Temple occupation and the tempo of collapse at Angkor Wat, Cambodia.

The 9th-15th century Angkorian state was Southeast Asia's greatest premodern empire and Angkor Wat in the World Heritage site of Angkor is one of its largest religious monuments. Here we use excavation and chronometric data from three field seasons at Angkor Wat to understand the decline and reorganization of the Angkorian Empire, which was a more protracted and complex process than historians imagined. Excavation data and Bayesian modeling on a corpus of 16 radiocarbon dates in particular demand a revised chronology for the Angkor Wat landscape. It was initially in use from the 11th century CE with subsequent habitation until the 13th century CE. Following this period, there is a gap in our dates, which we hypothesize signifies a change in the use of the occupation mounds during this period. However, Angkor Wat was never completely abandoned, as the dates suggest that the mounds were in use again in the late 14th-early 15th centuries until the 17th or 18th centuries CE. This break in dates points toward a reorganization of Angkor Wat's enclosure space, but not during the historically recorded 15th century collapse. Our excavation data are consistent with multiple lines of evidence demonstrating the region's continued ideological importance and residential use, even after the collapse and shift southward of the polity's capital. We argue that fine-grained chronological analysis is critical to building local historical sequences and illustrate how such granularity adds nuance to how we interpret the tempo of organizational change before, during, and after the decline of Angkor.

Bioprocess decision support tool for scalable manufacture of extracellular vesicles.

Newly recognized as natural nanocarriers that deliver biological information between cells, extracellular vesicles (EVs), including exosomes and microvesicles, provide unprecedented therapeutic opportunities. Large-scale and cost-effective manufacturing is imperative for EV products to meet commercial and clinical demands; successful translation requires careful decisions that minimize financial and technological risks. Here, we develop a decision support tool (DST) that computes the most cost-effective technologies for manufacturing EVs at different scales, by examining the costs of goods associated with using published protocols. The DST identifies costs of labor and consumables during EV harvest as key cost drivers, substantiating a need for larger-scale, higher-throughput, and automated technologies for harvesting EVs. Importantly, we highlight a lack of appropriate technologies for meeting clinical demands, and propose a potentially cost-effective solution. This DST can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes when commercializing EV products.

Decision Support Tools for Regenerative Medicine: Systematic Review.

BACKGROUND: Decisional tools have demonstrated their importance in informing manufacturing and commercial decisions in the monoclonal antibody domain. Recent approved therapies in regenerative medicine have shown great clinical benefits to patients. OBJECTIVE: The objective of this review was to investigate what decisional tools are available and what issues and gaps have been raised for their use in regenerative medicine. METHODS: We systematically searched MEDLINE to identify articles on decision support tools relevant to tissue engineering, and cell and gene therapy, with the aim of identifying gaps for future decisional tool development. We included published studies in English including a description of decisional tools in regenerative medicines. We extracted data using a predesigned Excel table and assessed the data both quantitatively and qualitatively. RESULTS: We identified 9 articles addressing key decisions in manufacturing and product development challenges in cell therapies. The decision objectives, parameters, assumptions, and solution methods were analyzed in detail. We found that all decisional tools focused on cell therapies, and 6 of the 9 reviews focused on allogeneic cell therapy products. We identified no available tools on tissue-engineering and gene therapy products. These studies addressed key decisions in manufacturing and product development challenges in cell therapies, such as choice of technology, through modeling. CONCLUSIONS: Our review identified a limited number of decisional tools. While the monoclonal antibodies and biologics decisional tool domain has been well developed and has shown great importance in driving more cost-effective manufacturing processes and better investment decisions, there is a lot to be learned in the regenerative medicine domain. There is ample space for expansion, especially with regard to autologous cell therapies, tissue engineering, and gene therapies. To consider the problem more comprehensively, the full needle-to-needle process should be modeled and evaluated.

Hip surgery and its evidence base: progress over a decade?

