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BACKGROUND: Ambient temperature and humidity are established environmental stressors with regard to influenza infections; however, mapping disease burden is difficult owing to the complexities of the underlying associations and differences in vulnerable population distributions. In this study, we aimed to quantify the burden of influenza attributable to non-optimal ambient temperature and absolute humidity in Japan considering geographical differences in vulnerability. METHODS: The exposure-lag-response relationships between influenza incidence, ambient temperature, and absolute humidity in all 47 Japanese prefectures for 2000-2019 were quantified using a distributed lag non-linear model for each prefecture; the estimates from all the prefectures were then pooled using a multivariate mixed-effects meta-regression model to derive nationwide average associations. Association between prefecture-specific indicators and the risk were also examined. Attributable risks were estimated for non-optimal ambient temperature and absolute humidity according to the exposure-lag-response relationships obtained before. RESULTS: A total of 25,596,525 influenza cases were reported during the study period. Cold and dry conditions significantly increased influenza incidence risk. Compared with the minimum incidence weekly mean ambient temperature (29.8 °C) and the minimum incidence weekly mean absolute humidity (20.2 g/m3), the cumulative relative risks (RRs) of influenza in cold (2.5 °C) and dry (3.6 g/m3) conditions were 2.79 (95% confidence interval [CI]: 1.78-4.37) and 3.20 (95% CI: 2.37-4.31), respectively. The higher RRs for cold and dry conditions were associated with geographical and climatic indicators corresponding to the central and northern prefectures; demographic, socioeconomic, and health resources indicators showed no clear trends. Finally, 27.25% (95% empirical CI [eCI]: 5.54-36.35) and 32.35% (95% eCI: 22.39-37.87) of all cases were attributable to non-optimal ambient temperature and absolute humidity (6,976,300 [95% eCI: 1,420,068-9,306,128] and 8,280,981 [95% eCI: 8,280,981-9,693,532] cases), respectively. CONCLUSIONS: These findings could help identify the most vulnerable populations in Japan and design adaptation policies to reduce the attributable burden of influenza due to climate variability.

DOI： 10.1016/j.envres.2024.120065

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It has been reported that the high-growth reassortant (HGR) A(H3N2) influenza viruses used for split influenza vaccine (SV) production have some amino acid substitutions in hemagglutinin due to egg adaptation during virus propagation, causing antigenic differences between HGR and epidemic viruses. To clarify whether inactivated whole-virus vaccine (WV) derived from the A(H3N2) HGR virus possessing egg adaptation could induce cross-protective immune responses against epidemic A(H3N2) viruses, the efficacy of WV was compared with that of SV in a ferret model. When the ferrets immunized with WV or SV derived from HGR A/Victoria/361/2011 (IVR-165) virus were challenged with the homologous virus A/Victoria/361/2011 (IVR-165) or its original cell-propagated A/Victoria/361/2011 virus, respectively, WV successfully shortened the duration of virus shedding of both challenge viruses, whereas SV shortened only that of the homologous virus, A/Victoria/361/2011 (IVR-165). When WV-immunized ferrets were challenged with A/Fukushima/69/2015 virus, which is an epidemic virus antigenically different from the A/Victoria/361/2011 virus, WV could shorten the duration of shedding of this virus. In addition, we found that early induction of nasal IgG and IgA antibodies by vaccines helped shorten the virus-shedding period, although this was dependent on the degree of difference in antigenicity of the challenge virus. These results indicate that vaccination with WV, not with SV, would be a solution to avoid decreased vaccine effectiveness due to the antigenic change of HGR virus by egg adaptation during virus propagation.

DOI： 10.1111/1348-0421.13179

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Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.

DOI： 10.1016/j.antiviral.2024.105956

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OBJECTIVES: This study aimed to map the incidence of acute respiratory infections (ARIs) among under-5 children in Indonesia, address the triple burden of malnutrition, and analyze the impact of malnutrition on ARIs, taking into account the environmental and wealth disparities in Indonesia. METHODS: This study utilized an ecological design, analyzing aggregate data from the Indonesia Nutrition Survey, 2022. It encompassed 33 provinces and 486 districts/cities, involving a total of 334 878 children under 5 years of age. Partial least squares structural equation modeling was employed to investigate the relationships among wealth, environment, malnutrition (stunting, wasting, and underweight), and ARIs. RESULTS: The proportion of ARI cases in Indonesia was generally concentrated in central Sumatra, the western and eastern parts of Java, and eastern Papua. In contrast, the northern part of Sumatra, central Kalimantan, central Sulawesi, and central Papua had a higher proportion of malnutrition cases compared to other regions. Negative associations were found between malnutrition and ARIs (path coefficient =-0.072; p<0.01) and between wealth and environment (path coefficient =-0.633; p<0.001), malnutrition (path coefficient=-0.399; p<0.001), and ARIs (path coefficient=-0.918; p<0.001). CONCLUSIONS: An increasing wealth index is expected to contribute to reducing ARIs, malnutrition and environmental burdens in the future. This study emphasizes the necessity for focused strategies that address both immediate health challenges and the underlying socioeconomic determinants to improve child health outcomes in the Indonesian context.

DOI： 10.3961/jpmph.24.246

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In this study, we describe the genetic characteristics of influenza A(H1N1)pdm09 strains detected in Myanmar from 2015 to 2019. Whole genomes from 60 A(H1N1)pdm09 virus isolates were amplified using real-time polymerase chain reaction and successfully sequenced using the Illumina iSeq100 platforms. Eight individual phylogenetic trees were retrieved for each segment along with those of the World Health Organization (WHO)-recommended Southern Hemisphere vaccine strains for the respective years. A(H1N1)pdm09 viruses from 2015 were found to belong to clade 6B, those from 2016 to 6B.1, 2017 to 6B.1A, and 2019 to 6B.1A.5a, and were genetically distinct from the Southern Hemisphere vaccine strains for the respective seasons, A/California/7/2009 and A/Michigan/45/2015. We observed one virus with intra-subtype reassortment, collected in the 2015 season. Importantly, three viruses possessed the H275Y substitution in the neuraminidase protein, appearing to be community-acquired without the prior administration of neuraminidase inhibitors. These viruses exhibited highly reduced susceptibility to oseltamivir and peramivir. This study demonstrates the importance of monitoring genetic variations in influenza viruses that will contribute to the selection of global influenza vaccines.

DOI： 10.3390/v16081300

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We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.

DOI： 10.1016/j.antiviral.2024.105938

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BACKGROUND: Enterovirus D68 (EV-D68) is an important reemerging pathogen that causes severe acute respiratory infection and acute flaccid paralysis, mainly in children. Since 2014, EV-D68 outbreaks have been reported in the United States, Europe, and east Asia; however, no outbreaks have been reported in southeast Asian countries, including Myanmar, during the previous 10 years. METHODS: EV-D68 was detected in nasopharyngeal swabs from children with acute lower respiratory infections in Myanmar. The samples were previously collected from children aged 1 month to 12 years who had been admitted to the Yankin Children Hospital in Yangon, Myanmar, between May 2017 and January 2019. EV-D68 was detected with a newly developed EV-D68-specific real-time PCR assay. The clade was identified by using a phylogenetic tree created with the Bayesian Markov chain Monte Carlo method. RESULTS: During the study period, nasopharyngeal samples were collected from 570 patients. EV-D68 was detected in 42 samples (7.4 %)-11 samples from 2017 to 31 samples from 2018. The phylogenetic tree revealed that all strains belonged to clade B3, which has been the dominant clade worldwide since 2014. We estimate that ancestors of currently circulating genotypes emerged during the period 1980-2004. CONCLUSIONS: To our knowledge, this is the first report of EV-D68 detection in children with acute lower respiratory infections in Yangon, Myanmar, in 2017-2018. Detection and detailed virologic analyses of EV-D68 in southeast Asia is an important aspect of worldwide surveillance and will likely be useful in better understanding the worldwide epidemiologic profile of EV-D68 infection.

DOI： 10.1016/j.jmii.2024.01.001

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This study measured IgG antibody titers against spike (S) and nucleocapsid (N) proteins of SARS-CoV-2 before vaccination and after the second and third doses of an mRNA vaccine in staff and residents of a nursing home in Niigata, Japan. The study included 52 staff members, of whom six (11.5%) were previously infected with SARS-CoV-2, and 32 older residents, of whom 22 (68.8%) were previously infected. All participants received the first two doses in April-July 2021 and a third dose in January-March 2022. In staff, the median anti-S antibody titers (interquartile range) in previously infected and SARS-CoV-2-naïve individuals before vaccination were 960 (592-1,926) and 0.5 (0.0-2.1) arbitrary units (AU)/mL. Anti-S antibody titers 5 months after the second and third doses in previously infected staff were 7,391 (5,230-7,747) and 10,195 (5,582-13,886) AU. In residents, the median anti-S antibody titers in previously infected and naïve individuals before vaccination were 734 (425-1,934) and 1.1 (0.0-3.1) AU/mL. Anti-S antibody titers at 5 months after the second and third doses in previously infected residents were 15,872 (9,683-21,557) and 13,813 (6,689-20,839) AU/mL; however, there were no significant differences in titers between the second and third doses in previously infected residents. Anti-N antibody titers were higher in previously infected than naïve individuals, and titers decreased chronologically.

DOI： 10.1016/j.jiac.2023.09.021

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INTRODUCTION: In Japan, a country at the forefront of population ageing, significant geographic variation has been observed in inpatient medical expenditures for older adults aged 75 and above (IMEP75), both at the small- and large-area levels. However, our understanding of how different levels of administrative (geographic) units contribute to the overall geographic disparities remains incomplete. Thus, this study aimed to assess the degree to which geographic variation in IMEP75 can be attributed to municipality-, secondary medical area (SMA)-, and prefecture-level characteristics, and identify key factors associated with IMEP75. METHODS: Using nationwide aggregate health insurance claims data of municipalities for the period of April 2018 to March 2019, we conducted a multilevel linear regression analysis with three levels: municipalities, SMA, and prefectures. The contribution of municipality-, SMA-, and prefecture-level correlates to the overall geographic variation in IMEP75 was evaluated using the proportional change in variance across six constructed models. The effects of individual factors on IMEP75 in the multilevel models were assessed by estimating beta coefficients with their 95% confidence intervals. RESULTS: We analysed data of 1,888 municipalities, 344 SMAs, and 47 prefectures. The availability of healthcare resources at the SMA-level and broader regions to which prefectures belonged together explained 57.3% of the overall geographic variance in IMEP75, whereas the effects of factors influencing healthcare demands at the municipality-level were relatively minor, contributing an additional explanatory power of 2.5%. Factors related to long-term and end-of-life care needs and provision such as the proportion of older adults certified as needing long-term care, long-term care benefit expenditure per recipient, and the availability of hospital beds for psychiatric and chronic care and end-of-life care support at home were associated with IMEP75. CONCLUSION: To ameliorate the geographic variation in IMEP75 in Japan, the reallocation of healthcare resources across SMAs should be considered, and drivers of broader regional disparities need to be further explored. Moreover, healthcare systems for older adults must integrate an infrastructure of efficient long-term care and end-of-life care delivery outside hospitals to alleviate the burden on inpatient care.

DOI： 10.3389/fpubh.2024.1306013

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To evaluate the changes in respiratory syncytial virus (RSV) collected between 2019 and 2022, we analyzed RSV-A and RSV-B strains from various prefectures in Japan before and after the COVID-19 pandemic. RT-PCR-positive samples collected from children with rapid test positivity at outpatient clinics in 11 prefectures in Japan were sequenced for the ectodomain of the G gene to determine the genotype. Time-aware phylogeographic analyses were performed using the second hypervariable region (HVR) of the G gene from 2012 to 2022. Of 967 samples, 739 (76.4%) were found to be RSV-positive using RT-PCR. RSV peaked in September 2019 but was not detected in 2020, except in Okinawa. Nationwide epidemics occurred with peaks in July 2021 and 2022. The genotype remained the same, ON1 for RSV-A and BA9 for RSV-B during 2019-2022. Phylogeographic analysis of HVR revealed that at least seven clusters of RSV-A had circulated previously but decreased to two clusters after the pandemic, whereas RSV-B had a single monophyletic cluster over the 10 years. Both RSV-A and RSV-B were transferred from Okinawa into other prefectures after the pandemic. The RSV epidemic was suppressed due to pandemic restrictions; however, pre-pandemic genotypes spread nationwide after the pandemic.

DOI： 10.3390/v15122382

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In this study, we aimed to characterize the nonlinear and multidelayed effects of multiple meteorological drivers on human respiratory syncytial virus (HRSV) infection epidemics in Japan. The prefecture-specific weekly time-series of the number of newly confirmed HRSV infection cases and multiple meteorological variables were collected for 47 Japanese prefectures from 1 January 2014 to 31 December 2019. We combined standard time-series generalized linear models with distributed lag nonlinear models to determine the exposure-lag-response association between the incidence relative risks (IRRs) of HRSV infection and its meteorological drivers. Pooling the 2-week cumulative estimates showed that overall high ambient temperatures (22.7 °C at the 75th percentile compared to 16.3 °C) and high relative humidity (76.4% at the 75th percentile compared to 70.4%) were associated with higher HRSV infection incidence (IRR for ambient temperature 1.068, 95% confidence interval [CI], 1.056-1.079; IRR for relative humidity 1.045, 95% CI, 1.032-1.059). Precipitation revealed a positive association trend, and for wind speed, clear evidence of a negative association was found. Our findings provide a basic picture of the seasonality of HRSV transmission and its nonlinear association with multiple meteorological drivers in the pre-HRSV-vaccination and pre-coronavirus disease 2019 (COVID-19) era in Japan.

DOI： 10.3390/v15091914

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Parechovirus-A (PeV-A) causes emerging infection in children, and clinical presentation depends on genotype. The virus has been investigated mainly in developed countries; however, data from developing countries, especially in Asia, are sparse. This study investigated whether PeV-A circulated in children in Myanmar. This retrospective study evaluated PeV-A in nasopharyngeal samples from children aged 1 month to 12 years who were hospitalized with acute lower respiratory infection at Yankin Children Hospital, Yangon, Myanmar, during the period from May 2017 to April 2019. Real-time polymerase chain reaction (PCR) was used to detect PeV-A, and PCR-positive samples were used for genotyping and phylogenetic analysis. In total, 11/570 (1.9%) of samples were positive for PeV-A; 7 were successfully genotyped by sequencing the VP3/VP1 region, as follows: PeV-A1 (n = 4), PeV-A5 (n = 1), PeV-A6 (n = 1), and PeV-A14 (n = 1). Median age was 10.0 months (interquartile range 4.0-12.0 months), and other respiratory viruses were detected in all cases. Phylogenetic analysis showed that all detected PeV-A1 strains were in clade 1 A, which was a minor clade worldwide. Four PeV-A genotypes were detected in Myanmar. The clinical impact of PeV-A in children should be evaluated in future studies.

DOI： 10.1002/jmv.28964

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BACKGROUND: This study assessed the differences in daily virus reduction and the residual infectivity after the recommended home stay period in Japan in patients infected with influenza and treated with baloxavir (BA), laninamivir (LA), oseltamivir (OS), and zanamivir (ZA). METHODS: We conducted an observational study on children and adults at 13 outpatient clinics in 11 prefectures in Japan during seven influenza seasons from 2013/2014 to 2019/2020. Virus samples were collected twice from influenza rapid test-positive patients at the first and second visit 4-5 days after the start of treatment. The viral RNA shedding was quantified using quantitative RT-PCR. Neuraminidase (NA) and polymerase acidic (PA) variant viruses that reduce susceptibility to NA inhibitors and BA, respectively, were screened using RT-PCR and genetic sequencing. Daily estimated viral reduction was evaluated using univariate and multivariate analyses for the factors such as age, treatment, vaccination status, or the emergence of PA or NA variants. The potential infectivity of the viral RNA shedding at the second visit samples was determined using the Receiver Operator Curve based on the positivity of virus isolation. RESULTS: Among 518 patients, 465 (80.0%) and 116 (20.0%) were infected with influenza A (189 with BA, 58 with LA, 181 with OS, 37 with ZA) and influenza B (39 with BA, 10 with LA, 52 with OS, 15 with ZA). The emergence of 21 PA variants in influenza A was detected after BA treatment, but NA variants were not detected after NAIs treatment. Multiple linear regression analysis showed that the daily viral RNA shedding reduction in patients was slower in the two NAIs (OS and LA) than in BA, influenza B infection, aged 0-5 years, or the emergence of PA variants. The residual viral RNA shedding potentially infectious was detected in approximately 10-30% of the patients aged 6-18 years after five days of onset. CONCLUSIONS: Viral clearance differed by age, type of influenza, choice of treatment, and susceptibility to BA. Additionally, the recommended homestay period in Japan seemed insufficient, but reduced viral spread to some extent since most school-age patients became non-infectious after 5 days of onset.

DOI： 10.1186/s12879-023-08140-z

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An influenza circulation was observed in Myanmar between October and November in 2021. Patients with symptoms of influenza-like illness were screened using rapid diagnostic test (RDT) kits, and 147/414 (35.5%) upper respiratory tract specimens presented positive results. All RDT-positive samples were screened by a commercial multiplex real-time polymerase chain reaction (RT-PCR) assay, and 30 samples positive for influenza A(H3N2) or B underwent further typing/subtyping for cycle threshold (Ct) value determination based on cycling probe RT-PCR. The majority of subtyped samples (n = 13) were influenza A(H3N2), while only three were B/Victoria. Clinical samples with low Ct values obtained by RT-PCR were used for whole-genome sequencing via next-generation sequencing technology. All collected viruses were distinct from the Southern Hemisphere vaccine strains of the corresponding season but matched with vaccines of the following season. Influenza A(H3N2) strains from Myanmar belonged to clade 2a.3 and shared the highest genetic proximity with Bahraini strains. B/Victoria viruses belonged to clade V1A.3a.2 and were genetically similar to Bangladeshi strains. This study highlights the importance of performing influenza virus surveillance with genetic characterization of the influenza virus in Myanmar, to contribute to global influenza surveillance during the COVID-19 pandemic.

