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��ࡱ�>��	_b����\]^������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������	��0��bjbjqq	>ee6�L���������������������87�����Fh_��(   j(�^)l�)8@FBFBFBFBFBFBF$)H��J:fF�*H("j(**fF��  1{F6/6/6/*�� � 2?6/*@F6/6/��8h�9 �����D�y�B���+�J9?�F0�FZ9�K�,�K �9�9K�:**6/*****fFfF6/***�F****��������������������������������������������������������������������K*********�	�:	Dear Sir/Madam
I am so happy that we have this opportunity to submit our article named� Comparison of Real-time RT- PCR assay with direct sequencing for detection of sensitivity or resistant to Oseltamivir in Influenza A/H3N2 viruses �in your journal. This is the first attempt for development of this method in Iran and this article has not published in any other journal. In this research the results obtained with Real-time RT-PCR method had good concordance with the nucleotide sequencing. 
Your consideration greatly appreciated.
I am eagerly looking forward to hearing from you.
Yours faithfully
Dr Talat Mokhtari Azad











Comparison of Real-time RT- PCR assay with direct sequencing for detection of sensitivity or resistant to Oseltamivir in Influenza A/H3N2 viruses
Mohammad Hadi Karbalaie Niya, , Jila Yavarian, Nazanin Zahra Shafiei Jandaghi, Shohreh Shahmahmoodi, Talat Mokhtari Azad*
Address for all authors: School of Public Health, Tehran University of Medical Sciences
Name of the institution work carried out: Virology department, School of Public Health, Tehran University of Medical Sciences
*Corresponding author: Virology department, School of Public Health, Tehran University of Medical Sciences, Telefax: +98(21)88962343 , mokhtari@tums.ac.ir
Running title: Sensitivity or resistant to Oseltamivir in A/H3N2 
Conflict of interest: None






Comparison of Real-time RT- PCR assay with direct sequencing for detection of sensitivity or resistant to Oseltamivir in Influenza A/H3N2 viruses
Abstract:
Background: Currently, there is an increasing risk of a worldwide influenza A virus epidemics not only influencing livestock but also humans, then research about the prophylaxis and treatment of these viruses and detection of drug resistant mutants is a must. Nowadays oseltamivir �the neuraminidase (NA) inhibitor� is the suitable drug for preventing and treatment of these viruses. Drug resistant viruses has already detected by mutations of the enzyme's active site in the neuraminidase gene that cause amino acid substitutions predominantly at positions like 119,274, 292. The objective of this research was the comparison of the Real-time RT-PCR assay with direct sequencing for detection of sensitivity or resistant to Oseltamivir in Influenza A/H3N2 viruses.
Methods: In this study Real-time RT-PCR assay was performed on influenza A/H3N2 NA gene for detection of resistant and sensitive viruses then conventional RT-PCR assay and nucleotide sequencing were performed towards confirmation and evaluation of mutation site sequences.
Results: Of 50 A/H3N2 specimens, all were negative for H274Y mutation by Real-time RT-PCR assay and the results were the same with sequence analysis of the NA gene and also there were no R292K mutation in these samples.
Conclusion: Quick and accurate recognition of drug resistant mutants is necessary for effective treatment strategies. Real-time RT-PCR assay is a rapid monitoring test which could be performed for detection of resistant influenza viruses and the results obtained with this method had good concordance with the nucleotide sequencing.
Keywords: Influenza A/H3N2 virus; Real-time RT-PCR; nucleotide sequencing; oseltamivir resistant


Introduction
	Influenza viruses are RNA viruses in the Orthomyxoviridae family  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1]. Annual influenza viruses morbidity and mortality and their important human pathogenicity are significant concern  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_2" \o "Carr, 2008 #3" 2]. Their prevention and treatment have a significant priority in many countries  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Redlberger-Fritz, 2012 #10" 3]. Influenza virus neuraminidase (NA) and M2 are the goals for antiviral therapy. M2 channel inhibitors and neuraminidase inhibitors (NAI) are two major classes of antivirals that licensed for influenza prevention and treatment  ADDIN EN.CITE <EndNote><Cite><Author>McKimm-Breschkin</Author><Year>2013</Year><RecNum>8</RecNum><DisplayText>(4)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McKimm-Breschkin, J. L.</author></authors></contributors><auth-address>CSIRO Materials Science and Engineering, Parkville, Victoria, Australia. mck245@csiro.au</auth-address><titles><title>Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>25-36</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279894</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279894</url></related-urls></urls><electronic-resource-num>10.1111/irv.12047</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_4" \o "McKimm-Breschkin, 2013 #8" 4]. The First drugs used particularly against influenza A viruses were M2 channel blockers named adamantanes (amantadine and rimantadine)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1, HYPERLINK \l "_ENREF_2" \o "Carr, 2008 #3" 2]. Rapidly the M2 inhibitor resistant mutants were appeared  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_2" \o "Carr, 2008 #3" 2]. The most common resistance mutations of M2 channel pore are V27A and S31N  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1]. Oseltamivir (tamiflu) and Zanamivir (relenza) are