Population-Wide Emergence of Antiviral Resistance during Pandemic Influenza

Background: The emergence of neuraminidase inhibitor resistance has raised concerns about the prudent use of antiviral drugs in response to the next influenza pandemic. While resistant strains may initially emerge with compromised viral fitness, mutations that largely compensate for this impaired fitness can arise. Understanding the extent to which these mutations affect the spread of disease in the population can have important implications for developing pandemic plans. Methodology/Principal Findings: By employing a deterministic mathematical model, we investigate possible scenarios for the emergence of population-wide resistance in the presence of antiviral drugs. The results show that if the treatment level (the fraction of clinical infections which receives treatment) is maintained constant during the course of the outbreak, there is an optimal level that minimizes the final size of the pandemic. However, aggressive treatment above the optimal level can substantially promote the spread of highly transmissible resistant mutants and increase the total number of infections. We demonstrate that resistant outbreaks can occur more readily when the spread of disease is further delayed by applying other curtailing measures, even if treatment levels are kept modest. However, by changing treatment levels over the course of the pandemic, it is possible to reduce the final size of the pandemic below the minimum achieved at the optimal constant level. This reduction can occur with low treatment levels during the early stages of the pandemic, followed by a sharp increase in drug-use before the virus becomes widely spread. Conclusions/Significance: Our findings suggest that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections

The effect of transmucosal 0.2mg/kg Midazolam premedication on dental anxiety, anaesthetic induction and psychological morbidity in children undergoing general anaesthesia for tooth extraction

<b>Background:</b> The project aims were to evaluate the benefit of transmucosal Midazolam 0.2mg/kg pre-medication on anxiety, induction behaviour and psychological morbidity in children undergoing general anaesthesia (GA) extractions. <b>Method:</b> 179 children aged 5-10 years (mean 6.53 years) participated in this randomised, double blind, placebo controlled trial. Ninety children had Midazolam placed in the buccal pouch. Dental anxiety was recorded pre operatively and 48 hours later using a child reported MCDAS-FIS scale. Behaviour at anaesthetic induction was recorded and psychological morbidity was scored by the parent using the Rutter Scale pre-operatively and again one-week later. Subsequent dental attendance was recorded at one, three and six months after GA. <b>Results:</b> Whilst levels of mental anxiety did not reduce overall, the most anxious patients demonstrated a reduction in anxiety after receiving midazolam premedicationmay (p=0.01). Neither induction behaviour nor psychological morbidity improved. Irrespective of group, parents reported less hyperactive (p= 0.002) and more prosocial behaviour (p=0.002) after the procedure:;, older children improved most (p=0.048), Post GA Dental attendance was poor and unrelated to after the procedure and unaffected by premedication. <b>Conclusion:</b> 0.2mg/kg buccal Midazolam provided some evidence for reducing anxiety in the most dentally anxious patients. However, induction behaviour, psychological morbidity and subsequent dental attendance were not found to alter between the premedication groups

The Effect of Map Boundary on Estimates of Landscape Resistance to Animal Movement

BACKGROUND: Artificial boundaries on a map occur when the map extent does not cover the entire area of study; edges on the map do not exist on the ground. These artificial boundaries might bias the results of animal dispersal models by creating artificial barriers to movement for model organisms where there are no barriers for real organisms. Here, we characterize the effects of artificial boundaries on calculations of landscape resistance to movement using circuit theory. We then propose and test a solution to artificially inflated resistance values whereby we place a buffer around the artificial boundary as a substitute for the true, but unknown, habitat. METHODOLOGY/PRINCIPAL FINDINGS: We randomly assigned landscape resistance values to map cells in the buffer in proportion to their occurrence in the known map area. We used circuit theory to estimate landscape resistance to organism movement and gene flow, and compared the output across several scenarios: a habitat-quality map with artificial boundaries and no buffer, a map with a buffer composed of randomized habitat quality data, and a map with a buffer composed of the true habitat quality data. We tested the sensitivity of the randomized buffer to the possibility that the composition of the real but unknown buffer is biased toward high or low quality. We found that artificial boundaries result in an overestimate of landscape resistance. CONCLUSIONS/SIGNIFICANCE: Artificial map boundaries overestimate resistance values. We recommend the use of a buffer composed of randomized habitat data as a solution to this problem. We found that resistance estimated using the randomized buffer did not differ from estimates using the real data, even when the composition of the real data was varied. Our results may be relevant to those interested in employing Circuitscape software in landscape connectivity and landscape genetics studies