DOI： 10.3390/v15020583

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To reduce vaccine hesitancy, it is important to identify factors that can intervene at the individual or community level. Social capital is a possible factor because it is associated with various vaccine hesitancy, such as for measles and influenza. However, limited studies have explored the association between social capital and vaccination for COVID-19, which is an unprecedented pandemic and infodemic. Therefore, this study aimed to clarify the association between social capital and COVID-19 vaccination during the pandemic. This cross-sectional study used quota sampling for an online-based survey. Participants were asked whether they had previously been vaccinated for COVID-19 and their intention to receive a COVID-19 vaccine booster. Social capital was evaluated using three measures (individual-level civic participation, social cohesion, and reciprocity). Multiple logistic regression analysis was performed to clarify the association between social capital and previous COVID-19 vaccination status as well as intention to receive a COVID-19 booster. Participants were 2,313 individuals, of whom 87.2% had received a COVID-19 vaccine; 72.3% intended to obtain a COVID-19 booster. Individuals with any social capital are more likely to receive a COVID-19 vaccination than those with none (OR: 1.73, 95%CI: 1.18-2.54; OR: 1.58, 95%CI: 1.22-2.05; OR: 3.05, 95%CI: 2.15-4.33). These indicators were also associated with the intention to receive a COVID-19 booster. Thus, our results suggest that among the general public, those with individual-level social capital are more likely to receive a COVID-19 vaccination than those with none. Social capital may be a factor that can reduce vaccine hesitancy during a pandemic.

DOI： 10.1080/21645515.2022.2086773

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An outbreak of coronavirus disease 2019 (COVID-19) occurred in a nursing home in Niigata, Japan, November 2020, with an attack rate of 32.0% (63/197). The present study was aimed at assessing the pre-vaccination seroprevalence almost half a year after the COVID-19 outbreak in residents and staff in the facility, along with an assessment of the performance of the enzyme-linked immunosorbent assay (ELISA) and the chemiluminescent immunoassay (CLIA), regarding test seropositivity and seronegativity in detecting immunoglobulin G (IgG) anti-severe acute respiratory syndrome 2 (SARS-CoV-2) antibodies (anti-nucleocapsid (N) and spike (S) proteins). A total of 101 people (30 reverse transcription PCR (RT-PCR)-positive and 71 RT-PCR-negative at the time of the outbreak in November 2020) were tested for anti-IgG antibody titers in April 2021, and the seroprevalence was approximately 40.0-60.0% for residents and 10.0-20.0% for staff, which was almost consistent with the RT-PCR test results that were implemented during the outbreak. The seropositivity for anti-S antibodies showed 90.0% and was almost identical to the RT-PCR positives even after approximately six months of infections, suggesting that the anti-S antibody titer test is reliable for a close assessment of the infection history. Meanwhile, seropositivity for anti-N antibodies was relatively low, at 66.7%. There was one staff member and one resident that were RT-PCR-negative but seropositive for both anti-S and anti-N antibody, indicating overlooked infections despite periodical RT-PCR testing at the time of the outbreak. Our study indicated the impact of transmission of SARS-CoV-2 in a vulnerable elderly nursing home in the pre-vaccination period and the value of a serological study to supplement RT-PCR results retrospectively.

DOI： 10.3390/v14112581

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This study aimed to analyze the genetic and evolutionary characteristics of the influenza A/H3N2 viruses circulating in Myanmar from 2015 to 2019. Whole genomes from 79 virus isolates were amplified using real-time polymerase chain reaction and successfully sequenced using the Illumina iSeq100 platforms. Eight individual phylogenetic trees were retrieved for each segment along with those of the World Health Organization (WHO)-recommended Southern Hemisphere vaccine strains for the respective years. Based on the WHO clades classification, the A/H3N2 strains in Myanmar from 2015 to 2019 collectively belonged to clade 3c.2. These strains were further defined based on hemagglutinin substitutions as follows: clade 3C.2a (n = 39), 3C.2a1 (n = 2), and 3C.2a1b (n = 38). Genetic analysis revealed that the Myanmar strains differed from the Southern Hemisphere vaccine strains each year, indicating that the vaccine strains did not match the circulating strains. The highest rates of nucleotide substitution were estimated for hemagglutinin (3.37 × 10-3 substitutions/site/year) and neuraminidase (2.89 × 10-3 substitutions/site/year). The lowest rate was for non-structural protein segments (4.19 × 10-5 substitutions/site/year). The substantial genetic diversity that was revealed improved phylogenetic classification. This information will be particularly relevant for improving vaccine strain selection.

DOI： 10.3390/v14112414

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We assess the effects of ambient temperature and mobility patterns on the transmissibility of COVID-19 during the epidemiological years of the pandemic in Japan. The prefecture-specific daily time-series of confirmed coronavirus disease 2019 (COVID-19) cases, meteorological variables, levels of retail and recreation mobility (e.g., activities, going to restaurants, cafes, and shopping centers), and the number of vaccinations were collected for six prefectures in Japan from 1 May 2020 to 31 March 2022. We combined standard time-series generalized additive models (GAMs) with a distributed lag non-linear model (DLNM) to determine the exposure-lag-response association between the time-varying effective reproductive number (Rt), ambient temperature, and retail and recreation mobility, while controlling for a wide range of potential confounders. Utilizing a statistical model, the first distribution of the mean ambient temperature (i.e., -4.9 °C) was associated with an 11.6% (95% confidence interval [CI]: 5.9-17.7%) increase in Rt compared to the optimum ambient temperature (i.e., 18.5 °C). A retail and recreation mobility of 10.0% (99th percentile) was associated with a 19.6% (95% CI: 12.6-27.1%) increase in Rt over the optimal level (i.e., -16.0%). Our findings provide a better understanding of how ambient temperature and mobility patterns shape severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. These findings provide valuable epidemiological insights for public health policies in controlling disease transmission.

DOI： 10.3390/v14102232

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BACKGROUND: Spread of variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an increase in children with coronavirus disease 2019 (COVID-19). In February 2021, clusters of the Alpha variant of SARS-CoV-2 started to be reported in Niigata, Japan, including a large nursery cluster. We investigated the transmission routes and household secondary attack rates (SARs) in this cluster. METHODS: Epidemiologic data related to a nursery cluster in Niigata, Japan, particularly child-origin and adult-origin SARs, were analyzed. VOCs were confirmed by whole-genome sequencing of virus from patients. RESULTS: In total, 42 persons (22 children and 20 adults) in the cluster were infected with the Alpha variant. In the nursery, 13 of 81 children (16.0%) and 4 of 24 teachers (16.7%) were infected. SARS-CoV-2 later spread to 25 persons (10 children and 15 adults) outside the nursery. Child-origin and adult-origin household SARs were 27.7% (13/47) and 47.0% (8/17) ( P = 0.11), respectively, which were higher than rates attributable to non-VOCs in previous studies. CONCLUSIONS: As compared with non-VOCs, the Alpha variant of SARS-CoV-2 exhibited high transmissibility among children and adults and may pose a high risk for household secondary transmission from SARS-CoV-2-infected children. Increased transmissibility of current or future VOCs could lead to greater transmission from children to adults or other children.

DOI： 10.1097/INF.0000000000003607

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BACKGROUND: This longitudinal study aimed to investigate how psychological distress levels changed from early to middle phases of the new coronavirus (COVID-19) pandemic depending on the living arrangements of individuals. METHODS: An internet-based, longitudinal survey of 2,400 Japanese people was conducted every 5-6 weeks between February 2020 and January 2021. The presence of severe psychological distress (SPD) was measured using the Kessler's psychological distress scale. Living arrangements were classified into two groups (ie, living alone or living with others). Mixed-effects logistic regression analysis was performed to assess whether changes in SPD status were different depending on living arrangements. RESULTS: Of 2,400 respondents, 446 (18.5%) lived alone. Although the proportion of SPD in both individuals living alone and those living with others increased to the same extent in the early phase of the pandemic, the distress levels decreased after the early phase of the pandemic in the group living with others, compared with the group living alone, for which SPD remained high. The odds ratio (OR) of developing SPD in interaction term with survey phases tended to be higher among those who lived alone than those who lived with others in Phase 6 (OR 1.89; 95% confidence interval [CI], 0.99-3.64) and Phase 7 (OR 1.88; 95% CI, 0.97-3.63). CONCLUSION: During the COVID-19 pandemic, those living alone are persistently at a higher risk of SPD compared to those living with others. Effective countermeasures targeting those living alone, such as enhancing online communication or providing psychological therapies, are essential.

DOI： 10.2188/jea.JE20210397

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Providing appropriate immunization information during the perinatal period is important for improving immunization rates among infants and children; however, the distribution of immunization information by healthcare workers (HCWs) is not standardized in Japan. We investigated HCWs’ attitudes toward childhood immunization and factors related to vaccine hesitancy. We conducted a cross-sectional descriptive survey of HCWs involved in childhood immunization in Niigata City, Japan, from November 2017 to January 2018. We assessed contextual, individual and group, and vaccine/vaccination-specific influences. Of 290 HCWs, 139 (47.9%) returned completed questionnaires. Most HCWs (87/139, 64.9%) reported providing immunization information verbally to parents; 51/87 (58.6%) spent fewer than five minutes doing so. Pediatricians provided vaccines based on the parents’ best interest, whereas public health nurses and midwives emphasized government policy. Nurses had greater hesitancy related to personal perceptions and social/peer factors than pediatricians (p < 0.001). Nurses were significantly more likely than pediatricians to suggest that children receive more shots than necessary (p < 0.01). Nurses tended to have more negative attitudes toward vaccination and little awareness of immunization promotion compared to pediatricians. Thus, all HCWs involved in childhood immunization should receive sufficient information to provide timely and appropriate immunization to infants and children.

DOI： 10.3390/vaccines10071055

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We quantified the effects of adherence to various non-pharmaceutical interventions (NPIs) on the seasonal influenza epidemic dynamics in Japan during 2020. The total monthly number of seasonal influenza cases per sentinel site (seasonal influenza activity) reported to the National Epidemiological Surveillance of Infectious Diseases and alternative NPI indicators (retail sales of hand hygiene products and number of airline passenger arrivals) from 2014−2020 were collected. The average number of monthly seasonal influenza cases in 2020 had decreased by approximately 66.0% (p < 0.001) compared to those in the preceding six years. An increase in retail sales of hand hygiene products of \1 billion over a 3-month period led to a 15.5% (95% confidence interval [CI]: 10.9−20.0%; p < 0.001) reduction in seasonal influenza activity. An increase in the average of one million domestic and international airline passenger arrivals had a significant association with seasonal influenza activity by 11.6% at lag 0−2 months (95% CI: 6.70−16.5%; p < 0.001) and 30.9% at lag 0−2 months (95% CI: 20.9−40.9%; p < 0.001). NPI adherence was associated with decreased seasonal influenza activity during the COVID-19 pandemic in Japan, which has crucial implications for planning public health interventions to minimize the health consequences of adverse seasonal influenza epidemics.

DOI： 10.3390/v14071417

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BACKGROUND: Homebound status is one of the most important risk factors associated with functional decline and long-term care in older adults. Studies show that neighborhood built environment and community social capital may be related to homebound status. This study aimed to clarify the association between homebound status for community-dwelling older adults and community environment-including social capital and neighborhood built environment-in rural and urban areas. METHODS: We surveyed people aged 65 years and older residing in three municipalities of Niigata Prefecture, Japan, who were not certified as requiring long-term care. The dependent variable was homebound status; explanatory variables were community-level social capital and neighborhood built environment. Covariates were age, sex, household, marital status, socioeconomic status, instrumental activities of daily living, the Geriatric Depression Scale-15, self-rated health, number of diseases under care, and individual social capital. The association between community social capital or neighborhood built environment and homebound status, stratified by rural/urban areas, was investigated using multilevel logistic regression analysis. RESULTS: Among older adults (n = 18,099), the homebound status prevalence rate was 6.9% in rural areas and 4.2% in urban areas. The multilevel analysis showed that, in rural areas, fewer older adults were homebound in communities with higher civic participation and with suitable parks or pavements for walking and exercising. However, no significant association was found between community social capital or neighborhood built environment and homebound status for urban older adults. CONCLUSION: Community social capital and neighborhood built environment were significantly associated with homebound status in older adults in rural areas.

DOI： 10.2188/jea.JE20200154

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Data on the clinical effectiveness of the novel anti-influenza drug baloxavir marboxil (baloxavir) in children remain limited. We conducted an observational study to compare the duration of fever and symptoms between baloxavir- and oseltamivir-treated children infected with influenza A and B. In total, 159 outpatients with influenza A(H1N1)pdm09 or B/Victoria-lineage infections, aged <19 years, during the 2019-2020 influenza season in Japan were enrolled and assessed the duration of fever and symptoms using the Kaplan-Meier method and a multivariate Cox proportional hazard regression model. Polymerase acidic (PA) variants were examined before and after baloxavir treatment. In the multivariable analysis, the duration of fever and symptoms was unaltered between the A(H1N1)pdm09 (n = 116) and B/Victoria-lineage (n = 43) groups. Conversely, the fever duration was marginally longer in the oseltamivir-treated group (n = 59) than in the baloxavir group (n = 100) (hazard ratio (HR) = 0.67, p = 0.05); however, the duration of symptoms was unaltered between the two groups (HR = 0.74, p = 0.11). No patient presented PA reduced susceptibility marker(s) before baloxavir treatment in the analyzed groups. The PA/E23K variant was detected in one case (1.5%, 1/66) of A(H1N1)pdm09 after baloxavir treatment. One case (2.0%, 1/50) of A(H1N1)pdm09 with an N295S substitution in neuraminidase was detected following oseltamivir treatment. These results suggested that the duration of fever was likely to be shorter with baloxavir than with oseltamivir, but the difference between influenza A (H1N1)pdm09 and B/Victoria-lineage was unclear. It is important to continue evaluating the clinical effectiveness of baloxavir and monitoring its drug susceptibility to the influenza virus.

DOI： 10.1016/j.antiviral.2022.105310

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BACKGROUND: Acute lower respiratory infection (ALRI) remains the leading cause of death in children worldwide, and viruses have been the major cause of ALRI. In Myanmar, ALRI is associated with high morbidity and mortality in children, and detailed information on ALRI is currently lacking. METHODS: This prospective study investigated the viral aetiologies, clinical manifestations, and outcomes of ALRI in hospitalised children aged 1 month to 12 years at the Yankin Children Hospital, Yangon, Myanmar from May 2017 to April 2019. The sample size was set to 300 patients for each year. Two nasopharyngeal swabs were obtained for the patients with suspected viral ALRI; one for rapid tests for influenza and respiratory syncytial virus (RSV), and the other for real-time PCR for the 16 ALRI-causing viruses. Pneumococcal colonization rates were also investigated using real-time PCR. Clinical information was extracted from the medical records, and enrolled patients were categorised by age and severity for comparison. RESULTS: Among the 5463 patients admitted with a diagnosis of ALRI, 570 (10.4%) were enrolled in this study. The median age of the patients was 8 months (interquartile range, 4-15 months). The most common symptoms were cough (93%) and difficulty in breathing (73%), while the most common signs of ALRI were tachypnoea (78%) and chest indrawing (67%). A total of 16 viruses were detected in 502 of 570 patients' samples (88%), with RSV B (36%) and rhinovirus (28%) being the most commonly detected. Multiple viruses were detected in 221 of 570 samples (37%) collected from 570 patients. Severe ALRI was diagnosed in 107 of 570 patients (19%), and RSV B and human rhinovirus were commonly detected. The mortality rate was 5%; influenza virus A (29%) and RSV B (21%) were commonly detected, and stunting and lack of immunization were frequently observed in such cases. Additionally, 45% (259/570) of the patients had pneumococcal colonization. CONCLUSIONS: Viral ALRI in hospitalised children with a median of 8 months has significant morbidity and mortality rates in Myanmar. RSV and rhinovirus were the most commonly detected from nasopharyngeal swabs, while influenza virus and RSV were the most frequently associated with fatal cases.

DOI： 10.1186/s12879-022-07342-1

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Responses to the early (February-July 2020) COVID-19 pandemic varied widely, globally. Reasons for this are multiple but likely relate to the healthcare and financial resources then available, and the degree of trust in, and economic support provided by, national governments. Cultural factors also affected how different populations reacted to the various pandemic restrictions, like masking, social distancing and self-isolation or self-quarantine. The degree of compliance with these measures depended on how much individuals valued their needs and liberties over those of their society. Thus, several themes may be relevant when comparing pandemic responses across different regions. East and Southeast Asian populations tended to be more collectivist and self-sacrificing, responding quickly to early signs of the pandemic and readily complied with most restrictions to control its spread. Australasian, Eastern European, Scandinavian, some Middle Eastern, African and South American countries also responded promptly by imposing restrictions of varying severity, due to concerns for their wider society, including for some, the fragility of their healthcare systems. Western European and North American countries, with well-resourced healthcare systems, initially reacted more slowly, partly in an effort to maintain their economies but also to delay imposing pandemic restrictions that limited the personal freedoms of their citizens.

DOI： 10.1098/rsfs.2021.0079

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We aimed to analyze the situation of the first two epidemic waves in Myanmar using the publicly available daily situation of COVID-19 and whole-genome sequencing data of SARS-CoV-2. From March 23 to December 31, 2020, there were 33,917 confirmed cases and 741 deaths in Myanmar (case fatality rate of 2.18%). The first wave in Myanmar from March to July was linked to overseas travel, and then a second wave started from Rakhine State, a western border state, leading to the second wave spreading countrywide in Myanmar from August to December 2020. The estimated effective reproductive number (Rt) nationwide reached 6-8 at the beginning of each wave and gradually decreased as the epidemic spread to the community. The whole-genome analysis of 10 Myanmar SARS-CoV-2 strains together with 31 previously registered strains showed that the first wave was caused by GISAID clade O or PANGOLIN lineage B.6 and the second wave was changed to clade GH or lineage B.1.36.16 with a close genetic relationship with other South Asian strains. Constant monitoring of epidemiological situations combined with SARS-CoV-2 genome analysis is important for adjusting public health measures to mitigate the community transmissions of COVID-19.

DOI： 10.3390/v14020259

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Vaccine hesitancy regarding the coronavirus disease 2019 (COVID-19) vaccine is widespread during the COVID-19 pandemic. Many recent studies have reported that the confidence of the vaccination and perceived risk were associated with vaccination intent, yet few studies have focused on other psychological factors. This study aimed to clarify the trends in COVID-19 vaccination intent and to identify the association between the 5C psychological antecedents and COVID-19 vaccination intent by sex and age in Japan. This was a longitudinal study conducted through an Internet-based survey from January 2021 to April 2021 before and after vaccine distribution in Japan, including 2,655 participants recruited by quota sampling. Participants were asked to indicate how likely they were to get vaccinated against COVID-19. In the second survey, the participants responded to questions regarding the 5C psychological antecedents: confidence, complacency, constraints (structural and psychological barriers), calculation (engagement in extensive information searching), and collective responsibility (willingness to protect others). Multiple logistic regression analysis was performed to clarify the association between the 5C psychological antecedents and COVID-19 vaccination intent in the second wave survey. COVID-19 vaccination intent improved from 62.1% to 72.4% after vaccine distribution, but no significant difference was found in young men. Confidence and collective responsibility were positively associated with vaccination intent, and calculation was negatively associated among all generations. COVID-19 vaccination intent may be affected not only by confidence and constraints but also by calculation and collective responsibility, and further research is needed.