NAI drugs that have efficiency and potential to treatment of influenza infections widely  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Redlberger-Fritz, 2012 #10" 3]. Until emergence of Oseltamivir resistant influenza A/H1N1 viruses during 2007/8, the NAI resistant influenza viruses were uncommon  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Chidlow, 2010 #5" 5]. These resistant mutants reported not only in influenza A/H1N1 viruses but also in influenza A/H5N1 subtypes  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Anton, 2010 #1" 6]. H275Y (H274Y in N2) mutation is the most common Oseltamivir resistant mutation where cytosine to thymine substitution occurs in nucleotide 824 of NA gene  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_7" \o "Smith, 2011 #11" 7]. The majority of circulating human influenza A/H3N2 viruses are now resistant, and the absence of appropriate protocol through using drugs help to  dominance of resistant mutants  ADDIN EN.CITE <EndNote><Cite><Author>Zambon</Author><Year>2013</Year><RecNum>12</RecNum><DisplayText>(8)</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zambon, M. C.</author></authors></contributors><auth-address>Microbiology Services Division: Colindale, Health Protection Agency, London, UK. maria.zambon@hpa.org.uk</auth-address><titles><title>Surveillance for antiviral resistance</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>37-43</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279895</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279895</url></related-urls></urls><electronic-resource-num>10.1111/irv.12050</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "Zambon, 2013 #12" 8]. Two other important mutations are E119V and R292K which confer high level of resistance in influenza A/H3N2 viruses  ADDIN EN.CITE <EndNote><Cite><Author>McKimm-Breschkin</Author><Year>2013</Year><RecNum>8</RecNum><DisplayText>(4)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McKimm-Breschkin, J. L.</author></authors></contributors><auth-address>CSIRO Materials Science and Engineering, Parkville, Victoria, Australia. mck245@csiro.au</auth-address><titles><title>Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>25-36</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279894</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279894</url></related-urls></urls><electronic-resource-num>10.1111/irv.12047</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_4" \o "McKimm-Breschkin, 2013 #8" 4]. Nowadays, phenotypic methods are gold standard for monitoring of antiviral resistance  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_9" \o "Bolotin, 2009 #2" 9]. Although, Sanger dideoxy sequencing analysis of NA gene also can be performed to detect mutations such as H274Y, R292K (that are highly associated with Oseltamivir resistant) and other drug resistance mutations. Both phenotypic and sequencing methods are labor intensive, time-consuming, expensive and require specialized equipment [9,10]. Therefore, the need for a quick, high throughput and short turn-around time method in order to expedite detection of NAI resistance makes sense. In this study we validate a Real-time RT-PCR assay for detection of histidine to tyrosine mutation at residue 274 of NA gene of Influenza A/H3N2 viruses and comparison the results with nucleotide sequencing and explore R292K mutation in NA gene. 
Materials and methods
In this study 50 influenza A/H3N2 positive samples, collected during 2012 in Iran were included. RNA was extracted by using High Pure Viral Nucleic Acid kit (Roche) according to the manufacturer's instructions. 
For detection of the H274Y mutation, Real-time RT-PCR assay was performed for influenza A/H3N2 NA gene then conventional RT-PCR assay and nucleotide sequencing were performed towards confirmation and evaluation of mutation site sequences. 
Primers and probes design: 
To design the H274Y Real-time RT-PCR assay, reference sequences were aligned by Clustal W program. Primers and probes were designed manually using the consensus sequences and evaluated by Bioedit version 7.1.3.0 (2011) and OLIGO5 in order to check the Tm and secondary structures. The sequence of primers and probes for H274Y assay are listed in table I. 
Laboratory procedures
Real-time RT-PCR was performed using 5 �l of RNA mixing with 12.5 �l of 2x Master Mix (Qiagen Quantitect Probe RT-PCR kit), 0.25 �l RT Mix, 2 �l of each forward and reverse primers, 1 �l of each sensitive and resistant probes and 1.25 �l of water. Real-time RT-PCR was carried out on the Rotorgene 6000 5-plex HRM termocycler using 1 cycle of 50�C for 30 min, 1 cycle of 95�C for 15 min, and 45 cycle of 94�C for 15 s, 59�C for 60 s, and 60�C for 60 s.  
To perform nucleotide sequencing, reverse transcription and amplification of the NA gene was performed using the One Step RT-PCR kit (Qiagen). 5 �l RNA was mixed with 10 �l of 5x One Step RT-PCR buffer, 2 �l of dNTP Mix (10mM each), 2 �l One Step RT-PCR Enzyme Mix, 2.5 �l of each forward and reverse primers at a final concentration of 25pM and 26 �l of RNase free water. Reverse transcription and amplification was performed by PeqLab termocycler at following conditions: 1 cycle at 60�C for 1 min, 1 cycle at 50�C for 30 min and 1 cycle at 95�C for 15 min, followed by 40 cycles of amplification at 94�C for 30s, 57�C for 30s and 72�C for 1 min, and a final extension cycle of 72�C for 10 min. Visualization on an Agarose gel was performed for PCR products. After validation of pure PCR products, they were sent for nucleotide sequencing. 
