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pathogenicity and transmissibility of current h3n2 swine influenza virus in southern china: a zoonotic potential.swine are considered as 'mixing vessels' of influenza a viruses and play an important role in the generation of novel influenza pandemics. in this study, we described that the h3n2 swine influenza (swh3n2) viruses currently circulating in pigs in guangdong province carried six internal genes from 2009 pandemic h1n1 virus (pmd09), and their antigenicity was obviously different from that of current human h3n2 influenza viruses or recommended vaccine strains (a/guangdong/1194/2019, a/hong kong/4801 ...202134132051
study of the host specificity of pb1-f2-associated virulence.influenza a viruses cause important diseases in both human and animal. the pb1-f2 protein is a virulence factor expressed by some influenza viruses. its deleterious action for the infected host is mostly described in mammals, while the available information is scarce in avian hosts. in this work, we compared the effects of pb1-f2 in avian and mammalian hosts by taking advantage of the zoonotic capabilities of an avian h7n1 virus. in vitro, the h7n1 virus did not behave differently when pb1-f2 wa ...202134125653
rapid differential detection of subtype h1 and h3 swine influenza viruses using a taqman-mgb-based duplex one-step real-time rt-pcr assay.swine influenza is an economically important respiratory disease in swine, but it also constantly poses a threat to human health. therefore, developing rapid, sensitive, and efficient detection methods for swine influenza virus (siv) is important. by aligning the haemagglutinin (ha) gene sequences of sivs circulating in china over a 10-year period, an h1 primer-probe set targeting both eurasian avian-like h1n1 (ea h1n1) and pandemic 2009 h1n1 ((h1n1)pdm09) lineages plus a h3 primer-probe set tar ...202134091783
diversity and reassortment rate of influenza a viruses in wild ducks and gulls.influenza a viruses (iavs) evolve via point mutations and reassortment of viral gene segments. the patterns of reassortment in different host species differ considerably. we investigated the genetic diversity of iavs in wild ducks and compared it with the viral diversity in gulls. the complete genomes of 38 iavs of h1n1, h1n2, h3n1, h3n2, h3n6, h3n8, h4n6, h5n3, h6n2, h11n6, and h11n9 subtypes isolated from wild mallard ducks and gulls resting in a city pond in moscow, russia were sequenced. the ...202134072256
exposure of wild boar to influenza a viruses in bavaria: analysis of seroprevalences and antibody subtype specificity before and after the panzootic of highly pathogenic avian influenza viruses a (h5n8).swine influenza a viruses (s-iav) circulate in wild boar populations worldwide. subtypes primarily reflect those actually present within the respective pig industry. accordingly, infections with swine h1n1, h1n2 and h3n2 have been reported for several regions of germany. as pigs are susceptible not only to s-iav but also to avian and human influenza a viruses, it is necessary to consider the possibility that new reassortant viruses with pandemic potential may arise in these new hosts. therefore, ...202133987931
comparison of n-linked glycosylation on hemagglutinins derived from chicken embryos and mdck cells: a case of the production of a trivalent seasonal influenza vaccine.n-linked glycosylation plays critical roles in folding, receptor binding, and immunomodulating of hemagglutinin (ha), the main antigen in influenza vaccines. chicken embryos are the predominant production host for influenza vaccines, but madin-darby canine kidney (mdck) cells have emerged as an important alternative host. in this study, we compared glycosylation patterns, including the occupancy of potential glycosylation sites and the distribution of different glycans, on the has of three strai ...202133937925
molecular characteristics, antigenicity, pathogenicity, and zoonotic potential of a h3n2 canine influenza virus currently circulating in south china.canine influenza viruses (civs) could be a source of influenza viruses which infect humans because canine are important companion pets. to assess the potential risk of h3n2 civs currently circulating in southern china to public health, biological characteristics of a/canine/guangdong/dy1/2019 (cady1/2019) were detected. cady1/2019 bound to both avian-type and human-type receptors. cady1/2019 had a similar ph value for ha protein fusion to human viruses, but its antigenicity was obviously differe ...202133767679
infection and risk factors of human and avian influenza in pigs in south china.the coinfection of swine influenza (si) strains and avian/human-source influenza strains in piggeries can contribute to the evolution of new influenza viruses with pandemic potential. this study analyzed surveillance data on si in south china and explored the spatial predictor variables associated with different influenza infection scenarios in counties within the study area. blood samples were collected from 7670 pigs from 534 pig farms from 2015 to 2017 and tested for evidence of infection wit ...202133744674
a quantitative approach to assess influenza a virus fitness and transmission in guinea pigs.efforts to estimate the risk posed by potentially pandemic influenza a viruses (iav), and to understand the mechanisms governing interspecies transmission, have been hampered by a lack of animal models that yield relevant and statistically robust measures of viral fitness. to address this gap, we monitored several quantitative measures of fitness in a guinea pig model: infectivity, magnitude of replication, kinetics of replication, efficiency of transmission, and kinetics of transmission. with t ...202133731462
caco-2 cells: a continuous cell line with sensitive and broad-spectrum utility for respiratory virus culture.primary rhesus monkey kidney cells (rhmk) can be used for the detection of respiratory viruses, including influenza and parainfluenza. the human colon adeno-carcinoma cell line, caco-2, has been previously used for the growth of multiple influenza viruses, including seasonal, novel and avian lineages.202133676967
the inactivated vaccine of reassortant h3n2 canine influenza virus based on internal gene cassette from pr8 is safe and effective.canine influenza (ci) is a contagious respiratory disease in dogs, which poses a threat to canine health. a safe, high-yield vaccine seed virus is critical for ci vaccine development. we developed a pr8-based reassortant h3n2 canine influenza virus (rt civ) using the reverse genetic method and evaluated its yield in canine kidney epithelial (mdck) cells, vero cells, and specific pathogen-free (spf) chicken embryos. mice and dogs were infected with rt civ, and the pathogenicity was evaluated. the ...202133524810
molecular identification and phylogenetic characterization of influenza a virus at a wildlife-livestock interface in mexico.influenza a virus (iav) outbreaks constitute a constant threat to public health and pose a remarkable impact on socio-economic systems worldwide. interactions between wild and domestic birds, humans and swine can lead to spillover events. backyard livestock systems in proximity to wetlands represent high-risk areas for viral spread. however, some gaps remain in our knowledge of iav transmission at the wildlife-livestock interface in mexico. hence, the study aimed at molecular identification and ...202033350099