BACKGROUND: The burden of traumatic and elective hip surgery is set to grow. With an increasing number of techniques and implants against the background of an aging population, the emphasis on evidence-based treatment has never been greater. The purpose of this study was to assess changes in the levels of evidence in the hip literature over a decade. MATERIALS AND METHODS: Articles pertaining to hip surgery from the years 2000 and 2010 in Hip International, Journal of Arthroplasty, Journal of Bone and Joint Surgery and The Bone and Joint Journal were analysed. Articles were ranked by a five-point level of evidence scale and by type of study, according to guidelines from the Centre for Evidence-based Medicine. RESULTS: 531 articles were analysed from 48 countries. The kappa value for the inter-observer reliability showed excellent agreement between the reviewers for study type (κ = 0.956, P < 0.01) and for levels of evidence (κ = 0.772, P < 0.01). Between 2000 and 2010, the overall percentage of high-level evidence (levels I and II) studies more than doubled (12 to 31 %, P < 0.001). The most frequent study type was therapeutic; the USA and UK were the largest producers of published work in these journals, with contributions from other countries increasing markedly over the decade. CONCLUSIONS: There has been a significant increase in high levels of evidence in hip surgery over a decade (P < 0.001). We recommend that all orthopaedic journals consider implementing compulsory declaration by authors of the level of evidence to help enhance quality of evidence. LEVEL OF EVIDENCE: Level 2: economic and decision analysis.

An outbreak of multi-drug resistant Escherichia coli urinary tract infection in an elderly population: a case-control study of risk factors.

BACKGROUND: Prevention of infection due to multi-drug resistant organisms is particularly challenging because of the spread of resistant bacteria beyond hospitals into the community, including nursing homes. This study aimed to identify risk factors for the acquisition of a multidrug resistant (MDR) Escherichia coli in a local outbreak. METHODS: Study participants were all aged over 65 years. Cases had the MDR E. coli isolated from a routine urine sample, and controls had a urine sample submitted to the laboratory in the same time period but the MDR E. coli was not isolated. Information from clinical records was used to identify risk factors both in the hospital and the community setting for acquisition of the MDR E. coli. RESULTS: 76 cases and 156 controls were identified and included in the study. In a multivariate analysis, risk factors statistically significantly associated with acquisition of the MDR E. coli were female gender (adjusted OR 3.2; 95 % confidence interval 1.5-6.9), level of care (high dependency OR 7.5; 2.2-25.7) compared with living independently), and in hospital prescription of antimicrobials to which the MDR E. coli was resistant (OR 5.6; 2.5-12.9). CONCLUSIONS: The major risk factors for the acquisition of a MDR E. coli were found to be residence in a nursing home and in-hospital prescription of antimicrobials to which the MDR E. coli was resistant. This emphasises that prevention of transmission of MDROs within a community needs to involve both hospitals and also other healthcare organizations, in this case nursing homes.

Chylothorax: pathophysiology, diagnosis, and management-a comprehensive review.

Chylothorax is a rare condition characterized by the accumulation of chyle in the pleural space. While it accounts for a small percentage of pleural effusions, chylothorax can lead to significant morbidity and mortality. This article provides a comprehensive overview of chylothorax, covering its relevant anatomy, aetiology, pathophysiology, clinical features, diagnosis, and management. Injury or disruption to the thoracic duct (which is responsible for chyle transport) leads to the development of chylothorax. This may result from trauma, such as iatrogenic injury during surgery, or non-traumatic causes, including malignancy, lymphatic disorders, and heart failure. Recognition of the underlying cause is essential to tailor management. Clinical presentation varies, with symptoms linked to rate of chyle accumulation and the causative condition. Diagnosis relies on pleural fluid analysis, with demonstration of elevated triglyceride levels (>110 mg/dL) and reduced cholesterol levels (<200 mg/dL) being the key diagnostic criteria employed in clinical practice. Various imaging modalities, including computed tomography (CT) scans and lymphatic-specific investigations, may be utilised to aid identification of the site of chyle leak, as well as determine the likely underlying cause. Chylothorax management is multifaceted, with conservative approaches such as dietary modification and pharmacological interventions often initiated as first-line treatment. Drainage of chylous effusion may be necessary for symptom relief. When conservative methods fail, interventional procedures like thoracic duct ligation or embolization can be considered. Due to the diverse aetiological factors and patient characteristics associated with chylothorax, individualized management strategies are recommended. Nonetheless, management of chylothorax is an evolving field with a paucity of high-quality evidence or standardized guidelines, highlighting the importance of ongoing research and a multidisciplinary approach to optimize individual patient care.

Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial.

BACKGROUND: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus. RESULTS: The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and -15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. CONCLUSIONS: In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose-response relationship.

Extending the Transformative Potential of Mindfulness Through Team Mindfulness Training, Integrating Individual With Collective Mindfulness, in a High-Stress Military Setting.

Mindfulness has come to be considered an important approach to help individuals cultivate transformative capacity to free themselves from stress and suffering. However, the transformative potential of mindfulness extends beyond individual stress management. This study contributes to a broadening of the scope of contemplative science by integrating the prominent, individually focused mindfulness meditation literature with collective mindfulness scholarship. In so doing, it aims to illuminate an important context in which mindfulness interventions are increasingly prevalent: workplaces. Typically, the intended effect of workplace mindfulness training is to help workers manage stress better. Since mindfulness in organizations impacts individual and collective processes, the study blends the above literatures to create a cross-level "next-generation" Team Mindfulness Training (TMT) pilot. Its potential in helping individuals and teams to manage work stress better is investigated via a two-phase mixed-methods research study in high-stress military work populations, and compared to a conventional ("first-generation") 8-week mindfulness meditation program based on mindfulness-based stress reduction (MBSR). Results suggest that compared to the "first-generation" mindfulness program, TMT seems no less effective in raising individual stress management skills, and may hold more promise in generating collective capacity to manage stress and unexpected difficulty, linked to an apparent interdependence between collective and individual mindfulness capacity development. Based on these empirical results, the study contributes to theory in three important ways: first, it outlines how individual and collective mindfulness in workplaces may be interdependent. Second, it explains why "next-generation" workplace training interventions should apply a cross-level approach. And third, it illustrates how its transformative potential for people at work, individually as well as collectively, can be extended by moving beyond an inward-looking meditation focus in mindfulness training. The study contributes to practice by providing a detailed outline of the pilot TMT program, and offers a series of follow-up research opportunities to inspire further scientific innovation in workplace mindfulness training, especially for high-stress work populations. The study's ultimate aim is to prompt a shift away from adapting clinically oriented, self-focused "first-generation" mindfulness training protocols, and towards mindfulness as team sport: a more prosocially oriented mindfulness science intent on generating wisdom and compassion, for one and all.

Gazing Long into a Clinical and Social Abyss? Treating Hypertrophic Scarring and Keloids.

This commentary discusses the unmet clinical and social needs associated with hypertrophic scars and keloids. The authors critically appraise these issues within the context of contemporary clinical standards of care and social mores catalyzed by the COVID-19 pandemic.

Dysphonia and dysphagia consequences of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS).

IMPORTANCE: Paediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 (PIMS-TS) is a novel disease first identified in 2020. Recent cohort studies have described the complex presentation and symptomatology. This paper provides detailed description of the dysphagia and dysphonia symptoms, management, and outcome. OBJECTIVE: To describe dysphagia and dysphonia in PIMS-TS. DESIGN: Retrospective cohort study. SETTING: Single tertiary and quaternary children's hospital. PARTICIPANTS: All 50 children treated for paediatric multisystem inflammatory disease between April and June 2020 were included in this study. MAIN OUTCOME(S) AND MEASURE(S): Dysphonia: GRBAS Perceptual Severity Scores, Vocal Handicap Index scores and the Vocal Tract Discomfort Scale. Dysphagia: Functional Oral Intake Scale. RESULTS: Fifty children met the diagnostic criteria for PIMS-TS. 33 (66%) were male. Median age was 10 years (range: 1-17). 36 (72%) were of Black, Asian or minority ethnic background. Nine (18%) required specialist assessment and management of dysphagia and/or dysphonia. Five (55%) were male with a median age of 9 years 7 months (range: 1-15 years). Symptoms typically resolved within three months. Two children presented with persisting dysphonia three months post-presentation. Neurological, inflammatory, and iatrogenic causes of dysphagia and dysphonia were identified. CONCLUSIONS AND RELEVANCE: Dysphonia and dysphagia are present in children with PIMS-TS. Further data is required to understand pathophysiology, estimate incidence, and determine prognostic factors. This preliminary data highlights the need for dysphagia and dysphonia screening and timely referral for specialist, multidisciplinary assessment and treatment to ensure short-term aspiration risk is managed and long-term, functional outcomes are optimised.