Nucleotide sequencing was performed using the ABI automated sequencer and the results were analyzed using Bioedit version 7.1.3.0 (2011) software. Consequently, the results of two assays were compared to show the sensitivity and specificity of these techniques.  
Results:
H274Y Real-time RT-PCR assay was performed on 50 samples collected in 2012. This group included hospitalized and non-hospitalized patients. All of 50 patient samples were positive for influenza A/H3N2 viruses (Ct>20) based on qReal-time RT-PCR.
The results were obtained by using two TaqMan probes labeled with FAM and Cy3 fluorescent reporters for wild type (H274) and mutant (Y274) detection, respectively. A sample containing the wild type strain will emit the fluorescent signal exclusively via the FAM channel (530nm) whereas a sample containing the Oseltamivir resistant variant with a nucleotide alteration at position 824 of the NA gene will emit the fluorescent via the Cy3 channel (570nm). Emitted signals are specific for both wild types and mutants.
Of the 50 samples, all were negative for the H274Y mutation by Real-time RT-PCR assay, then sequence analysis of the NA gene amplified from these samples confirmed the results of the Real-time RT-PCR assay. Besides that in analyzing the sequences there were no R292K mutation in these samples. Table II summarized the data for all of these patients.
Finally, we found that both nucleotide sequencing method and Real-time RT-PCR assay had the same efficiency for recognizing mutants from others and we haven�t any resistant viruses in this study.
Discussion:
The rapid evolution of the influenza virus genome indicates the needs for flexible diagnostic methods for monitoring and drug resistance mutations  ADDIN EN.CITE <EndNote><Cite><Author>Okomo-Adhiambo</Author><Year>2013</Year><RecNum>9</RecNum><DisplayText>(11)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okomo-Adhiambo, M.</author><author>Sheu, T. G.</author><author>Gubareva, L. V.</author></authors></contributors><auth-address>Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.</auth-address><titles><title>Assays for monitoring susceptibility of influenza viruses to neuraminidase inhibitors</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>44-9</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279896</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279896</url></related-urls></urls><electronic-resource-num>10.1111/irv.12051</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_11" \o "Okomo-Adhiambo, 2013 #9" 11]. Nowadays, NAI are the most effective drugs against influenza viruses. Recent reports of NAI resistance are a cause for concern  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1]. Drug resistant viruses have already detected by mutations of the enzyme's active site in the NA gene that cause amino acid substitutions predominantly at positions like 119, 274, 292  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1]. H274Y mutation because of a single nucleotide alteration at position 824 of NA gene causes virus resistant mutants to Oseltamivir  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1]. Hence, for the treatment the patients should be monitored for the nucleotide alterations of NA. If the mutation detected, alternative treatment will utilize, for instance, Zanamivir might survive the life of the patient  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Chutinimitkul, 2007 #6" 1].
Genotyping methods and immunological tests are mainly the existing methods for influenza surveillance  ADDIN EN.CITE <EndNote><Cite><Author>Cheng</Author><Year>2013</Year><RecNum>4</RecNum><DisplayText>(12)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cheng, T. J.</author><author>Wang, S. Y.</author><author>Wen, W. H.</author><author>Su, C. Y.</author><author>Lin, M.</author><author>Huang, W. I.</author><author>Liu, M. T.</author><author>Wu, H. S.</author><author>Wang, N. S.</author><author>Cheng, C. K.</author><author>Chen, C. L.</author><author>Ren, C. T.</author><author>Wu, C. Y.</author><author>Fang, J. M.</author><author>Cheng, Y. S.</author><author>Wong, C. H.</author></authors></contributors><auth-address>The Genomics Research Center, Academia Sinica, Taipei, Taiwan.</auth-address><titles><title>Chemical probes for drug-resistance assessment by binding competition (RABC): oseltamivir susceptibility evaluation</title><secondary-title>Angew Chem Int Ed Engl</secondary-title><alt-title>Angewandte Chemie</alt-title></titles><periodical><full-title>Angew Chem Int Ed Engl</full-title><abbr-1>Angewandte Chemie</abbr-1></periodical><alt-periodical><full-title>Angew Chem Int Ed Engl</full-title><abbr-1>Angewandte Chemie</abbr-1></alt-periodical><pages>366-70</pages><volume>52</volume><number>1</number><dates><year>2013</year><pub-dates><date>Jan 2</date></pub-dates></dates><isbn>1521-3773 (Electronic)&#xD;1433-7851 (Linking)</isbn><accession-num>23150231</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23150231</url></related-urls></urls><electronic-resource-num>10.1002/anie.201204062</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_12" \o "Cheng, 2013 #4" 12]. The immunological assays are quick but confined by antibody specificities  ADDIN EN.CITE <EndNote><Cite><Author>Cheng</Author><Year>2013</Year><RecNum>4</RecNum><DisplayText>(12)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cheng, T. J.</author><author>Wang, S. Y.</author><author>Wen, W. H.</author><author>Su, C. Y.</author><author>Lin, M.</author><author>Huang, W. I.</author><author>Liu, M. T.</author><author>Wu, H. S.</author><author>Wang, N. S.</author><author>Cheng, C. K.</author><author>Chen, C. L.</author><author>Ren, C. T.</author><author>Wu, C. Y.</author><author>Fang, J. M.</author><author>Cheng, Y. S.</author><author>Wong, C. H.</author></authors></contributors><auth-address>The Genomics Research Center, Academia Sinica, Taipei, Taiwan.