DOI： 10.1080/21645515.2021.1968217

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BACKGROUND: School closures are a subject of debate during the present coronavirus disease 2019 (COVID-19) pandemic. Because children are not the main driver of COVID-19 transmission in the community, school education must be prioritized in conjunction with appropriate infection prevention and control measures, as determined by local COVID-19 incidence. METHODS: We investigated the causes and transmission routes of a primary school cluster of COVID-19 that occurred during November and December 2020 in Niigata, Japan. RESULTS: In the cluster, the virus spread among teachers, then from teachers to students, and then to their family members. This primary school cluster comprised 26 infected patients and included teachers (13/33, 39%), students (9/211, 4%), and family members (4/65, 6%). The secondary attack rate from the 3 index teachers to the remaining 30 teachers was 33%; however, the rate to students was only 4%. Factors contributing to cluster formation include the fact that 2 of the index teachers continued working while symptomatic and that the environment and infection prevention measures in the teachers' room were inadequate. CONCLUSIONS: To open schools safely and without interruption, adequate measures to prevent COVID-19 infection in schools should be emphasized not only for children but also for teachers and their environment.

DOI： 10.1097/INF.0000000000003292

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OBJECTIVES: We aimed to identify the concerns, current implementation status and correct usage, and factors inhibiting implementation and correct use of a COVID-19 contact tracing application among the ordinary citizens in Japan. STUDY DESIGN: This was a cross-sectional study based on an internet survey completed by 2013 participants who were selected among registrants of an Internet research company between September 8 and 13, 2020. METHODS: Participants completed an online survey that included thoughts and concerns about the application, status of use, and questions about whether the application was being used correctly. We performed multiple logistic regression analysis to clarify the association between the use of the app and sociodemographic factors and user concerns. RESULTS: Of the 2013 respondents, 429 (21.3%) participants reported using this application, but only 60.8% of them used it correctly. The percentage of those having some concerns about the application ranged from 45.9% to 75.5%, with the highest percentage being 'doubts about effectiveness of apps for preventing spread of infection'. Multiple logistic regression analysis revealed, the main concerns inhibiting application use were insufficient knowledge of how to use it, privacy concerns, doubts about the effectiveness of the app, and concerns about battery consumption and communication costs. Additionally, the prevalence of the application was lower for lower-income individuals. CONCLUSIONS: The findings suggest that income may create inequalities in the efficacy and effectiveness of COVID-19 contact tracing applications. Awareness activity strategies to dispel such concerns and support low-income individuals may be needed.

DOI： 10.1016/j.puhip.2021.100125

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We aimed to clarify the status of hand hygiene practices among ordinary citizens during the COVID-19 pandemic in Japan, as well as the frequency of daily hand hygiene as an indicator of education and evaluation. This cross-sectional study was based on an internet survey completed by 2,149 participants (age range: 20-79 years, men: 51.0%, response rate: 89.5%), selected from June 23 to 28, 2020. The participants responded regarding the frequency of implementing hand hygiene at 5 moments (after returning from a public place, after using the toilet, after touching something outside, before eating food, and after blowing the nose, coughing, or sneezing). Additionally, the participants responded to the number of daily hand hygiene events. The cutoff value of the total number of daily hand hygiene events to determine whether hand hygiene was performed at all 5 time points was determined using receiver operating characteristic analysis. The mean number of hand hygiene events was 10.2 times/day. The prevalence of implementing hand hygiene at each moment ranged from 30.2% to 76.4%; only 21.1% of respondents practiced hand hygiene at all times. Both Youden Index and specificity were high when the cut-off value was 11 times/day. Therefore, the criterion of hand hygiene (≥11 times/day) may be useful in education and evaluation.

DOI： 10.7883/yoken.JJID.2020.631

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We studied genetic variation in the second hypervariable region (HVR) of the G gene of human respiratory syncytial virus (HRSV) from 1701 nasal swab samples collected from outpatients with acute respiratory infections at two general hospitals in the cities Yangon and Pyinmana in Myanmar from 2015 to 2018. HRSV genotypes were characterized using phylogenetic trees constructed using the maximum likelihood method. Time-scale phylogenetic tree analyses were performed using the Bayesian Markov chain Monte Carlo method. In total, 244 (14.3%) samples were HRSV-positive and were classified as HRSV-A (n = 84, 34.4%), HRSV-B (n = 158, 64.8%), and co-detection of HRSV-A/HRSV-B (n = 2, 0.8%). HRSV epidemics occurred seasonally between July (1.9%, 15/785) and August (10.5%, 108/1028), with peak infections in September (35.8%, 149/416) and October (58.2%, 89/153). HRSV infection rate was higher in children ≥1 year of age than in those <1 year of age (70.5% vs. 29.5%). The most common HRSV symptoms in children were cough (80%-90%) and rhinorrhea (70%-100%). The predominant genotypes were ON1for HRSV-A (78%) and BA9 for HRSV-B (64%). Time to the most recent common ancestor was 2014 (95% highest posterior density [HPD], 2012-2015) for HRSV-A ON1 and 2009 (95% HPD, 2004-2012) for HRSV-B BA9. The mean evolutionary rate (substitutions/site/year) for HRSV-B (2.12 × 10-2, 95% HPD, 8.53 × 10-3-3.63 × 10-2) was slightly higher than that for HRSV-A (1.39 × 10-2, 95% HPD, 6.03 × 10-3-2.12 × 10-2). The estimated effective population size (diversity) for HRSV-A increased from 2015 to 2016 and declined in mid-2018, whereas HRSV-B diversity was constant in 2015 and 2016 and increased in mid-2017. In conclusion, the dominant HRSV-A and HRSV-B genotypes in Myanmar were ON1 and BA9, respectively, between 2015 and 2018. HRSV-B evolved slightly faster than HRSV-A and exhibited unique phylogenetic characteristics.

DOI： 10.1016/j.meegid.2021.104927

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BACKGROUND: Non-pharmaceutical interventions (NPIs), such as sanitary measures and travel restrictions, aimed at controlling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may affect the transmission dynamics of human respiratory syncytial virus (HRSV). We aimed to quantify the contribution of the sales of hand hygiene products and the number of international and domestic airline passenger arrivals on HRSV epidemic in Japan. METHODS: The monthly number of HRSV cases per sentinel site (HRSV activity) in 2020 was compared with the average of the corresponding period in the previous 6 years (from January 2014 to December 2020) using a monthly paired t-test. A generalized linear gamma regression model was used to regress the time-series of the monthly HRSV activity against NPI indicators, including sale of hand hygiene products and the number of domestic and international airline passengers, while controlling for meteorological conditions (monthly average temperature and relative humidity) and seasonal variations between years (2014-2020). RESULTS: The average number of monthly HRSV case notifications in 2020 decreased by approximately 85% (p < 0.001) compared to those in the preceding 6 years (2014-2019). For every average \1 billion (approximately £680,000/$9,000,000) spent on hand hygiene products during the current month and 1 month before there was a 0.29% (p = 0.003) decrease in HRSV infections. An increase of average 1000 domestic and international airline passenger arrivals during the previous 1-2 months was associated with a 3.8 × 10- 4% (p < 0.001) and 1.2 × 10- 3% (p < 0.001) increase in the monthly number of HRSV infections, respectively. CONCLUSIONS: This study suggests that there is an association between the decrease in the monthly number of HRSV cases and improved hygiene and sanitary measures and travel restrictions for COVID-19 in Japan, indicating that these public health interventions can contribute to the suppression of HRSV activity. These findings may help in public health policy and decision making.

DOI： 10.1186/s12879-021-06461-5

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Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A (H1N1)pdm09 and A (H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 101 to 106 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A (H1N1)pdm09 viruses with PA/I38T substitutions and four A (H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A (H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.

DOI： 10.1016/j.antiviral.2021.105036

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Since the coronavirus disease 2019 (COVID-19) emerged in Wuhan, China, in December 2019, it has rapidly spread worldwide, and the number of cases is also increasing in Japan. The number of COVID-19 cases in Japan in the early stages was not uniform, and cases were largely concentrated in several prefectures. There was a strong, positive correlation between the distribution of COVID-19 cases and the number of foreign travelers as well as Chinese travelers, at prefectural level, with coefficients of 0.68 (P < 0.0001) and 0.60 (P < 0.0001), respectively. Moreover, phylogenetic tree analysis revealed that all the registered SARS-CoV-2 detected from January 23 to February 29, 2020, belonged to Chinese lineage, while those detected in March 2020 belonged to American and European lineages. Only 14 (20.3%) were infected outside Japan; however, the majority of the cases (79.7%) were infected domestically. In conclusion, a higher number of COVID-19 cases were identified in prefectures with more Chinese travelers, supporting the importance of enforcing policies that restrict the entry of overseas travelers to control COVID-19 spread. These findings highlight the risk of secondary transmission in the community caused by apparent or silently imported cases.

DOI： 10.7883/yoken.JJID.2020.471

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Vaccination could be a key protective measure against coronavirus disease 2019 (COVID-19), and it is important to understand the acceptability of the COVID-19 vaccine among the general public. However, there is no study on the acceptance of a COVID-19 vaccine in Japan. Therefore, this study aimed to describe the COVID-19 vaccine acceptance and hesitancy situation in Japan and assess the factors associated with such issues. This was a cross-sectional study based on an internet survey completed by 2956 people. Participants were asked to indicate how likely they were to get vaccinated for COVID-19. In addition, the participants responded to questions regarding sociodemographic factors, attitudes, and beliefs regarding COVID-19 infection and vaccination. The proportion of participants with a high likelihood of getting a COVID-19 vaccine was 62.1%. Multiple logistic regression analysis showed that vaccine acceptance was lower among several sociodemographic groups, such as women, adults aged 20-49 years, and those with a low-income level. Several psychological factors, especially the perceived effectiveness of the COVID-19 vaccine, and willingness to protect others by getting oneself vaccinated, were associated with vaccine acceptance. Our results indicate that the perceived effectiveness of the vaccine and willingness to protect others may play an important role in the acceptance of the COVID-19 vaccine.

DOI： 10.3390/vaccines9030210

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BACKGROUND: It has been indicated that the health impact of COVID-19 is potentially greater in individuals from lower socioeconomic status than in the overall population. AIMS: To examine how the spread of COVID-19 has altered the general public's mental health, and whether such changes differ in relation to individual income. METHOD: An online longitudinal survey was conducted at three different time periods during the pandemic. We recruited 1993 people aged 20-70 years, living in the Tokyo metropolitan area in Japan. Participants' mental health was measured with the six-item version of the Kessler Psychological Distress Scale; the existence of severe psychological distress was ascertained through the cut-off data. Multiple logistic and mixed-model ordinal logistic regression analyses were performed, with income as the independent variable. RESULTS: Of the participants, 985 were male, with a mean age of 50.5 (±15.8) years. Severe psychological distress percentages for each tested period were 9.3%, 11.2% and 10.7% for phases 1, 2 and 3, respectively. Between phases 1 and 2 or phases 2 and 3, the group that earned <£15 000 had significantly higher propensity to develop severe psychological distress than the group that earned ≥£45 000 (odds ratio 2.09, 95% CI 0.95-4.56 between phases 1 and 2; odds ratio 3.00, 95% CI 1.01-9.58 between phases 2 and 3). CONCLUSIONS: Although there has been significant deterioration in mental health among citizens during the COVID-19 pandemic, this was more significant among those with lower income. Therefore, mental health measures that focus on low socioeconomic groups may be necessary.

DOI： 10.1192/bjo.2021.5

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Few studies have examined the effects of inbound overseas travelers and meteorological conditions on the shift in human respiratory syncytial virus (HRSV) season in Japan. This study aims to test whether the number of inbound overseas travelers and meteorological conditions are associated with the onset week of HRSV epidemic season. The estimation of onset week for 46 prefectures (except for Okinawa prefecture) in Japan for 4-year period (2014-2017) was obtained from previous papers based on the national surveillance data. We obtained data on the yearly number of inbound overseas travelers and meteorological (yearly mean temperature and relative humidity) conditions from Japan National Tourism Organization (JNTO) and Japan Meteorological Agency (JMA), respectively. Multi-level mixed-effects linear regression analysis showed that every 1 person (per 100,000 population) increase in number of overall inbound overseas travelers led to an earlier onset week of HRSV epidemic season in the year by 0.02 week (coefficient -0.02; P<0.01). Higher mean temperature and higher relative humidity were also found to contribute to an earlier onset week by 0.30 week (coefficient -0.30; P<0.05) and 0.18 week (coefficient -0.18; P<0.01), respectively. Additionally, models that included the number of travelers from individual countries (Taiwan, South Korea, and China) except Australia showed that both the number of travelers from each country and meteorological conditions contributed to an earlier onset week. Our analysis showed the earlier onset week of HRSV epidemic season in Japan is associated with increased number of inbound overseas travelers, higher mean temperature, and relative humidity. The impact of international travelers on seasonality of HRSV can be further extended to investigations on the changes of various respiratory infectious diseases especially after the coronavirus disease 2019 (COVID-19) pandemic.

DOI： 10.1371/journal.pone.0248932

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The coronavirus disease 2019 (COVID-19) has caused a serious disease burden and poses a tremendous public health challenge worldwide. Here, we report a comprehensive epidemiological and genomic analysis of SARS-CoV-2 from 63 patients in Niigata City, a medium-sized Japanese city, during the early phase of the pandemic, between February and May 2020. Among the 63 patients, 32 (51%) were female, with a mean (±standard deviation) age of 47.9 ± 22.3 years. Fever (65%, 41/63), malaise (51%, 32/63), and cough (35%, 22/63) were the most common clinical symptoms. The median C t value after the onset of symptoms lowered within 9 days at 20.9 cycles (interquartile range, 17-26 cycles), but after 10 days, the median C t value exceeded 30 cycles (p < 0.001). Of the 63 cases, 27 were distributed in the first epidemic wave and 33 in the second, and between the two waves, three cases from abroad were identified. The first wave was epidemiologically characterized by a single cluster related to indoor sports activity spread in closed settings, which included mixing indoors with families, relatives, and colleagues. The second wave showed more epidemiologically diversified events, with most index cases not related to each other. Almost all secondary cases were infected by droplets or aerosols from closed indoor settings, but at least two cases in the first wave were suspected to be contact infections. Results of the genomic analysis identified two possible clusters in Niigata City, the first of which was attributed to clade S (19B by Nexstrain clade) with a monophyletic group derived from the Wuhan prototype strain but that of the second wave was polyphyletic suggesting multiple introductions, and the clade was changed to GR (20B), which mainly spread in Europe in early 2020. These findings depict characteristics of SARS-CoV-2 transmission in the early stages in local community settings during February to May 2020 in Japan, and this integrated approach of epidemiological and genomic analysis may provide valuable information for public health policy decision-making for successful containment of chains of infection.

DOI： 10.3389/fmicb.2021.749149

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BACKGROUND: This longitudinal study aimed to examine the changes in psychological distress of the general public from the early to community-transmission phases of the COVID-19 pandemic and to investigate the factors related to these changes. METHODS: An internet-based survey of 2,400 Japanese people was conducted in two phases: early phase (baseline survey: February 25-27, 2020) and community-transmission phase (follow-up survey: April 1-6, 2020). The presence of severe psychological distress (SPD) was measured using the Kessler's Six-scale Psychological Distress Scale. The difference of SPD percentages between the two phases was examined. Mixed-effects ordinal logistic regression analysis was performed to assess the factors associated with the change of SPD status between the two phases. RESULTS: Surveys for both phases had 2,078 valid respondents (49.3% men; average age, 50.3 years). In the two surveys, individuals with SPD were 9.3% and 11.3%, respectively, demonstrating a significant increase between the two phases (P = 0.005). Significantly higher likelihood to develop SPD were observed among those in lower (ie, 18,600-37,200 United States dollars [USD], odds ratio [OR] 1.95; 95% confidence interval [CI], 1.10-3.46) and the lowest income category (ie, <18,600 USD, OR 2.12; 95% CI, 1.16-3.86). Furthermore, those with respiratory diseases were more likely to develop SPD (OR 2.56; 95% CI, 1.51-4.34). CONCLUSIONS: From the early to community-transmission phases of COVID-19, psychological distress increased among the Japanese. Recommendations include implementing mental health measures together with protective measures against COVID-19 infection, prioritizing low-income people and those with underlying diseases.

DOI： 10.2188/jea.JE20200271

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We conducted a prospective, multicenter, non-randomized observational study to assess the duration of fever and symptoms of influenza A/H1N1pdm09 and A/H3N2 infected children < 19 years old treated with either baloxavir or oseltamivir. Additionally, these symptoms were investigated in association with pre- and post-baloxavir treatment-emergent polymerase acidic unit (PA) variants as compared to non-substituted viruses. Following receipt of informed consent, baloxavir was administered to 102 influenza A patients, and oseltamivir to 52 patients during the 2018-2019 influenza season in Japan. The average age was higher in the baloxavir treatment group compared to the oseltamivir treatment group (10.6 ± 2.7 versus 6.9 ± 2.9 years old, p < 0.01). The duration of fever and symptoms in baloxavir-treated A/H1N1pdm09 and A/H3N2-infected children did not differ from those in oseltamivir-treated groups (median 22.0, 11.8, 23.0, and 21.0 h, and median 114.5, 121.0, 123.0, and 122.0 h, respectively). One (1.2%) of 83 A/H3N2 patients possessed a PA/I38T substituted virus prior to treatment. The frequency of PA variants in post-treatment samples obtained 2-11 days after beginning of baloxavir was 12.5% (4/32) for A/H1N1pdm09 and 14.1% (9/64) for A/H3N2 when the total number of cases was used as the denominator, however, were 57.1% (4/7) and 33.3% (9/27) when PCR-positive cases at the time of second sampling was used as the denominator. The most frequent PA substitution was I38T (9), with E23K (1), I38K (1), I38M (1), and PA/I38S (1) also observed. The duration of fever and overall symptoms did not differ significantly following baloxavir treatment in individuals with PA variant viruses, non-substituted virus, or in those that were PCR negative at the second sampling (median 20, 24 and 11 h, and median 121, 115 and 121 h, respectively). Rebound of viral RNA load was observed in 13.5% (2/13) of PA variants but it was not associated with recurrence of fever and symptoms. Hence, prolonged fever or symptoms were not observed in children treated with baloxavir following emergence of PA variants, however, further studies are needed to evaluate the clinical impact of PA variants.

