Details of a Researcher - TUGAWA Takesi

Papers - TUGAWA Takesi

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A significant outbreak of respiratory human adenovirus infections among children aged 3-6 years in Hokkaido, Japan, in 2023.

Yuya Fukuda, Atsuo Togashi, Satoshi Hirakawa, Masaki Yamamoto, Shinobu Fukumura, Tomohiro Nawa, Nana Kushima, Satoshi Nakamura, Jun Kunizaki, Kouhei Nishino, Ryoma Kimura, Toshitaka Kizawa, Dai Yamamoto, Ryoh Takeuchi, Yuta Sasaoka, Masayoshi Kikuchi, Takuro Ito, Kazushige Nagai, Hirofumi Asakura, Sayaka Nishimura, Masaki Yoshida, Kousuke Tsuchida, Takeshi Tsugawa

Journal of medical virology 96 ( 7 ) e29780 2024.07 [Refereed] [International journal]

Authorship： Last author

Human adenovirus (HAdV) infections present diverse clinical manifestations upon infecting individuals, with respiratory infections predominating in children. We surveyed pediatric hospitalizations due to respiratory HAdV infections across 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to March 2024, recording 473 admissions. While hospitalizations remained below five cases per week from July 2019 to September 2023, a notable surge occurred in late October 2023, with weekly admissions peaking at 15-20 cases from November to December. There were dramatic shifts in the age distribution of hospitalized patients: during 2019-2021, 1-year-old infants and children aged 3-6 years represented 51.4%-54.8% and 4.1%-13.3%, respectively; however, in 2023-2024, while 1-year-old infants represented 19.0%-20.1%, the proportion of children aged 3-6 years increased to 46.2%-50.0%. Understanding the emergence of significant outbreaks of respiratory HAdV infections and the substantial changes in the age distribution of hospitalized cases necessitates further investigation into the circulating types of HAdV in Hokkaido Prefecture and changes in children's neutralizing antibody titers against HAdV.

Whole-genome analysis of human group A rotaviruses in 1980s Japan and evolutionary assessment of global Wa-like strains across half a century.

Yuya Fukuda, Kenji Kondo, Shuji Nakata, Yasuyuki Morita, Noriaki Adachi, Keiko Kogawa, Susumu Ukae, Yoshimasa Kudou, Shuhei Adachi, Masaki Yamamoto, Shinobu Fukumura, Takeshi Tsugawa

The Journal of general virology 105 ( 6 ) 2024.06 [Refereed] [International journal]

Authorship： Last author

Historically, the Wa-like strains of human group A rotavirus (RVA) have been major causes of gastroenteritis. However, since the 2010s, the circulation of non-Wa-like strains has been increasingly reported, indicating a shift in the molecular epidemiology of RVA. Although understanding RVA evolution requires the analysis of both current and historical strains, comprehensive pre-1980's sequencing data are scarce globally. We determined the whole-genome sequences of representative strains from six RVA gastroenteritis outbreaks observed at an infant home in Sapporo, Japan, between 1981 and 1989. These outbreaks were mainly caused by G1 or G3 Wa-like strains, resembling strains from the United States in the 1970s-1980s and from Malawi in the 1990s. Phylogenetic analysis of these infant home strains, together with Wa-like strains collected worldwide from the 1970s to 2020, revealed a notable trend: pre-2010 strains diverged into multiple lineages in many genomic segments, whereas post-2010 strains tended to converge into a single lineage. However, Bayesian skyline plot indicated near-constant effective population sizes from the 1970s to 2020, and selection pressure analysis identified positive selection only at amino acid 75 of NSP2. These results suggest that evidence supporting the influence of rotavirus vaccines, introduced globally since 2006, on Wa-like RVA molecular evolution is lacking at present, and phylogenetic analysis may simply reflect natural fluctuations in RVA molecular evolution. Evaluating the long-term impact of RV vaccines on the molecular evolution of RVA requires sustained surveillance.

Human transmission and outbreaks of feline-like G6 rotavirus revealed with whole-genome analysis of G6P[9] feline rotavirus.

Yuya Fukuda, Hajime Kusuhara, Reiko Takai-Todaka, Kei Haga, Kazuhiko Katayama, Takeshi Tsugawa

Journal of medical virology 96 ( 4 ) e29565 2024.04 [Refereed] [International journal]

Authorship： Last author

Group A rotaviruses (RVAs) are generally highly species-specific; however, some strains infect across species. Feline RVAs sporadically infect humans, causing gastroenteritis. In 2012 and 2013, rectal swab samples were collected from 61 asymptomatic shelter cats at a public health center in Mie Prefecture, Japan, to investigate the presence of RVA and any association with human infections. The analysis identified G6P[9] strains in three cats and G3P[9] strains in two cats, although no feline RVA sequence data were available for the former. A whole-genome analysis of these G6P[9] strains identified the genotype constellation G6-P[9]-I2-R2-C2-M2-A3-N2-T3-E3-H3. The nucleotide identity among these G6P[9] strains exceeded 99.5% across all 11 gene segments, indicating the circulation of this G6P[9] strain among cats. Notably, strain RVA/Human-wt/JPN/KF17/2010/G6P[9], previously detected in a 3-year-old child with gastroenteritis, shares high nucleotide identity (>98%) with Mie20120017f, the representative G6P[9] strain in this study, across all 11 gene segments, confirming feline RVA infection and symptomatic presentation in this child. The VP7 gene of strain Mie20120017f also shares high nucleotide identity with other sporadically reported G6 RVA strains in humans. This suggests that feline-origin G6 strains as the probable source of these sporadic G6 RVA strains causing gastroenteritis in humans globally. Moreover, a feline-like human G6P[8] strain circulating in Brazil in 2022 was identified, emphasizing the importance of ongoing surveillance to monitor potential global human outbreaks of RVA.

Molecular evolutionary analysis of novel NSP4 mono-reassortant G1P[8]-E2 rotavirus strains that caused a discontinuous epidemic in Japan in 2015 and 2018.

Yoshiki Fujii, Takeshi Tsugawa, Yuya Fukuda, Shuhei Adachi, Saho Honjo, Yusuke Akane, Kenji Kondo, Yoshiyuki Sakai, Toju Tanaka, Toshiya Sato, Yoshihito Higasidate, Noriaki Kubo, Toshihiko Mori, Shinsuke Kato, Ryo Hamada, Masayoshi Kikuchi, Yasuo Tahara, Kazushige Nagai, Toshio Ohara, Masaki Yoshida, Shuji Nakata, Atsuko Noguchi, Wakako Kikuchi, Hiromichi Hamada, Shoko Tokutake-Hirose, Makoto Fujimori, Masamichi Muramatsu

Frontiers in microbiology 15 1430557 - 1430557 2024 [Refereed] [International journal]

In the 2010s, several unusual rotavirus strains emerged, causing epidemics worldwide. This study reports a comprehensive molecular epidemiological study of rotaviruses in Japan based on full-genome analysis. From 2014 to 2019, a total of 489 rotavirus-positive stool specimens were identified, and the associated viral genomes were analyzed by next-generation sequencing. The genotype constellations of those strains were classified into nine patterns (G1P[8] (Wa), G1P[8]-E2, G1P[8] (DS-1), G2P[4] (DS-1), G3P[8] (Wa), G3P[8] (DS-1), G8P[8] (DS-1), G9P[8] (Wa), and G9P[8]-E2). The major prevalent genotype differed by year, comprising G8P[8] (DS-1) (37% of that year's isolates) in 2014, G1P[8] (DS-1) (65%) in 2015, G9P[8] (Wa) (72%) in 2016, G3P[8] (DS-1) (66%) in 2017, G1P[8]-E2 (53%) in 2018, and G9P[8] (Wa) (26%) in 2019. The G1P[8]-E2 strains (G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1) isolated from a total of 42 specimens in discontinuous years (2015 and 2018), which were the newly-emerged NSP4 mono-reassortant strains. Based on the results of the Bayesian evolutionary analyses, G1P[8]-E2 and G9P[8]-E2 were hypothesized to have been generated from distinct independent inter-genogroup reassortment events. The G1 strains detected in this study were classified into multiple clusters, depending on the year of detection. A comparison of the predicted amino acid sequences of the VP7 epitopes revealed that the G1 strains detected in different years encoded VP7 epitopes harboring distinct mutations. These mutations may be responsible for immune escape and annual changes in the prevalent strains.

Resurgence of human metapneumovirus infection and influenza after three seasons of inactivity in the post-COVID-19 era in Hokkaido, Japan, 2022-2023.

Yuya Fukuda, Atsuo Togashi, Satoshi Hirakawa, Masaki Yamamoto, Shinobu Fukumura, Tomohiro Nawa, Saho Honjo, Jun Kunizaki, Kouhei Nishino, Toju Tanaka, Toshitaka Kizawa, Dai Yamamoto, Ryoh Takeuchi, Yuta Sasaoka, Masayoshi Kikuchi, Takuro Ito, Kazushige Nagai, Hirofumi Asakura, Katsumasa Kudou, Masaki Yoshida, Takeshi Nishida, Takeshi Tsugawa

Journal of medical virology 95 ( 12 ) e29299 2023.12 [Refereed] [International journal]

Authorship： Last author

Following the coronavirus disease 2019 (COVID-19) outbreak in February 2020, incidences of various infectious diseases decreased notably in Hokkaido Prefecture, Japan. However, Japan began gradually easing COVID-19 infection control measures in 2022. Here, we conducted a survey of children hospitalized with human metapneumovirus (hMPV), influenza A and B, and respiratory syncytial virus infections in 18 hospitals across Hokkaido Prefecture, Japan, spanning from July 2019 to June 2023. From March 2020 to June 2022 (28 months), only 13 patients were hospitalized with hMPV, and two patients had influenza A. However, in October to November 2022, there was a re-emergence of hMPV infections, with a maximum of 27 hospitalizations per week. From July 2022 to June 2023 (12 months), the number of hMPV-related hospitalizations dramatically increased to 317 patients, with the majority aged 3-6 years (38.2%, [121/317]). Influenza A also showed an increase from December 2022, with a peak of 13 hospitalizations per week in March 2023, considerably fewer than the pre-COVID-19 outbreak in December 2019, when rates reached 45 hospitalizations per week. These findings suggest the possibility of observing more resurgences in infectious diseases in Japan after 2023 if infection control measures continue to be relaxed. Caution is needed in managing potential outbreaks.

Characteristics of intussusception among children in Hokkaido, Japan, during the pre- and post-rotavirus vaccine eras (2007-2016).

Yuya Fukuda, Yusuke Akane, Saho Honjo, Yukihiko Kawasaki, Hiroyuki Tsutsumi, Takeshi Tsugawa

Acta paediatrica (Oslo, Norway : 1992) 112 ( 4 ) 868 - 875 2023.04 [Refereed] [International journal]

Authorship： Last author , Corresponding author

AIM: To analyse the epidemiology of intussusception in Hokkaido Prefecture, Japan during a 10-year period spanning the introduction of the rotavirus (RV) vaccine (2007-2016). METHODS: Using a standard questionnaire, a retrospective surveillance was conducted across 17 hospitals with paediatric beds in Hokkaido Prefecture. We compared the data between the pre-vaccine era (2007-2011) and post-vaccine era (2012-2016). RESULTS: In total, 208 and 110 intussusception cases were in the pre- and post-vaccine eras, respectively. A significant reduction of the intussusception incidence in children aged <1 year was observed from the pre- to the post-vaccine era (102.4-56.5 per 100 000 infants; incidence rate ratio, 0.55; p = 0.004). There was a relatively high-positive RV antigen detection rate (29.4%, 5/17) during the RV epidemic period in Japan (March-May) in the pre-vaccine era. None of the intussusception cases in the 31 patients with a history of RV vaccination occurred within 1 month after the administration of an RV vaccine dose. CONCLUSIONS: The incidence of intussusception in children aged <1 year decreased significantly after RV vaccine introduction in Japan. Another survey is needed to determine how the incidence of intussusception has changed further since the introduction of routine RV vaccination in 2020.

Surveillance in hospitalized children with infectious diseases in Japan: Pre- and post-coronavirus disease 2019.

Yuya Fukuda, Takeshi Tsugawa, Yoshinobu Nagaoka, Akira Ishii, Tomohiro Nawa, Atsuo Togashi, Jun Kunizaki, Satoshi Hirakawa, Junya Iida, Toju Tanaka, Toshitaka Kizawa, Dai Yamamoto, Ryoh Takeuchi, Yoshiyuki Sakai, Masayoshi Kikuchi, Kazushige Nagai, Hirofumi Asakura, Rina Tanaka, Masaki Yoshida, Ryo Hamada, Yukihiko Kawasaki

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 11 ) 1639 - 1647 2021.11 [Refereed] [International journal]

Authorship： Corresponding author

INTRODUCTION: The epidemic of coronavirus disease 2019 (COVID-19) rapidly spread worldwide, and the various infection control measures have a significant influence on the spread of many infectious diseases. However, there have been no multicenter studies on how the number of hospitalized children with various infectious diseases changed before and after the outbreak of COVID-19 in Japan. METHODS: We conducted a multicenter, prospective survey for hospitalized pediatric patients in 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to February 2021. We defined July 2019 to February 2020 as pre-COVID-19, and July 2020 to February 2021 as post-COVID-19. We surveyed various infectious diseases by sex and age. RESULTS: In total, 5300 patients were hospitalized during the study period. The number of patients decreased from 4266 in the pre-COVID-19 period to 701 (16.4%) post-COVID-19. Patients with influenza and RSV decreased from 308 to 795 pre-COVID-19 to zero and three (0.4%) post-COVID-19. However, patients with adenovirus (respiratory infection) only decreased to 60.9% (46-28) of pre-COVID levels. Patients with rotavirus, norovirus, and adenovirus gastroenteritis decreased markedly post-COVID-19 to 2.6% (38-1), 27.8% (97-27) and 13.5% (37-5). The number of patients with UTIs was similar across the two periods (109 and 90). KD patients decreased to 31.7% (161-51) post-COVID-19. CONCLUSIONS: We suggest that current infection control measures for COVID-19 such as wearing masks, washing hands, and disinfecting hands with alcohol are effective against various infectious diseases. However, these effects vary by disease.