ha1 (hemagglutinin) quantitation for influenza a h1n1 and h3n2 high yield reassortant vaccine candidate seed viruses by rp-uplc.the only effective measure to decrease morbidity and mortality caused by the influenza virus in the human population is worldwide vaccination. vaccination produces neutralizing antibodies that target the ha1 subunit of the ha (hemagglutinin) protein and are strain specific. the effectiveness of new influenza vaccines are linked to two factors, the correct prediction of the circulating strains in the population in a particular season and the concentration of the ha1 protein in the vaccine formula ...202033341306
full-length genome sequences of the first h9n2 avian influenza viruses isolated in the northeast of algeria.h9n2 avian influenza viruses (aiv) has a worldwide geographic distribution and affects poultry of different types of production. h9n2 aiv was first reported in the northeast of algeria in april 2017, following an outbreak associated with high mortality, in broiler flocks. in the present study, we report full-length genome sequences of aiv h9n2, and the detailed phylogeny and molecular genetic analyses.202032680533
antiviral properties of extracts of streptomyces sp. smu 03 isolated from the feces of elephas maximus.actinobacteria are historically and continued to be an important source for drug discovery. the annual epidemics and periodic pandemics of humans induced by influenza a virus (iav) prompted us to develop new effective antiviral drugs with different modes of action. an actinobacterium of streptomyces sp. smu 03 was identified from the feces of elephas maximus in yunnan province, china. by employing an h5n1 pseudo-typed virus drug screening system, the anti-iav effect of the dichloromethane extrac ...202032330578
application of an improved micro-amount of virion enrichment technique (mivet) for the detection of avian influenza a virus in spiked chicken meat samples.highly sensitive detection of pathogens is effective for screening meat during quarantine inspection and export. the "micro-amount of virion enrichment technique" (mivet) was recently developed, which is a new method combining virus concentration with immunomagnetic beads and simple rna extraction with sodium dodecyl benzenesulfonate (sdbs) for the specific and sensitive detection of avian influenza viruses (aivs). aiv subtypes h3n2 and h4n2 were used to spike the surface of chicken breast meat ...202032193766
an r195k mutation in the pa-x protein increases the virulence and transmission of influenza a virus in mammalian hosts.in the 21st century, the emergence of h7n9 and h1n1/2009 influenza viruses, originating from animals and causing severe human infections, has prompted investigations into the genetic alterations required for cross-species transmission. we previously found that replacement of the human-origin pa gene segment in avian influenza virus (aiv) could overcome barriers to cross-species transmission. recently, it was reported that the pa gene segment encodes both the pa protein and a second protein, pa-x ...202032161172
influenza vaccines: the potential benefits of cell-culture isolation and manufacturing.influenza continues to cause severe illness in millions and deaths in hundreds of thousands annually. vaccines are used to prevent influenza outbreaks, however, the influenza virus mutates and annual vaccination is required for optimal protection. vaccine effectiveness is also affected by other potential factors such as the human immune system, a mismatch with the chosen candidate virus, and egg adaptation associated with egg-based vaccine production. this article reviews the influenza vaccine d ...202032128506
comparison of antigenic mutation during egg and cell passage cultivation of h3n2 influenza virus.when influenza viruses are cultured in eggs, amino acid mutations of the hemagglutinin may occur through egg adaptation. on the other hand, when influenza viruses are cultured in animal cells, no antigenic mutation occurs unlike in eggs. therefore, we examined whether the antigenic mutations actually occurred after passage of h3n2 (a/texas/50/2012) virus up to 15 times in eggs and mdck-sky3851 cells.202032095441
an oleanolic acid derivative inhibits hemagglutinin-mediated entry of influenza a virus.influenza a viruses (iav) have been a major public health threat worldwide, and options for antiviral therapy become increasingly limited with the emergence of drug-resisting virus strains. new and effective anti-iav drugs, especially for highly pathogenic influenza, with different modes of action, are urgently needed. the influenza virus glycoprotein hemagglutinin (ha) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potenti ...202032085430
morphological features and pathogenicity of mutated canine influenza viruses from china and south korea.the canine influenza virus (civ) has spread globally from east asia to the united states and mutated and evolved to generate various civs. since 2010, the mutant civs found in china and korea have presented increased virulence in mice, guinea pigs and ferrets, which has raised concerns about public health and outbreak of a severe canine flu. we analysed and compared the morphology, cellular uptake and pathogenicity of civ variants in host animals, to determine their characteristics. the chinese ...202031978278
influenza a virus infections in dromedary camels, nigeria and ethiopia, 2015-2017.we examined nasal swabs and serum samples acquired from dromedary camels in nigeria and ethiopia during 2015-2017 for evidence of influenza virus infection. we detected antibodies against influenza a(h1n1) and a(h3n2) viruses and isolated an influenza a(h1n1)pdm09-like virus from a camel in nigeria. influenza surveillance in dromedary camels is needed.202031855544
serological survey of influenza a virus infection in japanese wild boars (sus scrofa leucomystax).we conducted a serological survey to detect antibodies against influenza a virus (iav) in japanese wild boars in kagoshima prefecture, japan, between 2014 and 2017. seroprevalence against a pandemic-like swine h1n1 (h1n1pdm) virus was identified in 27.1% of specimens, and 1.7% were positive for both swine h1n2 and h3n2 viruses, indicating that wild boars could play an important role in the dynamics of h1n1pdm viral dispersion in the wild. the high frequency of positive results for sera against t ...201931595535
soluble recombinant hemagglutinin protein of h1n1pdm09 influenza virus elicits cross-protection against a lethal h5n1 challenge in mice.currently, influenza vaccines are produced using embryonated chicken eggs. recently, recombinant influenza vaccines have been developed as a potential alternative to egg-grown vaccines. in this study, we evaluated the efficacy of soluble recombinant hemagglutinin (ha) protein produced in human cell culture (expi293f cells) as an influenza vaccine against homosubtypic and heterosubtypic influenza virus challenges in mice. mice were immunized intramuscularly with purified soluble ha protein of h1n ...201931551968