Antiviral resistance during pandemic influenza: implications for stockpiling and drug use

<p>Abstract</p> <p>Background</p> <p>The anticipated extent of antiviral use during an influenza pandemic can have adverse consequences for the development of drug resistance and rationing of limited stockpiles. The strategic use of drugs is therefore a major public health concern in planning for effective pandemic responses.</p> <p>Methods</p> <p>We employed a mathematical model that includes both sensitive and resistant strains of a virus with pandemic potential, and applies antiviral drugs for treatment of clinical infections. Using estimated parameters in the published literature, the model was simulated for various sizes of stockpiles to evaluate the outcome of different antiviral strategies.</p> <p>Results</p> <p>We demonstrated that the emergence of highly transmissible resistant strains has no significant impact on the use of available stockpiles if treatment is maintained at low levels or the reproduction number of the sensitive strain is sufficiently high. However, moderate to high treatment levels can result in a more rapid depletion of stockpiles, leading to run-out, by promoting wide-spread drug resistance. We applied an antiviral strategy that delays the onset of aggressive treatment for a certain amount of time after the onset of the outbreak. Our results show that if high treatment levels are enforced too early during the outbreak, a second wave of infections can potentially occur with a substantially larger magnitude. However, a timely implementation of wide-scale treatment can prevent resistance spread in the population, and minimize the final size of the pandemic.</p> <p>Conclusion</p> <p>Our results reveal that conservative treatment levels during the early stages of the outbreak, followed by a timely increase in the scale of drug-use, will offer an effective strategy to manage drug resistance in the population and avoid run-out. For a 1918-like strain, the findings suggest that pandemic plans should consider stockpiling antiviral drugs to cover at least 20% of the population.</p

Psychological trauma and evidence for enhanced vulnerability for posttraumatic stress disorder through previous trauma among West Nile refugees

BACKGROUND: Political instability and the civil war in Southern Sudan have resulted in numerous atrocities, mass violence, and forced migration for vast parts of the civilian population in the West Nile region. High exposure to traumatic experiences has been particularly prominent in the Ugandan and Sudanese of the West Nile Region, representing an indication of the psychological strain posed by years of armed conflict. METHODS: In this study the impact of traumatic events on the prevalence and severity of posttraumatic stress disorder (PTSD) in a random sample of 3.339 Ugandan nationals, Sudanese nationals, and Sudanese refugees (1.831 households) of the West Nile region is assessed. RESULTS: Results show a positive correlation between the number of traumatic events and the number of endorsed PTSD symptoms. Of the 58 respondents who experienced the greatest number of traumatizing experiences, all reported symptoms which met the DSM-IV criteria for PTSD. CONCLUSIONS: There is a clear dose-effect relationship between traumatic exposure and PTSD in the studied populations with high levels of traumatic events. In this context, it is probable that any individual could develop PTSD regardless of other risk-factors once the trauma load reaches a certain threshold

Between-Population Outbreeding Affects Plant Defence

Between-population crosses may replenish genetic variation of populations, but may also result in outbreeding depression. Apart from direct effects on plant fitness, these outbreeding effects can also alter plant-herbivore interactions by influencing plant tolerance and resistance to herbivory. We investigated effects of experimental within- and between-population outbreeding on herbivore resistance, tolerance and plant fitness using plants from 13 to 19 Lychnis flos-cuculi populations. We found no evidence for outbreeding depression in resistance reflected by the amount of leaf area consumed. However, herbivore performance was greater when fed on plants from between-population compared to within-population crosses. This can reflect outbreeding depression in resistance and/or outbreeding effects on plant quality for the herbivores. The effects of type of cross on the relationship between herbivore damage and plant fitness varied among populations. This demonstrates how between-population outbreeding effects on tolerance range from outbreeding depression to outbreeding benefits among plant populations. Finally, herbivore damage strengthened the observed outbreeding effects on plant fitness in several populations. These results raise novel considerations on the impact of outbreeding on the joint evolution of resistance and tolerance, and on the evolution of multiple defence strategies

Role of Factor VII in Correcting Dilutional Coagulopathy and Reducing Re-operations for Bleeding Following Non-traumatic Major Gastrointestinal and Abdominal Surgery