Rotavirus vaccination in Japan: Efficacy and safety of vaccines, changes in genotype, and surveillance efforts.

Takeshi Tsugawa, Yusuke Akane, Saho Honjo, Kenji Kondo, Yukihiko Kawasaki

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 7 ) 940 - 948 2021.07 [Refereed] [International journal]

Authorship： Lead author , Corresponding author

In Japan, a monovalent rotavirus vaccine (RV1) and a pentavalent rotavirus vaccine (RV5) were launched as voluntary vaccinations in November 2011 and July 2012, respectively. Rotavirus (RV) vaccine coverage in Japan increased from 30.0% in 2012 to 78.4% in 2019. The number of RV gastroenteritis hospitalizations decreased after 2014 in Japan, and is expected to decrease further following the introduction of RV vaccines into the national immunization program in October 2020. The incidence rates of intussusception (IS) among children aged <1 year were 102.8 and 94.0 per 100,000 person-years in the pre-vaccine (2007-2011) and post-vaccine (2012-September 2014) eras, respectively. IS incidence did not increase following RV vaccine introduction in Japan. The efficacy and safety of RV vaccination were both documented in Japan. To reduce the risk of IS following RV vaccination, it is important that children receive a first dose of RV vaccine at age <15 weeks, preferably at age 2 months. Some strains that have emerged since RV vaccine introduction, such as DS-1-like G1P[8], eG3, and G8P[8], have spread nationwide. These three emerging genotypes did not affect the severity of the RV infection. Continuous city-level surveillance, using analysis of all 11 RV genome segments, is necessary to elucidate the genetic characteristics of prevalent RV strains. These efforts would also clarify the influence of vaccination on genetic changes of RV strains and the emergence of new genotypes.

Molecular characterization of the first human G15 rotavirus strain of zoonotic origin from the bovine species.

Takeshi Tsugawa, Yoshiki Fujii, Yusuke Akane, Saho Honjo, Kenji Kondo, Hiroshi Nihira, Hirokazu Kimura, Yukihiko Kawasaki

The Journal of general virology 102 ( 4 ) 2021.04 [Refereed] [International journal]

Authorship： Lead author , Corresponding author

Group A rotaviruses (RVAs) infect a wide variety of mammalian and avian species. Animals act as a potential reservoir to RVA human infections by direct virion transmission or by contributing genes to reassortants. Here, we report the molecular characterization of a rare human RVA strain Ni17-46 with a genotype G15P[14], isolated in Japan in 2017 during rotavirus surveillance in a paediatric outpatient clinic. The genome constellation of this strain was G15-P[14]-I2-R2-C2-M2-A13-N2-T9-E2-H3. This is the first report of an RVA with G15 genotype in humans, and sequencing and phylogenetic analysis results suggest that human infection with this strain has zoonotic origin from the bovine species. Given the fact that this strain was isolated from a patient with gastroenteritis and dehydration symptoms, we must take into account the virulence of this strain in humans.

Molecular and clinical characterization of the equine-like G3 rotavirus that caused the first outbreak in Japan, 2016.

Yusuke Akane, Takeshi Tsugawa, Yoshiki Fujii, Saho Honjo, Kenji Kondo, Shuji Nakata, Shinsuke Fujibayashi, Toshio Ohara, Toshihiko Mori, Yoshihito Higashidate, Kazushige Nagai, Masayoshi Kikuchi, Toshiya Sato, Shinsuke Kato, Yasuo Tahara, Noriaki Kubo, Kazuhiko Katayama, Hirokazu Kimura, Hiroyuki Tsutsumi, Yukihiko Kawasaki

The Journal of general virology 102 ( 3 ) 2021.02 [Refereed] [International journal]

Authorship： Corresponding author

Since 2013, equine-like G3 rotavirus (eG3) strains have been detected throughout the world, including in Japan, and the strains were found to be dominant in some countries. In 2016, the first eG3 outbreak in Japan occurred in Tomakomai, Hokkaido prefecture, and the strains became dominant in other Hokkaido areas the following year. There were no significant differences in the clinical characteristics of eG3 and non-eG3 rotavirus infections. The eG3 strains detected in Hokkaido across 2 years from 2016 to 2017 had DS-1-like constellations (i.e. G3-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2), and the genes were highly conserved (97.5-100 %). One strain, designated as To16-12 was selected as the representative strain for these strains, and all 11 genes of this strain (To16-12) exhibited the closest identity to one foreign eG3 strain (STM050) seen in Indonesia in 2015 and two eG3 strains (IS1090 and MI1125) in another Japanese prefecture in 2016, suggesting that this strain might be introduced into Japan from Indonesia. Sequence analyses of VP7 genes from animal and human G3 strains found worldwide did not identify any with close identity (>92 %) to eG3 strains, including equine RV Erv105. Analysis of another ten genes indicated that the eG3 strain had low similarity to G2P[4] strains, which are considered traditional DS-1-like strains, but high similarity to DS-1-like G1P[8] strains, which first appeared in Asia in 2012. These data suggest that eG3 strains were recently generated in Asia as mono-reassortant strain between DS-1-like G1P[8] strains and unspecified animal G3 strains. Our results indicate that rotavirus surveillance in the postvaccine era requires whole-genome analyses.

Rotavirus genotype and Vesikari score of outpatients in Japan in the vaccine era.

Mayumi Ono, Takeshi Tsugawa, Shuji Nakata, Kenji Kondo, Masatoshi Tatsumi, Hiroyuki Tsutsumi, Yukihiko Kawasaki

Pediatrics international : official journal of the Japan Pediatric Society 62 ( 5 ) 569 - 575 2020.05 [Refereed] [International journal]

Authorship： Corresponding author

BACKGROUND: Group A rotaviruses (RVs) are a major cause of severe gastroenteritis among infants and young children. In Japan, RV vaccines were introduced in 2011, leading to a reduction in severe gastroenteritis cases. Studies are required to assess the effectiveness of the vaccines and their effect on the prevalence of RV genotypes. METHODS: Fecal samples were collected from outpatients with RV gastroenteritis in a pediatric clinic in Sapporo, Japan, from 2010 to 2016. GPI genotypes were determined using reverse-transcription polymerase chain reaction. Clinical information and immunization records were obtained from outpatients after 2013. GPI genotypes and clinical features were compared between patients with and without a RV vaccine history. RESULTS: In total, 270 cases were genotyped. G1P[8]I1 (Wa-like G1P[8]) strains were dominant from 2010 to 2012. G1P[8]I2 (DS-1-like G1P[8]) strains appeared in 2012 and dominated in 2013 to 2015. G2P[4]I2 and G9P[8]I1 strains increased every 3 years (G2P[4]I2: 2011 and 2014, G9P[8]I1: 2010, 2013 and 2016). After the 2013 season, 137 cases were collected, 24 of which were vaccinated. Cases requiring drip infusion were fewer in the vaccination group than in the non-vaccination group (16.7% vs 52.2%). No patients required hospitalization in the vaccination group compared with 10.6% in the non-vaccination group. A severe Vesikari score was less common in the vaccination group than in the non-vaccination group (33.3% vs 78.8%). There was no significant difference in the GPI genotype distribution between the two groups. CONCLUSION: Rotaviruses vaccine effectiveness, regardless of GPI genotype, was confirmed in terms of alleviation of disease severity.

Effectiveness of monovalent and pentavalent rotavirus vaccines in Japanese children.

Kaoru Araki, Megumi Hara, Takeshi Tsugawa, Chisato Shimanoe, Yuichiro Nishida, Muneaki Matsuo, Keitaro Tanaka

Vaccine 36 ( 34 ) 5187 - 5193 2018.08 [Refereed] [International journal]

BACKGROUND: Rotavirus (RV) vaccination has been available in Japan since November 2011, but is not yet part of Japan's national immunisation programs. There are insufficient data on vaccine effectiveness (VE) among Japanese children. METHODS: Between the months of January and May in 2014 and 2015, we conducted active surveillance of gastroenteritis among children at 14 medical facilities. Rectal swabs from all patients with diarrhoea or vomiting were tested for RV by immunochromatography, and positive specimens were genotyped. Demographic data and immunisation records were obtained from a questionnaire completed by their parents/guardians or medical records. A test-negative case-control design was used to examine vaccine effectiveness (VE) using unconditional logistic regression analysis adjusted for possible confounding factors. RESULTS: Among the 1519 eligible subjects (children with acute gastroenteritis symptoms aged ≥2 months to <3 y visiting medical facilities) recruited, 487 cases and 925 controls were enrolled. Cases had more severe symptoms than controls, requiring more intensive treatment, including intravenous rehydration or hospitalisation. VE against all rotavirus gastroenteritis (RVGE) was 80.0% (95% confidence interval [CI], 72.8-85.5%), and VEs against RV1 and RV5 were similar, at 80.6% (95%CI, 70.7-87.1%) for RV1 and 80.4% (95% CI, 69.1-87.6%) for RV5. Although VEs of both vaccines decreased with age, VEs against all RVGE were >70% up to 2 years after vaccination. VEs increased with severity of RVGE, and VE against severe RVGE, requiring intravenous rehydration or hospitalisation, was 97.3% (95% CI, 88.8-99.3%). VEs of RV1 and RV5 against G1P[8] and G2P[4] were comparable, at RV1, 89.8% (95% CI, 78.2-95.5%) and 78.3% (95% CI, 23.6-93.8%); and RV5, 85.8% (95% CI, 72.8-92.6%) and 88.1% (95% CI, 10.1-98.4%), respectively. CONCLUSIONS: Rotavirus vaccines were effective in preventing mild to severe RVGE, irrespective of vaccine type, time since vaccination, or RV genotype.

Clinical and Molecular Characteristics of Human Rotavirus G8P[8] Outbreak Strain, Japan, 2014.

Kenji Kondo, Takeshi Tsugawa, Mayumi Ono, Toshio Ohara, Shinsuke Fujibayashi, Yasuo Tahara, Noriaki Kubo, Shuji Nakata, Yoshihito Higashidate, Yoshiki Fujii, Kazuhiko Katayama, Yuko Yoto, Hiroyuki Tsutsumi

Emerging infectious diseases ( CENTERS DISEASE CONTROL ) 23 ( 6 ) 968 - 972 2017.06 [Refereed] [International journal]

Authorship： Corresponding author

Human G3P[9] rotavirus strains possessing an identical genotype constellation to AU-1 isolated at high prevalence in Brazil, 1997-1999.

Takeshi Tsugawa, Kaitlin Rainwater-Lovett, Hiroyuki Tsutsumi

The Journal of general virology ( SOC GENERAL MICROBIOLOGY ) 96 ( Pt 3 ) 590 - 600 2015.03 [Refereed] [International journal]

Authorship： Lead author , Corresponding author

Rotavirus (RV) A is a very common cause of acute diarrhoea in infants and young children worldwide. Most human strains are classified into two major Wa-like and DS-1-like genotype constellations, whilst a minor third strain, AU-1, was described in 1989 among human RV isolates from Japan. AU-1 demonstrates a high degree of homology to a feline RV, FRV-1, which suggests interspecies transmission of feline RV. However, there has been no subsequent report of RVs possessing the AU-1 genotype throughout all 11 genes of the genome. Between March 1997 and December 1999, 157 RV-positive stool samples were collected from Brazilian children, and 16 of the RVs (10.2 %) were P[9] genotype. We analysed eight strains by almost full-genome sequencing. These eight strains were divided into two groups: five AU-1-like and three Wa-like strains. Four of the five AU-1-like strains had the AU-1-like genotype constellation throughout the 11 genes. The remaining AU-1-like strain was considered to be a reassortant strain comprosed of nine, two and one genes from the AU-1-like, Wa-like and G9 strains, respectively. The three Wa-like strains were considered to be reassortants comprising seven to eight genes and three to four genes from Wa-like and non-Wa-like strains, respectively. This report of human G3P[9] RV strains possessing the AU-1 genotype constellation throughout all genes demonstrates the stability and infectivity of the AU-1-like strain with its original genotype over distance and time.

Full sequence analysis of the original Sapporo virus.

Kaori Nakanishi, Masatoshi Tatsumi, Kazuko Kinoshita-Numata, Takeshi Tsugawa, Shuji Nakata, Hiroyuki Tsutsumi

Microbiology and immunology ( WILEY-BLACKWELL ) 55 ( 9 ) 657 - 60 2011.09 [Refereed] [International journal]

In this study, the full-length genome sequence of the prototype of sapovirus, namely Sapporo virus (SV82), was identified. Sapporo virus RNA was extracted from a fecal sample, amplified by RT-PCR and the PCR products sequenced directly and analyzed. Sequence analysis showed that Sapporo virus consists of 7433 nucleotides and has three open reading frames. The Sapporo strain shows 91.7% nucleotide sequence identity to the Manchester virus. Phylogenic analysis has also revealed the closeness of Sapporo virus to other sapovirus/genogroup I strains. Basic information on the evolutionary history of sapovirus analysis is provided here.

Whole genome sequence and phylogenetic analyses reveal human rotavirus G3P[3] strains Ro1845 and HCR3A are examples of direct virion transmission of canine/feline rotaviruses to humans.