systematic evaluation of suspension mdck cells, adherent mdck cells, and llc-mk2 cells for preparing influenza vaccine seed virus.suspension madin-darby canine kidney (mdck) cells (mdck-n), adherent mdck cells (mdck-c), and adherent rhesus monkey kidney llc-mk2 cells (llc-mk2d) were systematically evaluated for the preparation of influenza vaccine seed viruses for humans on the basis of primary virus isolation efficiency, growth ability, genetic stability of the hemagglutinin (ha) and neuraminidase (na) genes, and antigenic properties in hemagglutination inhibition (hi) test of each virus isolate upon further passages. all ...201931500967
h3n2 avian influenza viruses detected in live poultry markets in china bind to human-type receptors and transmit in guinea pigs and ferrets.the h3n2 influenza viruses became widespread in humans during the 1968 h3n2 pandemic and have been a major cause of influenza epidemics ever since. different lineages of h3n2 influenza viruses are also commonly found in animals. if a different lineage of h3n2 virus jumps to humans, a human influenza pandemic could occur with devastating consequences. here, we studied the genetics, receptor-binding properties, and replication and transmission in mammals of 15 h3n2 avian influenza viruses detected ...201931495283
antigenic pressure on h3n2 influenza virus drift strains imposes constraints on binding to sialylated receptors but not phosphorylated glycans.h3n2 strains of influenza a virus emerged in humans in 1968 and have continued to circulate, evolving in response to human immune pressure. during this process of "antigenic drift," viruses have progressively lost the ability to agglutinate erythrocytes of various species and to replicate efficiently under the established conditions for amplifying clinical isolates and generating vaccine candidates. we have determined the glycome profiles of chicken and guinea pig erythrocytes to gain insights i ...201931484755
incomplete influenza a virus genomes occur frequently but are readily complemented during localized viral spread.segmentation of viral genomes into multiple rnas creates the potential for replication of incomplete viral genomes (ivgs). here we use a single-cell approach to quantify influenza a virus ivgs and examine their fitness implications. we find that each segment of influenza a/panama/2007/99 (h3n2) virus has a 58% probability of being replicated in a cell infected with a single virion. theoretical methods predict that ivgs carry high costs in a well-mixed system, as 3.6 virions are required for repl ...201931387995
characterization of swine-origin h1n1 canine influenza viruses.host switch events of influenza a viruses (iavs) continuously pose a zoonotic threat to humans. in 2013, swine-origin h1n1 iavs emerged in dogs soon after they were detected in swine in the guangxi province of china. this host switch was followed by multiple reassortment events between these h1n1 and previously circulating h3n2 canine iavs (iavs-c) in dogs. to evaluate the phenotype of these newly identified viruses, we characterized three swine-origin h1n1 iavs-c and one reassortant h1n1 iav-c. ...201931287780
attachment patterns of human and avian influenza viruses to trachea and colon of 26 bird species - support for the community concept.avian influenza a viruses (aivs) have a broad host range, but are most intimately associated with waterfowl (anseriformes) and, in the case of the h13 and h16 subtypes, gulls (charadriiformes). host associations are multifactorial, but a key factor is the ability of the virus to bind host cell receptors and thereby initiate infection. the current study aims at investigating the tissue attachment pattern of a panel of aivs, comprising h3n2, h6n1, h12n5, and h16n3, to avian trachea and colon tissu ...201931057520
h5n8 and h7n9 packaging signals constrain ha reassortment with a seasonal h3n2 influenza a virus.influenza a virus (iav) has a segmented genome, which (i) allows for exchange of gene segments in coinfected cells, termed reassortment, and (ii) necessitates a selective packaging mechanism to ensure incorporation of a complete set of segments into virus particles. packaging signals serve as segment identifiers and enable segment-specific packaging. we have previously shown that packaging signals limit reassortment between heterologous iav strains in a segment-dependent manner. here, we evaluat ...201930760600
in silico thermodynamic stability of mammalian adaptation and virulence determinants in polymerase complex proteins of h9n2 virus.the polymerase complex proteins (pb2, pb1, and pa) are responsible primarily for the replication of avian influenza virus and play an important role in virus virulence, mammalian adaptation, and interspecies transmission. in this study; eight egyptian lpai-h9n2 viruses isolated from apparent healthy chickens and quails from 2014 to 2016. characterization of complete nucleotide sequences, phylogenetic and mutation analysis were carried out. the measurement of thermodynamic stability of the h9n2 p ...201830733797
identification of a divergent avian influenza h3n2 virus from domestic ducks in france.an avian influenza h3n2 virus was isolated from domestic ducks in france in 2016. although this french h3n2 virus possesses traits of an avian virus, the genetic distances observed for hemagglutinin (ha) and neuraminidase (na) show that these two genes most likely evolved independently from other avian influenza sequences.201830574576
serological evidence of h3n2 canine influenza virus infection among horses with dog exposure.currently, canine influenza virus (civ) h3n2 is continuously circulating in dog populations in china, korea, and the united states (us). both influenza sa-α-2,3-gal and sa-α-2,6-gal receptors have been observed in the respiratory tracts of both horses and dogs. hence, the increasing number of civ h3n2 cases in the world indicates a potential risk for transspecies transmission to horses with dog exposure. here, a seroepidemiological survey of civ h3n2 infections in horses was conducted using hema ...201930565867
serologic and virologic evidence of influenza a viruses in wild boars ( sus scrofa) from two different locations in italy.swine influenza viruses (sivs) have been repeatedly demonstrated to circulate in wild boar ( sus scrofa) populations, whereas no evidence of exposure to avian influenza viruses (aivs) has been described in wild boar. to better understand how different environments may influence the ecology of influenza a viruses (iavs) in wild suid populations, we examined biologic samples of wild boars from two study areas represented by an upland (ul) and a wetland (wl) in northern and central italy, respectiv ...201930235085
intranasal immunization of guinea pig with trivalent influenza antigen adjuvanted by cyclamen europaeum tubers extract.cyclamen europaeum tubers extract (cte) with concentration commonly used for human rhinosinusitis treatment was tested as mucosal adjuvant in experimental intranasal immunization of guinea pigs with concentrated commercially available influenza trivalent vaccine and subsequent infection with influenza strain a/california/04/2009 h1n1pdm. dual intranasal immunization with vaccine compound consisting of 7.5 µg of each hemagglutinin and 500 µg of cte in 50 µl induced reciprocal gmt on day 21 after ...201930225522
