128 research outputs found
Influenza A virus in natural and artificial environments
Influenza is caused by influenza A virus, a single stranded RNA virus of
the orthomyxoviridae family. In humans, it causes yearly outbreaks with
high morbidity and excess fatality rates as a direct effect. Placed in
its ecological niche however, in dabbling ducks, avian influenza virus
(AIV) induce quite mild disease. It is when the virus crosses the species
barrier that pathogenic traits are attributed to infection. Also
infection of close relatives to dabbling ducks, the domestic chicken,
cause morbidity and may in some cases change the virus into a highly
pathogenic variant with nearly 100% fatality rate. Being a very adaptable
virus, these spill-over events are frequent, and numerous species are
susceptible to influenza virus. When a subtype of influenza which has not
previously infected humans crosses the species barrier, adapts to humans
and spread easily, a pandemic event is imminent. There is no cure for
influenza infection, and vaccination is a cumbersome endeavor, so
currently the strategy when a pandemic strikes is damage control.
In this thesis, I have been involved in a surveillance project, to
increase our knowledge of how influenza travels across the globe with its
natural host. We have also used animal models to investigate the
pathological effects in mallard ducks and their susceptibility to
re-infection. Furthermore, we have evaluated the effect and the potential
risk of frivolous use of the anti-viral agent oseltamivir, and also
investigated a novel approach to the classic virus isolation method of
growing virus in embryonated chicken eggs (ECE s).
Indication was found in northern Alaska that prevalence of influenza is
probably not lower here than in other breeding areas for dabbling ducks,
as has been previously suggested. As these birds travel over the Bering
Strait, the reason for the genetic isolation of Eurasian and North
American influenza A strains remains unclear.
Inoculation of mallards equipped with subcutaneous data transmitters
indicated very little effect on the host and no stress above background
level, and all birds gained weight throughout the trial. Only in four of
six birds (65%) could a small temperature increase related to infection
be recorded. However, more studies in a natural environment need to be
conducted, to discern whether this variable is associated with an
ecological cost as the captive trial ducks had access to food ad libitum.
The most commonly used anti-viral drug, oseltamivir, is poorly degraded
in sewage plants and surface water, where dabbling ducks forage.
Extensive use of the drug thus increases environmental levels of the
active metabolite, oseltamivir carboxylate (OC). We show that mallards
inoculated with A/H1N1 in an OC enriched environment generates resistant
virus sporadically at OC level found today. Higher level of OC caused the
resistant subspecies to dominate the virus population, which is not
desirable in the influenza reservoir. An introduction of a OC-resistant
pandemic virus to the human population would render the only antiviral
defense toothless.
Isolation of influenza virus is traditionally performed by inoculation of
infectious material into embryonated chicken eggs. As the chicken host is
known to induce changes in AIV, we compared isolating and passaging two
viruses both in ECE s and embryonated mallard eggs. Both egg species
induced mutations in the primary passage, with no furthers changes in
subsequent passages. Only in ECE s did one virus maintain wild-type
configuration before one mutation was observed. Mallard eggs can based on
these results not be advocated as preferable to ECE s when isolating and
passaging AIV
Prevalence and Phylogeny of Coronaviruses in Wild Birds from the Bering Strait Area (Beringia)
Coronaviruses (CoVs) can cause mild to severe disease in humans and animals, their host range and environmental spread seem to have been largely underestimated, and they are currently being investigated for their potential medical relevance. Infectious bronchitis virus (IBV) belongs to gamma-coronaviruses and causes a costly respiratory viral disease in chickens. The role of wild birds in the epidemiology of IBV is poorly understood. In the present study, we examined 1,002 cloacal and faecal samples collected from 26 wild bird species in the Beringia area for the presence of CoVs, and then we performed statistical and phylogenetic analyses. We detected diverse CoVs by RT-PCR in wild birds in the Beringia area. Sequence analysis showed that the detected viruses are gamma-coronaviruses related to IBV. These findings suggest that wild birds are able to carry gamma-coronaviruses asymptomatically. We concluded that CoVs are widespread among wild birds in Beringia, and their geographic spread and frequency is higher than previously realised. Thus, Avian CoV can be efficiently disseminated over large distances and could be a genetic reservoir for future emerging pathogenic CoVs. Considering the great animal health and economic impact of IBV as well as the recent emergence of novel coronaviruses such as SARS-coronavirus, it is important to investigate the role of wildlife reservoirs in CoV infection biology and epidemiology