Takeshi Tsugawa, Yasutaka Hoshino

Virology ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 380 ( 2 ) 344 - 53 2008.10 [Refereed] [International journal]

Authorship： Lead author

Rotaviruses, the major causative agents of infantile diarrhea worldwide, are, in general, highly species-specific. Interspecies virus transmission is thought to be one of the important contributors involved in the evolution and diversity of rotaviruses in nature. Human rotavirus (HRV) G3P[3] strains Ro1845 and HCR3A have been reported to be closely related genetically to certain canine and feline rotaviruses (RVs). Whole genome sequence and phylogenetic analyses of each of these 2 HRVs as well as 3 canine RVs (CU-1, K9 and A79-10, each with G3P[3] specificity) and 2 feline RVs (Cat97 with G3P[3] specificity and Cat2 with G3P[9] specificity) revealed that (i) each of 11 genes of the Ro1845 and HCR3A was of canine/feline origin; (ii) canine and feline rotaviruses with G3P[3] specificity bore highly conserved species-specific genomes; and (iii) the Cat2 strain may have evolved via multiple reassortment events involving canine, feline, human and bovine rotaviruses.

Virological, serological, and clinical features of an outbreak of acute gastroenteritis due to recombinant genogroup II norovirus in an infant home.

Takeshi Tsugawa, Kazuko Numata-Kinoshita, Shinjiro Honma, Shuji Nakata, Masatoshi Tatsumi, Yoshiyuki Sakai, Katsuro Natori, Naokazu Takeda, Shinichi Kobayashi, Hiroyuki Tsutsumi

Journal of clinical microbiology ( AMER SOC MICROBIOLOGY ) 44 ( 1 ) 177 - 82 2006.01 [Refereed] [International journal]

Authorship： Lead author

Norovirus (NV) is an important cause of acute nonbacterial gastroenteritis worldwide. Recently, several sporadic cases due to naturally occurring recombinant NVs have been reported. In January 2000, there was an outbreak of gastroenteritis in an infant home in Sapporo, Japan. Of 34 residents of the home that were less than 2 years old, 23 developed gastrointestinal symptoms and NV infection was confirmed by conventional reverse transcription-PCR to detect the RNA polymerase region of genogroup II NV. In this virus, the RNA polymerase region shared 86% nucleotide identity with Hawaii virus but only 77% with Mexico virus; however, its capsid region shared only 70% identity with Hawaii virus but 90% with Mexico virus. On the other hand, both regions shared a higher 96% nucleotide identity with Arg320 virus, which was found in Mendoza, Argentina, in 1995 and considered to be a recombinant of Hawaii and Mexico viruses. The findings indicate that the virus involved in the outbreak was similar and may have evolved from the Arg320 virus. Clinically the cases were more severe than those of previously reported sporadic or outbreak cases of NV infection.

Crizotinib therapy for congenital embryonal rhabdomyosarcoma associated with an ATIC-ALK gene fusion.

Yusuke Akane, Masaki Yamamoto, Akira Takebayashi, Ryo Hamada, Keita Igarashi, Makoto Emori, Shintaro Sugita, Kohichi Takada, Tadashi Hasegawa, Takeshi Tsugawa

Pediatric blood & cancer 71 ( 9 ) e31148 2024.09 [Refereed] [International journal]

Authorship： Last author

Review of the past and present status of respiratory syncytial virus and rotavirus infections that commonly affect children.

Hiroyuki Tsutsumi, Takeshi Tsugawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2024.05 [Refereed] [International journal]

Respiratory syncytial virus (RSV) and rotavirus infections are long-standing infectious diseases that affect children worldwide. RSV and rotavirus were first discovered in clinical specimens in 1955 and 1973, respectively. From their discovery to the present day, significant progress has been made in understanding these two infections. The introduction of a simple and rapid antigen diagnostic test into clinical settings in the 1990s offered new insight into the clinical characteristics and epidemiology of these infections. Regarding therapeutics, symptomatic treatments have remained the mainstay; however, prophylactic humanized anti-RSV monoclonal antibodies have been developed and advances in structural biology may allow for more effective human anti-RSV monoclonal antibodies and novel RSV vaccines to be developed soon. For rotavirus, two vaccines have been licensed and broadly applied over the past 10 years, which have been successful clinically and have changed the epidemiology of rotavirus infections in Japan.

「データベースを用いた国内発症小児Coronavirus Disease 2019(COVID-19)症例の臨床経過に関する検討」最終報告

勝田友博, 天羽清子, 荒木かほる, 石和田稔彦, 大宜見力, 大城誠, 神谷元, 越田理恵, 清水直樹, 高野智子, 津川毅, 富樫篤生, 中野貴司, 西村直子, 野崎昌俊, 菱木はるか, 藤岡雅司, 保科隆之, 細矢光亮, 前田明彦, 水野由美, 宮崎雅仁, 吉川哲史, 和田泰三, 岩田敏, 尾内一信, 岡田賢司, 是松聖悟, 菅秀, 宮崎千明, 森内浩幸, 齋藤昭彦, 塚原宏一, 森岡一朗, 宮入烈, 多屋馨子, 日本小児科学会予防接種・感染症対策委員会

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 128 ( 5 ) 777 - 783 2024.05

専用データベースに日本小児科学会会員により任意で報告された臨床情報を用いて、2020年2月～2022年9月に発症した16歳未満の国内小児COVID-19患者10007例(男児5413例、女児4594例、年齢中央値6.1歳)の臨床的特徴を解析した。発症時期は、オミクロン株流行前が42.1%、オミクロン流行後が57.9%であった。オミクロン株流行前と比較して流行後は、初診時において37.5℃以上の発熱、乾性咳嗽、犬吠様咳嗽、喉頭痛、喘鳴、倦怠感、筋肉痛、関節痛、頭痛、痙攣、腹痛、悪心・嘔吐を認める割合が有意に増加した。慢性期症状の有無が追加報告された4669例中187例(4.0%)で発症後1ヵ月以降に何らかの症状が報告され、主な慢性期症状は発熱1.2%、咳嗽1.2%、嗅覚障害0.7%、味覚障害0.7%、倦怠感0.6%などであった。

「データベースを用いた国内発症小児Coronavirus Disease 2019(COVID-19)症例の臨床経過に関する検討」最終報告

勝田友博, 天羽清子, 荒木かほる, 石和田稔彦, 大宜見力, 大城誠, 神谷元, 越田理恵, 清水直樹, 高野智子, 津川毅, 富樫篤生, 中野貴司, 西村直子, 野崎昌俊, 菱木はるか, 藤岡雅司, 保科隆之, 細矢光亮, 前田明彦, 水野由美, 宮崎雅仁, 吉川哲史, 和田泰三, 岩田敏, 尾内一信, 岡田賢司, 是松聖悟, 菅秀, 宮崎千明, 森内浩幸, 齋藤昭彦, 塚原宏一, 森岡一朗, 宮入烈, 多屋馨子, 日本小児科学会予防接種・感染症対策委員会

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 128 ( 5 ) 777 - 783 2024.05

Children's cognition and attitudes during long-term cancer treatment: an ethnographic study.

Ryoko Michinobu, Masaki Yamamoto, Keita Igarashi, Yoshiyuki Sakai, Yusuke Akane, Dai Yamamoto, Akira Takebayashi, Takahiro Mikami, Hiroyuki Tsutsumi, Takeshi Tsugawa

BMJ paediatrics open 8 ( 1 ) 2024.04 [Refereed] [International journal]

Authorship： Last author

BACKGROUND: Cancer treatment for children is typically long-term and difficult, and the experience is unique for each child. When designing child-centred care, individuals' values and preferences are considered equally important as the clinical evidence; therefore, understanding children's thoughts and attitudes while they receive long-term treatment could offer valuable insights for better clinical practice. METHODS: We conducted long-term consecutive participatory observations and interviews with seven children, who were hospitalised and receiving cancer treatment for the first time. The daily observational data on those children's discourses, behaviours and interactions with health professionals were systematically collected and thematically examined. The analysis was expanded to explore significant narratives for each child to capture their narrative sequence over time. RESULTS: The initial analysis identified 685 narrative indexes for all observation data, which were categorised into 21 sub-codes. Those sub-codes were assembled into five main themes by thematic analysis: making promises with health professionals, learning about the treatment procedures through participation, taking care of oneself, increasing the range of activities one can perform and living an ordinary life. CONCLUSION: We observed a forward-looking attitude toward understanding cancer, accepting treatment and looking forward to the future among children undergoing in-hospital cancer treatment. In addition, the children developed cognitively, affectively and relationally throughout cancer treatment processes. These findings have implications for better clinical practice in child-centred care, including children's participation in shared decision-making in paediatric oncology.

Severe cervical abscess due to PVL-positive ST6562 MRSA-IVa, a presumptive variant of ST8-IVa USA300 clone in northern Japan.

Katsumasa Kudo, Takahiro Noda, Yuta Sasaoka, Atsuo Togashi, Meiji Soe Aung, Yoshiyuki Sakai, Takeshi Tsugawa, Nobumichi Kobayashi

New microbes and new infections 58 101230 - 101230 2024.04 [Refereed] [International journal]

Effects of probiotics in children with acute gastroenteritis: A systematic review and meta-analysis focusing on probiotics utilized in Japan.

Toru Higuchi, Munehiro Furuichi, Naonori Maeda, Takeshi Tsugawa, Kenta Ito

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 30 ( 4 ) 337 - 342 2024.04 [Refereed] [International journal]

BACKGROUND: Many randomized controlled trials and systematic reviews have evaluated the use of probiotics to treat acute infectious gastroenteritis. However, most probiotic species evaluated in previous large randomized controlled trials are unavailable in Japan. Our objective was to investigate the efficacy of probiotics utilized in Japan for acute gastroenteritis. METHODS: The inclusion criterion was a randomized controlled study that compared probiotics with a placebo to treat children younger than 18 years with acute infectious gastroenteritis. We excluded studies that did not contain the following species available in Japan: Bifidobacterium spp., Lactobacillus acidophilus, Enterococcus faecium, Clostridium butyricum, and Bacillus subtilis and studies in low- or lower-middle-income countries. We searched PubMed, CENTRAL, and Igaku Chuo Zasshi from their inception to November 27, 2022. After the risk of bias assessment, data on diarrhea duration, number of hospitalizations, length of hospital stay, and adverse effects were extracted. RESULTS: Fourteen studies were included in this meta-analysis. Diarrhea lasting longer than 48 h (7 articles, n = 878) was significantly lower in the probiotic group (risk ratio (RR) 0.70, 95 % confidence interval (CI) 0.59-0.83). The duration of diarrhea (14 articles; n = 1761) was 23.45 h (95 % CI 18.22-26.69) shorter in the probiotic group. Duration of hospitalization (6 articles; n = 971) was 17.73 h (95 % CI 6.9-28.56) shorter in the probiotic group. CONCLUSIONS: Although the certainty of evidence is very low, the use of probiotics for acute gastroenteritis in children may improve diarrhea approximately one day earlier. This study was registered with PROSPERO (CRD 42023405559).

「原因不明の小児急性肝炎に関する実態調査(二次調査)」報告

近藤宏樹, 多屋馨子, 天羽清子, 乾あやの, 笠原群生, 鈴木光幸, 田中孝明, 津川毅, 別所一彦, 保科隆之, 宮入烈, 虫明聡太郎, 吉川哲史, 齋藤昭彦, 塚原宏一, 森岡一朗, 須磨崎亮, 細矢光亮, 日本小児科学会予防接種・感染症対策委員会原因不明の小児の急性肝炎対策ワーキンググループ

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 128 ( 4 ) 668 - 680 2024.04

COVID-19パンデミック期の小児の急性肝炎原因不明の小児急性肝炎対策ワーキンググループのこれまでの活動と調査結果に関する報告

近藤宏樹, 多屋馨子, 天羽清子, 乾あやの, 笠原群生, 齋藤昭彦, 鈴木光幸, 田中孝明, 塚原宏一, 津川毅, 別所一彦, 保科隆之, 宮入烈, 森岡一朗, 吉川哲史, 虫明聡太郎, 須磨崎亮, 細矢光亮

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 128 ( 2 ) 165 - 165 2024.02

おたふくかぜワクチン接種後の副反応に関する全国調査報告

神谷元, 西藤成雄, 中野貴司, 菅秀, 奥山舞, 田中敏博, 中村豊, 森野紗衣子, 高梨さやか, 新井智, 木所稔, 岡田賢司, 天羽清子, 荒木かほる, 石和田稔彦, 大宜見力, 勝田友博, 越田理恵, 高野智子, 津川毅, 富樫篤生, 西村直子, 野崎昌俊, 菱木はるか, 保科隆之, 細矢光亮, 前田明彦, 水野由美, 宮崎雅仁, 吉川哲史, 和田泰三, 岩田敏, 尾内一信, 是松聖悟, 清水直樹, 森内浩幸, 宮崎千明, 宮入烈, 森岡一朗, 塚原宏一, 齋藤昭彦, 多屋馨子, 日本小児科学会予防接種・感染症対策委員会

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 128 ( 1 ) 92 - 104 2024.01

2020年1月から2023年3月までに1歳以上就学前の小児に対して乾燥弱毒生おたふくかぜワクチン(おたふくかぜワクチン)接種を行った医師を対象に、接種8週間後までの副反応が疑われる症状に関して情報収集を行った。8週間フォローできた58783例における無菌性髄膜炎(8例)・急性脳炎(1例)・髄膜脳炎(1例)・無菌性髄膜炎疑い(2例)の発生報告頻度は0.020%であり、前向きに8週間フォローできた44708例では無菌性髄膜炎(疑い2例を含む)6例の発生報告頻度は0.013%であった。頻度は低いものの、おたふくかぜワクチン株が検出された症例で急性脳炎やけいれん重積を認めた症例があったこと、1回目接種後に髄膜炎を疑う症状が一定の頻度で発生していたこと、無菌性髄膜炎6例(疑いを含む)のうち5例が1回目接種後に発生していたことなどが報告された。

Changing Patterns of Infectious Diseases Among Hospitalized Children in Hokkaido, Japan, in the Post-COVID-19 Era, July 2019 to June 2022.