</auth-address><titles><title>Chemical probes for drug-resistance assessment by binding competition (RABC): oseltamivir susceptibility evaluation</title><secondary-title>Angew Chem Int Ed Engl</secondary-title><alt-title>Angewandte Chemie</alt-title></titles><periodical><full-title>Angew Chem Int Ed Engl</full-title><abbr-1>Angewandte Chemie</abbr-1></periodical><alt-periodical><full-title>Angew Chem Int Ed Engl</full-title><abbr-1>Angewandte Chemie</abbr-1></alt-periodical><pages>366-70</pages><volume>52</volume><number>1</number><dates><year>2013</year><pub-dates><date>Jan 2</date></pub-dates></dates><isbn>1521-3773 (Electronic)&#xD;1433-7851 (Linking)</isbn><accession-num>23150231</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23150231</url></related-urls></urls><electronic-resource-num>10.1002/anie.201204062</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_12" \o "Cheng, 2013 #4" 12]. The most common genotyping methods for detecting NAI resistant mutations are RT-PCR, Sanger sequencing and Pyrosequencing  ADDIN EN.CITE <EndNote><Cite><Author>Okomo-Adhiambo</Author><Year>2013</Year><RecNum>9</RecNum><DisplayText>(11)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okomo-Adhiambo, M.</author><author>Sheu, T. G.</author><author>Gubareva, L. V.</author></authors></contributors><auth-address>Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.</auth-address><titles><title>Assays for monitoring susceptibility of influenza viruses to neuraminidase inhibitors</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>44-9</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279896</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279896</url></related-urls></urls><electronic-resource-num>10.1111/irv.12051</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_11" \o "Okomo-Adhiambo, 2013 #9" 11]. Whole genome sequencing is precise and instructive widely for identification of the virus genome changes, but is time-consuming, labor intensive, expensive and may determine components of mixed populations of viruses indiscriminately  ADDIN EN.CITE <EndNote><Cite><Author>Okomo-Adhiambo</Author><Year>2013</Year><RecNum>9</RecNum><DisplayText>(11)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okomo-Adhiambo, M.</author><author>Sheu, T. G.</author><author>Gubareva, L. V.</author></authors></contributors><auth-address>Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.</auth-address><titles><title>Assays for monitoring susceptibility of influenza viruses to neuraminidase inhibitors</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>44-9</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279896</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279896</url></related-urls></urls><electronic-resource-num>10.1111/irv.12051</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_11" \o "Okomo-Adhiambo, 2013 #9" 11]. Although, currently the choice method for detection of changes that creates resistant mutants is Sanger sequencing  ADDIN EN.CITE <EndNote><Cite><Author>Okomo-Adhiambo</Author><Year>2013</Year><RecNum>9</RecNum><DisplayText>(11)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okomo-Adhiambo, M.</author><author>Sheu, T. G.</author><author>Gubareva, L. V.</author></authors></contributors><auth-address>Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.</auth-address><titles><title>Assays for monitoring susceptibility of influenza viruses to neuraminidase inhibitors</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>44-9</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279896</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279896</url></related-urls></urls><electronic-resource-num>10.1111/irv.12051</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_11" \o "Okomo-Adhiambo, 2013 #9" 11].
In this study a total of 50 influenza A/H3N2 specimens were included. Real-time RT-PCR assay was performed for influenza A/H3N2 NA gene for detection of resistant (Y274) and sensitive (H274) viruses then conventional RT-PCR assay and nucleotide sequencing were performed towards confirmation and evaluation of mutation site sequences which the results showed no differences in these methods and there were no resistant mutant viruses in this study.
As reviewed in an article by Smith and colleagues in 2011, the rate of drug induced resistance was 2.9% (1/34) for A/H3N2 and more than 95% of influenza A/H3N2 virus infections in Europe were Oseltamivir sensitive  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_7" \o "Smith, 2011 #11" 7]. Phenotypic and genotypic screening in more than 2000 samples in Japan from 2004 to 2007 indicated that the rate of Oseltamivir resistance was <1% in order to the extensive drug use  ADDIN EN.CITE <EndNote><Cite><Author>Zambon</Author><Year>2013</Year><RecNum>12</RecNum><DisplayText>(8)</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zambon, M. C.</author></authors></contributors><auth-address>Microbiology Services Division: Colindale, Health Protection Agency, London, UK. maria.zambon@hpa.org.uk</auth-address><titles><title>Surveillance for antiviral resistance</title><secondary-title>Influenza Other Respi Viruses</secondary-title><alt-title>Influenza and other respiratory viruses</alt-title></titles><periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></periodical><alt-periodical><full-title>Influenza Other Respi Viruses</full-title><abbr-1>Influenza and other respiratory viruses</abbr-1></alt-periodical><pages>37-43</pages><volume>7 Suppl 1</volume><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1750-2659 (Electronic)&#xD;1750-2640 (Linking)</isbn><accession-num>23279895</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23279895</url></related-urls></urls><electronic-resource-num>10.1111/irv.12050</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "Zambon, 2013 #12" 8] in comparison with our study which there were not any resistant mutants.