DOI： 10.1016/j.antiviral.2020.104951

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Since the emergence of the COVID-19 pandemic, the use of face masks by healthy individuals for prevention has been attracting public attention. However, efficacy depends on proper usage. We set out to determine the prevalence of wearing masks to prevent COVID-19 and compliance with appropriate measures for the correct use of face masks among the general public in Japan where wearing medical masks is a "cultural" normality. This cross-sectional study was based on an internet-based survey completed by 2141 people (50.8% men, aged 20-79 years) who were selected among registrants of an Internet research company between 1 April and 6 April 2020. Participants were asked to indicate how often they wore masks for prevention and to what extent they practiced appropriate measures suggested by the World Health Organization. The prevalence of wearing masks was 80.9% and compliance rates with appropriate measures ranged from 38.3% to 83.5%. Only 23.1% complied with all recommendations. Compliance rates were overall low in men and persons with low household incomes. Our results, hence show that many citizens implement inaccurate measures when using face masks. Therefore, providing guidance on correct usage is essential when encouraging the use of face masks to prevent COVID-19.

DOI： 10.3390/ijerph17186484

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BACKGROUND: We investigated the association between age, duration of clinical symptoms and viral shedding in outpatient children infected with respiratory syncytial virus (RSV) in Japan. METHODS: Outpatients younger than 2 years of age, with suspected RSV infection between 2014 and 2018, were enrolled in the study. Following informed consent, nasal samples were collected at first and second clinic visits (with 0-9 days gap). RSV-A or -B infection and viral load were determined by real-time polymerase chain reaction. Clinical symptoms were recorded at first clinic visit, and fever and symptoms were recorded at home for up to 8 days. Association between clinical symptoms and patient characteristics, such as age, sex and birth weight, were analyzed using ordered logistic regression analysis. The association between viral reduction and estimated shedding period was examined using linear regression analysis. RESULTS: Among the 205 cases enrolled in the study, no difference was found in patient characteristics between RSV-A and -B infection. Duration of fever was prolonged with increased age. Duration of rhinorrhea and cough was shorter in females than in males and in groups with birth weight ≥3 kg than in those with <2.5 kg. Daily viral reduction increased and estimated viral elimination period decreased with age. CONCLUSIONS: Fever duration was found to increase while viral shedding decreased with patient age.

DOI： 10.1097/INF.0000000000002626

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OBJECTIVES: To clarify changes in the implementation of personal protective measures among ordinary Japanese citizens from the early phase of the COVID-19 outbreak to the community transmission phase. METHODS: This longitudinal, internet-based survey included 2141 people (50.8% men; 20-79 years). The baseline and follow-up surveys were conducted from February 25-27, 2020, and April 1-6, 2020, respectively. Participants were asked how often they implemented the five personal protective measures recommended by the World Health Organization (hand hygiene, social distancing, avoiding touching the eyes, nose and mouth, respiratory etiquette, and self-isolation) in the baseline and follow-up surveys. RESULTS: Three of the five personal protective measures' availability significantly improved during the community transmission phase compared to the early phase. Social distancing measures showed significant improvement, from 67.4% to 82.2%. However, the prevalence of avoiding touching the eyes, nose, and mouth, which had the lowest prevalence in the early phase, showed no significant improvement (approximately 60%). Multivariate logistic regression analysis revealed that men and persons of low-income households made fewer improvements than women and persons of high-income households. CONCLUSIONS: The availability of personal protective measures by ordinary citizens is improving; however, there is potential for improvement, especially concerning avoiding touching eyes, nose, and mouth.

DOI： 10.1016/j.ijid.2020.05.039

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BACKGROUND: Influenza is a major cause of morbidity and mortality worldwide. Following the 2009 pandemic, there was widened interest in studying influenza burden in all regions. However, since data from the World Health Organization (WHO) Middle East and North Africa (MENA) region remain limited, we aimed to contribute to the understanding of influenza burden in Lebanon. METHODS: A retrospective chart review extending over a period of 8 seasons from Jan 1st, 2008 till June 30th, 2016 at a tertiary care center in Beirut was performed. All cases confirmed to have influenza based on rapid antigen detection or/and polymerase chain reaction on a respiratory sample were included for analysis. Data on epidemiology, clinical presentation, complications, antiviral use and mortality were collected for analysis. RESULTS: A total of 1829 cases of laboratory-confirmed influenza were identified. Average annual positivity rate was 14% (positive tests over total requested). Both influenza A and B co-circulated in each season with predominance of influenza A. Influenza virus started circulating in December and peaked in January and February. The age group of 19-50 years accounted for the largest proportion of cases (22.5%) followed by the age group of 5-19 years (18%). Pneumonia was the most common complication reported in 33% of cases. Mortality reached 3.8%. The two extremes of age (< 2 years and ≥ 65 years) were associated with a more severe course of disease, hospitalization, intensive care unit (ICU) admission, complications, and mortality rate. Of all the identified cases, 26% were hospitalized. Moderate-to-severe disease was more likely in influenza B cases but no difference in mortality was reported between the two types. Antivirals were prescribed in 68.8% and antibiotics in 41% of cases. There seemed to be an increasing trend in the number of diagnosed and hospitalized cases over the years of the study. CONCLUSION: Patients with laboratory-confirmed influenza at our center had a high rate of hospitalization and mortality. A population based prospective surveillance study is needed to better estimate the burden of Influenza in Lebanon that would help formulate a policy on influenza control.

DOI： 10.1186/s12879-020-05013-7

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OBJECTIVES: To clarify the implementation status of personal protective measures by ordinary citizens in Japan during the coronavirus disease 2019 (COVID-19) outbreak. METHODS: This was a cross-sectional study based on internet-based survey. A total of 2400 people (50% male: 20-79 years) were selected between February 25 and 27, 2020, from registrants of an Internet research company, to complete a questionnaire. Participants were asked to indicate how often they implemented the following five personal protective measures recommended by the World Health Organization (hand hygiene, social distancing measures, avoiding touching the eyes, nose and mouth, respiratory etiquette, and self-isolation). In addition, the participants responded to questions regarding the daily frequency of hand hygiene events. RESULTS: The prevalence of the five personal protective measures ranged from 59.8% to 83.8%, with the lowest being avoiding touching the eyes, nose, and mouth. In total, 34.7% implemented all personal protective measures. The median daily hand hygiene events were 5 per day (25th percentile, 75th percentile: 3,8). CONCLUSIONS: The protective measures implemented by ordinary citizens are insufficient and further public awareness activities are required.

DOI： 10.1016/j.ijid.2020.04.014

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Poor sleep is associated with lifestyle, however, few studies have addressed the association between sleep quality and the neighborhood environment. This study aimed to investigate the associations between living environment factors and sleep quality in older people. Participants were community-dwelling people aged ≥65 years who participated in the 2010 Japanese Gerontological Evaluation Study. The data of 16,650 people (8102 men, 8548 women) were analyzed. Sleep quality (good or poor) was evaluated using a self-administered questionnaire. Multilevel Poisson regression analysis stratified by depressive status (measured by the Geriatric Depression Scale-15 [GDS]) was conducted with sleep quality as the dependent variable and social and physical environmental factors as explanatory variables. The 12,469 non-depressive respondents and 4181 depressive respondents were evaluated. The regression analysis indicated that non-depressive participants slept better if they lived in environments with few hills or steps (prevalence ratio [PR] = 0.75, 95% CI: 0.56-0.9) and with places where they felt free to drop in (PR = 0.51, 95% CI: 0.26-0.98). For depressive participants, these associations were not evident. Living alone, poor self-rated health, low income, and unemployment were associated with poor sleep quality. In addition to support with these individual factors, improving environmental factors at the neighborhood level may improve the sleep quality of community-dwelling older adults.

DOI： 10.3390/ijerph17041398

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A community outbreak of human influenza A(H1N1)pdm09 virus strains was observed in Myanmar in 2017. We investigated the circulation patterns, antigenicity, and drug resistance of 2017 influenza A(H1N1)pdm09 viruses from Myanmar and characterized the full genome of influenza virus strains in Myanmar from in-patients and out-patients to assess the pathogenicity of the viruses. Nasopharyngeal swabs were collected from out-patients and in-patients with acute respiratory tract infections in Yangon and Pyinmana City in Myanmar during January-December 2017. A total of 215 out-patients and 18 in-patients infected with A(H1N1)pdm09 were detected by virus isolation and real-time RT-PCR. Among the positive patients, 90.6% were less than 14 years old. Hemagglutination inhibition (HI) antibody titers against A(H1N1)pdm09 viruses in Myanmar were similar to the recommended Japanese influenza vaccine strain for 2017-2018 seasons (A/Singapore/GP1908/2015) and WHO recommended 2017 southern hemisphere vaccine component (A/Michigan/45/2015). Phylogenetic analysis of the hemagglutinin sequence showed that the Myanmar strains belonged to the genetic subclade 6B.1, possessing mutations of S162N and S164T at potential antigenic sites. However, the amino acid mutation at position 222, which may enhance the severity of disease and mortality, was not found. One case with no prior history of oseltamivir treatment possessed H275Y mutated virus in neuraminidase (NA), which confers resistance to oseltamivir and peramivir with elevated IC50 values. The full genome sequence of Myanmar strains showed no difference between samples from in-patients and out-patients, suggesting no additional viral mutations associated with patient severity. Several amino acid changes were observed in PB2, PB1, and M2 of Myanmar strains when compared to the vaccine strain and other Asian strains. However, no mutations associated with pathogenicity were found in the Myanmar strains, suggesting that viral factors cannot explain the underlying reasons of the massive outbreak in Myanmar. This study reported the first detection of an oseltamivir-resistant influenza virus in Myanmar, highlighting the importance of continuous antiviral monitoring and genetic characterization of the influenza virus in Myanmar.

DOI： 10.1371/journal.pone.0229601

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BACKGROUND: Self-isolation is an important personal protective measure in inhibiting the transmission of coronavirus disease 2019 (COVID-19) as people carry out economic and social activities amid its spread. Yet few studies have clarified the actual implementation status of self-isolation during an outbreak. This study aimed to reveal the actual implementation of self-isolation among Japanese workers during the COVID-19 outbreak and the factors inhibiting this measure. METHODS: This was a cross-sectional study based on an internet survey completed by 1,226 workers (60.0% men) living in 7 prefectures (i.e., Tokyo, Kanagawa, Saitama, Chiba, Ibaraki, Tochigi, and Gunma) who were selected among registrants of an Internet research company, between May 12 and 17, 2020. Participants were asked whether they had experienced fever or other cold symptoms between February 17, 2020 and the date of the survey. Those who responded affirmatively were asked where they had visited (e.g., hospital, work, and shopping for groceries or necessities) to clarify whether they had left the house within 7 days after symptom onset. We performed multivariate logistic regression analysis to clarify the relationship between going to work within 7 days after symptom onset and both sociodemographic factors and employment-related constraints. RESULTS: Of the survey participants, 82 had experienced fever or other cold symptoms (6.7%). Among these participants, 51 (62.2%) went to work within 7 days after symptom onset. A mere 17.1% practiced strict self-isolation. Multivariate logistic regression analysis revealed that those living outside the metropolitan area (i.e., Ibaraki, Tochigi, and Gunma), working as a company employee, and being unable to work from home were associated with going to work within 7 days after symptom onset. CONCLUSIONS: The prevalence of strict self-isolation among participants who experienced cold-like symptoms during the COVID-19 outbreak was extremely low, and 62.2% of these participants went to work within 7 days after symptom onset. This study highlights the need for further public awareness regarding self-isolation and countermeasures against factors that obstruct it.

DOI： 10.1186/s41182-020-00250-7

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BACKGROUND: We estimated influenza vaccine effectiveness (VE) in 2015-2016 season against medically attended, laboratory-confirmed influenza, when quadrivalent inactivated vaccine (IIV4) was first introduced in Japan, using test-negative case-control design. Influenza A(H1N1)pdm09 cocirculated with B/Yamagata and B/Victoria during the study period in Japan. METHOD: We based our case definition on two laboratory tests, real-time reverse transcription polymerase chain reaction (RT PCR), and virus isolation and compared VEs based on these tests. In addition, VE was evaluated by rapid diagnostic test (RDT). Nasopharyngeal swabs were collected from outpatients who visited clinics with influenza-like illness (ILIs) in Hokkaido, Niigata, Gunma and Nagasaki prefectures. RESULTS: Among 713 children and adults enrolled in this study, 578 were influenza positive by RT PCR including, 392 influenza A and 186 influenza B, while 135 were tested negative controls. The adjusted VE by RT PCR for all ages against any influenza was low protection of 36.0% (95% confidence interval [CI], 3.1% to 58.6%), for influenza A was 30.0% (95% CI: -10.0% to 55.5%), and influenza B was moderate 50.2% (95% CI: 13.3% to 71.4%). Adjusted VE for virus isolation for A(H1N1)pdm09 was 37.1% (95% CI: 1.7% to 59.7%), Yamagata lineage 51.3% (95% CI: 6.4% to 74.7%) and Victoria lineage 21.3% (95% CI: -50.0% to 58.9%). VE was highest and protective in 0-5 years old group against any influenza and influenza A and B/Yamagata, but the protective effect was not observed for other age groups and B/Victoria. RDT demonstrated concordant results with RT PCR and virus isolation. Sequencing of hemagglutinin gene showed that all A(H1N1)pdm09 belong to clade 6B including 31 strains (88.6%), which belong to clade 6B.1 possessing S162N mutations that may alter antigenicity and affect VE for A(H1N1)pdm09. CONCLUSIONS: IIV4 influenza vaccine during 2015-2016 was effective against A(H1N1)pdm09 and the two lineages of type B. Younger children was more protected than older children and adults by vaccination.

DOI： 10.1016/j.jvacx.2019.100011

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We investigated the circulation patterns of human influenza A and B viruses in Myanmar between 2010 and 2015 by analyzing full HA genes. Upper respiratory tract specimens were collected from patients with symptoms of influenza-like illness. A total of 2,860 respiratory samples were screened by influenza rapid diagnostic test, of which 1,577 (55.1%) and 810 (28.3%) were positive for influenza A and B, respectively. Of the 1,010 specimens that were positive for virus isolation, 370 (36.6%) were A(H1N1)pdm09, 327 (32.4%) were A(H3N2), 130 (12.9%) B(Victoria), and 183 (18.1%) were B(Yamagata) viruses. Our data showed that influenza epidemics mainly occurred during the rainy season in Myanmar. Our three study sites, Yangon, Pyinmana, and Pyin Oo Lwin had similar seasonality and circulating type and subtype of influenza in a given year. Moreover, viruses circulating in Myanmar during the study period were closely related genetically to those detected in Thailand, India, and China. Phylogeographic analysis showed that A(H1N1)pdm09 viruses in Myanmar originated from Europe and migrated to other countries via Japan. Similarly, A(H3N2) viruses in Myanmar originated from Europe, and disseminated to the various countries via Australia. In addition, Myanmar plays a key role in reseeding of influenza B viruses to Southeast Asia and East Asia as well as Europe and Africa. Thus, we concluded that influenza virus in Myanmar has a strong link to neighboring Asian countries, Europe and Oceania.

DOI： 10.1371/journal.pone.0210550

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Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections in children and immunocompromised individuals. A multi-center surveillance of the epidemiologic and molecular characteristics of RSV circulating in Lebanon was performed. The attachment (G) and fusion (F) glycoproteins were analyzed and compared to those reported regionally and globally. 16% (83/519) of the nasopharyngeal swabs collected during the 2016/17 season tested positive for RSV; 50% (27/54) were RSV-A and 50% (27/54) were RSV-B. Phylogenetic analysis of the G glycoprotein revealed predominance of the RSVA ON1 genotype, in addition to two novel Lebanese genotype variants, hereby named LBA1 and LBA2, which descended from the ON1 and NA2 RSV-A genotypes, respectively. RSV-B strains belonged to BA9 genotype except for one BA10. Deduced amino acid sequences depicted several unique substitutions, alteration of glycosylation patterns and the emergence of palivizumab resistance among the Lebanese viruses. The emergence of ON1 and other novel genotypes that are resistant to palivizumab highlights the importance of monitoring RSV globally.

DOI： 10.1371/journal.pone.0212687

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BACKGROUND: Neuraminidase inhibitors (NAIs) effectively treat influenza. The clinical effectiveness of four NAIs (oseltamivir, zanamivir, laninamivir, and peramivir) was evaluated against influenza A/H1N1pdm09, A/H3N2, and B viruses. Additionally, fever duration in patients infected with oseltamivir-resistant influenza A/H1N1pdm09 with the H275Y mutation was evaluated. METHODS: Patients aged <20 years who visited outpatient clinics in Japan with influenza-like illnesses were enrolled during 4 influenza seasons from 2012/2013 to 2015/2016. After obtaining informed consent, patients who tested positive for influenza with rapid tests received one of the four NAIs. Patients recorded their body temperature daily for 8 days from the first visit. The influenza strain was identified using real-time polymerase chain reaction. Univariate and multivariable analyses were used to evaluate factors influencing fever duration. In children aged ≤5 years treated with oseltamivir, fever duration in oseltamivir-resistant A/H1N1pdm09-infected patients was compared to that in oseltamivir-sensitive A/H1N1pdm09-infected patients. RESULTS: Of the 1,368 patients analyzed, 297 (21.7%), 683 (49.9%), and 388 (28.4%) were infected with influenza A/H1N1pdm09, A/H3N2, and B, respectively. In multivariable analysis factors associated with significantly prolonged fever duration included: treatment with laninamivir (hazard ratio [HR]: 0.78, p = 0.006, compared to oseltamivir), influenza B (HR: 0.58, p<0.001, compared to influenza A/H1N1pdm09), and a higher body temperature at the clinic visit (HR: 0.87 per degree Celsius, p<0.001). Increasing age was associated with a significantly shorter duration of fever (HR: 1.31 for 6-9 years old, p<0.001; and HR: 1.65 for 10-19 years old, p<0.001, respectively, compared to 0-5 years old). Following treatment with oseltamivir, fever duration was significantly longer for oseltamivir-resistant A/H1N1pdm09-infected patients (n = 5) than for oseltamivir-sensitive A/H1N1pdm09 infected patients (n = 111) (mean, 89 versus 40 hours, p<0.001). CONCLUSIONS: Our results revealed characteristic information on the effectiveness of the four NAIs and also on oseltamivir-resistant viruses that may affect patients' clinical care.