Yuya Fukuda, Atsuo Togashi, Satoshi Hirakawa, Masaki Yamamoto, Shinobu Fukumura, Tomohiro Nawa, Saho Honjo, Jun Kunizaki, Kouhei Nishino, Toju Tanaka, Toshitaka Kizawa, Dai Yamamoto, Ryoh Takeuchi, Yuta Sasaoka, Masayoshi Kikuchi, Takuro Ito, Kazushige Nagai, Hirofumi Asakura, Katsumasa Kudou, Masaki Yoshida, Takeshi Nishida, Takeshi Tsugawa

The Pediatric infectious disease journal 42 ( 9 ) 766 - 773 2023.09 [Refereed] [International journal]

Authorship： Last author

BACKGROUND: Many reports have reported a reduction in respiratory infectious diseases and infectious gastroenteritis immediately after the coronavirus disease 2019 (COVID-19) pandemic, but data continuing into 2022 are very limited. We sought to understand the current situation of various infectious diseases among children in Japan as of July 2022 to improve public health in the post-COVID-19 era. METHODS: We collected data on children hospitalized with infectious diseases in 18 hospitals in Japan from July 2019 to June 2022. RESULTS: In total, 3417 patients were hospitalized during the study period. Respiratory syncytial virus decreased drastically after COVID-19 spread in early 2020, and few patients were hospitalized for it from April 2020 to March 2021. However, an unexpected out-of-season re-emergence of respiratory syncytial virus was observed in August 2021 (50 patients per week), particularly prominent among older children 3-6 years old. A large epidemic of delayed norovirus gastroenteritis was observed in April 2021, suggesting that the nonpharmaceutical interventions for COVID-19 are less effective against norovirus. However, influenza, human metapneumovirus, Mycoplasma pneumoniae , and rotavirus gastroenteritis were rarely seen for more than 2 years. CONCLUSIONS: The incidence patterns of various infectious diseases in Japan have changed markedly since the beginning of the COVID-19 pandemic to the present. The epidemic pattern in the post-COVID-19 era is unpredictable and will require continued careful surveillance.

Rivaroxaban for severe superior sagittal sinus thrombosis in a child with ALL.

Masaki Yamamoto, Yusuke Akane, Ryo Hamada, Hiroyuki Kabutoya, Keita Igarashi, Sangnyon Kim, Takeshi Tsugawa

International journal of hematology 118 ( 3 ) 309 - 310 2023.09 [Refereed] [Domestic journal]

Authorship： Last author

Acute osteomyelitis/septic pulmonary embolism associated with familial infections caused by PVL-positive ST6562 MRSA-IVa, a presumptive variant of USA300 clone.

Nao Harada, Atsuo Togashi, Meiji Soe Aung, Jun Kunizaki, Kazutaka Nogami, Yoshinobu Nagaoka, Akira Ishii, Ima Kosukegawa, Wakiko Aisaka, Satoshi Nakamura, Tomohiro Wakabayashi, Takeshi Tsugawa, Nobumichi Kobayashi

IJID regions 8 16 - 18 2023.09 [Refereed] [International journal]

Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA) occasionally causes severe invasive infections. A 10-year-old immunocompetent boy in Hokkaido, the northern main island of Japan, was admitted with acute osteomyelitis of the right ilium, complicated by septic thrombophlebitis of the right common iliac vein and septic pulmonary embolism. As MRSA was isolated from blood and sputum samples of the patient, linezolid and vancomycin were initially used for treatment, and later clindamycin was added based on PCR-positive results for PVL genes. During his hospitalization, the patient was complicated by abscesses around the right ilium and septic arthritis of the right hip, which required surgical drainage. Prior to his admission, his youngest sister had developed a right breast abscess, and another sister and his mother developed contagious impetigo and hordeolum, respectively, during his hospitalization. These infections in the patient and his family members were caused by an identical PVL-positive MRSA strain belonging to ST6562, a single-locus variant of ST8. Due to the genetically close characteristics, this ST6562 MRSA was considered a genetic variant of the USA300 CA-MRSA clone (ST8-MRSA-IVa) predominating in the United States. The ST6562 MRSA-IVa is suggested to have occurred in Japan, associated with potential spread of the USA300 clone.

Therapeutic efficacy of intravenous infusion of mesenchymal stem cells in rat perinatal brain injury.

Kojiro Terada, Masanori Sasaki, Hiroshi Nagahama, Yuko Kataoka-Sasaki, Shinichi Oka, Ryo Ukai, Takahiro Yokoyama, Yusuke Iizuka, Takuro Sakai, Shinobu Fukumura, Takeshi Tsugawa, Jeffery D Kocsis, Osamu Honmou

Pediatric research 2023.07 [Refereed] [International journal]

BACKGROUND: Perinatal brain injury is multifactorial and primarily associated with brain prematurity, inflammation, and hypoxia-ischemia. Although recent advances in perinatal medicine have improved the survival rates of preterm infants, neurodevelopmental disorders remain a significant complication. We tested whether the intravenous infusion of mesenchymal stem cells (MSCs) had therapeutic efficacy against perinatal brain injury in rats. METHODS: Pregnant rats at embryonic day (E) 18 received lipopolysaccharide and the pups were born at E21. On postnatal day (PND) 7, the left common carotid artery of each pup was ligated, and they were exposed to 8% oxygen for 2 h. They were randomized on PND10, and MSCs or vehicle were intravenously infused. We performed behavioral assessments, measured brain volume using MRI, and performed histological analyses on PND49. RESULTS: Infused MSCs showed functional improvements in our model. In vivo MRI revealed that MSC infusion increased non-ischemic brain volume compared to the vehicle group. Histological analyses showed that cortical thickness, the number of NeuN+ and GAD67+ cells, and synaptophysin density in the non-ischemic hemisphere in the MSC group were greater than the vehicle group, but less than the control group. CONCLUSIONS: Infused MSCs improve sensorimotor and cognitive functions in perinatal brain injury and enhance neuronal growth. IMPACT: Intravenous infusion of MSCs improved neurological function in rats with perinatal brain injury, including motor, sensorimotor, cognitive, spatial, and learning memory. Infused MSCs increased residual (non-ischemic) tissue volume, number of neuronal cells, GABAergic cells, and cortical synapses in the contralesional (right) hemisphere. Intravenous administration of MSC might be suitable for the treatment of perinatal brain injury.

原因不明の小児急性肝炎に関する実態調査(一次調査)報告書

近藤宏樹, 多屋馨子, 天羽清子, 乾あやの, 笠原群生, 鈴木光幸, 田中孝明, 津川毅, 別所一彦, 保科隆之, 宮入烈, 虫明聡太郎, 吉川哲史, 齋藤昭彦, 塚原宏一, 森岡一朗, 須磨崎亮, 細矢光亮, 日本小児科学会予防接種・感染症対策委員会原因不明の小児の急性肝炎対策ワーキンググループ

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 127 ( 7 ) 1033 - 1038 2023.07

2022年より欧米から「原因不明の小児急性肝炎」について多くの報告があがるようになり、アデノウイルスや新型コロナウイルス感染症(COVID-19)流行との関連が疑われている。これまで本邦では小児の急性肝炎のサーベイランスが行われていないことから、今回、日本小児科学会会員が所属する全国の病院小児科責任者を対象に、2017年1月～2022年6月までの期間における同疾患の実態について質問紙調査を行い、947名より回答を得た。その結果、COVID-19流行前の報告数は2017年260名、2018年257名、2019年243名で、COVID-19流行中の報告数は2020年164名、2021年192名、2022年1～6月で113名と、COVID-19流行中の方が少ない傾向がみられた。COVID-19流行前は0歳および1～4歳群の症例数が他の年齢群と比較して多い傾向がみられたが、流行中はこれらの年齢群で減少が著明であった。地域別では、COVID-19流行前・流行後ともに、京都府・愛知県・福島県からの報告が多かった。

原因不明の小児急性肝炎に関する実態調査(一次調査)報告書

近藤宏樹, 多屋馨子, 天羽清子, 乾あやの, 笠原群生, 鈴木光幸, 田中孝明, 津川毅, 別所一彦, 保科隆之, 宮入烈, 虫明聡太郎, 吉川哲史, 齋藤昭彦, 塚原宏一, 森岡一朗, 須磨崎亮, 細矢光亮, 日本小児科学会予防接種・感染症対策委員会原因不明の小児の急性肝炎対策ワーキンググループ

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 127 ( 7 ) 1033 - 1038 2023.07

小児科医に潜在するワクチン忌避(Vaccine Hesitancy)に対する教育プログラム

勝田友博, 天羽清子, 荒木かほる, 石和田稔彦, 大宜見力, 神谷元, 越田理恵, 高野智子, 津川毅, 富樫篤生, 中野貴司, 西村直子, 野崎昌俊, 菱木はるか, 保科隆之, 細矢光亮, 前田明彦, 水野由美, 宮入烈, 宮崎雅仁, 吉川哲史, 和田泰三, 岩田敏, 尾内一信, 岡田賢司, 岡部信彦, 是松聖悟, 清水直樹, 菅秀, 宮崎千明, 森内浩幸, 大城誠, 藤岡雅司, 森岡一朗, 塚原宏一, 齋藤昭彦, 多屋馨子, 日本小児科学会予防接種・感染症対策委員会

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 127 ( 5 ) 787 - 794 2023.05

予防接種後有害事象(AEFI)および予防接種ストレス関連反応(ISRR)に関連する動画講義視聴が小児科医の予防接種に対する知識、態度、自信、役割認識、自己効力感、行動に与える影響を調査した。介入前評価(pre study)に回答した日本小児科学会会員368名をA群とB群に分けてA群にのみオンラインでISRRに関する約20分間の動画講義を配布し、pre studyから約1ヵ月後にA群・B群に介入後評価(Post study)を行った。Post studyの回答者A群74名、B群95名を対象に動画講義視聴による介入効果について検討した。その結果、AEFIおよびISRRに関連する調査によってA群・B群の知識レベルが向上したが、予防接種に対する態度、自信、役割認識、自己効力感、実際の接種行動に与える影響は限定的であった。

高クレアチンキナーゼ血症から偶発的に診断されたベッカー型7例を含む筋ジストロフィー9例の臨床的検討

伊藤拓郎, 福村忍, 土田晃輔, 山本晃代, 津川毅, 安藤悠開, 下村遼太郎, 飯塚裕典, 星野恵美子, 櫻井のどか, 平川賢史, 布施茂登, 森俊彦

臨床小児医学 ( (財)小児愛育協会 ) 70 ( 1-6 ) 15 - 19 2023.03 [Refereed]

筋ジストロフィー(muscular dystrophy;MD)は,偶発的に高クレアチンキナーゼ(creatine kinase;CK)血症でみつかることがある。今回,明らかな運動発達遅滞がなく偶発的に高CK血症でMDと診断された9例について後方視的に検討した。性別は全例男性であり,診断名は8例がジストロフィン異常症(ベッカー型7例,中間型1例),1例がカルパイン異常症であった。また,9例中5例の患者で家族から運動の苦手さを指摘されていなかった。発見時CKは,中央値15,489.5U/L(499～30,480U/L)だった。うちベッカー型MDの1例はCKの中央値が1,589U/L(56～3,122U/L)で,非感染時の採血でCK値が正常化していた。4例がDMD遺伝子MLPA(multiplex ligation-dependent probe amplification)法で変異がみつからず,筋生検で診断された。本人への告知は4例に行い,2例が12歳,2例が15歳時だった。全例告知後の受け入れは良好だった。本人への告知の時期は中学生頃を目処に,児の理解力と家族の支援体制を総合的に考慮して行う必要がある。(著者抄録)

交通外傷を契機に発症した甲状腺クリーゼの女児例

下村遼太郎, 石井玲, 高尾魁, 萩原絢哉, 北田文華, 千葉充将, 津川毅

臨床小児医学 ( (財)小児愛育協会 ) 70 ( 1-6 ) 51 - 56 2023.03 [Refereed]

Authorship： Last author

甲状腺クリーゼ(thyroid storm;TS)は,何らかの誘因によりコントロール不良の甲状腺中毒症が増悪し,甲状腺ホルモン過剰への代償不全から多臓器不全に至る病態である。致死率は10%を超え,早期の介入が求められる。誘因として抗甲状腺薬のアドヒアランス不良,感染症,手術や外傷などのストレスがあるが,交通外傷に続発した報告は少ない。今回,われわれは交通外傷を契機に発症したTSの女児例を経験した。症例は13歳女児,交通外傷で当院救急部へ搬送され,顔面頸部を含む多発骨折に対して緊急手術を実施された。搬入時から発熱,頻脈を認めていたが,術後も持続し不穏状態も遷延した。入院9日目,FT4 5.82ng/dL,TSH<0.01μIU/mLが判明し,当科へコンサルトされた。未受診のBasedow病を背景としたTSの診断に至り,治療を開始し速やかに症状の改善を得た。交通外傷後の発熱や頻脈,意識障害の鑑別は多岐にわたるが,TSは予後も考慮し早期に鑑別にあげる必要がある。(著者抄録)

Bacillus Calmette-Guérin-induced lupus vulgaris in a patient with Mendelian susceptibility to mycobacterial disease caused by a novel STAT1 variation.

Aika Shionoya, Yuko Yoto, Tokimasa Hida, Aki Ishikawa, Tadashi Hasegawa, Takeshi Tsugawa, Hisashi Uhara

The British journal of dermatology 188 ( 1 ) 142 - 143 2023.01 [Refereed] [International journal]

Parental Decision-Making in Cancer Therapy: A Long-Term Observational Study.