Influenza Virus in a Natural Host, the Mallard: Experimental Infection Data
Wild waterfowl, particularly dabbling ducks such as mallards (Anas platyrhynchos), are considered the main reservoir of low-pathogenic avian influenza viruses (LPAIVs). They carry viruses that may evolve and become highly pathogenic for poultry or zoonotic. Understanding the ecology of LPAIVs in these natural hosts is therefore essential. We assessed the clinical response, viral shedding and antibody production of juvenile mallards after intra-esophageal inoculation of two LPAIV subtypes previously isolated from wild congeners. Six ducks, equipped with data loggers that continually monitored body temperature, heart rate and activity, were successively inoculated with an H7N7 LPAI isolate (day 0), the same H7N7 isolate again (day 21) and an H5N2 LPAI isolate (day 35). After the first H7N7 inoculation, the ducks remained alert with no modification of heart rate or activity. However, body temperature transiently increased in four individuals, suggesting that LPAIV strains may have minor clinical effects on their natural hosts. The excretion patterns observed after both re-inoculations differed strongly from those observed after the primary H7N7 inoculation, suggesting that not only homosubtypic but also heterosubtypic immunity exist. Our study suggests that LPAI infection has minor clinically measurable effects on mallards and that mallard ducks are able to mount immunological responses protective against heterologous infections. Because the transmission dynamics of LPAIVs in wild populations is greatly influenced by individual susceptibility and herd immunity, these findings are of high importance. Our study also shows the relevance of using telemetry to monitor disease in animals
Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan
Severe human malaria is attributable to an excessive sequestration of Plasmodium falciparumâinfected and uninfected erythrocytes in vital organs. Strains of P. falciparum that form rosettes and employ heparan sulfate as a host receptor are associated with development of severe forms of malaria. Heparin, which is similar to heparan sulfate in that it is composed of the same building blocks, was previously used in the treatment of severe malaria, but it was discontinued due to the occurrence of serious side effects such as intracranial bleedings. Here we report to have depolymerized heparin by periodate treatment to generate novel glycans (dGAG) that lack anticoagulant-activity. The dGAGs disrupt rosettes, inhibit merozoite invasion of erythrocytes and endothelial binding of P. falciparumâinfected erythrocytes in vitro, and reduce sequestration in in vivo models of severe malaria. An intravenous injection of dGAGs blocks up to 80% of infected erythrocytes from binding in the micro-vasculature of the rat and releases already sequestered parasites into circulation. P. falciparumâinfected human erythrocytes that sequester in the non-human primate Macaca fascicularis were similarly found to be released in to the circulation upon a single injection of 500 ÎŒg of dGAG. We suggest dGAGs to be promising candidates for adjunct therapy in severe malaria
Discovery of Samarium, Europium, Gadolinium, and Terbium Isotopes
Currently, thirty-four samarium, thirty-four europium, thirty-one gadolinium,
and thirty-one terbium isotopes have been observed and the discovery of these
isotopes is discussed here. For each isotope a brief synopsis of the first
refereed publication, including the production and identification method, is
presented.Comment: To be published in At. Data Nucl. Data Table
Protocol for a prospective collaborative systematic review and meta-analysis of individual patient data from randomised controlled trials of vasoactive drugs in acute stroke: the Blood pressure in Acute Stroke Collaboration, stage-3 (BASC-3)
Rationale
Despite several large clinical trials assessing blood pressure lowering in acute stroke, equipoise remains, particularly for ischaemic stroke. The âBlood pressure in Acute Stroke Collaborationâ (BASC) commenced in the mid 1990s focusing on systematic reviews and meta-analysis of blood pressure lowering in acute stroke. From the start, BASC planned to assess safety and efficacy of blood pressure lowering in acute stroke using individual patient data.