DOI： 10.1371/journal.pone.0224683

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Influenza B viruses of both the Yamagata and the Victoria lineages are implicated in a large proportion of the morbidity and mortality associated with influenza outbreaks. In this study, we characterized the full genomes of 53 influenza B viruses isolated during 2012-2015 in three Asian countries: Japan, Myanmar, and Vietnam. Analysis of the hemagglutinin (HA) genes revealed co-circulation of both the Yamagata and Victoria lineages within the same season in these countries. Our analysis revealed, that a large proportion of viruses circulating during 2013-2014 in Japan and Vietnam were mismatched to the vaccine supporting the rationale for using quadrivalent vaccines. Molecular analysis of the neuraminidase (NA) genes did not reveal any of the previously reported substitutions associated with reduced susceptibility to neuraminidase inhibitors (NAIs). However, one isolate from Nagasaki displayed reduced inhibition by NAIs, associated with an NA-M426I substitution (N2-numbering). Phylogenetic analysis of the eight genome segments identified a 6 + 2 reassortant strain belonging to the Victoria lineage that circulated in Japan during the 2013-2014 season. This strain appears to have evolved from a descendent of a B/Brisbane/60/2008-like strain in an intra-lineage reassortment event involving the nucleoprotein (NP) and nonstructural (NS) genes. Therefore, influenza B strains circulating worldwide continue to evolve via complex reassortment events, which contribute to their survival and the emergence of new strains. These findings highlight the need for ongoing genome-wide studies of circulating viruses and assessing the implications of these evolutionary events on the vaccines.

DOI： 10.1016/j.meegid.2018.04.016

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OBJECTIVES: Influenza infection can cause severe pneumonia, which is sometimes fatal, particularly in older adults. Influenza results in 3-5 million cases of severe illness and about 250 000 to 500 000 deaths annually worldwide. Social participation in the context of influenza infection is controversial because, although social participation is beneficial in maintaining physical function and mental health, it also increases the risk of contact with infected people. This study examined the association between social participation and influenza infection in Japanese adults aged 65 years or older. DESIGN: Cross-sectional study. SETTING: Japanese functionally independent adults aged 65 years or older. PARTICIPANTS: Among the respondents to the Japan Gerontological Evaluation Study (JAGES) 2013 survey, which took place during the period from October to December 2013, 12 231 men and 14 091 women responded to questions on influenza vaccination and influenza infection. OUTCOME MEASURES: Using JAGES data for 12 231 men and 14 091 women aged ≥65 years, we examined the association between social participation and influenza infection. The association between influenza infection and number of groups in which respondents participated was investigated among adults aged≥65 years, stratified by vaccination status and sex. RESULTS: Unvaccinated women who participated in two or more social activities were 2.20 times (95% CI 1.47 to 3.29) as likely to report an influenza infection as those who reported no social participation. In contrast, vaccinated women who participated in two or more social groups had no additional risk of influenza infection as compared with female elders with no social participation. Among men, participation in social activities was not significantly associated with influenza infection, regardless of vaccination status. CONCLUSIONS: Social participation was associated with a higher risk of influenza infection among unvaccinated older women, which suggests a need for further efforts to promote influenza vaccination, particularly among socially active elderly women.

DOI： 10.1136/bmjopen-2017-016876

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We investigated the genetic diversity, the circulation patterns, and risk for hospital admission of human respiratory syncytial virus (HRSV) strains in Japan between 2012 through 2015. During the study period, 744 HRSV-positive cases were identified by rapid diagnostic test. Of these, 572 samples were positive by real-time PCR; 400 (69.9%) were HRSV-A, and 172 (30.1%) were HRSV-B. HRSV-A and -B alternated as the dominant strain in the subsequent seasons. Phylogenetic tree analysis of the second hyper-variable region of the G protein classified the HRSV-A specimens into NA1 (n = 242) and ON1 (n = 114) genotypes and the HRSV-B specimens into BA9 (n = 60), and BA10 (n = 27). The ON1 genotype, containing a 72-nucleotide duplication in the G protein's second hyper-variable region, was first detected in the 2012-2013 season but it predominated and replaced the older NA1 HRSV-A in the 2014-2015 season, which also coincided with a record number of HRSV cases reported to the National Infectious Disease Surveillance in Japan. The risk of hospitalization was 6.9 times higher for the ON1 genotype compared to NA1. In conclusion, our data showed that the emergence and predominance of the relatively new ON1 genotype in Japan was associated with a record high number of cases and increased risk for hospitalization.

DOI： 10.1371/journal.pone.0192085

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We report five cases of community- and hospital-acquired infections with oseltamivir- and peramivir-resistant A(H1N1)pdm09 viruses possessing the neuraminidase (NA) H275Y mutation during January-February 2016 in Japan. One case was hospitalized and was receiving oseltamivir for prophylaxis. The remaining four cases were not taking antiviral drugs at the time of sampling. These cases were geographically distant and epidemiologically unrelated. The five viruses showed ~300-fold rise in IC50 values against oseltamivir and peramivir, defined as highly reduced inhibition according to the WHO definition. Overall, the prevalence of the H275Y A(H1N1)pdm09 viruses was 1.8 % (5/282). The resistant viruses possessed the V241I, N369 K, and N386 K substitutions in the NA that have been previously reported among A(H1N1)pdm09 to alter transmission fitness. Analysis of Michaelis constant (Km) revealed that two of the isolates had reduced NA affinity to MUNANA, while the other three isolates displayed a slightly decreased affinity compared to the sensitive viruses. Further studies are needed to monitor the community spread of resistant viruses and to assess their transmissibility.

DOI： 10.1007/s11262-016-1396-9

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Objectives Personal income affects dental status in older people. However, the impact of income inequality on dental status at the community level (junior high school district) is unclear. The purpose of this study was to examine the association between dental status and community level income inequity after adjust for individual socio-economic status in Japanese older adults, and to verify the relative income hypothesis, also known as the Wilkinson hypothesis.Methods We used data from the Japan Gerontological Evaluation Study (JAGES) conducted in Niigata city. JAGES is a postal survey of functionally independent adults aged 65 years or older. We enrolled 4,983 respondents (response rate 62.3%) and used data on 3,980 of them after excluding incomplete data. We evaluated health condition and socio-economic status using questionnaires. The Gini coefficient, as an indicator of income inequality, was calculated by junior high school district (57 districts) based on the data from the questionnaire. Additionally, the Pearson's coefficient of correlation was calculated to evaluate the association between the mean number of remaining teeth and the community level Gini coefficient. Then we evaluated the mean number of remaining teeth among the groups stratified by the Gini coefficient conditions. Next, we conducted a multilevel analysis using an ordinal logistic regression model. The number of remaining teeth was set as the dependent variable, while sex, age, household size, education, smoking status, diabetes treatment, current living conditions, and equivalent income were used as independent variables at the individual level. The Gini coefficient and average equivalent income in the junior high school district were used as independent variables at the community level.Results The Pearson's correlation coefficient for the relationship between the Gini coefficient and the mean number of remaining teeth in the junior high school district was -0.44 (P<0.01). Wider income disparity area (Gini coefficient≧0.35) revealed a significantly small number of remaining teeth (P<0.001). The multilevel analysis showed that a higher Gini coefficient and a lower average equivalent income at the community level were significantly associated with a lower number of remaining teeth, and with educational attainment, smoking status, current living conditions, and equivalent income at the individual level, after adjusting for sex and age. On the other hand, educational attainment at the individual level, and average equivalent income at the community level were not significant factors after adjusting for all individual level variables.Conclusion This study showed that, in addition to individual socio-economic status, income inequality at the community level was significantly associated with number of remaining teeth in Japanese older adults. Although the precise mechanism of this association is still unclear, our result supports the relative income hypothesis.

DOI： 10.11236/jph.64.4_190

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BACKGROUND: Influenza A viruses of swine (IAV-S) cause acute and subclinical respiratory disease. To increase our understanding of the etiology of the subclinical form and thus help prevent the persistence of IAV-S in pig populations, we conducted active virologic surveillance in Vietnam, the second-largest pig-producing country in Asia, from February 2010 to December 2013. RESULTS: From a total of 7034 nasal swabs collected from clinically healthy pigs at 250 farms and 10 slaughterhouses, we isolated 172 IAV-S from swine at the weaning and early-fattening stages. The isolation rate of IAV-S was significantly higher among pigs aged 3 weeks to 4.5 months than in older and younger animals. IAV-S were isolated from 16 large, corporate farms and 6 family-operated farms from among the 250 farms evaluated. Multivariate logistic regression analysis revealed that "having more than 1,000 pigs" was the most influential risk factor for IAV-S positivity. Farms affected by reassortant IAV-S had significantly larger pig populations than did those where A(H1N1)pdm09 viruses were isolated, thus suggesting that large, corporate farms serve as sites of reassortment events. CONCLUSIONS: We demonstrate the asymptomatic circulation of IAV-S in the Vietnamese pig population. Raising a large number of pigs on a farm has the strongest impact on the incidence of subclinical IAV-S infection. Given that only some of the corporate farms surveyed were IAV-S positive, further active monitoring is necessary to identify additional risk factors important in subclinical infection of pigs with IAV-S in Vietnam.

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The current School Health and Safety Act in Japan states that children with influenza infection should stay home until day 6(th) after symptoms onset. This was an amendment of a previous version recommending school return on day 3 after defervescence. Here, we investigated the duration of fever and virus shedding after laninamivir treatment in 7 children infected with influenza A(H3N2) virus and 21 children with influenza B virus in relation to the school return timing recommended by the School Health and Safety Act during the 2011-2012 influenza season. Nasal discharge was collected on the first, second, and third hospital visits and virus titers were assessed by virus culture and real-time PCR. Duration of fever after laninamivir treatment was 1 day longer for influenza B than for influenza A(H3N2). Virus detection rates with 50% tissue culture infectious dose and viral RNA were highest at the first visit and gradually decreased at subsequent visits. Virus positivity rates were detectable at the time of defervescence in less than half of the enrolled patients (14.3-42.9%). Virus shedding rates were similarly low (0.0-19.0%) on day 3 or later from defervescence and on day 6 or later from fever onset (school return dates per the old and current School Health and Safety Act) regardless of the influenza type. In conclusion, despite the higher efficacy of laninamivir against A(H3N2) viruses than B viruses, viral shedding is low after return to school for both types, regardless of the version of the School Health and Safety Act.

DOI： 10.1620/tjem.238.113

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Influenza A viruses evolve at a high rate requiring continuous monitoring to maintain the efficacy of vaccines and antiviral drugs. We performed next generation sequencing analysis of 100 influenza A/H3N2 isolates collected in four Asian countries (Japan, Lebanon, Myanmar, and Vietnam) during 2012-2015. Phylogenetic analysis revealed several reassortment events leading to the circulation of multiple clades within the same season. This was particularly evident during the 2013 and 2013/2014 seasons. Importantly, our data showed that certain lineages appeared to be fitter and were able to persist into the following season. The majority of A/H3N2 viruses continued to harbor the M2-S31N mutation conferring amantadine-resistance. In addition, an S31D mutation in the M2-protein, conferring a similar level of resistance as the S31N mutation, was detected in three isolates obtained in Japan during the 2014/2015 season. None of the isolates possessed the NA-H274Y mutation conferring oseltamivir-resistance, though a few isolates were found to contain mutations at the catalytic residue 151 (D151A/G/N or V) of the NA protein. These variations did not alter the susceptibility to neuraminidase inhibitors and were not detected in the original clinical specimens, suggesting that they had been acquired during their passage in MDCK cells. Novel polymorphisms were detected in the PB1-F2 open-reading frame resulting in truncations in the protein of 24-34 aminoacids in length. Thus, this study has demonstrated the utility of monitoring the full genome of influenza viruses to allow the detection of the potentially fittest lineages. This enhances our ability to predict the strain(s) most likely to persist into the following seasons and predict the potential degree of vaccine match or mismatch with the seasonal influenza season for that year. This will enable the public health and clinical teams to prepare for any related healthcare burden, depending on whether the vaccine match is predicted to be good or poor for that season.

DOI： 10.3389/fmicb.2016.00262

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Influenza management and surveillance programs in Japan possess several unique features. The national influenza surveillance is affiliated with National Epidemiological Surveillance for Infectious Diseases (NESID) and features sentinel outpatient surveillance, virological surveillance, and reports on hospitalization, mortality, and influenza-associated encephalopathy. Of note, information on the number of student absences and class/grade/school closures due to influenza are also reported to the government and made publically available. A private online influenza surveillance portal by volunteer doctors provides a real-time information source for the Japanese clinicians and the general public. For influenza treatment, three classes of drugs are approved and covered by national medical insurance in Japan: M2 inhibitors, neuraminidase inhibitors (NAIs), and a polymerase inhibitor. Four NAIs, oseltamivir, zanamivir, laninamivir, and peramivir, are licensed in Japan and are prescribed to seven to eight million patients annually. NAIs are prescribed to any influenza outpatient rather than being limited to severe cases. The majority (80-95 %) of patients start the treatment within 48 h of onset. Laninamivir and peramivir were used almost solely in Japan, until the approval of the latter drug by the FDA. Observational studies showed that the two drugs have equal effectiveness as oseltamivir and zanamivir. The Japanese approach to influenza surveillance and management has facilitated bringing new influenza antivirals to the markets and has driven innovative research in this field. New classes of antivirals, including polymerase inhibitors and cap-dependent endonuclease inhibitor, provide novel tools for treatment of influenza in Japan and the rest of the world.

DOI： 10.1007/s40506-016-0085-5

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Influenza vaccination is considered the single most important medical intervention for the prevention of influenza. The dose of trivalent influenza vaccine in children was increased almost double since 2011/12 season in Japan. We estimated the influenza vaccine effectiveness for children 1-11 years of age using rapid test kits in Isahaya City, involving 28,884 children-years, over two consecutive influenza seasons (2011/12 and 2012/13). Children were divided into two groups, vaccinated and unvaccinated, according to their vaccination record, which was obtained from an influenza registration program organized by the Isahaya Medical Association for all pediatric facilities in the city. There were 14,562 and 14,282 children aged from 1-11 years in the city in 2011 and 2012 respectively. In the 2011/12 season, the overall vaccine effectiveness in children from 1-11 years of age, against influenza A and B were 23% [95% confidence interval (CI): 14%-31%] and 20% [95% CI: 8%-31%], respectively. In the 2012/13 season, vaccine effectiveness against influenza A and B was 13% (95% CI: 4%-20%) and 9% (95% CI: -4%-21%), respectively. The vaccine effectiveness was estimated using the rapid diagnosis test kits. Age-stratified estimation showed that vaccine effectiveness was superior in younger children over both seasons and for both virus types. In conclusion, the trivalent influenza vaccine has a significant protective effect for children 1-11 years of age against influenza A and B infection in the 2011/12 season and against influenza A infection in the 2012/13 season in a community in Japan.

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The emergence of antiviral drug-resistant influenza viruses highlights the need for alternative therapeutic strategies. Elucidation of host factors required during virus infection provides information not only on the signaling pathways involved but also on the identification of novel drug targets. RNA interference screening method had been utilized by several studies to determine these host factors; however, proteomics data on influenza host factors are currently limited. In this study, quantitative phosphoproteomic analysis of human lung cell line (A549) infected with 2009 pandemic influenza virus A (H1N1) virus was performed. Phosphopeptides were enriched from tryptic digests of total protein of infected and mock-infected cells using a titania column on an automated purification system followed by iTRAQ labeling. Identification and quantitative analysis of iTRAQ-labeled phosphopeptides were performed using LC-MS/MS. We identified 366 phosphorylation sites on 283 proteins. Of these, we detected 43 upregulated and 35 downregulated proteins during influenza virus infection. Gene ontology enrichment analysis showed that majority of the identified proteins are phosphoproteins involved in RNA processing, immune system process and response to infection. Host-virus interaction network analysis had identified 23 densely connected subnetworks. Of which, 13 subnetworks contained proteins with altered phosphorylation levels during by influenza virus infection. Our results will help to identify potential drug targets that can be pursued for influenza antiviral drug development.

DOI： 10.1016/j.virusres.2013.11.012

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Coughing plays an important role in influenza transmission; however, there is insufficient information regarding the viral load in cough because of the lack of convenient and reliable collection methods. We developed a portable airborne particle-collection system to measure the viral load; it is equipped with an air sampler to draw air and pass it through a gelatin membrane filter connected to a cone-shaped, megaphone-like device to guide the cough airflow to the membrane. The membrane was dissolved in a medium, and the viral load was measured using quantitative real-time reverse transcriptase-polymerase chain reaction and a plaque assay. The approximate viral recovery rate of this system was 10% in simulation experiments to collect and quantify the viral particles aerosolized by a nebulizer. Using this system, cough samples were collected from 56 influenza A patients. The total viral detection rate was 41% (23/56), and the viral loads varied significantly (from <10, less than the detection limit, to 2240 viral gene copies/cough). Viable viruses were detected from 3 samples with ≤18 plaque forming units per cough sample. The virus detection rates were similar among different groups of patients infected with different viral subtypes and during different influenza seasons. Among patients who did not receive antiviral treatment, viruses were detected in one of six cases in the vaccinated group and four of six cases in the unvaccinated group. We found cases with high viral titers in throat swabs or oral secretions but very low or undetectable in coughs and vice versa suggesting other possible anatomical sites where the viruses might be mixed into the cough. Our system is easy to operate, appropriate for bedside use, and is useful for comparing the viral load in cough samples from influenza patients under various conditions and settings. However, further large-scale studies are warranted to validate our results.

DOI： 10.1371/journal.pone.0103560

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The prevalence and timing of emergence of oseltamivir-resistant seasonal and pandemic influenza A (H1N1) viruses in Myanmar in 2008 and 2009 are described in this report. In 2008, the oseltamivir-resistant seasonal H1N1 virus was detected at a lower rate (6%) and emerged at least 2 months later when compared with neighboring countries. Similarly, the prevalence of pandemic H1N1 virus was low (3%) and the timing of emergence was late (August 2009) in Myanmar. Interestingly, we detected three isolates that were resistant to both amantadine and oseltamivir. Limited movement of people into the country is attributed to the delayed emergence of drug-resistant seasonal and pandemic A(H1N1) viruses.