Ryoko Michinobu, Masaki Yamamoto, Yoshiyuki Sakai, Takahiro Mikami, Keita Igarashi, Kotoe Iesato, Akira Takebayashi, Tsukasa Hori, Hiroyuki Tsutsumi, Takeshi Tsugawa

Clinical pediatrics 99228221150606 - 99228221150606 2023.01 [Refereed] [International journal]

Authorship： Last author

Parental participation in shared decision-making in children's cancer therapy is essential because parents advocate for and support their children's wishes. However, little research has focused on this issue. We conducted a longitudinal observational study of 7 parents whose child had received their first cancer treatment. We recorded parents' behaviors, interactions, and narratives in 1 pediatric ward and 2 outpatient clinics. The recordings were systematically conducted and thematically analyzed using variable-oriented and process-oriented modes to assess the causal relationships among phenomena. We found 4 themes describing the processes by which parents developed and participated in shared decision-making. The first 2 themes reflected the development of reciprocal parental relationships and parent-other child relationships. These 2 types of relationship generated mutual trust and a sense of solidarity among parents (the third theme). This, in turn, became the foundation for parents to share decision-making with health care professionals (the fourth theme).

Sequence analysis of a feline- and porcine-origin G3P[9] rotavirus A strain in a child with acute gastroenteritis in Japan.

Yuya Fukuda, Kaoru Araki, Megumi Hara, Yuji Yamashita, Shuhei Adachi, Saho Honjo, Atsuo Togashi, Satoshi Hirakawa, Shinobu Fukumura, Masaki Yamamoto, Takeshi Tsugawa

Archives of virology 168 ( 2 ) 45 - 45 2023.01 [Refereed] [International journal]

Authorship： Last author , Corresponding author

We isolated the rare G3P[9] rotavirus strain RVA/Human-wt/JPN/R11-035/2015/G3P[9] from a 2-year-old girl presenting with vomiting and diarrhea who had daily contact with cats in Japan, 2015. Full-genome analysis revealed that the R11-035 strain had an AU-1-like genetic constellation, except for the NSP3 (T) gene: G3-P[9]-I3-R3-C3-M3-A3-N3-T1-E3-H6. Phylogenetic analysis showed that strain R11-035 is closely related to human/feline-like human strains, and only the NSP3 (T1) gene was clustered together with Taiwanese porcine strains. We postulate that the R11-035 strain was directly transmitted from a cat to the patient and acquired its NSP3 gene through intergenotype reassortment with porcine strains before being transmitted to humans.

コロナウイルス感染症2019流行下における国内小児医療の現状に関する調査

中村幸嗣, 勝田友博, 清水直樹, 神谷元, 天羽清子, 大城誠, 菅秀, 津川毅, 西村直子, 菱木はるか, 藤岡雅司, 細矢光亮, 水野由美, 吉川哲史, 和田泰三, 石和田稔彦, 是松聖悟, 中野貴司, 宮入烈, 尾内一信, 相澤悠太, 庄司健介, 齋藤昭彦, 森内浩幸, 多屋馨子, 日本小児科学会予防接種・感染症対策委員会

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 127 ( 1 ) 84 - 89 2023.01

国内の地域偏在を調整後に無作為に抽出した小児科1次医療施設100施設、2次医療施設100施設と全ての3次医療施設119施設を候補として、2020年4月(I期)、2020年10月(II期)、2021年4月(III期)の各時点における診療体制についてインターネットを介してアンケート調査した。回答があったのは1次医療施設27施設(回答率27%)、2次医療施設19施設(回答率19%)、3次医療施設72施設(回答率61%)であった。発熱患者の診療応需についてはコロナウイルス感染症2019(COVID-19)接触歴を有する場合、1次医療施設で応需困難となったのはI期で29.6%であったが、II期22.2%、III期14.8%と経時的に減少した。COVID-19患者の診療体制はIII期においても3次医療施設の約半数で軽症・無症状患者の診療が応需されていた。面会制限は大多数の施設で導入され、面会禁止とした施設がIII期においても2次医療施設の63.2%、3次医療施設の38.9%で存在した。

データベースを用いた国内小児新型コロナウイルス感染症の臨床症状に関する評価

勝田友博, 清水直樹, 神谷元, 天羽清子, 大城誠, 菅秀, 津川毅, 西村直子, 菱木はるか, 藤岡雅司, 細矢光亮, 水野由美, 吉川哲史, 和田泰三, 石和田稔彦, 是松聖悟, 中野貴司, 宮入烈, 尾内一信, 齋藤昭彦, 森内浩幸, 多屋馨子, 日本小児科学会予防接種・感染症対策委員会

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 127 ( 1 ) 79 - 83 2023.01

2020年2月～2022年4月に専用データベースに報告された小児コロナウイルス感染症2019患者のうち、0～15歳の5411例(男児2889例、女児2522例)の急性期における臨床的特徴を解析した。オミクロン株流行により感染経路は家庭内感染から学校・幼稚園・保育所へ変化した。オミクロン株流行期に初発症状でけいれん発作を起こした割合は1～4歳で13.4%、5～11歳で7.4%、オミクロン株流行期に初発症状で悪心・嘔吐を認めた割合は1～4歳で12.2%、5～11歳で22.6%、12～15歳で14.6%であり、いずれもデルタ株流行前またはデルタ株流行期と比較して大幅に増加した。最終的に全体の約2%にけいれんを伴う合併症が報告された。肺炎の合併率は変異株の違いによる変化をほとんど認めなかった。発症後28日を超えた症例報告書が提出された1697例(男児899例、女児798例、年齢中央値6.3歳)のうち、55例(3.2%)に発症後28日を超えても何らかの症状が残存した。

Acute and Postacute Clinical Characteristics of Coronavirus Disease 2019 in Children in Japan.

Tomohiro Katsuta, Yuta Aizawa, Kensuke Shoji, Naoki Shimizu, Kenji Okada, Takashi Nakano, Hajime Kamiya, Kiyoko Amo, Naruhiko Ishiwada, Satoshi Iwata, Makoto Oshiro, Nobuhiko Okabe, Seigo Korematsu, Shigeru Suga, Takeshi Tsugawa, Naoko Nishimura, Haruka Hishiki, Masashi Fujioka, Mitsuaki Hosoya, Yumi Mizuno, Isao Miyairi, Chiaki Miyazaki, Tsuneo Morishima, Tetsushi Yoshikawa, Taizo Wada, Kazunobu Ouchi, Hiroyuki Moriuchi, Keiko Tanaka-Taya, Akihiko Saitoh

The Pediatric infectious disease journal 42 ( 3 ) 240 - 246 2022.11 [Refereed] [International journal]

BACKGROUND: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan. METHODS: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021. RESULTS: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups aged 1-4 and 5-11 years, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%). CONCLUSIONS: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients.

Rhinovirus Infection and Virus-Induced Asthma

Yuriko Hayashi, Mitsuru Sada, Tatsuya Shirai, Kaori Okayama, Ryusuke Kimura, Mayumi Kondo, Mitsuaki Okodo, Takeshi Tsugawa, Akihide Ryo, Hirokazu Kimura

Viruses ( MDPI AG ) 14 ( 12 ) 2616 - 2616 2022.11 [Refereed]

While the aetiology of asthma is unclear, the onset and/or exacerbation of asthma may be associated with respiratory infections. Virus-induced asthma is also known as virus-associated/triggered asthma, and the reported main causative agent is rhinovirus (RV). Understanding the relationship between viral infections and asthma may overcome the gaps in deferential immunity between viral infections and allergies. Moreover, understanding the complicated cytokine networks involved in RV infection may be necessary. Therefore, the complexity of RV-induced asthma is not only owing to the response of airway and immune cells against viral infection, but also to allergic immune responses caused by the wide variety of cytokines produced by these cells. To better understand RV-induced asthma, it is necessary to elucidate the nature RV infections and the corresponding host defence mechanisms. In this review, we attempt to organise the complexity of RV-induced asthma to make it easily understandable for readers.

Detailed Molecular Interactions between Respiratory Syncytial Virus Fusion Protein and the TLR4/MD-2 Complex In Silico.

Mao Akagawa, Tatsuya Shirai, Mitsuru Sada, Norika Nagasawa, Mayumi Kondo, Makoto Takeda, Koo Nagasawa, Ryusuke Kimura, Kaori Okayama, Yuriko Hayashi, Toshiyuki Sugai, Takeshi Tsugawa, Haruyuki Ishii, Hisashi Kawashima, Kazuhiko Katayama, Akihide Ryo, Hirokazu Kimura

Viruses 14 ( 11 ) 2022.10 [Refereed] [International journal]

Molecular interactions between respiratory syncytial virus (RSV) fusion protein (F protein) and the cellular receptor Toll-like receptor 4 (TLR4) and myeloid differentiation factor-2 (MD-2) protein complex are unknown. Thus, to reveal the detailed molecular interactions between them, in silico analyses were performed using various bioinformatics techniques. The present simulation data showed that the neutralizing antibody (NT-Ab) binding sites in both prefusion and postfusion proteins at sites II and IV were involved in the interactions between them and the TLR4 molecule. Moreover, the binding affinity between postfusion proteins and the TLR4/MD-2 complex was higher than that between prefusion proteins and the TLR4/MD-2 complex. This increased binding affinity due to conformational changes in the F protein may be able to form syncytium in RSV-infected cells. These results may contribute to better understand the infectivity and pathogenicity (syncytium formation) of RSV.

Liver Enzyme Elevation Related to Human Parainfluenza Virus Type 3 Infection.

Yoshimasa Kudo, Tomohiro Wakabayashi, Shuichi Miyamoto, Yuta Sasaoka, Yoshiyuki Sakai, Takeshi Tsugawa

The Pediatric infectious disease journal 41 ( 10 ) e437-e438 2022.10 [Refereed] [International journal]

Authorship： Last author

A novel ZC4H2 variant in a female with severe respiratory complications.

Tomohiro Wakabayashi, Miyako Mizukami, Kojiro Terada, Aki Ishikawa, Shiro Hinotsu, Masaki Kobayashi, Koji Kato, Tomoo Ogi, Takeshi Tsugawa, Akihiro Sakurai

Brain & development 44 ( 8 ) 571 - 577 2022.09 [Refereed] [International journal]

INTRODUCTION: An X-linked ZC4H2 variant is associated with a variety of phenotypes that have abnormalities related to external malformation and neurodevelopment. There have been no reports on severe respiratory dysfunction resulting in surgical treatments not being possible due to the deformity resulting from in this disease. Here we report a female with arthrogryposis multiplex congenita with a severe respiratory complication. CASE: A two-year-old girl had arthrogryposis multiplex congenita at delivery and subsequently had hypotonia and feeding difficulty. A novel ZC4H2 frameshift variant was identified by whole-exome sequencing in her genome. At eight months, she had recurrent aspiration pneumonia. A tracheostomy and gastrostomy were required; however, surgical intervention was not possible because of her short neck and complicated airway. CONCLUSION: We compared this case with previous reports. The truncation group had more described phenotypes than the non-truncation group. The patient had the most severe respiratory dysfunction in truncating variant.

Molecular Evolution of the Pseudomonas aeruginosa DNA Gyrase gyrA Gene.

Mitsuru Sada, Hirokazu Kimura, Norika Nagasawa, Mao Akagawa, Kaori Okayama, Tatsuya Shirai, Soyoka Sunagawa, Ryusuke Kimura, Takeshi Saraya, Haruyuki Ishii, Daisuke Kurai, Takeshi Tsugawa, Atsuyoshi Nishina, Haruyoshi Tomita, Mitsuaki Okodo, Shinichiro Hirai, Akihide Ryo, Taisei Ishioka, Koichi Murakami

Microorganisms 10 ( 8 ) 2022.08 [Refereed] [International journal]

DNA gyrase plays important roles in genome replication in various bacteria, including Pseudomonasaeruginosa. The gyrA gene encodes the gyrase subunit A protein (GyrA). Mutations in GyrA are associated with resistance to quinolone-based antibiotics. We performed a detailed molecular evolutionary analyses of the gyrA gene and associated resistance to the quinolone drug, ciprofloxacin, using bioinformatics techniques. We produced an evolutionary phylogenetic tree using the Bayesian Markov Chain Monte Carlo (MCMC) method. This tree indicated that a common ancestor of the gene was present over 760 years ago, and the offspring formed multiple clusters. Quinolone drug-resistance-associated amino-acid substitutions in GyrA, including T83I and D87N, emerged after the drug was used clinically. These substitutions appeared to be positive selection sites. The molecular affinity between ciprofloxacin and the GyrA protein containing T83I and/or D87N decreased significantly compared to that between the drug and GyrA protein, with no substitutions. The rate of evolution of the gene before quinolone drugs were first used in the clinic, in 1962, was significantly lower than that after the drug was used. These results suggest that the gyrA gene evolved to permit the bacterium to overcome quinolone treatment.

Genotypes and transmission routes of noroviruses causing sporadic acute gastroenteritis among adults and children, Japan, 2015-2019.