Diachronic modeling of the population within the medieval Greater Angkor Region settlement complex.

Angkor is one of the world's largest premodern settlement complexes (9th to 15th centuries CE), but to date, no comprehensive demographic study has been completed, and key aspects of its population and demographic history remain unknown. Here, we combine lidar, archaeological excavation data, radiocarbon dates, and machine learning algorithms to create maps that model the development of the city and its population growth through time. We conclude that the Greater Angkor Region was home to approximately 700,000 to 900,000 inhabitants at its apogee in the 13th century CE. This granular, diachronic, paleodemographic model of the Angkor complex can be applied to any ancient civilization.

Biotechnology Governance 2.0: A Proposal for Minimum Standards in Biotechnology Corporate Governance.

Based on experience and the existing limited research literature in biotechnology corporate governance, the authors propose potential attributes of minimum corporate governance standards for biotechnology companies, as a basis for further quantitative and qualitative research. The authors assert that the recent proliferation of biotechnology start-up organizations is substantively changing inter- and intraorganizational cultures throughout the health care sector via a "cascade of governance." Therefore, governance decisions and actions-both positive and negative-that are instituted in start-up biotech companies may set new norms for other start-up biotech companies, the larger (bio)pharmaceutical companies by which they are acquired and the range of health care subsector actors that interact with biotechnology companies. The authors stress the importance of appropriate, proportionate, and consistent biotech corporate governance throughout company lifecycles, not simply to support value inflection or as a response to a crisis. Fail to govern, fail to succeed-for investors and, most importantly, for patients.

Massive Open Online Courses (MOOC) Evaluation Methods: Protocol for a Systematic Review.

BACKGROUND: Massive open online courses (MOOCs) have increased in popularity in recent years. They target a wide variety of learners and use novel teaching approaches, yet often exhibit low completion rates (10%). It is important to evaluate MOOCs to determine their impact and effectiveness, but little is known at this point about the methodologies that should be used for evaluation. OBJECTIVE: The purpose of this paper is to provide a protocol for a systematic review on MOOC evaluation methods. METHODS: We will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines for reporting this protocol. We developed a population, intervention, comparator, and outcome (PICO) framework to guide the search strategy, based on the overarching question, "What methods have been used to evaluate MOOCs?" The review will follow six stages: 1) literature search, 2) article selection, 3) data extraction, 4) quality appraisal, 5) data analysis, and 6) data synthesis. RESULTS: The systematic review is ongoing. We completed the data searches and data abstraction in October and November 2018. We are now analyzing the data and expect to complete the systematic review by March 2019. CONCLUSIONS: This systematic review will provide a useful summary of the methods used for evaluation of MOOCs and the strengths and limitations of each approach. It will also identify gaps in the literature and areas for future work. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12087.

Systematic review protocol: an assessment of the post-approval challenges of autologous CAR-T therapy delivery.