DOI： 10.1111/irv.12030

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Two new influenza virus neuraminidase inhibitors (NAIs), peramivir and laninamivir, were approved in 2010 which resulted to four NAIs that were used during the 2010-2011 influenza season in Japan. This study aims to monitor the susceptibility of influenza virus isolates in 2009-2010 and 2010-2011 influenza seasons in Japan to the four NAIs using the fluorescence-based 50% inhibitory concentration (IC₅₀) method. Outliers were identified using box-and-whisker plot analysis and full NA gene sequencing was performed to determine the mutations that are associated with reduction of susceptibility to NAIs. A total of 117 influenza A(H1N1)pdm09, 59 A(H3N2), and 18 type B viruses were tested before NAI treatment and eight A(H1N1)pdm09 and 1 type B viruses were examined from patients after NAI treatment in the two seasons. NA inhibition assay showed type A influenza viruses were more susceptible to NAIs than type B viruses. The peramivir and laninamivir IC₅₀ values of both type A and B viruses were significantly lower than the oseltamivir and zanamivir IC₅₀ values. Among influenza A(H1N1)pdm09 viruses, the prevalence of H274Y viruses increased from 0% in the 2009-2010 season to 3% in the 2010-2011 season. These H274Y viruses were resistant to oseltamivir and peramivir with 200-300 fold increase in IC₅₀ values but remained sensitive to zanamivir and laninamivir. Other mutations in NA, such as I222T and M241I were identified among the outliers. Among influenza A(H3N2) viruses, two outliers were identified with D151G and T148I mutations, which exhibited a reduction in susceptibility to oseltamivir and zanamivir, respectively. Among type B viruses, no outliers were identified to the four NAIs. For paired samples that were collected before and after drug treatment, three (3/11; 27.3%) H274Y viruses were identified among A(H1N1)pdm09 viruses after oseltamivir treatment but no outliers were found in the laninamivir-treatment group (n=3). Despite widespread use of NAIs in Japan, the prevalence of NAI-resistant influenza viruses is still low.

DOI： 10.1016/j.antiviral.2013.06.003

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BACKGROUND: Norovirus (NoV) is a major cause of gastroenteritis during the autumn and winter seasons in Japan as well as in other temperate climate regions. Most outbreaks are thought to occur by secondary attacks through person-to-person infection by fecal-oral route. Severe cases are found in young children or patients with chronic diseases. Clarifying the patterns of epidemic diffusion is important for considering effective monitoring and surveillance as well as possible prevention. METHODS: We considered the predominant viral genotype from the laboratory result obtained from Infectious Agents Surveillance Report (IASR) of National Institute of Infectious Diseases (NIID). We investigated the increase of NoV cases nationwide for the 2006-07 to 2008-09 seasons using sentinel gastroenteritis data collected from about 3000 pediatric clinics on National Epidemiological Surveillance of Infectious Diseases (NESID) acquired from the kriging method in the geographic information system (GIS). RESULTS: During these three seasons, the majority of the detected virus was GII.4, which ranged from 60.4 to 88.9%. The number of cases (per sentinel site) at the peak week was 22.81 in the 2006-07 season and it decreased in the following seasons. NoV cases began to increase earlier in the southern areas and gradually extended into the northern areas, similarly, over the seasons. The average period from when the increase of cases was detected in the southern area to when it reached the northern area was 12.7 weeks. CONCLUSION: The decrease of the number of sentinel cases at the peak week may suggest the development of herd immunity after a period of high prevalence. Although the NoV epidemic is thought to be associated with cold weather, its cases first increased in the southern area with relatively warm temperature, indicating there are other climate factors involved. Geographic study using the sentinel data could enhance the monitoring and surveillance of and preparedness against epidemics.

DOI： 10.1371/journal.pone.0071696

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BACKGROUND: Japan has implemented various school actions during seasonal influenza outbreaks since the 1950's under the School Health Law. However, the effective duration, extent, and timing of closures remain unresolved. MATERIALS AND METHODS: We conducted a retrospective study on the relationship between elementary class closures and influenza outbreak control during four consecutive influenza seasons from the 2004-2005 to 2007-2008 school years in Joetsu, Niigata, Japan. Among a total of 1,061 classes of 72 schools, 624 cases of influenza outbreaks were documented among 61 schools. RESULTS: Class closures were carried out in a total of 62 cases in response to influenza outbreak, which was defined as a student absentee rate of greater than 10% due to influenza or influenza-like illness. Of these cases, two-day class closures were conducted the day after reaching a 10% student absentee rate in 28 cases and other types of closures were initiated in 34 cases. A markedly higher number of outbreak cases ended within one week for two-day class closures compared to the other types of closures (82.1% vs. 20.6%, respectively). The significant association between two-day class closures and interruption of an outbreak within one week was confirmed using a multivariable model adjusted for the season, grade, day of the week of an outbreak start, and absentee rate on the day of an outbreak start (OR, 3.18; 95% CI, 1.12-9.07; p = 0.030). CONCLUSIONS: Our results suggest that a two-day class closure carried out the day after reaching a 10% absentee rate is an effective approach for mitigating influenza outbreaks in elementary schools.

DOI： 10.1371/journal.pone.0074716

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The clinical effectiveness of the newly released neuraminidase inhibitors (NAIs) laninamivir and peramivir has not been sufficiently evaluated in influenza-infected patients in clinical and practical settings. In this study, we analyzed the clinical data of 211 patients infected with influenza A virus subtype H3N2 (A(H3N2)) and 45 patients infected with influenza A virus subtype H1N1pdm (A(H1N1)pdm09) who received the NAIs oseltamivir, zanamivir, laninamivir, or peramivir during the 2010-2011 influenza season. The duration of fever from the first dose of the NAI to fever alleviation to <37.5 °C was evaluated as an indicator of the clinical effectiveness of the NAIs in the influenza-infected patients. For the A(H3N2)-infected patients, Kaplan-Meier analysis showed the peramivir treatment group had the fastest time of fever alleviation to <37.5 °C (median 17.0 h, 95 % confidence interval [CI] 7.2-26.8 h) of the four treatment groups. No significant difference was found in the time to fever alleviation among the other antivirals, oseltamivir, zanamivir, and laninamivir. Results of multivariate analysis, using a Cox proportional-hazards model (hazard ratio 3.321) adjusted for the factors age, sex, body weight, vaccination status, time from onset to the clinic visit, and body temperature showed significantly faster fever alleviation in the peramivir treatment group compared with the oseltamivir treatment group. For the A(H1N1)pdm09-infected patients, only the oseltamivir and zanamivir treatment groups were compared, and no significant difference in time to alleviation of fever was observed between the two groups. Based on a cycling probe real-time polymerase chain reaction (PCR) assay, none of the A(H1N1)pdm09 strains in this study had the H275Y mutation conferring oseltamivir resistance. Further evaluation of the clinical effectiveness of the newly released NAIs for influenza-infected patients, including those infected with A(H1N1)pdm09, is needed.

DOI： 10.1007/s10156-012-0428-1

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BACKGROUND: Annual influenza epidemics occur worldwide resulting in considerable morbidity and mortality. Spreading pattern of influenza is not well understood because it is often hampered by the quality of surveillance data that limits the reliability of analysis. In Japan, influenza is reported on a weekly basis from 5,000 hospitals and clinics nationwide under the scheme of the National Infectious Disease Surveillance. The collected data are available to the public as weekly reports which were summarized into number of patient visits per hospital or clinic in each of the 47 prefectures. From this surveillance data, we analyzed the spatial spreading patterns of influenza epidemics using weekly weighted standard distance (WSD) from the 1999/2000 through 2008/2009 influenza seasons in Japan. WSD is a single numerical value representing the spatial compactness of influenza outbreak, which is small in case of clustered distribution and large in case of dispersed distribution. RESULTS: We demonstrated that the weekly WSD value or the measure of spatial compactness of the distribution of reported influenza cases, decreased to its lowest value before each epidemic peak in nine out of ten seasons analyzed. The duration between the lowest WSD week and the peak week of influenza cases ranged from minus one week to twenty weeks. The duration showed significant negative association with the proportion of influenza A/H3N2 cases in early phase of each outbreak (correlation coefficient was -0.75, P = 0.012) and significant positive association with the proportion of influenza B cases in the early phase (correlation coefficient was 0.64, P = 0.045), but positively correlated with the proportion of influenza A/H1N1 strain cases (statistically not significant). It is assumed that the lowest WSD values just before influenza peaks are due to local outbreak which results in small standard distance values. As influenza cases disperse nationwide and an epidemic reaches its peak, WSD value changed to be a progressively increasing. CONCLUSIONS: The spatial distribution of nationwide influenza outbreak was measured by using a novel WSD method. We showed that spreading rate varied by type and subtypes of influenza virus using WSD as a spatial indicator. This study is the first to show a relationship between influenza epidemic trend by type/subtype and spatial distribution of influenza nationwide in Japan.

DOI： 10.1186/1476-072X-11-20

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BACKGROUND: Pandemic influenza A(H1N1) 2009 virus was first detected in Japan in May 2009 and continued to circulate in the 2010-2011 season. This study aims to characterize human influenza viruses circulating in Japan in the pandemic and post-pandemic periods and to determine the prevalence of antiviral-resistant viruses. METHODS: Respiratory specimens were collected from patients with influenza-like illness on their first visit at outpatient clinics during the 2009-2010 and 2010-2011 influenza seasons. Cycling probe real-time PCR assays were performed to screen for antiviral-resistant strains. Sequencing and phylogenetic analysis of the HA and NA genes were done to characterize circulating strains. RESULTS AND CONCLUSION: In the pandemic period (2009-2010), the pandemic influenza A(H1N1) 2009 virus was the only circulating strain isolated. None of the 601 A(H1N1)pdm09 virus isolates had the H275Y substitution in NA (oseltamivir resistance) while 599/601 isolates (99.7%) had the S31N substitution in M2 (amantadine resistance). In the post-pandemic period (2010-2011), cocirculation of different types and subtypes of influenza viruses was observed. Of the 1,278 samples analyzed, 414 (42.6%) were A(H1N1)pdm09, 525 (54.0%) were A(H3N2) and 33 (3.4%) were type-B viruses. Among A(H1N1)pdm09 isolates, 2 (0.5%) were oseltamivir-resistant and all were amantadine-resistant. Among A(H3N2) viruses, 520 (99.0%) were amantadine-resistant. Sequence and phylogenetic analyses of A(H1N1)pdm09 viruses from the post-pandemic period showed further evolution from the pandemic period viruses. For viruses that circulated in 2010-2011, strain predominance varied among prefectures. In Hokkaido, Niigata, Gunma and Nagasaki, A(H3N2) viruses (A/Perth/16/2009-like) were predominant whereas, in Kyoto, Hyogo and Osaka, A(H1N1)pdm09 viruses (A/New_York/10/2009-like) were predominant. Influenza B Victoria(HA)-Yamagata(NA) reassortant viruses (B/Brisbane/60/2008-like) were predominant while a small proportion was in Yamagata lineage. Genetic variants with mutations at antigenic sites were identified in A(H1N1)pdm09, A(H3N2) and type-B viruses in the 2010-2011 season but did not show a change in antigenicity when compared with respective vaccine strains.

DOI： 10.1371/journal.pone.0036455

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In eight successive seasons (2001 to 2009), a total of 726 human respiratory syncytial virus (HRSV) infections from a total of 1,560 children with acute lower respiratory tract illness were identified. Molecular analysis of the attachment (G) protein gene confirmed that 52 (7.8%) children were infected more than once with any of the 3 genotypes of HRSV-A (genotypes GA5, NA1, and NA2) and/or 6 genotypes of HRSV-B (genotypes BA4, BA5, and BA7 to BA10). Repeated infections in 46 cases (82.1%) occurred in the next season, and only one case occurred in the same season (10-day interval). First infections were 33 (63.5%) HRSV-A cases and 19 (36.5%) HRSV-B cases, whereas second infections occurred in 35 (67.3%) HRSV-A cases and 17 (32.7%) HRSV-B cases. Third infections were attributed to 4 (100.0%) HRSV-A cases. Homologous subgroup reinfections were detected in 28 cases, 23 HRSV-A cases and 5 HRSV-B cases (P = 0.005), whereas homologous genotype reinfections were detected only for 5 HRSV-A cases (2GA5 and 3NA2) but not any HRSV-B case. Heterologous subgroup reinfections were detected in 28 cases, 12 cases from HRSV-A-to-HRSV-B reinfections and 16 cases from HRSV-B-to-HRSV-A reinfections. Genotypes NA1 and NA2 had higher numbers of heterologous genotype infections than did other genotypes. Our observations suggest that repeated infections occur more frequently in HRSV-A strains than in HRSV-B strains, and heterologous genotype reinfections occur more frequently than homologous genotype reinfections, especially in the case of the emerging genotypes NA1 and NA2 of HRSV-A strains that circulated in the community during our study period.

DOI： 10.1128/JCM.02132-10

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OBJECTIVE: To describe outbreaks of nosocomial influenza infection with molecular methods and to elucidate the viral linkages among outbreak case patients including both inpatients and healthcare workers (HCWs). SETTING: A 180-bed acute and long-term care hospital in Japan. METHODS: Retrospective observational study of nosocomial outbreaks of infection with influenza A/H3N2. Together with information about onset dates and vaccination history, we obtained nasopharyngeal swab samples from individuals with cases of influenza or influenza-like illness (ILI). The hemagglutinin genes of the recovered viruses were sequenced and compared, along with those of community-circulating strains, for similarity by phylogenetic tree analysis. RESULTS: The outbreaks occurred from February 26 through April 3, 2007, during the 2006-2007 epidemic season, and they involved 11 patients and 13 HCWs. The 2 outbreaks involved 2 different genotypes of influenza A/H3N2 viruses. These virus variants were closely related to the influenza strains that were circulating in the community during the same epidemic season. CONCLUSION: This study showed the dissemination of highly homologous influenza virus variants among inpatients and HCWs within a short period, as a result of nosocomial transmission. These strains were also similar to influenza strains that were circulating in the community.

DOI： 10.1086/658671

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BACKGROUND: The spread of influenza viruses in a community are influenced by several factors, but no reports have focused on the relationship between the incidence of influenza and characteristics of small neighborhoods in a community. We aimed to clarify the relationship between the incidence of influenza and neighborhood characteristics using GIS and identified the type of small areas where influenza occurs frequently or infrequently. METHODS: Of the 19,077 registered influenza cases, we analyzed 11,437 influenza A and 5,193 influenza B cases that were diagnosed by the rapid antigen test in 66-86 medical facilities in Isahaya City, Japan, from 2004 to 2008. We used the commercial geodemographics dataset, Mosaic Japan to categorize and classify each neighborhood. Furthermore, we calculated the index value of influenza in crude and age adjusted rates to evaluate the incidence of influenza by Mosaic segmentation. Additional age structure analysis was performed to geodemographics segmentation to explore the relationship between influenza and family structure. RESULTS: The observed number of influenza A and B patients in the neighborhoods where young couples with small children lived was approximately 10-40% higher than the expected number (p < 0.01) during all seasons. On the contrary, the number of patients in the neighborhoods of the aging society in a rural area was 20-50% lower than the expected number (p < 0.01) during all seasons. This tendency was consistent after age adjustment except in the case of influenza B, which lost significance in higher incidence areas, but the overall results indicated high transmission of influenza in areas where young families with children lived. CONCLUSIONS: Our analysis indicated that the incidence of influenza A and B in neighborhood groups is related to the family structure, especially the presence of children in households. Simple statistical analysis of geodemographics data is an effective method to understand the differences in the incidence of influenza among neighborhood groups, and it provides a valuable basis for community strategies to control influenza.

DOI： 10.1186/1471-2334-11-36

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Neuraminidase inhibitors are agents used against influenza viruses; however, the emergence of drug-resistant strains is a major concern. Recently, the prevalence of oseltamivir-resistant seasonal influenza A (H1N1) virus increased globally and the emergence of oseltamivir-resistant pandemic influenza A (H1N1) 2009 viruses was reported. In this study, we developed a cycling probe real-time PCR method for the detection of oseltamivir-resistant seasonal influenza A (H1N1) and pandemic influenza A (H1N1) 2009 viruses. We designed two sets of primers and probes that were labeled with 6-carboxyfluorescein or 6-carboxy-X-rhodamine to identify single nucleotide polymorphisms (SNPs) that correspond to a histidine and a tyrosine at position 275 in the neuraminidase protein, respectively. These SNPs confer susceptibility and resistance to oseltamivir, respectively. In the 2007-2008 season, the prevalence of oseltamivir-resistant H1N1 viruses was 0% (0/72), but in the 2008-2009 season, it increased to 100% (282/282). In the 2009-2010 season, all of the pandemic influenza A (H1N1) 2009 viruses were susceptible to oseltamivir (0/73, 0%). This method is sensitive and specific for the screening of oseltamivir-resistant influenza A (H1N1) viruses. This method is applicable to routine laboratory-based monitoring of drug resistance and patient management during antiviral therapy.

DOI： 10.1128/JCM.01401-10

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The objective of this study was to characterize the off-seasonal influenza virus A subtype H3N2, which caused an outbreak in an elderly hospital in Niigata, Japan. Virus isolates were subtyped by the hemagglutination-inhibition test and screened for antiviral drug sensitivity by real-time PCR using cycling probe technology the and 50% inhibitory concentration (IC(50)) method. Whole genome sequencing was performed in order to determine the phylogeny of the outbreak virus. Seven virus isolates were analyzed in this study, and the results showed that all belonged to the influenza virus A (H3N2). These viruses exhibited the S31N mutation in M2, which confers resistance to amantadine. The results of the IC(50) analysis showed that these viruses were sensitive to both oseltamivir and zanamivir. Whole genome analysis revealed that the virus was similar to the A/Perth/16/2009 strain and that it is a triple reassortant virus with a 3+3+2 pattern of segment recombination.

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BACKGROUND: Little is known about whether neuraminidase inhibitors are effective for children infected with oseltamivir-resistant influenza A(H1N1) viruses. METHODS: Children aged 15 years and younger having influenza-like illness and who visited outpatient clinics within 48 hours of fever onset were enrolled from 2006-2007 to 2008-2009 influenza seasons in Japan. Patients received oseltamivir, zanamivir, or no treatment after screening by a rapid antigen test. Nasopharyngeal swabs were collected before antiviral therapy and were used for virus isolation. Oseltamivir resistance was determined by detection of the H275Y mutation in neuraminidase, and susceptibility test using neuraminidase inhibition assay. Daily body temperature was evaluated according to drug type and susceptibility by univariate and multivariate analyses. RESULTS: Of 1647 patients screened, 238 oseltamivir-resistant H1N1 cases (87 oseltamivir-treated, 64 zanamivir-treated, and 87 nontreated) and 110 oseltamivir-susceptible cases (60 oseltamivir-treated and 50 nontreated) were evaluated. In oseltamivir-resistant cases, fever on days 4 to 5 after the start of treatment was significantly higher in oseltamivir-treated and nontreated than in zanamivir-treated patients (P < 0.05). In oseltamivir-susceptible cases, fever was significantly lower in oseltamivir-treated than nontreated on days 3 to 6 (P < 0.01). Similar findings were obtained for duration of the fever and proportion of recurrent fever. Reduced effectiveness of oseltamivir was more prominent in children 0 to 6 years old than in those 7 to 15 years old. Multiple logistic regression analysis showed that lower age, nontreatment, and oseltamivir treatment of oseltamivir-resistant patients were factors associated with the duration of the longer fever. CONCLUSIONS: Infection with oseltamivir-resistant viruses significantly reduced the effectiveness of oseltamivir, and this tendency was more apparent in younger children.