Aims
To determine the optimal management of blood pressure in patients with acute stroke, encompassing both intracerebral haemorrhage and ischaemic stroke. Secondary aims are to assess which clinical and therapeutic factors may alter the optimal management of high blood pressure in patients with acute stroke and to assess the effect of vasoactive treatments on haemodynamic variables.
Methods and design
Individual patient data from randomised controlled trials of blood pressure management in participants with ischaemic stroke and/or intracerebral haemorrhage enrolled during the ultra-acute (pre-hospital), hyper-acute (<6 hours), acute (<48 hours) and sub-acute (<168 hours) phases of stroke.
Study outcomes
The primary effect variable will be functional outcome defined by the ordinal distribution of the modified Rankin Scale; analyses will also be carried out in prespecified subgroups to assess the modifying effects of stroke-related and pre-stroke patient characteristics. Key secondary variables will include clinical, haemodynamic and neuroradiological variables; safety variables will comprise death and serious adverse events.
Discussion
Study questions will be addressed in stages, according to the protocol, before integrating these into a final overreaching analysis. We invite eligible trials to join the collaboration
Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards
Oseltamivir (TamifluÂź) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008â2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 ”g/L and 80 ”g/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 ”g/L of OC and rapidly dominated the viral population at 80 ”g/L. IC50 for OC was increased from 2â4 nM in wild-type viruses to 400â700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58â293 ng/L during seasonal outbreaks and are expected to reach ”g/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals
Thrombolysis ImPlementation in Stroke (TIPS): evaluating the effectiveness of a strategy to increase the adoption of best evidence practice â protocol for a cluster randomised controlled trial in acute stroke care
The National Institute for Health Research Hyperacute Stroke Research Centres and the ENCHANTED trial: the impact of enhanced research infrastructure on trial metrics and patient outcomes
Background
The English National Institute for Health Research Clinical Research Network first established Hyperacute Stroke Research Centres (HSRCs) in 2010 to support multicentre hyperacute (<â9âh) and complex stroke research. We assessed the impact of this investment on research performance and patient outcomes in a post-hoc analysis of country-specific data from a large multicentre clinical trial.
Methods
Comparisons of baseline, outcome and trial metric data were made for participants recruited to the alteplase-dose arm of the international Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) at National Institute for Health Research Clinical Research Network HSRCs and non-HSRCs between June 2012 and October 2015.
Results
Among 774 ENCHANTED United Kingdom participants (41% female; mean age 72âyears), 502 (64.9%) were recruited from nine HSRCs and 272 (35.1%) from 24 non-HSRCs. HSRCs had higher monthly recruitment rates (median 1.5, interquartile interval 1.4â2.2 vs. 0.7, 0.5â1.3; pâ=â0.01) and shorter randomisation-to-treatment times (2.6 vs. 3.1âmin; pâ=â0.01) compared to non-HSRCs. HSRC participants were younger and had milder stroke severity, but clinically important between-group differences in 90-day death or disability outcomes remained after adjustment for minimisation criteria and important baseline variables at randomisation, whether defined by ordinal modified Rankin scale score shift (adjusted OR 0.82, 95% CI 0.62â1.08; pâ=â0.15), scores 2 to 6 (adjusted OR 0.71, 95% CI 0.50â1.01; pâ=â0.05), or scores 3 to 6 (adjusted OR 0.82, 95% CI 0.57â1.17; pâ=â0.27). There was no significant difference in symptomatic intracerebral haemorrhage, nor heterogeneity in the comparative treatment effects between low- and standard-dose alteplase by HSRCs or non-HSRCs.
Conclusions
Infrastructure investment in HSRCs was associated with improved research performance metrics, particularly recruitment and time to treatment with clinically important, though not statistically significant, improvements in patient outcomes
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
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