that would be used to contaminate municipal water supplies in the united states. the plot was discovered when the officer attempted to acquire several items that were "unrelated to his work." several other attempts are worth mentioning here: • in members of the right-wing group order of the rising sun were found in possession of - kg of typhoid bacteria cultures that were allegedly to be used to contaminate the water supplies of several midwestern cities. anton dilger produces anthrax and glanders bacterium to infect horses intended for the warfront. notable and documented use of bacteria against animals. june , delegates in switzerland create a geneva protocol banning the use of chemical and bacteriological methods of warfare. first international effort to limit use of biologicals in warfare. the japanese army gives general ishii control of three biological research centers, including one in manchuria. most despicable character in bioweapons history gets his start. great britain begins taking steps toward establishing its own biological weapons research project. allies start to develop a program. july nixon announces that the united states will renounce the use of any form of deadly biological weapons that either kill or incapacitate. the end of an era in us offensive biological weapons research, production, and storage. april , the biological weapons convention, which bans all bioweapons, is completed and opened for signature. seventy-nine nations signed the treaty, including the soviet union. march , the biological weapons convention officially goes into force; the us senate also finally ratifies the geneva protocol. political will to ban biological weapons on the international front. april nearly people die from an accidental release of anthrax spores in the soviet city of sverdlovsk. the united states suspects that anthrax bacterial spores were accidentally released from a soviet military biological facility. the rajneeshees contaminate food with salmonella bacterium in a small town in oregon to influence local elections. these small-scale incidents keep us mindful that some biological agents are easy to acquire and utilize in crimes and small-scale acts of terrorism. salmonella bacteria in a small town in oregon. it was the largest scale act of bioterrorism in us history. more than cases of salmonellosis resulted from the salad bar contamination. it was later discovered that the rajneeshees wanted to influence the local county elections. cult members obtained the salmonella strain through the mail from american type culture collection and propagated the liquid cultures in their compound's medical clinic. • in a home laboratory producing botulinum toxin was discovered in paris. this laboratory was linked to a cell of the german-based bäder meinhof gang. • in minnesota, four members of the patriots council, an antigovernment extremist group, were arrested in for plotting to kill a us marshal with ricin. the group planned to mix the homemade ricin with a chemical that speeds absorption (dimethylsulfoxide) and then smear it on the door handles of the marshal's car. the plan was discovered and all four men were arrested and the first to be prosecuted under the us biological weapons anti-terrorism act of . • in aum shinrikyo, a japanese doomsday cult, became infamous for an act of chemical terrorism when members released sarin gas into the tokyo subway. what many people do not know about the group is that it developed and attempted to use biological agents (anthrax, q fever, ebola virus, and botulinum toxin) on at least other occasions. despite several releases, it was unsuccessful in its use of biologicals. this program is examined more thoroughly in chapter case studies. • several small-scale incidents involving the biological poison ricin (refer to fig. . mississippi man was convicted of crimes related to these incidents and sentenced to years in prison. • in a philadelphia man sent a romantic rival a scratch-and-sniff birthday card laced with ricin. in he was convicted on several charges related to the incident and subsequently received a sentence of - years in prison. on june , , president george w. bush uttered these remarks from the white house at the signing of hr , the public health security and bioterrorism response act of : bioterrorism is a real threat to our country. it' s a threat to every nation that loves freedom. terrorist groups seek biological weapons; we know some rogue states already have them…it' s important that we confront these real threats to our country and prepare for future emergencies. it is clear that september and the anthrax attacks of sent the country to war and sparked several initiatives against all forms of terrorism. biological agents have some unique characteristics that make weaponizing them attractive to the would-be terrorist. most biological weapons are made up of living microorganisms, which means that they can replicate once disseminated. this possibility amplifies the problem and the effect of the weapon in several ways. first, some agents are capable of surviving in various different hosts. the target might be humans, but the disease may manifest in other animal hosts, such as companion animals (pets). in doing so, the problem may be more difficult to control. second, when people become infected with a disease-causing organism, there is an incubation period before signs of illness are apparent. during this incubation period and the periods of illness and recovery, the pathogen may be shed from the victim, causing the contagion to spread (a possibility only with diseases that are transmitted from person to person). there is no rule of thumb for how many people might be infected from a single patient. however, the nature of contagion clearly compounds the problem well beyond the initial release of the agent. in this instance the initial victims from the intentional outbreak become more weapons for the perpetrator, spreading the problem with every step they take. as grigg et al. ( ) stated so precisely in their paper, "when the threat comes from the infected population, selfdefense becomes self-mutilation." the would-be terrorist could surely derive great pleasure from watching government officials and responders tread on the civil liberties of such victims as they attempt to limit the problem from spreading among the population. making an effective biological weapon is no easy undertaking. the process and complexity depends largely on the pathogen selected to be "weaponized." if the pathogen is a spore-forming bacteria, such as b. anthracis (the causative agent of anthrax), there are five essential steps: germination, vegetation, sporulation, separation, and weaponization. the first three steps are designed to get small quantities of seed stock to propagate into a starter culture, grow them to a significant stage of growth in the proper volume, and turn those active cells into spores. the goal of the last two steps is to separate the spores from the dead vegetative cells and spent media. all five steps have dozens of secondary steps. in addition, each of the five steps requires a fairly sophisticated and well-equipped laboratory if the goal is to develop a sizable quantity of refined materials. weaponization is a term that applies to the processes necessary to purify, properly size, stabilize, and make biological agents ideally suited for dissemination. stabilization and dissemination are important issues because of the susceptibility of the biological agents to environmental degradation, not only in storage but also in application. these issues are problems whether the end use is for biological weapons, pharmaceuticals, cosmetics, pesticides, or food-related purposes. the susceptibility of the organisms to inactivation by the environment varies with the agent. as an example, anthrax spores released into the environment may remain viable for decades, whereas plague bacterium may survive for only a few hours. loss of viability or bioactivity is likely to result from exposure to physical and chemical stressors, such as exposure to ultraviolet radiation (sunlight), high surface area at air-water interfaces (frothing), extreme temperature or pressure, high salt concentration, dilution, or exposure to specific inactivating agents. this requirement of stabilization also extends to the methods of delivery because the organisms are very susceptible to degradation in the environments associated with delivery systems. the primary means of stabilization for storage or packaging are concentration; freeze drying (lyophilization); spray drying; formulation into a stabilizing solid, liquid, or gaseous solution; and deep freezing. methods of concentration include vacuum filtration, ultrafiltration, precipitation, and centrifugation. freeze drying is the preferred method for long-term storage of bacterial cultures because freeze-dried cultures can be easily dehydrated and cultured via conventional means. freeze-dried cultures may remain viable for more than years. deep freezing of biological products is another long-term storage technique for species and materials not amenable to freeze drying. the method involves storage of the contained products in liquid nitrogen freezers (− °c/− °f) or ultralow-temperature mechanical freezers (− °c/− °f). culturing viruses is a more costly and tenuous process because host cells are required for viral propagation. this means that cultures of host cells must be kept alive, often in an oxygen-deficient and temperature-stable atmosphere. in some cases, viruses may be more fragile when deployed as weapons, some becoming inactive on drying. biological toxins can be difficult to produce and purify, each requiring its own special set of circumstances. two specific examples are covered in subsequent chapters when those agents are discussed in detail. however, past bioweapons programs have determined that these agents are most effective when prepared as a freeze-dried powder and encapsulated. biological attacks by a terrorist group are apparently not easy to conduct or a practical option. if they were easy or practical, then many terrorist groups and hostile states would have done so long ago and frequently. our experience today with acts of biological terrorism has to do mainly with small-scale, limited attacks. however, if one were to acquire the means to produce the weapons, as described here, or purchase viable, sophisticated materials on the black market, a small group of persons could bring about the infection of a large percentage of targeted persons. clinical illness could develop within a day of dispersal and last for as long as - weeks. in a civil situation, major subway systems in a densely populated urban area could be targeted for a biological agent strike, resulting in massive political and social disorganization. it would take little weaponized material to bring about the desired effect. looking at this potential comparatively on a weight-toweight basis, approximately g of b. anthracis (anthrax) spores could kill as many people as a ton of the nerve agent sarin. with bioweapons in hand, small countries or terrorist groups might develop the capability to deliver small quantities of agents to a specific target. under appropriate weather conditions and with an aerosol generator delivering -to -μm particle-sized droplets, a single aircraft could disperse kg ( lb) of anthrax over a -km area ( , acres) and theoretically cause million deaths in a population density of , people/km (us dod, ada , ). much has been made of the potential of aerosolized powders and respiratory droplets in factual and fictitious biothreat scenarios. the largest infectious disease outbreak in the history of the united states occurred in april . the event was caused by an accidental waterborne contamination. the outbreak of cryptosporidiosis, which occurred in the greater milwaukee area, was estimated to have caused more than , people to become ill with gastroenteritis among a population of . million (mackenzie et al., ) . approximately people were hospitalized and about people died as a result of the outbreak. the milwaukee outbreak was attributed to failure of filtration processes at one of the two water treatment plants that served the city. several deficiencies were found at the plant, including problems relating to a change in the type of water treatment chemicals used for coagulation of contaminants before the filtration step. weather conditions at the time were unusual, with a heavy spring snowmelt leading to high source water turbidity and wind patterns that may have changed normal flow patterns in lake michigan, the raw water source for the city. describe the fundamental difference between biodefense and biosecurity. the secrecy of bioweapons programs of the previous century has been uncloaked. some of the most insidious disease agents ever to afflict humans, animals, and plants have been mass produced and perfected for maximum effectiveness. terrorist groups and rogue states may be seeking to develop bioweapons capabilities. these significant developments in bioweapons gave military leaders and politicians cause for great concern over the past few decades. the military necessity to protect the force and defend the homeland is the goal of a good biodefense program. simply put, biodefense is the need for improved national defenses against biological attacks. these are national programs, mostly planned and carried out by military forces and other government agencies. initially, biodefense programs require an intelligence-gathering capability that strives to determine what may be in the biological weapons arsenal of an aggressor. intelligence is needed to guide biodefense research and development efforts aimed at producing and testing effective countermeasures (ie, vaccines, therapeutic drugs, and detection methods). in addition, a real-time reporting system should be developed so that officials can be informed about an emerging threat before an agent has a chance to affect armed forces and millions of people in the homeland. the development of integrated systems for detecting and monitoring biological agents is instrumental to this goal. although most biodefense initiatives rest with the military, civilian government agencies contribute greatly to the biodefense posture. this is evident by the increases in cbf over the past few years and will be discussed in great detail in part iv of this book. on the other hand, biosecurity refers to the policies and measures taken for protecting a nation's food supply and agricultural resources from accidental contamination and deliberate attacks of bioterrorism. as i sit here today writing the second edition of this book, i am reflecting on the most recent concerns that we have for biological threats in modern society. for what it is worth, we seem to be much less concerned about acts of bioterrorism and/or biowarfare than we were - years ago. instead i see a great deal of concern, and rightfully so, for emerging infectious diseases and reemerging biological threats. we are also keenly aware of the accidental release of biological agents from research and reference laboratories. to illustrate these points we will briefly discuss four items of international interest that have been emphasized in the media: accidental shipment of live anthrax-positive controls samples, the / ebola outbreak in west africa, cases of middle east respiratory syndrome coronavirus (mers-cov) in south korea and saudi arabia, and a massive outbreak of highly pathogenic avian influenza (hpai). as previously mentioned, concerns for biological threat led to a wellspring of funding (nearly $ billion in years) for civilian biodefense programs in the united states. with all of this money the united states was able to build tremendous capabilities to detect and diagnose the agents and the diseases, respectively. with this money a few medical countermeasures (vaccines and treatments) were developed and produced. centers of excellence were funded and highly secure containment (biosafety level ) laboratories were built. with these new programs, testing modalities, and laboratories came the need to provide a ready supply of positive control agents and contracting opportunities for private biotechnology firms. as one very recent example, the us army laboratory in dugway proving grounds, utah, provided positive control samples of anthrax (b. anthracis) spores to public and private laboratories. before shipment, the spores had been propagated in the army laboratory and were exposed to gamma radiation to ensure no living spores were in the vials being provided. upon receipt of the samples, one laboratory in maryland questioned the integrity of the contents of the vial they received because there was no "death certificate" accompanying the samples. out of an abundance of caution they removed a small portion of the vial and streaked it onto sheep blood agar plates. to their amazement, several days later the plates showed growth and tested positive for anthrax. they immediately notified the cdc and the army. the cdc initiated an investigation and notified the media of the incident. the investigation showed that the living anthrax samples had been shipped to laboratories in us states and other countries (usa today, ) . once again the seeds of our destruction are sprouting, and some are of the opinion that we are our own worst enemy. more than laboratory incidents involving potential bioterror germs were reported to federal regulators during through . ebola virus was first discovered in in the sudan and zaire. ebola virus exists naturally in fruit bats, with sylvatic transmission to other mammals and sometimes humans when they consume raw or undercooked meat from an infected animal. infection with ebola virus in humans leads to severe viral hemorrhagic fever (vhf), which is often fatal (cdc, ) . in march an outbreak of ebola virus disease (evd) began in guinea, a western african nation. public health agencies at all levels failed to react quickly to the outbreak and it quickly spread to urban areas in liberia and sierra leone. subsequently, evd spread to nigeria and senegal. international air travel brought evd to the united states and europe, although the number of cases was very small and the threat was stamped out with ample infection control procedures in health-care facilities and aggressive public health measures for those exposed to actual case patients (cdc, ) . this is the largest outbreak of evd in history. at the time of this writing, the outbreak has been quelled by a "better late than never" effort. volunteers and medical relief groups from the united states and other countries received special training and deployed to west africa to help identify cases and treat the victims (see fig. . ) . however, new cases continue to be reported from guinea and sierra leone. as of june , , there have been , evd cases (suspect, probable, and confirmed) worldwide with approximately deaths; this equates to a % mortality rate (who, a) . to most the threat of ebola virus remains distant and out of mind. however, the stark reality is that international travel can interject evd into any populace on any continent within a matter of days. no country, person, or organization is immune to this threat. what makes evd such a great concern? first, ebola virus is a us health and human services category a agent. it meets all of the criteria for such a designation. evd results in high morbidity and mortality. evd requires special preparedness measures for public health and health care. evd is spread from person to person. evd can lead to panic and social disruption (cdc, ) . with this outbreak in particular, we are seeing all four criteria fulfilled. to make things worse, there is no food and drug administration (fda)-approved vaccine for humans and no fda-approved drug for treating vhf case patients. in a health-care setting, evd patients receive supportive care (hydration therapy) and rarely experimental drugs (cdc, ) . perhaps the only good thing to come from this outbreak is the development of a vaccine for ebola virus. there are currently three vaccine candidates undergoing phase iii clinical trials in west africa (who, b) . a case study on this outbreak is offered in chapter case studies of this book. how have international and national attitudes toward the biological threat changed since the early post- / era? include some discussion about the reality of versus the potential for biological threats. mers-cov (see fig. . ) was recognized by the world health organization (who) as a newly emerging pathogen in (berry et al., ) . the initial case where virus isolation and characterization came from occurred in jeddah, saudi arabia. subsequent infections were reported in middle eastern countries (jordan, qatar, and the united arab emirates), with a few cases also identified in europe, north africa, and the united states. mers-cov leads to severe respiratory illness in susceptible patients and is spread through person-to-person contact. ( ). the program had been designed to educate participants who would be deployed as members of the west african ebola response team as to the proper protocols to be followed when treating evd patients. the two participants were displaying the personal protective equipment worn by treatment specialists who would be interacting with evd patients. courtesy of the cdc/nahid bhadelia, md. south korea has recently been the epicenter of the largest outbreak of mers-cov outside of the middle east, reporting cases and deaths (who, c). the outbreak in south korea was traced to a single infected traveler. once again, this demonstrates the vulnerability to unexpected outbreaks of unusual diseases that all countries share in this highly mobile world. a report from a joint who-south korean investigation of this outbreak identified several reasons for the severity of the outbreak in south korea. these include a lack of awareness among health-care workers and the general public about mers-cov, the practice of "doctor shopping" (seeking care at multiple hospitals), people visiting infected patients in multibed hospital rooms, substandard infection control and prevention measures in health-care facilities, and contact of infected mers-cov patients in crowded emergency rooms. nearly all of the country's confirmed mers-cov patients were infected while seeking care or visiting hospital patients (boston globe, ) . more about mers-cov and other emerging pathogens is in chapter category c diseases and agents. hpai has been very much in the news since when the novel strain h n jumped from domestic bird populations (poultry) to humans in south east asia (ryan, ) . h n was very much feared by public health and government officials for its pandemic potential. since there have only been approximately cases of h n infection in humans, with a mortality rate of approximately % (hhs, ) . since that time, numerous other novel strains have emerged. in fact, a novel h n arose out of swine in and was the cause of a mild pandemic in humans. more recently, the novel strains h n and h n have been found to be the cause of major morbidity and mortality in poultry operations (chicken and turkey) in the united states, with detections affecting more than million birds (usda, ) . refer to fig. . for a graphic representation of this outbreak. the financial impact on the poultry growers and the egg and meat industry has been enormous. more can be found on this topic in chapter recent animal disease outbreaks and lessons learned. from this first chapter we can now understand and appreciate the scope and importance of biological threats and see where they may be and have become the desire of terrorist groups and the makings of weapons of mass destruction. biowarfare has a history. the major events are important in helping us understand the issues related to using biological substances against an adversary. we now know the difference between biosecurity and biodefense and can relate them to homeland security and homeland defense, respectively. we also know how expensive these programs are because nearly $ billion has been spent on civilian biodefense since fy in the united states alone. as discussed herein, there is a significant difference in the reality and the potential of bioterrorism. bioterrorism on a large scale is a low-probability event. bioterrorism and biocrimes on a small scale (eg, small amount of ricin directed at one or a few individuals) are fairly routine occurrences with little potential. biological threats remain very much in the news. recent examples, such as laboratory incidents, the ebola outbreak of / , the outbreak of mers-cov in south korea, and the hpai outbreak affecting poultry in the united states, make us aware that we must remain vigilant and utilize the biosecurity and biodefense programs to help us identify and respond to these accidental exposures and emerging threats. • biodefense. the collective efforts of a nation aimed at improving defenses against biological attacks. within these efforts are programs and agencies working toward increasing data collection, analysis, and intelligence gathering. the intelligence is applied to programs aimed at mitigating the effects of bioweapons by developing vaccines, therapeutics, and detection methods to increase the defensive posture. ultimately, biodefense initiatives protect the military forces and the citizens from the effects of biological attack. • biosecurity. the policies and measures taken for protecting a nation's food supply and agricultural resources from accidental contamination and deliberate attacks of bioterrorism. • bioterrorism. the intentional use of microorganisms or toxins derived from living organisms to cause death or disease in humans or the animals and plants on which we depend. bioterrorism might include such deliberate acts as introducing pests intended to kill us food crops; spreading a virulent disease among animal production facilities; and poisoning water, food, and blood supplies. • biowarfare, also known as germ warfare. the use of any organism (bacteria, virus, or other disease-causing organism) or toxin found in nature as a weapon of war. it is meant to incapacitate or kill an adversary. • pathogen. a specific causative agent of disease, mostly thought of as being an infectious organism (eg, bacteria, virus, rickettsia, protozoa). • weaponization. when applied to biologicals, the term implies a process of taking something natural and making it harmful through enhancing the negative characteristics of it. with biological agents, one might weaponize the agent by making more lethal, more stable, and more easily delivered or disseminated against an intended target. there is considerable debate about the use of this term. • zoonotic disease. an animal disease that may be transmitted to humans. • how was the decision made to begin the us biological weapons program? • what are the significant events in the history of biowarfare? what makes them significant? • when president nixon said that "mankind already holds in its hands too many of the seeds of its own destruction" in november , what did he mean by that? • weaponizing a biological agent is easy to do, right? • no one knows exactly who perpetrated the anthrax attacks of , and there has been no repeat of them since. why do you think we have seen no repeat of the anthrax attacks since ? the center for arms control and nonproliferation has an online course in biosecurity. type the url that follows into your internet browser and click on view course and select unit : "the history of biological weapons." the six sections in this unit provide an excellent overview and reinforce the material presented in the subheading about the history of biowarfare: www.armscontrolcenter.org/resources/biosecurity_course. the cdc's emergency and preparedness website offers a segmented video short lesson on the history of bioterrorism. the seven sections give a general overview on bioterrorism and separate vignettes on anthrax, plague, tularemia, vhfs, smallpox, and botulism: www.bt.cdc.gov/training/historyofbt. biohazard: the chilling true story of the largest covert biological weapons program in the world-told from the inside by the man who ran it. random house forensic application of microbiological culture analysis to identify mail intentionally contaminated with bacillus anthracis spores identification of new respiratory viruses in the new millennium. viruses south korea faulted on mers response biological warfare: a historical perspective clouds of secrecy. the army's germ warfare tests over populated areas the malaria capers: more tales of parasites and people, research, and reality guns, germs and steel: the fates of human societies medical aspects of chemical and biological warfare: a textbook in military medicine inside the spore wars. controversial contracts, bureaucratic bungling-the fed's biodefense drug program is a mess. how did it go so wrong? time the biological disaster challenge: why we are least prepared for the most devastating threat and what we need to do about it scientists and the history of biological weapons. a brief historical overview of the development of biological weapons in the twentieth century billions for biodefense: federal agency biodefense funding, fy -fy a massive outbreak in milwaukee of cryptosporidium infection transmitted through the public water supply germs: biological weapons and america's secret war the conspiracy of pontiac and the indian war after the conquest of canada a history of influenza rotting face: smallpox and the american indian pandemic influenza: emergency planning and community preparedness postal testing increasing five years after anthrax deaths billions for biodefense: federal agency biodefense budgeting, fy -fy federal agency biodefense funding, fy -fy the indian wars of pennsylvania killer strain: anthrax and a government exposed microbiology. an introduction ebola virus disease update on avian influenza findings the militarily critical technologies list part ii: weapons of mass destruction technologies h n avian flu (h n bird flu). available at hundreds of bioterror lab mishaps cloaked in secrecy army lab lacked effective anthrax-killing procedures for years biological and toxin weapons: research, development and use from the middle ages to world health organization ebola vaccines, therapies and diagnostics middle east respiratory syndrome coronavirus (mers-cov) -republic of korea key: cord- -hqnem zs authors: ji, ying-jie; duan, xue-zhang; gao, xu-dong; li, lei; li, chen; ji, dong; li, wen-gang; wang, li-fu; meng, yu-hua; yang, xiao; ling, bin-fang; song, xue-ai; gu, mei-lei; jiang, tao; koroma, she-ku m.; bangalie, james; duan, hui-juan title: clinical presentations and outcomes of patients with ebola virus disease in freetown, sierra leone date: - - journal: infect dis poverty doi: . /s - - - sha: doc_id: cord_uid: hqnem zs background: clinical and laboratory data were collected and analysed from patients with ebola virus disease (evd) in jui government hospital in freetown, sierra leone, where patients with evd were received and/or treated from october , to march , during the west africa evd outbreak. methods: the study admitted patients with confirmed evd and followed them up till the endpoint (recovery or death). evd was confirmed by quantitative rt-pcr assays detecting blood ebola virus (ebov). results: among the lab-confirmed evd cases in jui government hospital, recovered and died, with an overall survival rate of . %. patients under the age of years had a lower survival rate ( . %). most non-survivors ( . %) died within days after admission and the mean hospitalization time for non-survivors was . ± . days. more than half survivors ( . %) turned blood ebov negative within weeks after admission and the mean hospitalization time for survivors was . ± . days. high blood viral load (≥ ( ) copies/ml) was found to be predictive of the non-survival outcome as indicated by the receiver operating characteristic (roc) curve analysis. the probability of patients’ survival was less than % when blood viral load was greater than ( ) copies/ml. multivariate analyses showed that blood viral load (p = . ), confusion (p = . ), abdominal pain (p = . ), conjunctivitis (p = . ), and vomiting (p = . ) were factors independently associated with the outcomes of evd patients. conclusions: most death occurred within week after admission, and patients at the age of or younger had a lower survival rate. most surviving patients turned blood ebov negative within – weeks after admission. factors such as high blood viral load, confusion, abdominal pain, vomiting and conjunctivitis were associated with poor prognosis for evd patients. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. please see additional file for translations of the abstract into the six official working languages of the united nations. ebola virus disease (evd), previously known as ebola haemorrhagic fever, is a rare and deadly disease caused by infection with one of the ebola virus strains. a large-scale outbreak of haemorrhagic fever occurred in southern sudan between june and november . it was transmitted by close personal contact and by use of contaminated needles and syringes in hospitals/clinics [ ] . this outbreak led to the further recognition of the disease, which was subsequently named ebola haemorrhagic fever. since then, outbreaks have occurred sporadically in africa. a evd outbreak was the largest in scale in history, affecting multiple countries in west africa. in the outbreak, the first lab-confirmed evd patient was reported in may, in guinea and since then the zaire ebola virus (zebov) has rapidly spread across sierra leone and to other west africa countries. from march to december , ,there were reported evd infections (including confirmed, probable, and suspected) and reported deaths in west africa. a total of confirmed infections and deaths of health care workers were reported in guinea, liberia, and sierra leone [ ] . as of december , , the sierra leone national ebola response center (nerc) reported a cumulative total of confirmed evd cases with deaths (excluding probable and suspected cases) [ ] . situated on the atlantic coast, freetown is the capital and the largest city of sierra leone, and is densely populated with over million people. due to the heavy population, freetown and its surrounding western region was the most affected area in this epidemic. as of december , , confirmed cases had been reported in this region, accounting for . % of the country's total evd reported cases [ ] . evd imposed a significant economic burden on the west african countries affected. some studies suggest that due to evd deaths, life expectancy may have declined in liberia and sierra leone to a new low since - [ ] . this dramatic healthcare crisis, coupled with human rights and global security concerns, underscored the urgent need for developing resilient healthcare systems, and called for the domestic and international aides and investments in these african countries [ ] . the clinicians of the chinese medical team (cmt) managed evd patients in an ebola holding and treatment center in jui government hospital, which is also known as sierra leone-china friendship hospital. being one of the best hospitals in freetown, jui government hospital received suspected evd patients during the period of october , and march , , of whom were confirmed infected with the virus. all of the cmt clinicians were from beijing hospital, the largest specialized hospital in china for infectious disease treatment. the same hospital had successfully managed and controlled the outbreak of severe acute respiratory syndrome (sars), a/h n influenza, and some other public health emergencies in china. in this study, we described the clinical presentations, clinical courses, and the treatment outcomes of all evd patients admitted in jui government hospital for care. we hope this paper provide further understanding and insights into pathophysiology, clinical manifestations and treatment impact of end outcomes of evd. a retrospective, observational study was conducted using data collected from all patients with confirmed evd who were admitted to the holding and treatment center of jui government hospital from october , to march , . diagnosis of evd was made in accordance with the criteria set by the world health organization (who) in the standard operating procedures (sop) for managing evd. because jui government hospital was designated as an ebola holding center (ehc) on october , , but was not approved as an ebola treatment center (etc) until january , , confirmed evd patients received at this hospital between october , and january , were immediately transferred to other treatment centres once confirmed. after january , , all confirmed patients except pregnant women were treated in jui government hospital; the confirmed evd patients who were pregnant women were transferred to a designated etc (p.t.s. ebola treatment center). we carried out follow-up studies and data collections from all confirmed patients (both the patients treated in jui government hospital and those transferred to other hospitals) before we finished our mission in march . data collected included observations such as the duration of hospitalization, the date when blood ebov turned negative, and the endpoint (recovery or death). the determination of recovery was based on the clinical presentations and the interpretation of laboratory findings. discharge from hospitalization was considered when the following criteria were met: ) three or more days without fever or any other significant symptom, ) significant improvement in clinical presentations, ) a relatively good general condition, and ) a negative pcr result for blood ebov on the third day of being asymptomatic. if a patient continued to suffer symptoms or their condition was not improving, but it was suspected to be unrelated to evd, then two blood ebov tests were carried out h apart, with at least one test being done days or more after the onset of symptoms. if both test results were negative, patients were discharged or referred to a normal hospital for further care. the study protocol adhered to the declaration of helsinki, and the ethical clearance was obtained from military hospital medical ethics committee and the sierra leone ethics and scientific review committee, respectively. the patients were routinely evaluated for clinical presentations. data collected included vital signs at admission, medical history, time points when blood ebov turned negative, durations of hospital stay, and outcome. within h upon admission, ebov detection assays were carried out via quantitative rt-pcr using whole blood samples. if the patient died quickly and the blood samples were not collected due to time constraints or poor venous access after death, ebov detection was carried out using oral swab samples from corpses. samples were collected at : o'clock every day and results were generated within h. samples were obtained using jui government hospital's collection and processing protocols, which was described in the emergencyresponse guidelines established by the sierra leone ministry of health and sanitation. diagnosis testing for ebov was performed by china cdc mobile laboratory. total rna was extracted from patient peripheral blood samples or swab samples in bio-safety level (bsl- ) facilities. ebola viral rna was then detected using detection kit for ebola virus subtype zaire rna (puruikang biotech co. ltd, with pcr fluorescence probing) according to the manufacturer's recommendations [ ] . for quantification purposes, the amplicon concentrations were converted to copies of ebov per milliliter (method provided by china cdc mobile laboratory). the care protocols for confirmed ebola cases before and after june , were similar and were in accordance with the sop of who and the ministry of health of sierra leone. the treatment protocol was as follows: all adult patients received mg of vitamin k and mg of sodium artesunate immediately upon admission. after h all adult patients with confirmed evd received g of ceftriaxone every h, mg of metronidazole every h, - ml of ringer's lactate every h, and - ml of dextrose saline ( % and . %, respectively) every h. all the above medications were administered intravenously. adult patients also received a mg zinc sulfate tablet daily, a mg acetaminophen tablet every h, and mg of ondansetron injection intravenously as needed for nausea or vomiting. after the first days, continuing therapy included a mg metronidazole tablet every h for days, a mg cefuroxime tablet every h for days, and a mg acetaminophen tablet every h. the protocol for children was similar but the dosage was adjusted according to their body weight. oral rehydration solution and juice were provided on an as needed basis. we transfused more fluid to the patients with profound gi losses and those unable to take oral fluids or medications. currently, early supportive care, empiric antibiotic therapy, and maintenance of water and electrolyte balance are the basic interventions to treat evd due to the lack of specific anti-ebov drugs. every etc designed their treatments protocol according to the protocols for viral haemorrhagic fever under the urgent interim guidance for case management established by the who and endorsed by the ministry of health, which were similar. statistical analyses were performed with the aid of spss, version . . (spss inc., chicago, il, usa). the overall survival rate was compared using log-rank test. univariate and multivariate analyses were carried out using the logistic regression model. the intergroup comparisons were performed using chi square test. receiver operating characteristic (roc) curve was plotted using the log value of blood ebov viral load and the survival rate. all the statistical tests were two-tailed, and a p-value of less than . was considered statistically significant. a total of suspected evd patients were admitted to jui government hospital, among which were confirmed with evd. all patients with confirmed evd received supportive treatment and were followed up to the endpoint (recovery or death). among the confirmed evd patients, were transferred to other treatment centres and treated in our centre. of the total confirmed, were female and were male, recovered and died, with an overall survival rate of . % (females . %, males . %). no significant difference was found between the survival rates of females and males (p = . ). the average age of the evd patients was . ± . years, and the median age was years, interquartile range were years and years (iqr, - ). the youngest patient was month old, and the oldest years old. the ages were separated by the following groups: patients ( . %) were under the age of , patients ( . %) between and , patients ( . %) between and , and patients ( . %) above the age of . the median age was (iqr, - ) for the non-survivors and (iqr, - ) for the survivors. the mean hospitalization time for survivors was . ± . days, and the median was (iqr, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. the surviving patients were discharged after they had been asymptomatic for h, and they had been tested negative for blood ebov using rt-pcr assay. the mean hospitalization time for non-survivors was . ± . days, and the median was (iqr, - ) days. we investigated how long it took for the blood ebov to turn negative in the surviving patients. all survivors were followed up from the time of diagnosis (when blood ebov was first detected) to the time of recovery. the median time for a surviving evd patient to become blood ebov negative was . ± . days, and the range was from days to days. of the total number of survivors observed, . % ( cases) turned negative for blood ebov within weeks after the diagnosis, and . % ( cases) turned negative weeks after the diagnosis (fig. ). among the evd patients who received treatment, died (the fatality rate . %). of the nonsurviving