In conclusion, quick and accurate recognition of drug resistant mutants is applicable for effective treatment strategies. The results obtained with Real-time RT-PCR method had good concordance with the nucleotide sequencing. Although Real-time RT-PCR method may not  be able to detect new mutations or is not as sensitive as phenotyping method but  in laboratories that are only equipped with Real-time PCR machine, this technique would be useful in detection of sensitivity or resistance to Oseltamivir or other influenza antivirals.
Thus, we suggest the use of Real-time RT-PCR assay as rapid and highly practical monitoring test which could be performed for detection of point mutations. 
Conflict of interest: None
Acknowledgments: We would like to thank entire staff of National Influenza Center, Virology department, School of Public Health, Tehran University of Medical Sciences. This study was financially supported by Tehran University of Medical Sciences.

References:
 ADDIN EN.REFLIST 1.	Chutinimitkul S, Suwannakarn K, Chieochansin T, Mai le Q, Damrongwatanapokin S, Chaisingh A, et al. H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes. J Virol Methods 2007;139:44-9.
2.	Carr MJ, Sayre N, Duffy M, Connell J, Hall WW. Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses. J Virol Methods 2008;153:257-62.
3.	Redlberger-Fritz M, Aberle SW, Strassl R, Popow-Kraupp T. Rapid identification of neuraminidase inhibitor resistance mutations in seasonal influenza virus A(H1N1), A(H1N1)2009, and A(H3N2) subtypes by melting point analysis. Eur J Clin Microbiol Infect Dis 2012;31:1593-601.
4.	McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respi Viruses 2013;7:25-36.
5.	Chidlow GR, Harnett GB, Williams SH, Tempone SS, Speers DJ, et al. The detection of oseltamivir-resistant pandemic influenza A/H1N1 2009 viruses using a real-time RT-PCR assay. J Virol Methods 2010;169:47-51.
6.	Anton A, Lopez-Iglesias AA, Tortola T, Ruiz-Camps I, Abrisqueta P, et al. Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors. Diagn Microbiol Infect Dis 2010;68:214-9.
7.	Smith JR, Rayner CR, Donner B, Wollenhaupt M, Klumpp K, Dutkowski R. Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience. Adv Ther 2011;28:927-59.
8.	Zambon MC. Surveillance for antiviral resistance. Influenza Other Respi Viruses 2013;7:37-43.
9.	Bolotin S, Robertson AV, Eshaghi A, De Lima C, Lombos E, et al. Development of a novel real-time reverse-transcriptase PCR method for the detection of H275Y positive influenza A H1N1 isolates. J Virol Methods 2009;158:190-4.
10.	Hindiyeh M, Ram D, Mandelboim M, Meningher T, Hirsh S, et al. Rapid detection of influenza A pandemic (H1N1) 2009 virus neuraminidase resistance mutation H275Y by real-time reverse transcriptase PCR. J Clin Microbiol 2010;48:1884-7.
11.	Okomo-Adhiambo M, Sheu TG, Gubareva LV. Assays for monitoring susceptibility of influenza viruses to neuraminidase inhibitors. Influenza Other Respi Viruses 2013;7:44-9.
12.	Cheng TJ, Wang SY, Wen WH, Su CY, Lin M, et al. Chemical probes for drug-resistance assessment by binding competition (RABC): oseltamivir susceptibility evaluation. Angew Chem Int Ed Engl 2013;52:366-70.


Table I- Sequence of primers and probes for H274Y assay.
Name5�                3'1Forward Primer(H3F678)                                                                                5'-GGA GTC AGA ATG CGT TTG TAT C-3'2Reverse Primer(H3R876)                                                                          5'-GAG CCT TTC CAG TTG TCT CTG-3'3Sensitive Probe                  FAM-AAAATCGTTCATACTAGCACATTGTCAGGAA-BHQ14Resistant Probe                 Cy3-AAAATCGTTCATACTAGCATATTGTCAGGAA-BHQ2

Table II- Results of the detection of H274Y mutation by nucleotide sequencing and Real-time RT-PCR assay.