DOI： 10.1097/INF.0b013e3181de9d24

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Phylogenetic analysis of respiratory syncytial virus (RSV) group B genotype BA strains from the 2002-2003 to 2009-2010 seasons collected in Niigata, Japan, revealed four distinct clusters, designated new BA genotypes BA7, BA8, BA9, and BA10. These new genotypes were not associated with large outbreaks in the community.

DOI： 10.1128/JCM.00646-10

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The emergence of antiviral drug-resistant strains of the influenza virus in addition to the rapid spread of the recent pandemic A(H1N1) 2009 virus highlight the importance of surveillance of influenza in identifying new variants as they appear. In this study, genetic characteristics and antiviral susceptibility patterns of influenza samples collected in Lebanon during the 2008-09 season were investigated. Forty influenza virus samples were isolated from 89 nasopharyngeal swabs obtained from patients with influenza-like illness. Of these samples, 33 (82.5%) were A(H3N2), 3 (7.5%) were A(H1N1), and 4 (10%) were B. All the H3N2 viruses were resistant to amantadine but were sensitive to oseltamivir and zanamivir; while all the H1N1 viruses were resistant to oseltamivir (possessed H275Y mutation, N1 numbering, in their NA) but were sensitive to amantadine and zanamivir. In the case of influenza B, both Victoria and Yamagata lineages were identified (three and one isolates each, respectively) and they showed decreased susceptibility to oseltamivir and zanamivir when compared to influenza A viruses. Influenza circulation patterns in Lebanon were very similar to those in Europe during the same season. Continued surveillance is important to fully elucidate influenza patterns in Lebanon and the Middle East in general, especially in light of the current influenza pandemic.

DOI： 10.1002/jmv.21795

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OBJECTIVE: Major disasters can affect the health status of the victims. However, the effects on the health status of those involved in disaster relief operations are unclear. The aim of this study was to clarify how disaster-related administrative workloads affect the cardiovascular risk factors of local governmental staff. METHODS: A big earthquake struck the central area of Niigata Prefecture, Japan, in October 2004. Thereafter, the Niigata Prefectural Government was engaged in intensive disaster relief operations until March 2005. We compared the changes in the cardiovascular risk factor measurements of 4035 governmental staff members across this period in terms of their workloads due to the relief operations. RESULTS: Compared with the staff having the lowest workloads, those with the highest workloads showed significantly greater increases of BMI, systolic blood pressure (SPB) and serum total cholesterol for men as well as SBP and diastolic blood pressure for women even after cessation of the intensive operations. They had an approximately two-fold higher risk of SBP elevation by 10 mmHg than those with the lowest workloads; the age-adjusted odds ratio (95% confidence interval) was 2.02 (1.47-2.79) for men and 1.82 (1.21-2.75) for women. CONCLUSION: Workloads during disaster relief operations can cause prolonged worsening of blood pressure levels and some other cardiovascular risk factors among local governmental staff. Therefore, when a disaster occurs, health management should be considered not only for the victims, but also for the local governmental staff.

DOI： 10.1097/HJH.0b013e328336ed70

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The emergence and widespread occurrence of antiviral drug-resistant seasonal human influenza A viruses, especially oseltamivir-resistant A/H1N1 virus, are major concerns. To understand the genetic background of antiviral drug-resistant A/H1N1 viruses, we performed full genome sequencing of prepandemic A/H1N1 strains. Seasonal influenza A/H1N1 viruses, including antiviral-susceptible viruses, amantadine-resistant viruses, and oseltamivir-resistant viruses, obtained from several areas in Japan during the 2007-2008 and 2008-2009 influenza seasons were analyzed. Sequencing of the full genomes of these viruses was performed, and the phylogenetic relationships among the sequences of each individual genome segment were inferred. Reference genome sequences from the Influenza Virus Resource database were included to determine the closest ancestor for each segment. Phylogenetic analysis revealed that the oseltamivir-resistant strain evolved from a reassortant oseltamivir-susceptible strain (clade 2B) which circulated in the 2007-2008 season by acquiring the H275Y resistance-conferring mutation in the NA gene. The oseltamivir-resistant lineage (corresponding to the Northern European resistant lineage) represented 100% of the H1N1 isolates from the 2008-2009 season and further acquired at least one mutation in each of the polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), hemagglutinin (HA), and neuraminidase (NA) genes. Therefore, a reassortment event involving two distinct oseltamivir-susceptible lineages, followed by the H275Y substitution in the NA gene and other mutations elsewhere in the genome, contributed to the emergence of the oseltamivir-resistant lineage. In contrast, amantadine-resistant viruses from the 2007-2008 season distinctly clustered in clade 2C and were characterized by extensive amino acid substitutions across their genomes, suggesting that a fitness gap among its genetic components might have driven these mutations to maintain it in the population.

DOI： 10.1128/JCM.01532-09

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In 2007 and 2008 in Myanmar, we detected influenza viruses A (H3N2) that exhibited reduced sensitivity to both zanamivir and amantadine. These rare and naturally occurring viruses harbored a novel Q136K mutation in neuraminidase and S31N mutation in M2.

DOI： 10.3201/eid1603.091321

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Amantadine is one of the antiviral agents used to treat influenza A virus infections, but resistant strains have widely emerged worldwide. In the present study, we developed a novel method to detect amantadine-resistant strains harboring the Ser31Asn mutation in the M2 gene based on the cycling probe method and real-time PCR. We also studied the rate of amantadine resistance in the 2007-2008 influenza season in Japan. Two different primer and cycling probe sets were designed for A/H1N1 and A/H3N2 each to detect a single nucleotide polymorphism corresponding to Ser/Asn at residue 31 of the M2 protein. By using nasopharyngeal swabs from patients with influenza-like and other respiratory illnesses and virus isolates, the specificity and the sensitivity of the cycling probe method were evaluated. High frequencies of amantadine resistance were detected among the A/H1N1 (411/663, 62%) and A/H3N2 (56/56, 100%) virus isolates collected from six prefectures in Japan in the 2007-2008 influenza season. We confirmed that the cycling probe method is suitable for the screening of both nasopharyngeal swabs and influenza virus isolates for amantadine-resistant strains and showed that the incidence of amantadine resistance among both A/H1N1 and A/H3N2 viruses remained high in Japan during the 2007-2008 season.

DOI： 10.1128/JCM.00698-09

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BACKGROUND: A substantial increase in oseltamivir-resistant A(H1N1) influenza viruses was reported in Europe in late 2007. OBJECTIVES: To monitor the antiviral susceptibility profile of human A(H1N1) influenza viruses in Japan during the 2007-2008 and 2008-2009 seasons. STUDY DESIGN: Viruses were obtained from respiratory samples of patients with influenza collected in Japan between December 2007 and April 2008 (n=1046) and between December 2008 and April 2009 (n=1789). Oseltamivir resistance was determined by an H274Y-specific real-time PCR cycling probe assay and a neuraminidase inhibition assay. Amantadine resistance was assessed by sequencing the M2 gene. Sequencing of the hemagglutinin and NA genes was performed to infer phylogenetic relationships between different strains. RESULTS: Three of 687 (0.4%) A(H1N1) viruses from the 2007-2008 season and 745 of 745 (100%) viruses from the 2008-2009 season carried the NA-H274Y substitution and demonstrated a >300-fold reduction in oseltamivir susceptibility. All oseltamivir-resistant viruses from the 2008-2009 season possessed an A193T substitution in the receptor-binding domain of the hemagglutinin. Amantadine resistance was detected in 431 of 687 (62.7%) and 0 of 745 (0.0%) of the A(H1N1) viruses from the 2007-2008 and 2008-2009 seasons, respectively. CONCLUSIONS: A dramatic surge in oseltamivir-resistant A(H1N1) viruses possessing the NA-H274Y substitution was detected in Japan during the 2008-2009 season. The emergence of oseltamivir-resistant viruses was facilitated by mutations in the viral genome. Intensified surveillance, including phenotypic assays and sequencing of the hemagglutinin, neuraminidase, and M2 gene would allow monitoring of the spread and evolution of drug-resistant influenza virus variants.

DOI： 10.1016/j.jcv.2009.11.003

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BACKGROUND: The prevalence of amantadine-resistant influenza A/H3N2 viruses (belonging to the N-lineage), possessing an S31N mutation in the M2 protein and S193F and D225N substitutions in their HA1 subunit, has significantly increased worldwide since 2005. The aim of this study was to clarify the genomic events contributing to the evolution and continuity of the N-lineage amantadine-resistant viruses. METHODS: The full genome sequence of A/H3N2 isolates, including both amantadine-resistant and amantadine-sensitive viruses, collected in Japan between 2006 and 2008, was determined and phylogenetically compared with isolates obtained from the database. RESULTS: On the basis of the full genome sequence analysis, the N-lineage could be further divided into three genetically related clades: N1 (A/Wisconsin/67/2005-like amantadine-resistant viruses from years 2005-2007), N2 (amantadine-sensitive viruses from 2007) and N3 (A/Brisbane/10/2007-like amantadine-resistant viruses from 2007 and 2008). The 2006/2007 season showed cocirculation of antigenic variants of amantadine-resistant viruses of clades N1 and N3 in addition to the N2-sensitive viruses. In the 2007/2008 season, the clade N3 amantadine-resistant lineage dominated and replaced other strains. Phylogenetic analysis of each individual segment suggested that N2 and N3 were generated from two independent reassortment events involving clade N1 viruses and pre-N-lineage strains. CONCLUSIONS: Our data show that several reassortment events have contributed to the evolution of amantadine-resistant A/H3N2 strains and, consequently, to the successful spread of this lineage. Although amantadine resistance is caused by single amino acid mutations in the M2 protein, genome-wide adjustment involving multiple genes appears to be necessary to obtain efficient replication and transmission of resistant viruses. Such adjustments are attainable through reassortment of segments among different virus lineages.

DOI： 10.3851/IMP1538

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Human respiratory syncytial virus (HRSV) is a common etiological agent of acute lower respiratory tract disease in infants. We report the molecular epidemiology of HRSV in Niigata, Japan, over six successive seasons (from 2001 to 2007) and the emerging genotypes of HRSV subgroup A (HRSV-A) strains. A total of 488 HRSV samples were obtained from 1,103 screened cases in a pediatric clinic in Niigata. According to the phylogenetic analysis, among the PCR-positive samples, 338 HRSV-A strains clustered into the previously reported genotypes GA5 and GA7 and two novel genotypes, NA1 and NA2, which were genetically close to GA2 strains. One hundred fifty HRSV-B strains clustered into three genotypes, namely, GB3, SAB3, and BA, which has a 60-nucleotide insertion in the second hypervariable region of the G protein. The NA1 strains emerged first, in the 2004-2005 season, and subsequently, the NA2 strain emerged in the 2005-2006 season. Both strains caused large epidemics in the 2005-2006 and 2006-2007 seasons. The average age of children who were infected with NA2 strains was significantly higher than that of those infected with GA5 and the frequency of reinfection by NA2 was the highest among all genotypes, suggesting that this genotype possessed new antigenicity for evading past host immunity. This is the first paper to show a possible correlation between an emerging genotype, NA2, and large outbreaks of HRSV in Japan. Continuing studies to follow up the genetic changes and to clarify the mechanism of reinfection in HRSV are important steps to understand HRSV infections.

DOI： 10.1128/JCM.00115-09

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To clarify seasonal influenza patterns and the prevalence of amantadine-resistant influenza A viruses in Okinawa, located at the southern extremity of Japan in a subtropical climate, we conducted a laboratory-based study of influenza virus infections from 2001 to 2007. The annual outbreaks tended to show two peaks in Okinawa, in summer and winter, although the main islands of Japan, located in a temperate climate area, showed only winter influenza activity. Epidemic types and subtypes in Okinawa mostly matched those on the main islands of Japan in winter and those in Taiwan in summer. Rates of amantadine resistance dramatically increased, from 7.3% in the November 2002-to-March 2003 season to 90.0% in summer 2005, and a similarly high rate of resistance continued for the rest of the study period. Phylogenetic analysis of the hemagglutinin gene of A/H3N2 isolates collected from 2002 to 2007 revealed a monophyletic lineage that was divided into four period groups. Each group included amantadine-sensitive and -resistant viruses within independent clusters. In the November 2005-to-March 2006 season, all of the amantadine-resistant viruses were clustered in clade N, with dual (position 193 and 225) amino acid mutations in their HA1 subunits. In 2005, clade N amantadine-resistant viruses existed in Okinawa several months before the circulation of this clade on the main islands of Japan. In conclusion, surveillance in Okinawa to monitor influenza virus circulation is important for elucidating the dynamics of virus transmission in a border area between temperate and subtropical areas, as Okinawa is one of the best sentinel points in Japan.

DOI： 10.1128/JCM.01760-08

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No mutations were detected in the hemagglutinin gene of influenza A/H3N2 virus isolates from patients undergoing short-term amantadine treatment. However, genetic changes occurred after serial passage in either MDCK or MDCK-SIAT1 cells. Our results showed that only a few mutations were observed in MDCK-SIAT1-passaged isolates in the presence of amantadine.

DOI： 10.1128/JCM.00892-08

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A total of 1,041 human influenza A virus isolates were collected at a clinic in Niigata, Japan, during eight influenza seasons from 2000 to 2007. The H3N2 subtype accounted for 75.4% of the isolates, and the rest were H1N1. Extremely high rates of amantadine-resistant strains of H3N2 subtype were observed in 2005/2006 (100%) and 2006/2007 (79.4%), while amantadine-resistant strains of H1N1 subtype were only detected in 2006/2007 (48.2%). Sequence and phylogenetic analysis of the HA1 subunit of the hemagglutinin (HA) gene revealed a characteristic linear trunk in the case of H3N2 viruses and a multi-furcated tree in the case of H1N1 and showed a higher sequence diversity among H3N2 strains than H1N1 strains. Mutations in the HA1 from both subtypes were mainly found in the globular region, and only one-third of these were retained for two or more successive years. Higher diversity of H3N2 viruses was mainly attributable to a higher fixation rate of non-synonymous mutations and to a lesser extent to a higher nucleotide substitution rate than for H1N1. Our analysis showed evidence of four positively selected sites in the HA1 of H1 and five sites in that of H3, four of which were novel. Finally, acquisition or loss of N-glycosylation sites was shown to contribute to the evolution of influenza A virus, especially in the case of H3N2, which had a higher tendency to acquire new glycosylation sites.

DOI： 10.1007/s00705-009-0309-9

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OBJECTIVES: To perform genetic analysis of influenza A and B viruses in Myanmar from 2005 to 2007 and to determine the prevalence of amantadine-resistant influenza A viruses. METHODS: Phylogenies of the HA and NA genes were analyzed and mutations in M2 that confer resistance to amantadine were screened. RESULTS: Influenza in Myanmar exhibited seasonality, which coincided during the rainy season from June to August. Out of 2,618 samples, 76 influenza A and 132 influenza B viruses were isolated. Phylogenetic analysis showed that in 2005, 11 A/H1N1 isolates formed one cluster with A/Solomon Islands/3/2006 and were amantadine-sensitive strains. One A/H3N2 isolate was amantadine-resistant harboring S31N mutation in M2 and possessing S193F and D225N substitutions in HA (clade N), similar to A/Wisconsin/67/2005. No viruses were isolated in 2006 due to sample storage failure. In 2007, all 64 A/H3N2 isolates were amantadine-resistant and similar to A/Brisbane/10/2007. For influenza B, 3 Yamagata-lineage and 17 Victoria-lineage isolates were detected in 2005 and 112 Victoria-lineage viruses were isolated in 2007. All Victoria-lineage isolates were reassortants possessing NA derived from the Yamagata lineage. CONCLUSION: Continuous surveillance in tropical countries is important for elucidating the seasonality of influenza and determining the molecular characteristics of circulating strains.

DOI： 10.1159/000237738

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BACKGROUND: Seasonality characterizing influenza epidemics suggests susceptibility to climate variation. El Niño southern oscillation (ENSO), which involves two extreme events, El Niño and La Niña, is well-known for its large effects on inter-annual climate variability. The influence of ENSO on several diseases has been described. OBJECTIVES: In this study, we attempt to analyze the possible influence of ENSO on the timing of the annual influenza activity peak using influenza-like illness report data in Japan during 1983-2007. MATERIALS: Influenza surveillance data for 25 influenza epidemics, available under the National Epidemiological Surveillance of the Infectious Diseases, was used in this study. ENSO data were obtained from the Japan Meteorological Agency. RESULTS: Influenza-like illness peak week varied largely during the study period, ranging between 4th and 11th weeks (middle of winter to early spring). The average of peak week during ENSO cycles (n = 11, average = 4.5 +/- 0.9) was significantly earlier than in non-ENSO years (n = 14, average = 7.6 +/- 2.9; P = 0.01), but there was no significant difference in the peak timing between hot (El Niño) and cold (La Niña) phases. Earlier peaks of influenza activity were observed in 16, out of 25, epidemics. These coincided with 10 (90.9%) out of 11 ENSO and 6 (85.7%) out of seven large-scale epidemics. CONCLUSION: Influenza activity peak occurred earlier in years associated with ENSO and/or large scale epidemics.

DOI： 10.1111/j.1750-2659.2008.00047.x

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Influenza A virus has the ability to overcome immunity from previous infections through the acquisition of genetic changes. Thus, understanding the evolution of the viruses in humans is important for the surveillance and the selection of vaccine strains. A total of 30 influenza A/H3N2 viruses and 35 influenza A/H1N1 viruses that were collected in Vietnam from 2001 to 2006 were used to analyze the evolution of the hemagglutinin (HA), neuraminidase (NA), and matrix protein (M) genes. Phylogenetic analysis of individual gene segments revealed that the HA and the NA genes of the influenza A viruses evolved in a sequential way. However, the evolutionary pattern of the M gene proved to be nonlinear and was not linked with that of the HA and NA genes. Genetic drift in HA1 segments, especially in the antigenic sites of A/H3N2 viruses, occurred more frequently in A/H3N2 viruses than it did in A/H1N1 viruses. Two reassortants, one influenza A/H3N2 strain and one A/H1N1 strain, were found on the basis of the phylogenetic analysis of the three genes. While both genetic mutation and reassortment contributed to their evolution, the frequency of genetic changes and reassortment events differs between the two subtypes. As influenza viruses circulate throughout the year, we emphasize the importance of surveillance in tropical and subtropical zones, where the emergence of new strains may be detected earlier than it is in temperate zones.

