University of Vermont Medical Center Critical Care Transport Community Paramedicine Pilot Inclusion/Exclusion Criteria and Supplemental Materials

The University of Vermont Medical Center (UVMMC) Critical Care Transport (CCT) team received a grant in 2020 to trial one Community Paramedic to reduce high volume utilizers of UVMMC’s ED enrolled in Vermont’s accountable care organization (ACO), OneCareVT. That summer, this team helped develop and analyze the implications of that program. The current literature surrounding Community Paramedicine was explored, focusing particularly on studies that analyzed costs savings of these programs, rural areas with similar populations as Vermont, and the average cost of an ED visit. The reviewed literature and annotations are included in this work. Initially, our plan was to analyze data obtained from the Critical Care Transport team’s pilot program. However, the program was slated to begin at the beginning of April 2020 and was postponed in the wake of the COVID-19 pandemic. The department’s Community Paramedic was instead reallocated to set up the drive-through COVID-19 testing site for Chittenden County. The reallocation of resources from UVMMC’s CCT team prompted this team’ to pivot efforts toward the fundamental establishment of the program – particularly patient selection. 78 high utilizers of UVMMC’s ED for six months in 2020 were reviewed. Following the chart review trends in chronic underlying conditions and chief complaints were established within this cohort. With these data, inclusion criteria and exclusion criteria for a community paramedic pilot program were generated further taking into the considerations the abilities and limitations of community paramedics, safety, and other community resources available for this patient population. These criteria are included within this work. With the pivot from data collection to assisting with program set up, a mail-out letter to send to potential patients who might benefit from the program was written. Additionally, a script for contacting these patients via telephone to enroll them in the program was also written. These resources are also included within this work

Efficacy of CMX001 as a Prophylactic and Presymptomatic Antiviral Agent in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination

Development of CMX001 for the Treatment of Poxvirus Infections

CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It has proven effective in reduction of morbidity and mortality in animal models of human smallpox, even after the onset of lesions and other clinical signs of disease. CMX001 and CDV are active against all five families of double-stranded DNA (dsDNA) viruses that cause human morbidity and mortality, including orthopoxviruses such as variola virus, the cause of human smallpox. However, the clinical utility of CDV is limited by the requirement for intravenous dosing and a high incidence of acute kidney toxicity. The risk of nephrotoxicity necessitates pre-hydration and probenecid administration in a health care facility, further complicating high volume CDV use in an emergency situation. Compared with CDV, CMX001 has a number of advantages for treatment of smallpox in an emergency including greater potency in vitro against all dsDNA viruses that cause human disease, a high genetic barrier to resistance, convenient oral administration as a tablet or liquid, and no evidence to date of nephrotoxicity in either animals or humans. The apparent lack of nephrotoxicity observed with CMX001 in vivo is because it is not a substrate for the human organic anion transporters that actively secrete CDV into kidney cells. The ability to test the safety and efficacy of CMX001 in patients with life-threatening dsDNA virus infections which share many basic traits with variola is a major advantage in the development of this antiviral for a smallpox indication

Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells

The FcRH4 transmembrane molecule, a member of the Fc receptor homologue family, can potently inhibit B cell receptor (BCR) signaling. We show that cell surface expression of this immunoregulatory molecule is restricted to a subpopulation of memory B cells, most of which lack the classical CD27 marker for memory B cells in humans. The FcRH4+ and FcRH4− memory B cells have undergone comparable levels of immunoglobulin isotype switching and somatic hypermutation, while neither subpopulation expresses the transcription factors involved in plasma cell differentiation. The FcRH4+ memory cells are morphologically distinctive large lymphocytes that express the CD69, CD80, and CD86 cell activation markers. They are also shown to be poised to secrete high levels of immunoglobulins in response to stimulation with T cell cytokines, but they fail to proliferate in response either to BCR ligation or Staphylococcus aureus stimulation. A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces. Cell surface FcRH4 expression thus marks a unique population of memory B cells with distinctive morphology, functional capabilities, and tissue localization

Seven-membered ring scaffolds for drug discovery: access to functionalised azepanes and oxepanes through diazocarbonyl chemistry

Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction

Anticipatory ethnography:design fiction as an input to design ethnography

Here we consider design ethnography, and design fiction. We cast these two approaches, and the design endeavor itself, as forward-looking processes. Exploring the means by which design ethnography and design fiction derive their value reveals the potential for a mutually beneficial symbiosis. Our thesis argues that design ethnography can provide design fiction with the methods required to operationalize the practice in industry contexts. Meanwhile design fiction can provide design ethnographers a novel way of extending the temporal scope of the practice, thus deriving actionable insights that are applicable further into the future. “While we are more than ever aware of both the promise and the threat of technological advance, we still lack the intellectual means and political tools for managing progress.” Andrew Feenber

Minority HIV-1 Drug Resistance Mutations Are Present in Antiretroviral Treatment–Naïve Populations and Associate with Reduced Treatment Efficacy

Using real-time PCR to detect HIV resistance mutations present at low levels, Jeffrey Johnson and colleagues investigate prevalence and clinical implications of minority transmitted mutations

Comparison of blood and synovial fluid Th17 and novel peptidase inhibitor 16 Treg cell subsets in juvenile idiopathic arthritis

Objective. Early recognition and treatment of juvenile idiopathic arthritis (JIA) can prevent joint damage and minimize side effects of medication. The balance between proinflammatory and antiinflammatory mechanisms is known to be important in JIA, and we therefore investigated T cell subsets including Th cells, autoaggressive Th17 cells, and regulatory T cells (Treg), including a novel Treg subset in peripheral blood (PB) and synovial fluid (SF) of patients with JIA. Methods. Fifty children with JIA were enrolled in our study. Frequency, phenotype, and function of T lymphocytes in PB and SF were characterized using flow cytometry. Migration capabilities of PB and SF cells were compared. Results. Synovial T cells showed different phenotype and function compared with PB T cells, with an increased proportion of memory T cells, expression of CCR4, CCR5, CXCR3, interleukin 23R, and an increased ratio of Th17 to Treg. Although Treg were increased in SF compared with the PB, we found a significant decrease in the numbers of peptidase inhibitor 16 (PI16)+ Treg in active joints compared with peripheral blood. Coexpression of CCR4 and CCR6 was reduced on PI16+ Treg in PB and SF of patients with JIA compared with healthy children, however the ability of these cells to migrate toward their ligands was unaffected. Conclusion. This is a comprehensive characterization of novel PI16+ Treg and Th17 cells in matched blood and synovial fluid samples of patients with JIA. Despite an increased number of Treg within the inflamed joint, lower numbers of PI16+ Treg but high numbers of Th17 cells might contribute to the inability to control disease.Randall H. Grose, Deborah J. Millard, Chris Mavrangelos, Simon C. Barry, Heddy Zola, Ian C. Nicholson, Weng Tarng Cham, Christina A. Boros and Doreen Krumbiege

Nuclear Actin and Lamins in Viral Infections

Lamins are the best characterized cytoskeletal components of the cell nucleus that help to maintain the nuclear shape and participate in diverse nuclear processes including replication or transcription. Nuclear actin is now widely accepted to be another cytoskeletal protein present in the nucleus that fulfills important functions in the gene expression. Some viruses replicating in the nucleus evolved the ability to interact with and probably utilize nuclear actin for their replication, e.g., for the assembly and transport of capsids or mRNA export. On the other hand, lamins play a role in the propagation of other viruses since nuclear lamina may represent a barrier for virions entering or escaping the nucleus. This review will summarize the current knowledge about the roles of nuclear actin and lamins in viral infections