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

Pressed for Space: The Effects of Justification and the Printing Process on Fifteenth-Century Orthography

There is a long-held belief that, prior to the standardisation of written English, printers altered spellings to justify their type. I investigate this claim through an analysis of spelling changes in William Caxton’s two editions of the Canterbury Tales—by examining text within one book, written by one author, and set by one compositor, the only difference between the sections of verse and the sections of prose should be the requirement for justification within the latter. Were the compositors altering spellings to justify their type, we would expect to see a greater number of altered spellings in the prose sections of text. This is not what the results of this study show—instead there is no statistically significant difference between the frequency of spelling changes in justified and non-justified text. However, there is a significantly higher number of abbreviations introduced into the justified text. These results suggest that the compositor of Caxton’s second edition Canterbury Tales did not change spellings to justify his type

Constituting Citizenship Through the Emotions: Singaporean Transmigrants in London

10.1080/00045600903102857Annals of the Association of American Geographers994788-80

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses

TOI-2119: A transiting brown dwarf orbiting an active M-dwarf from NASA’s TESS mission

We report the discovery of TOI-2119b, a transiting brown dwarf (BD) that orbits and is completely eclipsed by an active M-dwarf star. Using light curve data from the Transiting Exoplanet Survey Satellite mission and follow-up high-resolution Doppler spectroscopic observations, we find the BD has a radius of $R_b = 1.08 \pm 0.03{\rm R_J}$, a mass of $M_b = 64.4 \pm 2.3{\rm M_J}$, an orbital period of $P = 7.200865 \pm 0.00002$ days, and an eccentricity of $e=0.337\pm 0.002$. The host star has a mass of $M_\star = 0.53 \pm 0.02{\rm M_\odot}$, a radius of $R_\star= 0.50 \pm 0.01{\rm R_\odot}$, an effective temperature of $T_{\rm eff} = 3621 \pm 48$K, and a metallicity of $\rm [Fe/H]=+0.06\pm 0.08$. TOI-2119b joins an emerging population of transiting BDs around M-dwarf host stars, with TOI-2119 being the ninth such system. These M-dwarf--brown dwarf systems typically occupy mass ratios near $q = M_b/M_\star \approx 0.1-0.2$, which separates them from the typical mass ratios for systems with transiting substellar objects and giant exoplanets that orbit more massive stars. The nature of the secondary eclipse of the BD by the star enables us to estimate the effective temperature of the substellar object to be $2030\pm 84$K, which is consistent with predictions by substellar evolutionary models.Comment: 14 pages, 13 figures, 4 tables, accepted in MNRA

Optimizing care in osteoporosis: The Canadian quality circle project

<p>Abstract</p> <p>Background</p> <p>While the Osteoporosis Canada 2002 Canadian guidelines provided evidence based strategies in preventing, diagnosing, and managing this condition, publication and distribution of guidelines have not, in and of themselves, been shown to alter physicians clinical approaches. We hypothesize that primary care physicians enrolled in the Quality Circle project would change their patient management of osteoporosis in terms of awareness of osteoporosis risk factors and bone mineral density testing in accordance with the guidelines.</p> <p>Methods</p> <p>The project consisted of five Quality Circle phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 circle members formed 34 quality circles and participated in the study. The generalized estimating equations approach was used to model physician awareness of risk factors for osteoporosis and appropriate utilization of bone mineral density testing pre and post educational intervention (first year of the study). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.</p> <p>Results</p> <p>After the 1^styear of the study, physicians' certainty of their patients' risk factor status increased. Certainty varied from an OR of 1.4 (95% CI: 1.1, 1.8) for prior vertebral fracture status to 6.3 (95% CI: 2.3, 17.9) for prior hip fracture status. Furthermore, bone mineral density testing increased in high risk as compared with low risk patients (OR: 1.4; 95% CI: 1.2, 1.7).</p> <p>Conclusion</p> <p>Quality Circle methodology was successful in increasing both physicians' awareness of osteoporosis risk factors and appropriate bone mineral density testing in accordance with the 2002 Canadian guidelines.</p

Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

Coronaviruses (CoVs) have emerged from animal reservoirs to cause severe and lethal disease in humans, but there are currently no FDA-approved antivirals to treat the infections. One class of antiviral compounds, nucleoside analogues, mimics naturally occurring nucleosides to inhibit viral replication. While these compounds have been successful therapeutics for several viral infections, mutagenic nucleoside analogues, such as ribavirin and 5-fluorouracil, have been ineffective at inhibiting CoVs. This has been attributed to the proofreading activity of the viral 3′-5′ exoribonuclease (ExoN). β-d-N4-Hydroxycytidine (NHC) (EIDD-1931; Emory Institute for Drug Development) has recently been reported to inhibit multiple viruses. Here, we demonstrate that NHC inhibits both murine hepatitis virus (MHV) (50% effective concentration [EC50] = 0.17 μM) and Middle East respiratory syndrome CoV (MERS-CoV) (EC50 = 0.56 μM) with minimal cytotoxicity. NHC inhibited MHV lacking ExoN proofreading activity similarly to wild-type (WT) MHV, suggesting an ability to evade or overcome ExoN activity. NHC inhibited MHV only when added early during infection, decreased viral specific infectivity, and increased the number and proportion of G:A and C:U transition mutations present after a single infection. Low-level NHC resistance was difficult to achieve and was associated with multiple transition mutations across the genome in both MHV and MERS-CoV. These results point to a virus-mutagenic mechanism of NHC inhibition in CoVs and indicate a high genetic barrier to NHC resistance. Together, the data support further development of NHC for treatment of CoVs and suggest a novel mechanism of NHC interaction with the CoV replication complex that may shed light on critical aspects of replication. IMPORTANCE The emergence of coronaviruses (CoVs) into human populations from animal reservoirs has demonstrated their epidemic capability, pandemic potential, and ability to cause severe disease. However, no antivirals have been approved to treat these infections. Here, we demonstrate the potent antiviral activity of a broad-spectrum ribonucleoside analogue, β-d-N4-hydroxycytidine (NHC), against two divergent CoVs. Viral proofreading activity does not markedly impact sensitivity to NHC inhibition, suggesting a novel interaction between a nucleoside analogue inhibitor and the CoV replicase. Further, passage in the presence of NHC generates only low-level resistance, likely due to the accumulation of multiple potentially deleterious transition mutations. Together, these data support a mutagenic mechanism of inhibition by NHC and further support the development of NHC for treatment of CoV infections

Couple-oriented prenatal HIV counseling for HIV primary prevention: an acceptability study

<p>Abstract</p> <p>Background</p> <p>A large proportion of the 2.5 million new adult HIV infections that occurred worldwide in 2007 were in stable couples. Feasible and acceptable strategies to improve HIV prevention in a conjugal context are scarce. In the preparatory phase of the ANRS 12127 Prenahtest multi-site HIV prevention trial, we assessed the acceptability of couple-oriented post-test HIV counseling (COC) and men's involvement within prenatal care services, among pregnant women, male partners and health care workers in Cameroon, Dominican Republic, Georgia and India.</p> <p>Methods</p> <p>Quantitative and qualitative research methods were used: direct observations of health services; in-depth interviews with women, men and health care workers; monitoring of the COC intervention and exit interviews with COC participants.</p> <p>Results</p> <p>In-depth interviews conducted with 92 key informants across the four sites indicated that men rarely participated in antenatal care (ANC) services, mainly because these are traditionally and programmatically a woman's domain. However men's involvement was reported to be acceptable and needed in order to improve ANC and HIV prevention services. COC was considered by the respondents to be a feasible and acceptable strategy to actively encourage men to participate in prenatal HIV counseling and testing and overall in reproductive health services.</p> <p>Conclusions</p> <p>One of the keys to men's involvement within prenatal HIV counseling and testing is the better understanding of couple relationships, attitudes and communication patterns between men and women, in terms of HIV and sexual and reproductive health; this conjugal context should be taken into account in the provision of quality prenatal HIV counseling, which aims at integrated PMTCT and primary prevention of HIV.</p

Re-visiting Meltsner: Policy Advice Systems and the Multi-Dimensional Nature of Professional Policy Analysis

10.2139/ssrn.15462511-2