No.Sample typeH274Y274InterpretationNucleotide 82450  A/H3N2 samplesThroat swabPositiveNegativeWild typeC









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la�yt\%6�8�9�;�<�>�?�A�B�^�_�`�a�b�c�����������������������������$dh�d�d[$\$a$gd�CO$a$d��`�b�c�d�{�|�}�~������������������h']:h\%CJOJQJaJh�:jh�~�UmHnHuh�mHnHujh�~�Uh-zh�<&P1�h:p�f<0��/ ��=!��"��#��$��%�������(2bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1�D<EndNote><Cite><Author>Carr</Author><Year>2008</Year><RecNum>3</RecNum><DisplayText>(2)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carr, M. J.</author><author>Sayre, N.</author><author>Duffy, M.</author><author>Connell, J.</author><author>Hall, W. W.</author></authors></contributors><auth-address>National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.</auth-address><titles><title>Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>257-62</pages><volume>153</volume><number>2</number><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution</keyword><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral/*genetics</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/*drug effects/genetics/isolation &amp; purification</keyword><keyword>Influenza, Human/*virology</keyword><keyword>Microbial Sensitivity Tests</keyword><keyword>*Mutation</keyword><keyword>Neuraminidase/genetics</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction/methods</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>18718489</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18718489</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2008.07.011</electronic-resource-num></record></Cite></EndNote>�D<EndNote><Cite><Author>Carr</Author><Year>2008</Year><RecNum>3</RecNum><DisplayText>(2)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carr, M. 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W.</author></authors></contributors><auth-address>National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.</auth-address><titles><title>Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>257-62</pages><volume>153</volume><number>2</number><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution</keyword><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral/*genetics</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/*drug effects/genetics/isolation &amp; purification</keyword><keyword>Influenza, Human/*virology</keyword><keyword>Microbial Sensitivity Tests</keyword><keyword>*Mutation</keyword><keyword>Neuraminidase/genetics</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction/methods</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>18718489</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18718489</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2008.07.011</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_2�	D<EndNote><Cite><Author>Redlberger-Fritz</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(3)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Redlberger-Fritz, M.</author><author>Aberle, S. W.</author><author>Strassl, R.</author><author>Popow-Kraupp, T.</author></authors></contributors><auth-address>Department of Virology, Medical University Vienna, Kinderspitalgasse 15, 1095, Vienna, Austria.</auth-address><titles><title>Rapid identification of neuraminidase inhibitor resistance mutations in seasonal influenza virus A(H1N1), A(H1N1)2009, and A(H3N2) subtypes by melting point analysis</title><secondary-title>Eur J Clin Microbiol Infect Dis</secondary-title><alt-title>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</alt-title></titles><periodical><full-title>Eur J Clin Microbiol Infect Dis</full-title><abbr-1>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</abbr-1></periodical><alt-periodical><full-title>Eur J Clin Microbiol Infect Dis</full-title><abbr-1>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</abbr-1></alt-periodical><pages>1593-601</pages><volume>31</volume><number>7</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>*Drug Resistance, Viral</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/drug effects/*genetics</keyword><keyword>Influenza A Virus, H3N2 Subtype/drug effects/*genetics</keyword><keyword>*Mutation, Missense</keyword><keyword>Neuraminidase/*genetics</keyword><keyword>RNA, Viral/genetics</keyword><keyword>Transition Temperature</keyword><keyword>Viral Proteins/*genetics</keyword><keyword>Virology/*methods</keyword></keywords><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1435-4373 (Electronic)&#xD;0934-9723 (Linking)</isbn><accession-num>22089329</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22089329</url></related-urls></urls><electronic-resource-num>10.1007/s10096-011-1482-9</electronic-resource-num></record></Cite></EndNote>�	D<EndNote><Cite><Author>Redlberger-Fritz</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(3)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Redlberger-Fritz, M.</author><author>Aberle, S. W.</author><author>Strassl, R.</author><author>Popow-Kraupp, T.</author></authors></contributors><auth-address>Department of Virology, Medical University Vienna, Kinderspitalgasse 15, 1095, Vienna, Austria.</auth-address><titles><title>Rapid identification of neuraminidase inhibitor resistance mutations in seasonal influenza virus A(H1N1), A(H1N1)2009, and A(H3N2) subtypes by melting point analysis</title><secondary-title>Eur J Clin Microbiol Infect Dis</secondary-title><alt-title>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</alt-title></titles><periodical><full-title>Eur J Clin Microbiol Infect Dis</full-title><abbr-1>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</abbr-1></periodical><alt-periodical><full-title>Eur J Clin Microbiol Infect Dis</full-title><abbr-1>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</abbr-1></alt-periodical><pages>1593-601</pages><volume>31</volume><number>7</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>*Drug Resistance, Viral</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/drug effects/*genetics</keyword><keyword>Influenza A Virus, H3N2 Subtype/drug effects/*genetics</keyword><keyword>*Mutation, Missense</keyword><keyword>Neuraminidase/*genetics</keyword><keyword>RNA, Viral/genetics</keyword><keyword>Transition Temperature</keyword><keyword>Viral Proteins/*genetics</keyword><keyword>Virology/*methods</keyword></keywords><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1435-4373 (Electronic)&#xD;0934-9723 (Linking)</isbn><accession-num>22089329</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22089329</url></related-urls></urls><electronic-resource-num>10.1007/s10096-011-1482-9</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_3sD���y������K�	_ENREF_4�D<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1, 2)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite><Cite><Author>Carr</Author><Year>2008</Year><RecNum>3</RecNum><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carr, M. J.