INTRODUCTION: Following recent regulatory approvals of two chimeric antigen receptor T-cell (CAR-T) therapies, the field now faces a number of post-approval challenges. These challenges are in some respects defined and, in others, uncertain due to the nascence of the field. At present, information pertaining to such post-approval challenges are scattered in various previous reviews or raised in singular papers reporting experience in working with the therapy. This systematic review is designed to evaluate and summarise the post-approval challenges for robust delivery of CAR-T therapies to inform future work on the optimisation of CAR-T delivery to patients. METHODS AND ANALYSIS: We will search Medline, EMBASE (OvidSP), BIOSIS & Web of Science, Cochrane Library, ICER database, NICE Evidence Search, CEA Registry, WHOLIS WHO Library and Scopus for studies published between 2014 and the present. In addition, a Google search for grey literature such as bioprocess blog posts, opinion pieces, press releases and listed companies involved in CAR-T development annual reports will be conducted. Two authors will independently screen the titles and abstracts identified from the search and accept or reject the studies according to the study inclusion criteria and any discrepancies will be discussed and resolved. The quality of the selected literature will be assessed using the Critical Appraisal Skills Programme(CASP) Systematic Review checklist and grey literature will be assessed using the Authority, Accuracy, Coverage, Objectivity, Date, Significance (AACODS) checklist. Data from eligible publications will be categorised using a flowchart and extracted using a data abstraction form. Qualitative and quantitative analysis of the post-approval challenges of CAR-T therapies will be conducted based on the results attained. ETHICS AND DISSEMINATION: The executed study will be published in a peer-reviewed journal in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The findings from this review will be used to inform the development of an optimisation model for robust delivery of CAR-T therapies using a systems engineering approach. TRIAL REGISTRATION NUMBER: CRD42018109756.

Data and Corporate Governance in Pharma and Digital Health: A Necessary Regulatory Convergence.

Data and Corporate Governance in Pharma and Digital Health: A Necessary Regulatory Convergence.

Protocol for a mixed-methods evaluation of a massive open online course on real world evidence.

INTRODUCTION: Increasing number of Massive Open Online Courses (MOOCs) are being used to train learners at scale in various healthcare-related skills. However, many challenges in course delivery require further understanding, for example, factors exploring the reasons for high MOOC dropout rates, recorded low social interaction between learners and the lack of understanding of the impact of a course facilitators' presence in course engagement. There is a need to generate further evidence to explore these detriments to MOOC course delivery to enable enhanced course learning design. The proposed mixed-methods evaluation of the MOOC was determined based on the MOOC's aims and objectives and the methodological approaches used to evaluate this type of a course. The MOOC evaluation will help appraise the effectiveness of the MOOC in delivering its intended objectives. This protocol aims to describe the design of a study evaluating learners knowledge, skills and attitudes in a MOOCs about data science for healthcare. METHODS AND ANALYSIS: Study participants will be recruited from learners who have registered for the MOOC. On registration, learners will be given an opportunity to opt into the study and complete informed consent. Following completion of the course, study participants will be contacted to complete semistructured interviews. Interviews will be transcribed and coded using thematic analysis, with data analysed using two evaluation models: (1) the reach, effectiveness, adoption, implementation, maintenance framework and the (2) Kirkpatrick model drawing data from pre and post-course surveys and post-MOOC semi-structured interviews. The primary goal of the evaluation is to appraise participants' knowledge, skills and attitude after taking the MOOC. ETHICS AND DISSEMINATION: Ethics approval for this study was obtained from Imperial College London through the Education Ethics Review Process (EERP) (EERP1617-030). A summary of the research findings will be reported through a peer-reviewed journal and will be presented at an international conference.

Real-world evidence for postgraduate students and professionals in healthcare: protocol for the design of a blended massive open online course.

