Rabbitpox in New Zealand White Rabbits: A Therapeutic Model for Evaluation of Poxvirus Medical Countermeasures Under the FDA Animal Rule

The elimination of smallpox as an endemic disease and the obvious ethical problems with clinical challenge requires the efficacy evaluation of medical countermeasures against smallpox using the FDA Animal Rule. This approach requires the evaluation of antiviral efficacy in an animal model whose infection recapitulates the human disease sufficiently well enough to provide predictive value of countermeasure effectiveness. The narrow host range of variola virus meant that no other animal species was sufficiently susceptible to variola to manifest a disease with predictive value. To address this dilemma, the FDA, after a public forum with virologists in December 2011, suggested the development of two animal models infected with the cognate orthopoxvirus, intradermal infection of rabbits and intranasal infection of mice, to supplement the non-human primate models in use. In this manuscript, we describe the development of an intradermal challenge model of New Zealand White rabbits with rabbitpox virus (RPXV) for poxvirus countermeasure evaluation. Lethality of RPXV was demonstrated in both 9 and 16-weeks old rabbits with an LD50 < 10 PFU. The natural history of RPXV infection was documented in both ages of rabbits by monitoring the time to onset of abnormal values in clinical data at a lethal challenge of 300 PFU. All infected animals became viremic, developed a fever, exhibited weight loss, developed secondary lesions, and were euthanized after 7 or 8 days. The 16-weeks RPXV-infected animals exhibiting similar clinical signs with euthanasia applied about a day later than for 9-weeks old rabbits. For all animals, the first two unambiguous indicators of infection were detection of viral copies by quantitative polymerase chain reaction and fever at 2 and 3 days following challenge, respectively. These biomarkers provide clinically-relevant trigger(s) for initiating therapy. The major advantage for using 16-weeks NZW rabbits is that older rabbits were more robust and less subject to stress-induced death allowing more reproducible studies

International patient preferences for physician attire: results from cross-sectional studies in four countries across three continents.

OBJECTIVE The patient-physician relationship impacts patients' experiences and health outcomes. Physician attire is a form of nonverbal communication that influences this relationship. Prior studies examining attire preferences suffered from heterogeneous measurement and limited context. We thus performed a multicentre, cross-sectional study using a standardised survey instrument to compare patient preferences for physician dress in international settings. SETTING 20 hospitals and healthcare practices in Italy, Japan, Switzerland and the USA. PARTICIPANTS Convenience sample of 9171 adult patients receiving care in academic hospitals, general medicine clinics, specialty clinics and ophthalmology practices. PRIMARY AND SECONDARY OUTCOME MEASURES The survey was randomised and included photographs of a male or female physician dressed in assorted forms of attire. The primary outcome measure was attire preference, comprised of composite ratings across five domains: how knowledgeable, trustworthy, caring and approachable the physician appeared, and how comfortable the respondent felt. Secondary outcome measures included variation in preferences by country, physician type and respondent characteristics. RESULTS The highest rated forms of attire differed by country, although each most preferred attire with white coat. Low ratings were conferred on attire extremes (casual and business suit). Preferences were more uniform for certain physician types. For example, among all respondents, scrubs garnered the highest rating for emergency department physicians (44.2%) and surgeons (42.4%). However, attire preferences diverged for primary care and hospital physicians. All types of formal attire were more strongly preferred in the USA than elsewhere. Respondent age influenced preferences in Japan and the USA only. CONCLUSIONS Patients across a myriad of geographies, settings and demographics harbour specific preferences for physician attire. Some preferences are nearly universal, whereas others vary substantially. As a one-size-fits-all dress policy is unlikely to reflect patient desires and expectations, a tailored approach should be sought that attempts to match attire to clinical context

Understanding patient preference for physician attire in ambulatory clinics: a cross-sectional observational study

OBJECTIVES We explored patient perceptions regarding physician attire in different clinical contexts and resultant effects on the physician-patient relationship. SETTING The 900-bed University Hospital Zurich, Switzerland. PARTICIPANTS A convenience sample of patients receiving care in dermatology, infectious diseases and neurology ambulatory clinics of the University Hospital Zurich participated in a paper-based survey. PRIMARY AND SECONDARY OUTCOME MEASURES The survey instrument was randomised and showed photographs of male or female physicians wearing various forms of attire. On the basis of the respondents' ratings of how the physician's attire affected perceptions across five domains (knowledgeable, trustworthy, caring, approachable and comfort with the physician), a composite preference score for attire was calculated as the primary outcome. Secondary outcomes included variation in preferences by respondent characteristics and context in which care was provided. RESULTS Of 834 patient respondents (140 in dermatology, 422 in infectious diseases and 272 in neurology), 298 (36%) agreed that physician attire was important. When compared with all available choices, the combination of white scrubs with white coat was rated highest while a business suit ranked lowest. Variation in preferences and opinions for attire were noted relative to respondent demographics and the clinical setting in which the survey was administered. For example, compared with younger patients, respondents ≥65 years of age more often reported that physician dress was both important to them and influenced how happy they were with their care (p=0.047 and p=0.001, respectively). CONCLUSIONS Outpatients at a large Swiss University hospital prefer their physicians to be dressed in white scrubs with white coat. Substantial variation among respondents based on demographics, type of physician and clinical setting were observed. Healthcare systems should consider context of care when defining policies related to dress code