patients, . % died within days after admission, . % died during the first week, and more than . % died within weeks (fig. ) . to investigate the survival rate of evd patients in different age groups, the evd patients were divided into three groups (age - , age - , and ≥ years). the results showed that the survival rate for group - was statistically lower than that of group - (p = . ) or group ≥ (p = . ) (fig. ) . but the survival rates for group - and group ≥ were not statistically different (p = . , kaplan-meier estimate) (fig. ). in addition, we categorized the patients using the median age ( years) or years as the cutoffs, and applied the same statistical analysis, but no statistically significant difference was found in the survival rates between groups. we also looked into whether high viral load in the blood was an indicator for high fatality rate. a receiver operating characteristic (roc) curve was plotted using the blood viral values and the survival outcomes of the evd patients. among the patients, died within h of admission. such patients were tested positive using only oral swab samples, and were excluded from this analysis. a total of patients with detectable blood ebov virus were included in the roc curve analysis. the numbers of ebov copies were converted to log values for further analysis. the results showed that the viral loads had a high predictive power of patients' outcome (p < . ). the areas under operator curve (auoc) were . ( % ci: . - . ). from the roc curve, when the log viral value was greater than , the probability of patients' survival was less than %; and when it was greater than , the probability of patients' survival was less than %. these results suggested that the viral loads can be used as a potential prognostic biomarker for evd patients (fig. a) . we selected copies/ml as the cutoff value to divide the patients into two groups (ebov ≥ copies/ ml and < copies/ml), and applied statistical analysis fig. the time lapsed before survivors turned negative for blood ebov, and the time lapsed before non-survivors died. all patients were confirmed with evd in sierra leone (fig. b) . kaplan-meier estimate showed that when the blood ebov titer was greater than copies/ml, the fatality rate was . % -remarkably higher than that of the group with less than copies/ml viral load ( . %) (p = . ). we analysed the clinical presentations of the evd patients at the time of admission, of which of the patients were excluded due to incomplete data, making the total number of patients studied and included in the analysis to . ( . %), pain behind eyes ( . %), confusion ( . %), and skin rash ( . %). a number of variables between survivors and non survivors were shown to be significantly different amongst the evd positive patients with known outcomes including vomiting (p < . ), abdominal pain (p = . ), jaundice (p < . ), conjunctivitis (p = . ), and confusion (p < . ) (fig. ) . to further explore which factors were associated with the survival of evd patients, a number of factors, including a variety of symptoms (absent or present), age (years), gender (male or female), viral load (log copies/ml), and treatment outcomes (survival or death) were included in the univariate and multivariate analyses ( table ). the univariate analysis showed that vomiting, abdominal pain, jaundice, conjunctivitis, confusion, and the viral load (p < . ) were good candidates for the final logistic regression model. the multivariate analyses showed that higher viral load, severe confusion, vomiting, abdominal pain, and conjunctivitis indicated poor prognosis in evd patients (table ) . jui government hospital in freetown, sierra leone was approved as an ehc on oct , to receive suspected evd patients. once the evd cases were confirmed, the patients were transferred to other etcs such as p.t.s. , in the previous published reports, no detailed data was available on how soon the blood ebov turned negative in evd patients. our observation revealed that blood ebov turned negative very slowly-only . % patients turned blood ebov negative in weeks. this partially explained why evd spread so widely and persisted for so long in west africa. the surviving evd patients in our study were discharged after the symptoms remained absent for h, and the blood samples were negative for ebov in two consecutive tests with quantitative rt-pcr assay. the mean hospitalization time for surviving patients was . ± . days. in other studies, the researchers continued to monitor ebov rna levels in sputum, saliva, conjunctiva swabs, stool, urine, and sweat using real-time rt-pcr assay after the blood ebov rna turned negative. they found that urine samples remained positive for ebov rna for as long as days after blood turned negative,and sweat samples remained positive throughout the observation period for an additional days ( days after blood became ebov rna negative [ ] ). another study reported that ebov existed in cerebral spinal fluids and semen for much longer in evd patients [ ] . even varkey and colleagues described a patient who recovered from evd and subsequently showed severe unilateral uveitis during convalescence. in this case, viable zaire ebola virus was detected in aqueous humour weeks after the onset of evd and weeks after the clearance of ebov from the blood [ ] . such findings warrant further investigations in the future. although it was unclear whether or not such residual viruses were pathogenic, these findings suggested that when evd patients are recovered and discharged, they should be put on continued quarantine for a period of time to avoid close contact with other people. the case fatality rates (cfr) of evd was reported to be between % and % [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in our study, the total mortality rate was . % for confirmed cases, which was similar to that in the previous reports. as a trend observed in this outbreak, the fatality rate was more than % during the early stage, and dropped to %- % at a later stage. this may be attributable to the public's poor awareness of this disease, the delay in seeking treatment, the inadequate measures for diagnosis and treatment, and the limited media coverage when the outbreak erupted. later, as more awareness came from the international medical associations causing more international medical teams to arrive, the public became better educated and the patients started to receive more effective diagnosis and treatment. thus at the later stage of the virus outbreak, early discovery, early diagnosis, and early treatment helped bring the fatality rate down. we also made observations about the length of the hospital stay for the non-survivors. we found that most non-survivors died within days after admission, which was consistent with other reports [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . only % died after day upon admission. this indicated that evd has high degree of virulence. it also suggested that early diagnosis and early treatment is critical to the patients' survival. just as some scholars stated, the lack of public awareness of the disease as well as the lack of synergy among governments and international organizations contributed to the current epidemic [ ] . the public should be educated and instructed to seek medical attention as early as they notice any symptoms, and the proactive treatment should be deployed as soon as the patients are admitted. the age factor has been noted in the past evd outbreaks and remains an important factor in the current outbreak [ ] [ ] [ ] . the previous reports showed that older age was associated with worse outcomes, and the association between the two was often attributable to increased coexisting conditions in the elderly [ , , , ] . in contrast, we did not find statistically significant differences between the age of non-survivors and survivors in our study (median age: (iqr: - ) vs. (iqr: - ); average age: . ± . vs. . ± . ). in order to determine the association between age and prognosis, we grouped the patients using different cutoffs, including median age ( ), the cutoffs used in other studies (age , , ), and multiple age groups at intervals of years. in our comparison of the different age groups, no association was found between age group and prognosis. one distinction in our study was that the mortality rate for younger patients under the age of was higher than the other age groups. this may be explained as follows: in the beginning of the evd outbreak, adult patients encountered many complications such as diarrhoea-related electrolyte disorders and secondary infections, but soon received sufficient fluid therapy in many etcs, so the mortality rate dropped among those patients. but for young children, since there was a shortage of paediatricians in many centres, the paediatric patients may not always have received sufficient attention or optimized therapy [ ] . the young children were unable to care for themselves and their daily fluid intake was not always guaranteed while solely depending on the limited hospital resources. additionally, poor access to iv vessels in paediatric patients may limit both the amount and the flow rate of fluid administered. we also found that patients who presented the highest viral loads had the worst outcome, as had been the case for other strains of ebola virus [ , , , ] . although the diagnostic value was excellent for postmortem swab samples [ ] , it was unclear how a cycle threshold (ct) value from an oral swab correlates with that from a whole blood sample, therefore the viral load data for the oral swab samples ( / ) were not included in the analysis. the relationship between the viral load (copies of ebov per milliliter) and the fatality rate was investigated. roc curve analysis was plotted and a positive correlation was found between the two. a low viral load was associated with a better survival outcome, whereas a high viral load was an important indicator for fatality rate. our finding was consistent with those of the previous reports [ , , , ] . based on this finding, it is plausible to assign patients with virus load of ≥ copies/ml to dedicated wards, where they can receive enhanced medical support and palliative care if resources allow, given their increased risk of death. it is noteworthy that the cases for which evd was confirmed using oral swab samples were all severely ill patients who died soon after admission. exclusion of these cases may have introduced some bias in our results. evd was formerly named ebola haemorrhagic fever, and bleeding is one of its hallmarks. bleeding was noted among patients in previous outbreaks. however, in this outbreak, the reported bleeding rates ranged from . % [ ] to . % [ ] . in our study, only of patients ( . %) suffered from visible bleeding during their hospitalization, which is a relatively low number when comparing to other reports [ ] . this suggested that bleeding may not be a major characteristic of evd patients in this outbreak. such discrepancy may be associated with the evolvement of the virus's pathogenicity as its genes undergo mutations. finally, we analysed which factors were associated with patients' outcomes. the incidences of various symptoms in evd patients reported here are consistent with those of previous reports, with only minor differences. the most common evd manifestations on admission were fever, weakness, loss of appetite, vomiting, cough, abdominal pain, headache, joint pain, and diarrhoea. in addition to factors such as age and viral load, previous studies described many other important factors associated with fatal outcomes, including hiccups, haemorrhagic signs, fever, weakness, dizziness, diarrhoea, myalgia, difficulty breathing, extreme fatigue, vomiting, mental symptoms, loss of appetite, confusion, and conjunctivitis [ - , , ] . the multivariate analyses in each study may include one or more of the aforementioned presentations. this indicated that: first, none of the clinical manifestations observed among patients in this outbreak was unique; and second, the way the patient history information was collected may vary in each study. in our study, the multivariate analyses showed that ebov viral load, abdominal pain, confusion, conjunctivitis, and vomiting were independently associated with the death outcome of evd patients. it is understandable that high viral load is related to fatality rate, and that digestive discomfort may be associated with patients' prognosis. in our study, the most powerful predictor of mortality in the multivariable regression model was confusion at admission (p value = . ), with an odds ratio of . ( % ci: . - . ) favouring mortality. this finding indicated that the more severe the condition was at the time of admission, the higher the risk of death. we observed that due the lack of peculiar presentations of evd and the less-developed health care capacity in africa, many patients failed to seek medical attention promptly after they experienced some non-specific symptoms such as fever, thus delaying the diagnosis and treatment. some patients died on their way to the hospital, some died upon arrival before the physicians had the opportunity to examine them, and yet some died on day ( / ) or day ( / ) after admission. in these circumstances, it was too late for the patients to receive proper treatment for such a severe disease. therefore, we should raise the public's awareness that early discovery, early diagnosis, and early treatment are essential. early proactive intervention can significantly improve the prognosis of the patients. in our clinical observations, we found that the clinical presentations in this evd outbreak was primarily severe gastro enteric symptoms, such as nausea and lack of appetite accompanied by excessive vomiting and severe diarrhoea. although due to the limitations of the medical equipment, we were unable to carry out laboratory tests to determine the cause of death for each non-survivor, we suspected that the loss of body fluids, abnormal metabolism, electrolytes imbalance, and hypovolemic shock, which were all secondary to the severe digestive tract disorder, may have been the immediate causes in the death of most non-surviving patients. the patients are usually extremely weak after the onset of the disease and cannot eat or drink by themselves; therefore it is essential for the medical staff, while taking precautions to protect themselves, to administer adequate fluids to the patients as early and as quickly as possible. early initiation of proactive fluid therapy, particularly in the first days of hospitalization and even before the ebov test results are received, is vital to saving patients' lives and reducing fatality rate. a few limitations exist in our study. first was the limitation of the data. there were many challenges regarding the collection of accurate clinical and epidemiological data on site in west africa. heavy workload, language barriers, and lack of an information technology infrastructure which would otherwise allow healthcare professionals to record data electronically at the point of patient contact, had all contributed to the incomplete data presented in our study. the second limitation was that no analysis was available for the time period between symptom onset and admission, and in most cases it was difficult to pinpoint the exact date when symptom started. the majority of the patients were not able to recall or describe when the symptoms started; it was especially so for the more severe patients. another drawback is the limitations on the clinical observations. as we described previously, some patients were transferred to other etcs before jui government hospital became a designated etc, and the treatment protocols in the other etcs may not always be consistent with the evd sop. gi losses and electrolyte disturbances may be the major causes of death in many evd patients. laboratory tests that provide comprehensive data on patients' haematological and biochemical indicators can help delineate the cause of death. more importantly, it may also provide instructions for treatment, thus reducing fatality rate. unfortunately, we did not have a crosscontamination-proof testing facility in place while our centre was serving as an ehc or in its early stage of serving as an etc. therefore, we were unable to determine whether the non-survivors died of evd complications, related co-infections, or some other causes. we only evaluated the severity of the illness by the clinical manifestations, and transfused more fluid for the patients with profound gi losses and those unable to take oral fluids or medications. the biochemical testing and the testing for co-infection with malaria were not launched until a later stage due to the limitation of laboratory facilities. even then, such data was only collected from a limited number of patients. while the data was of some help to the treatment, it was not sufficient for a meta-analysis. in addition, we were not able to analyse the association between the treatment protocols and the outcome. during the months of treatment, three different health care teams rotated and the physicians were on - h shifts. the medical staff professionals had different ways of practicing, thus the medical history, symptoms and signs were recorded in different manners. in conclusion, for the patients confirmed with evd, the survival rate was . %. some surviving patients did not become blood ebov negative until weeks after admission or later. most non-surviving patients died within week after admission. patients under the age of years and those with high viral load had a higher fatality rate. patients who presented confusion, vomiting, abdominal pain, and conjunctivitis at the time of admission were at higher risk of death. such patients should be the priority of medical attention and should be put under intensive treatment, particularly during the first week of hospitalization. additional file : multilingual abstracts in the six official working languages of the united nations. (pdf kb) world health organization international study team. ebola hemorrhagic fever in sudan world health organization: ebola situation report - ebola virus disease update-december assessing the direct effects of the ebola outbreak on life expectancy in liberia, sierra leone and guinea indirect costs associated with deaths from the ebola virus disease in west africa ebola virus outbreak investigation a case of severe ebola virus infection complicated by gram-negative septicemia andré-von arnim a. clinical presentation and management of severe ebola virus disease persistence of ebola virus in ocular fluid during convalescence clinical presentation of patients with ebola virus disease in conakry, guinea clinical illness and outcomes in patients with ebola in sierra leone clinical predictors of mortality in patients with ebola virus disease ebola outbreak in conakry, guinea: epidemiological, clinical, and outcome features clinical features of patients with ebola virus disease in sierra leone ebola outbreak in rural west africa: epidemiology, clinical features and outcomes the contribution of ebola viral load at admission and other patient characteristics to mortality in a médecins sans frontières (msf) ebola case management centre (cmc) high survival rates and associated factors among ebola virus disease patients hospitalized at donka national hospital, conakry, guinea ebola wreaks havoc in sierra leone a limited outbreak of ebola haemorrhagic fever in etoumbi ebola hemorrhagic fever, democratic republic of the congo, : determinants of survival proportion of deaths and clinical features in bundibugyo ebola virus infection who ebola response team. ebola virus disease in west africa -the first months of the epidemic and forward projections rapid diagnosis of ebola hemorrhagic fever by reverse transcription-pcr in an outbreak setting and assessment of patient viral load as a predictor of outcome utility of oral swab sampling for ebola virus detection in guinea pig model basic clinical and laboratory features of filoviral hemorrhagic fever clinical features of patients isolated for suspected ebola virus disease at connaught hospital we thank all staffs of beijing hospital and all members of our families for their hard work and emotional support during we fought again ebola. we thank all nurses, cleaners and managers from sierra leone for their positive teamwork. we thank editors and reviewers for their warm works and valuable comments. no.availability of data and materials authors do not wish to share raw data for readers to open access due to privacy or legal concerns. but we can give our main statistical data as an affiliated file to editors and reviews for reproducing and testing research results.authors' contributions yjj, xzd, xdg, and hjd contributed to the design of the study. yjj, xzd, xdg, ll, cl, dj, wgl, lfw, yhm, xy, bfl, xas, mlg, and hjd entered ebola wards, implemented the field work and collected the on-site data in sierra leone. tj helped with the diagnosis test. yjj, xzd, smk and jb collected the follow-up data. yjj, xzd, xdg and hjd wrote the manuscript. all authors read and approved the final draft. the authors declare that they have no competing interests. the study has been approved by the military hospital medical ethics committee and the committee's reference number is d. the written informed consent was waived because of retrospective, observational study. • we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- -opvs ejd authors: masiira, ben; antara, simon n; kazoora, herbert b; namusisi, olivia; gombe, notion t; magazani, alain n; nguku, patrick m; kazambu, ditu; gitta, sheba n; kihembo, christine; sawadogo, bernard; bogale, tatek a; ohuabunwo, chima; nsubuga, peter; tshimanga, mufuta title: building a new platform to support public health emergency response in africa: the afenet corps of disease detectives, – date: - - journal: bmj glob health doi: . /bmjgh- - sha: doc_id: cord_uid: opvs ejd public health emergency (phe) response in sub-saharan africa is constrained by inadequate skilled public health workforce and underfunding. since , the african field epidemiology network (afenet) has been supporting field epidemiology capacity development and innovative strategies are required to use this workforce. in , afenet launched a continental rapid response team: the afenet corps of disease detectives (acodd). acodd comprises field epidemiology graduates and residents and was established to support phe response. since , afenet has deployed the acodd to support response to several phes. the main challenges faced during acodd deployments were financing of operations, acodd safety and security, resistance to interventions and distrust of the responders by some communities. our experience during these deployments showed that it was feasible to mobilise and deploy acodd within hours. however, the sustainability of deployments will depend on establishing strong linkages with the employers of acodd members. phes are effectively controlled when there is a fast deployment and strong linkages between the stakeholders. there are ongoing efforts to strengthen phe preparedness and response in sub-saharan africa. acodd members are a competent workforce that can effectively augment phe response. acodd teams mentored front-line health workers and community health workers who are critical in phe response. public health emergence response in sub-saharan africa is constrained by inadequacies in a skilled workforce and underfunding. acodd can be utilised to overcome the challenges of accessing a skilled public health workforce. to improve health security in sub-saharan africa, more financing of phe response is needed. the risk that infectious agents will continue to kill humans in the st century is highest in africa. according to the who, africa experiences more than disease outbreaks and other health emergencies annually. from the beginning of , african countries have been facing one of the greatest challenges: the covid- pandemic. the covid- pandemic started in china in december and rapidly spread across the globe. such public health emergencies (phes) expose the fragility of emergency response systems in africa. for example, the ebola virus disease (evd) epidemic in west africa claimed > lives and cost billions of us dollars in socioeconomic losses. for an effective phe response, the global health security agenda recommends countries to have at least one field epidemiologist (trained at the advanced or intermediate levels) per population. other authors have suggested a coverage three to five field epidemiologists per million population. however, data at the african field epidemiology network (afenet) show that the sub-saharan region summary box ► innovative strategies can be applied to leverage the inadequate public health workforce to address public health challenges including emergencies. ► acodd was established to support ministries of health to overcome the challenges of rapidly mobilising and deploying adequate and skilled public health workforce. ► public health emergency response in sub-saharan africa is still constrained by underfunding. ► it is feasible to mobilise and deploy acodd member within hours to support ministries of health to respond to emergencies. ► lack of effective community engagement can result into violence against the rapid responders. ► psychosocial support can be a game changer in addressing difficult situations faced by rapid responders such as distrust. has only % of the required number of field epidemiologists. afenet was established in to support field epidemiology workforce development in sub-saharan africa. during the ministerial round acodd's organisational structure is summarised in figure . there are three levels of acodd management; the afenet secretariat, regional and country levels. at the afenet secretariat, the head of afenet (who reports to the afenet board of directors) provides overall strategic leadership, the head of programmes provides overall technical leadership and the acodd focal person (fp) coordinates operations across the network. at regional level, acodd operations are led by the afenet regional technical coordinator (rtc). at country level, the acodd operations are led by the country fp who is the fetp resident advisor. details of the acodd management team responsibilities are summarised in table . acodd has supported response to several emergencies including disease outbreaks, mass gathering event-based surveillance, polio surveillance and natural disasters such as cyclone idai in the southern africa region. outlined below are the key disease outbreaks where acodd members were deployed. the ninth ebola virus disease outbreak in the democratic republic of the congo, may-july soon after acodd was launched, afenet received a request from the drc ministry of health to support the response to the evd outbreak in Équateur province. this evd outbreak had been declared on may . between may and july , afenet, in collaboration with the us centres for disease control and prevention (cdc), deployed a team of acodd members to support the national rrt contributing a total of person-days of deployment. acodd members investigated alerts of which were confirmed with evd, identified contacts of which were followed up, mentored front-line health workers and conducted a total of community sensitisation sessions. other acodd members were involved in screening of passengers at five priority points of entry (poes) and points of control (pocs) to identify suspected cases of evd surveillance. the acodd conducted data analysis and compiled and presented daily updates that helped inform the outbreak response strategies. this outbreak was quickly contained and the minister of health announced its end on july . the outbreak had a total of evd cases of which were confirmed, were probable, died (case fatality ratio: %). of the cases, occurred in bikoro health zone, occurred in iboko health zone and occurred in wangata health zone. as part of the mohcc rrt, acodd teams investigated cholera cases, identified cases through active cholera case search and participated in outbreak data analysis. acodd members with clinical background supported case management teams at health facilities and assessed compliance to treatment protocols by case management teams. a team of acodd participated in conducting risk communication, community a total of acodd members were deployed in rotations for days contributing a total of person-days. once in the field, acodd members had a meeting with the field incident commander and the district health leadership to get an understanding of the outbreak and to finalise the terms of reference. acodd teams investigated alerts none of which was confirmed with evd and listed contacts of which ( %) were followed up and tested negative after completing the follow-up period. the acodd reviewed medical records at health facilities to identify suspected evd cases and out of these records nine suspected cases were identified and all tested negative for evd. in addition, the acodd screened travellers at poes, participated in community-based and event-based surveillance, community sensitisation, psychosocial support and data analysis. the response team initially found surveillance and contact tracing difficult due to community mistrust and false information. for example, there was information that suspected patients with ebola admitted to the etu and their contacts are killed by a 'lethal injection' in order to prevent further transmission of evd. these rumours made one of the high-risk contacts to go into hiding. when the high-risk contact was traced in one of the remote locations, he rejected ebola vaccination despite several visits by the teams. however, after days of counselling by the psychosocial team, the high-risk contact eventually accepted evd vaccination. because of the community mistrust and misinformation, the rrt adopted a community-led surveillance and contact tracing strategy. under this approach, community health workers known as village health teams (vhts) were trained. the vhts conducted contact tracing under the close supervision from the contact tracing teams. during field activities, acodd teams mentored health workers and vhts. this evd outbreak involved three confirmed cases, all of whom died (case fatality ratio, cfr: %) and all had an epidemiological link to a confirmed case who died in drc. many of the acodd teams faced community resistance and constant security challenges, amidst the increase in the spread of the outbreak, which had a negative impact on the response. on july , who declared this outbreak as a public health emergency of international concern. afenet received grants from the us cdc and the world bank to enhance response efforts. these funds were used to implement surveillance training to enhance ebola response and readiness (steer) for the front-line health workers, community health workers and acodd deployment. steer focused on building the capacity in evd surveillance, ipc and risk communication. a total of health workers and community health workers in evd affected health areas were trained. by december , the rrts were starting to register success with new evd cases reported during the week of november to december compared with cases during the week of - september . by march , there was no new confirmed evd case since february , and a total of evd cases had been reported of which were confirmed cases, probable cases and cases had died (case fatality ratio of %). as of march , there were signs that the epidemic had been contained with the last cases all reported from a small geographical area within beni health zone. acodd response to the covid- pandemic as soon as the chinese government declared the covid- outbreak, countries on the african continent activated their emergency preparedness and response mechanisms. by january , who declared the pandemic a phe of global emergency of international concern. in early february , the acodd fps started working with afenet to mobilise acodd members to be on stand-by to support ministries of health and technical bmj global health agencies/networks such as the who, us cdc, global outbreak alert and response network and africa cdc. acodd teams across afenet member countries supported various activities including ( ) coordination and planning, ( ) development of the national response plans, ( ) adapting the who covid- case definition to country contexts, ( ) investigation of suspected cases, ( ) poe screening, ( ) contact tracing, ( ) training of rrts and screeners at poes, ( ) risk communication and ( ) supporting the development of protocols and standard operating procedures (sops). afenet supported africa cdc to recruit acodd epidemiologists to strengthen covid- capabilities among african countries. these volunteers supported coordination and planning, building capacities for surveillance, laboratory, ipc and case management, policy development and provided technical support to public health emergency operation centres to develop incident action plans and sops. acodd teams faced four key challenges during deployment and these are highlighted below. the bulk of afenet operations are supported by the us cdc and the united states agency for international development. between august and march , afenet received requests for acodd support from member countries of which ( %) were funded. acodd deployments were largely supported using the funds generated from indirect project costs while some deployments received direct support from the us cdc. although afenet uses a cost-effective model for acodd deployment, available funding has been insufficient to meet the growing demand for acodd support. a more sustainable strategy for funding of phe response should be led by the african governments. however, investigations have shown that the majority of countries in africa allocate below % of their total budget to the health sector. availability of acodd for deployment because majority of acodd are not employed by afenet, their availability to support phe response depends on their release by employers. during deployments, some of the acodd members could only serve a short duration in the field which presented a challenge of recruiting and orientation of new volunteers. although afenet has been able to mobilise adequate numbers of acodd members during emergencies, mobilisation is anticipated to be difficult in large-scale phes which require a bigger workforce. the safety of rrts is one of the critical elements for an effective response. overall, acodd and other responders operated in a safe and secure environment in most of the deployments. however, the response to the evd outbreak in drc was substantially hampered by insecurity. acodd teams in insecure areas always operated in constant fear of being attacked by the armed groups. on april , a doctor who was deployed by who was brutally murdered at the butembo university hospital. on the night of november , armed rebel forces attacked a camp at biakato mines and killed four health workers. the deteriorating security situation led to the evacuation of several rrt members, including acodd members, to goma city on december . resistance to interventions and distrust of the responders although the acodd participated in community sensitisation during the tenth evd outbreak in drc and the sixth evd outbreak in uganda, community resistance and distrust remained a key challenge. in both outbreaks, lack of trust was primarily driven by false information, misperceptions and ignorance about control strategies. whereas in uganda the distrust was easily controlled through community engagement, the responders in drc faced a more complex situation. a mob attacked one of the etus in drc resulting into patients and caregivers fleeing and one of the caregivers was killed. activities such as identification of new cases and safe, dignified burials were dangerous to implement in some areas because of violence from the residents. community resistance and distrust was also documented during the response to the west africa evd outbreak. lessons learned although fetps started over two decades ago in sub-saharan africa, the region is still faced with a scarcity of field epidemiologists. during acodd launch, the participants were engaged in discussions about the anticipated challenges related to acodd deployment. the key anticipated challenges elicited from participants included difficulty in mobilising adequate numbers of acodd members, lack of interest in responding to outbreaks due to highly infectious pathogens such as evd, and delays or non-release of the acodd members by their employers. our experience showed that its feasible to mobilise and deploy adequate numbers of acodd members within hours after receiving requests from ministries of health. many acodd members felt motivated to participate in rapid response within their countries and beyond. the acodd members employed within government ministries were easily released compared with those in the private health sector. all acodd deployments were approved and effected by the ministries of health. before field deployment, predeployment briefings were conducted with a special focus on discussing the terms of reference. acodd members were integrated into the national rrt and their daily operations were under the direct supervision of ministries of health. although the deployments were largely successful, sustainability will rely on establishing strong linkages with organisations that employ the acodd members. afenet is continuously sensitising and engaging the organisations that employ the acodd members to ensure that they release them during emergencies. the final key lesson learnt was that phes were effectively controlled when the responders were rapidly deployed and when there was strong collaboration between the key stakeholders. an analysis of the evd outbreak in west africa showed that a well-coordinated faster response would have halted the propagation of the outbreak. opportunities considerable efforts are ongoing in the sub-saharan africa region to strengthen preparedness and response to phes. from its founding in afenet, in collaboration with the us cdc, universities and other technical partners, has been contributing to health systems strengthening. acodd members are a skilled workforce that can be utilised to support emergency response. the afenet cost-effective strategy for acodd deployment is centred on in-country field epidemiologists; with recruitment from other countries only done once the in-country acodd have been exhausted. the recruitment strategy provides an added advantage in that the acodd members are well versed with the country context and can easily communicate to the target populations as opposed to recruiting external acodd members. during deployments, acodd teams interacted, worked with and learnt from other experienced responders. furthermore, in areas where the acodd members were deployed, they were involved in mentoring the front-line health workers and community health workers. effective public health preparedness and response in sub-saharan africa is constrained by inadequate skilled human resources and underfunding. the acodd platform is afenet's innovative strategy to deploy the existing field epidemiology workforce to support phe response. experience from these deployments has shown that the acodd can be rapidly mobilised and deployed to the field. the contributions of the acodd since its establishment is a clear demonstration of leveraging the existing workforce to solve the complex public health challenges that threaten health security in sub-saharan africa. the deficiencies in financing the health sector in sub-saharan africa emphasise the need for african governments to devote more financial support and resources for phe response. african field epidemiology network, kampala, uganda global public health solutions, atlanta, georgia, usa african field epidemiology network, harare, zimbabwe twitter notion t gombe @gombent contributors bm participated in conception of the manuscript, supervision of acodd deployments, synthesis of field experiences and writing all the drafts of the manuscript. sa participated in conception of the study, supervision of deployments, writing and reviewing of the manuscript and approval of the manuscript. hbk participated in conception and supported manuscript writing at all stages. on wrote the field experiences from the uganda acodd deployment and participated in reviewing and writing of the manuscript at all stages. ntg wrote the field experiences from zimbabwe, supervised acodd deployment and participated in writing of the manuscript at all stages. anm wrote the field experiences from drc acodd deployments and participated in writing of the manuscript at all stages. pmn participated in writing and reviewing of the manuscript at all stages. dk wrote supervised acodd deployment in drc and participated in writing of the manuscript at all stages. sng, ck, bs and atb participated in writing and reviewing of the manuscript at all stages. co participated in conception of the study, supervision deployments and reviewing of the manuscript. pn participated in study conception, writing and reviewing of the manuscript at all stages. mt participated in conception of the study, supervision deployments, writing and reviewing of the manuscript and gave final approval of the manuscript. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. competing interests none declared. patient consent for publication not required. provenance and peer review not commissioned; externally peer reviewed. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. ben masiira http:// orcid. org/ - - - x emerging infectious diseases in africa in the st century world health organization. who health emergencies programme in the african region: annual report available: http:// apps. who. int/ ebola/ current-situation/ ebola-situation-report the economic and social burden of the ebola outbreak in west africa global health security agenda: ghsa workforce development action package (ghsa action package detect- ) strengthening public health surveillance and response using the health systems strengthening agenda in developing countries afenet. ministerial resolutions on african field epidemiology network (afenet) democratic republic of congo: ebola virus disease -external situation report ebola virus disease democratic republic of congo: external situation report / democratic republic of the congo. external situation report promoting equitable health care financing in the african context: current challenges and future prospects world health organization. state of health financing in the african region responder killed in attack on the butembo hospital armed groups kill ebola health workers in eastern dr congo msf suspends congo ebola effort after deadly clinic attacks an epidemic of suspicion -ebola and violence in the drc social and cultural factors behind community resistance during an ebola outbreak in a village of the guinean forest region the health impact of the - ebola outbreak field epidemiology training programmes in africa -where are the graduates? post-ebola reforms: ample analysis, inadequate action key: cord- - f ljuk authors: parisot, nelly; chiang, william k. title: commentary date: - - journal: ann emerg med doi: . /j.annemergmed. . . sha: doc_id: cord_uid: f ljuk nan practices, including appropriate use of personal protective equipment (ppe), is essential to protect them and their patients because health care-associated transmission has played a part in transmission during previous outbreaks. , to implement prevention and control measures in both guinea and liberia, ministries of health, with assistance from médecins sans frontières, the world health organization, and others, put in place ebola treatment centers to provide better patient care and interrupt virus transmission. teams from cdc traveled to guinea and liberia at the end of march as part of a response by the global outbreak alert and response network to assist the respective ministries of health in characterizing and controlling the outbreak through collection of case reports, interviewing of patients and family members, coordination of contact tracing, and consolidation of data into centralized databases. cases are categorized into one of case definitions: suspected (alive or dead person with fever and at least additional symptoms, or fever and a history of contact with a person with hemorrhagic fever or a dead or sick animal, or unexplained bleeding), probable (meets the suspected case definition and has an epidemiologic link to a confirmed or probable case), or confirmed (suspected or probable case that also has laboratory confirmation). in late april, it appeared that the outbreak was slowing when liberia did not report new cases for several weeks after april , and the number of new reported cases in guinea decreased to for the week of april . since then, however, the evd outbreak has resurged, with neighboring sierra leone reporting its first laboratory-confirmed case on may , liberia reporting a new case on may that originated in sierra leone, and guinea reporting a new high of cases for the week of may . as of june , the total evd case count reported for all countries combined was , including laboratoryconfirmed, probable, and suspected cases, with deaths (case-fatality rate¼ %). guinea had reported cases ( laboratory-confirmed, probable, and suspected), with deaths (case-fatality rate¼ %) across districts. sierra leone had reported cases ( laboratory-confirmed, probable, and suspected), with deaths (case-fatality rate¼ %) across districts and the capital, freetown. liberia had reported cases ( confirmed, probable, and suspected), with deaths (case-fatality rate¼ %) across districts. major challenges faced by all partners in the efforts to control the outbreak include its wide geographic spread, weak health care infrastructures, and community mistrust and resistance. retrospective case investigation has indicated that the first case of evd might have occurred as early as december . to control the outbreak, additional strategies such as involving community leaders in response efforts are needed to alleviate concerns of hesitant and fearful populations so that health care workers can care for patients in treatment centers and thorough contact tracing can be performed. enhancing communication across borders with respect to disease surveillance will assist in the control and prevention of more cases in this evd outbreak. in june , the world health organization, through the global outbreak alert and response network, requested additional support from cdc and other partners, necessitating the deployment of additional staff members to guinea and sierra leone to further coordinate efforts aimed at halting and preventing virus transmission. persistence of the outbreak necessitates high-level regional and international coordination to bolster response efforts among involved and neighboring nations and other response partners to expeditiously end this outbreak. health organization during the course of months. the case fatality rate is % in patients with definitive clinical outcomes. in the past months, the media have focused significant attention on the spread of the virus to the developed world. on september , , the first case of imported ebv diagnosed in the united states occurred in texas. the diagnosis was missed during the patient's initial emergency department (ed) visit and the patient was discharged home. detection of a case requires a careful travel and exposure history. symptomatic patients with travel to endemic regions within the incubation period of days need immediate isolation and evaluation. patients at highest risk of becoming infected are those with direct bodily fluid contact with ebola-infected patients; those with participation in funeral rites and handling of bats, rodents, and primates in endemic areas; and persons who have handled laboratory specimens without appropriate ppe. all personnel caring for patients with suspected illness must use contact and droplet protection with appropriate ppe until the diagnosis of evd is excluded. the initial symptoms of evd are nonspecific and include fever, malaise, loss of appetite, vomiting, diarrhea, headaches, myalgia, arthralgia, and abdominal pain. , delayed hemorrhagic symptoms occur in approximately % of cases. , major bleeding is uncommon. most patients with fever and other constitutional symptoms who are from endemic regions and presenting to eds in the united states are more likely to have illness caused by something other than ebola virus, including malaria, rickettsial infections, dengue, salmonella typhi and paratyphi infections, and lassa fever. the ed workflow for these patients includes managing the acute illness, screening for ebola, evaluating for alternative diagnoses, and limiting transmission risk to hospital personnel and other patients. in general, patients with high epidemiologic risk and some symptoms, or those with some epidemiologic risk and severe symptoms, will need specific testing for ebola. state and local health departments should be contacted immediately to assist in coordinating with cdc in providing additional guidance on diagnosis and management. ed testing should include cbc count, electrolytes and renal function, and liver function tests. leukopenia, thrombocytopenia, and elevated liver function tests are commonly associated but not specific for evd. , thick and thin blood smears for malaria should be obtained; however, performance of blood smears for malaria could pose special risk to laboratory workers if ebola has not yet been ruled out, and the laboratory should be notified in as soon as the diagnosis is suspected for precautionary purposes. additional safety precautions include using plastic tubes for blood collection, limiting unnecessary blood testing (for more information, see http://www. cdc.gov/vhf/ebola/hcp/interim-guidance-specimen-collectionsubmission-patients-suspected-infection-ebola.html), and notifying state and local health departments. a limited number of local health department laboratories, along with the cdc, have the capacity to perform real-time reverse transcription polymerase chain reaction testing for ebola. medical facilities with close proximity and previous communications with these centers may be able to obtain ebola results rapidly. treatment is mostly supportive, with fluid resuscitation, electrolyte repletion, pressors, and respiratory support. although there are no controlled data, the significantly lower mortality of marburg virus infections in europe in compared with that in africa ( % versus %) reinforces the role of supportive therapy in filovirus infections. it will be interesting to examine the clinical outcomes of evd patients treated in developed countries in the current outbreak when more data are available. experimental treatments, including antiviral drugs, antibody therapy, and vaccines, are currently in accelerated phases of testing. eds have had to prepare and manage various public health outbreaks and biological terrorism concerns in the past decades, including anthrax, smallpox vaccination, severe acute respiratory syndrome, middle east respiratory syndrome coronavirus, measles, influenza, and tuberculosis. vigilance is imperative, and protocols for response to potential cases should be in place in every health care facility according to guidance from the cdc and state and local health departments. protocols should include screening at triage for possible geographic or contact exposure, isolation and infection control, laboratory testing, and cleaning and disposal of equipment and waste. patients with suspected ebola should be treated only by those using standard, contact, droplet, and airborne precautions, with impervious coverage of the entire body and respiratory protection for all persons entering the room. standard ppe includes double gloving, impervious body suit, leg and boot covers, impervious gown, and powered air purifying respirator or face hood with n mask. additional precautions may be indicated in certain situations such as copious secretions or aerosol-inducing procedures (http://www.cdc.gov/vhf/ebola/hcp/infectionprevention-and-control-recommendations.html). risk of transmission to health care workers is greatest when ppe and infection precautions are not strictly used. , proper training and the use of a direct observer is imperative, especially with the donning and removal of ppe (http://www.cdc.gov/vhf/ebola/ hcp/procedures-for-ppe.html). transmission risk may be lower for ed personnel when compared to inpatient staff because lower viral load early in the course of illness and less direct patient contact time. cdc guidelines for the evaluation, isolation, and management of evd have changed and will continue to evolve during the current outbreak. it is vital to keep abreast with the latest updates. although significant global resources and collaboration have been mobilized to combat the current ebola outbreak in west africa, emergency providers and eds must be vigilant and well prepared to serve in the front line against a potential global outbreak. world health organization. global alert and response: ebola virus disease (evd) emergence of zaire ebola virus disease in guinea-preliminary report world health organization médecins sans frontières. filovirus haemorrhagic fever guideline ebola-marburg viral diseases fruit bats as reservoirs of ebola virus control of communicable diseases manual multiple ebola virus haemorrhagic fever outbreaks in gabon ebola virus haemorrhagic fever ebola in west africa: gaining community trust and confidence centers for disease control and prevention (cdc) emergence of zaire ebola virus disease in guinea-preliminary report who: ebola response roadmap update october who ebola response team. ebola virus disease in west africa-the first months of the epidemic and forward projections ebola haemorrhagic fever ebola hemorrhagic fever in kikwit, democratic republic of the congo: clinical observations in patients spectrum of disease and relation to place of exposure among ill returned travelers outbreak of filovirus hemorrhagic fever: time to refocus on the patient basic clinical and laboratory features of filoviral hemorrhagic fever assessment of the risk of ebola virus transmission from bodily fluids and fomites ebola haemorrhagic fever outbreak in masindi district, uganda: outbreak description and lessons learned impact factor impact factor score, one of many metrics of a journal's influence, is a measure of the frequency with which the average article in a journal has been cited over a given period of time impact factor rose to an all-time high this year, to . . annals' score ranks # out of journals in emergency medicine key: cord- -yc wxgid authors: martínez, miguel j.; salim, abdulbaset m.; hurtado, juan c.; kilgore, paul e. title: ebola virus infection: overview and update on prevention and treatment date: - - journal: infect dis ther doi: . /s - - - sha: doc_id: cord_uid: yc wxgid in and , the largest ebola virus disease (evd) outbreak in history affected large populations across west africa. the goal of this report is to provide an update on the epidemic and review current progress in the development, evaluation and deployment of prevention and treatment strategies for evd. relevant information was identified through a comprehensive literature search using medline, pubmed and cinahl complete and using the search terms ebola, ebola virus disease, ebola hemorrhagic fever, west africa outbreak, ebola transmission, ebola symptoms and signs, ebola diagnosis, ebola treatment, vaccines for ebola and clinical trials on ebola. through july , a total of , evd cases and , deaths were reported from all affected countries. several therapeutic agents and novel vaccines for evd have been developed and are now undergoing evaluation. concurrent with active case investigation, contact tracing, surveillance and supportive care to patients and communities, there has been rapid progress in the development of new therapies and vaccines against evd. continued focus on strengthening clinical and public health infrastructure will have direct benefits in controlling the spread of evd and will provide a strong foundation for deployment of new drugs and vaccines to affected countries when they become available. the unprecedented west africa ebola outbreak, response measures, and ensuing drug and vaccine development suggest that new tools for ebola control may be available in the near future. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. . the scope and severity of the evd outbreak underscore the urgent need for development and evaluation of affordable therapeutic and prophylactic agents that can be made available for at-risk populations across africa. over the past months, the west africa evd outbreak has provided an important opportunity to consider use of and evaluate several therapeutic and prophylactic agents (e.g., vaccines) to determine their safety and efficacy [ , ] . for this review, we considered published and [ ] [ ] [ ] . in , a novel third genus of filovirus named cuevavirus was reported from post-mortem tissues of bats collected in in northern spain [ ] . cuevavirus has not been grown in cell culture, and its pathogenic potential for humans remains unknown. to date, a single species (lloviu cuevavirus) has been approved by the international committee on taxonomy of viruses (ictv) [ ] . the current west africa outbreak is caused by zaire ebolavirus, which shows % identity to ebov strains from the drc and gabon [ ] . the genome of ebov contains seven genes named nucleoprotein (np), virion protein (vp) , vp , vp , vp , glycoprotein (gp) and l protein [ ] . each one of these genes encodes a corresponding structural protein. part of the nucleocapsid and, together with vp , interferes with innate host immunity. the surface gp is responsible for the attachment to the cellular receptor and viral entry. l protein is the rna-dependent rna polymerase [ ] [ ] [ ] [ ] [ ] [ ] . early reports suggest that the ebov variant of the - west africa outbreak accumulated mutations that may have an impact on the performance of certain diagnostic tests or even on the efficacy of several experimental treatments. gire et al. analyzed the genetic sequence of ebov genomes from patients in the four most affected countries of the west african region [ ] . they found significant rates of genomic variation in ebov in the current outbreak when compared with the ebov genomic sequence in the ebola outbreak in the drc. although the impact of these mutations on the diagnostic tests and experimental therapeutics has not yet been proven, some mutations exist in viral genes that are targeted by primers of some reverse transcription-polymerase chain reaction (rt-pcr) protocols [ ] , as well as mutations in the binding sites of target proteins of some experimental treatments such as anti-gp monoclonal antibodies [ ] . in , hoenen and colleagues studied full-length sequences of two clusters of ebov imported from mali and found that the gene sequence of ebov has remained stable during the current ebola outbreak [ ] . ebola viruses have been responsible for outbreaks in six african countries [ ] . historically, the outbreaks have affected hundreds of individuals where effective control of outbreaks was achieved primarily through isolation of cases and contact tracing. however, from , evd outbreaks have been recognized almost every year with substantial variation in morbidity and case-fatality rates ranging from % to % [ ] . high case-fatality rates have been associated with the zaire and sudan subtypes [ ] . in the ongoing ebola outbreak, the overall case-fatality rate has been estimated to be approximately % for west africa and other affected countries [ ] . most recently, although the number of cases has declined substantially ( fig. ) , evd cases continue to be reported (please see the supplemental table for details) in guinea, liberia and sierra leone with who ebola situation reports noting weekly cases in july [ ] . in july , situation report statistics from the who suggest that the greatest current burden of evd is found in guinea (n = ) and sierra leone (n = ). liberia reported the lowest evd case number (n = ) in the week of june through july [ ] . the search for the natural reservoir host of ebov has been a matter of investigation during the last decades. there is mounting evidence that a number of mammal species may harbor and transmit the virus. several bat species (i.e., epomops franqueti, hypsignathus monstrosus and myonycteris torquata) have been found to carry filoviruses [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ , ] . patients often present to health care providers within week of symptom onset [ , ] . in the early clinical phase of evd, patients manifest signs and symptoms that mimic common tropical illnesses (e.g., dengue, malaria, typhoid fever and other viral infections) [ , , ] . patients with evd. these investigators found hemorrhage, shortness of breath and myalgia were independently associated with death [ ] . clinical deterioration may progress rapidly resulting in death within to days. vulnerable populations include children under the age of years, pregnant women and the elderly [ ] . evd in these groups also include unspecific symptoms in the clinical presentation. qin et al. did not find differences related to mortality between patients less than years of age and others between to years old, but they found that patients aged \ years had a much lower case fatality rate than those aged [ years [ / ( . % ) and / ( . %), respectively, with p = . ] and that survivors attended ebola treatment centers earlier after the onset of symptoms [ ] . no evidence suggests that pregnant women are more susceptible to ebov infection than the general population. however, they might be at increased risk of severe illness and fetal loss. although no large series are available, the fetal outcome is generally fatal. immune suppression and a systemic inflammatory response due to the release of cytokines and other proinflammatory mediators lead to the impairment of vascular, coagulation and immune systems [ ] . this can result in multiorgan failure and shock resembling a septic shock syndrome. massive fluid losses due to intense vomiting and profuse diarrhea can result in dehydration and hypovolemic shock [ ] . severe lymphopenia as well as significant deterioration of renal and liver functions, which may be reflected in high blood urea nitrogen, serum creatinine and hepatic enzymes (i.e., aminotransferases and alkaline phosphatase), can occur [ , , ] . since ebov is a contagious pathogen, the who and centers for disease control (cdc) have issued recommendations for proper handling of biological specimens from suspected cases of evd [ , ] . extreme caution should take place at all stages (i.e., specimen acquisition, transport, processing and testing) of specimen processing, and appropriate biosafety laboratory procedures must be used when handling biological specimens from patients with suspected evd. tests such as loop-mediated isothermal amplification (lamp) assays [ , ] . prior to , antigen detection methods [e.g., enzyme-linked immunosorbent assay (elisa)] were the gold standard for ebov detection in some outbreaks [ ] . in the acute phase of evd, elisa has a relatively high sensitivity ( %), but ebov antigen levels decline as disease progresses, rendering lower sensitivity for antigen detection - weeks following symptom onset [ , ] . several other antigen detections tests are currently under evaluation and may be deployed in the near future to complement rt-pcr testing [ ] . elisa testing has been largely replaced by rt-pcr, which permits more rapid detection and can now be deployed in mobile (portable) testing platforms in outbreak settings [ ] . detection of igm antibodies against ebov is performed by elisa in the first week after the onset of symptoms with a peak of igm levels occurring in the nd week of illness [ , , ] . igm antibodies are cleared at variable rates from to months after illness onset [ ] . data showed that serology can be highly specific for the evd diagnosis but less sensitive in the intensive care unit setting. hence, antibody testing may be less clinically useful in the diagnosis and management of critically ill evd patients [ ] . although igg antibodies appear soon after the igm and may persist for years [ ], a substantial number of evd patients have died before they develop an igg antibody response [ ] . nucleic acid tests (nats), particularly rt-pcr, are regarded as the gold standard for evd diagnosis, in part because of their high sensitivity and specificity in detecting the ebola viral genome. this is generally accomplished by international mobile teams deployed in institutions such as the european mobile laboratory or cdc. rt-pcr is a rapid and highly sensitive nucleic acid amplification test to detect ebov nucleic acid [ ] . the sensitivity and specificity of rt-pcr are approximately % and %, respectively [ ] . within the first days of illness, molecular assays may not detect the viral genome, which may lead to false-negative results. therefore, rt-pcr should be repeated in subsequent samples [ , ] . to minimize false-negative results, proper sampling, collection, storage or transportation, and a proper rt-pcr technique have to be implemented to avoid cross-contamination [ , ] . quantitative rt-pcr has been developed and could possibly be used to monitor the viral load since data suggest high viremia might be associated with unfavorable outcomes and death [ , ] . for those patients receiving experimental treatments, ebov viral load monitoring could be useful to assess treatment response [ ] . the the provision of clinical supportive care is now a cornerstone of evd patient management, which includes rehydration, nutrition, analgesics and blood transfusion when appropriate, though no clear evidence proves their effectiveness [ ] . a key aspect of supportive care is the maintenance of intravascular volume with oral rehydration solution (ors) or intravenous fluids that provide appropriate electrolyte replacement. the use of antiemetics and antidiarrheal agents may also be important for patients with persistent vomiting and diarrhea [ , , ] favipirarvir is a nucleotide analog and viral rna polymerase inhibitor with a wide range of antiviral effects against numerous negative-or positive-strand rna viruses [ ] [ ] [ ] [ ] [ ] [ ] . initially, favipiravir was developed to treat influenza viruses, and a phase iii clinical trial was completed in which favipiravir was tested on several thousands of people and proven to be safe and effective [ ] . recently, favipiravir has also shown efficacy against ebov in vitro and in vivo in a mouse model [ ] been established, although early treatment in high-risk or potentially ebov-exposed individuals may be an option [ ] . oral administration of bcx may be feasible, although the pharmacokinetic data suggest that the intramuscular route may provide more favorable therapeutic levels [ ] . brincidofovir is a prodrug of cidofovir and a fairly recent oral nucleotide analog that prevents viral replication by inhibiting dna polymerase [ ] . brincidofovir has shown broad-spectrum antiviral activity against dna viruses such as herpes viruses and adenovirus and is currently in a phase iii clinical trial against cytomegalovirus and adenovirus [ , ] . although the exact mechanism of action for brincidofovir in evd is not yet well understood, brincidofovir may interfere with rna polymerase of ebov. the us fda has put brincidofovir on fast-track approval for treatment of evd based on in vitro data alone [ ] . a phase ii open-label multicenter study to assess the safety and efficacy of brincidofovir against ebov in humans has been withdrawn prior recruitment (clinicaltrials.gov identifier: nct ). as a result of the dramatic decline in the number of new cases in liberia in the month of january where the trial was first initiated, chimerix, inc., decided to discontinue the trial with no further discussions [ ] . there are a number of known agents and newly identified compounds that have shown anti-ebov activity. for example, compound is a benzodiazepine derivative that also prevents ebov entry into the host cells [ ] . preliminary analysis suggests that compound binds near a hydrophobic pocket near the ebov gp and gp interface. analysis of this compound suggests that it may have activity against several filoviruses including ebov [ ] . no animal or human trials have been reported to date. nsc is a small molecule, which has an antioxidant property, and was found to inhibit many viruses, including ebov, lassa virus, venezuelan equine encephalitis virus and rift valley fever virus [ ] . this compound, a reactive oxygen species, has shown in vitro activity against ebov as well as some evidence in the ebov mouse model for protection against lethal ebov infection at a treatment dose of mg/kg/injection (higher doses did not improve survival in the mouse model). further studies of this or related compounds in mouse and other animal models may be warranted to elucidate their role in the treatment of ebov and other filovirus infections. of additional interest are compounds that have been proven to be effective in preventing the entry of filoviruses, including ebov, into host cells [ ] . lj- binds to lipid membranes and prevents virus-cell fusion across a wide range of viruses. additional research will be needed to understand how such compounds can be optimally formulated to maximize both the safety and pharmacologic activity in vivo. fgi- , fgi- , and fgi- are a group of broad-spectrum antiviral agents that inhibit viral replication in a dose-dependent manner among multiple and genetically distinct viruses including ebov, bunyaviruses, dengue virus, hiv and hepatitis c virus [ ] . using a mouse model, aman et al. found that fgi- yields a protection after a challenge with a lethal dose of ebov. aman and colleagues showed that protection was also found when fgi- was administered in a prophylactic fashion. in related studies, fgi- and fgi- are also small molecules that inhibit filovirus infection and are found to protect ebov-or marburg-infected mice, although their mechanism of actions are unclear [ , ] . [ ] . for use of cp or cwb, the who has provided guidance to improve the safety of product development as well as safety for patients who receive these products [ ] [ ] [ ] . convalescent sera-based therapy may cause some toxicity related problems, such as transmission of undetected pathogen(s) and transfusion reactions. a recent case report from treating a spanish nurse who had contracted ebov during her care to a patient with evd in spain shed some light on the issue of using experimental therapeutics including cp [ ] . the infected nurse had received convalescent sera from two survivors of evd, high-dose favipiravir and other supportive care treatment. on the th day of clinical disease, the nurse developed clinical signs and symptoms suggestive of post-transfusion acute lung injury, which was managed conservatively without the need of supportive mechanical ventilation. although purified igg can lower these risks, lot-to-lot variation remains a potential problem. previous experience also highlights the risk of antibody-dependent enhancement of ebov infection [ ] . could overcome future zmapp shortages. using magnifection, . g of zmapp can be extracted and purified from kg n. benthamiana leaf biomass [ ] . while this product holds promise, a major hurdle in its future utility is to manufacture large quantities of each monoclonal antibody from plants in a way that ensures sustained high yield of monoclonal antibodies at reasonable cost [ ] . to overcome potential rate-limiting steps in large-scale production, zmapp can be manufactured using chinese hamster ovary (cho) cells. in despite the high safety profile compared with other newly discovered antivirals, these agents cannot be used alone because of their low efficacy, but they can be used in combination with other treatments available including supportive care measures. interferon: since its discovery in , interferon has not been widely used because of the associated adverse events [ ] . the potential use of interferons in the treatment of evd is rooted in the evidence that ebov interferes with functions of type i interferons [ ] [ ] [ ] . previous pre-clinical research showed that exogenous interferon-a or interferon-b could delay the occurrence of viremia or prolong survival time, but could not save animals from death [ , ] nhps (usually rhesus and cynomolgus macaque) can be infected with non-adapted strains and best mimic disease progression in humans, and therefore they are considered the ''reference'' animal model for vaccine studies [ ] . differences can also be found in the ebov antigens included in the vaccines. promising in providing more timely and accurate ebov detection, there will be a need for additional research to study optimal strategies for deploying these diagnostics to locations where testing is most needed. in the near future, there is a substantial likelihood that one or more drugs and vaccines will be approved for use in the treatment and prevention of evd. the 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ebola virus vaccines: an overview of current approaches evaluation in nonhuman primates of vaccines against ebola virus role of vp phosphorylation in the ebola virus replication cycle key: cord- - hau yge authors: macintyre, c. raina; chughtai, abrar ahmad; seale, holly; richards, guy a.; davidson, patricia m. title: respiratory protection for healthcare workers treating ebola virus disease (evd): are facemasks sufficient to meet occupational health and safety obligations? date: - - journal: int j nurs stud doi: . /j.ijnurstu. . . sha: doc_id: cord_uid: hau yge nan virus to the zaire ev is % (baize et al., ) . unlike past outbreaks, the current outbreak of evd has not been contained and has resulted in social unrest, breakdown in law and order, shortages of personal protective equipment (ppe) and depletion of the healthcare workforce, with over healthcare workers (hcws) becoming infected and hcw deaths as of th august (world health organization (who), c). the inability to contain this outbreak has been blamed variously on lapses in infection control, shortages of ppe and other supplies, myths and misconceptions about evd, and the fact that it is occurring in large cities rather than small villages. hcws, many of whom are nurses, are on the frontline of the response, and their occupational health and safety is critical to control of the outbreak and maintenance of the health workforce during a crisis. the who, the us centers for disease control ( ) and several other countries recommend surgical masks for hcws treating ebola (centers for disease control and prevention, a-c; world health organization, d-f) whilst other countries (the department of health uk, ) and mé decins sans frontiè res (msf) have recommend the use of respirators (sterk, ) (table ) . we question the recommendations for surgical masks and outline evidence on the use of respiratory protection for hcws, and the issues that must be considered when selecting the most appropriate type of protection. there is ongoing debate and lack of consensus around the use of respiratory protection for hcws for respiratory diseases, including influenza, which is reflected in inconsistencies between policies and guidelines across healthcare organizations and countries (chughtai et al., ) . in the healthcare setting facemasks (medical/surgical masks) are generally used to protect wearers from splashes and sprays of blood or body fluids and to prevent spread of infection from the wearer, while a respirator is intended for respiratory protection (siegel et al., ) . the mode of disease transmission is one factor which influences the selection of facemasks or respirators -for example, facemasks are recommended for infections transmitted through contact and droplets, while respirators are recommended for airborne infections. such guidelines are based on often tenuous theoretical principles informed by limited experimental evidence, given the lack of data drawn from the complex clinical environment. transmission is not fully elucidated for many infections, spread can occur by multiple modes and the relative contribution of each mode may not be precisely quantified. further, host related factors can mediate the severity of the disease. some diseases exclusively transmit through the airborne route in natural setting (e.g. tuberculosis), while other diseases mainly transmit through the droplet or contact modes but short range respiratory aerosols are generated during high risk procedures which increases the risk of infection transmission (roy and milton, ) . for example, the primary mode of influenza transmission is thought to be droplet (reflected in guidelines which largely recommend surgical masks), but there is increasing evidence that it is also spread by shortrange respiratory aerosols (bischoff et al., ; tellier, ) . for severe acute respiratory syndrome (sars), data supported both droplet and airborne transmission (centers for disease control and prevention, a-c; yu et al., ) . airborne precautions have even been recommended for measles and varicella-zoster viruses despite a lack of data (siegel et al., ) . to date, only four randomized controlled clinical trials (rcts) and five papers on the clinical efficacy of facemasks in the healthcare setting have been published (jacobs et al., ; loeb et al., ; macintyre et al., macintyre et al., , macintyre et al., , b . one of these had only subjects (jacobs et al., ) , and one had subjects (loeb et al., ) . the largest rcts conducted (by authors crm, hs and colleagues) on n respirators and masks, with and subjects, respectively, showed a benefit associated with using n respirators and failed to show any benefit of surgical masks (macintyre et al., . in one of the trials, the majority of laboratory confirmed infections were with respiratory syncytial virus and influenza, neither of which are thought to be predominantly airborne . these data support the concept that transmission of viruses is multimodal and caution against dogmatic paradigms about pathogens and their transmission, particularly when the disease in question has a high case-fatality rate and no proven pharmaceutical interventions. respirators are designed for respiratory protection and are indicated for infections transmitted by aerosols (macintyre et al., . however, this is based purely on the fact that they have superior filtration capacity, and can filter smaller particles. the guidelines fail to consider that respirators offer the additional benefit of being fitted, therefore creating a seal around the face. it is also possible that the seal achieved by a respirator may be an additional benefit over and above the superior filtration that they offer. respirators are not regulated by fit however, only on filtration capacity (with filtration of airborne particles being the sole consideration in guidelines), but the seal offered by a respirator adds to the protection when compared to other mask types. the risk of infection with respiratory pathogens increases three-fold during aerosol-generating procedures (agps) such as intubation and mechanical ventilation (macintyre et al., a) . respirators are generally recommended in these situations for diseases that are known to be transmitted though the droplet route such as influenza and sars (chughtai et al., ) , so the fact that they are not recommended more broadly for a disease with a much higher case-fatality rate such as evd, is concerning. the inability to control the west african ebola outbreak has led to debate around the mode of transmission of ev, with some public health agencies suggesting aerosol transmission (murray et al., ) . current evidence suggests that human to human transmission occurs predominantly though direct contact with blood and body secretions, (world health organization (who), a) and this is the basis of the who and the cdc recommendations for facemasks to protect hcws from evd. however, like influenza and sars, there is some evidence of aerosol transmission of evd. in an observational study from the democratic republic of congo, of the evd cases who visited the home of an evd patient, had contact with the infected case while the remaining five had no history of any contact, which points to transmission through some other mode (roels et al., ) . there is some evidence from experimental animal studies that evd can be transmitted without direct contact; however these studies generally do not differentiate between droplet and airborne transmission (dalgard et al., ; jaax et al., ; johnson et al., ) . in one study, six monkeys were divided into three groups and each group was exposed to low-dose or high-dose aerosolized ev and aerosolized uninfected cell culture fluid (control), respectively. all four monkeys exposed to ev developed infection . jaax et al. found that two of three control monkeys caged in the same room as monkeys with evd, m apart, died of evd . studies have also shown that pigs may transmit ev though direct contact or respiratory aerosols (kobinger et al., ) . in one study, monkeys without direct contact contracted ebv from infected pigs in separate enclosures (weingartl et al., ) . it was not clear whether transmission was due to respiratory aerosols or large droplets. the first infection occurred in a monkey caged near the air ventilation system and positive air samples identified through real time polymerase chain reaction (pcr), which raised the possibility of airborne transmission. however, pigs cough and sneeze more than humans and thus have more capacity to generate aerosols. furthermore, in pigs evd mainly affects the lungs while in primates, it mainly affects the gastrointestinal tract and is excreted in the faeces. as with influenza, the transmission characteristics of evd may also change due to temperature and humidity, and it should be noted that the experimental studies on ev transmission were conducted at low temperature and humidity, which might have favoured aerosol transmission. a recent study has shown that nonhuman primate to nonhuman primate transmission is mainly through contact, with airborne transmission being unlikely (alimonti et al., ) . finally it must be emphasized that ev transmission in high-risk situations is not well studied, particularly during agps, in the handling of human remains or exposure to surgical smoke due to new surgical technologies like laser or diathermy. although the cdc does recommend a respirator during agps for evd patients, aerosols may be created in the absence of aerosol-generating procedures. evidence suggests that aerosols from vomitus can transmit norovirus, and sars was likely transmitted via faecal aerosols (barker et al., ; marks et al., ; mckinney et al., ; yu et al., ) . staff contacts of two hcws infected with ebola in , who were treated in south africa, took universal precautions, with respirators used for high-risk procedures, and no further cases occurred in potential contacts (richards et al., ) . the report of this outbreak (by author gar) has been cited in support of the who and cdc guidelines (klompas et al., ) , however in south africa one hcw contracted ebv when using normal surgical attire during placement of a central line in a patient with undiagnosed ebv. this occurred despite no obvious lapse in infection control. in contrast, once ebv had been diagnosed in the hcw, respirators, impermeable one-piece suits and visors were used (according to south african guidelines), and no further infections occurred despite procedures such as intubation, mechanical ventilation, dialysis, central line placement and the insertion of a swan ganz catheter (richards et al., ) . when determining recommendations for the protection of hcws, guidelines should not be based solely on one parameter, the presumed mode of transmission. a riskanalysis approach is required that takes into account all relevant factors which could impact on the occupational health and safety of hcws (fig. ) . the severity of the outcome (case-fatality rate and disease severity) must be considered. any level of uncertainty around modes of transmission must also be evaluated, particularly if the disease has a high case-fatality rate. in addition, the availability of pre-and post-exposure prophylaxis or treatment must be considered. the immune status and co-morbidities in hcws should also be considered, as some hcws may be innately more vulnerable to infection. as the ageing of the nursing workforce occurs in developed countries, there is likely to be a high proportion of hcws with chronic conditions. in this case, facemasks have been recommended for hcws by cdc and who because of the assumption that ev is not transmitted via the airborne route. however, there is uncertainty about transmission, the consequences of evd infection are severe, there is no proven treatment, vaccine or post-exposure prophylaxis. recommending a surgical mask for evd has much more serious implications than for influenza, which has a far lower case-fatality rate and for which there are easily accessible vaccines and antiviral therapy. further, numerous hcws have succumbed to evd during this epidemic, including senior physicians experienced in treating evd and presumably less likely to have suffered lapses in infection control (world health organization, d-f). aside from these factors, it is also important to consider the perspectives of the staff member. in this highly stressful situation, staff members will want to be reassured that they are using the highest level of protection and are not putting themselves and their families/colleagues at risk. this is especially important if the outbreak escalates and additional staff members are required to assist. staff may refuse to treat patients unless they feel adequately protected. we feel the recommendations for masks do not apply risk analysis methods appropriately, and are solely based on the low probability of non-contact modes of ev spread. previous guidance provided by the who and cdc for ''infection control for viral haemorrhagic fevers in the african health care setting'' in were more conservative, with both organizations recommending the preferred use of respirators first line and surgical masks and cloth masks as a last option (centers for disease control, ) . why then, during the worst outbreak of evd in history, with the most virulent ev strain and with hundreds of hcws succumbing to the disease is it considered adequate for them to wear surgical masks? the high case-fatality rate warrants the use of better protection such as a respirator and full body suit with face shield, where it can be provided. there appears to be a double standard in recommendations for laboratory scientists working with ev, who must adhere to the highest level of biocontainment (bsl ) when working with the virus. (centers for disease control and prevention, a-c; department of health and aging australia, ) further, in contrast to hcws, laboratory fig. . factors to consider in making recommendations for respiratory protection of health workers*. *cost, supply and logistics may affect implementation of guidelines, but should not drive recommendations for best practice. workers are exposed to the virus in a highly controlled, sterile environment in which there is less risk of transmission than in the highly unstable, contaminated and unpredictable clinical environment. the perceived inequity inherent in these inconsistent guidelines may also reduce the willingness of hcws to work during an evd outbreak. table shows recommendations of the selected organizations and countries regarding the use of masks/ respirators for