production and application of anti-nucleoprotein igy antibodies for influenza a virus detection in swine.influenza a virus (iav) causes an important respiratory disease in mammals and birds leading to concerns in animal production industry and public health. usually, antibodies produced in mammals are employed in diagnostic tests. however, due to animal welfare concerns, technical advantages and the high cost of production, alternatives to the production of antibodies in mammals have been investigated. the aim of this study was to produce egg yolk immunoglobulin (igy) in laying hens against a highl ...201830158073
the development and study of recombinant immunoglobulin a to hemagglutinins of the influenza virus.we obtained recombinant variants of human antibody fi6 broadly specific to hemagglutinins of the influenza a virus. on the basis of a bi-promoter (cmv, hef1-htlv) vector, we developed genetic constructs for the expression of the heavy and light chains of the immunoglobulins of iga1-, iga2m1-, and igg-isotypes. following transfection and selection, stable chinese hamster ovary (cho) cell lines were produced. the antibodies of iga1-, iga2m1-, and igg-isotypes were purified from culture media. we p ...202030116613
insertion-responsive microneedles for rapid intradermal delivery of canine influenza vaccine.in this study, we present transcutaneous influenza vaccination using a novel tip-separable microneedle system called insertion-responsive microneedles (irmns). irmns are composed of dissolvable hyaluronic acid (ha) tips and biocompatible polycaprolactone (pcl) bases, the tip of which is instantly separated from the base during microneedle insertion and retraction. vaccine antigens derived from canine influenza virus (a/canine/vc378/2012; h3n2) were successfully coated on ha tips by rapidly freez ...201830102940
serosurvey for influenza virus subtypes h3n8 and h3n2 antibodies in free-ranging canids in pennsylvania, usa.canine influenza virus (civ) subtypes h3n8 and h3n2 are endemic among domestic dog ( canis lupus familiaris ) populations in the northeastern us. infection of free-ranging carnivores with influenza virus has been sporadically reported. generalist mesocarnivores that exploit anthropogenic, peri-urban habitats share a wide interface with domestic dogs that allows for the transmission of infectious disease. to investigate the potential exposure of free-ranging canids to civ in pennsylvania, us, ser ...201930096030
serological survey of influenza a viruses in domestic and wild suidae in corsica (france), a mediterranean island environment.corsica is a mountainous french island in the north-western mediterranean sea. it is a rural area, where pig farming is a major economic activity. although no acute respiratory outbreaks due to swine influenza a viruses (swiavs) have ever been reported in this free-ranging pig breeding system, influenza a viruses (iavs) could be circulating within this pig population. a serological study was conducted as a first approach to domestic pigs and wild boars. serum samples from 543 pigs raised on 91 d ...201830086855
infection of novel reassortant h1n2 and h3n2 swine influenza a viruses in the guinea pig model.novel h1n2 and h3n2 swine influenza a viruses (iavs) were identified in commercial farms in chile. these viruses contained h1, h3 and n2 sequences, genetically divergent from iavs described worldwide, associated with pandemic internal genes. guinea pigs were used as human surrogate to evaluate the infection dynamics of these reassortant viruses, compared with a pandemic h1n1 virus. all viruses replicated and were shed in the upper respiratory tract without prior adaptation although h1n2 viruses ...201830053826
anti-influenza a viral butenolide from streptomyces sp. smu03 inhabiting the intestine of elephas maximus.actinobacteria are a phylum of bacteria known for their potential in producing structurally diversified natural products that are always associated with a broad range of biological activities. in this paper, using an h5n1 pseudo-typed virus drug screening system combined with a bioassay guided purification approach, an antiviral butanolide (1) was identified from the culture broth of streptomyces sp. smu03, a bacterium isolated from the feces of elephas maximus in yunnan province, china. this co ...201829976861
comparison of the virulence of three h3n2 canine influenza virus isolates from korea and china in mouse and guinea pig models.avian-origin h3n2 canine influenza virus (civ) has been the most common subtype in korea and china since 2007. here, we compared the pathogenicity and transmissibility of three h3n2 civ strains [chinese civ (js/10), korean civ (kr/07), and korean recombinant civ between the classic h3n2 civ and the pandemic h1n1 virus (mv/12)] in balb/c mouse and guinea pig models. the pandemic h1n1 (ca/09) strain served as the control.201829716608
a lipid/dna adjuvant-inactivated influenza virus vaccine protects rhesus macaques from uncontrolled virus replication after heterosubtypic influenza a virus challenge.influenza a virus (iav) vaccines offer little protection from mismatched viruses with antigenically distant hemagglutinin (ha) glycoproteins. we sought to determine if a cationic lipid/dna complex (cldc) adjuvant could induce heterosubtypic protection if added to a whole inactivated iav vaccine (wiv).201829701840
functional growth inhibition of influenza a and b viruses by liquid and powder components of leaves from the subtropical plant melia azedarach l.we evaluated the anti-influenza-virus effects of melia components and discuss the utility of these components. the effects of leaf components of melia azedarach l. on viruses were examined, and plaque inhibition tests were performed. the in vivo efficacy of m. azedarach l. was tested in a mouse model. leaf components of melia azedarach l. markedly inhibited the growth of various influenza viruses. in an initial screening, multiplication and haemagglutination (ha) activities of h1n1, h3n2, h5, an ...201829633076
ns segment of a 1918 influenza a virus-descendent enhances replication of h1n1pdm09 and virus-induced cellular immune response in mammalian and avian systems.the 2009 pandemic influenza a virus (iav) h1n1 strain (h1n1pdm09) has widely spread and is circulating in humans and swine together with other human and avian iavs. this fact raises the concern that reassortment between h1n1pdm09 and co-circulating viruses might lead to an increase of h1n1pdm09 pathogenicity in different susceptible host species. herein, we explored the potential of different ns segments to enhance the replication dynamics, pathogenicity and host range of h1n1pdm09 strain a/gies ...201829623073
broad-spectrum neutralization of avian influenza viruses by sialylated human milk oligosaccharides: in vivo assessment of 3'-sialyllactose against h9n2 in chickens.two sialylated human milk oligosaccharides (shmos) 3'-sialyllactose (3'-sl) and 6'-sialyllactose (6'-sl) were accessed for their possible antiviral activity against six different subtypes of thirteen avian influenza (ai) viruses in vitro. 3'-sl exhibited promising antiviral activity against almost all subtypes of tested ai viruses in hemagglutination inhibition assay, whereas 6'-sl showed activity against few selected h1n1, h1n2, and h3n2 subtype strains. 3'-sl has minimum inhibitory concentrati ...201829416087