</author><author>Sayre, N.</author><author>Duffy, M.</author><author>Connell, J.</author><author>Hall, W. W.</author></authors></contributors><auth-address>National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.</auth-address><titles><title>Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>257-62</pages><volume>153</volume><number>2</number><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution</keyword><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral/*genetics</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/*drug effects/genetics/isolation &amp; purification</keyword><keyword>Influenza, Human/*virology</keyword><keyword>Microbial Sensitivity Tests</keyword><keyword>*Mutation</keyword><keyword>Neuraminidase/genetics</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction/methods</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>18718489</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18718489</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2008.07.011</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1sD���y������K�	_ENREF_2�D<EndNote><Cite><Author>Carr</Author><Year>2008</Year><RecNum>3</RecNum><DisplayText>(2)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carr, M. J.</author><author>Sayre, N.</author><author>Duffy, M.</author><author>Connell, J.</author><author>Hall, W. W.</author></authors></contributors><auth-address>National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.</auth-address><titles><title>Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>257-62</pages><volume>153</volume><number>2</number><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution</keyword><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral/*genetics</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/*drug effects/genetics/isolation &amp; purification</keyword><keyword>Influenza, Human/*virology</keyword><keyword>Microbial Sensitivity Tests</keyword><keyword>*Mutation</keyword><keyword>Neuraminidase/genetics</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction/methods</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>18718489</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18718489</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2008.07.011</electronic-resource-num></record></Cite></EndNote>�D<EndNote><Cite><Author>Carr</Author><Year>2008</Year><RecNum>3</RecNum><DisplayText>(2)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carr, M. J.</author><author>Sayre, N.</author><author>Duffy, M.</author><author>Connell, J.</author><author>Hall, W. W.</author></authors></contributors><auth-address>National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.</auth-address><titles><title>Rapid molecular detection of the H275Y oseltamivir resistance gene mutation in circulating influenza A (H1N1) viruses</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>257-62</pages><volume>153</volume><number>2</number><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution</keyword><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral/*genetics</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/*drug effects/genetics/isolation &amp; purification</keyword><keyword>Influenza, Human/*virology</keyword><keyword>Microbial Sensitivity Tests</keyword><keyword>*Mutation</keyword><keyword>Neuraminidase/genetics</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction/methods</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>18718489</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18718489</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2008.07.011</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_2bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1�	D<EndNote><Cite><Author>Redlberger-Fritz</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(3)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Redlberger-Fritz, M.</author><author>Aberle, S. W.</author><author>Strassl, R.</author><author>Popow-Kraupp, T.</author></authors></contributors><auth-address>Department of Virology, Medical University Vienna, Kinderspitalgasse 15, 1095, Vienna, Austria.</auth-address><titles><title>Rapid identification of neuraminidase inhibitor resistance mutations in seasonal influenza virus A(H1N1), A(H1N1)2009, and A(H3N2) subtypes by melting point analysis</title><secondary-title>Eur J Clin Microbiol Infect Dis</secondary-title><alt-title>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</alt-title></titles><periodical><full-title>Eur J Clin Microbiol Infect Dis</full-title><abbr-1>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</abbr-1></periodical><alt-periodical><full-title>Eur J Clin Microbiol Infect Dis</full-title><abbr-1>European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology</abbr-1></alt-periodical><pages>1593-601</pages><volume>31</volume><number>7</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>*Drug Resistance, Viral</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Influenza A Virus, H1N1 Subtype/drug effects/*genetics</keyword><keyword>Influenza A Virus, H3N2 Subtype/drug effects/*genetics</keyword><keyword>*Mutation, Missense</keyword><keyword>Neuraminidase/*genetics</keyword><keyword>RNA, Viral/genetics</keyword><keyword>Transition Temperature</keyword><keyword>Viral Proteins/*genetics</keyword><keyword>Virology/*methods</keyword></keywords><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1435-4373 (Electronic)&#xD;0934-9723 (Linking)</isbn><accession-num>22089329</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22089329</url></related-urls></urls><electronic-resource-num>10.1007/s10096-011-1482-9</electronic-resource-num></record></Cite></EndNote>�	D<EndNote><Cite><Author>Redlberger-Fritz</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(3)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Redlberger-Fritz, M.