evd for hcws and laboratory workers. only the uk and south african guidelines have consistent guidelines for hcws and laboratory scientists, with respirators recommended for confirmed cases of viral haemorrhagic fever (including evd) (department of health, south africa ; superior health council, belgium , the department of health uk, ). among healthcare organizations, only msf recommends respirators for evd, and notably, in contrast to other international agencies including who, no msf worker has developed evd during the west african outbreak (thomson, ) . in conclusion, whilst ev is predominantly spread by contact with blood and body fluids, there is some uncertainty about the potential for aerosol transmission. there is rct evidence for respirators (but not masks) providing protection against non-aerosolised infections, and an abundance of evidence that transmission of pathogens in the clinical setting is rarely unimodal. where uncertainty exists, the precautionary principle (that action to reduce risk should not await scientific certainty) should be invoked and guidelines should be consistent and err on the side of caution. moreover, a clear description of risk should be provided to hcws (jackson et al., ) . given the predominant mode of transmission, every hcw death from ebola is a potentially preventable death. it is highly concerning that a recent commentary suggests hcws do not need a mask at all ''to speak with conscious patients, as long as a distance of - metres is maintained'' (martin-moreno et al., ) . this fails to consider the changeability and unpredictability of the clinical environment and disregards the rights of the hcw. it is also unrealistic to believe a hcw can constantly keep track of their distance from a patient in the hectic acute care setting. we accept that cost, supply and logistics may, in some settings, preclude the use of respirators, but guidelines should outline best practice in the ideal setting, with discussion about contingency plans should the ideal recommendation be unfeasible. importantly, in the absence of sufficient evidence, recommendations should be conservative and estimation of risk considered. recommendations should be developed using a risk analysis framework, with the occupational health and safety of hcws being the primary consideration. cr macintyre has conducted several investigatordriven trials of respirators vs face masks, one of which was funded by an australian research council linkage grant, where the industry partner was m, a manufacturer of ppe. m also provided supplies of surgical masks and respirators for the investigator-driven trials in health workers in china. h seale was also involved in this research as a co-investigator. a chugtai has had filtration testing of masks for his phd thesis conducted by m australia. evaluation of transmission risks associated with in vivo replication of several high containment pathogens in a biosafety level laboratory emergence of zaire ebola virus disease in guinea -preliminary report effects of cleaning and disinfection in reducing the spread of norovirus contamination via environmental surfaces infection prevention and 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recommendations to the attention of healthcare professionals and health authorities regarding the identification of and care delivered to suspected or confirmed carriers of highly contagious viruses (of the ebola or marburg type) in the context of an epidemic outbreak in west africa available at: www.shea-online.org/portals/ /pdfs/belgian-guidelines-ebola aerosol transmission of influenza a virus: a review of new studies ebola virus disease (evd) outbreaks in west africa. important information for clinicians in secondary or tertiary care available at: www management of hazard group viral haemorrhagic fevers and similar human infectious diseases of high consequence. advisory committee on dangerous pathogens available at: www ebola & marburg outbreak control guidance manual. version . transmission of ebola virus from pigs to non-human primates. sci. rep. , . world health organization (who), a. ebola and marburg virus disease epidemics: preparedness, alert, control, and evaluation available at ebola virus disease -democratic republic of congo available at unprecedented number of world health organization (who) ebola virus disease update -west africa infection prevention and control guidance for care of patients with suspected or confirmed filovirus haemorrhagic fever in health-care settings evidence of airborne transmission of the severe acute respiratory syndrome virus we acknowledge dr. kathleen harriman, phd, mph, rn, chief, vaccine preventable diseases epidemiology section, immunization branch, california department of public health for comments and reviewing the final manuscript. key: cord- -lrk ty authors: mohammed, abdulaziz; sheikh, taiwo lateef; gidado, saheed; poggensee, gabriele; nguku, patrick; olayinka, adebola; ohuabunwo, chima; waziri, ndadilnasiya; shuaib, faisal; adeyemi, joseph; uzoma, ogbonna; ahmed, abubakar; doherty, funmi; nyanti, sarah beysolow; nzuki, charles kyalo; nasidi, abdulsalami; oyemakinde, akin; oguntimehin, olukayode; abdus-salam, ismail adeshina; obiako, reginald o. title: an evaluation of psychological distress and social support of survivors and contacts of ebola virus disease infection and their relatives in lagos, nigeria: a cross sectional study − date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: lrk ty background: by september , an outbreak of ebola viral disease (evd) in west african countries of guinea, liberia, sierra leone, senegal and nigeria, had recorded over and probable or confirmed cases and deaths respectively. evd, an emerging infectious disease, can create fear and panic among patients, contacts and relatives, which could be a risk factor for psychological distress. psychological distress among this subgroup could have public health implication for control of evd, because of potential effects on patient management and contact tracing. we determined the prevalence, pattern and factors associated with psychological distress among survivors and contacts of evd and their relatives. methods: in a descriptive cross sectional study, we used general health questionnaire to assess psychological distress and oslo social support scale to assess social support among participants who survived evd, listed as evd contacts or their relatives at ebola emergency operation center in lagos, nigeria. factors associated with psychological distress were determined using chi square/odds ratio and adjusted odds ratio. results: the mean age and standard deviation of participants was +/ - . years. of participants, ( . %) were females, ( . %) had a tertiary education and ( . %) were health workers. most frequently occurring psychological distress were inability to concentrate ( . %) and loss of sleep over worry ( . %). losing a relation to evd outbreak (or = . , % ci, . – . ) was significantly associated with feeling unhappy or depressed while being a health worker was protective (or = . , % ci, . – . ). adjusted odds ratio (aor) showed losing a relation (aor = . , % ci, . – . ) was a predictor of “feeling unhappy or depressed”, loss of a relation (aor = . , % ci, . – . ) was a predictor of inability to concentrate. conclusions: survivors and contacts of evd and their relations develop psychological distress. development of psychological distress could be predicted by loss of family member. it is recommended that psychiatrists and other mental health specialists be part of case management teams. the clinical teams managing evd patients should be trained on recognition of common psychological distress among patients. a mental health specialist should review contacts being monitored for evd for psychological distress or disorders. the west african outbreak of ebola virus disease (evd) began in guinea in december [ ] . the outbreak involved sustained transmission in guinea, liberia, and sierra leone [ ] . by september , , the total number of probable and confirmed cases was , with deaths recorded from five countries in west africa namely, guinea, liberia, nigeria, senegal, and sierra leone [ ] . the first known case of evd was reported in nigeria on th july , through a man who travelled to lagos, nigeria, via lomé, togo and accra, ghana [ ] . as of th september , the total number of confirmed evd cases in nigeria was ( in lagos and in port harcourt) of which had survived and seven reported dead. four hundred and seventy contacts had completed days of follow up necessary to rule out evd infection. the news of evd spread into nigeria created widespread media attention, which initially focused mainly on the high infectivity and case fatality, with the potential to create fear and panic. also, the process of infection control and prevention necessary for the control of emerging infectious disease (eid) like evd involves the use of personal protective equipment, quarantine, and isolation [ ] , all of which may be associated with fear and anxiety. public apprehension of newly detected emerging infectious disease with high morbidity and mortality had been previously described. joffe et al. [ ] described pattern of public response to emerging infectious diseases like evd. this general public response pattern includes distancing the disease from self, blame of particular entities for the disease's origin and/or spread, and stigmatization of those who have contracted it and/or who are represented as having intensified its spread. the process may be driven by worry, fear and anxiety, which necessitate a psychosocial intervention as part of all outbreak response to eids like evd. in a study to assess the psychological impact of the outbreak of severe acute respiratory syndrome on hospital employees, about % of the respondents had experienced high levels of post-traumatic stress symptoms [ ] . researches conducted during evd outbreaks tend to focus on clinical manifestations and epidemiology of evd with little or no study on psychosocial impact or distress associated with evd. a study in democratic republic of congo described the feelings and experiences of survivors of ebola epidemic [ ] . they described psychosocial consequences among survivors to include fear of falling seriously ill, denial, fear of being accused by neighbors and shame. others included rejection by society, belief that the infection was a divine punishment, lack of income, and intense grief for colleagues who did not survive the epidemic. the previous study did not include use of a standardized instrument for evaluation of psychological distress and social support available to the respondents. no previous study that employed the use of standardized instruments like ghq or oss to measure psychological distress or social support among survivors and contacts of evd or their relatives was found after a literature review. we set out to determine the prevalence and pattern of psychological distress among the survivors, relatives and contacts of evd. we also assessed the social support available for the survivors, relatives and contacts of evd. finally, we determined factors associated with psychological distress. the study was conducted in lagos state. lagos state is located in the southwestern part of nigeria and has an estimated land area of km ( sq ml). the metropolitan area consists of islands, such as lagos island and extension into the adjacent mainland. the lagos international airport is the busiest of all the international airports in nigeria [ ] . we conducted a descriptive cross sectional study. the study population consisted of persons listed as survivors and contacts by the emergency operations center (eoc) for evd in lagos and a first-degree relation judged to be the primary care giver by the evd patient or contact. inclusion criteria survivors . persons confirmed as a case of evd in the present outbreak response and had been managed in the isolation ward of the response. . persons confirmed cured and discharged from isolation ward by case management team. persons determined by the contact tracing team to have been a contact of a known confirmed case of evd using standard protocol [ ] . . contacts who are being actively followed up or had completed the follow up period. . must be a first-degree relation (father, mother, spouse, child or sibling) who was adjudged to have actively supported the survivor during case management or contacts during contact tracing. . not currently living in lagos. we estimated that by interviewing a third of survivors and contacts in the line list of the contact tracing team as at the time of the evaluation and their relatives, we will be able to achieve the minimum sample size of calculated using the leslie and kish formula [ ] for estimating sample size for cross-sectional study. where: n = minimum sample size zα set at % significant level = . p = estimates of proportion of study population with psychological distress. we used the prevalence of % ( . ) psychological consequences of severe acute respiratory syndrome (similar eid to evd) among hospital workers in china. the calculated sample size was . the calculated sample size was adjusted for small population size (n = ) using the formula for finite population correction. where: n f = the desired sample size when population is less than , n = the desired sample size when the population is more than , n = the estimate of the evd survivors and contact or their relations ( ) as at the time of study for this study we targeted respondents we randomly selected the contacts for the study using the contact tracing team line list of all contacts with over people listed during the duration of the study. of the eight cases listed as survivors during the time of study, four were interviewed during the study period. for every contact or survivor selected for the study, we attempted to interview a first-degree relation (spouse, parent, child or full sibling) identified by the survivor/contact, if available and also meeting the case definition for a relation. we designed a socio-demographic questionnaire to collect information on the respondents' age, gender, marital status, local government area (lga) of residence, and level of education. we also asked if respondents had loss a relation due to the evd outbreak. the general health questionnaire -item version (ghq ) was used to assess psychological distress among the study participants. the general health questionnaire (ghq) is a screening questionnaire, designed for screening individuals with a diagnosable psychiatric disorder [ ] . the ghq does not generate specific psychiatric diagnosis but rather screens for individuals with possible disorders. in its original version, it had items (ghq- ), which were reduced to (ghq- ), and items (ghq- ) [ ] . the -item general health questionnaire (ghq- ) is the most extensively used screening instrument for common mental disorders in addition to being a more general measure of psychological wellbeing. the psychometric properties of ghq have been evaluated in several studies [ , ] . the oslo social support scale (oss) was used to assess patients' social support base during the period. the oslo -item social support scale provides a brief measure of social functioning and has been considered a good predictor of mental health [ ] . it covers different fields of social support, as it measures the number of people the respondent feels close to, the interest and concern shown by others, and ease of obtaining practical help. the oslo social support scale had been validated in nigeria [ ] . respondents who answered "difficult" or "very difficult" to the question "how easy can you get help from neighbors?" were defined as having difficulty getting help from neighbors during need. respondents who answered "none" or " - " to the question "how many people are close to you that you can count on if you have serious problems?" were defined as having less than people who they can count on for help for serious problem. finally those who answered "no", "little", or "uncertain" to the question "how much concern do people show in what you are doing", were defined as having people showing little concern in what they are doing. due to the interest in the pattern of psychological distress and social support among the respondents we analyzed each variable in the ghq and oss separately instead of using aggregate scores we recruited five resident doctors of the nigerian field epidemiology and laboratory training program [ ] as data collectors, who were part of the contact tracing team and had extensive experience with data collection from prior activities. they were trained for a period of days on the use of the study questionnaires and interview techniques prior to the onset of the study. data collection took place over a period of weeks and the average duration of each interview was min. data were entered into epi info . . , cleaned and edited for inconsistencies before analysis. we summarized our findings using frequencies, means (with standard deviation) and proportions. we used odds ratio (or) with % confidence interval ( % ci) to check for statistically significant associations and unconditional logistic regression to check for independent predictors of psychological distress. the evaluation was part of the evd outbreak response and was therefore exempted from ethical clearance by the evd emergency operation center in lagos. the evd emergency operation center however read and cleared the protocol before onset of the study. written informed consent was obtained from each participant after complete description of the study. as part of the response to evd, all the contacts, relatives and survivors who reported or had noticeable distress irrespective of whether they were part of this study or not, had access to counseling and other forms of treatment from the members of the psychosocial subgroup of the clinical management team. those found to have clinically significant psychological morbidity were counseled and all assessed to require specialist care were referred to the neuropsychiatric hospital, lagos. a total of interviews were conducted, of which three were disqualified because the interviews were not completed. the mean age of participants was +/ - . years, age range - years. of the participants, four ( . %) were survivors, ( . %) were contacts, ( . %) were contact relations and one ( . %) was a survivor relation (table ) . two thirds of the participants were females and ( . %) had a tertiary education. forty-five ( . %) were health workers and about half ( . %) resided in eti-osa local government area (lga) of lagos state ( table ) . the most frequently occurring psychological distress among all respondents were "not been able to concentrate on what you are doing" ( . %) and "lost much sleep over worry" ( . %). the least occurring psychological distress was "been thinking of yourself as worthless" ( . %). "not been able to concentrate on what you are doing" and "lost much sleep over worry" were the most frequently occurring psychological distress among survivors ( % and %, respectively) and among contacts ( . and . % respectively). only ( . %) of the participants reported "can count on less than people for help for serious problem" ( table ) . losing a relation to the evd outbreak (or = . , % ci, . - . ) was significantly associated with the psychological distress of "feeling unhappy or depressed" while being a health worker (or = . , % ci, . - . ) was protective. having no tertiary education (or = . , % ci, . - . ) was significantly protective against "not been able to concentrate", while living in eti-osa lga (or = . , % ci, . - . ) was significantly associated with "not feeling reasonable happy". all the four survivors reported they had, "not been able to concentrate" (table ) . losing a relation (aor = . , % ci, . - . ) remained an independent predictor of the psychological distress of "feeling unhappy or depressed". loss of a relation (aor = . , % ci, . - . ) remained an independent predictor of the psychological distress of "not been able to concentrate" while having no tertiary education (aor = . , % ci, . - . ) remained a protective factor against "not been able to concentrate" (table ). the most frequently occurring psychological distress among the respondents: inability to concentrate, losing much sleep over worry and being unhappy or depressed are key clinical features of anxiety, depression and post traumatic stress disorders (ptsd) as described in the diagnostic and statistical manual (dsm) of mental disorders [ ] . though the individual psychological distress does not amount to a neuropsychiatric disorder, it does indicate the presence of some psychological distress among the respondents that may have the potential to progress if not properly managed. evd can be perceived as a life-threatening event that meets a key diagnostic criterion of ptsd in dsm [ ] . the development of ptsd following life-threatening event has been demonstrated among nigerians [ ] and among health workers who had contact with severe acute respiratory syndrome (sars) [ ] . other less severe disorders caused by reaction to extremely stressful situations such as acute stress reaction and adjustment disorders could also present with the above psychological distress. the psychological distress of being unable to concentrate could be mistaken for cognitive impairment by the clinical management team if it occurs in a patient with evd, could be confused for viral encephalopathy or onset of brain damage secondary to evd infection. a case of adjustment disorder, in a survivor of the nigerian evd outbreak, initially diagnosed as having brain damage secondary to viral encephalitis is an example [ ] . losing a relation during this evd outbreak was significantly associated with being unhappy or depressed. this could be dismissed as a usual response to bereavement in people, but the feelings of depression (whether from normal grief or psychopathological) could have implication for the management of patients with evd or for the contact tracing team while monitoring contacts for clinical manifestation of evd. it could affect judgment and thus reduce cooperation with either the clinical management team or contact tracing team. feelings of depression could also cause patients or contacts of evd to tolerate emerging symptoms of evd thereby not reporting them to the management team. this could people show little or no concern in what you are doing ( . ) ( . ) ( . ) ( . ) complicate overall clinical impression of the patient or cause problems with determining the exact time of onset of clinical symptoms. the effect of an evd contact, with feelings of depression, failing to disclose important clinical symptoms may lead to delayed or failed recognition of evd onset with far reaching public health importance. the psychological stress of bereavement can mimic severe depression but also bereavement has long been described as a risk factor for development of depression [ ] . furthermore, it has been suggested that risk factors for common mental health problems arising from the evd outbreak such as witnessing and caring for individuals who are severely ill, perceived life threat, substantial mortality and bereavement, and the deaths of trained health care workers, in conjunction with the lack of well-trained mental health professionals in countries experiencing evd outbreak in west africa could amplify the risks of developing enduring psychological distress and progression to psychopathology by those affected [ ] . although the psychological distress the extensive social support base of the nigerian community, which is not limited to the immediate family members, may have helped the social support respondents had. poor social support was only a problem to less than a quarter of the respondents. this may have been due to the relatives not being aware of what the respondents were going through. overall, only few of the respondents demonstrated poor social support, respondents who had little or no interest shown in their activities were more likely to lack self-confidence. having no tertiary education, which was protective of inability to concentrate, may not be an entirely positive finding because it could reflect the lack of insight into the implication of an infection with evd by those without tertiary education. the study found loss of a relation to be an independent predictor of feelings of unhappiness or depression and inability to concentrate. contacts or survivors who have lost close relations should be considered at high risk of developing psychological distress or even psychological disorders. loss of a relation is a traumatic experience that has been shown to be a predictor of ptsd [ ] and depression [ ] among persons exposed to traumatic experience in nigeria. therefore the psychosocial response team for evd outbreak should prioritize this subgroup of contacts and survivors for special monitoring and evaluation. the contact tracing teams following up this subgroup of contacts should include a member of the psychosocial response team with training in detection of psychological distress/disorders. the findings of this study are subject to the following limitations. we only assessed for psychological distress and not disorders. only few survivors were sampled which limited the ability to independently look at the dynamics of psychological distress among them. the evaluation could not interview the anticipated number of relatives because some of the contacts did not inform their immediate family members about their status as evd contacts and therefore could not be interviewed. despite these limitations, we are confident the findings of this study reflect the possible psychological distress following being a survivor or contact of evd or a relation to any. we concluded that survivors and contacts of evd or their relatives develop psychological distress that could be predicted by loss of a relation and recommended that mental health specialists and social workers be part of the case management team of the response to evd outbreak. the clinical teams managing evd patients should be trained on recognition of psychological distress among the patients and recognition of common psychiatric disorders like depression that could follow evd infection, and special attention should be paid to those who have lost a relation. we also recommended the follow up of all survivors/contacts with increased risk of developing psychological distress or disorders for a minimum period of months by a mental health specialist for early detection of mental health disorders following evd. the findings of this study were shared with the ebola emergency operation center in lagos and the main findings were equally presented to the meeting of the association of psychiatrists and allied professionals in nigeria. nigerian center for disease control, abuja, nigeria. lagos state ministry of health, lagos, nigeria. department of medicine, ahmadu bello university, zaria, nigeria. emergence of zaire ebola virus disease in guinea -preliminary report ebola -underscoring the global disparities in health care resources who ebola response team. ebola virus disease in west africa -the first months of the epidemic and forward projections who. ebola situation in port harcourt, nigeriano title infection prevention and control recommendations for hospitalized patients with known or suspected ebola hemorrhagic fever public apprehension of emerging infectious diseases: are changes afoot? the psychological impact of the sars epidemic on hospital employees in china: exposure, risk perception, and altruistic acceptance of risk survey among survivors of the ebola epidemic in kikwit, democratic republic of congo: their feelings and experiences muhammed international airport contact tracing during an outbreak of ebola virus disease survey sampling a scaled version of the general health questionnaire using the -item general health questionnaire (ghq- ) to assess the psychological health of malaysian college students the -item general health questionnaire (ghq- ): reliability, external validity and factor structure in the spanish population is the gds- better than the ghq- for screening depression in elderly people in the community? the bambui health aging study (bhas) social support -consequences for individual and society psychometric properties of the -item oslo social support scale among clinical students of bayero university kano nfeltp involvement in ebola response in nigeria american psychiatric association. diagnostic and statistical manual of mental disorders psycho-trauma, psychosocial adjustment, and symptomatic post-traumatic stress disorder among internally displaced persons in kaduna psychiatric treatment of a health care worker after infection with ebola virus in lagos, nigeria a meta-analysis of risk factors for depression in adults and children after natural disasters the ebola outbreak and mental health: current status and recommended response correlates of depression among internally displaced persons after postelection violence in kaduna, north western nigeria submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution submit your manuscript at www the authors declare that they have no competing interests.authors' contributions am conceived the study and developed the initial and subsequent drafts. key: cord- -dbrp vxc authors: gibbs, shawn g.; herstein, jocelyn j.; le, aurora b.; beam, elizabeth l.; cieslak, theodore j.; lawler, james v.; santarpia, joshua l.; stentz, terry l.; kopocis-herstein, kelli r.; achutan, chandran; carter, gary w.; lowe, john j. title: review of literature for air medical evacuation high-level containment transport date: - - journal: air medical journal doi: . /j.amj. . . sha: doc_id: cord_uid: dbrp vxc abstract introduction aeromedical evacuation (ae) is a challenging process, further complicated when a patient has a highly hazardous communicable disease (hhcd). we conducted a review of the literature to evaluate the processes and procedures utilized for safe ae high-level containment transport (ae-hlct) of patients with hhcds. methods a literature search was performed in pubmed/medline (from through january ). authors screened abstracts for inclusion criteria and full articles were reviewed if the abstract was deemed to contain information related to the aim. results our search criteria yielded publications and were separated based upon publication dates, with the natural break point being the beginning of the - ebola virus disease epidemic. best practices and recommendations from identified articles are subdivided into pre-flight preparations, inflight operations, and post-flight procedures. conclusions limited peer-reviewed literature exists on ae-hlct, including important aspects related to healthcare worker fatigue, alertness, shift scheduling, and clinical care performance. this hinders the sharing of best practices to inform evacuations and equip teams for future outbreaks. despite the successful use of different aircraft and technologies, the unique nature of the mission opens the opportunity for greater coordination and development of consensus standards for ae-hlct operations. air medical evacuation (ae) is a challenging process, further complicated when a patient has a highly hazardous communicable disease (hhcd). the ease of air travel, tourism, and expansion of international commerce exposes all regions of the world to these diseases. the preference is to treat patients with hhcds on-site, rather than transport from the outbreak area ; however, high-level containment transport (hlct) evacuations may be preferred when ) there is an incapacity of the local infrastructure to provide care, ) there is a potential detrimental effect to local health care workers (hcws) (ie, the patient is a colleague), ) the outbreak is in an active war or conflict zone, ) it is a policy decision (to increase volunteerism), or ) there are local or national political concerns. regardless, successful ae hclts of patients with hhcds requires a discussion on risks, benefits, planning, training, and resources. the to ebola virus disease (evd) epidemic prompted multiple ae hlcts; at least nations conducted ae hlcts for at least patients with evd within the country and internationally. [ ] [ ] [ ] [ ] the ae-hlcts were conducted by single-patient isolation transports. since that epidemic, multiple groups have developed ae hlct systems enabling simultaneous isolation and care of multiple patients; these include the us department of state containerized bio-containment system and the us department of defense (dod) transport isolation system. the us centers for disease control and prevention issued ae guidance for evd in . although portions of the guidance were broadly applicable, it was evd specific, lacked discussion of logistical challenges, and did not include experiences from recently conducted ae hlcts. no ae hlcts during the epidemic had secondary transmissions although they were conducted differently by each organization. some evacuation procedures were preestablished and drilled, whereas others were based on situational needs. ae hlct has increased since it was introduced in the s, but no literature review comparing approaches has been published. a literature review queried the intersection of key words "biological warfare" and "aeromedical evacuation" or "transportation of patients" and yielded a single citation; today, that same search yields results. [ ] [ ] [ ] [ ] this study's purpose is to provide a more comprehensive evaluation of the processes and procedures used for safe ae hlcts of patients with hhcds in preflight, in-flight, and postflight environments. a literature search was performed in pubmed/medline (from through january ) with the following terms: ) "aeromedical isolation," ) "aeromedical evacuation" or "transportation of patients" or "air ambulance" or "hems" or "helicopter" and "ebola" or "lassa" or "viral hemorrhagic" or "highly infectious" or "highly hazardous" or "contagious" or "communicable" or "middle east respiratory syndrome (mers)" or "sars" or "smallpox", and ) "mobile" or "transport" and "high-level isolation" or "high containment". authors screened abstracts for the following inclusion criteria: peer-reviewed literature, written in english, and described ae hlct of persons with an hhcd. diseases considered highly hazardous were identified based on the following definition by the european network for highly infectious diseases: "an infection that is easily transmissible from person to person; life-threatening; presents a serious hazard in the health-care setting and the community; and requires specific control measures (e.g., high-level isolation)." this definition is understood to include various viral hemorrhagic fevers, severe acute respiratory syndrome (sars), and other easily transmissible emerging infectious diseases. articles were reviewed if the abstract contained information related to the aim, with those focused exclusively on ground transport or ae of non-hhcd patients excluded. the search terms yielded publications; met the inclusion criteria and were included in the study (tables and ). the articles were separated based on publication dates, with the natural break point being the to evd epidemic. thoms et al discussed drawing on the operational experience from phoenix air corporation, a private organization that began ae hlcts in when it developed the aeromedical biological containment system. the us department of state, united nations, and other governments used that single-patient transport system for ae hlcts of patients with evd in to . although phoenix air corporation's ae hlct experience is widely known, details of their procedures and policies were not published in peer-reviewed literature and were not available. planning for and executing ae hlcts must account for multiple variables; our review is organized around "preflight, in-flight, and postflight" environments. a broad spectrum of diseases was covered in the reviewed articles, including airborne diseases, biological warfare agents, , , and viral hemorrhagic fevers. articles published before targeted many diseases (table ) , whereas articles published after (table ) focused almost exclusively on evd. pre- articles included considerations for airborne isolation, whereas post- articles stressed contact isolation associated with evd. the reviewed articles understated the considerable collaborations involved in ae hlct decision making because most only vaguely mentioned frequent discussions and multiagency requests must occur before transport. [ ] [ ] [ ] nicol et al did indicate that the decision to evacuate patients is a "complex process that considers the clinical, public health, and political contexts." although no article identified a decision-making rubric for deploying ae hlct assets, several discussed factors involved in the decision-making process (eg, recommendations by domestic and international agencies). lotz and raffin indicated their transport met recommendations set by the world health organization for medical evacuation of patients with high infectious risk ( - hours). thoms et al noted that ". . . u.s. military policy is to treat highly infectious patients 'in place', and avoid unnecessary evacuation to the u.s." but acknowledged instances in which transport would occur, such as index cases or for political considerations. given the current emphasis on military participation in nation-building efforts, it is unlikely that adequate resources for "treatment in place" will be present during future outbreaks. as such, the military may become increasingly reliant on ae hlcts. patient stability and survivability were noted as principal factors in the decision to conduct an ae hlct; a patient moved before the onset of severe disease manifestations is preferable and, at times, a requirement for transport because of limited isolation units. , , , [ ] [ ] [ ] ae hlct places additional stressors associated with altitude on the patient that impact their physical condition (eg, hypoxia and claustrophobia). , , , , articles identified a lack of local facilities with resources and capabilities as a reason for domestic or international evacuation. , , volunteers supporting humanitarian endeavors overseas are often assured that they will be repatriated should they become ill, as was the case during the to evd epidemic when at least evd-infected hcws/volunteers were evacuated to their home countries. no reviewed articles detailed the types, duration, requirements, or frequency of training. biselli et al noted training includes personal protective equipment (ppe), patient management on ground and inflight, and equipment decontamination, whereas christopher and eitzen, which detailed a royal air force mission, remarked on the benefit of in-flight, just-in-time training that occurred on the flight to the patient, while also stating that the mission resulted in routine air transport isolator exercises. as with many fields, it is difficult to determine applicable training and exercise needs for ae hlct. organizations work internally (considering equipment, mission, and personnel) to determine the appropriate training and delivery to maintain competency. the regulations and legal limitations associated with the ae hlct were not fully explored in any reviewed article. two articles mentioned the need to adhere to organizational policies, , noted a requirement to obtain consent from governments for transports and one stated ae hlct teams routinely seek diplomatic clearance when flying over other nations, but none discussed applicable federal or international regulations. withers and christopher , discussed the need for regulations to address the unpredictable reaction of the international community in a hhcd event but primarily focused on the biological weapons and toxin convention protocol. schilling et al discussed the need for flight certification to ensure materials are deemed safe to fly. withers and adams et al detailed preference for long-range capable aircrafts to limit refueling stops. all us military aircraft used in ae hlct missions are capable of midair refueling and are able to eliminate stops for fuel and/or extend flights to avoid the airspace of hostile or reluctant nations. four studies mentioned the importance of effective communication and coordination among partners, but none discussed details of communication plans. , , , seven articles did identify organizations that would be contacted to initiate a transport, albeit at a high level. , , , , , , thoms et al detailed crew predeparture briefings. the article by christopher and eitzen was the only one to detail communication plans with the patient in-flight, namely, -way radios between team members and patients. ewington et al and thoms et al detailed the space layout within the c aircraft that both evacuations used, including placement and securing of the isolation unit. thoms et al detailed "aircraft containment zones" for patient areas within the aircraft where hcws and crew could move within the aircraft and procedures and level of ppe that hcws and crew would need for each zone. nicol et al also demarcated clean and dirty zones for confirmed patients and established a corridor for access to toilets and eating spaces for exposed, asymptomatic cases. zone designation lends the ability to transport multiple patients at different stages of disease progression for the same disease or, more likely, to transport both suspected and confirmed patients. in the air medical transportation of a lassa fever patient from nigeria to germany, the following zones were established: a containment zone where the patient was located, a crew zone where ppe was not worn, and a neutral zone between the that was also available for plane-related emergency procedures. withers and christopher , stated that military "flight nurses know that cabin airflow is 'top to bottom, front to back' on the c- a nightingale; therefore, contagious patients are placed as far aft and as low as possible." withers and christopher , also noted particular considerations (eg, high-efficiency particulate air systems, air exchanges/hour, and negative pressure zones) are made on the ventilation systems within each aircraft for potential dispersion of aerosolized microbes from a contagious patient that is either uncontained in an isolation unit or may have been unknowingly contagious. the professional training level of ae hlct personnel varied ( table ). the articles by thoms et al and nicol et al were the only ones that explicitly noted the care team could be augmented with additional support to ensure adequate staff levels for the full flight dependent on the number of patients transported and, in the case of thoms et al, for flight duration; however, no details were provided on the targeted staffing-to-patient ratio or the flight duration that would demand augmented staff. although a critical issue, the time personnel spent in ppe is not extensively discussed. schilling et al noted a portable anteroom is used for ppe donning and doffing when flights exceeded hours. lamb noted the ae hlct team worked shifts consisting of nurse and paramedic, enabling the rest of the team to eat, sleep, and rest. other articles lacked analysis and recommendations for hcw fatigue x indicates the subject was included in the article. and shift rotation during longer transports. ppe can be cumbersome and trigger hcw physiological and psychological distress-even in environmentally controlled biocontainment facilities -and may be exacerbated at altitude. appropriate work-rest cycles; considerations to time in ppe; and fatigue, alertness, and clinical performance monitoring are important during ae hlct. the objective analysis of these factors is necessary to maximize performance and safety. every article mentioned the importance of proper ppe use, but few detailed ppe ensembles, and none described donning and doffing