Objective The objective of this study is to evaluate the effectiveness of rfVIIa in reducing blood product requirements and re-operation for postoperative bleeding after major abdominal surgery. Background Hemorrhage is a significant complication after major gastrointestinal and abdominal surgery. Clinically significant bleeding can lead to shock, transfusion of blood products, and re-operation. Recent reports suggest that activated rfVIIa may be effective in correcting coagulopathy and decreasing the need for re-operation. Methods This study was a retrospective review over a 4-year period of 17 consecutive bleeding postoperative patients who received rfVIIa to control hemorrhage and avoid re-operation. Outcome measures were blood and clotting factor transfusions, deaths, thromboembolic complications, and number of re-operations for bleeding. Results Seventeen patients with postoperative hemorrhage following major abdominal gastrointestinal surgery (nine pancreas, four sarcoma, two gastric, one carcinoid, and one fistula) were treated with rfVIIa. In these 17 patients, rfVIIa was administered for 18 episodes of bleeding (dose 2,400-9,600 mcg, 29.8-100.8 mcg/kg). Transfusion requirement of pRBC and FFP were each significantly less than pre-rfVIIa. Out of the 18 episodes, bleeding was controlled in 17 (94%) without surgery, and only one patient returned to the operating room for hemorrhage. There were no deaths and two thrombotic complications. Coagulopathy was corrected by rfVIIa from 1.37 to 0.96 (p&lt;0.0001). Conclusion Use of rfVIIa in resuscitation for hemorrhage after non-traumatic major abdominal and gastrointestinal surgery can correct dilutional coagulopathy, reducing blood product requirements and need for re-operation

High-Throughput Analysis of Calcium Signalling Kinetics in Astrocytes Stimulated with Different Neurotransmitters

Astrocytes express a wide range of receptors for neurotransmitters and hormones that are coupled to increases in intracellular Ca2+ concentration, enabling them to detect activity in both neuronal and vascular networks. There is increasing evidence that astrocytes are able to discriminate between different Ca2+-linked stimuli, as the efficiency of some Ca2+ dependent processes – notably release of gliotransmitters – depends on the stimulus that initiates the Ca2+ signal. The spatiotemporal complexity of Ca2+ signals is substantial, and we here tested the hypothesis that variation in the kinetics of Ca2+ responses could offer a means of selectively engaging downstream targets, if agonists exhibited a “signature shape” in evoked Ca2+ response. To test this, astrocytes were exposed to three different receptor agonists (ATP, glutamate and histamine) and the resultant Ca2+ signals were analysed for systematic differences in kinetics that depended on the initiating stimulus. We found substantial heterogeneity between cells in the time course of Ca2+ responses, but the variation did not correlate with the type or concentration of the stimulus. Using a simple metric to quantify the extent of difference between populations, it was found that the variation between agonists was insufficient to allow signal discrimination. We conclude that the time course of global intracellular Ca2+ signals does not offer the cells a means for distinguishing between different neurotransmitters

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Elevated c-Src is linked to altered cell–matrix adhesion rather than proliferation in KM12C human colorectal cancer cells

Elevated expression and/or activity of c-Src, the prototype of the Src family of protein tyrosine kinases, is associated with the development of human colon cancer. However, despite the known pleiotropic effects of these kinases in promoting (a) cell growth downstream of growth factor receptors, and (b) the dynamic regulation of integrin adhesions in fibroblast model systems, their precise role in epithelial cancer cells is unknown. Here we addressed whether elevated expression and activity of cellular Src alters cell proliferation and/or cell–matrix adhesion in cancer cells from the Fidler model of colorectal metastasis. Although elevated Src correlates with ability to metastasise to the liver after intrasplenic injection, we found that this was not linked to enhanced growth, either in vitro or in vivo as sub-cutaneous tumours. However, elevated Src was associated with enhanced attachment to extracellular matrix. In addition, adhesion to fibronectin, was suppressed by agents that inhibited Src activity, while enforced elevation of Src in non-metastatic cells was sufficient to stimulate adhesion to fibronectin and enhanced assembly of adhesion complexes, without influencing cell growth. Thus, we conclude that one role of elevated Src in human colon cancer cells is to modulate integrin-dependent cell–matrix attachment and formation of adhesion structures, which may, in turn, influence cell motility and integrin-dependent cellular responses