Saho Honjo, Koji Kuronuma, Yoshihiro Fujiya, Mami Nakae, Susumu Ukae, Hiroshi Nihira, Masaki Yamamoto, Yusuke Akane, Kenji Kondo, Satoshi Takahashi, Hirokazu Kimura, Hiroyuki Tsutsumi, Yukihiko Kawasaki, Takeshi Tsugawa

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 104 105348 - 105348 2022.08 [Refereed] [International journal]

Authorship： Last author , Corresponding author

Noroviruses (NoVs) are major causes of acute viral gastroenteritis at all ages worldwide. The molecular epidemiology of sporadic cases remains poorly understood, especially in adults. Additionally, no studies have analyzed the transmission route in sporadic acute gastroenteritis. In this study, we investigated cases of very mild sporadic NoV acute gastroenteritis in adults (medical staff) who do not visit the outpatient clinic and child outpatients. We also evaluated genotype differences between adults and children and possible transmission routes in adults during 5 years. The number of NoV positives were 58 in adults and 124 in children. In adults, the NoV positivity rate in this study was higher (64.4%) than that in previous reports of outpatients (10%) and inpatients (5%) in the United State. This finding suggested that the NoV positivity rate might be high in adults with very mild acute gastroenteritis. In adults, human-to-human transmission rates from children and food-borne transmission (raw oysters) were 21.6% (11/51) and 19.6% (10/51), respectively. Among adults, GII.2, GII.4, and GII.17 were the predominant genotypes, with rates of 32.7%, 30.9%, and 21.8%, respectively. Among children, GII.4 and GII.2 were the predominant genotypes, with rates of 45.5% and 40.6%, respectively. GII.17 was only detected in 0.8% (1/123) of children. Trends in NoV genotypes are expected to differ depending on the patient's age. Investigating sporadic cases including the patient's background (age and transmission route) may be helpful to monitor the trend of NoV strains, forecast prevalent NoV GII genotypes, and develop NoV vaccines.

Delayed dexamethasone treatment at initiation of oxygen supplementation for coronavirus disease 2019 is associated with the exacerbation of clinical condition.

Yuta Ibe, Tomoyuki Ishigo, Satoshi Fujii, Yoshihiro Fujiya, Koji Kuronuma, Takeshi Tsugawa, Satoshi Takahashi, Masahide Fukudo

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 7 ) 875 - 883 2022.07 [Refereed] [International journal]

INTRODUCTION: Coronavirus disease 2019 (COVID-19) frequently causes inflammatory lung injury as its symptoms progress. While dexamethasone reportedly reduces inflammation and prevents progression to respiratory failure, the appropriate time to administer dexamethasone in patients with COVID-19 remains unclear. METHODS: This was a single-center, retrospective cohort study, where we consecutively enrolled patients hospitalized with COVID-19 who received oxygen and oral dexamethasone (n = 85). We assessed the association between the number of days to the initiation of dexamethasone and the cumulative rate of exacerbation defined as death or initiation of mechanical ventilation within 28 days of symptom onset. RESULTS: The optimal cut-off value from the initiation of oxygen supplementation to that of dexamethasone administration was two days (sensitivity, 85%; specificity, 59%), whereas that from oxygen saturation (SpO2) < 95% to the initiation of dexamethasone administration was five days (sensitivity, 78%; specificity, 59%). adjusting for age, sex, body mass index, Charlson comorbidity index score, time of oxygen supplementation (two or more days), and SpO2 < 95% (five or more days), Cox regression analysis results showed that delayed dexamethasone administration since the initiation of oxygen supplementation was significantly associated with a higher risk of death or greater need for mechanical ventilation (hazard ratio: 5.51, 95% confidence interval, 1.79-16.91). CONCLUSIONS: In patients with COVID-19 and hypoxemia, early administration of dexamethasone, preferably less than two days from initiation of oxygen supplementation, may be required to improve clinical outcomes.

House Dust Mite Subcutaneous Immunotherapy and Lung Function Trajectory in Children and Adolescents with Asthma.

Kazutaka Nogami, Mizuho Nagao, Takafumi Takase, Yasuaki Yasuda, Shingo Yamada, Mayumi Matsunaga, Miyuki Hoshi, Kana Hamada, Yu Kuwabara, Takeshi Tsugawa, Takao Fujisawa

Children (Basel, Switzerland) 9 ( 4 ) 2022.04 [Refereed] [International journal]

Background: Allergen-specific immunotherapy is currently the only disease-modifying treatment for allergic asthma, and it has been shown to improve control of asthma while reducing both drug use and asthma exacerbations. However, its effects on lung function—especially its long-term effects—remain controversial. We aimed to identify factors associated with a possible beneficial effect of allergen-specific immunotherapy on lung function in asthma by retrospectively evaluating the long-term changes in lung function in children with asthma who received house dust mite subcutaneous immunotherapy (HDM-SCIT). Methods: We enrolled children with asthma who had undergone HDM-SCIT for more than 1 year. Clinical information and lung function measurements were retrieved from the electronic chart system. To characterize the trajectory of lung function change, we performed linear regression analysis to evaluate the maximal expiratory flow at 50% of the forced vital capacity during two periods: before and during HDM-SCIT. Slopes from a least-squares regression line for the two periods, i.e., S1 before HDM-SCIT and S2 during HDM-SCIT, were compared. The subjects were then classified into two groups: an improving group (Group I) defined as S2 − S1 > 0, and a declining group (Group D) defined as S2 − S1 < 0. The clinical factors at the start of HDM-SCIT were compared between the two groups. Results: A total of 16 patients were analyzed. Eight patients were classified into each of Group I and Group D. The mean ages were 10.5 and 11.8 years, and the mean treatment periods were 4.1 and 3.9 years. Group I had a significantly lower blood eosinophil count and a significantly higher HDM-specific IgE level than Group D. Logistic regression showed a strong relationship between those two markers and the lung function trajectory. Conclusion: Control of the blood eosinophil count in highly HDM-sensitized patients may increase the beneficial effect of HDM-SCIT on lung function.

繰り返す腰椎穿刺により脳脊髄液漏出をきたした脊髄性筋萎縮症I型の1例

加藤辰輔, 土田晃輔, 福村忍, 津川毅

臨床小児医学 ( (財)小児愛育協会 ) 69 ( 1-6 ) 55 - 59 2022.03 [Refereed]

Authorship： Last author

はじめに:ヌシネルセンは、脊髄性筋萎縮症に対するアンチセンス・オリゴヌクレオチド製剤で、髄腔内に投与される。今回、繰り返す腰椎穿刺により、脳脊髄液漏出をきたした脊髄性筋萎縮症I型を経験した。症例:脊髄性筋萎縮症I型の5歳女児。2歳よりL3-4間に23ゲージ針穿刺によるヌシネルセン髄腔内投与を4ヵ月ごとに繰り返した。12回目の投与後、穿刺部より髄液の漏れおよび腰部皮下浮腫を生じた。頭痛などの症状は認めず、圧迫、安静により、数日で浮腫、髄液漏は消失した。以後は穿髄間を変更し、再発は認めていない。14回目を最後に、経口のアンチセンス・オリゴヌクレオチド製剤に切り替えた。考察:繰り返す腰椎穿刺の際は、髄液漏の出現に注意が必要である。リスク回避には、穿刺髄間を同一にしないこと、細く非侵襲的な脊髄針の選択、経口製剤へ移行が考慮される。(著者抄録)

Transient personality changes with bilateral thalamic infarction in a 12-year-old girl.

Shuhei Adachi, Shinobu Fukumura, Shinsuke Kato, Takeshi Mikami, Takeshi Tsugawa

Pediatrics international : official journal of the Japan Pediatric Society 64 ( 1 ) e15352 2022.01 [Refereed] [International journal]

Authorship： Last author

Long-term sensor-augmented pump therapy for neonatal diabetes mellitus: a case series.

Yuya Fukuda, Akira Ishii, Hotaka Kamasaki, Shintaro Fusagawa, Kojiro Terada, Lisa Igarashi, Masaki Kobayashi, Shigeru Suzuki, Takeshi Tsugawa

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 31 ( 3 ) 178 - 184 2022 [Refereed] [Domestic journal]

Authorship： Last author

Neonatal diabetes mellitus (NDM) is a rare metabolic disorder that is mainly present in the first 6 months of life and necessitates insulin treatment. Sensor-augmented pump (SAP) therapy has been widely used in children with type 1 diabetes mellitus, but its use in patients with NDM is limited. We report three patients with NDM who received SAP therapy using the MiniMed™ 640G system starting in the neonatal period. Two patients were treated for 3 months, and one patient continued treatment up to an age of 22 mo. The MiniMed 640G system can automatically suspend insulin delivery (SmartGuard™ Technology) to avoid hypoglycemia when the sensor glucose level is predicted to approach the predefined threshold. We suggest that SmartGuard Technology is particularly useful for infants in whom hypoglycemia cannot be identified. The MiniMed 640G system automatically records the trends of sensor glucose levels and the total daily dose of insulin, which can make the management more accurate and reduce the family's effort. SAP therapy for patients with NDM automatically prevents severe hypoglycemia and is useful for long-term management; however, attention should be paid to its application.

Detailed Evolutionary Analyses of the F Gene in the Respiratory Syncytial Virus Subgroup A.

Mariko Saito, Hiroyuki Tsukagoshi, Mitsuru Sada, Soyoka Sunagawa, Tatsuya Shirai, Kaori Okayama, Toshiyuki Sugai, Takeshi Tsugawa, Yuriko Hayashi, Akihide Ryo, Makoto Takeda, Hisashi Kawashima, Nobuhiro Saruki, Hirokazu Kimura

Viruses 13 ( 12 ) 2021.12 [Refereed] [International journal]

We performed evolution, phylodynamics, and reinfection-related antigenicity analyses of respiratory syncytial virus subgroup A (RSV-A) fusion (F) gene in globally collected strains (1465 strains) using authentic bioinformatics methods. The time-scaled evolutionary tree using the Bayesian Markov chain Monte Carlo method estimated that a common ancestor of the RSV-A, RSV-B, and bovine-RSV diverged at around 450 years ago, and RSV-A and RSV-B diverged around 250 years ago. Finally, the RSV-A F gene formed eight genotypes (GA1-GA7 and NA1) over the last 80 years. Phylodynamics of RSV-A F gene, including all genotype strains, increased twice in the 1990s and 2010s, while patterns of each RSV-A genotype were different. Phylogenetic distance analysis suggested that the genetic distances of the strains were relatively short (less than 0.05). No positive selection sites were estimated, while many negative selection sites were found. Moreover, the F protein 3D structure mapping and conformational epitope analysis implied that the conformational epitopes did not correspond to the neutralizing antibody binding sites of the F protein. These results suggested that the RSV-A F gene is relatively conserved, and mismatches between conformational epitopes and neutralizing antibody binding sites of the F protein are responsible for the virus reinfection.

Stereotyped Upper Limb Movement in MECP2 Duplication Syndrome.

Tomohiro Wakabayashi, Shinobu Fukumura, Satoru Takahashi, Kenji Kurosawa, Shuichi Miyamoto, Kosuke Tsuchida, Shinsuke Kato, Takeshi Tsugawa, Yoshiyuki Sakai, Yukihiko Kawasaki

Neurology 97 ( 2 ) 92 - 94 2021.07 [Refereed] [International journal]

The clinical characteristics of pediatric coronavirus disease 2019 in 2020 in Japan

Tomohiro Katsuta, Naoki Shimizu, Kenji Okada, Keiko Tanaka‐Taya, Takashi Nakano, Hajime Kamiya, Kiyoko Amo, Naruhiko Ishiwada, Satoshi Iwata, Makoto Oshiro, Nobuhiko Okabe, Ryutaro Kira, Seigo Korematsu, Shigeru Suga, Takeshi Tsugawa, Naoko Nishimura, Haruka Hishiki, Masashi Fujioka, Mitsuaki Hosoya, Yumi Mizuno, Mahito Mine, Isao Miyairi, Chiaki Miyazaki, Ichiro Morioka, Tsuneo Morishima, Tetsushi Yoshikawa, Taizo Wada, Hiroshi Azuma, Koichi Kusuhara, Kazunobu Ouchi, Akihiko Saitoh, Hiroyuki Moriuchi

Pediatrics International ( Wiley ) 2021.07 [Refereed]

Children's decision making in cancer therapy: A long-term observational study.

Ryoko Michinobu, Masaki Yamamoto, Tsukasa Hori, Takahiro Mikami, Keita Igarashi, Kotoe Iesato, Akira Takebayashi, Takeshi Tsugawa, Yukihiko Kawasaki, Hiroyuki Tsutsumi

Pediatrics international : official journal of the Japan Pediatric Society 64 ( 1 ) e14700 2021.03 [Refereed] [International journal]

BACKGROUND: The survival rate of children with cancer has increased substantially in recent years. Shared decision making (i.e., the ability of children with cancer to express their will and share it with medical personnel) has become a particularly important issue. The nature and developmental processes of children's decision making in hospital should be understood. There is, however, a lack of research in this area. METHODS: From January 2016 to March 2018, we conducted a longitudinal qualitative observational study, within the context of medical anthropology, in a hospital pediatric ward in Japan. We investigated the nature and development of decision making among seven children aged 5-12 years with hematologic cancers. We recorded their everyday behaviors, interactions, narratives, and events in the ward. The recording was conducted systematically and thematically analyzed using both variable-oriented and process-oriented modes to assess causal relationships between the phenomena. RESULTS: The thematic analysis identified three thematic scenes in which children developed their will regarding cancer treatment: (1) adjusting to hospital life, (2) forming friendships with other children, and (3) communicating with medical personnel. Sharing information, building trusting relationships, and sharing treatment goals with medical personnel were identified as forms of children's participation in medical decision making. Through cultivated friendships, children's peer groups were sources of resilience and strength in overcoming difficulties in hospital life. CONCLUSIONS: The development of children's decision making in a pediatric oncology ward was based on various rich human relationships. Such relationships should be promoted to substantially improve shared decision making.

Transient Angioedema of the Small Bowel because of Intravenous Nonionic Iodinated Contrast Media.

Tomohiro Wakabayashi, Yuta Sasaoka, Yoshiyuki Sakai, Shuichi Miyamoto, Takeshi Tsugawa, Yukihiko Kawasaki

The Journal of pediatrics 230 264 - 265 2021.03 [Refereed] [International journal]

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge, attitudes, and beliefs regarding infant immunization in Japan.