Overview of the MOSAiC expedition - Atmosphere

With the Arctic rapidly changing, the needs to observe, understand, and model the changes are essential. To support these needs, an annual cycle of observations of atmospheric properties, processes, and interactions were made while drifting with the sea ice across the central Arctic during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition from October 2019 to September 2020. An international team designed and implemented the comprehensive program to document and characterize all aspects of the Arctic atmospheric system in unprecedented detail, using a variety of approaches, and across multiple scales. These measurements were coordinated with other observational teams to explore cross-cutting and coupled interactions with the Arctic Ocean, sea ice, and ecosystem through a variety of physical and biogeochemical processes. This overview outlines the breadth and complexity of the atmospheric research program, which was organized into 4 subgroups: atmospheric state, clouds and precipitation, gases and aerosols, and energy budgets. Atmospheric variability over the annual cycle revealed important influences from a persistent large-scale winter circulation pattern, leading to some storms with pressure and winds that were outside the interquartile range of past conditions suggested by long-term reanalysis. Similarly, the MOSAiC location was warmer and wetter in summer than the reanalysis climatology, in part due to its close proximity to the sea ice edge. The comprehensiveness of the observational program for characterizing and analyzing atmospheric phenomena is demonstrated via a winter case study examining air mass transitions and a summer case study examining vertical atmospheric evolution. Overall, the MOSAiC atmospheric program successfully met its objectives and was the most comprehensive atmospheric measurement program to date conducted over the Arctic sea ice. The obtained data will support a broad range of coupled-system scientific research and provide an important foundation for advancing multiscale modeling capabilities in the Arctic

Developing Vaccines to Improve Preparedness for Filovirus Outbreaks: The Perspective of the USA Biomedical Advanced Research and Development Authority (BARDA)

Outbreaks of viral hemorrhagic fever caused by filoviruses have become more prevalent in recent years, with outbreaks of Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV) all occurring in 2022 and 2023. While licensed vaccines are now available for EBOV, vaccine candidates for SUDV and MARV are all in preclinical or early clinical development phases. During the recent outbreak of SUDV virus disease, the Biomedical Advanced Research and Development Authority (BARDA), as part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, implemented key actions with our existing partners to advance preparedness and enable rapid response to the outbreak, while also aligning with global partners involved in the implementation of clinical trials in an outbreak setting. Beyond pre-existing plans prior to the outbreak, BARDA worked with product sponsors to expedite manufacturing of vaccine doses that could be utilized in clinical trials. While the SUDV outbreak has since ended, a new outbreak of MARV disease has emerged. It remains critical that we continue to advance a portfolio of vaccines against SUDV and MARV while also expediting manufacturing activities ahead of, or in parallel if needed, outbreaks

Ectromelia Virus Disease Characterization in the BALB/c Mouse: A Surrogate Model for Assessment of Smallpox Medical Countermeasures

In 2007, the United States– Food and Drug Administration (FDA) issued guidance concerning animal models for testing the efficacy of medical countermeasures against variola virus (VARV), the etiologic agent for smallpox. Ectromelia virus (ECTV) is naturally-occurring and responsible for severe mortality and morbidity as a result of mousepox disease in the murine model, displaying similarities to variola infection in humans. Due to the increased need of acceptable surrogate animal models for poxvirus disease, we have characterized ECTV infection in the BALB/c mouse. Mice were inoculated intranasally with a high lethal dose (125 PFU) of ECTV, resulting in complete mortality 10 days after infection. Decreases in weight and temperature from baseline were observed eight to nine days following infection. Viral titers via quantitative polymerase chain reaction (qPCR) and plaque assay were first observed in the blood at 4.5 days post-infection and in tissue (spleen and liver) at 3.5 days post-infection. Adverse clinical signs of disease were first observed four and five days post-infection, with severe signs occurring on day 7. Pathological changes consistent with ECTV infection were first observed five days after infection. Examination of data obtained from these parameters suggests the ECTV BALB/c model is suitable for potential use in medical countermeasures (MCMs) development and efficacy testing

The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule

Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a Tier 1 select agent. The natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCM) in human populations. Development and licensure of tularemia therapeutics and vaccines need to occur under the Food and Drug Administration's (FDA's) Animal Rule under which efficacy studies are conducted in well-characterized animal models that reflect the pathophysiology of human disease. The Tularemia Animal Model Qualification (AMQ) Working Group is seeking qualification of the cynomolgus macaque (Macaca fascicularis) model of pneumonic tularemia under Drug Development Tools Qualification Programs with the FDA based upon the results of studies described in this manuscript. Analysis of data on survival, average time to death, average time to fever onset, average interval between fever and death, and bacteremia; together with summaries of clinical signs, necropsy findings, and histopathology from the animals exposed to aerosolized F. tularensis Schu S4 in five natural history studies and one antibiotic efficacy study form the basis for the proposed cynomolgus macaque model. Results support the conclusion that signs of pneumonic tularemia in cynomolgus macaques exposed to 300–3,000 colony forming units (cfu) aerosolized F. tularensis Schu S4, under the conditions described herein, and human pneumonic tularemia cases are highly similar. Animal age, weight, and sex of animals challenged with 300–3,000 cfu Schu S4 did not impact fever onset in studies described herein. This study summarizes critical parameters and endpoints of a well-characterized cynomolgus macaque model of pneumonic tularemia and demonstrates this model is appropriate for qualification, and for testing efficacy of tularemia therapeutics under Animal Rule