</author><author>Aberle, S. 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purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>bD<EndNote><Cite><Author>Chutinimitkul</Author><Year>2007</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chutinimitkul, S.</author><author>Suwannakarn, K.</author><author>Chieochansin, T.</author><author>Mai le, Q.</author><author>Damrongwatanapokin, S.</author><author>Chaisingh, A.</author><author>Amonsin, A.</author><author>Landt, O.</author><author>Songserm, T.</author><author>Theamboonlers, A.</author><author>Poovorawan, Y.</author></authors></contributors><auth-address>Center of Excellence in Viral Hepatitis Research, Chulalongkorn University, Bangkok 10330, Thailand.</auth-address><titles><title>H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes</title><secondary-title>J Virol Methods</secondary-title><alt-title>Journal of virological methods</alt-title></titles><periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></periodical><alt-periodical><full-title>J Virol Methods</full-title><abbr-1>Journal of virological methods</abbr-1></alt-periodical><pages>44-9</pages><volume>139</volume><number>1</number><keywords><keyword>Antiviral Agents/*pharmacology</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Fluorescent Dyes</keyword><keyword>Influenza A Virus, H5N1 Subtype/genetics/*isolation &amp; purification</keyword><keyword>Oseltamivir/*pharmacology</keyword><keyword>Polymerase Chain Reaction/*methods</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0166-0934 (Print)&#xD;0166-0934 (Linking)</isbn><accession-num>17055070</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17055070</url></related-urls></urls><electronic-resource-num>10.1016/j.jviromet.2006.09.007</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1uD���y������K�
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_ENREF_11�	D<EndNote><Cite><Author>Smith</Author><Year>2011</Year><RecNum>11</RecNum><DisplayText>(7)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, J. R.</author><author>Rayner, C. R.</author><author>Donner, B.</author><author>Wollenhaupt, M.</author><author>Klumpp, K.</author><author>Dutkowski, R.</author></authors></contributors><auth-address>Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, PBMT Bldg 74/3O Z1.06, CH-4070, Basel, Switzerland. james.smith.js1@roche.com</auth-address><titles><title>Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience</title><secondary-title>Adv Ther</secondary-title><alt-title>Advances in therapy</alt-title></titles><periodical><full-title>Adv Ther</full-title><abbr-1>Advances in therapy</abbr-1></periodical><alt-periodical><full-title>Adv Ther</full-title><abbr-1>Advances in therapy</abbr-1></alt-periodical><pages>927-59</pages><volume>28</volume><number>11</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antiviral Agents/administration &amp; dosage/adverse effects/pharmacokinetics</keyword><keyword>Child</keyword><keyword>Drug Monitoring</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Humans</keyword><keyword>*Influenza A Virus, H1N1 Subtype/drug effects/pathogenicity</keyword><keyword>Influenza A Virus, H5N1 Subtype/*drug effects</keyword><keyword>Influenza B virus/*drug effects</keyword><keyword>*Influenza, Human/epidemiology/therapy/virology</keyword><keyword>*Oseltamivir/administration &amp; dosage/adverse effects/economics/pharmacokinetics</keyword><keyword>Pandemics/*prevention &amp; control</keyword><keyword>Pharmacovigilance</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Product Surveillance, Postmarketing</keyword><keyword>Vaccination/economics/methods</keyword><keyword>World Health Organization</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1865-8652 (Electronic)&#xD;0741-238X (Linking)</isbn><accession-num>22057727</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22057727</url></related-urls></urls><electronic-resource-num>10.1007/s12325-011-0072-7</electronic-resource-num></record></Cite></EndNote>�	D<EndNote><Cite><Author>Smith</Author><Year>2011</Year><RecNum>11</RecNum><DisplayText>(7)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="pp9t9z2a8a5xsfettanxx9w4rdrx9ra2pszx">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, J. R.</author><author>Rayner, C. R.</author><author>Donner, B.</author><author>Wollenhaupt, M.</author><author>Klumpp, K.</author><author>Dutkowski, R.</author></authors></contributors><auth-address>Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, PBMT Bldg 74/3O Z1.06, CH-4070, Basel, Switzerland. james.smith.js1@roche.com</auth-address><titles><title>Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience</title><secondary-title>Adv Ther</secondary-title><alt-title>Advances in therapy</alt-title></titles><periodical><full-title>Adv Ther</full-title><abbr-1>Advances in therapy</abbr-1></periodical><alt-periodical><full-title>Adv Ther</full-title><abbr-1>Advances in therapy</abbr-1></alt-periodical><pages>927-59</pages><volume>28</volume><number>11</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antiviral Agents/administration &amp; dosage/adverse effects/pharmacokinetics</keyword><keyword>Child</keyword><keyword>Drug Monitoring</keyword><keyword>Drug Resistance, Viral</keyword><keyword>Humans</keyword><keyword>*Influenza A Virus, H1N1 Subtype/drug effects/pathogenicity</keyword><keyword>Influenza A Virus, H5N1 Subtype/*drug effects</keyword><keyword>Influenza B virus/*drug effects</keyword><keyword>*Influenza, Human/epidemiology/therapy/virology</keyword><keyword>*Oseltamivir/administration &amp; dosage/adverse effects/economics/pharmacokinetics</keyword><keyword>Pandemics/*prevention &amp; control</keyword><keyword>Pharmacovigilance</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Product Surveillance, Postmarketing</keyword><keyword>Vaccination/economics/methods</keyword><keyword>World Health Organization</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1865-8652 (Electronic)&#xD;0741-238X (Linking)</isbn><accession-num>22057727</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22057727</url></related-urls></urls><electronic-resource-num>10.1007/s12325-011-0072-7</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_7sD���y������K�	_ENREF_8�$$If�!vh5�t5�5��#vt#v#v�:V�l
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