Aya Saitoh, Akihiko Saitoh, Tomohiro Katsuta, Mahito Mine, Hajime Kamiya, Isao Miyairi, Naruhiko Ishiwada, Makoto Oshiro, Ryutaro Kira, Naoki Shimizu, Shigeru Suga, Takeshi Tsugawa, Masashi Fujioka, Chiaki Miyazaki, Ichiro Morioka, Seigo Korematsu, Takashi Nakano, Keiko Tanaka-Taya, Tetsushi Yoshikawa, Satoshi Iwata, Koichi Kusuhara, Hiroshi Azuma, Hiroyuki Moriuchi, Nobuhiko Okabe, Mitsuaki Hosoya, Hiroyuki Tsutsumi, Kenji Okada

Vaccine 38 ( 50 ) 8049 - 8054 2020.11 [Refereed] [International journal]

BACKGROUND: Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan. METHODS: This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups. RESULTS: We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01). CONCLUSION: The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood.

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico.

Mitsuru Sada, Takeshi Saraya, Haruyuki Ishii, Kaori Okayama, Yuriko Hayashi, Takeshi Tsugawa, Atsuyoshi Nishina, Koichi Murakami, Makoto Kuroda, Akihide Ryo, Hirokazu Kimura

Microorganisms 8 ( 10 ) 2020.10 [Refereed] [International journal]

Favipiravir was initially developed as an antiviral drug against influenza and is currently used in clinical trials against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). This agent is presumably involved in RNA chain termination during influenza virus replication, although the molecular interactions underlying its potential impact on the coronaviruses including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) remain unclear. We performed in silico studies to elucidate detailed molecular interactions between favipiravir and the SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus RNA-dependent RNA polymerases (RdRp). As a result, no interactions between favipiravir ribofuranosyl-5'-triphosphate (F-RTP), the active form of favipiravir, and the active sites of RdRps (PB1 proteins) from influenza A (H1N1)pdm09 virus were found, yet the agent bound to the tunnel of the replication genome of PB1 protein leading to the inhibition of replicated RNA passage. In contrast, F-RTP bound to the active sites of coronavirus RdRp in the presence of the agent and RdRp. Further, the agent bound to the replicated RNA terminus in the presence of agent, magnesium ions, nucleotide triphosphate, and RdRp proteins. These results suggest that favipiravir exhibits distinct mechanisms of action against influenza virus and various coronaviruses.

疲労骨折を契機に炎症反応と乖離した再燃を認めた慢性再発性多発性骨髄炎(Chronic recurrent multifocal osteomyelitis:CRMO)の1例

木澤敏毅, 稲澤奈津子, 伊藤希美, 東舘義仁, 長岡由修, 石井玲, 津川毅, 鎌崎穂高, 要藤裕孝, 川崎幸彦

小児リウマチ ( (一社)日本小児リウマチ学会 ) 10 ( 1 ) 38 - 43 2019 [Refereed]

発症3年後より血清の炎症反応と臨床症状に乖離を認めた慢性再発性多発性骨髄炎の女児を経験した。症例は発症時9歳女児。反復する多発性の骨痛を認め当院に紹介。採血で臨床症状に一致した炎症反応の上昇と画像にて骨髄炎を確認でき、骨生検にて悪性疾患、感染症を否定できたことからChronic recurrent multifocal osteomyelitis(CRMO)と診断し、NSAIDsやステロイドにて寛解していた。発症3年後に認めた疲労骨折を契機に炎症反応の上昇を認めないにも関わらず、右脛骨の疼痛が増悪し痛みのため歩行困難となった。MRI及び骨シンチを行ったところ、右脛骨部に骨髄炎の残存を確認し、炎症反応陰性のCRMOと診断した。これまでの治療に加え、ビスフォスフォネート製剤を開始するも無効であり、院内倫理委員会許可のもとTNF阻害剤であるInfliximab(IFX)を開始したところ臨床的寛解を認め、通常の生活が可能となった。(著者抄録)

Tetanus in a partially immunized child.

Yusuke Akane, Takeshi Tsugawa, Tsukasa Hori, Atsuo Togashi, Yuko Yoto, Natsuko Inazawa, Nozomi Ito, Ryoko Kyan, Mitsutoshi Senoh, Haru Kato, Hiroyuki Tsutsumi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy ( Elsevier B.V. ) 24 ( 12 ) 980 - 982 2018.12 [Refereed] [International journal]

A case report of cutaneous polyarteritis nodosa in siblings.

Toshitaka Kizawa, Yuko Yoto, Miyako Mizukami, Takeshi Tsugawa, Takako Takeuchi, Hotaka Kamasaki, Yasue Ishii-Osai, Toshiharu Yamashita, Kazushige Nagai, Tsukasa Hori, Hiroyuki Tsutsumi

Modern rheumatology 28 ( 6 ) 1049 - 1052 2018.11 [Refereed] [International journal]

Cutaneous polyarteritis nodosa (CPAN) is characterized by a necrotizing vasculitis of small and medium-sized arteries in the skin, which can be associated with fever, arthralgia, myalgia, and neuropathy, but, unlike polyarteritis nodosa (PAN), there is no visceral involvement. CPAN is rare in childhood. We report two siblings who developed CPAN during childhood. Interestingly, both had Mediterranean fever gene (MEFV) mutation, i.e. heterozygous E148Q. They also shared HLA-A24, -DR15 alleles. Simultaneous occurrence of MEFV mutation and HLA alleles with CPAN has never been reported in Japan. These cases could provide some hereditary clue for the development of CPAN.

Adrenocortical carcinoma characterized by gynecomastia: A case report.

Takako Takeuchi, Yuko Yoto, Akira Ishii, Takeshi Tsugawa, Masaki Yamamoto, Tsukasa Hori, Hotaka Kamasaki, Kazutaka Nogami, Takanori Oda, Akihiro Nui, Sachiko Kimura, Takuya Yamagishi, Keiko Homma, Tomonobu Hasegawa, Maki Fukami, Yoko Watanabe, Hidehiko Sasamoto, Hiroyuki Tsutsumi

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology ( Jeff Corporation Co. Ltd ) 27 ( 1 ) 9 - 18 2018 [Refereed] [Domestic journal]

We present a 4-yr-old boy with adrenocortical carcinoma (ACC), diagnosed due to the appearance of gynecomastia as the presenting symptom. Six months prior to admission, an acute growth spurt along with the development of bilateral breast swelling was observed. He did not present any features of virilization, including enlargement of the testes, increase in testis volume, and penis size. Laboratory investigations showed gonadotropin-independent hypergonadism, with low LH/ FSH levels and elevated estradiol/testosterone levels. Abdominal computed tomography revealed a large heterogeneous mass adjacent to the right kidney and below the liver. Pathological investigations of the biopsy specimen demonstrated that the tumor was an ACC. Pre- and post-operative combination chemotherapy with mitotane was administered and surgical resection was carried out. Post-surgery, the elevated estradiol/testosterone concentrations reverted to within the reference range. Urinary steroid profile and tissue concentration analysis of estradiol and testosterone indicated the presence of estrogen in the ACC tissue. An investigation for TP53 gene aberrations revealed the presence of a germline point mutation in exon 4 (c.215C>G (p.Pro72Arg)). In ACC, the most common symptom is virilization, and feminization, characterized by gynecomastia, is very rare. However, a diagnostic possibility of ACC should be considered when we encounter patients who have developed gynecomastia without the influence of causative factors such as obesity or puberty, and do not present with the typical signs of virilization.

Virus infection and children

Hiroyuki Tsutsumi, Yuko Yoto, Tsukasa Hori, Takeshi Tsugawa, Masaki Yamamoto

Sapporo Medical journal ( Sapporo Medical University ) 86 ( 1-6 ) 1 - 8 2017.12

Following the lead of Dr. Toru Nakao and Emeritus Professor Shunzo Chiba, we have conducted epidemiological and virological research on viral infections frequently observed in children. The present report is an overview of the research we have conducted. Amongst our research, we have demonstrated that the genetic evolution of the respiratory syncytial virus (RSV) undergoes both geographical and temporal clustering. Additionally, we have shown that the cytomegalovirus (CMV), a DNA virus, is widely disseminated under very stable genetic conditions. We have also clarified the situation concerning the genetic evolution of rotaviruses collected in Sapporo. In addition, we have attempted to identify the virulence-associated genome mutations of murine and human rotaviruses. Furthermore, we have indicated how the considerable genetic mutations of human parvovirus B19 could be associated with outbreaks of exanthema infectiosum every few years. Finally, we have examined viral reactivation in patients who underwent allogeneic hematopoietic stem cell transplantation and identified human herpesvirus 6 as a prominent pathogen causing important clinical events in these patients.

Pneumococcal vaccination reduces the risk of community-acquired pneumonia in children.

Junko Hasegawa, Mitsuru Mori, Hirofumi Ohnishi, Takeshi Tsugawa, Tsukasa Hori, Yuko Yoto, Hiroyuki Tsutsumi

Pediatrics international : official journal of the Japan Pediatric Society ( WILEY ) 59 ( 3 ) 316 - 320 2017.03 [Refereed] [International journal]

BACKGROUND: The seven-valent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2009, after which there was a rapid decline in invasive pneumococcal disease. There are few data, however, on the effectiveness of PCV7 against community-acquired pneumonia (CAP). We conducted an ambispective cohort study among children aged 0-6 years old who attended day-care centers. METHODS: A total of 624 children at 10 day-care centers in Sapporo, Japan participated in the study. The parents reported whether their child had received PCV7 one or more times, as well as the exact dates of vaccination from records in maternal and child health handbooks marked by pediatricians. Each CAP event was reported by parents according to doctor diagnosis. A Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and 95%CI of CAP incidence reduced by PCV7 inoculation. RESULTS: During the observational period, 94 subjects contracted CAP. After adjusting for potentially confounding variables, inoculation with PCV7 was significantly associated with a reduced risk of CAP (HR, 0.22; 95%CI: 0.13-0.34). On stratified analysis by age, PCV7 was significantly associated with a reduced risk of CAP in both children aged <3 years (HR, 0.31; 95%CI: 0.14-0.71), and those ≥3 years (HR, 0.20; 95%CI: 0.09-0.43). CONCLUSION: PCV7 is highly effective in reducing the risk of CAP in children attending day-care centers.

Genomic changes detected after serial passages in cell culture of virulent human G1P[8] rotaviruses.

Takeshi Tsugawa, Hiroyuki Tsutsumi

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases ( ELSEVIER SCIENCE BV ) 45 6 - 10 2016.11 [Refereed] [International journal]

Authorship： Lead author , Corresponding author

Serial passages of a virulent mouse rotavirus in cell cultures caused a loss of virulence in mice. To gain insight into the genomic mutations in human rotavirus during cell culture and its attenuation in humans, we serially passaged three wild type human G1P[8] rotavirus strains (Wa, DC3695, DC5685) derived from diarrheal stool samples up to 60 times in two different cell cultures (human colon adenocarcinoma cell line: HT29, and primary African green monkey kidney cells: primary AGMK). We sequenced the whole genomes of 60 times-passaged strains and compared them with those of the original viruses. Most substitutions were detected in VP4, followed by substitutions in VP7 and NSP4 genes. Substitution at amino acid 385 in the putative VP4 fusion domain and substitution T45M in NSP4 genes were detected in all AGMK-passaged strains, respectively. These genomic changes are likely to correlate with a loss of rotavirus virulence in humans.

An adolescent case of familial hyperparathyroidism with a germline frameshift mutation of the CDC73 gene.

Takako Takeuchi, Yuko Yoto, Takeshi Tsugawa, Hotaka Kamasaki, Atsushi Kondo, Jiro Ogino, Tadashi Hasegawa, Naoya Yama, Sawa Anan, Shinya Uchino, Aki Ishikawa, Akihiro Sakurai, Hiroyuki Tsutsumi

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology ( Jeff Corporation Co. Ltd ) 24 ( 4 ) 185 - 9 2015.10 [Refereed] [Domestic journal]

A 13-yr-old boy who complained of persistent nausea, vomiting and weight loss had hypercalcemia and an elevated intact PTH level. Computed tomography confirmed two tumors in the thyroid gland. The tumors were surgically removed and pathologically confirmed as parathyroid adenoma. Because his maternal aunt and grandmother both had histories of parathyroid tumors, genetic investigation was undertaken for him, and a germline frameshift mutation of the CDC73 gene was identified. CDC73 gene analysis should be done on individuals who are at risk of familial hyperparathyroidism, including those who are asymptomatic, and they should be followed for potential primary hyperparathyroidism and associated disorders including resultant parathyroid carcinoma.

Pneumococcal vaccination reduced the risk of acute otitis media: Cohort study.

Junko Hasegawa, Mitsuru Mori, Satoko Showa, Aiko Matsushima, Hirofumi Ohnishi, Takeshi Tsugawa, Yuko Yoto, Hiroyuki Tsutsumi

Pediatrics international : official journal of the Japan Pediatric Society ( WILEY-BLACKWELL ) 57 ( 4 ) 582 - 5 2015.08 [Refereed] [International journal]

BACKGROUND: Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2009, and after that invasive pneumococcal disease has gradually decreased. There are few data, however, on the effectiveness of PCV7 against acute otitis media (AOM) in Japan. METHODS: From 10 daycare centers in Sapporo, Japan, 614 parents participated in the survey. Each parent reported whether their child subject had received one or more doses of PCV7, and, if so, the exact dates of receiving PCV7 were verified by reviewing their maternal and child health handbooks marked by a pediatrician. AOM was diagnosed by otorhinolaryngologist or pediatrician. Cox's proportional hazard model was used for calculating the hazard ratio (HR) of AOM incidence reduced by PCV7 inoculation. RESULTS: Inoculation of PCV7 significantly reduced the risk of AOM (crude HR, 0.63; 95%CI: 0.50-0.79). Adjusting for potentially confounding variables reduced the risk further (adjusted HR, 0.32; 95%CI: 0.23-0.44). On stratification by subject age on 30 April 2012, PCV7 was significantly associated with a reduced risk of AOM in both infants < 3 years old, and in children ≥ 3 years. CONCLUSION: PCV7 is effectiveness in reducing the risk of AOM both in infants < 3 years old, and in young children ≥ 3 years in Japan.