differential responses of innate immunity triggered by different subtypes of influenza a viruses in human and avian hosts.innate immunity provides first line of defense against viral infections. the interactions between hosts and influenza a virus and the response of host innate immunity to viral infection are critical determinants for the pathogenicity or virulence of influenza a viruses. this study was designed to investigate global changes of gene expression and detailed responses of innate immune systems in human and avian hosts during the course of infection with various subtypes of influenza a viruses, using ...201729322931
syrian hamster as an animal model for the study of human influenza virus infection.ferrets and mice are frequently used as animal models for influenza research. however, ferrets are demanding in terms of housing space and handling, whereas mice are not naturally susceptible to infection with human influenza a or b viruses. therefore, prior adaptation of human viruses is required for their use in mice. in addition, there are no mouse-adapted variants of the recent h3n2 viruses, because these viruses do not replicate well in mice. in this study, we investigated the susceptibilit ...201729212926
novel reassortant h3n2 avian influenza virus isolated from domestic ducks in eastern china in 2016.h3 subtype avian influenza virus (aiv) poses a great threat to public health, and so investigating its epidemiology is of great importance. a novel reassortant h3n2 aiv strain was isolated from a live poultry market in eastern china. the strain's genes originated from h1n1, h3, and h7 aivs. thus, the genome information of the h3n2 isolate will help to investigate further the epidemiology of h3 subtype aivs in china.201729192070
a y161f hemagglutinin substitution increases thermostability and improves yields of 2009 h1n1 influenza a virus in cells.vaccination is the primary strategy for influenza prevention and control. however, egg-based vaccines, the predominant production platform, have several disadvantages, including the emergence of viral antigenic variants that can be induced during egg passage. these limitations have prompted the development of cell-based vaccines, which themselves are not without issue. most importantly, vaccine seed viruses often do not grow efficiently in mammalian cell lines. here we aimed to identify novel hi ...201829118117
colocalization of intracellular specific iga (iciga) with influenza virus in patients' nasopharyngeal aspirate cells.inhibition of viral replication by iciga antibodies has only been observed with in vitro studies using epithelial cell lines in transwell cultures. this effect appears to involve an interaction between polymeric immunoglobulin a (piga) and viral particles within an intracellular compartment, since iga is transported across polarized cells. polyclonal guinea pig antisera against purified influenza a virus and mouse antisera prepared against influenza a/h3n2 hemagglutinin (ha0) cleavage loop pepti ...201829102516
infection of ferrets with influenza virus elicits a light chain-biased antibody response against hemagglutinin.the domestic ferret (mustela putorius furo) is a commonly used animal model for the study of influenza virus infection and vaccination. recently, our group has developed murine mabs with specificity for the κ (igκ) and λ (igλ) l chains of ferret ig. these mabs were used to quantify the abundance of igκ and igλ in serum and to evaluate l chain usage of the ab response against the hemagglutinin (ha) protein elicited by influenza infection. after influenza a infection of immunologically naive ferre ...201729079697
cross-reactive influenza-specific antibody-dependent cellular cytotoxicity-mediating antibodies in hiv-infected indian individuals.the influenza-specific antibodies mediating antibody-dependent cellular cytotoxicity (adcc) may be important in protection against influenza. however, it is not known whether immunocompromised individuals such as hiv-infected persons who have never been vaccinated with influenza vaccine have such a response.201728776433
mutation signature in neuraminidase gene of avian influenza h9n2/g1 in egypt.the low pathogenic avian influenza (lpai) h9n2 subtype has become the most prevalent and widespread in many asian and middle eastern countries. it causes an enzootic situation in commercial poultry and known as a potential facilitator virus that can be transmitted to human from birds. the neuraminidase (na) gene plays an important role the release and spread of the virus from infected cells and throughout the bird. the complete nucleotide sequences of the na gene of seven h9n2 viruses collected ...201728770242
molecular epidemiology of a novel re-assorted epidemic strain of equine influenza virus in pakistan in 2015-16.a widespread epidemic of equine influenza (ei) occurred in nonvaccinated equine population across multiple districts in khyber pakhtunkhwa province of pakistan during 2015-2016.201728757141
seasonal h3n2 and 2009 pandemic h1n1 influenza a viruses reassort efficiently but produce attenuated progeny.reassortment of gene segments between coinfecting influenza a viruses (iavs) facilitates viral diversification and has a significant epidemiological impact on seasonal and pandemic influenza. since 1977, human iavs of h1n1 and h3n2 subtypes have cocirculated with relatively few documented cases of reassortment. we evaluated the potential for viruses of the 2009 pandemic h1n1 (ph1n1) and seasonal h3n2 lineages to reassort under experimental conditions. results of heterologous coinfections with ph ...201728637755
[impact of mutations in nucleoprotein on replication of influenza virus a/hong kong/1/68/162/35 reassortants at different temperatures].the nucleoprotein (np) of influenza virus is a multifunctional rna binding protein. the role of np in the adaptation of influenza viruses to a host has been experimentally proved. ambiguous data are available on the role of nucleoprotein in the attenuation of influenza a viruses, which is characterized by ability to replicate at low temperature (26°c) and inability to replicate at high temperature (39°c). influenza virus donor strain a/hong kong/1/68/162/35 (h3n2), adapted to growth at low tempe ...201728537245
antiviral activity of phenanthrenes from the medicinal plant bletilla striata against influenza a virus.influenza represents a serious public health concern. the emergence of resistance to anti-influenza drugs underlines the need to develop new drugs. this study aimed to evaluate the anti-influenza viral activity and possible mechanisms of 12 phenanthrenes from the medicinal plant bletilla striata (orchidaceae family).201728532402
vaccination with killed but metabolically active e. coli over-expressing hemagglutinin elicits neutralizing antibodies to h1n1 swine origin influenza a virus.there is a need for a fast and simple method for vaccine production to keep up with the pace of a rapidly spreading virus in the early phases of the influenza pandemic. the use of whole viruses produced in chicken eggs or recombinant antigens purified from various expression systems has presented considerable challenges, especially with lengthy processing times. here, we use the killed but metabolically active (kbma) escherichia coli (e. coli) to harbor the hemagglutinin (ha) of swine origin inf ...201728492063
