Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430.

Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.

AVI-7288 for Marburg Virus in Nonhuman Primates and Humans.

BACKGROUND: AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined. METHODS: We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3:1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans. RESULTS: Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P<0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates. CONCLUSIONS: This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans. (Funded by the Department of Defense; ClinicalTrials.gov number, NCT01566877.).

Educating Parents About Pediatric Research: Children and Clinical Studies Website Qualitative Evaluation.

A gap in information about pediatric clinical trials exists, and parents remain uncertain about what is involved in research studies involving children. We aimed to understand parent perspectives about pediatric clinical research after viewing the online Children and Clinical Studies (CaCS) program. Using a qualitative descriptive study design, we conducted focus groups with parents and phone interviews with physicians. Three themes emerged providing approaches to improve parent's understanding of clinical research by including strategies where parents (a) hear from parents like themselves to learn about pediatric research, (b) receive general clinical research information to complement study-specific details, and (c) are provided more information about the role of healthy child volunteers. Parents found the website a valuable tool that would help them make a decision about what it means to participate in research. This tool can assist parents, providers, and researchers by connecting general information with study-specific information.

Oral cancer awareness among community-dwelling senior citizens in Illinois.

The study assessed participant awareness of oral cancer (OC), risk factors, signs and symptoms, and history of an OC screening exam and whether a relationship exists between these factors and the participant's age, level of education, socioeconomic status (SES), ethnicity, and gender. It was a descriptive survey research with a non-randomized sample. Participants were a convenience sample of seniors participating in a congregate dining program of the DuPage County Senior Citizens Council. Data was collected through a written, self-administered survey. Sixty-two surveys were completed, with an overall response rate of 66%. A statistically significant relationship was found between the level of education and awareness of OC risk factors (r = 0.26; P = 0.04). An inverse relationship was found between the level of education and the level of OC awareness questions, "have you ever heard about OC?" (r = -0.37; P = 0.004), and "how much do you know about OC?" (r = 0.35; P = 0.008). A trend toward significance was noted for the level of education and awareness of OC signs and symptoms (r = 0.24; P = 0.06). The levels of OC awareness in the seniors were lower than the general population. Seniors in the lower SES strata and who have low education levels are of particular concern, and it is important to conduct further studies tailored towards populations with these combined factors. Additional research is needed to determine how to best communicate OC awareness and implement programs specifically for this high-risk group.

Learning health system benefits: Development and initial validation of a framework.

Introduction: Implementation of research findings in clinical practice often is not realized or only partially achieved, and if so, with a significant delay. Learning health systems (LHSs) hold promise to overcome this problem by embedding clinical research and evidence-based best practices into care delivery, enabling innovation and continuous improvement. Implementing an LHS is a complex process that requires participation and resources of a wide range of stakeholders, including healthcare leaders, clinical providers, patients and families, payers, and researchers. Engaging these stakeholders requires communicating clear, tangible value propositions. Existing models identify broad categories of benefits but do not explicate the full range of benefits or ways they can manifest in different organizations. Methods: To develop such a framework, a working group with representatives from six Clinical and Translational Science Award (CTSA) hubs reviewed existing literature on LHS characteristics, models, and goals; solicited expert input; and applied the framework to their local LHS experiences. Results: The Framework of LHS Benefits includes six categories of benefits (quality, safety, equity, patient satisfaction, reputation, and value) relevant for a range of stakeholders and defines key concepts within each benefit. Applying the framework to five LHS case examples indicated preliminary face validity across varied LHS approaches and revealed three dimensions in which the framework is relevant: defining goals of individual LHS projects, facilitating collaboration based on shared values, and establishing guiding tenets of an LHS program or mission. Conclusion: The framework can be used to communicate the value of an LHS to different stakeholders across varied contexts and purposes, and to identify future organizational priorities. Further validation will contribute to the framework's evolution and support its potential to inform the development of tools to evaluate LHS impact.

A qualitative inquiry of patient-reported outcomes: the case of lower urinary tract symptoms.

