118 research outputs found
Oseltamivir-Resistant Influenza Viruses A (H1N1), Norway, 2007–08
Resistance was not associated with oseltamivir use or more severe disease
The mechanism of resistance to favipiravir in influenza.
Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance
Profinite rigidity for Seifert fibre spaces
An interesting question is whether two 3-manifolds can be distinguished by
computing and comparing their collections of finite covers; more precisely, by
the profinite completions of their fundamental groups. In this paper, we solve
this question completely for closed orientable Seifert fibre spaces. In
particular, all Seifert fibre spaces are distinguished from each other by their
profinite completions apart from some previously-known examples due to Hempel.
We also characterize when bounded Seifert fibre space groups have isomorphic
profinite completions, given some conditions on the boundary
Expansion in perfect groups
Let Ga be a subgroup of GL_d(Q) generated by a finite symmetric set S. For an
integer q, denote by Ga_q the subgroup of Ga consisting of the elements that
project to the unit element mod q. We prove that the Cayley graphs of Ga/Ga_q
with respect to the generating set S form a family of expanders when q ranges
over square-free integers with large prime divisors if and only if the
connected component of the Zariski-closure of Ga is perfect.Comment: 62 pages, no figures, revision based on referee's comments: new ideas
are explained in more details in the introduction, typos corrected, results
and proofs unchange
Quivers, YBE and 3-manifolds
We study 4d superconformal indices for a large class of N=1 superconformal
quiver gauge theories realized combinatorially as a bipartite graph or a set of
"zig-zag paths" on a two-dimensional torus T^2. An exchange of loops, which we
call a "double Yang-Baxter move", gives the Seiberg duality of the gauge
theory, and the invariance of the index under the duality is translated into
the Yang-Baxter-type equation of a spin system defined on a "Z-invariant"
lattice on T^2. When we compactify the gauge theory to 3d, Higgs the theory and
then compactify further to 2d, the superconformal index reduces to an integral
of quantum/classical dilogarithm functions. The saddle point of this integral
unexpectedly reproduces the hyperbolic volume of a hyperbolic 3-manifold. The
3-manifold is obtained by gluing hyperbolic ideal polyhedra in H^3, each of
which could be thought of as a 3d lift of the faces of the 2d bipartite
graph.The same quantity is also related with the thermodynamic limit of the BPS
partition function, or equivalently the genus 0 topological string partition
function, on a toric Calabi-Yau manifold dual to quiver gauge theories. We also
comment on brane realization of our theories. This paper is a companion to
another paper summarizing the results.Comment: 61 pages, 16 figures; v2: typos correcte
Discrete element modelling of scaled railway ballast under triaxial conditions
The aim of this study is to demonstrate the use of tetrahedral clumps to model scaled railway ballast using the discrete element method (DEM). In experimental triaxial tests, the peak friction angles for scaled ballast are less sensitive to the confining pressure when compared to full-sized ballast. This is presumed to be due to the size effect on particle strength, whereby smaller particles are statistically stronger and exhibit less abrasion. To investigate this in DEM, the ballast is modelled using clumps with breakable asperities to produce the correct volumetric deformation. The effects of the quantity and properties of these asperities are investigated, and it is shown that the strength affects the macroscopic shear strength at both high and low confining pressures, while the effects of the number of asperities diminishes with increasing confining pressure due to asperity breakage. It is also shown that changing the number of asperities only affects the peak friction angle but not the ultimate friction angle by comparing the angles of repose of samples with different numbers of asperities
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Cross sectional investigation of a COVID-19 outbreak at a London Army barracks: Neutralising antibodies and virus isolation.
