Language：English   Publisher：Elsevier BV  

DOI： 10.1016/j.bone.2024.117311

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.nmni.2024.101462

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Introduction Climate change is a decisive factor affecting human health. While many epidemiological studies have investigated the acute impacts of ambient temperature on mortality and morbidity, the global burden of infectious gastroenteritis linked to temperature changes remains largely unexplored. Therefore, we aimed to examine the exposure-response associations between ambient temperature and infectious gastroenteritis incidence throughout Japan and quantify the temperature-related morbidity burden. Methods Weekly time-series data from 2000 to 2019, encompassing meteorological factors and infectious gastroenteritis cases, were collected from all 47 Japanese prefectures. A two-stage time-series design was employed. In the first stage, quasi-Poisson regression models combined with distributed lag non-linear models were used for each prefecture. In the second stage, a multivariate meta-analysis was conducted to derive national estimates. The attributable fractions were determined for both low and high temperatures, categorized as temperatures below or above the minimum risk temperature, respectively. Results The analysis included 19,571,939 infectious gastroenteritis cases. The exposure-response association between temperature and infectious gastroenteritis cases was non-linear, exhibiting an approximate M-shaped relationship. Overall, 51.7% (95% empirical confidence interval (eCI): 42.6, 58.4) of infectious gastroenteritis cases were attributable to non-optimal temperatures in Japan. The attributable fraction to low temperatures was 47.6% (95% eCI: 38.5, 54.2), whereas that of high temperatures was 4.1% (95% eCI: 2.4, 5.5). Conclusion The majority of the temperature-related infectious gastroenteritis burden in Japan was attributable to lower temperatures. Our findings indicate that public health strategies aimed at mitigating the burden of infectious gastroenteritis should take temperature levels into account.

DOI： 10.7759/cureus.76367

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.nmni.2024.101516

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVES: Although there is epidemiological evidence that ambient temperature affects influenza transmission, the relationship between temperature and specific influenza virus types remains inadequately studied. This study aimed to investigate the association between ambient temperature exposure and the incidence counts of influenza A and B viruses in Kawasaki City, Japan. METHODS: Daily data on influenza A and B cases and meteorological variables were collected from Kawasaki City, Japan, spanning from March 2014 to December 2019. A time-series quasi-Poisson regression model, in conjunction with a distributed lag non-linear model, was utilized to explore the exposure-response relationship between short-term influenza risk and daily mean temperature. RESULTS: The study encompassed 181,895 patients with influenza. Our findings indicated that cold temperatures significantly heightened the risk of influenza A and B virus infections. The overall cumulative relative risk of influenza A was 5.08 (95% confidence interval 3.64-7.08) at cold temperatures (5th percentile, 5.6°C) compared with the median temperature (17.7°C) and 2.50 (1.82-3.44) for influenza B. CONCLUSIONS: This study suggests that the short-term effects of temperature on influenza transmission are type-specific. It offers crucial insights for future research on the complex associations between ambient temperature and respiratory infectious diseases.

DOI： 10.1016/j.ijregi.2024.100479

Scopus

PubMed

researchmap

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: Although several studies have investigated the effects of temperature on the incidence of tuberculosis (TB) in a single city or region, few studies have investigated the variations in this association using nationwide data. This study aimed to quantify the association between temporal variations in TB incidence and temperature across Japan. Methods: The data on the weekly number of newly confirmed TB cases and meteorological variables in 47 Japanese prefectures from 2007 to 2019 were collected. The exposure-response relationships between TB incidence and temperature were quantified using a distributed lag nonlinear model for each prefecture, and estimates from all prefectures were then pooled using a meta-regression model to derive nationwide average associations. Results: This study included 335,060 patients with TB. Compared to those with minimum risk temperature on TB incidence (10th percentile at 4.45°C), people who were exposed to the highest temperature concentrations had a 52.0% (relative risk 1.52, 95% confidence interval 1.04-2.23) higher risk for TB incidence at the 99th percentile (30.1°C). Our results also emphasized the heterogeneity of these associations in different prefectures. Conclusions: Strengthening monitoring and public health strategies aimed at controlling temperature-related TB may be more effective when tailored to region-specific meteorological conditions.

DOI： 10.1016/j.ijregi.2024.100384

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Mycoplasma pneumoniae (M. pneumoniae) is a major cause of upper and lower respiratory tract infections and respiratory tract disease in humans. While accumulated pieces of epidemiological evidence suggest an association between meteorological factors and the risk of M. pneumoniae pneumonia, comprehensive nationwide studies on this topic are lacking. We aimed to systematically assess the effect of meteorological factors such as mean temperature and relative humidity on the incidence of M. pneumoniae pneumonia in Japan over a 15-year period from 2005 to 2019. The exposure - response relationships between incidence of M. pneumoniae pneumonia, mean temperature, and relative humidity in all 47 Japanese prefectures (covering whole country) for 2005 - 2019 were quantified by using a distributed lag non-linear model for each prefecture and the estimates from all the prefectures were then pooled using a multivariate mete-regression model to derive nationwide average associations. The study encompassed a total of 162,845 M. pneumoniae pneumonia cases. Our findings indicate that seasonal variations in weekly mean temperature and relative humidity were positively associated with the incidence of M. pneumoniae pneumonia. Specifically, when considering - 1.3 °C as the reference, the relative risk (RR) peaked at 16.8 °C (with RRs of 1.50, 95% confidence interval (CI): 1.32-1.70). Similarly, when using 45.5% relative humidity as the reference, the RR reached its peak at 87.7% (with RRs of 1.49, 95% CI: 1.33-1.67). These results emphasize the necessity of implementing climate change adaptation strategies and public health interventions in regions vulnerable to M. pneumoniae pneumonia.