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In recent years, a dramatic increase of amantadine-resistant influenza A has occurred globally, but limited data have been available on the clinical course of patients developed amantadine-resistant viruses. We compared fever reduction between patients who developed resistance or remained sensitive in a pediatric clinic in Niigata, Japan, from 2000 to 2006. A total of 2,802 clinical samples were collected from patients who visited the pediatric outpatient clinic with influenza like illness during the seven influenza epidemic seasons. Patients were divided into 4 groups and analyzed for the fever reduction after amantadine treatment: emerged amantadine-resistant (n = 15); amantadine-sensitive (n = 35); patients administered no antiviral drugs (n = 42); and oseltamivir-treated patients (n = 320), which served as references. All 4 groups showed alleviation of fever up to day 3. The amantadine-resistant group had a significant recurrence of fever on day 4 and/or 5, and as a consequence, the course of illness was prolonged. Considering the pattern of fever, recurrent and persistent patterns were found significantly at higher rates in children with emerged resistant virus compared to other groups, and the age tended to be younger in amantadine-resistant compared to amantadine-sensitive group (3.9 +/- 3.0 vs 6.7 +/- 4.1 years old, n.s.). Therefore, we concluded that younger children were prone to develop amantadine-resistance after treatment and showed a significant recurrence of fever on day 4 and/or 5, and the course of illness was consequently prolonged.

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Oseltamivir has been used for treatment of influenza A and B infections, but recent reports documented that it was less active against the latter. We compared the effectiveness of oseltamivir in children between laboratory confirmed influenza A and B over 4 influenza seasons from 2001 to 2005 in a pediatric clinic in Japan. Among 1,848 patients screened, 299 influenza A and 209 influenza B patients were administered oseltamivir (treated groups), and 28 influenza A and 66 influenza B patients were assigned as non-treated groups. The duration of fever, defined as period when patients had the maximum temperature higher than 37.5 degrees C in three-time measurements in a day after the clinic visit, was evaluated among the four groups. In uni-variate analysis, the duration of fever was shorter for treated group than non-treated for influenza A (1.8 +/- 0.9 days vs 2.6 +/- 1.3 days, p < 0.01), but it was not significant for influenza B (2.4 +/- 1.3 days vs 2.8 +/- 1.2 days, p = 0.9). The fever duration was longer in treated influenza B than A patients (p < 0.01). Multi-variate analysis indicated younger age (< 6 years old) and higher body temperature at the clinic visit prolonged the duration of fever. Adjusted average duration of fever indicated that oseltamivir was effective for both types, but more effective on influenza A, and the benefit increased for younger children. Our data provide evidence that oseltamivir is beneficial for influenza infections, but the effectiveness is differed by type and age.

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Substantial increase in amantadine-resistant influenza A (H3N2) was reported in Asia and North America in 2005. In this study the frequency and genetic characteristics of amantadine-resistant influenza A, circulated in Japan in 2005-2006 season, were investigated. Isolates were tested by amantadine susceptibility test (TCID(50)/0.2 ml method), and sequencing of the M2 gene to identify mutations that confer resistance. Additionally, the hemagglutinin (HA) and neuraminidase (NA) genes of the viruses were examined. In total, 415 influenza A isolates from six prefectures were screened, and 231 (65.3%) of 354 influenza A (H3N2) were amantadine-resistant, with a serine to asparagine (S31N) change in the M2 gene. However, none of 61 A (H1N1) isolates were resistant. In addition, genetic analyses of the HA gene showed all amantadine-resistant viruses clustered in one (named clade N), possessing specific double mutations at 193, serine to phenylalanine (S193F), and at 225, asparatic acid to asparagine (D225N), and sensitive viruses belonged to another group (clade S). The clinical presentations at the clinical visit did not differ between patients shedding clade N virus and those shedding clade S virus. None of the patients had received previous treatment with amantadine. The results indicate an unusually high prevalence and wide circulation of the amantadine-resistance influenza A (H3N2) in Japan in the 2005-2006 season. These strains had the characteristic double mutations in the HA, in addition to the M2 mutation responsive for resistance. Antiviral resistance monitoring should be intensified and maintained for rapid feedback into treatment strategies, and selection of alternative therapeutic agents.

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OBJECTIVES: Due to high vaccine coverage in Niigata, we had no outbreaks of measles from 1997 to 2003 but an opportunity to study the role of sporting events in the propagation of an epidemic was experienced in the spring of the latter year. METHODS: Mandatory measles case reports were requested from all high schools in Niigata, which covered a school year, date of onset, club activity, vaccination status, and hospitalization. RESULTS: With national marathon and kendo (Japanese fencing) meetings for high school students, measles outbreaks occurred at 27 high schools with 192 patients (186 students and 6 teachers) in Niigata. Of 64 unvaccinated patients, 14 (21.9%) were hospitalized and 6 (6.2%) of 97 vaccinated patients. Mostly single cases were encountered at high schools in which index cases had a vaccination history, whereas at a high school in which index cases had no vaccination history, the total number of cases per school increased, mostly within more than 3 cases (p<0.05). CONCLUSION: We conclude that sporting events, even if outdoors, might be a risk factor for measles infections. Appropriate actions to control outbreaks should be performed promptly in collaboration with related personnel and institutions.

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In this study, we report the effectiveness of trivalent inactivated influenza vaccination (TIV) for severely multiply handicapped persons/children (SMHPs) in the 2005-2006 season. In 77 SMHPs, A/New York/55/2004 (H3N2) which was the changed vaccine-strain showed significant differences in the geometric mean titers (P<0.05) and seroprotection rates (P<0.01) between pre- and post-vaccination. A/New Caledonia/20/99 (H1N1) and B/Shanghai/361/2002, which were the unchanged vaccine-strains, showed no significant differences. We defined the potential responders as those who can achieve 1:40 or more hemagglutination inhibition (HAI) titer after vaccination with any vaccine-strain. Therefore, the rate of potential responders is equivalent to the rate of seroprotection, estimated to be 40-60% among the SMHPs and >80% among the control group in this study. In the SMHPs, even potential responders could only achieve limited HAI titers (1:40-80) even after repeated vaccination. In contrast, the control group showed higher HAI titers compared to the SMHPs for the unchanged vaccine-strains caused by the priming effect. These data suggest that it might be difficult for SMHPs (including potential responders) to achieve the priming effect by the current TIV. Consequently, they cannot obtain a booster effect.

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An off-season community influenza outbreak with high prevalence of amantadine-resistant influenza A/H3N2 occurred during September-October 2005 in Nagasaki Prefecture, Japan, prior to standard influenza circulation. A total of 48 patients with influenza-like-illness (ILI) visited a clinic during the outbreak and 27 (69.2%) of 39 ILI patients were positive for influenza A with rapid antigen testing (Quick Vue Rapid SP Influ). Nine patients were not tested because their symptoms were compatible for influenza without examination. Nasopharyngeal swabs were obtained from 4 of 27 rapid test positive patients, and influenza H3N2 strain was isolated from one out of four. The 4 nasopharyngeal samples were positive for influenza A M2 gene in polymerase chain reaction, and sequencing results all showed identical mutation at position 31, serine to asparagine (S31N) in the gene, conferring amantadine resistance. The phylogenetic tree analysis demonstrated that the hemagglutinin (HA) gene sequences of the 4 samples formed a distinct cluster (named clade N) from recent circulating H3N2 strains, characterized by dual mutations at position 193, serine to phenylalanine (S193F), and at position 225, asparatic acid to asparagine (D225N). Our findings suggested that an off-season community influenza outbreak in Nagasaki was caused by a distinct clade in H3N2 (named clade N), which possessed characteristics of amantadine resistance.

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BACKGROUND: Many reports about the preventative effects of inactivated influenza vaccine have been published, targeting persons with underlying medical conditions. However, the effectiveness for severely multiply handicapped persons/children (SMHPs) is not yet well established. METHODS: The study group consisted of 79 SMHPs (36 males and 43 females, aged 18-66 years), with long-term hospitalization in Niigata National Hospital. We compared serum antibody responses before and after two-doses vaccination. RESULTS: Before vaccination for the 2004-2005 season, SMHPs showed continuously high HAI titer in A/New Caledonia/20/99(H1N1)-strain from March to October in 2004. The seroprotection rates were increased after the first dose, but no remarkable change was seen after the second dose in all three strains. Subjects less than 30 years old (< or = 29 group) had a high antibody titers against all three strains compared with subjects aged >40 years old. On the other hand, in the seroconversion rates, there were no significant differences in age, gender, and severity of symptoms. CONCLUSIONS: According to our study, SMHPs are low responders except < or = 29 group and the influenza vaccine effectiveness is more affected by their age than severity of symptoms. We suggest a recommendation for influenza vaccination especially in SMHPs; inactivated influenza virus vaccine (one dose) should be performed during the previous fall. In addition, further studies are needed about chemoprophylaxis, which can prevent influenza outbreaks in SMHPs.

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OBJECTIVE: To evaluate the antibody response to influenza vaccines in nursing home residents and healthcare workers (HCWs) and its relation to residents' functional and chronic disease status during four successive seasons. DESIGN: Before-after study. SETTING: Nine nursing homes during the 1998-1999 season and two during the 1999-2000, 2000-2001, and 2001-2002 seasons. PARTICIPANTS: Two hundred fifty-nine residents and 79 HCWs during the 1998-1999 season; 180 and 71, respectively, during the 1999-2000 season; 162 and 71, respectively, during the 2000-2001 season; and 153 and 79, respectively, during the 2001-2002 season. RESULTS: Multivariate analysis indicated that the mean fold increase in the geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies and the response rate (the proportion of vaccinees resulting in a significant, at least fourfold increase in antibody titer) were good and no significant differences occurred for almost all strains in both residents and HCWs. The GMTs of HI antibodies and the protection rate (the proportion of participants with HI antibody titers > or = 40) were increased in both residents and HCWs, but were significantly lower for almost all strains in residents than in HCWs. Furthermore, multivariate analysis indicated that subdivision of residents into three groups by level of daily activities and into four groups according to underlying diseases revealed only minor differences in immune responses. CONCLUSIONS: Antibody responses to the influenza vaccine were lower in residents than in HCWs. However, residents showed similar antibody responses regardless of their level of daily activity or underlying diseases.

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BACKGROUND: Human metapneumoviruses (hMPVs) are recognized as a leading cause of respiratory infections in young infants in many countries. The objective of this study was to identify links between hMPV and influenza virus infections among children with influenza-like illness. METHOD: This study was conducted in 2 influenza seasons (2002-2003 and 2003-2004) at 2 pediatric outpatient clinics in Niigata city, Japan. Nasopharyngeal swabs or aspirates were collected from influenza-like illness patients, and hMPV and influenza were detected by reverse transcription-polymerase chain reaction (RT-PCR). A nucleotide sequence of 352 nucleotides segment of the F gene was performed. RESULTS: A total of 765 influenza viruses and 84 hMPV were identified from 1498 nasopharyngeal swabs or aspirates by virus isolation and RT-PCR, respectively. hMPV-positive rates in patients with influenza-like illness were 5.7 and 5.2% in the 2002-2003 and 2003-2004 seasons, respectively. Epidemic curves of influenza and hMPV patients showed similar patterns with peaks in February in 2 influenza seasons. hMPV infections occurred frequently in infants and school children. Approximately 46% of hMPV patients were coinfected with influenza A viruses, but those coinfected cases were not clinically distinct from the others. No coinfection with influenza B viruses was found. Phylogenetic analysis of the hMPV fusion gene sequences revealed that 2 distinct hMPV cocirculated and that completely identical strains in subgroup A were observed over 2 years. CONCLUSIONS: HMPV plays an important pathogenic role in patients with influenza-like illness in winter seasons, often in coinfections with influenza A viruses.

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To study the molecular epidemiology of respiratory syncytial virus (RSV) in a community, children with acute respiratory symptoms at a pediatric outpatient clinic in Niigata, Japan, were analyzed over three seasons from November 2001 to July 2004. Of 499 nasopharyngeal aspirate specimens, 185 (37.1%) were RSV positive, and only 8 (4.5%) of 177 patients were shown by the reverse transcription (RT)-PCR method to be reinfected. RSV infection occurred beginning in the early winter, and the rates declined in the spring. The predominant subgroup changed from A to B and returned to A over the three seasons. Phylogenetic analysis also revealed that multiple genotypes cocirculated each year, with genotype GA5 of subgroup A predominating in the 2001-2002 and the 2003-2004 seasons. A new genotype of subgroup B (named BA, according to the nomenclature for viruses) with a 60-nucleotide insertion in the second variable region of the attachment glycoportein protein was predominant as an emerging strain in the 2002-2003 season, but this was not associated with new epidemiological or clinical features, unlike the cases of disease caused by other genotypes in the other seasons. In conclusion, our molecular analysis of RSV confirms that multiple genotypes cocirculate each year and that the genotype predominating may shift with the season. Support for determination of the genotype by RT-PCR as an effective tool for characterization of RSV circulation patterns in the community is provided.

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From 1992 to 1999, we analyzed >2.5 million cases of influenzalike illness (ILI). Nationwide influenza epidemics generally lasted 3-4 months in winter. Kriging analysis, which illustrates geographic movement, showed that the starting areas of peak ILI activity were mostly found in western Japan. Two spreading patterns, monotonous and multitonous, were observed. Monotonous patterns in two seasons featured peak ILI activity that covered all of Japan within 3 to 5 weeks in larger epidemics with new antigenic variants of A/H3N2. Multitonous patterns, observed in the other five seasons, featured peak ILI activity within 12 to 15 weeks in small epidemics without new variants. Applying the kriging method allowed better visualization and understanding of spatiotemporal trends in seasonal ILI activity. This method will likely be an important tool for future influenza surveillance in Japan.

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At present, three licensed antiviral influenza agents are available in Japan: amantadine, zanamivir, and oseltamivir. These antiviral agents can be used for controlling and preventing influenza, but they are not a substitute for vaccination. Amantadine is an antiviral drug with activity against influenza A viruses, but not influenza B viruses. Persons who have influenza A infection and who are treated with amantadine can shed sensitive viruses early in the course of treatment and later shed drug-resistant viruses, especially after 5-7 days of therapy. Such persons can benefit from therapy even when resistant viruses emerge. In screening for amantadine susceptibility, enzyme-linked immunoassays, plaque reduction assays, and TCID50/0.2 ml titration are employed. The molecular changes associated with resistance have been identified as single-nucleotide changes, leading to corresponding amino acid substitutions in one of four critical sites, amino acids 26, 27, 30, and 31, in the transmembrane region of the M2 protein. The polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis method is quite useful. Resistant viruses have been circulated in outbreak situations at nursing homes where amantadine was used not only for treating influenza virus infection but also for Parkinson's disease. Measures should be taken to reduce contact, as much as possible, between persons taking and those not taking antiviral drugs for treatment or chemoprophylaxis.

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In two influenza seasons during which H1N1 and H3N2 cocirculated, resistance was more frequent in H3N2 strains than in H1N1 strains after amantadine treatment. Predominant amino acid substitutions in M2 protein occurred at position 31 (serine to asparagine) in H3N2 strains and at position 27 (valine to alanine) in H1N1 strains.

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Mortality from coronary heart disease in Japan is the among lowest recorded in the industrialized nations; however, little is known about the rate of events including nonfatal cases. A survey of event registration and a review of death certificates was carried out to estimate event rates of acute myocardial infarction (AMI) and coronary deaths in the largest 2 cities of the Niigata prefecture where there are 480,720 residents aged between 15 and 65 years. The definitions for these cardiac events used for the WHO-MONICA project were: (1)'definite AMI', (2) 'possible AMI or coronary death' (not including unclassifiable fatal events), and (3) 'unclassifiable fatal events'. Age-adjusted rates for AMI and coronary deaths (per 100,000/year) according to the registration survey were 54.6 for men and 7.2 for women according to definition 1 and 41.9 for men, and 5.3 for women according to definition 2. When data from the death certificate review were taken into account for the estimation, these rates increased to 80.6 for men and 14.2 for women according to definition 1, and 50.0 for men and 9.0 for women according to definition 2. These estimated rates are considerably lower than those in other industrialized nations surveyed in the WHO-MONICA project, and these findings are consistent with those from other studies conducted in Japan.

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OBJECTIVE: To evaluate the effectiveness of influenza vaccines against influenza-like illness (ILI) among nursing home residents. DESIGN: Prospective, nonrandomized, cohort study. SETTING: Nine nursing homes during the 1998-1999 influenza season and 11 nursing homes during the 1999-2000 influenza season in Niigata Prefecture, Japan. PARTICIPANTS: Six hundred ninety-nine residents and 440 healthcare workers (HCWs) during the first season, and 930 residents and 517 HCWs during the second season, with vaccination rates ranging from 0% to 97.7%. RESULTS: Overall, ILI decreased from 24.3% during the 1998-1999 season to 8.8% during the 1999-2000 season. Multivariate analysis adjusted for several factors, including gender, age, underlying diseases, and resident and HCW vaccination rates, failed to demonstrate clear individual protection of residents (relative risk [RR], 1.42; P = .2 for the first season; RR, 0.95; P = .9 for the second season). However, vaccination rates of 60% or greater for residents and HCWs reduced the risk of ILI, and also could prevent outbreaks during the 2 seasons. Highly impaired activities of daily living and chronic respiratory diseases were significantly associated with increased ILI. CONCLUSIONS: A high vaccination rate for both residents and HCWs may reduce the risk of ILI and institutional outbreaks in nursing homes.

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Annual consumption of amantadine increased abruptly after its approval for the treatment of influenza A virus infections in Japan in 1998, and the emergence of amantadine-resistant viruses is now a matter of concern. To detect resistant influenza A virus strains, we have developed a PCR-restriction fragment length polymorphism (PCR-RFLP) analysis for nasopharyngeal swabs. Three different primer sets for nested PCR were designed to incorporate restriction sites into the amplicon to differentiate single-amino-acid substitutions at positions 27, 30, and 31 that confer resistance in the transmembrane domain of the M2 protein. Each PCR product was digested with respective endonucleases (BspLU11I for amino acid change at position 27, HhaI for position 30, and ScaI for position 31), and the polymorphisms were determined by electrophoresis. Thirty-four (24.1%) of 141 PCR-positive samples had resistance patterns in eight nursing homes in the 1998-1999 season. Thirty-one viruses (91.2%) showed a change at position 31 (serine to asparagine), three viruses (8.8%) showed a change at position 30 (alanine to threonine), and none showed a change at position 27. The incidence of resistant viruses did not show any significant difference between four facilities where amantadine was used mainly for influenza treatment and four other facilities where it was used only for Parkinson's disease, values being 27.6 and 16.3%, respectively. We have confirmed that the PCR-RFLP method is useful for detecting amantadine-resistant strains directly from nasopharyngeal swabs and that resistant viruses were circulating in nursing homes where the drug was used not only for influenza virus but also for Parkinson's disease.

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