Background: Military personnel in enclosed societies are at increased risk of respiratory infections. We investigated an outbreak of Coronavirus Disease 2019 in a London Army barracks early in the pandemic. Methods: Army personnel, their families and civilians had nasal and throat swabs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcriptase -polymerase chain reaction (RT-PCR), virus isolation and whole genome sequencing, along with blood samples for SARS-CoV-2 antibodies. All tests were repeated 36 days later. Findings: During the first visit, 304 (254 Army personnel, 10 family members, 36 civilians, 4 not stated) participated and 24/304 (8%) were SARS-CoV-2 RT-PCR positive. Infectious virus was isolated from 7/24 (29%). Of the 285 who provided a blood sample, 7% (19/285) were antibody positive and 63% (12/19) had neutralising antibodies. Twenty-two (22/34, 64%) individuals with laboratory-confirmed infection were asymptomatic. Nine SARS-CoV-2 RT-PCR positive participants were also antibody positive but those who had neutralising antibodies did not have infectious virus. At the second visit, no new infections were detected, and 13% (25/193) were seropositive, including 52% (13/25) with neutralising antibodies. Risk factors for SARS-CoV-2 antibody positivity included contact with a confirmed case (RR 25.2; 95% CI 14-45), being female (RR 2.5; 95% CI 1.0-6.0) and two-person shared bathroom (RR 2.6; 95% CI 1.1-6.4). Interpretation: We identified high rates of asymptomatic SARS-CoV-2 infection. Public Health control measures can mitigate spread but virus re-introduction from asymptomatic individuals remains a risk. Most seropositive individuals had neutralising antibodies and infectious virus was not recovered from anyone with neutralising antibodies. Funding: PHE
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Reinfection with new variants of SARS-CoV-2 after natural infection: a prospective observational cohort in 13 care homes in England.
Background: Understanding the duration of protection and risk of reinfection after natural infection is crucial to planning COVID-19 vaccination for at-risk groups, including care home residents, particularly with the emergence of more transmissible variants. We report on the duration, neutralising activity, and protection against the alpha variant of previous SARS-CoV-2 infection in care home residents and staff infected more than 6 months previously. Methods: We did this prospective observational cohort surveillance in 13 care homes in Greater London, England. All staff and residents were included. Staff and residents had regular nose and throat screening for SARS-CoV-2 by RT-PCR according to national guidelines, with ad hoc testing of symptomatic individuals. From January, 2021, antigen lateral flow devices were also used, but positive tests still required RT-PCR confirmation. Staff members took the swab samples for themselves and the residents. The primary outcome was SARS-CoV-2 RT-PCR positive primary infection or reinfection in previously infected individuals, as determined by previous serological testing and screening or diagnostic RT-PCR results. Poisson regression and Cox proportional hazards models were used to estimate protective effectiveness of previous exposure. SARS-CoV-2 spike, nucleoprotein, and neutralising antibodies were assessed at multiple timepoints as part of the longitudinal follow-up. Findings: Between April 10 and Aug 3, 2020, we recruited and tested 1625 individuals (933 staff and 692 residents). 248 participants were lost to follow-up (123 staff and 125 residents) and 1377 participants were included in the follow-up period to Jan 31, 2021 (810 staff and 567 residents). There were 23 reinfections (ten confirmed, eight probable, five possible) in 656 previously infected individuals (366 staff and 290 residents), compared with 165 primary infections in 721 susceptible individuals (444 staff and 277 residents). Those with confirmed reinfections had no or low neutralising antibody concentration before reinfection, with boosting of titres after reinfection. Kinetics of binding and neutralising antibodies were similar in older residents and younger staff. Interpretation: SARS-CoV-2 reinfections were rare in older residents and younger staff. Protection from SARS-CoV-2 was sustained for longer than 9 months, including against the alpha variant. Reinfection was associated with no or low neutralising antibody before reinfection, but significant boosting occurred on reinfection. Funding: Public Health England
What Is the Optimal Therapy for Patients with H5N1 Influenza?
Nicholas White discusses optimal dosing of oseltamivir, Robert Webster and Elena Govorkova discuss combination antiviral therapy, and Timothy Uyeki discusses clinical care of patients with H5N1
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