BACKGROUND: Patient-reported outcomes are a valuable tool for assessing healthcare, particularly for symptom-based conditions that lack definitive physiological measures of treatment efficacy. OBJECTIVE: To explore the value of qualitative methods for understanding and developing patient-reported outcomes of medical care for symptom-based conditions by examining the case of lower urinary tract symptoms. METHODS: Semistructured interviews were conducted with a diverse community sample of 90 respondents who had spoken with a provider about their urinary symptoms. Content and thematic analyses were conducted for the areas of symptom relief, patient adherence, and satisfaction with care according to gender, race or ethnicity, and socioeconomic status. RESULTS: Across social groups, most patients experienced either no symptom relief or partial relief, reported that they adhered to recommendations, and were satisfied with the care received. The primary reason for no symptom relief was not receiving a treatment recommendation. For patients, even partial relief made symptoms more manageable both physically and emotionally. Satisfaction with care was mediated by the quality of the patient-provider relationship as well as expectations other than symptom relief, particularly for patients of low socioeconomic status. DISCUSSION: Patients' assessments of the outcomes of seeking medical care for this symptom-based condition broadened the criteria for quality of care beyond providing a cure. For healthcare providers, this can widen the path for meeting patient needs, even without complete symptom relief. For providers and researchers, as the evidence base expands to include patient reports, the context provided by a qualitative approach can enhance understanding of patients' perspectives and the ability to construct meaningful quantitative measures.

Talking with others about stigmatized health conditions: implications for managing symptoms.

We investigated the influence of social ties on symptom management and help seeking, using urinary symptoms as a case study. Talking with others about these symptoms was common and both facilitated and hindered symptom management and help seeking. In some cases, talking with others resulted in gaining a sense of identification with others suffering the same symptoms, receiving assistance to ease the burden of symptoms, obtaining suggestions to help manage symptoms, and learning information about available treatments. In other cases, talking with others served to normalize symptoms to such an extent that individuals saw no need to manage their symptoms differently.

Establishing evidence-based pharmacologic treatments for neonatal abstinence syndrome: A retrospective case study.

Translation of research discoveries into health impact can take many years, creating delays in improving clinical outcomes. One approach to promoting timely translation is to examine successful cases in order to understand facilitators and strategies for overcoming barriers. We examined the development of evidence-based management for neonatal abstinence syndrome (NAS) at one academic medical center, with a primary focus on pharmacologic treatment. Despite a substantial increase in NAS case incidence starting in the early 2000s, significant sociocultural, policy, and regulatory barriers limited collaborative NAS research. Facilitators for translation encompassed: 1) pursuing research of societal interest, 2) building an effective interdisciplinary team, 3) intentionally linking clinical, research, and advocacy efforts, 4) broad stakeholder engagement across clinical, policy, and research arenas, and 5) leveraging local resources. Challenges included lack of commercially available U.S. Food and Drug Administration approved neonatal drug formulations, legal and regulatory barriers related to off-label and illicit use of opioids, recruitment for a treatment associated with drug withdrawal syndromes, misalignment of research design needs with real-world scenarios, and episodic funding. Benefits of successful translation included improvements in clinical care, reduced healthcare costs related to NAS, and enhanced legislative, policy, and research strategies to support broader neonatal investigations.

Preclinical immunogenicity and efficacy of a candidate COVID-19 vaccine based on a vesicular stomatitis virus-SARS-CoV-2 chimera.

BACKGROUND: To investigate a vaccine technology with potential to protect against coronavirus disease 2019 (COVID-19) and reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a single vaccine dose, we developed a SARS-CoV-2 candidate vaccine using the live vesicular stomatitis virus (VSV) chimeric virus approach previously used to develop a licensed Ebola virus vaccine. METHODS: We generated a replication-competent chimeric VSV-SARS-CoV-2 vaccine candidate by replacing the VSV glycoprotein (G) gene with coding sequence for the SARS-CoV-2 Spike glycoprotein (S). Immunogenicity of the lead vaccine candidate (VSV∆G-SARS-CoV-2) was evaluated in cotton rats and golden Syrian hamsters, and protection from SARS-CoV-2 infection also was assessed in hamsters. FINDINGS: VSV∆G-SARS-CoV-2 delivered with a single intramuscular (IM) injection was immunogenic in cotton rats and hamsters and protected hamsters from weight loss following SARS-CoV-2 challenge. When mucosal vaccination was evaluated, cotton rats did not respond to the vaccine, whereas mucosal administration of VSV∆G-SARS-CoV-2 was found to be more immunogenic than IM injection in hamsters and induced immunity that significantly reduced SARS-CoV-2 challenge virus loads in both lung and nasal tissues. INTERPRETATION: VSV∆G-SARS-CoV-2 delivered by IM injection or mucosal administration was immunogenic in golden Syrian hamsters, and both vaccination methods effectively protected the lung from SARS-CoV-2 infection. Hamsters vaccinated by mucosal application of VSV∆G-SARS-CoV-2 also developed immunity that controlled SARS-CoV-2 replication in nasal tissue. FUNDING: The study was funded by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and The International AIDS Vaccine Initiative, Inc. (IAVI), New York, USA. Parts of this research was supported by the Biomedical Advanced Research and Development Authority (BARDA) and the Defense Threat Reduction Agency (DTRA) of the US Department of Defense.