procedures. ewington et al noted that decontamination procedures were overseen by a designated and trained ppe monitor but lacked details on the ppe level or type. dindart et al stated their personnel used "full ppe" with no details provided; however, based on article images, it appears they used the world health organization−recommended ppe (goggles, procedure masks, fluid-resistant hood, fluidresistant coveralls, gloves, and boots). thoms et al described their use of "coveralls, multiple pairs of surgical gloves, rubber outer boots and a powered air purifying respirator (papr) system to prevent skin exposure"; christopher and eitzen and withers and christopher described similar configurations. schilling et al discussed the physical stress of working in a respirator but did not specify type; however, images indicate a ppe configuration similar to thoms et al. nicol et al repeatedly noted that once sealed, patient care during transport with the trexlar air transport isolator (t-ati) does not require staff to wear ppe. although lamb did not specify in-flight use, ppe similar to that described in the article by dindart et al was used for personnel that helped transport the patient onto the aircraft. most articles indicated that a portable isolation unit, such as the air transport isolators used by the italian air force and british military (previously used by usamriid), the t-ati currently used by the british military, the vickers aircraft transport isolator (previously used by usamriid), or the human stretcher transit isolator-total containment (oxford) limited (hsti-tcol) used domestically in guinea, were operated in-flight. , , , , , , the hsti-tcol was described in detail with significant limitations, including the inability to restrain the patient during turbulence or place items (eg, medicine, devices) into the unit once the patient is enclosed. although these portable units were described in varying levels of detail, each offered complete enclosure for a single patient, barrier protection for the hcws, and high-efficiency particulate air−filtered negative pressure air. , , most depended on batteries with a hour life, whereas others had the ability to use the aircraft's electrical system. , experiments showed that portable isolation chambers may leak or rupture when exposed to an explosive decompression ; therefore, contingency procedures should be in place. sweden and italy use a combined ground and air transport whereby a specially designed and equipped ambulance is driven inside of a c- . the patient remains in the ambulance in-flight; essentially, the ambulance becomes an isolation unit. this combination reduces loading time and the likelihood of aircraft contamination. the british military uses a dedicated road transport vehicle for the t-ati positioned at the receiving air base for seamless transport to the destination facility. a major limitation of transport systems was the inability to house multiple patients. newer systems currently in validation seek to alleviate this limitation. the transport isolation system is a dod containment modality designed and approved for loading onto c- and c- military aircraft; each system (aluminum frame with clear plastic liner that maintains a negative pressure isolation environment) is capable of moving multiple patients simultaneously, and such systems can be accommodated on the larger c- platform. the containerized bio-containment system is a us state department−sponsored platform similar to a hard-sided shipping container with viewing ports and a negative-pressure isolation environment. it has the capability to transport patients simultaneously with space for multiple caregivers and is designed to be loaded onto the c- (not yet approved by the us air force) or the boeing airframe. , procedures/capabilities in-flight care provided during ae hlcts will not be equivalent to that available at a dedicated health care facility. however, several articles detailed the ability to provide a wide range of medical procedures in-flight (eg, endotracheal incubation and defibrillation) , , , ; other articles implied in-flight procedures were limited to monitoring. the type of isolation unit limits capabilities in-flight; for example, the hsti-tcol detailed in the study by dindart et al is a sealed pod and enables only limited interventions (eg, intravenous rehydration and antiemetics). in reviewing articles and operational experiences for evd, we found a lack of consideration and planning for liquid and solid waste. there is a general underestimation of the volumes of both produced in-flight and an unclear understanding of the rules and regulations that govern waste during each transport phase. lotz and raffin and ewington et al indicated waste generated by the patient in-flight were kept within the isolation unit but segregated from the patient. upon transport completion, the isolation unit was enveloped, and all associated waste destroyed , ; however, methods for packaging, transporting, and subsequent waste destruction were not described. thoms et al stated a transportable lavatory would be included on the aircraft and used to capture liquid waste but did not discuss the handling and storage of solid wastes generated in-flight (eg, ppe). nicol et al noted waste can be minimized in-flight by using containers with absorbent powder or solidifying agents but did not detail the process. lamb discussed the process of double bagging ppe used for patient receival with the intention to dispose with waste generated in-flight but did not elaborate. dindart et al indicated that waste generated in-flight would be collected and incinerated postflight; however, no details were provided. withers and christopher , discussed criteria for a decontaminating compound (eg, effective within a short time, in low concentrations with low human toxicity, stable shelf life, and compatible with aircraft materials). this stressed the importance of the compound compatibility with aircraft materials. only nicol et al mentioned the existence of a mortuary protocol if the patient were to pass away in-flight, stating only that a death inflight is "managed with standard procedures, which vary depending on the jurisdiction of the flight." in the case of a death in-flight, a decision would have to be made to either continue to the destination or return to the departure origin based on factors such as distance traveled, available fuel, political considerations, and other patients awaiting transport. although such a decision would be made in communication with decision makers on the ground, preliminary discussions of this contingency would be beneficial. several potential in-flight emergency scenarios were discussed. ewington et al acknowledged the potential of an isolation unit breach and noted the medical engineer would conduct repairs immediately. in discussing emergency evacuation procedures, thoms et al noted crew would don patients in ppe to reduce exposure and minimize contact with rescuers or nonmission personnel. postflight details were limited in most reviewed articles. dindart et al stated "the plane is decontaminated using a chlorine solution at every point of contact between the pod and the plane, which take about min." thoms et al indicated that a dilution of disinfectant solution calla (zip-chem products, morgan hill, ca) and sani-wipes (disposables international, incorporated, orangeburg, ny) were available during the transport. it also stated that postflight "medical crewmembers and/or equipment will be decontaminated per current policy"; however, there were no policy details. lotz and raffin indicated that "disinfection of the cabin of the aircraft and medical equipment with nocolyse (oxy'pharm; champigny-sur-marne, france) spray (hydrogen peroxide, catalyst, biosurfactant)" is conducted after mission conclusion. schilling et al detailed the use of formaldehyde fumigation as the final decontamination posttransport and indicated that sweden used a nonflammable peracetic acid for decontamination of the staff. nicol et al stated the t-ati system was fumigated with vaporized hydrogen peroxide and the frame decontaminated and returned for reuse after days. tsai et al detailed the use of bleach solution spray on the isolation unit and ppe before air transport of patients with sars, and the use of water spray and desiccation on the isolation unit upon transport completion. wilson and driscoll also reported the use of bleach for surface decontamination before boarding the aircraft. posttransport decontamination of aircraft differed. efficacy is the primary intention; however, decontamination agents must also comply with aircraft material compatibility. the viability and stability of pathogens differ; therefore, decontamination methods may be adapted based on the hhcd. lufthansa technik, a german laboratory, found disinfectant components effective against hhcds while also aircraft compatible (alcohol, formaldehyde, and hydrogen peroxide) and detailed standard operating procedures for aircraft disinfection. more research and information on regulations are needed to support safe aircraft decontamination. waste disposal details were lacking. two articles indicated waste was incinerated , but did not specify how it was packaged or transported before incineration. likewise, nicol et al noted the isolator envelope is autoclaved on-site and disposed of as regulated clinical waste after decontamination but did not provide additional details. in the united states, the terminal disposal of category a waste (of which evd and many other hhcds are classified) is costly and requires specific packaging and a vendor with a department of transportation special permit to move and process the waste. all transporting organizations should have written protocols and procedures for the terminal disposal of category a waste and, when necessary, preidentify a certified vendor if the waste is not able to be autoclaved, incinerated, or deactivated on-site to downgrade the hazardous materials classification. thoms et al mentioned only that an infectious disease physician might screen medical personnel postflight. tsai et al indicated that personnel performed twice daily temperature monitoring for days after a sars transport. lamb noted that personnel were monitored for only hours after returning to the united kingdom because the transported patient later tested negative for lassa fever and positive for malaria. as with monitoring of hcws providing care in high-level containment facilities, postmission monitoring of crew and hcws should be included in written protocols to minimize the opportunity for further transmission. there are limitations to this review. ae of trauma patients and cases of other communicable diseases that are not highly hazardous may offer important considerations for operating procedures that were not included in this review. there also exists an inherent bias in the exclusion of non−english language documents, as well as the lack of access to publicly available non−peer-reviewed resources produced by various organizations. additionally, our review was conducted specifically searching for "highly hazardous" and "highly infectious" diseases. other terms are also used, but these were not included in the literature because we were aware that european high-level containment facilities and the majority of federal documents used the terms "highly infectious" or "highly hazardous communicable" diseases before and during the evd epidemic. moreover, this review focuses specifically on ae of patients with hhcds; clearly, the ground transportation facet is a critical component of the safe movement of such patients and has its own challenges and risks. since the evd epidemic, the us state department and dod have developed systems for ae hlcts of multiple patients of varying levels of hhcd acuity during the same operation. although ae hclt during the evd epidemic was managed within phoenix air corporation's capabilities, a larger global epidemic may demand scalability. ae hlct systems advancement with increased space and ability to perform care within the unit enables more advanced patient care procedures than available in single-patient isolation. however, with the improved capability for in-flight care, discussions are needed on what medical procedures should be conducted in-flight, focusing on minimizing aerosol generation. additionally, post- reviewed articles (table ) reflect the increasing staffing demands for patients with evd; the transport of multiple patients with hhcds will only enhance the resource-intensive nature of these missions. ae hlct poses significant risks to crews. high hhcd mortality rates and the unstable environment inherent in aes require policies and procedures to decrease transmission risks and maximize patient management. the designation of high-level isolation facilities in the united states and europe narrows the list of potential receiving facilities; procedures should be well discussed and thoroughly exercised between transporting organizations and their respective receiving facilities. a future outbreak of a hhcd is likely; advancing the field of ae hlct is critical. there is limited peer-reviewed literature available on ae hlct, including important aspects related to hcw fatigue, alertness, shift scheduling, and clinical care performance. few experienced teams have published details on their processes, experience, and operations, and this limited breadth of literature hinders the sharing of best practices to inform evacuations and equip teams for future outbreaks. despite the successful use of different aircraft and technologies, the unique nature of the mission opens the opportunity for greater coordination and the development of consensus standards for ae hlct operations. supplementary material associated with this article can be found, in the online version, at doi: . /j.amj. . . . mobile high-containment isolation: a unique patient care modality long-range transportation of ebolaexposed patients: an evidence-based protocol the immediate psychological and occupational impact of the sars outbreak in a teaching hospital pre-hospital transportation in western countries for ebola patients, comparison of guidelines aerial medical evacuation of health workers with suspected ebola virus disease in guinea conakry-interest of a negative pressure isolation pod-a case series transferring patients with ebola by land and air: the british military experience clinical management of ebola virus disease in the united states and europe guidance on air medical transport (amt) for patients with ebola virus disease (evd) aeromedical evacuation: management of acute and stabilized patient aeromedical evacuation of biological warfare casualties: a treatise on infectious diseases on aircraft new scenarios in major accidents−use and adaption of current concepts to ward off damage jubail−an aeromedical staging facility during the gulf conflict: discussion paper association for professionals in infection control and epidemiology inc. and centers for disease control and prevention framework for the design and operation of high-level isolation units: consensus of the european network of infectious diseases how phoenix air entered the ebola business transporting patient with suspected sars air evacuation under high-level biosafety containment: the aeromedical isolation team transporting patients with lethal contagious infections aeromedical transfer of patients with viral hemorrhagic fever aeromedical evacuation using an aircraft transit isolator of a patient with lassa fever european concepts for the domestic transport of highly infectious patients the added value of preparedness for aeromedical evacuation of a patient with ebola containment aircraft transit isolator evaluation of infection control practices during an ae neuilly sur seine, france: advisory group for aerospace research and development ebola virus disease: preparedness and infection control lessons learned from two biocontainment units world health organization. personal protective equipment in the context of filovrius disease outbreak response airplane transport isolators may lose leak tightness after rapid cabin decompression ready for the challenge: dobbins selected as home for new biocontainment system mil/desktopmodules/articlecs/print.aspx?portalid= &moduleid= &ar-ticle= nebraska biocontainment unit perspective on disposal of ebola medical waste disinfection of aircraft: appropriate disinfectants and standard operating procedures for highly infectious diseases need for aeromedical evacuation high-level containment transport guidelines key: cord- -xinkqs u authors: muñoz-fontela, césar; mcelroy, anita k. title: ebola virus disease in humans: pathophysiology and immunity date: - - journal: marburg- and ebolaviruses doi: . / _ _ sha: doc_id: cord_uid: xinkqs u viruses of the ebolavirus genus cause sporadic epidemics of severe and systemic febrile disease that are fueled by human-to-human transmission. despite the notoriety of ebolaviruses, particularly ebola virus (ebov), as prominent viral hemorrhagic fever agents, and the international concern regarding ebola virus disease (evd) outbreaks, very little is known about the pathophysiology of evd in humans and, in particular, about the human immune correlates of survival and immune memory. this lack of basic knowledge about physiological characteristics of evd is probably attributable to the dearth of clinical and laboratory data gathered from past outbreaks. the unprecedented magnitude of the evd epidemic that occurred in west africa from to has allowed, for the first time, evaluation of clinical, epidemiological, and immunological parameters in a significant number of patients using state-of-the-art laboratory equipment. this review will summarize the data from the literature regarding human pathophysiologic and immunologic responses to filoviral infection. ebola virus (ebov) is the prototypic member of the ebolavirus genus in the filoviridae family of negative-sense, single-stranded rna viruses. discovered in during the first documented outbreak of ebola virus disease (evd) in the town of yambuku in northern zaire (today democratic republic of the congo), ebov has since caused sporadic human disease outbreaks of varying magnitude in equatorial african countries (sanchez et al. a ). in march , an ebov variant later named ebov makona was first detected in guinea. this variant was responsible for a -year-long epidemic that affected tens of thousands of people in several west african countries, collapsing the healthcare systems of three of them. ebov makona rampaged through both rural and urban areas, and underscored previously poorly characterized features of evd, like sexual transmission and virus persistence after recovery rowe et al. ; chughtai et al. ; deen et al. ; fischer et al. ; rodriguez et al. ; varkey et al. ; uyeki et al. a) . the scientific and clinical knowledge of human evd before its appearance in west africa was very limited. the scarcity of human cases and their occurrence in rural areas of equatorial africa limited research, as did confinement of filovirus research to biosafety level containment laboratories. in addition, basic studies on evd pathophysiology have been hampered by the lack of susceptible small animal models with competent immunity. for example, laboratory mice, a commonly used disease model, are completely resistant to nonadapted ebov. before , evd was described as an acute hemorrhagic fever, thus earning its former name ebola hemorrhagic fever (ehf); case fatality rates of up to % had been reported. the disease was characterized by lymphopenia, disseminated intravascular coagulation (dic), immunosuppression, and a systemic inflammatory response resembling septic shock (feldmann and geisbert ) . while many of these observations have been strengthened by findings from the west african evd outbreak, some of the previous hypotheses have been revised. perhaps one of the most surprising findings has been the low overall number of human cases presenting with bleeding (schieffelin et al. ) , as well as the lack of correlation between bleeding and disease severity (schieffelin et al. ; mcelroy et al. a, b) . these findings triggered the change in disease nomenclature from ebola hemorrhagic fever to ebola virus disease. moreover, the finding that evd correlates with robust immune activation rather than immunosuppression mcelroy et al. a) , and the ability of the virus to persist in several body fluids long after recovery (varkey et al. ; uyeki et al. a; sow et al. ; green et al. ; deen et al. ) have changed our current view of evd and have prompted new directions in research and new public health policies. here we will aim to integrate these novel findings within the current human evd model, and will discuss future research directions. several ebolaviruses cause evd, and while differences may exist between the diseases caused by the individual viruses, this review will focus on evd as a disease caused by all known viruses in the ebolavirus genus (ebolaviruses) that are pathogenic for humans. the reader will note that most of the available data come from infections caused by ebov rather than the other pathogenic viruses in this genus: sudan virus (sudv), bundibugyo virus (bdbv), and taï forest virus (tafv). the related marburgviruses, marburg virus (marv) and ravn virus (ravv), will be mentioned where appropriate data are available, but unfortunately, information on marburg virus disease (mvd), which is caused by both of them, is still lacking. epidemiological data collected over the last years indicate that human infection with ebov occurs mainly through close contact with infected body fluids. this probably occurs during both spillover events (e.g., contact with infected blood during butchering of bushmeat) and human-to-human transmission. there is no evidence that direct contact with bats causes ebov spillover into humans (mari saez et al. ; leroy et al. ), but infection with marv and ravv via direct or indirect contact with egyptian rousettes (fruit bats of the species rousettus aegyptiacus) (amman et al. ; schuh et al. ) , has been documented. human visits to caves or mines in which these bats roost have been directly associated with the development of mvd (bausch et al. ; centers for disease and prevention ; adjemian et al. ) , strongly indicating that mucosal or skin contact with bat droppings is sufficient to initiate marv infection in humans. with the exception of the first evd outbreaks in zaire, which were linked to substantial percutaneous needle transmission (ebola haemorrhagic fever in zaire / ), most of the data since the early s suggest that exposing skin and mucosae to ebov while conducting activities like body washing during traditional funerals or caring for sick relatives in the household is sufficient for human-to-human transmission of ebov dowell et al. ; francesconi et al. ) . early data collected from a laboratory exposure to sudv even suggest that skin abrasions may not be necessary to allow ebolavirus entry through the skin (emond et al. ) . these findings raise questions regarding how ebolavirus infection takes place in skin and mucosae, and which cells are involved in the primary amplification of the virus. antigen-presenting cells are a putative initial target of ebov infection and previous research in animal models of disease has indicated that dendritic cells (dcs) and macrophages are early and preferred targets of ebov and support virus replication (geisbert et al. a) . both dcs and macrophages can also be productively infected by ebov in vitro (gupta et al. (gupta et al. , mahanty et al. ; bosio et al. ) , and ebov prevents activation of in vitro-derived dcs, mainly through the action of vp and vp (yen et al. ; jin et al. ; ilinykh et al. ) . to further complicate things, a great deal of research over the last decade has been devoted to defining the ontogeny and specific function of dc subsets in mice and humans. the emerging picture is that several cell subsets exist with overlapping and nonoverlapping functions, and these subsets can be roughly classified into classical, plasmacytoid, and inflammatory dcs in humans (see (haniffa et al. ) for an excellent review). whether ebov can equally infect different dc subsets is not known, but some of the existing evidence suggest that it cannot (leung et al. ) . for example, a number of cellular receptors have been involved in the attachment of ebov virions to target cells. these receptors include several c-type lectins present on the surface of dcs, such as dendritic cell-specific icam- -grabbing non-integrin (dc-sign) (simmons et al. ) and liver/lymph node sign (l-sign) . dcs of the epidermis and mucosal epithelium do not express these molecules, but langerhans cells in the skin and cd + dcs in mucosal epithelium do express the c-type lectin langerin (merad et al. ) . in fact, studies in monkeys and pigs have indicated that dc-sign + cells are scarce in the dermis and the lamina propria or submucosa in the steady state (schwartz et al. ; huang et al. ), suggesting that other cell types may be targets for early ebov replication. initiating ebov infection may depend on attachment to target cells via tim- and tim- , which are highly expressed in mucosal epithelia (rhein et al. ; kondratowicz et al. ) . initial virus amplification could then lead to inflammation and infiltration of a high number of myeloid cells expressing dc-sign and other described ebov attachment factors, like triggering receptor expressed on myeloid cells (trem- ) expressed by neutrophils (mohamadzadeh et al. ) , and human macrophage c-type lectin specific for galactose/n-acetylgalactosamine (hmgl) expressed by macrophages (takada et al. ) . the elucidation of the initial steps by which ebov establishes productive infection in a host organism is highly needed to understand the mechanisms by which the virus disseminates from the initial site of entry to the body, and perhaps to design medical countermeasures aimed at preventing virus spread. as mentioned above, dcs and macrophages are early targets of ebov infection. due to the migratory potential of dcs, these immune cells may participate in disseminating ebov from the initial points of entry to the draining lymph nodes (geisbert et al. a ). this strategy is commonly used by other viruses, including sars coronavirus , toscana virus (cusi et al. ) , and measles virus (mesman et al. ) , for dissemination in the host. however, perhaps due to the lack of suitable in vivo models for kinetic studies of ebov, the involvement of dcs in ebov dissemination has not been experimentally addressed. in any case, the specific subsets of cells responsible for ebov dissemination remain to be identified. it is plausible that tissue-resident dcs or inflammatory dcs derived from infiltrating monocytes are important for ebov dissemination. both myeloid dc populations are migratory and can transport a variety of antigens from inflamed tissues to the draining lymph nodes (leon et al. ; ersland et al. ) . conversely, macrophages and neutrophils are less likely to participate in ebov dissemination due to their low mobility and nonproductive infection, respectively (mohamadzadeh et al. ) . recent studies have demonstrated that human evd is associated with loss of peripheral blood monocytes, in particular nonclassical cd + monocytes ) which have been proposed as the main antiviral monocyte subset (cros et al. ). even though this study did not demonstrate direct infection of cd + by ebov, it raised the possibility that this cell subset could be involved in virus dissemination. in fact, cd + monocytes are also called patrolling monocytes due to their ability to attach to endothelial cells in a lfa- -dependent manner and to extravasate into inflamed tissues where they differentiate into inflammatory dcs and macrophages (cros et al. ; auffray et al. ). this hypothesis is also substantiated by a previous study that demonstrated that ebov particles can attach to monocytes and enter these cells only when the monocyte differentiation program has started, that is, during their differentiation into dcs and macrophages in inflamed tissues (martinez et al. ) . the identification of the dc subsets specifically involved in filovirus dissemination is a highly relevant topic of study, because the function of dcs can be enhanced or inhibited, ex vivo or in vivo, by antigen delivery or use of molecules and antibodies. therefore, dcs are putative immunotherapeutic targets for postexposure evd treatment (klechevsky and banchereau ) . for example, the ligand of the dc co-stimulatory molecule cd (scd l) is commonly used to enhance dc-mediated antigen presentation (kornbluth and bot ) , and previous studies have demonstrated a correlation between circulating levels of scd l and survival after sudv infection (mcelroy et al. a, b) . in addition, poor activation profiles of circulating antigen-presenting cells have been correlated with severe evd . these findings provide a rationale for the use of dc enhancers as immunotherapy candidates in filovirus disease. another key driver of ebov dissemination may be the cytokine microenvironment, since these innate immune signaling molecules play an important role in recruiting myeloid cells, which are putative ebov targets, to sites of inflammation. a considerable body of research exists on cytokine and chemokine responses during evd. despite some conflicts, in general, these data correlate fatal outcomes during evd with high concentrations of pro-inflammatory cytokines (e.g., il- ), pro-inflammatory chemokines (e.g., ip- ), and anti-inflammatory cytokines (il-ra and il- ), overall suggesting a general dysregulation in the expression of these key immune signaling molecules (hutchinson and rollin ; gupta et al. ; wauquier et al. ; baize et al. ; villinger et al. ). an inability to control viral replication is likely leading to continued innate immune stimulation. data from asymptomatic human cases have shown an even greater magnitude of cytokine and chemokine upregulation, followed by rapid downregulation of this response in association with control of viral replication (leroy et al. (leroy et al. , , suggesting that cytokine/chemokine dysregulation is a consequence of uncontrolled viral replication rather than a primary mediator of pathogenesis. type i interferons (ifn-i) are key antiviral cytokines, and perhaps one of the more conflicting aspects of comparing ebov experimental and clinical human data is the role of ifn-i in ebov immunity and pathogenesis. importantly, ifn-i not only induces an antiviral state in infected and bystander cells during early virus infection, but also is a key modulator in the transition between innate and adaptive immunity. by enhancing natural killer cell function, antigen presentation by dcs, and expansion of effector t cells, ifn-i bridges natural and acquired antiviral immunity (see (mcnab et al. ) for a review), so elucidating its functions during human evd is highly relevant to understanding disease pathogenesis. ifn is critical in protecting laboratory mice from ebov (brannan et al. ; bray et al. ) , but data are somewhat conflicting in nonhuman primates (nhps) and humans smith et al. ; villinger et al. ; yen et al. ) . higher levels of ifn-alpha were associated with fatal evd cases (villinger et al. ), but higher ifn-beta was associated with less severe evd ) and ifn-beta administration prolonged survival in nonhuman primates (smith et al. ) . however, as ifn responses are highly dynamic, drawing conclusions regarding human pathogenesis is difficult. for example, evd survivors may mount early and robust ifn responses that keep viral replication at bay, while patients who succumb to evd may display higher ifn levels later on due to increased viral replication and inflammation. interestingly, recent studies have shown that patients who survive and patients who succumb to evd both show robust t cell activation (mcelroy et al. a; ruibal et al. ) . since dcs are the only antigen-presenting cells capable of priming naïve t cells (banchereau and steinman ) , these results suggest at least two possibilities. on one hand, infected dcs may retain their capacity to initiate t cell-specific responses, as has been shown in other viral infections (wahid et al. ; rivera and mcguire ; kvale et al. ). on the other hand, some dc subsets may be spared from infection and thus able to prime ebov-specific t cells. the generation of this ebov-specific adaptive immunity is the topic of the next two sections. while innate immune responses may play a chief role in controlling early ebov replication in humans, the current model identifies the character (though not necessarily the magnitude) of adaptive immunity as the main factor driving viral clearance and recovery. both humoral and cellular immunity seem to be required for ebov clearance in humans, a hypothesis strengthened by the finding that evd patients mount robust adaptive immune responses (mcelroy et al. a; ruibal et al. ) with high numbers of circulating plasmablasts and ebov-specific t cells. the more difficult task is assessing whether adaptive immune responses mark substantial differences between fatal and surviving patients. initial studies supported the idea that early development of igm and isotype switching to igg correlated with positive outcome. indeed, a high percentage of patients with fatal outcomes do not seem to develop igm . these field studies are also in agreement with findings in patients evacuated into europe or the us for medical treatment during the recent west african evd outbreak. surviving evd patients mounted early igm responses and showed upregulation of serum igg over the course of the disease, which was correlated with viral clearance (kreuels et al. ; wolf et al. ) . conversely, deficient or diminished igm and igg responses have been reported in fatal cases of both evd and mvd (van paassen et al. ; baize et al. ) . however, limited field data also indicate survivors who did not develop igg, as well as patients who died after developing detectable circulating anti-ebov antibodies (onyango et al. ). in addition, limited clinical data obtained from the sudv-caused evd outbreak in gulu, uganda, did not reveal significant differences between the humoral responses in fatal and nonfatal evd, with very late expression of igg in both groups that was unrelated with viral clearance . as in many other aspects of evd immunology, the kinetics of antibody responses in a statistically relevant cohort of acute-stage patients with defined outcomes must be studied. antibodies play many roles during the immune response to pathogens, including neutralization and antibody-dependent killing of virus-infected cells by targeting them to fc receptor bearing cells (adcc) or complement (cmc). neutralizing antibodies (n ab ) probably play a small role in recovery from acute evd, since in many survivors n ab are not detectable until weeks or even months after recovery (luczkowiak et al. ; sobarzo et al. ). this is a puzzling and as yet unexplained finding. one of the plausible hypotheses is that disrupting lymphoid architecture during acute evd infection may compromise germinal center formation and b cell affinity maturation, a feature that has been observed during lassa fever (carrion et al. ). however, this hypothesis does not reconcile easily with the levels of circulating plasmablasts in patients in the acute stage of illness (mcelroy et al. a) , or with the limited focal necrosis observed in human biopsy samples of lymphoid tissues (martines et al. ) . one interesting possibility is that the long filament shape of filovirus virions may require a highly diverse repertoire of n ab for effective neutralization. in fact, studies have found greater b cell clonality in evd survivors than in individuals with b cell memory against hiv- or influenza a virus (bornholdt et al. b ). still, this cannot be the whole story, as similar delays in n ab production have been described in other viral hemorrhagic fevers (e.g., lassa fever). perhaps more importantly, delayed n ab production strongly suggests long-term virus or antigen persistence, which is in agreement with duration of post-evd sequelae (see below). nevertheless, long-term survivors develop effective n ab , mainly directed against several epitopes of the ebolaviral gp , (bornholdt et al. a, b; misasi et al. ; corti et al. ). many of the described n ab isolated from survivors are directed against the gp , glycan cap as well as against the region bridging gp and gp , which seem to be epitopes amenable for antibody-based therapeutics like zmapp (murin et al. ). importantly, a number of studies in surviving patients have highlighted the presence of naturally occurring n ab with cross-reactivity against other ebolaviruses and even against marv (olal et al. ; misasi et al. ; bornholdt et al. a ). these findings strongly suggest that antibody-mediated immune memory may provide long-term protection against secondary infection with filoviruses, and may have important implications for public health measures (e.g., recruiting survivors as caregivers in future outbreaks). currently, the relative importance of n ab versus other antibody-mediated mechanisms, such as adcc and cmc, is unclear, even though most protective antibodies probably act through both neutralization and adcc/cmc activation (schmaljohn and lewis ) . antibodies with both neutralizing and adcc capacity have been detected in evd survivors more than a decade after recovery , and adcc is probably an important mechanistic feature of zmapp (olinger et al. ). in addition to dissecting whether or not neutralization and adcc specifically contribute to evd immunity, it is important to determine the kinetics of antibody-mediated immunity from acute infection to long-term recovery. lack of information on evd antibody kinetics and ebov-specific quantitative activity is probably largely responsible for the lack of protective effect demonstrated by convalescent plasma therapy (van griensven et al. ). this therapeutic strategy has putative applicability for field outbreak conditions, but requires characterization of the virus specific activity in the product as well as optimization to ensure transfer of sufficient quantities of protective antibodies. t cells, particularly cd t cells, are essential for clearance of acute viral infections. naïve t cells react to stimulation with pathogen-specific peptides by massively expanding, differentiating into effector cells and migrating to peripheral infection sites for elimination of infected cells (see (zhang and bevan ) for a review). because naïve cd t cells can be activated only by dcs (banchereau and steinman ) , the initial assumption was that ebov-induced dc inactivation would in turn result in poor t cell priming and overall inability of the host to eliminate infection. this hypothesis was substantiated by early studies demonstrating that, despite being spared from infection, many t cells underwent apoptosis during human evd (baize et al. ; wauquier et al. ) . while this observation is still valid, data gathered mainly during the recent west african outbreak have suggested that lymphocytes in general display very dynamic kinetics during evd, which may include early proliferation followed by lymphopenia (kreuels et al. ; wolf et al. ) . similar dynamics occur during other systemic viral infections and during pro-inflammatory disorders such as sepsis (luan et al. ) , suggesting that perhaps lymphopenia is not a differential characteristic of evd. a substantial difference between earlier studies and those carried out in the context of the recent outbreak has been the application of multiparametric flow cytometry, which has allowed for the first time collection of phenotypic and functional information from single cells in unprecedented detail. these studies have revealed that, in fact, evd is characterized by massive t cell activation rather than inhibition in both surviving and fatal cases. co-expression of activation markers such as cd and hla-dr, as well as proliferation markers like ki- , were detected in a significant percentage of cd and cd t cells in evd patients (mcelroy et al. a; ruibal et al. ) and were comparable with the magnitude of activation observed in other acute infections or after vaccination (lindgren et al. ; miller et al. ) . of note, since co-expression of cd and hla-dr is correlated with engagement of the t cell receptor (appay et al. ) , these findings strongly suggest that proper t cell priming by antigen-presenting cells occurs during evd in humans. additionally, these findings were comparable between patients receiving experimental therapy (mcelroy et al. a ) and those who received supportive care in the field , indicating that robust t cell activation is a characteristic of evd unrelated to treatment. a paramount question, therefore, is why robust t cell activation does not lead to viral clearance during evd. to some extent, this lack of t cell effectiveness may be related to defects in negative immune checkpoints, namely the molecular mechanisms that control the transition from activation to immune homeostasis and that are essential for autoimmune control (buchbinder and desai ) . two such mechanisms are triggered by the t cell co-inhibitor molecules, programmed cell death- (pd- ) and cytotoxic t-lymphocyte-associated protein (ctla- ). an earlier review already hypothesized that t cell dysfunction during filovirus infection could be related to high expression of pd- and ctla- in t cells (mohamadzadeh et al. ) , which leads to a nonfunctional but reversible status termed t cell exhaustion (wherry ) . studies from the recent west african evd outbreak found that peripheral blood t cells from evd patients expressed high levels of pd- and ctla- (mcelroy et al. a; ruibal et al. ) , which were significantly higher in fatal cases . as a follow-up to these observational studies, determining the correlation between high expression of t cell inhibitory molecules and t cell function and apoptosis will be important. determining this correlation will most likely require relevant in vivo models that can reproduce this t cell phenotype. utilizing immunotherapeutic approaches to block pd- and ctla- function during postexposure filovirus infection treatment may provide an interesting opportunity. several therapeutic products are licensed extensively to block pd- and ctla- in several types of cancer, thereby restoring t cell function (see (sharma and allison ) for a review). another important and related question is whether broad and polyfunctional t cell responses lead to increased disease manifestations, like in hantavirus (cardio) pulmonary syndrome (terajima and ennis ), or to decreased susceptibility, as in dengue virus - infections (weiskopf et al. ). to answer this question, an exhaustive analysis of ebov t cell immunodominance in humans must be performed, which is still not available. previous evidence shows that the viral nucleoprotein (np) drives most of the cd t cell response (mcelroy et al. a; sundar et al. ; wilson and hart ) . this finding is consistent with the observation that hla alleles recognizing conserved filovirus np epitopes provide protection against sudv infection (sanchez et al. b) . additional studies of hla association with evd outcomes in a statistically significant cohort of patients are highly needed to strengthen these initial observations. the finding that np drives most of the cd t cell response also has significant implications for vaccine design and may explain, at least to some extent, why most gp , -based vaccines induce poor t cell immunity (agnandji et al. ; ewer et al. ; zhu et al. ) . the degree to which electrolyte abnormalities contribute to evd pathogenesis was not appreciated in earlier outbreak responses because real-time serum electrolyte data were not available. the ability to acquire these measurements in patients during the west african evd outbreak, as well as the degree of