INTRODUCTION: There is an increased need for improving data science skills of healthcare professionals. Massive open online courses (MOOCs) provide the opportunity to train professionals in a sustainable and cost-effective way. We present a protocol for the design and development of a blended MOOC on real-world evidence (RWE) aimed at improving RWE data science skills. The primary objective is to provide the opportunity to understand the fundamentals of RWE data science and to implement methods for analysing RWD. The blended format of MOOC will combine the expertise of healthcare professionals joining the course online with the on-campus students. We expect learners to take skills taught in MOOC and use them to seek new employment or to explore entpreneurship activities in these domains. METHODS AND ANALYSIS: The proposed MOOC will be developed through a blended format using the Analysis, Design, Development, Implementation and Evaluation instructional design model and following the connectivist-heutagogical learning theories (as a hybrid MOOC). The target learners will include postgraduate students and professionals working in the health-related roles with interest in data science. An evaluation of MOOC will be performed to assess MOOCs success in meeting its intended outcomes and to improve future iterations of the course. ETHICS AND DISSEMINATION: The education course design protocol was approved by EIT Health (grant 18654) as part of the EIT Health CAMPUS Deferred Call for Innovative Education 2018. Results will be published in a peer-reviewed journal.

A phase II, double-blind, placebo-controlled, ascending-dose study of Eritoran (E5564), a lipid A antagonist, in patients undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Lipid A, the toxic moiety of endotoxin, is linked to multiple complications after cardiac surgery, including fever, vasodilation, and pulmonary and renal dysfunction. The lipid A antagonist eritoran (or E5564) prevents endotoxin-induced systemic inflammation in animals and humans. In this study we assessed the safety of eritoran administration in patients undergoing cardiac surgery and obtained preliminary efficacy data for the prophylaxis of endotoxin-mediated surgical complications. METHODS: A double-blind, randomized, ascending-dose, placebo-controlled study was conducted at nine hospitals. Patients undergoing coronary artery bypass graft and/or cardiac valvular surgery with cardiopulmonary bypass were enrolled. Patients received a 4-h infusion of placebo (n = 78) vs 2 mg (n = 24), 12 mg (n = 26), or 28 mg (n = 24) of eritoran initiated approximately 1 h before cardiopulmonary bypass. RESULTS: No significant safety concerns were identified with continuous safety monitoring, and enrollment continued to the highest prespecified dose (28 mg). No statistically significant differences were observed in most variables related to systemic inflammation or organ dysfunction/injury. CONCLUSIONS: This Phase II safety study suggests that the administration of the novel lipid A antagonist, eritoran, is not associated with overt toxicity in cardiac surgical patients. Blocking lipid A with eritoran does not appear to confer any clear benefit to elective cardiac surgical patients.

Safety, pharmacokinetics, and pharmacodynamics of E5564, a lipid A antagonist, during an ascending single-dose clinical study.

E5564, a structural analog of the lipid A portion of lipopolysaccharide (LPS), is a potent antagonist of the biochemical and physiologic effects of LPS in several in vitro and in vivo models and is currently under clinical development as a possible therapeutic for the treatment of sepsis and septic shock. The objectives of this study were to (1) assess the safety and tolerability of E5564 following a 30-minute intravenous (i.v.) infusion, (2) evaluate the pharmacokinetic profile of E5564, and (3) measure the ability of E5564 to block LPS stimulation ex vivo in blood taken from subjects up to 8 hours after ending the infusion. Healthy male volunteers (n = 7/dose group) were randomly assigned to each of four dose levels (350, 1000, 2000, or 3500 micrograms). Within each dose group, 5 subjects received drug and 2 received placebo. E5564 or matching placebo was administered by a 30-minute infusion, and blood samples were collected at predetermined time points. All doses of E5564 were demonstrated to be safe and well tolerated. E5564 plasma concentrations were determined using a validated LC/MS/MS method. The Cmax and AUC of E5564 increased in a dose-proportional manner. E5564 pharma-cokinetics were characterized by a slow clearance (0.67-0.95 mL/h/kg), a small volume of distribution (41-54 mL/kg), and a relatively long elimination half-life (42-51 h). As measured in the ex vivo assay, E5564 inhibited LPS-induced tumor necrosis factor-alpha (TNF-alpha) in a dose-dependent manner, and at the higher doses (2 and 3.5 mg), antagonistic activity was measurable up to 8 hours postinfusion. E5564 lacked LPS-like agonist activity at doses up to 3.5 mg. Taken together, we believe that E5564 is a safe, potent antagonist of LPS in blood and will likely benefit patients in the treatment of LPS-related diseases.