Race and ethnic differences in health beliefs about lower urinary tract symptoms.

BACKGROUND: Health beliefs are an important mediator between the experience of symptoms and health behaviors, and these beliefs can vary by race or ethnicity. OBJECTIVES: The aim of this study was to better understand the gap between experiencing symptoms and not seeking medical care by examining health beliefs about lower urinary tract symptoms across race and ethnic groups. METHOD: Qualitative, semistructured interviews were conducted with 35 Black, Hispanic, and White people who reported at least one urinary symptom but had not spoken with a healthcare provider about the symptom(s). Drawing on Shaw's framework of health behavior and outcomes, a range of beliefs was examined: cause, consequence, continuation, and treatability. Interviews were transcribed, coded, and analyzed for themes according to race or ethnic background. RESULTS: The belief that lower urinary tract symptoms are a typical part of aging and not amenable to medical treatment was most common among White respondents. Black respondents more commonly attributed their symptoms to personal behaviors over which they had control and therefore did not require medical care. Hispanic respondents appeared more often to live with uncertainty about the cause of their symptoms and an accompanying concern about a future health consequence. DISCUSSION: The combination of a range of health beliefs to form a cognitive representation made sense of the behavior of not seeking medical care. The finding that sociocultural differences shaped these cognitive representations underscores the need for cultural competency in patient assessment and education. Results have implications for theories of health behavior and indicate further research with larger samples, additional psychosocial influences, and other symptoms.

Patients' experiences of seeking health care for lower urinary tract symptoms.

A gap between experiencing symptoms and receiving effective treatment persists for people with lower urinary tract symptoms (LUTS), even for those who seek health care. In order to better understand how patients experience treatment seeking for LUTS, we interviewed a racially diverse sample of 90 men and women with a range of LUTS about their experiences seeking care. Thematic analysis revealed that patients often disclosed urinary symptoms first to primary care providers during a general examination or a visit for another health problem. Patients seek provider assistance typically when symptoms have intensified or are causing worry, and a desire for treatment trumps potential embarrassment; among women patients, feeling comfortable with a provider also is important for disclosing LUTS.

Investigation of the Cultural Competence of Dental Hygienists Practicing in a Region of Low Diversity.

Purpose: The profession of dental hygiene is lacking in racial and ethnic diversity, a contributory factor to providing culturally competent patient care. The purpose of the study was to determine the cultural competence (CC) of licensed dental hygienists (DHs) in a region of low racial and ethnic diversity and explore the contributory factors.Methods: modified version of the Cultural Competency Assessment (CCA), a survey developed using the 3-D Model of Culturally Congruent Care was used to identify the levels of (CC) of DHs practicing in a area of low diversity. Utah was identified as a region of low racial and ethnic diversity. DHs holding a license to practice in the state of Utah were invited to participate in the 35-item, electronically delivered survey. Multiple regression was used to analyze associations between cultural competence and salient participant characteristics.Results: Of the 3,231 RDHs invited to participate, 673 responses were included for analysis, for a 20% response rate. The mean score was 10.153 (SD=1.3), indicating moderate cultural competence, unequally distributed between cultural awareness and sensitivity and culturally competent behavior scores. Possessing a graduate degree, cultural education during dental hygiene school, cultural continuing education, and employment in public health, significantly predicted CC. The regression model was significant F(8,664)=8.616 (p<0.0005) with a small effect size (R 2=0.094).Conclusion: Education and types of practice experiences were predictors of CC. Specific educational interventions that may influence the various components of cultural competency were not determined. Dental hygiene providers possessed moderate CC however there was a disconnect in translating awareness into behavior, possibly reinforced by environments lacking racial and ethnic diversity with limited opportunities to develop and exercise CC.

Pilot test of an accrual Common Metric for the NIH Clinical and Translational Science Awards (CTSA) Consortium: Metric usefulness.