profuse watery diarrhea that was reported, have brought to the forefront the severity of electrolyte imbalances in evd and the impact electrolytes could have on patient outcome. such data were first collected during the sudv outbreak in gulu, uganda, in - , during which elevated bun/cre levels and hypocalcemia were associated with severe disease and fatal outcomes ). data from african cohorts (hunt et al. ) combined with data from repatriated patients who were cared for in developing nations (uyeki et al. b ) have revealed potassium abnormalities, hyponatremia, hypomagnesemia, and hypocalcemia. some of these alterations may be related to acute renal injury that is also common among severely ill patients; others might be related to volume and electrolyte imbalance secondary to profuse watery diarrhea. the clinical consequences of electrolyte imbalances could include cardiac arrhythmias, seizures, or coma. indeed, % of the repatriated patients exhibited arrhythmia or electrocardiographic changes, one patient had seizures, and three were in a coma (uyeki et al. b) . electrolyte levels are easily measured blood chemistry parameters that can be corrected with electrolyte and fluid administration. such measures may have contributed to improved outcomes during the recent outbreak, as one evd treatment center that incorporated these data into patient management had a case fatality rate of only %, significantly lower than the and % rates reported from two other treatment centers in sierra leone (hunt et al. ; schieffelin et al. ; lanini et al. ) . multiple lines of evidence have suggested that the endothelium is dysfunctional during evd. while endothelial cells are directly infected, they do not show significant cytopathic effect, and endothelial infection is thought to occur during the terminal phase of the illness (martines et al. ; geisbert et al. c) . the overall dysfunction of the endothelium is thought to be an indirect effect of pro-inflammatory cytokines like tnf-alpha (villinger et al. ; feldmann et al. ) , or other molecules, like nitric oxide, that increase the permeability of the endothelium during inflammation . increased levels of several pro-inflammatory cytokines and chemokines are associated with evd-related deaths (baize et al. ; wauquier et al. ; gupta et al. ; hutchinson and rollin ; mcelroy et al. a, b) . infected antigen-presenting cells, such as macrophages, dcs, or monocytes are the presumed source of these cytokines (feldmann et al. ; gupta et al. ) , and these cytokines lead to endothelial activation. increased vascular permeability due to loosening of the endothelial barrier is a normal and necessary physiologic function that allows cells and biomolecules to reach sites of inflammation, but widespread activation in many inflammatory diseases results in fluid movement that can be detrimental to the host. clinical and laboratory findings in evd, including tachypnea (with or without pulmonary edema), hypotension, oliguria, tachycardia, impaired distal perfusion, hypoalbuminemia, and hemoconcentration, are consistent with fluid extravasation into extravascular spaces secondary to increased vascular permeability uyeki et al. b; hunt et al. ; chertow et al. ). this constellation of clinical findings is thought ultimately to lead to hypovolemic shock in fatal cases. in recent years, additional evidence that dysfunctional endothelia contribute to the disease process include the findings of increased levels of sicam, thrombomodulin, pe-cam, and p-selectin in patients with severe or fatal disease (mcelroy et al. a, b) . all of these biomarkers, when released into the plasma, indicate an activated endothelium and/or breakdown of endothelial intercellular junctions. an activated endothelium is both pro-inflammatory and pro-coagulant, and likely contributes both to the ongoing inflammatory response that characterizes severe evd and to the coagulopathy that has been observed in some patients (discussed in more detail below). also noteworthy is the sometimes conflicting body of evidence implicating the viral glycoprotein (gp , ) in endothelial dysfunction. the ebov gp gene coding region produces two proteins based on a transcriptional editing site, the soluble gp (sgp) and the full-length structural gp , (sanchez et al. ) . the full-length gp , produced by pseudotyped retrovirus or virion-like particles (vlps) can bind to and activate endothelial cells, leading to increased endothelial permeability (wahl-jensen et al. ; yang et al. ). sgp has been detected in the plasma of infected individuals , and, in fact, inhibits tnf-mediated increases in vascular permeability in vitro, perhaps suggesting a compensatory mechanism to control virus-induced inflammation. a third form of the protein, known as shed gp, is shed from the surface of infected cells in vitro and increases permeability of cultured endothelial cells (escudero-perez et al. ) . while shed gp was detected in infected guinea pigs, it has not yet been detected in vivo in humans. finally, overexpression of gp , in explanted human, porcine, or nhp blood vessels leads to increased endothelial permeability and endothelial cytotoxicity mediated by the mucin domain of the protein (yang et al. ) . the relevance of this finding to evd is unclear, since endothelial cells are infected long after endothelial function has already been compromised, and do not show cytopathic effects when infected in vitro (geisbert et al. c) . taken together, these data suggest that the various forms of ebov gp may modulate endothelial function, but the precise role of the protein in human evd pathogenesis is unclear. the moniker "viral hemorrhagic fever" was applied to ebov evd during the first outbreak identified in , and was appropriate because % of fatal cases had hemorrhagic manifestations, mostly melena (ebola haemorrhagic fever in zaire zaire / . this outbreak was unique, because the route of virus transmission was via injection in approximately one-third of the patients, and this mode of entry could have contributed to the manifestations and severity of disease (the authors note that all patients who were infected by injection died). notably, a concurrent outbreak of sudv-caused evd also had high frequencies ( %) of hemorrhagic manifestations. however, in several of the larger subsequent outbreaks where appropriate data were available, significantly fewer patients had hemorrhagic manifestations of disease: % (ebov ), % (sudv ) , and % (bdbv ) (okware et al. ; macneil et al. ; bwaka et al. ) . additionally, in these three outbreaks, no association was observed between bleeding and death, arguing against the commonly held belief that hemorrhage equates to a fatal outcome. furthermore, in the western african outbreak, hemorrhagic manifestations were rarely reported; fewer than % of all patients from liberia and sierra leone had any bleeding symptom recorded (chertow et al. ; schieffelin et al. ; lado et al. ; yan et al. ; dallatomasina et al. ; li et al. ; qin et al. ) , but two reports from a single center in guinea reported bleeding in and % of patients (barry et al. ; bah et al. ) . perhaps reported differences in hemorrhage frequency are related to genetic or nutritional factors that cannot be controlled for in observational reports. regardless, hemorrhaging can occur during evd, but is not the most prominent feature. in contrast, hemorrhage does seem to be a common ( - % of patients) feature of mvd, based upon limited data from the two largest outbreaks to date (colebunders et al. ; roddy et al. ) . hemorrhaging is a clinical sign that can be secondary to multiple types of hematologic disorders. in the simplest terms, two general categories of hematologic disorders manifest clinically as bleeding: low levels of platelets and coagulation factor deficiencies (hunt ) . platelet counts have not been routinely measured in patients with evd, but in one study of patients with evd during the west african outbreak, platelet counts were not especially low, ranging -  / l (normal range is - ) (hunt et al. ) . interestingly, the same phenomenon was noted years ago in the nhp model, and while absolute platelet counts were not very low, platelet function was severely affected as a result of in vivo activation and degranulation (fisher-hoch et al. ) . no measurements of platelet function have been reported to date in humans. however, elevated levels of scd l were observed in surviving patients with evd caused by sudv (mcelroy et al. a, b) . since platelets are the major source of scd l in the bloodstream (henn et al. ) , this finding suggests platelet activation in humans during evd. these data suggest a process that consumes platelet functional activity in severe or fatal evd; this process would be consistent with the finding that in lethal nhp studies of evd, scd l levels are elevated initially, but decline to undetectable at the time of death (ebihara et al. ) . marv might be a bit different, since in the original report of the first outbreak in europe in , most patients had severe thrombocytopenia, sometimes less than  /l (martini ) , coincident with significant hemorrhage in about half of the patients. finally, the type of bleeding often described in evd (and mvd) patients-epistaxis, conjunctival hemorrhages, bleeding into the gi tract and from the oral cavity-is mostly mucosal in nature, consistent with loss of platelet numbers or function. the second general category of hematologic disorders that manifest as bleeding is deficiency in coagulation factors. coagulation factors are quantitated clinically by measuring partial thromboplastin time (ptt) and prothrombin time (pt) to evaluate the intrinsic and extrinsic coagulation pathways. unfortunately, these measurements have only been reported in case studies, and provide no consensus regarding the levels of pt and ptt during evd. this is a clear information gap that needs to be addressed. an early report on marv states that ptt and pt were measured in patients, but the values obtained did not explain the observed severity of the hemorrhaging (martini ) . dic is often seen in critically ill patients, especially those with sepsis, and involves both low platelet counts and coagulation factor deficiencies. the bleeding seen in patients with evd is often reported as due to dic, although whether the criteria for dic are met is unknown because the necessary laboratory tests are not routinely available. dic laboratory features include thrombocytopenia, elevated fibrin split products, prolonged pt, and consumption of fibrinogen (levi et al. ). as noted above, the level of thrombocytopenia seen in evd patients rarely meets the criteria to assign a dic score, but elevated fibrin split products (such as d-dimer) have been measured retrospectively, are elevated in evd patients, and are associated with fatal outcomes . pt measurements are normal in the few available case reports (sueblinvong et al. ) , and fibrinogen levels were not associated with outcome or hemorrhagic manifestations (mcelroy et al. a (mcelroy et al. , b, . measurement of dic markers is clearly an area that requires additional study for clarification. less conventional evaluations of factors involved in coagulation pathways have also been conducted. thrombomodulin, a protein expressed on endothelial cells, has anticoagulant properties in the microenvironment of the cell surface. when present in the plasma, thrombomodulin can act more globally, as shown in one family with a genetic deficiency that results in elevated levels of free plasma thrombomodulin in association with a bleeding disorder (langdown et al. ) . endothelial cells also release thrombomodulin when they become activated. elevated plasma levels of thrombomodulin were associated with both hemorrhage and death in sudv patients, and with more severe disease in a cohort of evd patients (mcelroy et al. a (mcelroy et al. , b, , suggesting that loss of this protein from the endothelial surface exacerbates both endothelial dysfunction and coagulopathy during evd. additionally, tissue factor, which is implicated in coagulopathy observed in nhps (geisbert et al. b) , was also elevated in patients with severe evd . von willebrand factor (vwf), a protein that is present in both platelets and endothelial cells and mediates interactions between platelets and the damaged endothelium, was elevated both in sudv-infected patients with hemorrhage and in pediatric sudv-infected patients with fatal outcomes. it was also elevated in ebov-infected patients with severe disease (mcelroy et al. b . a complex interplay of activated endothelial cells, activated platelets, inflammation, and coagulopathy is clearly at work during evd. how intervening in any one aspect of the network impacts human disease is still unknown. it would be invaluable to determine the effects on evd outcome of readily available clinical products that affect aspects of these processes. some compounds of interest are statins, which stabilize the endothelium; soluble gpiba, which inhibits the interaction between platelets and vwf; and scd l, which appears to be consumed during severe disease. one key and largely unaddressed question is the role of co-infections and co-morbidities in evd pathogenesis. especially relevant to patient populations in the affected african nations are the possible contributions of malnutrition and malarial co-infection in the disease process. malnutrition is prevalent in the regions affected by evd (wirth et al. ) , and long-standing malnutrition leads to defects in both innate and adaptive cellular immune responses (schaible and kaufmann ) . malnutrition may contribute to the high case fatality rates observed during evd outbreaks in africa as compared to filoviral infections in patients repatriated to the us and europe (uyeki et al. b; martini ) . malaria co-infection is likely to increase evd-related mortality, although this has not been rigorously evaluated, a study of the effects of various antimalarial drugs has been conducted during the west african outbreak. antimalarial drugs were routinely given to evd-positive patients at the etc in foya, liberia; during a time of artesunate-lumefantrine shortage, artesunate-amodiaquine was prescribed. while the amodiaquine preparation was associated with improved survival in malaria-negative patients, interestingly suggesting a direct antiviral effect, this effect was lost in the malaria-positive patients, suggesting that malaria and evd co-infection lead to worse outcomes even when malaria is treated (gignoux et al. ) . also of potential consequence are co-infections with hiv or other hepatotropic viruses. hiv co-infection has only been examined in one study; during the sudv outbreak in gulu, % of the tested patients were hiv- -positive by antibody testing. no differences in evd outcome were observed based upon hiv status in this study (mcelroy et al. a, b) , but no cd counts were obtained, so it is possible that all cases were newly acquired and the patients were not yet immune-compromised enough for hiv- infection to influence evd outcome. one study evaluated publicly available next-generation sequencing data, and using a cohort of patients, posited that co-infection with gb virus c (a common, clinically innocuous pegivirus infection) results in improved outcomes during evd infection (lauck et al. ) . the results were somewhat confounded by the fact that age is a major determinant of both gb virus c infection and outcome during evd. a special mention must be made that early data regarding the effect of age on ebov susceptibility (dowell ) and outcome (mupere et al. ; mcelroy et al. a, b) have been repeatedly observed in large cohorts during the west african outbreak (team et al. ; faye et al. ; li et al. ; schieffelin et al. ; bower et al. ). case fatality rates are high in children under , lowest in school-aged children, reaching a nadir around puberty, and increase again to peak in the elderly. this phenomenon has been seen in other infectious diseases in children, and suggests perhaps that school-aged children are in the perfect immunologic window of life, with a fully mature and functioning immune system without the alterations that occur secondary to the influence of sex hormones. to date, only one study has examined pediatric patients for laboratory evidence of this protective effect in evd; this study demonstrated that pediatric patients have viral loads similar to adult patients (mcelroy et al. a, b) and thus do not appear to control the viremia better. however, higher levels of rantes, a t cell chemokine, were associated with pediatric survival, an association not seen in adults. thus, stronger immune responses in pediatric patients might contribute to better outcomes, but this remains to be proven definitively and will require additional research efforts. perhaps one of the most striking findings during the western african evd outbreak has been the identification of severe sequelae in evd survivors long after recovery. these sequelae have important implications both for medical treatment and for public health. in , one year before the identification of ebov in zaire, marv was successfully isolated from the ocular fluid of a convalescent patient with uveitis (gear et al. ) . a later follow-up study described arthralgia, myalgia, and abdominal pain as common sequelae in evd survivors of the kikwit outbreak . similar findings in individuals long after recovery from bdbv infection (clark et al. ) suggest that post-recovery sequelae may be common in filovirus infections. to date, ebov rna has been detected in semen, ocular fluid, cerebrospinal fluid, breast milk, and other body fluids in evd survivors for several weeks or even months after discharge (green et al. ; chughtai et al. ) . moreover, infectious virus has been isolated from semen (uyeki et al. a) , ocular fluid (varkey et al. ) , saliva, and breast milk , and epidemiological evidence of sexual ebov transmission has been established (mate et al. ) . an important task will be determining the pathogenic potential of virus isolates from semen compared to those of blood from the same patient. because sexual transmission seems to be uncommon (based on the large numbers of male survivors and few sexual transmission events), virus isolates from semen may be less infectious, either due to attenuating mutations or inactivation by ebov-specific antibodies secreted at the mucosal surface. in general, the pathogenic features of evd sequelae and their putative physiological mechanisms are poorly understood. importantly, many of the symptoms reported by evd survivors, as well as some of the observed signs like uveitis and skin desquamation, suggest an inflammatory syndrome. indeed, immune activation persists after the acute phase of evd (mcelroy et al. a; rowe et al. ) , strongly suggesting continuous immune stimulation and postinfection autoimmunity. these hypotheses still need to be experimentally tested, but are consistent with virus persistence in immunoprivileged sites. alternatively, sustained inflammation could be due to deposition of immune complexes in the joints or to viral antigen persistence, as seen commonly in alphavirus infections and influenza a virus infection respectively (hoarau et al. ; tamburini et al. ; tappe et al. ) . since some, but not all, evd survivors suffer sequelae, the factors leading to post-evd syndrome must be determined. co-morbidities and co-infections are likely contributing to sequelae development, particularly those involving immune phenomena like bystander t cell activation (fujinami et al. ) . also, a positive correlation has been described between viremia levels during the acute phase of evd and increased risk of sequelae (mattia et al. ) . these findings suggest that during infection, ebov may be confined to immunoprivileged sites by treatment or by the host immune response, leading to viral persistence, 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immunogenicity of a novel recombinant adenovirus type- vector-based ebola vaccine in healthy adults in china: preliminary report of a randomised, double-blind, placebo-controlled, phase trial key: cord- -w bpeqzg authors: wong, samson sai-yin; wong, sally cheuk-ying title: ebola virus disease in nonendemic countries date: - - journal: journal of the formosan medical association doi: . /j.jfma. . . sha: doc_id: cord_uid: w bpeqzg the west african outbreak of ebola virus disease was unprecedented in its scale and has resulted in transmissions outside endemic countries. clinicians in nonendemic countries will most likely face the disease in returning travelers, either among healthcare workers, expatriates, or visiting friends and relatives. clinical suspicion for the disease must be heightened for travelers or contacts presenting with compatible clinical syndromes, and strict infection control measures must be promptly implemented to minimize the risk of secondary transmission within healthcare settings or in the community. we present a concise review on human filoviral disease with an emphasis on issues that are pertinent to clinicians practicing in nonendemic countries. the largest outbreak of ebola virus disease (evd) in history has renewed interest in filoviruses and has provided an unprecedented impetus to the development of new therapeutics and vaccines for this highly lethal infection. hemorrhagic fevers caused by ebola and marburg virusesdalso collectively known as filoviral hemorrhagic fever (fhf)dpreviously caused dramatic, albeit limited, outbreaks in central africa. their impact on global health was rather small (except in the realm of biological warfare research) because of the high mortality rate, lack of effective antiviral therapies and vaccines, and potential for person-to-person transmission. the west african outbreak of evd proved that these filoviruses should no longer be considered as merely regional problems. a short review of evd and its clinical relevance to the nonendemic countries is presented. the current epidemic is caused by zaïre ebolavirus; however, references will also be made to the related marburgvirus, which shares many virological, clinical, and epidemiological characteristics. conflicts of interest: the authors have no conflicts of interest relevant to this article. the order mononegavirales consists of enveloped, nonsegmented, negative-sense, single-stranded rna viruses. the family filoviridae comprises three genera: cuevavirus, ebolavirus, and marburgvirus. in , the sole species of cuevavirus, lloviu cuevavirus, was described. it was discovered during an investigation of massive die-offs of miniopterus schreibersii bats in france, spain, and portugal in ; and the virus was detected in bat carcasses collected from northern spain. the genus ebolavirus the name "filovirus" describes a unique morphological characteristic of the viruses. the virions are generally filamentous (in latin, filum means "thread") with a diameter of approximately nm and a highly variable length of e , nm. they may also appear as branched filaments, short rods, u-shaped, circular, or hairpin-shaped. , the genomes of ebov and marv are approximately kb and consist of seven genes (from the to end): nucleoprotein (np), vp , vp , glycoprotein (gp), vp , vp , and rna-dependent rna polymerase (l). , ebolavirus expresses an additional protein through transcriptional editing of the gp gene. in addition to gp, a smaller secreted glycoprotein (sgp) is produced and excreted extracellularly. , at c, ebov and marv are stable and resist desiccation, which probably explains their stability in aerosol droplets. , they are however inactivated by heat and common disinfectants such as detergents, phenolics, and hypochlorites. the usual heat treatment of clinical samples at c for minutes may fail to render the specimen noninfectious. thermal inactivation at c for minutes or c for minutes is necessary. e gamma irradiation readily inactivates the filoviruses, although this method may not be readily available in routine clinical or laboratory settings. the genetics and molecular biology of the filoviral genome have been previously reviewed. , in addition to the essential functions for viral replication and assembly, many viral proteins exert their effects on the host immune system and may contribute to the pathogenesis of the infection (table ) . , , e , , , for example, vp and vp inhibit the normal antiviral activities of type i interferons at multiple steps of the pathway, whereas sgp may contribute to immune evasion by absorbing anti-gp antibodies (i.e., antigenic subversion). e because of the essential roles of many viral proteins in replication and assembly, some viral proteins (e.g., vp and vp ) are potential targets for antiviral agent development. , in recent years, the pathogenesis of fhf has been better elucidated. filoviruses are pantropic with the ability to infect different host cell types. the initial cells in which the viruses replicate are likely dendritic cells, macrophages, monocytes, and kupffer cells at the site of entry. a large number of lectins (e.g., dc-sign and l-sign) and immunorecognition receptors [i.e., triggering receptors expressed in myeloid cells (trem)] can serve as receptors for the viruses. after the initial multiplication in the aforementioned cell types, the viruses are transported to the reticuloendothelial system (e.g., lymph nodes, spleen, liver) and other organs where infection of other cell types occur. the resulting massive necrosis and end organ damage are reflected in the histopathology of human and primate infection models with necrosis in the liver, kidneys, lungs, lymphoid tissues, and other organs. , in addition, various mechanisms contribute to the development of coagulopathy and disseminated intravascular coagulation, which is a hallmark of viral hemorrhagic fevers. patients with fhf develop significant platelet dysfunction (which is not merely accountable for by thrombocytopenia), and this is contributed to by platelet activation and decreased vascular endothelium production of prostacyclin. another important target in the pathogenesis of fhf is the endothelium. human and primate endothelial cells are susceptible to infection by ebov, although direct cyopathic effects are not an important factor in the development of vasculopathy and coagulopathy. the release of vasoactive table filovirus genes and their functions. , , e , , , factors (e.g., nitric oxide) or cytokines and chemokines from monocytes and macrophages (e.g., tumor necrosis factor-alpha, interferons, monocyte chemoattactant protein- , interleukin- ) could be important in the genesis of vascular damage. the combined effects of increased secretions of proinflammatory cytokines, activation of the coagulation cascade, consumption and/or reduced production of protein c, thrombocytopenia and platelet dysfunction, hepatic damage with impaired production of coagulation factors, and vascular damage contribute to the development of coagulopathy in fhf. protective humoral and cellular immune responses can be demonstrated in patients who survive, and antibody levels persist for years. in addition to the various immune evasion mechanisms alluded to previously [e.g., binding of anti-gp antibodies by sgp (i.e., immune subversion), suppression of innate immune responses, and inhibition of interferon pathways], other potential virulence and pathogenic mechanisms of filoviruses such as the np and vp proteins have been identified. the generation of antibodies towards gp is critical for the protective efficacy of vaccines. ebolavirus and marv are geographically restricted to and cause outbreaks in sub-saharan africa; however, rebov is found in nonhuman primates and pigs in the philippines (table ) . , , , , , the first filovirus was discovered in after an outbreak of marburg hemorrhagic fever infection in germany. this infection originated from cercopithecus aethiops monkeys that were imported from uganda. in , the first natural outbreak of zebov occurred in northern zaïre (now called the democratic republic of the congo). in , sebov was discovered in an outbreak in nzara in sudan. in e , bebov caused an outbreak in uganda, followed by another outbreak in the democratic republic of the congo in . , in , tafv was discovered in a swiss biologist who acquired the infection in the republic of côte d'ivoire (i.e., the ivory coast). in , rebov was first discovered in monkeys (macaca fascicularis) that were exported from the philippines to reston, virginia, usa the infected monkeys were subsequently exported to italy ( e ) and to texas ( ) . cynomolgus macaques in the philippines are naturally infected, as are pigs. the rebov virus appears to be nonpathogenic to humans. e human filovirus infections are primary zoonotic diseases with a high propensity for interpersonal transmission. the primary animal reservoir of ebov and marv are bats (especially fruit bats). bats support long-term viral replication without developing the disease. virological and serological studies have confirmed filoviral infection in diverse bat species. , , in the philippines, china, and bangladesh, there is also evidence of rebov (and possibly other filoviral) infection in bats. e cases of fhf have been epidemiologically linked to contact with bat carcasses, spelunking among tourists, and outbreaks among gold miners who work in caves. e peak seasons of bat marv infection have been correlated with the incidence of human "spillover"infections. primates are also naturally infected with filoviruses, although they are likely to be infected by natural reservoir hosts (e.g., bats) and are not considered important reservoirs. , primates, nevertheless, remain important vectors for the introduction of the disease into humans in rural africa, and wild animal mortality sometimes precede human outbreaks of evd. other mammals that can be infected by evd include pigs (especially by rebov and zebov) and dogs; however, their role in causing human evd outbreaks is uncertain. e human infections typically occur with a few patterns of transmission. inhabitants of endemic areas, especially individuals dwelling in forests with occupational exposure to wild animals (e.g., hunters and people handling bushmeat), may develop symptomatic or subclinical infections, presumably because of the exposure to animal reservoirs of the virus. in some cases of human infection, a history of direct exposure to animal carcasses (such as primates, bats, duiker antelopes, and porcupines) or indirect exposure to bats in caves has occurred. e , , these single or multiple introductions to human populations may result in short chains of human transmission. when fhf patients are admitted to healthcare facilities where infection control measures are inadequate, a large outbreak may occur with transmission to other patients and healthcare workers. hospitals have been a major amplifying and disseminating factor in many previous outbreaks of fhf in africa. direct person-to-person transmission of ebov and marv occurs via blood or body fluids by percutaneous inoculation or by mucosal exposures. e during an outbreak of sebov, the virus was detected by viral culture or reverse transcription polymerase chain reaction (rt-pcr) in patients' saliva, skin swab, stool, tears, breast milk, and semen, but not in environmental samples. in view of the persistence of the viruses in semen and breast milk at days and days, respectively, after illness onset, , the use of condoms and withholding breastfeeding are recommended during convalescence. more than % of patients in the kitwit outbreak in the democratic republic of the congo had secondary cases in the household; the risk was highest for people with direct physical contact with the body fluids of symptomatic patients and exposure to patients in the late stages of the disease; this finding can be explained by the high viral load at this phase of disease. reusing needles or other medical instruments without adequate sterilization, needle stick injuries, lack of isolation facilities, and inadequate and inappropriate use of personal protective equipment all contribute to explosive hospital outbreaks. african burial customs of washing dead bodies and transporting bodies without barrier precautions further transmit the disease in the community. , , , infected pigs can transmit rebov to nonhuman primates via the airborne route and nonhuman primates can be infected experimentally by the inhalation of droplets (droplet size of . e . mm), although parenterally infected primates do not transmit the infection via the airborne route. e true airborne transmission of ebov between humans has likewise not been documented. up to % of patients in some ebov outbreaks may have no known contact or exposure history, although it remains unclear whether this is because of fomites, true airborne transmission, or inadequate investigation. , , , table outbreaks of human filovirus infection. , , , , , virus the ongoing evd outbreak at the time of this writing is unique in two aspects: ( ) its unprecedented scale and ( ) its origination in west africa (guinea) rather than in central africa. the first case occurred in guinea in february , and subsequently spread to the african countries of liberia, sierra leone, nigeria, senegal, and mali. in october , the world health organization declared the epidemic over in senegal and nigeria. , further epidemiological investigations suggested the index case was probably a year-old child who died on december , in southern guinea. the infection was subsequently transmitted from the child to family members, a village midwife, and a healthcare worker; some of these patients later caused outbreaks in different areas of guinea. ebola virus disease has caused infection in local healthcare workers of whom ( %) workers died (as of january , ); four of these infected healthcare workers were citizens of the united states of america, spain, and the united kingdom who returned to their respective countries for further management. on the other hand, asymptomatic infection was described in , as evidenced by seroconversion in % of close contacts of patients, in two zebov outbreaks in gabon. in % ( / ) of the seroconverted asymptomatic contacts, rt-pcr of the peripheral blood mononuclear cells was positive for the virus, and viremia persisted up to weeks in some contacts. another line of evidence for asymptomatic infections comes from seroprevalence studies in africa, in which . e . % of the surveyed population in central africa was seropositive for ebov with the seroprevalence consistently higher among forest-dwelling populations and hunters. e the incubation period of evd varies from days to days (commonly, e days), but a recent analysis of the cases in the zebov outbreak in kitwit suggested that the mean incubation period was . days, and the maximum incubation period was up to days. a biphasic illness has been described with an apparent remission of e days in between. , , e the disease usually begins abruptly with nonspecific symptoms such as fever ( e % of patients, ut infra), malaise ( e %), headache ( e %), sore throat, odynophagia or dysphagia ( e %), hiccoughs ( e %), and nonproductive cough ( e %). abdominal pain ( e %) or nausea and vomiting ( e %) often precede the onset of diarrhea ( e %), usually days after the onset of illness). the abdomen can be tender on palpation. in the absence of supportive therapy, diarrhea and vomiting may lead to fluid depletion and electrolyte disturbances such as hypokalemia. other symptoms include arthralgia or myalgia ( e %), chest pain ( e %), and conjunctival injection ( e %). a diffuse erythematous rash ( e %) appears towards the end of the st week which will later desquamate. the nonpruritic rash appears first on the trunk, and then spreads to the entire body with sparing of the face. three early symptoms of bilateral conjunctival injection, rash, and sore throat are suggestive of evd in the differential diagnosis. after the appearance of the rash, patients may either gradually recover or, in severe cases, progress over e days to the full-blown hemorrhagic fever syndrome with petechiae ( %), gum bleeding ( e %), melaena ( e %), hemoptysis ( e %), hematemesis ( e %), epistaxis ( e %), hematuria ( e %), menorrhagia, bleeding at venipuncture sites ( e %), and show features of disseminated intravascular coagulation. , the typical hemorrhagic fever picture, however, occurs only in approximately % of the patients (range, e %). , other manifestations in the late stage include evidence of multiorgan failure such as circulatory shock, obtundation, tachypnea, renal shutdown, convulsion, delirium, and coma. fever is often absent at this stage. death often occurs between days and , whereas patients who survive will show improvement around days to . intrauterine death is common in pregnant patients. mortality among pregnant women is substantial but may not be significantly higher than for nonpregnant patients; and pregnant women do not have an increased susceptibility to the infection. , survivors tend to improve from the nd week of illness. they make a slow recovery during which arthralgia (which could be asymmetric and migratory and often involves the large joints), uveitis, conjunctivitis, orchitis, parotitis, hearing loss, and tinnitus may occur. , chronic infection by filoviruses has not been documented, but male patients may shed the virus in the semen for e days after the onset of illness, and the transmission of marv has occurred via sexual intercourse. , , , common laboratory findings include lymphopenia, thrombocytopenia, elevated aminotransferases, hyperproteinemia, proteinuria, and prolonged prothrombin and activated partial thromboplastin time. with the progression of disease, evidence of disseminated intravascular coagulation and renal failure will appear. disease progression is also associated with worsening lymphopenia and rising antigenemia. compared to survivors, patients with fatal evd are more likely to have tachypnea. patients with disease also have a significantly higher level of viremia and a much weaker humoral immune response to the infection. significant differences in a number of cytokine and chemokine levels have also been detected between patients with nonfatal and fatal evd; in particular, the levels of many proinflammatory cytokines and nitric oxide are higher in nonsurvivors (with the possible exception of bebov), whereas the level of t cells and cd þ t cells were lower. , , e a high viral load is of prognostic significance. in sebov fhf, patients with fatal cases had an average of e (up to ) copies of rna/ml of serum, compared to the approximately copies of rna/mll of serum in survivors. patients with marv fhf likewise have high levels of viremia in blood with a median level of .  (range, .  e .  )/ml of serum serum. there are no pathognomonic signs or symptoms in the early stages of evd. the most useful history is epidemiological linkage to possible cases by travel history or by contact with known or suspected cases. laboratory investigations are necessary to confirm the diagnosis. other differential diagnoses (vide infra) should be excluded, as appropriate. all clinical specimens must be handled with great care from their collection to transport and testing in the laboratories. laboratory-acquired infection of ebov has occurred via percutaneous exposures. marburgvirus retains its infectivity in dried blood for at least days. filoviruses can be inactivated by heat [ c for minutes or c for minutes; or c for minutes in the presence of . % (final concentration) sodium dodecyl sulfate or . % (final concentration) tween ] or inactivated by % sodium deoxycholate solution, acetone, diethyl ether, % formalin, methanol, sodium hypochlorite, glutaraldehyde, % peracetic acid, phenolic disinfectants, and osmium tetroxide (used in fixation for electron microscopy). ultraviolet light is an effective means for surface disinfection. depending on the type of specimen and testing methodology, treatment of the sample with either triton x- , tween , sodium dodecyl sulfate, beta-propiolactone, chloramine b, or % acetic acid (ph . ) should be done before routine hematological, biochemical, and serological testing. heat inactivation is recommended for blood sodium, potassium, magnesium, urate, urea, creatinine, bilirubin, glucose, and c-reactive protein; however, other methods of inactivation would be necessary for calcium, phosphate, albumin, transaminases, gammaglutamyltransferase, and creatine kinase determination. standard virological techniques also apply to the diagnosis of fhf. these include viral culture, electron microscopy, serological tests using antigen or antibody detection, and nucleic acid amplification. , filoviruses can be cultivated from clinical specimens (especially blood and liver samples); however, because of the associated biohazards, a viral culture is notdand should not bedroutinely performed, except in facilities that can handle biosafety level agents. electron microscopy, which has excellent specificity because of the unique morphology of filoviruses, is also not routinely performed because of biosafety considerations, limited availability of electron microscope facilities in routine diagnostic settings, and the relatively high viral load necessary for visualization. the detection antibodies [e.g., immunoglobulin m (igm) or immunoglobulin g (igg)] is commonly achieved using immunofluorescent assays and enzyme-linked immunoassay (elisa) against recombinant np, gp, vp , vp , or vp antigens. e the appearance of igm and igg antibodies occurs at approximately days and e days, respectively, after the onset of illness. various antigen detection assays have been developed for the diagnosis of fhf and some have been used in field situations. the techniques include antigencapture elisa, immunofluorescent assay, dot-immunobinding assay, immunofiltration assay with different genus-specific or species-specific reactivity towards common targets such np, gp, and vp proteins. , , a practical limitation of these serological assays is the limited availability of these tests in laboratories in nonendemic countries. nucleic acid amplification is the diagnostic test of choice because of its high sensitivity (especially in the early phase of illness); its ability to differentiate between different agents of viral hemorrhagic fever; and its relatively lower biohazard, if the viruses are appropriately inactivated; and because antigen and antibody assays are often unavailable in laboratories in nonendemic countries. when the viral load is determined by quantitative assays, prognostic information can also be obtained. the most commonly used test is rt-pcr. a reverse transcriptioneloop-mediated isothermal amplification assay has also been developed for ebov and marv. , all diagnostic nucleic acid amplification tests must be adequately validated before being used clinically. if appropriately validated, the use of multiplex pcr/rt-pcr allows simultaneous detection of multiple pathogens that cause hemorrhagic fever. , the provision of nucleic acid amplification tests should preferably be centralized in national or regional reference laboratories to ensure adequate biosafety containment and quality of results. the rna of ebov can be detected in the sera by rt-pcr e hours earlier than by antigen capture; in some studies, it is detectable on day of the illness. , however, the viral load gradually reaches its peak at approximately e days after the onset of the disease. retesting is therefore necessary if rt-pcr is initially negative but clinical suspicion is high, especially when the first sample was obtained within days of the onset of disease. blood is the most commonly used sample for rt-pcr. oral fluid specimens can be a viable alternative to blood samples for rt-pcr in situations in which blood taking may be difficult or infeasible. common targets for nucleic acid amplification include the l, gp, and np genes. , , , , clinical management and vaccine development treatment of fhf is primarily supportive owing to the unavailability of approved, specific antiviral agents. concurrent infections such as malaria or bacterial sepsis should be treated, as appropriate. fluid and electrolyte replacement, blood product transfusion, renal replacement therapy, and ventilatory support such as extracorporeal membrane oxygenation should be administered, as necessary. , various experimental therapeutic approaches have been attempted in experimental animals or clinically; however, no randomized controlled trials prove their efficacy. examples include recombinant inhibitor of factor vii (rnapc ), recombinant human activated protein c, and interferon-beta. e as in cases of other severe viral infections, convalescent plasma from recovered patients has been used to treat fhf. this was deployed with apparent benefits in the evd outbreak in kitwit. the world health organization (who) published a guideline on the collection and preparation of convalescent plasma for use in the outbreak situation; however, the who recognizes the uncertainties in the efficacy of this treatment. cocktails of monoclonal antibodies have similarly been used recently with some success in reducing the mortality of ebov infection in nonhuman primates. these antibodies have been produced in plants and in mice. e based on these studies, an optimized cocktail of plant-derived monoclonal antibodies, called the zmapp, was produced; it protected % of rhesus macaques infected up to days with ebov. these antibodies have been used experimentally for treating human ebov patients in the west african outbreak, although the actual benefit to human evd remains to be confirmed. a second approach to the treatment of fhf lies in the development of specific antiviral agents. a current nucleotide analogue is favipiravir (t- ), which was developed and approved in japan for the treatment of influenza. favipiravir inhibits viral rna-dependent rna polymerase of the influenza virus. it was subsequently found to exhibit in vitro antiviral activities against certain other rna viruses such as bunyaviruses, arenaviruses, flaviviruses, alphaviruses, norovirus, and ebov. e animal studies also demonstrate the efficacy of favipiravir in the treatment of junín virus, arenavirus, and ebov hemorrhagic fevers, and the drug was used to treat human evd in the west african epidemic. e a dosing regimen of favipiravir for use in a clinical trial for the treatment of evd has been published. another nucleotide analogue, brincidofovir (a lipid conjugate of cidofovir), was previously developed to treat infections due to dna viruses such as adenoviruses, herpesviruses, and orthopoxviruses; the drug was granted emergency investigational new drug applications in october by the united states (us) food and drug administration for evaluation in evd treatment, and a clinical trial was started in january in monrovia, liberia. e the nucleoside analogue bcx was recently shown to inhibit rna polymerase of negative-and positive-sense rna viruses via chain termination effects. its in vivo activity against marv was demonstrated in guinea pigs and cynomolgus macaques. the development of bcx for human clinical trials will require a long time. another approach involves the screening of currently available nonantimicrobials for their activities on filoviruses. compounds such as selective estrogen receptor modulators (e.g., clomiphene, toremifene), amiodarone, dronedarone, and verapamil have antifilovirus activity in cell cultures and/or murine models. , in addition, rna interference using small interfering rnas provide postexposure protection of animals infected with ebov and marv. e a third approach to the specific management of filoviral infections explores the potential of postexposure prophylaxis. such regimens would benefit exposed healthcare workers and other social contacts, and laboratory staff experiencing accidental exposures. protective immunity towards filoviruses does exist, as demonstrated in the possible benefits of convalescent plasma and animal studies, in which humoral immunity (i.e., igg) protects against ebov infection. animals studies also confirm that passive immunization by neutralizing monoclonal antibodies is protective in primates. previously examined filovirus vaccine candidates that elicit protective humoral immunity experimentally include ebov-like particles containing gp, np, and vp ; replication-deficient ebov mutants that lack the vp gene; and ebov gp-containing fragment or fusion protein. e a phase clinical trial has tested dna vaccines encoding the glycoproteins of ebov and marv. one of the most promising vaccine candidates for filoviruses is the recombinant vesicular stomatitis virus-based vaccine system that expresses filoviral gp. this system elicits protective immunity against zebov, sebov, bebov, and marv; it also offers substantial postexposure prophylaxis in primate and murine models. e the vaccine was used for postexposure prophylaxis in a laboratory staff person who sustained a needle stick injury with zebov in . a similar vaccine system used replication-defective recombinant adenovirus that expressed ebov gp was protective in animal models. , phase clinical trials of the vesicular stomatitis virus-based and adenovirus-based vaccines began in late . ebola virus disease as a problem in nonendemic countries: issues on prevention and control the containment of fhf outbreaks in endemic countries requires substantial resources in coordination between the public health system and other authorities of the countries, surveillance of the disease, education and engagement of local citizens, isolation and treatment facilities, and laboratory support. , these requirements are often beyond the capability of endemic countries. significant international assistance is usually needed to contain major outbreaks. the discussion on these public health issues is beyond the scope of this article. for health authorities in nonendemic countries, a preparedness plan for emerging infections is an indispensable component of the public health system. the development and adoption of preparedness and response plans for emerging infectious diseases are first fostered in anticipation of pandemic influenza. the outbreaks of severe acute respiratory syndrome (sars), pandemic influenza a (i.e., h n ), middle east respiratory syndrome coronavirus (mers-cov), and, more recently, avian influenza a (i.e., h n ) and evd underscore the importance of such pre-emptive plans in preventing or mitigating the effects of disease transmission. , the details may vary, depending on the nature of the pathogens; however, key components in public health response include risk assessment; communication and education; establishing a rapid response team and management team to coordinate responses between different government ministries; monitoring and surveillance; providing adequate facilities and supplies for quarantine and infection control; developing laboratory diagnostics; and where appropriate, antimicrobial and vaccination policies, and/or stockpiling. , for clinicians in nonendemic countries, fhf will mostly be encountered in travelers returning from endemic areas. the sars epidemic and influenza a (h n ) pandemic demonstrated the efficiency of international traveldespecially air traveldin the global spread of infectious diseases. , as a continent, africa has a relatively small number of international travelers (only oceania has a smaller number of international tourist arrivals), although the exportation of fhf to nonendemic countries is well documented in the present epidemic. it is tempting to consider establishing travel restrictions to limit the spread of evd outside of africa; however, the actual benefit of such policies is limited. at the time of this writing, the who has issued no travel restrictions to the affected countries. however, it is prudent to issue health warnings to potential visitors to affected countries. pretravel education on transmission routes, precautionary measures, self-monitoring of signs and symptoms, and availability of medical care in destination countries should be provided. as in other subspecialties of travel medicine, the visiting friends and relatives (vfrs) are at particularly high risk of contracting travel-related infections. despite the fact that publicity and health alerts are often announced to the general public, vfrs do not always receive the necessary information on the risks because of cultural differences, language barriers, or different perceptions. hence, efforts must be targeted to vfrs (especially african communities in this context) to reduce the risk of disease importation. remote infrared thermal scanners have been used as a means of fever screening at airports in some countries. the practice first gained popularity during the sars epidemic, and was subsequently evaluated in the influenza a (h n ) pandemic. e to a lesser extent, this method has also been used for the screening of other febrile illness such as dengue fever. infrared thermal scanning is relatively popular in asian countries such as taiwan, japan, korea, and hong kong, and it is usually used in conjunction with health questionnaires for self-reported symptoms such as fever and travel history. the tympanic temperature would be measured for suspected cases. the sensitivity, specificity, and positive predictive value of thermal scanning are affected by a variety of factors such as the instruments used, the threshold temperature, the part of the body being measured, the distance of the instruments from the individual, and the previous use of antipyretic agents. patients in the incubation period of an infection obviously will not be detected by this screening method. despite the relatively low sensitivity, specificity, and positive predictive values of infrared thermal scanning, some investigators consider it a useful adjunctive measure for border screening, although it cannot be relied on as the sole method for screening. e contact tracing must be promptly initiated for any potential contacts of returned travelers diagnosed with a communicable infectious disease such as evd. detailed guidance on contact tracing for patients with evd and other forms of viral hemorrhagic fevers have been published. , all suspected contacts must undergo individual risk assessments, based on the travel history, the epidemic situation in the affected countries, and the nature of potential exposure before and during travel. detailed instructions and information must be provided to the contacts, who will then be monitored for fever and the development of symptoms. the monitoring may be performed in the community or within healthcare facilities, during which some limitations indor at least, advice againstdthe freedom to travel within the community or country may be necessary and interference of daily activities may be inevitable. close and empathetic liaison between the contacts and health departments is essential to ensure compliance with monitoring and to minimize psychological impacts. a preparedness plan for contact tracing, disease surveillance, clinical management, isolation precautions, and outbreak management must be in place to manage such incidents in nonendemic countries. hemorrhagic fever remains an uncommon cause of fever in returned travelers, although it is severe clinically and has substantial public health implications. the risk of fhf in returned travelers is low. ten cases of marburg hemorrhagic fever were reported from to , and all patients had a travel history to africa. cases of imported evd (excluding the nonpathogenic rebov) were described in south africa in (zebov) and in switzerland in (tafv). other causes of fever in such settings must be excluded by appropriate laboratory investigations. these include (depending on the itinerary and exposure history) other causes of fever with or without hemorrhagic presentations such as meningococcal infections, severe sepsis due to other bacterial infections (including rare infections such as anthrax and plague as guided by the clinical picture and exposure history), leptospirosis, typhoid and other causes of enteric fever, rickettsioses, malaria, trypanosomiasis, visceral leishmaniasis, dengue fever, and yellow fever. in particular, malaria (which is a very common treatable cause of fever in returned travelers and is endemic in sub-saharan africa) must be excluded by appropriate testing. depending on the travel destination, other causes of viral hemorrhagic fever have to be considered such as lassa fever, hantavirus infection, crimean-congo hemorrhagic fever, and rift valley fever. the travel history should also include human contacts with sick individuals in the community (e.g., attending local funerals) or in healthcare facilities (as in the case of volunteer workers). another important exposure history is interaction with bats and other wild animals (especially primates). for example, a history of spelunking has resulted in fhf among local citizens and foreign visitors. cases of marburg hemorrhagic fever have occurred after exposure of visitors to bats in caves in kenya and uganda. , when fhf is suspected based on travel and/or exposure histories, pre-emptive isolation is essential to minimize the risk of subsequent interpersonal spread, until the diagnosis is excluded. the routes of transmission of filoviruses are well documented. transmission can be interrupted, provided that proper infection control and public health measures are implemented. detailed infection control guidelines on caring for patients with fhf have been published. , e in essence, the principles of isolation and use of personal protective equipment are not significantly different from standard precautions and transmissionbased precautions (i.e., contact, droplet, and airborne) that are universally practiced in healthcare facilities. however, numerous studies and reviews have confirmed that the compliance with the choice and use of personal protective equipment among healthcare workers are almost always suboptimal. e essential factors that ensure the optimal implementation of infection control protocols are adequate training of healthcare workers on isolation procedures and on the appropriate use of personal protective equipment, preferably by interactive training with clear instructions; adequate manpower and organizational support; and the availability of timely and adequate guidance and support. e such training should not be limited to staff working in clinical areas; it must also include other healthcare workers such as laboratory workers and paramedical personnel. the key elements of infection control consist of patient placement (e.g., isolation facilities), strict adherence to hand hygiene (e.g., the who's "five moments for hand hygiene"), proper use of personal protective equipment such as gloves (e.g., double gloves in special circumstances), waterproof gowns, respiratory protection (e.g., surgical masks, respirators during aerosol-generating procedures), eye protection, rubber boots, and safe handling of sharp objects. support staff engaged in environmental disinfection, funerals, and burial services must also be adequately trained on the proper use of personal protective equipment and chemical disinfectants, and on the handling of human remains to ensure adequate disinfection and minimize the risk of accidental exposure to the virus. , , conclusion filoviral hemorrhagic fevers are uncommon, but they pose real clinical and public health threats to countries outside endemic areas. the routes of transmission, clinical manifestations, and infection 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in health-care settings, with focus on ebola personal protective equipment in the context of filovirus disease outbreak response. rapid advice guideline management of hazard group viral haemorrhagic fevers and similar human infectious diseases of high consequence european network for diagnostics of imported viral diseases. management and control of viral haemorrhagic fevers and other highly contagious viral pathogens canadian nosocomial infection surveillance program. are health care workers protected? an observational study of selection and removal of personal protective equipment in canadian acute care hospitals compliance with isolation precautions at a university hospital a review of the evidence for suboptimal compliance of healthcare practitioners to standard/universal infection control precautions sars hospital investigation team. factors associated with critical-care healthcare workers' adherence to recommended barrier precautions during the toronto severe acute respiratory syndrome outbreak behind the mask: determinants of nurse's adherence to facial protective equipment barriers to implementing infection prevention and control guidelines during crises: experiences of health care professionals guidance for safe handling of human remains of ebola patients in u.s. hospitals and mortuaries supplementary guidance for handling of dead bodies of suspected/confirmed ebola virus disease (evd) the ebola virus vp protein functions as a type i ifn antagonist ebolavirus vp binding to karyopherins is required for inhibition of interferon signaling ebola virus disease centers for disease control and prevention. chronology of marburg hemorrhagic fever outbreaks key: cord- -kxyo rfv authors: stephens, david s.; ribner, bruce s.; gartland, bryce d.; feistritzer, nancye r.; farley, monica m.; larsen, christian p.; fox, john t. title: ebola virus disease: experience and decision making for the first patients outside of africa date: - - journal: plos med doi: . /journal.pmed. sha: doc_id: cord_uid: kxyo rfv david stephens and colleagues describe their experience of treating patients with ebola virus disease at emory university in the united states. multiple resources at emory university, in particular those of the academic medical center, euh, emory healthcare, and the robert w. woodruff health sciences center, the faculty, nurses, staff, and leadership of these units, and our communications and other emory university support teams. the successful treatment and discharge of these first two patients by august , , was only the first chapter of the impact of this outbreak on emory, the us, europe, and the global community. at least individuals have now been treated outside of africa (us: , europe: , with five deaths). the us, europe, and the rest of the world can expect to continue to be touched by this epidemic and by future communicable disease outbreaks. the strategic and tactical lessons and challenges presented by providing care for the first and subsequent us evd patients at emory university provide an opportunity to share lessons that may help others. specific clinical and immunological features and diagnostic and detailed management issues of the patients at emory are reported separately [ ] [ ] [ ] [ ] [ ] . it is very important to acknowledge the tremendous inequity between evd care available in our academic medical center versus sites in west africa. this disparity, illustrated by this outbreak, will require much future work to address. background euh is the flagship clinical care facility for emory healthcare, staffed by , emory school of medicine faculty physicians, with over , employees, , admissions, and , outpatient visits annually. the hospital has one of the highest case-mix indexes (a measure of complexity of illness treated) among the university healthsystem consortium (uhc)-ranked facilities. emory had established strong programs in health care delivery, quality, infectious diseases (id), infection control and biosafety, immunology, vaccines, and public health that were important to its ability to respond to this series of events. the serious communicable diseases unit (scdu) (fig , box ) of euh is a special isolation unit. this unit was designed and constructed in following the anthrax bioterrorism event but was also created, given the global connectivity of atlanta and its institutions, to address naturally acquired, highly communicable emerging infectious diseases such as evd. the unit was built and set up in close collaboration with and with financial support from the adjacent cdc to provide care for cdc scientists and staff who have contracted highly communicable infectious diseases in laboratory settings or while traveling abroad. the id program at euh was built to provide expertise in hospital epidemiology, antimicrobial management, transplant infectious diseases, and clinical microbiology. for over a decade, emory university was an active member of the nih research centers of excellence (rce) in biodefense and was the site for the biosafety training program for select pathogens of the southeast regional center of excellence for emerging infections and biodefense (serceb) rce. this particular program provided invaluable expertise, equipment, and support for the evd effort. emory id and emory healthcare (ehc) also created the travelwell clinic, an outpatient clinic available for assessment and evaluation of pre-and post-travelers and supporting major atlanta corporations and the cdc. emory's travelwell is part of a -site worldwide travel network (geosentinel) with a -year database of , entries of those who either had returned ill following travel to liberia, sierra leone, guinea, or nigeria or had just emigrated from one of those countries. the request for medical care for the initial patients came from the missionary organizations samaritan's purse and serving in mission (sim) usa and from the patients themselves. the decision was coordinated through the us state department and the cdc. euh and ehc leadership made the decision to accept the patients-a decision made quickly but not lightly. the decision was based on the need, confidence in the overall preparedness of euh, and the more than a decade plus of training and preparation to address highly communicable diseases at euh (box and box ). importantly, as an academic medical center and research institution, the decisions were also based upon what we might learn in treating these patients (e.g., advancing knowledge about human health) and how such knowledge could be applied to the current outbreak. procedures a patient could need, from mechanical ventilation to hemodialysis, can be performed in the unit. ( ) medical staff who are providing direct patient care use a locker room to change into full-body protective suits and masks, which shield them from blood and bodily fluids. ( ) family members are able to speak with patients through glass windows in the unit; patients have access to phones and laptop computers. the windows also allow observation of procedures and detection of contamination events. ( ) a dedicated laboratory that has the capacity to perform blood counts, routine chemistries, blood gas measurements, urinalysis, and tests for a variety of infectious agents was built specifically for use with the isolation unit. ( ) all liquid waste is disinfected and flushed, and disposable waste is autoclaved and incinerated. at the peak of the ebola patient's illness, up to bags a day of medical waste were produced. image credit: emory university; illustrator: damien scogin; licensed under a creative commons attribution . international license. different outside perspectives and guidance were initially provided about the level of biosafety needed for evd. ebola viruses have a very low infectious dose, - aerosolized organisms, in nonhuman primate models [ ] and can reach extremely high levels in blood (up to rna copies per ml of serum [ ] ), stool, sweat, and other body secretions. exposure of health care workers to infected body fluids via emesis, sweat, urine, saliva, diarrhea, or blood is a significant concern. there was also initial concern that this strain was not behaving epidemiologically as expected and the personal protective equipment (ppe) guidelines in africa were not fully effective in prevention of transmission. further, we had to demonstrate our ability to safely manage these patients. to achieve the lowest risk to health care personnel, the highest level of biosafety was initially employed. this included maxair powered air-purifying respirators (paprs), fluid-resistant body suits along with cover aprons, double gloves and shoe covers, and wiping down all box . the scdu • the scdu was designed (fig ) to provide an extraordinarily high level of clinical isolation with more enhanced capacities than are normally provided to isolate patients in many hospital settings. the unit has a special outside entrance for emergency use and is separated from patient care areas in order to not impact other clinical services. it was the first of three such high-level civilian facilities in the us. • the scdu was constructed (purposely to provide rapid isolation, security, flexibility, and access to special resources) within the euh clinical research unit. the clinical research unit has been in existence for some years and supports clinical research through the national institutes of health (nih)-funded clinical and translational science awards (ctsa) program. the scdu offers on-call, highly trained staff operating under standardized, ready-to-go protocols for providing care for patients infected with highly communicable contagious diseases. • while not necessary for treatment of evd, the isolation rooms feature negative pressure air handling, air changes per hour, with laminar flow and high-efficiency particulate air (hepa)-filtering completed before the air is % exhausted outside of the hospital (no recirculation). general and intensive care can be provided. the scdu was activated on two previous occasions. the first was in for a cdc worker with concern for having been infected with severe acute respiratory syndrome (sars) in hong kong, china. the second was in for a cdc employee in angola with potential marburg virus hemorrhagic fever. while unit activation has been infrequent, intensive training in this unit to maintain a state of readiness has been continuous for well over a decade, including detailed preparation for transport of patients and the training of nurses and physicians. • a virtual tour of the scdu and videos addressing many of the most frequently asked questions, together with access to all scdu policies and standard operating procedures (sops), are available on the emory education web site: www.emoryhealthcare.org/ ebolaprep [ ] . surfaces with us environmental protection agency (epa)-registered disinfectants (no spraying) when doffing ppe. other key biosafety sops developed were autoclaving within the unit for waste management, followed by disposal of regulated medical waste off-site after it had been autoclaved; decontamination; and handling of laboratory samples and waste. the consequences of transmission stressed the need for the highest level of biosafety. the importance of the ehso office in reinforcing the prior training of personnel and monitoring the clinical staff for consistency and adherence to biosafety from training sessions to practices in real-time clinical care cannot be overemphasized. this included how to "don and doff" impermeable fluid-resistant body suits, proper use of paprs, coordination of the disposal of waste, and the handling and transport of lab samples. ehso also helped prepare and support the team psychologically, challenging them with spills and other incidents to practice remaining calm in the face of potential unexpected occurrences. team engagement demonstrated the importance of melding the philosophies of clinical treatment/practice and biocontainment/biosafety. feedback from frontline physicians, nurses, and hospital staff highlighted • the scdu medical team is led by the scdu director, an id trained physician who has spearheaded for over a decade efforts in establishing the protocols, training, education, and operations of the unit in conjunction with the cdc. three other faculty members of the department of medicine, four additional id physicians, two pathologists, five medical technologists, and critical care nurses also support the unit. • an scdu unit director, clinical nurse specialist, and team coordinator handle logistics, organize training sessions, determine supply needs, and establish nursing schedules. nurses provide care in -hour stretches to minimize donning and doffing of personal protective equipment. the overall effort has directly involved over staff and support personnel. • the primary focus of training was on biosafety for all individuals who provided direct care or handled body fluids. all of these individuals received mandatory education and training, followed by strict competency verification before medical or nursing staffs were permitted to provide care for these patients. • effective and assertive communication was central to the safety of the scdu team. use of the buddy system was an essential element of the focus on individual and colleague safety. because communication was so important, the team developed rules to govern direct patient care communication as well as within daily team huddles. these rules were reviewed each morning during the daily huddle and served as a platform to empower all members of the team, regardless of role, to facilitate communication and to maintain strict sops. the contributions of ehso to the effort and the value of the ehso biodefense education and training expertise. waste management for evd is a significant hurdle. evd results in copious amounts of vomit and diarrhea with up to liters of fluid lost by patients each day. up to large "bags" per day • the hospital support team was led by the ceo of euh. the chief medical and nursing officers of ehc and euh, and in particular the vice president of operations of euh, were also heavily involved in leading the support efforts. during the care and treatment of the evd patients, an operations team of key administrators and nursing and physician leadership met twice a day. despite the extensive preplanning, opportunities to refine and improve both clinical and operations were noted, and all aspects of the hospital services were involved. pharmacy, environmental services, engineering/facilities support, and pastoral care/counseling were especially important. • other id faculty, including a pediatric id specialist with experience in evd, provided support for the frontline medical team. periodic conference calls focused on support, therapeutic options in treating patients, and issues of postexposure prophylaxis, vaccines, surge planning, protocol development, and discussions of research as it related to evd. to facilitate the necessary availability of scdu dedicated id providers, alternate faculty were recruited to cover the regular duties of the scdu physicians. id support also included contacting key national and international research leaders in evd; evaluating, contacting, and obtaining, through outside groups, experimental vaccines and new drugs for ebola; and communicating with the cdc, fda, nih, and other federal agencies, other university partners, and biotech/industry contacts, all of which were essential in the effort. • the emory environmental health and safety office (ehso) was engaged immediately after the call for ongoing support. while clinical care settings are very different from those of labs, ehso staff included individuals with expertise in training on biosafety level bsl and laboratory safety, which was helpful in translating to our clinical care situation. conversations were conducted by ehso with other national biosafety leaders in evd. (see "biosafety.") • the scdu team was also supported by the department of emergency medicine and the emory office of critical event preparedness and response focusing on the complexity of patient transport and emergency care. they worked closely before and during the event with phoenix air group, the air ambulance transport service, and the grady hospital ambulance service. critical care established a / medical intensive care unit (micu) attending coverage for critical care management issues including airway management and line placement issues. other subspecialties, such as renal medicine, were required on a case-by-case basis. the location of the scdu away from other patient care units of euh significantly reduced the impact on our other health care delivery and patient operations. dhcpp at cdc provided critical help to the unit for viral loads, specialized assays, and other support. of regulated medical waste were generated by our first two patients. a large-capacity autoclave was mobilized, with postautoclaved waste stored in -gallon leak-proof rubber waste containers in the scdu until removal and incineration. all waste in toilets was disinfected with an epa-registered disinfectant before flushing. importantly, no traces of ebola rna on "hightouch surfaces" such as beds and bathrooms were detected during active care or after patient discharge prior to terminal decontamination with vaporized hydrogen peroxide. guiding principles for communications included consistent messaging and protecting patient privacy while educating the public. internal communications with a focus on transparency and education, within the bounds of confidentiality of medical information and protecting our patients' privacy, were vital. these included meetings with euh hospital leadership and staff to address concerns, frequent emails and other communications with all faculty and staff at ehc and emory, making sure instructions/checklists were in place, and facilitating the dissemination of protocols. to avoid unauthorized access to electronic medical records, a chart-warning flag was implemented. confidentiality of medical information regulations were repeatedly stressed to all medical staff, residents, and fellows. in external communications and interface with the media, the emory communications teams tirelessly addressed media logistics, developed web and social media material, worked closely with governmental and nongovernmental external groups, developed talking points, and prepared the hospital and scdu teams for communications venues. to maximize our preparedness and to address national concerns, press conferences and media interviews were conducted, and an evd questions and answers document was developed and posted. the story exploded in broadcast print and social media. over , media stories have been written linking emory and ebola. emory communications created an emory healthcare ebola preparedness protocols website (www.emoryhealthcare.org/ebolaprep) [ ] to make our clinical and biosafety protocols and other information widely available to the public. to date, , registrants have downloaded these educational materials. the admissions heightened ebola and other bio-threat concerns both locally and nationally. questions about potential evd patients began to occur immediately in our health care system and throughout the us. we developed and disseminated flow diagrams, algorithms, and sops [ ] for evaluating patients in emergency rooms and other health care provider settings where evd was a consideration. cdc guidelines as they became available and current evd articles were also disseminated. our teams engaged local, regional, state, and national health care groups, and guidance was provided to questions about travelers from the region coming to emory, to airlines flying to west africa, and to multinational corporations based in west africa. travelers' diarrhea with fever and malaria are the problems most commonly encountered by travellers to west africa. however, yellow fever along with lassa fever, endemic in west africa as well, can cause similar symptoms to those of ebola. typhoid and less frequently diseases such as dengue and other viral syndromes can cause such signs/symptoms, though not usually as severe. the intersection of the seasonal influenza epidemic with returning cdc workers from west africa further amplified the evaluations of febrile episodes. timely initial screening-with establishment of contact and droplet precautions early while the risk assessment, including an extensive travel history and the evaluation of exposure risk and symptoms, was continued-was emphasized. policies and procedures for the continuing care of our discharged patients were also developed [ ] . as noted, a highly trained group of faculty, nurses, biosafety support, and other providers staff the euh scdu. while no trainees (e.g., fellows, residents, or students) served on the direct care team, trainees benefitted from the experience of the unit and clinical experience with evd through conferences and other education venues (e.g., public health grand rounds and id seminars). an evd "micro vignette" and other educational materials were developed for resident and fellow education. further, id and other specialty fellows have been integrated into the management planning for evd patients, educated on the broader policies and procedures of the unit, are involved with the development of protocols for the management of ebola patients who present to the emergency department (ed) or other clinical settings, and are educated about the collective experiences in treating the patients. in addition, a massive open online course (mooc) "ebola at emory: patients to populations" has been launched [ ] , an ebola academic learning community was established, and other efforts to educate and support graduate and undergraduate student activities were undertaken. emory faculty and staff also actively participate in national education and training efforts, including multiple presentations at national meetings, engagement in training forums sponsored by the cdc and the us department of health and human services (hhs), writing publications and communications, and conducting press conferences. fifty-five us hospitals, including many in academic medical centers, have now been designated as ebola treatment centers. work was initiated to better understand evd pathogenesis and therapeutic options [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , including optimal patient management, fluid and electrolyte replacement, and dialysis [ ] [ ] ; evaluation of concomitant infections (e.g., malaria or lassa fever); levels of evd viremia, monitoring viral rna in body sites [ ] and environmental samples; tracking evd specific immune responses [ ] ; evaluation of available investigational drugs and their safety, risks, and benefits; options for immune therapy (monoclonal antibodies [mabs], convalescent sera) and available supplies; available investigational vaccines [ , ] , best practices in clinical operational management; and postexposure prophylaxis. in addition, the generation of new knowledge about evd biosafety, infection control, and waste management has resulted from this event. these activities have now expanded as a broader institutional effort that includes new drug discovery for evd, generation of human ebola mabs, expanded study of evd glycobiology, focus on biomarkers as correlates of clinical evd outcome, work on the ecology and the emergence of evd and other tropical-associated zoonoses, clinical trials of ebola vaccine, and modeling the spread and control of evd in west africa. this work required close coordination with and the support of the emory institutional review board (irb), collaboration with the fda, establishment of emergency investigational new drugs (inds), and work with drug and biologic manufacturers and with multiple other governmental agencies. these and other evd research and scholarly projects generated by the decision continue at emory. the event also led to broad faculty engagement across all parts of the institution through the creation of an emory ebola task force and ebola faculty and community discussion forum [ ] . the task force includes leaders from across the campus and is directed at facilitating cross-cutting institutional initiatives such as evd research, education and training activities, input into public policy issues around evd, development of an institutional travel policy to west africa, establishing procedures for trainee involvement in ebola care, and the support of the humanitarian, research and control efforts in west africa. evd has arrived in north america and europe and impacted us globally. academic medical centers can be expected to be at the frontline to address evd and other highly communicable infectious agents in the future. our experience (box ) with evd emphasized prepared infrastructure and coordination of clinical care, hospital and emergency operations, transportation, infection control, biocontainment, communications, and education and training initiatives. unanticipated major challenges can be expected. the importance of detailed planning, preparedness, and team work across multiple academic and health care units, the emphasis on biosafety, key partnerships with environmental health and safety and institutional communications, and working closely with governmental agencies and outside collaborators to manage these threats is highlighted. • communicable infectious diseases will continue to be global threats to human health and have the potential to cause repeated humanitarian disasters. • our experience as an academic health center with evd emphasized the importance of preparation, communications, and implementation: coordination, detailed planning, and teamwork across governmental, nongovernmental, academic, and health care units the institutional experience, while providing the opportunity to effectively care for these individuals, has led to best practice information and the education and training of others, created key academic, governmental, and community partnerships, expanded research programs in evd, and resulted in the development and communication of new knowledge about this emerging disease. mobilizing our diverse academic community to work collaboratively on this global problem is also an important long-term outcome. ebola haemorrhagic fever emergence of zaire ebola virus disease in guinea estimating the future number of cases in the ebola epidemic-liberia and sierra leone who ebola response team. ebola virus disease in west africa-the first months of the epidemic and forward projections clinical care of two patients with ebola virus disease in the united states successful delivery of rrt in ebola virus disease laboratory test support for ebola patients within a high-containment facility care of patients with ebola virus disease emory healthcare ebola preparedness protocols clinical recognition and management of patients exposed to biological warfare agents rapid diagnosis of ebola hemorrhagic fever by reverse transcription-pcr in an outbreak setting and assessment of patient viral load as a predictor of outcome ebola virus disease: an evolving epidemic the use of tkm- and convalescent plasma in patients with ebola virus disease in the united states performance of bedside diagnostic ultrasound in an ebola isolation unit: the emory university hospital experience human ebola virus infection results in substantial immune activation emergency postexposure vaccination with vesicular stomatitis virus-vectored ebola vaccine after needlestick persistence of ebola virus in ocular fluid during convalescence ebola faculty and community discussion forum the authors wish to thank and recognize the key contributions of emory faculty and staff, the woodruff health sciences center, emory university hospital and emory healthcare, and especially the scdu team [ ] , the scd unit coordinator, emory healthcare nursing services, emory medical laboratories, emory university and woodruff health sciences center communications and public affairs, emory environmental health and safety office, the emory ebola task force and other key emory leaders, the cdc and other us federal and georgia partners, samaritan's purse and sim usa, and the patients themselves in this effort. we also thank dianne watson for excellent administrative support. contributed to the writing of the manuscript: dss bsr bdg nrf mmf cpl jtf. wrote the first draft of the manuscript: dss. agree with the manuscript's results and conclusions: dss bsr bdg nrf mmf cpl jtf. all authors have read, and confirm that they meet, icmje criteria for authorship. key: cord- -ibli rq authors: to, kelvin k.w.; chan, jasper f.w.; tsang, alan k.l.; cheng, vincent c.c.; yuen, kwok-yung title: ebola virus disease: a highly fatal infectious disease reemerging in west africa date: - - journal: microbes infect doi: . /j.micinf. . . sha: doc_id: cord_uid: ibli rq ebolavirus can cause a highly fatal and panic-generating human disease which may jump from bats to other mammals and human. high viral loads in body fluids allow efficient transmission by contact. lack of effective antivirals, vaccines and public health infrastructures in parts of africa make it difficult to health workers to contain the outbreak. ebolavirus has been known to cause outbreaks of severe hemorrhagic fever with high fatality in africa since [ ] . however, ebolavirus has been out of the spotlight of the clinical and scientific community because it mainly affects remote villages involving at most few hundred people, and these outbreaks often stopped spontaneously. in , a large ebolavirus outbreak occurred in west africa. this outbreak was first reported from guinea in march , although epidemiological investigation suggested that the first fatal case had occurred in december [ ] . the outbreak then spread to liberia, sierra leone, nigeria, senegal, and mali in africa. the first case diagnosed outside africa was reported from usa on september , [ ] . in october , three nurses acquired ebolavirus locally in the united states and spain which has generated huge media attention and public panic. the west africa ebolavirus outbreak is unprecedented in many ways. firstly, this is the largest ebolavirus outbreak recorded in history, with over , cases and a mortality rate of . % [ ] . secondly, the outbreak involved major cities, including conakry in guinea, free-town in sierra leone, monrovia in liberia, and lagos in nigeria [ , ] . the involvement of major cities increases the risk of rapid local dissemination, spread to neighboring countries, and transcontinental spread by air travel, and therefore presenting a major health threat to the entire world [ ] . here, we review the basic science, epidemiology and clinical aspects of ebolavirus which are relevant for the control of the current outbreak. ebolavirus, together with marburgvirus and cuevavirus, are the three genera belonging to the family filoviridae in the order mononegavirales [ ] . four species within the ebolavirus genus can cause fatal human disease, including sudan gabon, which are located in central and east africa. zaire and sudan ebolavirus are responsible for most outbreaks, and these species are associated with highest case-fatality rates, ranging from e % and e %, respectively. taï forest ebolavirus caused illness in an ethnologist who performed a necropsy on an infected chimpanzee in in cote d'ivoire of west africa [ ] . bundibugyo ebolavirus has only been associated with two outbreaks since , with relatively low case-fatality rate [ ] . reston ebolavirus can cause disease in pigs and be fatal in monkeys [ ] , but has not been definitively associated with any human disease, although asymptomatic infection, diagnosed with serological test, was identified in persons with contacts with infected monkeys and pigs [ , ] . in addition to clinically apparent evd outbreaks, seroepidemiology studies showed that there is a high prevalence seropositive individuals, suggesting that asymptomatic or mild infection can occur [ ] . in a study testing blood samples collected from individuals from randomly selected village in gabon between and , . % of samples were found have ebolavirus-specific antibodies using elisa [ ] . ebolavirus-specific antibodies can also be found in individuals from areas without apparent evd outbreak. for example, ebolavirus-specific antibodies, detected using indirect immunofluorescence slide test, were found in . % of healthy individuals from a rainforest area of liberia in the early s [ ] . though these serological test results have not been confirmed by neutralization antibody study, it is highly likely that asymptomatic and mildly symptomatic infections are much more common than severely symptomatic and fatal illness. the current west africa evd outbreak started in december , when cases first appeared in meliandou village, gu eck edou of guinea (table ) [ ] . the index patient was a -year-old child with fever, black stool, and vomiting, with symptom onset on december , , and died days later. the disease then spread to other villages of the gu eck edou district, and also macenta and kissidougou district. the first peak occurred in march when patients were diagnosed with evd in liberia. the second peak occurred in may and june , coinciding with the first report of cases from sierra leone. contact tracing found that the initial cases in sierra leone attended a funeral of a highly respected "traditional healer", who has treated patients with evd in guinea [ , ] . there was a large increase in cases since july . the first case in nigeria was a traveler from liberia, who has caused an outbreak involving laboratoryconfirmed cases from july to september [ ] . senegal and mali reported the first imported cases on august and october , , respectively [ ] . the first case of evd diagnosed outside africa was confirmed on september , [ ] . the patient, from liberia, arrived in usa on september , and developed symptoms on september . a separate evd outbreak, also caused by zaire ebolavirus, has occurred in drc since july [ ] . as of october , , the drc outbreak has involved cases with deaths [ ] . together with these epidemiological data, viral genomic data has provided important information on the origin and the transmission dynamics of the west africa ebolavirus strain. phylogenetic analysis using the whole genome sequences of ebolavirus strains from patients revealed that the west africa evd outbreak is caused by a zaire ebolavirus lineage that is most closely related to the one causing the evd outbreak in drc [ ] . molecular dating suggested that this west african lineage likely diverged from the central african lineage in [ ] . analysis of the ebolavirus strains from guinea and sierra leone showed that they are highly similar, which is in agreement with the findings from contact tracing (fig. ) . however, there are two distinct lineages of ebolavirus in sierra leone which were estimated to have diverged in april . this finding suggests that the virus has further mutated either in guinea or in sierra leone [ ] . on the other hand, the ebolavirus strain causing the drc evd outbreak in july is another zaire strain most closely related to drc outbreak zaire strain [ ] , confirming that this is a separate outbreak. before , the largest evd outbreak affected less than people. however, in the current outbreak, there are already , cases and deaths as of october , [ ] . further studies must be undertaken to understand the viral and environmental factors that contribute to the unprecedented scale of this outbreak. it is still uncertain at this stage whether the virus has become more transmissible in human or has increased environmental stability. it is unclear why zaire ebolavirus suddenly appear in west africa. the only human case of ebolavirus infection in west africa before the outbreak occurred years ago. epidemiological investigation suggested that the first patient was a -year-old child in meliandou village, gu eck edou. one postulation is the spread of the virus by fruit bats from central africa [ ] , but this will require confirmation by further field studies. humans can acquire the infection from infected animals or infected persons. the index patients of evd outbreaks are usually persons working in forests, caves or mines. many of these index patients are bushmeat hunters with direct contact with animals. in the natural setting, transmission from animals usually involves direct contact with the animal or handling of the carcasses. however, most humans acquire the infection through direct person-to-person transmission that can occur via direct contact with body fluids. many clusters occurred when people attended the funeral of an infected patient [ , ] . a caseecontrol study showed that household contacts with direct physical contact with the ill patient or cadaver and exposure to body fluids were risk factors for acquiring infections [ ] . ebolavirus can be transmitted directly through broken skin or mucous membranes from the blood, body fluid, and secretions of the infected person, as the virus could be detected in blood, urine, saliva, seminal fluid, breast milk, tears, stool, skin, and swabs from vagina, rectum and conjunctiva [ ] . virus shedding can be prolonged. reverse-transcriptase polymerase chain reaction (rt-pcr) remained positive in the blood for up to days, in the vaginal, rectal and conjunctival swab for up to days, and in the seminal fluid for up to days [ ] . live virus could be isolated from a patient's seminal fluid days after symptom onset. transmission through environmental surfaces is possible. it was shown that live ebolavirus can survive on dried glass or plastic surface for up to days [ ] . studies have shown that lower temperature and higher absolute humidity are associated with evd outbreaks [ ] . animal studies showed that other routes may be possible. reston ebolavirus can be transmitted from pigs to cynomolgus macaques without direct contact, suggesting that ebolavirus can be transmitted from animal reservoirs to humans without direct contact [ ] . studies in rhesus macaques showed that ebolavirus given orally can cause fatal infections [ ] . aerosol transmission in macaques has been documented [ ] , but this route of transmission has not been documented in humans. almost all cases in the current outbreak are related to person-to-person transmission. the effective reproduction numbers for the outbreak were estimated to be . for guinea, . for liberia, . for nigeria, and . for sierra leone [ ] . hospital-acquired infections are common. during the evd outbreak, the index case had transmitted the virus to healthcare workers and hospitalized patients with at least generations of person-to-person transmission [ ] . during the current outbreak, at least healthcare workers were infected, with at least deaths [ ] . in addition, ebolavirus is also transmitted indirectly when the broken skin or mucous membranes come into contact with the contaminated environment or items such as soiled clothing, bed linen, or used needles. unsterilized syringe was associated with the outbreak in zaire [ ] . in one study, the virus could also be found on the doctor's blood-stained glove and the bloody intravenous insertion site, but was not found on the patient's surrounding environment [ ] . laboratory-acquired infections from accidental puncture while handling infected materials have been reported [ , ] . in a detailed analysis of confirmed and probable ebolavirus cases in guinea, liberia, nigeria and sierra leone from december , to september , , the median age was years with an interquartile range from to years. the male to female ratio was : [ ] . the incubation period is usually e days, but can be as short as days and as long as days [ ] . in the current outbreak, the mean incubation period was . days, with % of patients had symptom onset within days. ebolavirus has been found in several animals, including bats, primates (chimpanzee, gorilla), rodents (rats, mice, shrews), duikers (cephalophus species), and pigs [ ] . although ebolavirus-specific antibody can be detected in up to . % of serum samples from dogs in ebolavirus endemic areas [ ] , there have not been any reports on the isolation of ebolavirus or detection of ebolavirus nucleic acid from dog's samples. in some animals, ebolavirus causes epidemic fatal disease. it was estimated that after the ebolavirus outbreak in the drc between and , there were %, % and % reductions in the chimpanzee, gorilla and duiker populations, respectively [ ] . bats have been proposed to be the source of ebolavirus. bats have been known to be the source of several human viruses including severe acute respiratory syndrome-related coronavirus (sars-cov), hendra virus, nipah virus, menangle virus, rabies virus and lyssaviruses [ , ] . ebolavirus was first reported to be found in the fruit bat species hypsignathus monstrosus, epomops franqueti and myonycteris torquata, which were captured during the and outbreak in gabon and the drc [ ] . during the investigation of the outbreak in drc, it was found that the affected area has a large palm plantation where migratory fruit bats settled for food between april and may, and that the first human case ate a freshly killed bat which was bought from a hunter in may [ ] . ebolavirus is not limited to africa. serological study showed that antibodies against zaire and reston ebolavirus could be detected in fruit bats from bangladesh [ ] , while reston ebolavirus could be detected in fruit bats from the philippines [ ] . a study in china showed that up to . % of bats were seropositive for ebolavirus [ ] . the most common bats species with ebolavirus identified in china include rousettus leschenaultia, hipposideros pomona, miniopterus schreibersii, pipistrellus pipistrellus, myotis ricketti, in which other novel viruses have also been identified [ e ]. reston ebolavirus have been found in domestic pigs in the philippines and china [ , ] . antibodies specific against all ebolavirus species have been found in apes of indonesia [ ] . like all filoviruses, ebolavirus is a filamentous enveloped virus with a negative-sense, non-segmented single-stranded genome of about kb, measuring nm in diameter and up to nm in length [ ] . the end of the viral genome consists of a non-coding region, followed by genes (nucleoprotein [ , and then a non-coding region at the end. each gene encodes one protein, except for the gp gene, which encodes three glycoproteins. the full-length gp is produced by rna editing, in which the two reading frames are joined together by slippage of viral polymerase at an editing site, generating an mrna transcript that allows read-through translation of gp. gp contains gp subunit for host cell receptor binding and the gp subunit for cell-virion membrane fusion. the soluble gp (sgp) is generated by an unedited transcript, which is much more abundant than gp [ ] . a third protein, called small soluble gp (ssgp), is produced via rna editing [ ] . gp, vp and vp are associated with membrane, while np, vp , vp , and l protein bind to the viral genome, which are required for viral genome replication and transcription. vp is also required for the assembly of nucleocapsid. the viral life cycle starts when gp attaches to cell surface receptors [ , ] . although ebolavirus can bind to host cell surface dendritic cell (dc)-specific icam -grabbing nonintegrin (sign) (dc-sign), liver and lymph node sign (l-sign) and t cell immunoglobulin and mucin domaincontaining (tim ), it is currently unclear which cell surface receptor is most important. after attachment, viral entry occurs via macropinocytosis and clathrin-mediated endocytosis [ ] . after entry, the virus is then trafficked into endosome. inside the endosome, several factors are required for the fusion of the viral and endosomal membrane to occur, including acidification of the endosome, and priming and triggering of the gp. priming of gp occurs when gp , which is bound to gp , is cleaved into the kda gp by cathepsin l and then to kda by cathepsin b. triggering occurs when the kda gp undergoes conformational change to expose the fusion loop [ ] . another important event in the fusion step is the binding of the endosomal membrane protein, niemann-pick c (npc ), to cleaved gp [ ] . viral genome replication and transcription then take place in the cytoplasm, which require the viral polymerase l protein, vp , vp and np. vp is required for nucleocapsid formation and assembly. viral transcription is also regulated by vp [ ] . the gp, after modification in the golgi, is trafficked to the plasma membrane, where it is associated with other proteins. virus budding and release then occur, and require the matrix protein vp . in addition to the viral life cycle, these viral proteins are also involved in the pathogenesis of the infection. gp can cause destruction of endothelial cells [ , ] . several lines of evidence suggest that the sgp is important in the modulation of host inflammatory response and immune defense. in vitro, sgp can inhibit the neutralizing activity of anti-gp antibody [ ] . sgp also subverts anti-gp immune response by inducing a host antibody that competes for the binding site of anti-gp antibody [ ] . sgp can also interact with neutrophils, although the receptor for this interaction is controversial [ , ] . on the other hand, sgp may limit the virulence of the virus. recombinant ebolavirus without sgp are less cytotoxic than those with sgp [ ] . sgp can protect endothelial cells from tnf-a [ ] . sgp can also bind to gp , but the importance of this finding requires further study [ ] . vp also inhibits the innate immune rig-i signaling, interferon(ifn)-a and ifn-b production, and dendritic cell maturation [ ] . vp is important in the inhibition of ifn signaling [ , ] . it is currently unclear whether the west africa ebolavirus strain possesses unique characteristics that favor its spread among the human populations. one possible reason is the higher mutation rate. it has been shown that the mutation rate in the current outbreak is about twice as high than that in previous outbreaks [ ] . decontamination methods for ebolavirus include heat inactivation at e c for h or at c for min, g-irradiation, chemicals, including formalin and quaternary ammonium ion, and nanoemulsions, which disrupts the membrane [ ] . in most cases, ebolavirus likely enters the body via breaks in the skins or mucous membranes. infection of monocytes, macrophages and dendritic cells helps to disseminate the virus to the lymph nodes via the lymphatics, and to the liver and spleen via the blood. notably, ebolavirus does not infect lymphocytes, although lymphocyte depletion occurs due to apoptosis [ ] . when the infected monocytes, macrophages or dendritic cells move out of the lymph nodes and spleen, the virus can disseminate to other organs [ ] . ebolavirus can also infect endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells, and epithelial cells. since patients with severe disease have higher viral load in blood, uncontrolled viral replication may play an important role in the pathogenesis of severe evd [ ] . macroscopically, there are hemorrhagic lesions on the skin, mucous membranes, and visceral organs at autopsy. microscopic examination reveals necrosis in many organs, including the liver, spleen, kidneys and gonads [ ] . in the liver, there is also evidence of apoptosis, microvesicular steatosis and kupffer cell hyperplasia. councilman bodies, which are apoptotic liver cells that have dislodged from adjacent hepatocytes, may be present. eosinophilic oval or filamentous cytoplasmic inclusions may be present, and they are aggregates of ebolavirus np. examination of the lung shows hemorrhages and diffuse alveolar damage. infection of the adrenal gland has been documented in humans [ ] . adrenal necrosis may be one possible pathogenic mechanisms leading to hypotension. marked coagulopathy is a hallmark of evd. disseminated intravascular coagulation frequently occurs. it is believed that tissue factors secreted from monocytes/macrophages are related to the coagulopathies in macaques [ ] . the level of protein c is reduced during coagulopathy [ ] . protein c is important in inflammatory response. a study in which rnapc and rhapc-treated rhesus macaque had better outcome, had higher levels of genes transcriptionally regulated by ccaat/ enhancer-binding protein alpha, tumor protein , and megakaryoblastic leukemia and myocardin-like protein [ ] . although the virus can infect endothelial cells, vascular lesions are not seen in postmortem tissues, and therefore the severe bleeding is unlikely to be related to the direct destruction of the blood vessels by the ebolavirus. similar to other causes of severe sepsis, cytokine/chemokine dysregulation occurs in patients with severe disease. fatal cases had high levels of mip- b, il- , il- , and il- [ ] . in one study, asymptomatic patients had elevated levels of il- b, il- , tnfa, mcp- , mip- a and mip- b in the plasma [ ] . however, in one study, gene expression levels of cytokines in peripheral blood mononuclear cells from infected patients were not different from that of non-infected patients. the level of plasma nitric oxide is higher in fatal than that of non-fatal cases [ ] . the high levels of nitric oxide may have contributed to lymphocyte apoptosis, tissue and vascular damage, and may be associated with the hemodynamic instability seen in fatal cases. one of the major innate defense mechanisms against viral infection is the ifn pathway. ifn are produced by cells upon viral infection, and induced several proteins, including the ifn-induced transmembrane proteins (ifitms). it has been shown that the type ifns and the ifitm , and to a lesser extent ifitm , restrict the cell entry of ebolavirus [ ] . as mentioned above, the viral proteins vp and vp interfere with the ifn pathway which may in turn dampen the priming effect on the adaptive immune response, thus allowing the virus to replicate to high titers. the importance of humoral and cell-mediated immune response is illustrated by a study comparing survived and fatal cases [ ] . ebolavirus-specific igm and igg were detected in all survivors during the early course of illness, with positive titer detected as early as days after symptom onset. in contrast, only one third and none of fatal cases had detectable igm and igg response, respectively. activation of cytotoxic t cells, as indicated by the upregulation of fasl and perforin mrna expression, was observed at the time of viral clearance for survivors, and the levels of ifng, soluble fas and soluble fasl were low during the recovery phase, suggestive of a regulated cytotoxic t cell response during the recovery phase. for the fatal cases, the levels of ifng, soluble fas and soluble fasl were elevated and increasing before death, suggestive of massive activation of cytotoxic t cells. after natural infection, neutralizing antibodies are produced in some patients. persistent serum-neutralizing activity and igg immunoreactivity for at least years after infection have been found in some survivors [ ] . monoclonal antibodies against gp have been shown to protect non-human primates from lethal infection as both post-exposure prophylaxis [ e ] and treatment [ , ] . the level of anti-gp igg highly correlated with survival in guinea pigs and cynomolgus macaques which were vaccinated by gp expressed in adenovirus or vesicular stomatitis virus vectors [ ] . antibodies are also critical in conferring protection for cynomolgus macaques after vaccination with recombinant vesicular stomatitis virus expressing gp [ ] . vaccine studies in animals have provided clues to the contribution of cell mediated immunity in conferring protection. mice study showed that virus-like particles induced protective immunity only in wild type mice but not in nk-cell depleted mice, therefore suggesting that nk cells are important in protective immunity [ ] . the role of t cells is controversial. while one study showed that cd þ t cells are required for conferring protection [ ] , another study showed that it is not required [ ] . despite a high case-fatality rate, there are many individuals with asymptomatic infections, as evidenced by a high percentage of seropositive individuals. although many factors may determine whether a patient develops symptomatic disease, host genetic differences likely play an important role, as in other infectious diseases [ , ] . mice with different genetic backgrounds had different susceptibility to ebolavirus infection, and possibly related to the variations in the tek gene responsible for coagulation [ ] . evd typically progresses rapidly with multisystem involvements, and in particular coagulopathy leading to severe hemorrhage. during the early stage of illness, the patients usually exhibit an acute onset of non-specific flu-like symptoms, including fever, chills, myalgia, and headache, followed by gastrointestinal symptoms including abdominal pain, nausea, vomiting and diarrhea [ ] . respiratory symptoms, such as cough and sore throat may also occur. a maculopapular rash typically occurs on day e after symptom onset, and is associated with erythema and desquamation. hemorrhagic phenomenon then appears, which can include petechiae or ecchymoses, uncontrolled oozing from venipuncture sites, and mucosal hemorrhages. however, it should be noted that massive hemorrhage occurs in fewer than half of patients and is seldom the cause of death. in the outbreak, unexplained bleeding was reported in only % of patients [ ] . hypovolemia can develop rapidly. as in other causes of severe sepsis, complications including disseminated intravascular coagulopathy and multi-organ failure can occur. death usually occurs between days and after symptom onset. survivors usually improved on day e , when neutralizing antibodies start to develop. in the convalescent phase, myelitis, recurrent hepatitis, psychosis and uveitis may develop [ ] . for pregnant women, there may be an increased risk of severe illness and death. there is also an increased risk of spontaneous abortion and pregnancy-related hemorrhage. in the outbreak in drc, fetal or neonatal loss occurred in all third trimester pregnancies [ ] . in fact, the first case of evd in sierra leone was a pregnant woman with miscarriage [ ] . blood test may show thrombocytopenia, leukopenia, hepatic dysfunction with elevated levels of aspartate aminotransferase more than that of alanine aminotransferase, amylase and d-dimer. hemolysis is severe especially in the acute stage [ ] . blood film may also show atypical lymphocytes [ ] . renal impairment usually appears by the end of the first week. fatal cases have higher viral load in the blood [ , ] . despite a fatal disease in over % of infected patients, some individuals did not develop symptoms. during the evd outbreaks in gabon in , asymptomatic individuals with direct exposure to infected materials were identified [ ] . eleven of these patients developed specific igm and igg response to ebolavirus. furthermore, rt-pcr for ebolavirus was positive in the peripheral blood mononuclear cell samples from of these seropositive individuals. positive-strand rna, the presence of which suggests active replication, was detected in individuals. since high grade viremia occurs in the acute period, the preferred diagnostic test is rt-pcr of the blood. rt-pcr targeting the np can be performed in the serum, plasma, whole blood, or oral fluid [ , ] . rnaemia can be detected on the day of symptom onset with viral loads of about e logs copies per ml. the viral load increases rapidly and reaches to logs on day of symptom onset. the level of rnaemia peaks on about day after symptom onset, and the level of rnaemia is higher in fatal cases than that in survivors [ ] . antigen-capture elisa can also be used on blood samples, but is less sensitive than rt-pcr [ ] . a rapid immunochromatographic assay for the detection of ebolavirus antigen, which claimed to provide result in min, was recently announced by the france's atomic energy commission [ ] . viral culture from the blood using vero e is usually positive in the acute stage, but should not be performed except in biosafety level facilities. viral particles may be seen in the serum under electron microscope, which was used in the confirmation of the first cases in the current outbreak [ ] . other than blood samples and oral fluids, the virus can also be detected in other body fluids, but these are not usually used for diagnosis. serum igm is useful during the convalescent phase, but is not useful in the acute setting. serum igg is not reliable, as one study showed that out of survivors did not have detectable igg levels at the time when viral antigen was no longer detected [ ] . several biomarkers have been proposed to be associated with adverse outcomes. in addition to elevated cytokine/chemokine levels, levels of thrombomodulin and ferritin are also elevated in patients with poor outcome, while the scd l, a protein produced by platelet responsible for repairing damaged endothelium, is higher in survivors [ ] . currently, the cornerstone in the management of patients with evd is supportive care. although this is taken for granted in developed countries, these supportive measures are usually lacking in the most affected areas with poor healthcare infrastructures. aggressive volume and electrolyte management, oral and intravenous nutrition, medications to control fever and gastrointestinal distress, and medications to treat pain, anxiety and agitation are important measures [ ] . coinfections should be actively sought and treated appropriately [ ] . there are currently no licensed antiviral drugs to treat evd. before the outbreak, specific therapy has been used in humans with some success. during the evd outbreak, a male investigator pricked himself while transferring homogenized liver from an infected guinea pig [ ] . six days after the injury, he developed fever, central abdominal pain and nausea. on the same day, he started to receive a -day course of human ifn million units every h administered intramuscularly. the human ifn was prepared by stimulating peripheral lymphocytes with sendai virus in vitro. on day after the injury, he received ml of convalescent sera which was obtained from infected people from zaire, and the viral load was reduced from . guineapig infective units per ml to - guinea-pig infective units per ml. on day after the injury, he received the nd infusion of convalescent sera. he eventually recovered. subsequently in the ebolavirus outbreak in kikwit, of patients who received blood donated from convalescent patients survived [ ] . both convalescent plasma and ifn-b were later tested in rhesus macaques, but only convalescent plasma was found to improve survival [ , ] . in the evd outbreak, convalescent plasma has been given to several patients, but the efficacy of convalescent plasma remains to be determined. in addition to convalescent plasma and ifn-b, several experimental treatments have been shown to improve survival in non-human primates ( table ). the first strategy employs the antiviral effect of neutralizing antibodies, either through direct administration of the antibodies or through active immunization. monoclonal antibody cocktails targeting different sites of the ebolavirus were shown to protect primates [ , , ] . zmapp, a cocktail of monoclonal antibodies that are originally contained in the preparation mb- (consisting of human or human-mouse chimeric mabs c c , h f and c d ), and zmab (consisting of murine mabs m h , m g and m g targeting gp) have been shown to protect rhesus macaques from lethal challenge when given up to days post infection [ ] . post-exposure vaccine, such as the vesicular stomatitis virus-based vaccine, can elicit anti-gp antibodies and improve the survival of rhesus macaques when given e min post infection [ ] . the second strategy is to inhibit the activity of virus proteins. antisense oligonucleotides target the viral l protein and vp proteins, can also improve survival of infected rhesus macaques [ , ] . the third strategy aims to ameliorate the deleterious host immune response. recombinant nematode anticoagulant protein c and recombinant human activated protein c could alleviate the coagulopathy and improve survival in animal models [ , ] . however, the clinical efficacy of recombinant human activated protein c is questioned because a randomized double-blind placebo-controlled study did not show survival benefit in patients with septic shock [ ] . among these experimental treatments, monoclonal antibody cocktail (zmapp) and small interfering rna (tkm-ebola) have been used in patients during the current outbreak [ , ] . both antibody and rna-based therapy might be limited to a particular species, and may become ineffective if there are mutations affecting the related antigenic epitopes or gene targets. the efficacy of these experimental treatments in humans remains to be determined. several drugs currently undergoing clinical trials have antiviral activity against ebolavirus. one of the most promising is nucleotide analog brincidofovir (cmx- ), which is a lipid-conjugated prodrug of cidofovir that is converted intracellularly to cidofovir. brincidofovir is currently undergoing phase iii clinical trials for adenovirus and cytomegalovirus infection. this drug has in vitro activity against ebolavirus [ ] , and has been used as an experimental treatment in the current outbreak [ ] . repurposing of licensed drugs has been considered for the treatment of evd as in other emerging infectious diseases which have no specific antiviral treatment [ e ] ( table ). the ic of clomiphene, chloroquine and imatinib table experimental post-exposure prophylaxis/treatment after lethal ebolavirus challenge in non-human primates. are above the peak serum level in humans, and therefore these are unlikely useful clinically. both toremifene and favipiravir had peak serum levels above the ic , and both of these drugs have shown to improve survival in mouse models [ , ] . toremifene can achieve plasma concentrations of about mm at a high dose of mg/day that are inhibitory in cell culture (ic e mm in vero cells). however the murine model utilizing a high dose of mg/kg initiated at h post infection can only achieve a % survival [ ] . moreover prolonged qtc changes have been reported at a dose of mg once daily [ ] . thus clinical trials should consider dosage adjustment, cardiac and electrolyte monitoring. favipiravir also appears effective in mice model, and has been administered to a patient in france [ ] . although the efficacy of these drugs in humans is uncertain especially when non-human primate treatment data are not available, they may be considered when better options are not available and the benefit-risk ratio is favorable. since fusion of the viral and cellular membrane in the endosome plays an important role in the viral life cycle, several studies have used chemical libraries to screen for molecules which can inhibit processes in the fusion step. using this strategy, molecules that can inhibit cathepsin-l mediated cleavage of gp [ ] and binding of gp and npc [ ] have been identified. the experience of post-exposure prophylaxis in humans mainly comes from laboratory accidents. in , a scientist from the us army medical research institute of infectious diseases (usamriid) suffered from a needlestick injury while working with mouse-adapted variant of zaire ebolavirus [ ] . as post-exposure prophylaxis, he received a liveattenuated recombinant vesicular stomatitis virus expressing gp of zaire ebolavirus h after the accident. the scientist had fever h after receiving the vaccine, but otherwise remained asymptomatic. three phase- clinical trials have been conducted. the first trial used an adenovirus-based vaccine expressing gp, involving subjects in the vaccine group and subjects in the placebo group [ ] . the vaccine group was further divided into a high dose and a low dose group. specific antibody response developed in % for recipients of high dose vaccine. the vaccine was well-tolerated. two vaccine recipients were complicated by the development of antiphospholipid antibody, and one vaccine recipient developed fever > c. in the second trial, two gp (zaire and sudan) dna vaccines were expressed in a vr- expression vector and produced in escherichia coli [ ] . there were subjects in the vaccine group and subjects in the placebo group. specific antibody responses to at least one of the vaccine antigens developed in all vaccine recipients. this second vaccine is also well-tolerated. in the vaccine group, subject developed raised creatine phosphokinase (associated with vigorous exercise) and subject developed herpes zoster. the third trial (vrc study) evaluated a dna vaccine encoding the wild type gp antigens from zaire and sudan ebolavirus which is produced in e. coli [ ] . ten subjects were enrolled. there were no serious adverse events. the vaccine elicited specific antibodies against both gp antigens. at the time of writing, two other vaccines are undergoing phase i clinical trials [ ] . vaccines against ebolavirus consisting of virus-vectors such as adenovirus type , human parainfluenza virus type , vesicular stomatitis virus; virus-like particles with vp , np and gp, and recombinant ebolavirus have been tested in animal models [ ] . the efficacy of these vaccines in humans awaits further studies. current evidence suggests that ebolavirus is transmitted via contact with contaminated body fluid or the contaminated environment, and therefore the practice of contact precautions with appropriate personal protection equipment (ppe) is of utmost importance when handling suspected or confirmed cases of evd. healthcare workers should preferably work in pairs so as to mutually guard against breaks in infection control measures. they are required to put on the ppe in the following sequence, from n respirator, water repellent cap or hood, full length shoe cover or boot, water resistant gown, face shield, and long nitrile gloves. if the patient has hemorrhagic symptoms, double nitrile gloves should be worn. in table licensed drugs with antiviral activity against ebolavirus. view of the high virulence and mortality, patients suspected to have evd should be isolated in airborne isolation room in the developed countries, although who allows cohorted nursing in the designated areas with dedicated instruments, where access should be restricted in the developing countries with limited isolation facilities [ ] . degowning remains the most critical procedure for the healthcare workers. the most contaminated ppe should be removed first, from long nitrite gloves, water resistant gown, full length shoe cover or boot, face shield, water repellent cap or hood, and finally n respirator. hand hygiene with alcohol-based hand rub should be performed in each step of degowning. when the hand is visibly soiled, it should be washed with soap and water. healthcare workers must be well trained and audited for the proper procedure of gowning and degowning. when the suspected or confirmed case of evd dies, the healthcare and mortuary workers are required to wear ppe as described above. the dead body is placed in double bags with leak-proof characteristic of no less than mm thick. absorbent material should be put under the body and placed in the first bag. the surface of each body bag is wiped with , ppm sodium hypochlorite solution. the bags are sealed and labeled with the indication of highly-infectious material (category ) and moved to the mortuary immediately. viewing in funeral parlor, embalming and hygienic preparation are not allowed. the dead body should not be removed from the body bag and should be sent to cremation as soon as possible. since the outbreak was first reported to who on march , , the situation continues to deteriorate, and the consequences can be catastrophic in terms of lost lives but also severe socioeconomic disruption and a high risk of spread to other countries. on august , , who declares the evd outbreak in west africa a "public health emergency of international concern". preparedness and response plan were made available in most of the health authorities all over the world. the aim is to detect the first imported case for early isolation in order to prevent local transmission in the community and healthcare setting. risk assessment in the port health, emergency room, and outpatient clinics for any patient fulfilling both clinical and epidemiological criteria for evd is important. for the clinical definition, patient suffering from a sudden onset of fever with over c, or having at least one of the following signs including inexplicable bleeding, bloody diarrhea, bleeding from gums, bleeding into skin or eye, or hematuria should be alerted, while the epidemiological definition includes close contact with a confirmed or probable case of evd or resided in or history of travel to an affected area or countries within days before onset of symptoms. for healthcare workers working in volunteer medical services or non-government organizations, who have direct contact with patients in the affected areas or countries, should also perform medical surveillance for at least days after leaving the affected areas or countries. they are required to seek medical advice promptly if there are any symptoms of fever, diarrhea, vomiting, rash or bleeding during medical surveillance. one of the major problems with the current outbreak is the panic associated with the disease. many patients with symptom did not seek medical care because of the fear of contracting the disease from the hospital [ ] . therefore, the local governments and health authorities should focus on the health education and give a clear instruction to the person for seeking early medical attention in the unaffected areas of africa. however, when the community transmission of ebolavirus is uncontrolled, implementation of home quarantine for up to days (one incubation period) can be considered. home quarantine measure had been used to control the community spread of sars in beijing, taiwan, singapore, and toronto [ ] . however, the public health staff is expected to face unprecedented challenges in implementing an extensive quarantine policy, as they have a dual role of monitoring compliance and providing support of daily necessities to people in quarantine. the countries next to the affected areas require implementing border control measures to screen for any suspected case of ebolavirus. although these measures may adversely affect the international travel and economy, it may be worthwhile to implement such a strict measure to control this re-emerging infectious disease with high mortality and psychological fear in a timely manner. humans are constantly under the threat of infectious diseases. some emerging infectious diseases have been especially important in human history with significant loss of population, economic disruption and political instability. yersinia pestis caused the black death in europe, killing up to one-third of the population [ ] . the e cholera outbreak after the major earthquake in haiti reminded us that a seemingly easyto-treat and control infection can cause large outbreaks when the infrastructure is damaged [ ] . sars coronavirus, mers coronavirus, and the avian influenza viruses have caused epidemics with major health and economic effects [ e ]. the current west africa evd outbreak is unprecedented in that this is the largest evd outbreak with local transmission outside africa. one of the major differences from previous outbreaks is that it has affected crowded major cities in west africa where the infrastructure has been heavily damaged due to civil wars. the rapid spread is facilitated by the efficient person-to-person transmission due to high viral loads in blood, bodily secretions and the contaminated environment. the large amount of virus particles shed in body fluid makes this virus very contagious, even among healthcare workers who are already equipped with ppe. whole genome study showed that the current west africa ebolavirus strain is phylogenetically distinct from previous outbreak strains, and this current ebolavirus strain has higher mutation rate than previous strains. however, it is currently not known whether this strain is particularly virulent or transmissible. currently, there are major gaps in our understanding of the disease due to the lack of systematic 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