immunogenicity and safety of a quadrivalent inactivated influenza virus vaccine compared with a comparator quadrivalent inactivated influenza vaccine in a pediatric population: a phase 3, randomized noninferiority study.seqirus 2010 southern hemisphere split-virion trivalent inactivated influenza vaccine (iiv3) was associated with increased febrile reactions in children. studies in vitro concluded that increasing concentrations of splitting agent decreased residual lipids and attenuated proinflammatory cytokine signals associated with fever. we assessed immunogenicity and safety of a quadrivalent inactivated influenza vaccine (iiv4; produced using higher concentration of splitting agent) versus a united states- ...201728390934
discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors.in search of novel anti-influenza agents with higher potency, a series of acylguanidine oseltamivir carboxylate analogues were synthesized and evaluated against influenza viruses (h1n1 and h3n2) in vitro. the representative compounds with strong inhibitory activities (ic50 <40nm) against neuraminidase (na) were further tested against the na from oseltamivir-resistant strain (h259y). among them, compounds 9 and 17 were potent na inhibitors that exhibited a 5 and 11-fold increase in activity compa ...201728385598
dose sparing and lack of dose response relationship with an influenza vaccine in adult and elderly patients -a randomised, double-blind clinical trial.the currently licensed seasonal trivalent influenza vaccines contain 15 micrograms of hemagglutinin per strain for adult, and up to 60 micrograms for elderly patients. however, due to recent shortages, dose sparing to increase production capacity would be highly desirable. in the present study, we attempted to find a dose-response relationship for immunogenicity and thus, the optimal dose for seasonal influenza vaccines in adult and elderly patients.201728378403
[a prospective study to assess the burden of influenza-related hospitalizations and emergency department visits among children in bilbao, spain (2010-2011)].this study was undertaken to estimate the burden of morbidity associated with laboratory-confirmed influenza in children below 15 years of age.201728363360
characteristics of seasonal influenza a and b in latin america: influenza surveillance data from ten countries.the increased availability of influenza surveillance data in recent years justifies an actual and more complete overview of influenza epidemiology in latin america. we compared the influenza surveillance systems and assessed the epidemiology of influenza a and b, including the spatio-temporal patterns of influenza epidemics, in ten countries and sub-national regions in latin america.201728346498
clinical and serologic responses after a two-dose series of high-dose influenza vaccine in plasma cell disorders: a prospective, single-arm trial.patients with multiple myeloma (mm) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with mm.201728343904
virological surveillance of influenza a subtypes isolated in 2014 from clinical outbreaks in canadian swine.influenza a viruses (iavs) are respiratory pathogens associated with an acute respiratory disease that occurs year-round in swine production. it is currently one of the most important pathogens in swine populations, with the potential to infect other host species including humans. ongoing research indicates that the three major subtypes of iav-h1n1, h1n2, and h3n2-continue to expand in their genetic and antigenic diversity. in this study, we conducted a comprehensive genomic analysis of 16 iavs ...201728335552
molecular characterization and phylogenetic analysis of human influenza a viruses isolated in iran during the 2014-2015 season.influenza a viruses are an important cause of severe infectious diseases in humans and are characterized by their fast evolution rate. global monitoring of these viruses is critical to detect newly emerging variants during annual epidemics. here, we sought to genetically characterize influenza a/h1n1pdm09 and a/h3n2 viruses collected in iran during the 2014-2015 influenza season. a total of 200 nasopharyngeal swabs were collected from patients with influenza-like illnesses. swabs were screened f ...201728331993
neutralizing activities against seasonal influenza viruses in human intravenous immunoglobulin.influenza viruses a/h1n1, a/h3n2, and b are known seasonal viruses that undergo annual mutation. intravenous immunoglobulin (ivig) contains anti-seasonal influenza virus globulins. although the virus-neutralizing (vn) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. in this study, variations in hemagglutination inhibition (hi) and vn titers against seasonal influenza viruses in ivig lots over extended time periods were exam ...201728331286
heterologous packaging signals on ha, but not na or ns, limit influenza a virus reassortment.influenza a virus (iav) rna packaging signals serve to direct the incorporation of iav gene segments into virus particles, and this process is thought to be mediated by segment-segment interactions. these packaging signals are segment- and strain-specific, and as such, they have the potential to impact reassortment outcomes between different iav strains. our study aimed to quantify the impact of packaging signal mismatch on iav reassortment using the human seasonal influenza a/panama/2007/99 (h3 ...201728331085
characterization and mechanisms of anti-influenza virus metabolites isolated from the vietnamese medicinal plant polygonum chinense.polygonum chinense linn. is a common medicinal plant in southeast asia and has been used in traditional medicine in vietnam. the plant contains phytochemicals with various biological properties; however, its antiviral effect has not yet been demonstrated. this study was aimed to evaluate the anti-influenza virus activity of crude extracts of p. chinense, to characterize antiviral metabolites therefrom and to investigate their mechanisms of antiviral action.201728327126
poly-γ-glutamic acid/chitosan nanogel greatly enhances the efficacy and heterosubtypic cross-reactivity of h1n1 pandemic influenza vaccine.in 2009, the global outbreak of an influenza pandemic emphasized the need for an effective vaccine adjuvant. in this study, we examined the efficacy of poly-γ-glutamic acid/chitosan (pc) nanogel as an adjuvant for the influenza vaccine. pc nanogel significantly enhanced antigen-specific cross-presentation and cytotoxic t lymphocyte (ctl) activity. compared with alum, the protective efficacy of the pandemic h1n1 influenza (ph1n1) vaccine was substantially increased by pc nanogel, with increased h ...201728322289
estimates of hospitalization attributable to influenza and rsv in the us during 1997-2009, by age and risk status.estimates of influenza and respiratory syncytial virus (rsv) burden must be periodically updated to inform public health strategies. we estimated seasonal influenza- and rsv-attributable hospitalizations in the us from 1997 to 2009 according to age and risk status (nct01599390).201728320361
cytokines induced during influenza virus infection.influenza a virus is one of the major human pathogens. the influenza infection can pass out without any subclinical symptoms or infestation can appear in upper respiratory tract as well as in lower respiratory tract where it can result in lethal outcome. both innate and adaptive immune responses are activated shortly after infection providing protection against infection. many activities of the cells of innate and adaptive immunity are coordinated by cytokines. however, inordinate or disbalanced ...201728302021