The Common Metrics Initiative aims to develop and field metrics to improve research processes within the national Clinical and Translational Science Award (CTSA) Consortium. A Median Accrual Ratio (MAR) common metric was developed to assess the results of efforts to increase subject accrual into a set of clinical trials within the expected time period. A pilot test of the MAR was undertaken at Tufts Clinical and Translational Science Institute (CTSI) with eight CTSA Consortium hubs. Post-pilot interviews were conducted with 9 CTSA Principal Investigators (PIs) and 23 pilot team members. Over three-quarters (78%) of respondents reported that the MAR could be useful for performance improvement, but also described limitations or concerns. The most commonly cited barrier to MAR use for performance improvement was difficulty in interpreting the single value that is produced. Most respondents were interested in using the MAR to assess recruitment at an individual trial level. Majority of respondents (63%) had mixed opinions about aggregating metric results across the CTSA Consortium for comparison or benchmarking. Collecting data about additional contextual factors, and comparing accrual between subgroups, were cited as potentially helping address concerns about aggregation. Significant challenges remain in ensuring that the MAR can be sufficiently useful for collaborative process improvement. We offer recommendations to potentially improve metric usefulness.

Implementing Common Metrics across the NIH Clinical and Translational Science Awards (CTSA) consortium.

The Clinical and Translational Science Award (CTSA) Consortium and the National Center for Advancing Translational Science (NCATS) undertook a Common Metrics Initiative to improve research processes across the national CTSA Consortium. This was implemented by Tufts Clinical and Translational Science Institute at the 64 CTSA academic medical centers. Three metrics were collaboratively developed by NCATS staff, CTSA Consortium teams, and outside consultants for Institutional Review Board Review Duration, Careers in Clinical and Translational Research, and Pilot Award Publications and Subsequent Funding. The implementation program included training on the metric operational guidelines, data collection, data reporting system, and performance improvement framework. The implementation team provided small-group coaching and technical assistance. Collaborative learning sessions, driver diagrams, and change packages were used to disseminate best and promising practices. After 14 weeks, 84% of hubs had produced a value for one metric and about half had produced an initial improvement plan. Overall, hubs reported that the implementation activities facilitated their Common Metrics performance improvement process. Experiences implementing the first three metrics can inform future directions of the Common Metrics Initiative and other research groups implementing standardized metrics and performance improvement processes, potentially including other National Institutes of Health institutes and centers.

Evaluation of initial progress to implement Common Metrics across the NIH Clinical and Translational Science Awards (CTSA) Consortium.

INTRODUCTION: The Clinical and Translational Science Awards (CTSA) Consortium, about 60 National Institutes of Health (NIH)-supported CTSA hubs at academic health care institutions nationwide, is charged with improving the clinical and translational research enterprise. Together with the NIH National Center for Advancing Translational Sciences (NCATS), the Consortium implemented Common Metrics and a shared performance improvement framework. METHODS: Initial implementation across hubs was assessed using quantitative and qualitative methods over a 19-month period. The primary outcome was implementation of three Common Metrics and the performance improvement framework. Challenges and facilitators were elicited. RESULTS: Among 59 hubs with data, all began implementing Common Metrics, but about one-third had completed all activities for three metrics within the study period. The vast majority of hubs computed metric results and undertook activities to understand performance. Differences in completion appeared in developing and carrying out performance improvement plans. Seven key factors affected progress: hub size and resources, hub prior experience with performance management, alignment of local context with needs of the Common Metrics implementation, hub authority in the local institutional structure, hub engagement (including CTSA Principal Investigator involvement), stakeholder engagement, and attending training and coaching. CONCLUSIONS: Implementing Common Metrics and performance improvement in a large network of research-focused organizations proved feasible but required substantial time and resources. Considerable heterogeneity across hubs in data systems, existing processes and personnel, organizational structures, and local priorities of home institutions created disparate experiences across hubs. Future metric-based performance management initiatives across heterogeneous local contexts should anticipate and account for these types of differences.

Do common metrics add value? Perspectives from NIH Clinical and Translational Science Awards (CTSA) Consortium hubs.

