Detection of Resistance Mutations to Antivirals Oseltamivir and Zanamivir in Avian Influenza A Viruses Isolated from Wild Birds

The neuraminidase (NA) inhibitors oseltamivir and zanamivir are the first-line of defense against potentially fatal variants of influenza A pandemic strains. However, if resistant virus strains start to arise easily or at a high frequency, a new anti-influenza strategy will be necessary. This study aimed to investigate if and to what extent NA inhibitor–resistant mutants exist in the wild population of influenza A viruses that inhabit wild birds. NA sequences of all NA subtypes available from 5490 avian, 379 swine and 122 environmental isolates were extracted from NCBI databases. In addition, a dataset containing 230 virus isolates from mallard collected at Ottenby Bird Observatory (Öland, Sweden) was analyzed. Isolated NA RNA fragments from Ottenby were transformed to cDNA by RT-PCR, which was followed by sequencing. The analysis of genotypic profiles for NAs from both data sets in regard to antiviral resistance mutations was performed using bioinformatics tools. All 6221 sequences were scanned for oseltamivir- (I117V, E119V, D198N, I222V, H274Y, R292K, N294S and I314V) and zanamivir-related mutations (V116A, R118K, E119G/A/D, Q136K, D151E, R152K, R224K, E276D, R292K and R371K). Of the sequences from the avian NCBI dataset, 132 (2.4%) carried at least one, or in two cases even two and three, NA inhibitor resistance mutations. Swine and environmental isolates from the same data set had 18 (4.75%) and one (0.82%) mutant, respectively, with at least one mutation. The Ottenby sequences carried at least one mutation in 15 cases (6.52%). Therefore, resistant strains were more frequently found in Ottenby samples than in NCBI data sets. However, it is still uncertain if these mutations are the result of natural variations in the viruses or if they are induced by the selective pressure of xenobiotics (e.g., oseltamivir, zanamivir)

Multinationality and performance literature: a critical review and future research agenda

The literature on the relationship between the degree of multinationality (M) and performance (P) in the context of multinational enterprises (MNEs) has attracted a large volume of research in the past 50 years. Yet, the theoretical foundations and the empirical conclusions concerning the nature of M–P relationship vary greatly, thus call for a critical review and assessment. We examine 135 articles in 39 leading scholarly journals and classic books published during the period 1960–2015. We use an inductive approach and a qualitative content analysis methodology for our comprehensive and critical review of the literature. We incorporate international business, finance, and accounting perspectives in our analysis. We review the conceptualization and measurement of M, P, the findings on M–P relationships, methodologies, and geographic focus. We identify six key inconsistencies in the existing research, which cause ambiguity in the relevant findings. We make eight recommendations for future research to address these inconsistencies. Thus, our study contributes to the central debate in this research field

Evaluation of geomorphic expressions of bedrock Channels in the Western Ghats of southern Kerala, India, through quantitative analysis

Geomorphic expressions embedded within the bedrock channels, originating from the southernmost part of the Western Ghats, India, are quantitatively characterized through well-defined geomorphic indices using digital elevation models (DEM) and geographical information system (GIS) tools. Drainage basin asymmetry (Af), transverse topographic symmetry factor (T), longitudinal profile, stream length gradient index (SL), hypsometric integral and curve (Ihyp), spatial parameters like drainage density (Dd) and dissection index (DI) are used for extraction of information related to the characteristic pattern and behaviour associated with the Karamana river and its two major tributaries. The independent and cumulative analysis of each geomorphic indices indicates adjustment of Karamana river in response to the tectonic activities. Karamana basin, while showing symmetric character as a single unit, exhibits segments of asymmetric nature associated with the terrain tilting and is evidenced from the variable directional oscillation from E, SSE, S, NW and W. Varying characteristics of the longitudinal profiles and abrupt change in the SL index suggest knick points and uplift of the terrain due to tectonic processes. The influence of tectonic process over the stream characteristics is confirmed by identifying higher levels of SL anomalies in unique lithology. The inferences correlate with the low drainage density and high dissection index zones in the region with varying influence of tectonic processes. Though, the Karamana river basin as a single unit shows old age characteristics in the hypsometric analysis and symmetric nature, the longitudinal profile-assisted SL and SL anomaly indices are found to be capable of revealing evidences of differential effects of tectonic activities over the stream characteristics. The deductions are in agreement with field observations on landforms and channel attributes

The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza : a systematic review of systematic reviews

Controversy has arisen regarding the effectiveness of neuraminidase inhibitors (NIs), especially against influenza-related complications. A literature search was performed to critically assess the evidence collected by the available systematic reviews (SRs) regarding the benefits and disadvantages of NIs (oseltamivir, zanamivir) compared to placebos in healthy and at-risk individuals of all ages for prophylaxis and treatment of seasonal influenza. A SR was done using the Cochrane Database of Systematic Reviews, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects, and Medline (January 2006-July 2012). Two reviewers selected SRs based on randomized clinical trials, which were restricted to intention-to-treat results, and they assessed review (AMSTAR) and study quality indicators (GRADE). The SRs included (N = 9) were of high quality. The efficacy of NIs in prophylaxis ranged from 64% (16-85) to 92% (37-99); the absolute risk reduction ranged from 1.2% to 12.1% (GRADE moderate to low). Clinically relevant treatment benefits of NIs were small in healthy adults and children suffering from influenza-like illness (GRADE high to moderate). Oseltamivir reduced antibiotic usage in healthy adults according to one SR, but this was not confirmed by other reviews (GRADE low). Zanamivir showed a preventive effect on antibiotic usage in children (95% (77-99);GRADE moderate) and on the occurrence of bronchitis in at-risk individuals (59% (30-76);GRADE moderate). No evidence was available on the treatment benefits of NIs in elderly and at-risk groups and their effects on hospitalization and mortality. In oseltamivir trials, nausea, vomiting and diarrhea were significant side-effects. For zanamivir trials, no adverse effects have been reported. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of oseltamivir or zanamivir for the prophylaxis and treatment of healthy individuals. No relevant benefits of these NIs on complications in at-risk individuals have been established