a novel benzo-heterocyclic amine derivative n30 inhibits influenza virus replication by depression of inosine-5'-monophospate dehydrogenase activity.influenza virus is still a huge threat to the world-wide public health. host inosine-5'- monophosphate dehydrogenase (impdh) involved in the synthesis of guanine nucleotides, is known to be a potential target to inhibit the replication of viruses. herein, we evaluated antiviral activity of a benzo-heterocyclic amine derivative n30, which was designed to inhibit impdh.201728298229
in situ self-assembly of gold nanoparticles on hydrophilic and hydrophobic substrates for influenza virus-sensing platform.nanomaterials without chemical linkers or physical interactions that reside on a two-dimensional surface are attractive because of their electronic, optical and catalytic properties. an in situ method has been developed to fabricate gold nanoparticle (au np) films on different substrates, regardless of whether they are hydrophilic or hydrophobic surfaces, including glass, 96-well polystyrene plates, and polydimethylsiloxane (pdms). a mixture of sodium formate (hcoona) and chloroauric acid (haucl ...201728290527
quantitative proteomic approach identifies vpr binding protein as novel host factor supporting influenza a virus infections in human cells.influenza a virus infections are a major cause for respiratory disease in humans, which affects all age groups and contributes substantially to global morbidity and mortality. iav have a large natural host reservoir in avian species. however, many avian iav strains lack adaptation to other hosts and hardly propagate in humans. while seasonal or pandemic influenza a virus (iav) strains replicate efficiently in permissive human cells, many avian iav cause abortive non-productive infections in thes ...201728289176
a broadly reactive human anti-hemagglutinin stem monoclonal antibody that inhibits influenza a virus particle release.many broadly reactive human monoclonal antibodies against the hemagglutinin (ha) stem of influenza a virus have been developed for therapeutic applications. these antibodies typically inhibit viral entry steps, especially the ha conformational change that is required for membrane fusion. to better understand the mechanisms by which such antibodies inhibit viral replication, we established broadly reactive human anti-ha stem antibodies and determined the properties of these antibodies by examinin ...201728286060
pathogenicity and transmission of triple reassortant h3n2 swine influenza a viruses is attenuated following turkey embryo propagation.genetic lineages of swine influenza a viruses (sivs) have recently been established in turkeys in the united states. to identify molecular determinants that are involved in virulence and transmission of sivs to turkeys, we sequentially passaged two triple reassortant h3n2 siv isolates from minnesota in ten day old specific-pathogen free (spf) turkey embryos and tested them in seven-day old turkey poults. we found that siv replication in turkey embryos led to minimal mutations in and around the r ...201728284612
h1n1 influenza viruses varying widely in hemagglutinin stability transmit efficiently from swine to swine and to ferrets.a pandemic-capable influenza virus requires a hemagglutinin (ha) surface glycoprotein that is immunologically unseen by most people and is capable of supporting replication and transmission in humans. ha stabilization has been linked to 2009 ph1n1 pandemic potential in humans and h5n1 airborne transmissibility in the ferret model. swine have served as an intermediate host for zoonotic influenza viruses, yet the evolutionary pressure exerted by this host on ha stability was unknown. for over 70 c ...201728282440
prevention of influenza virus induced bacterial superinfection by standardized echinacea purpurea, via regulation of surface receptor expression in human bronchial epithelial cells.viral infections may predispose the airways to secondary bacterial infections that can lead to unfavorable progression of principally self-limiting illnesses. such complicated respiratory infections include pneumonia, bronchitis, sinusitis, acute otitis media, and sepsis, which cause high morbidity and lethality. some of the pathogenic consequences of viral infections, like the expression of bacterial adhesion receptors and the disturbance of physical barrier integrity due to inflammation, may c ...201728279802
generation of a live attenuated influenza vaccine that elicits broad protection in mice and ferrets.new influenza vaccines that provide effective and broad protection are desperately needed. live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. however, recent formulations of live attenuated influenza vaccines (laivs) have not been protective. we combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate w7-791, a live attenuated mutant virus strain. ...201728279345
serological response to trivalent inactivated influenza vaccine in hiv-infected adults in singapore.a cohort of 81 hiv-infected participants received seasonal trivalent inactivated influenza vaccine (tiv) and their humoral responses were monitored using hemagglutination inhibition (hai) assay and enzyme-linked immunosorbent assay (elisa). three weeks after the vaccination, the percentage of the cohort that had an hai titer of >1:40 was 35% (for h1n1), 43% (for h3n2) and 19% (for influenza b). an increase in hai titer can be achieved by an increase in magnitude of the antibody responses, which ...201728277090
molecular characterization of neuraminidase genes of influenza a(h3n2) viruses circulating in southwest india from 2009 to 2013.molecular characterization of neuraminidase (na) gene of 25 influenza a(h3n2) virus isolates (2009-2013) archived at the manipal centre for virus research was carried out. the annual rate of amino acid substitutions in the n2 gene of influenza a(h3n2) virus isolates was 0.2-0.6%. out of the 25 na sequences analyzed, catalytic site mutations were observed in three isolates. two of the mutations (d151g and e276g) were detected in functional catalytic residues, and an e227v mutation was detected in ...201728271163
phylogenetic relationships of the ha and na genes between vaccine and seasonal influenza a(h3n2) strains in korea.seasonal influenza is caused by two influenza a subtype (h1n1 and h3n2) and two influenza b lineage (victoria and yamagata) viruses. of these antigenically distinct viruses, the h3n2 virus was consistently detected in substantial proportions in korea during the 2010/11-2013/14 seasons when compared to the other viruses and appeared responsible for the influenza-like illness rate peak during the first half of the 2011/12 season. to further scrutinize possible causes for this, we investigated the ...201728257427
[pharmacoepidemiological study of the course of influenza and other acute respiratory viral infections in risk groups].to identify risk factors (rfs) for the development of bacterial complications and the prolonged course of influenza and other acute respiratory viral infections (arvis) among inpatients treated in russian healthcare facilities in the post-pandemic period; to determine the clinical presentation of the disease (flu-like syndrome) in risk-group people and to evaluate the efficacy of antiviral therapy with arbidol (umifenovir).201728252630