DOI： 10.1007/s00484-024-02712-7

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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 E23K/G, or I38M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6 to 100 %), a polymorphism and a mixture of PA/E23K/G, and I38M/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 hours and a median symptom duration of 93.7 hours, 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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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 334,848 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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)北隆館  

感染症疫学研究の特定領域では,様々な流行伝播の時系列変動の決定要因を探索し,実測的な疾病負荷の定量化やそれに伴う流行予測を実装する事で,公衆衛生政策に資する情報の提示を目指す事が多い。新型コロナウイルス感染症の流行に於いても,気候変動,非医薬品的介入,ワクチン接種,変異株の出現など多岐に渡るイベントが発生した。この現象に連関する様に,インフルエンザやRSウイルスなど様々な感染症の疫学像の劇的な変化が観察された。本稿では,これらの呼吸器感染症の流行伝播に纏わる,筆者らの研究成果を論考し,幾つかの疫学的知見の整理を読者諸氏と展開したい。(著者抄録)

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.31662/jmaj.2023-0150

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本国際保健医療学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to quantify the exposure-lag-response relationship between short-term changes in ambient temperature and absolute humidity and the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Japan. The prefecture-specific daily time-series of newly confirmed cases, meteorological variables, retail and recreation mobility, and Government Stringency Index were collected for all 47 prefectures of Japan for the study period from 15 February 2020 to 15 October 2022. Generalized conditional Gamma regression models were formulated with distributed lag nonlinear models by adopting the case-time-series design to assess the independent and interactive effects of ambient temperature and absolute humidity on the relative risk (RR) of the time-varying effective reproductive number (Rt). With reference to 17.8 °C, the corresponding cumulative RRs (95% confidence interval) at a mean ambient temperatures of 5.1 °C and 27.9 °C were 1.027 (1.016-1.038) and 0.982 (0.974-0.989), respectively, whereas those at an absolute humidity of 4.2 m/g3 and 20.6 m/g3 were 1.026 (1.017-1.036) and 0.995 (0.985-1.006), respectively, with reference to 10.6 m/g3. Both extremely hot and humid conditions synergistically and slightly reduced the Rt. Our findings provide a better understanding of how meteorological drivers shape the complex heterogeneous dynamics of SARS-CoV-2 in Japan.

DOI： 10.3390/pathogens12111307

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本国際保健医療学会  

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02041&link_issn=&doc_id=20230123380006&doc_link_id=%2Feh5jofih%2F2022%2F003704%2F007%2F0231-0233%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Feh5jofih%2F2022%2F003704%2F007%2F0231-0233%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

われわれは、2018/2019年シーズンにバロキサビル マルボキシル(以下バロキサビル)における薬剤感受性低下株の出現頻度や臨床経過について調査を実施した。10歳前後のA型インフルエンザ患者103名にバロキサビルを投与後、A/H1N1pdm09で患者全体の6.3%(2/32)に、A/H3N2では患者全体の10.9%(7/64)にPA/I38T変異株が出現した。また、投与後ウイルス陽性になった患者ベースでは、A/H1N1pdm09で28.6%(2/7)、A/H3N2で25.9%(7/27)にPA/I38T変異が出現した。バロキサビル投与後PA/I38T変異株があった患者、変異がなかった患者、ウイルス陰性の3群で有熱期間を比較したところ、それぞれ中央値0.83日、1.00日、0.45日であり統計的に有意な差は認められなかった。投与前患者では、A/H1N1pdm09でPA/I38T変異はなく(0.48、0%)、A/H3N2では1.0%(1/101)であった。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J03514&link_issn=&doc_id=20200608070002&doc_link_id=%2Fai1infua%2F2020%2F002102%2F003%2F0075-0079%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1infua%2F2020%2F002102%2F003%2F0075-0079%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本臨床ウイルス学会  

近年、わが国ではインフルエンザウイルスが例年とくらべかなり早い時期に報告されている。これまでわが国では、インフルエンザウイルスは12～3月にかけての冬季に流行することが通常であったが、2019年では8～9月の時点で流行の立ち上がりが観測され、季節外れの地域流行が確認された。一般的に、インフルエンザウイルスの流行は気温や相対湿度などの気象条件と関連していることが報告されており、温暖化などの影響も考えられている。さらに近年のグローバル化の影響に伴って海外からの渡航客が増えている現状があり、わが国においても海外からの渡航客がインフルエンザなどの感染症を持ち込んできている可能性も十分考えられる。特に熱帯/亜熱帯地域からの訪日渡航客が増えるなか、このような人の流れがわが国各地で起きている季節外れのインフルエンザ流行に関連している可能性がある。このようなグローバリゼーションに伴い、インフルエンザは冬だけではなく夏にも季節外れに散見されるようになってきた。本稿では、わが国におけるインフルエンザウイルスの流行が季節外れに目立った要因について筆者らの調査結果を交えつつ概説を行いたい。(著者抄録)

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap

researchmap