INTRODUCTION: The Clinical and Translational Science Awards (CTSA) Consortium, a network of academic health care institutions with CTSA hubs, is charged with improving the national clinical and translational research enterprise. The CTSA Consortium and the NIH National Center for Advancing Translational Sciences implemented the Common Metrics Initiative comprised of standardized metrics and a shared performance improvement framework. This article summarizes hubs' perspectives on its value during the initial implementation. METHODS: The value was assessed across 58 hubs. Survey items assessed change in perceived ability to manage performance and advance clinical and translational science. Semi-structured interviews elicited hubs' perspectives on meaningfulness and value-added of the Common Metrics Initiative and hubs' recommendations. RESULTS: Hubs considered their abilities to manage performance to have improved, but there was no change in perceived ability to advance clinical and translational science. The initiative added value by providing a formal structured process, enabling strategic conversations, facilitating improvements in processes, providing an external impetus for improvement, and providing justification for funds invested. Hubs were concerned about the usefulness of the metrics chosen and whether the value-added was sufficient relative to the effort required. Hubs recommended useful benchmarking, disseminating best practices and promoting peer-to-peer learning, and expanding the use of data to inform the initiative. CONCLUSIONS: Implementing Common Metrics and a performance improvement framework yielded concrete short-term benefits, but concerns about usefulness remained, particularly considering the effort required. The Common Metrics Initiative should focus on facilitating cross-hub collaboration around metrics that address high-priority impact areas for individual hubs and the Consortium.

Scientific Review Committees as part of institutional review of human participant research: Initial implementation at institutions with Clinical and Translational Science Awards.

INTRODUCTION: Scientific quality and feasibility are part of ethics review by Institutional Review Boards (IRBs). Scientific Review Committees (SRCs) were proposed to facilitate this assessment by the Clinical and Translational Science Award (CTSA) SRC Consensus Group. This study assessed SRC feasibility and impact at CTSA-affiliated academic health centers (AHCs). METHODS: SRC implementation at 10 AHCs was assessed pre/post-intervention using quantitative and qualitative methods. Pre-intervention, four AHCs had no SRC, and six had at least one SRC needing modifications to better align with Consensus Group recommendations. RESULTS: Facilitators of successful SRC implementation included broad-based communication, an external motivator, senior-level support, and committed SRC reviewers. Barriers included limited resources and staffing, variable local mandates, limited SRC authority, lack of anticipated benefit, and operational challenges. Research protocol quality did not differ significantly between study periods, but respondents suggested positive effects. During intervention, median total review duration did not lengthen for the 40% of protocols approved within 3 weeks. For the 60% under review after 3 weeks, review was lengthened primarily due to longer IRB review for SRC-reviewed protocols. Site interviews recommended designing locally effective SRC processes, building buy-in by communication or by mandate, allowing time for planning and sharing best practices, and connecting SRC and IRB procedures. CONCLUSIONS: The CTSA SRC Consensus Group recommendations appear feasible. Although not conclusive in this relatively short initial implementation, sites perceived positive impact by SRCs on study quality. Optimal benefit will require local or federal mandate for implementation, adapting processes to local contexts, and employing SRC stipulations.

Referral and timing of referral to hospice care in nursing homes: the significant role of staff members.

PURPOSE: Given concerns about end-of-life care for many nursing home (NH) residents, this study sought to understand factors influencing hospice referral or nonreferral as well as timing of referral. DESIGN AND METHODS: We conducted semistructured interviews with personnel from seven participating NHs and two hospices. We interviewed NH directors of nursing regarding facility referral practices and conducted interviews with 34 NH nurses, 30 NH aides, and 17 hospice nurses knowledgeable about the factors that led to the hospice status of 32 NH decedents. Selected decedents varied by diagnosis and hospice status (received hospice for >7 days,

Intracellular conversion and in vivo dose response of favipiravir (T-705) in rodents infected with Ebola virus.

During the 2013-2016 Ebola virus (EBOV) outbreak in West Africa, our team at USAMRIID evaluated the antiviral activity of a number of compounds, including favipiravir (T-705), in vitro and in mouse and nonhuman primate (NHP) models of Ebola virus disease. In this short communication, we present our findings for favipiravir in cell culture and in mice, while an accompanying paper presents the results of NHP studies. We confirmed previous reports that favipiravir has anti-EBOV activity in mice. Additionally, we found that the active form of favipiravir is generated in mice in tissues relevant for the pathogenesis of EBOV infection. Finally, we observed that protection can be achieved in mice down to 8 mg/kg/day, which is lower than the dosing regimens previously reported. An accompanying paper reports the results of treating nonhuman primates infected with EBOV or with Marburg virus with oral or intravenous favipiravir.