mid-season real-time estimates of seasonal influenza vaccine effectiveness in persons 65 years and older in register-based surveillance, stockholm county, sweden, and finland, january 2017.systems for register-based monitoring of vaccine effectiveness (ve) against laboratory-confirmed influenza (lci) in real time were set up in stockholm county, sweden, and finland, before start of the 2016/17 influenza season, using population-based cohort studies. both in stockholm and finland, an early epidemic of influenza a(h3n2) peaked in week 52, 2016. already during weeks 48 to 50, analyses of influenza ve in persons 65 years and above showed moderately good estimates of around 50%, then r ...201728251891
emergence of a novel subclade of influenza a(h3n2) virus in london, december 2016 to january 2017.we report the molecular investigations of a large influenza a(h3n2) outbreak, in a season characterised by sharp increase in influenza admissions since december 2016. analysis of haemagglutinin (ha) sequences demonstrated co-circulation of multiple clades (3c.3a, 3c.2a and 3c.2a1). most variants fell into a novel subclade (proposed as 3c.2a2); they possessed four unique amino acid substitutions in the ha protein and loss of a potential glycosylation site. these changes potentially modify the h3n ...201728251889
triple-reassortant influenza a virus with h3 of human seasonal origin, na of swine origin, and internal a(h1n1) pandemic 2009 genes is established in danish pigs.this report describes a triple-reassortant influenza a virus with a ha that resembles h3 of human seasonal influenza from 2004 to 2005, n2 from influenza a virus already established in swine, and the internal gene cassette from a(h1n1)pdm09 has spread in danish pig herds. the virus has been detected in several danish pig herds during the last 2-3 years and may possess a challenge for human as well as animal health.201728245096
comparison of influenza epidemiological and virological characteristics between outpatients and inpatients in zhejiang province, china, march 2011-june 2015.given the rapid rate of global spread and consequently healthcare costs related to influenza, surveillance plays an important role in monitoring the emerging pandemics in china. however, the characteristics of influenza in southeast of china haven't been fully studied. our study use the surveillance data collected from 16 sentinel hospitals across zhejiang province during march 2011 through june 2015, including the demographic information and respiratory specimens from influenza-like illness (il ...201728241447
nasopharyngeal protein biomarkers of acute respiratory virus infection.infection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. we sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza a/h3n2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. unbiased proteomic discovery analysis identified 3285 peptides corr ...201728238698
viral co-infections among children with confirmed measles at hospitals in hanoi, vietnam, 2014.to characterize viral co-infections among representative hospitalized measles cases during the 2014 hanoi outbreak.201728237484
cryptoporic acid e from cryptoporus volvatus inhibits influenza virus replication in vitro.influenza virus infection is a global public health issue. the efficacy of antiviral agents for influenza virus has been limited by the emergence of drug-resistant virus strains. thus, there is an urgent need to identify novel antiviral therapies. our previous studies have found that cryptoporus volvatus extract can potently inhibit influenza virus replication in vitro and in vivo. however, the effective component of cryptoporus volvatus, which mediates the antiviral activity, hasn't been identi ...201728232246
a case of influenza a (h3n2) complicated by community-acquired pneumonia and death in a young healthy adult during the 2013-2014 season.with multiple available vaccines and antivirals, seasonal influenza a is typically a self-limited acutely debilitating illness in young healthy adults. here, we illustrate unexpected morbidity and mortality in a relatively young and healthy patient seen at a large tertiary care academic medical center for seasonal influenza a (h3n2) complicated by community-acquired pneumonia, hypoxic respiratory failure, septic shock, and death.201728229066
safe recombinant outer membrane vesicles that display m2e elicit heterologous influenza protection.recombinant, escherichia coli-derived outer membrane vesicles (romvs), which display heterologous protein subunits, have potential as a vaccine adjuvant platform. one drawback to romvs is their lipopolysaccharide (lps) content, limiting their translatability to the clinic due to potential adverse effects. here, we explore a unique romv construct with structurally remodeled lipids containing only the lipid iva portion of lps, which does not stimulate human tlr4. the romvs are derived from a genet ...201728215994
novel multiplex assay platforms to detect influenza a hemagglutinin subtype-specific antibody responses for high-throughput and in-field applications.detections of influenza a subtype-specific antibody responses are often complicated by the presence of cross-reactive antibodies. we developed two novel multiplex platforms for antibody detection. the multiplexed magnetic fluorescence microsphere immunoassay (magpix) is a high-throughput laboratory-based assay. chembio dual path platform (dpp) is a portable and rapid test that could be used in the field.201728207986
distinct susceptibility and applicability of mdck derivatives for influenza virus research.madin-darby canine kidney (mdck) cells are widely utilized as a substrate for influenza virus isolation and propagation due to the high yields of virus. here we compared the conventional mdck cell line, mdck-siat1 and mdck-london for viral production, cell survival, and suitability in testing antivirals using six influenza strains including two h1n1 (pandemic and epidemic strains), three h3n2 and one influenza b strain. overall our results suggest that mdck-london cell line is superior for virus ...201728207898
interim estimates of 2016-17 seasonal influenza vaccine effectiveness - united states, february 2017.in the united states, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months (1). each influenza season since 2004-05, cdc has estimated the effectiveness of seasonal influenza vaccine to prevent influenza-associated, medically attended, acute respiratory illness (ari). this report uses data, as of february 4, 2017, from 3,144 children and adults enrolled in the u.s. influenza vaccine effectiveness network (u.s. flu ve network) during november 28, 2016-februa ...201728207689
prospective surveillance of antiviral resistance in hospitalized infants less than 12 months of age with a(h3n2) influenza infection and treated with oseltamivir.infants exhibit elevated influenza virus loads and prolonged viral shedding, which may increase the risk for resistance development, especially in cases of suboptimal exposure to antiviral therapy.201728205506
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