Quantitation of human parvovirus B19 DNA in erythema infectiosum and aplastic crisis.

Aki Ishikawa, Yuko Yoto, Takeshi Tsugawa, Hiroyuki Tsutsumi

Journal of medical virology ( WILEY-BLACKWELL ) 86 ( 12 ) 2102 - 6 2014.12 [Refereed] [International journal]

Several publications concerning the methods of real-time PCR for human parvovirus B19 (B19V) have appeared and some case reports mention B19V DNA loads. However, no large-scale study quantitating levels of B19V DNA in common or representative B19V manifestations such as erythema infectiosum and aplastic crisis has been performed. Consequently, using the TaqMan PCR assay, the B19V load in a large sample of subjects with erythema infectiosum or aplastic crisis was quantitated. Sixty-five subjects in the acute phase of erythema infectiosum were involved, and in addition 22 serum samples from seven subjects with B19V-associated aplastic crisis complicating chronic hemolytic anemia were also analyzed. In the acute phase of erythema infectiosum the median B19V DNA load in the serum samples from the acute phase of erythema infectiosum was 7.63 × 10(5) genomes/ml, (range from 4.48 × 10(3) to 8.31 × 10(6) genomes/ml). The serum B19V DNA load during the acute phase of aplastic crisis complicating chronic hemolytic anemia was extremely high, that is 10(10) -10(13) genomes/ml, and decreased gradually to around 10(5) genomes/ml over 1-2 months. Although all subjects followed an almost uniform and typical clinical course of erythema infectiosum, there was a large individual variation of B19V DNA loads, that is differences of over 1,000 times. Extremely high B19V loads were observed in subjects with aplastic crisis. This study is the first large scale report of studies of the B19V DNA loads in subjects with erythema infectiosum and aplastic crisis, the most common and significant clinical manifestations by B19V infections.

Ankyloblepharon-ectodermal-defects-cleft lip/palate症候群(AEC症候群)の1例

重冨浩子, 白石真大, 野口聡子, 石川淑, 浅沼秀臣, 新飯田裕一, 木澤敏毅, 津川毅, 竹内孝子, 鎌崎穂高, 要藤裕孝, 堤裕幸

臨床小児医学 ( (財)小児愛育協会 ) 62 ( 1-6 ) 32 - 34 2014.12 [Refereed]

日齢0男児。出生時に広範囲の皮膚剥離と口唇口蓋裂を認め、生後1時間で当院NICUに搬送となった。入院時、眼瞼癒着と口唇口蓋裂、頭部・背部・四肢を中心に全身の30%に表皮剥離を認め、発赤とびらんを伴っていた。日齢2に皮膚生検を実施し、遺伝子解析にてTP63遺伝子の変異を確認し、Ankyloblepharon-ectadermal-defects-cleft lip/palate症候群の診断に至った。体幹と四肢の皮膚剥離は清拭やワセリン塗布、シートによる保護で順調な上皮化が得られたが、頭皮は浸出液が持続した。日齢29に口蓋裂の外科治療目的で転院となったが、この時点でも頭皮の皮膚病変は完全な上皮化が得られなかった。なお、眼瞼癒合はその後自然軽快した。

Longitudinal analysis of VP7 gene of group A human rotavirus G2P[4] strains circulating in the pre-vaccine era in Sapporo, Japan from 1991 to 2011.

Masatoshi Tatsumi, Yoshinobu Nagaoka, Takeshi Tsugawa, Yuko Yoto, Tsukasa Hori, Hiroyuki Tsutsumi

Microbiology and immunology ( WILEY-BLACKWELL ) 58 ( 9 ) 540 - 4 2014.09 [Refereed] [International journal]

Rhabdomyolysis associated with human parvovirus B19 infection in a patient with Fukuyama-type congenital muscular dystrophy.

Aki Ishikawa, Yuko Yoto, Kazuhiro Ohya, Takeshi Tsugawa, Hiroyuki Tsutsumi

Journal of child neurology ( SAGE PUBLICATIONS INC ) 29 ( 7 ) 977 - 9 2014.07 [Refereed] [International journal]

Patients with Fukuyama-type congenital muscular dystrophy sometimes experience transient exacerbations of muscle weakness. We took care of a 9-year-old boy with Fukuyama-type congenital muscular dystrophy who presented with acute respiratory failure and decreased exercise ability with marked elevation of serum creatine kinase indicating rhabdomyolysis. At that time, his younger sister suffered from erythema infectiosum. Although he had no particular symptoms, he was tested and proven to have acute human parvovirus B19 infection based on detection of anti-B19 IgM and parvovirus B19 DNA in his serum. His acute rhabdomyolysis was possibly triggered by human parvovirus B19 infection.

trisomy8が診断の一助となった小児期発症腸管Behcet病の1例

木澤敏毅, 津川毅, 竹内孝子, 鎌崎穂高, 要藤裕孝, 五十嵐敬太, 山本雅樹, 堀司, 畠山直樹, 斉藤淳人, 東海林黎吉, 堤裕幸

小児リウマチ ( (一社)日本小児リウマチ学会 ) 5 ( 1 ) 52 - 56 2014.06 [Refereed]

腸管Behcet病と診断した12歳男児を経験した。児は幼少時より非周期的に反復する発熱、口腔内アフタを呈し、血液検査では炎症反応の上昇を認めていたが各種培養は陰性であった。不明熱、周期性発熱としてCT、MRI、シンチグラムに加え、骨髄穿刺を施行したところ、染色体検査でtrisomy 8と判明した。trisomy 8の存在から腸管Behcet病を疑い内視鏡検査を実施したところ、食道下部及び回盲部に円形の潰瘍を複数個所に認めたため、trisomy 8に伴う腸管Behcet病と診断した。trisomy 8に伴う骨髄異形成症候群(myelodysplastic syndrome:MDS)の報告が散見されているが、血球系には異常を認めなかった。不明熱の診断過程にて骨髄染色体の異常が診断につながった希有な症例であり、腸管Behcet病の発症機序を考えるうえで非常に興味深い症例と考えられた。(著者抄録)

Virulence-associated genome mutations of murine rotavirus identified by alternating serial passages in mice and cell cultures.

Takeshi Tsugawa, Masatoshi Tatsumi, Hiroyuki Tsutsumi

Journal of virology ( AMER SOC MICROBIOLOGY ) 88 ( 10 ) 5543 - 58 2014.05 [Refereed] [International journal]

Authorship： Lead author , Corresponding author

UNLABELLED: Although significant clinical efficacy and safety of rotavirus vaccines were recently revealed in many countries, the mechanism of their attenuation is not well understood. We passaged serially a cell culture-adapted murine rotavirus EB strain in mouse pups or in cell cultures alternately and repeatedly and fully sequenced all 11 genes of 21 virus samples passaged in mice or in cell cultures. Sequence analysis revealed that mouse-passaged viruses that regained virulence almost consistently acquired four kinds of amino acid (aa) substitutions in VP4 and substitution in aa 37 (Val to Ala) in NSP4. In addition, they gained and invariably conserved the 3' consensus sequence in NSP1. The molecular changes occurred along with the acquisition of virulence during passages in mice and then disappeared following passages in cell cultures. Intraperitoneal injection of recombinant NSP4 proteins confirmed the aa 37 site as important for its diarrheagenic activity in mice. These genome changes are likely to be correlated with rotavirus virulence. IMPORTANCE: Serial passage of a virulent wild-type virus in vitro often results in loss of virulence of the virus in an original animal host, while serial passage of a cell culture-adapted avirulent virus in vivo often gains virulence in an animal host. Actually, live attenuated virus vaccines were originally produced by serial passage in cell cultures. Although clinical efficacy and safety of rotavirus vaccines were recently revealed, the mechanism of their attenuation is not well understood. We passaged serially a murine rotavirus by alternating switch of host (mice or cell cultures) repeatedly and sequenced the eleven genes of the passaged viruses to identify mutations associated with the emergence or disappearance of virulence. Sequence analysis revealed that changes in three genes (VP4, NSP1, and NSP4) were associated with virulence in mice. Intraperitoneal injection of recombinant NSP4 proteins confirmed its diarrheagenic activity in mice. These genome changes are likely to be correlated with rotavirus virulence.

【小児内分泌学の進歩2015】カルシウム代謝副甲状腺腫の確定までに長期間を要した原発性副甲状腺機能亢進症の1例

竹内孝子, 鎌崎穂高, 津川毅, 要藤裕孝, 近藤敦, 山直也, 荻野次郎, 堤裕幸

ホルモンと臨床 ( (有)医学の世界社 ) 62 ( 5 ) 431 - 434 2014.05 [Refereed]

Characterization of the NSP4 gene of group A human rotavirus G1P[8] strains circulating in Sapporo, Japan from 1987 to 2000.

Masatoshi Tatsumi, Yoshinobu Nagaoka, Takeshi Tsugawa, Yuko Yoto, Tsukasa Hori, Hiroyuki Tsutsumi

Journal of medical virology ( WILEY-BLACKWELL ) 86 ( 2 ) 354 - 9 2014.02 [Refereed] [International journal]

The genetic diversity of the NSP4 gene of rotavirus G1P[8] strains obtained in Sapporo was analyzed, Japan from 1987 to 2000. Sixty-four strains, which were distributed across the whole study period, were included. All G1P[8] NSP4 genes detected in this study belonged to genotype E1, which divided into at least three lineages. The Sapporo rotavirus G1P[8] isolates were found in each lineage. The mean estimated substitution rate was 1.40 × 10(-3) nucleotide substitutions per site per year, which was comparable to that of the G1P[8] VP7 gene. Comparison of the deduced NSP4 amino acid sequences showed genetic diversity at the center of antigenic site II, but not in the enterotoxic domain. This report represents the first investigation of the genetic diversity and evolution of group A rotavirus NSP4 genes in Asia.

Phylogenetic and computational structural analysis of VP7 gene of group a human rotavirus G1P[8] strains obtained in Sapporo, Japan from 1987 to 2000.

Yoshinobu Nagaoka, Masatoshi Tatsumi, Takeshi Tsugawa, Yuko Yoto, Hiroyuki Tsutsumi

Journal of medical virology ( WILEY-BLACKWELL ) 84 ( 5 ) 832 - 8 2012.05 [Refereed] [International journal]

Many studies indicate that G1P[8] genotypes are the most prevalent rotavirus strains worldwide. Although two vaccines have been licensed and their value proven in many countries, continuous surveillance for genetic evolution of circulating rotavirus strains before and after the introduction of the vaccines is desirable. G and P typing were carried out on all field strains isolated during 1987-2000 in Sapporo, Japan. Phylogenetic analysis for the VP7 gene of rotavirus G1P[8] strains was performed. Amino acid substitutions were mapped on the predicted three-dimensional VP7 protein image. G1P[8] genotype predominated. One hundred thirteen strains with G1P[8] genotype were analyzed. Phylogenetic studies of the VP7 gene classified these strains into three lineages. The mean estimated substitution rate was 7.25 × 10(-4) nucleotide substitutions per site per year. One predominant lineage contained the mutant strains which had VP7 amino acid substitutions at residue 91 and 212 that is in the neutralization domains. They were estimated to locate in or near intersubunit boundary of VP7 trimer. It is suggested that the most prevalent G1P[8] lineage strains in Sapporo obtained some survival advantages by changing the neutralization domains of VP7.

Detection of enteric viruses in rectal swabs from children with acute gastroenteritis attending the pediatric outpatient clinics in Sapporo, Japan.

Kaori Nakanishi, Takeshi Tsugawa, Shinjiro Honma, Shuji Nakata, Masatoshi Tatsumi, Yuko Yoto, Hiroyuki Tsutsumi

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology ( ELSEVIER SCIENCE BV ) 46 ( 1 ) 94 - 7 2009.09 [Refereed] [International journal]

BACKGROUND: Gastroenteritis is a world-wide disorder. Numerous studies to identify causative viral agents have been reported for hospitalized patients but there are only a few for outpatients with mild symptoms who are usually managed in the outpatient clinics. OBJECTIVES: Our aim was to clarify the epidemiological and clinical characteristics of acute gastroenteritis in children who visited the outpatient clinics with various complaints suggestive of gastroenteritis. STUDY DESIGN: From December 2003 to December 2005, 877 rectal swabs were collected from patients attending outpatient clinics in Sapporo, Japan. Viral genomes of major five enteric viruses (rotavirus, norovirus, adenovirus, astrovirus and sapovirus) and bocavirus were investigated by RT-PCR or PCR. RESULTS: At least one viral agent was found in 326 (37.2%) cases of the 877 studied. Rotaviruses were the most prevalent and were detected in 143 (16.3%) followed by norovirus in 116 (13.2%), adenovirus in 42 (4.8%), astrovirus in 40 (4.6%) and sapovirus in 15 (1.7%) cases. Bocavirus was detected in only 4 (0.5%) cases. Frequent diarrhea and frequent vomiting were prominent in rotavirus and norovirus infection, respectively. CONCLUSIONS: The prevalence of each enteric virus in outpatients resembled that previously estimated in hospitalized patients, although the detection rate of rotavirus was slightly low. The contribution of bocavirus appears to be small.

Guillain-Barre syndrome with meningoencephalitis after Campylobacter jejuni infection.

Takeshi Tsugawa, Koki Nikaido, Toshiaki Doi, Michiaki Koga, Keiichiro Susuki, Tomoki Kubota, Hiroyuki Tsutsumi

The Pediatric infectious disease journal ( LIPPINCOTT WILLIAMS & WILKINS ) 23 ( 10 ) 966 - 8 2004.10 [Refereed] [International journal]

Authorship： Lead author

A 14-year-old boy presented with progressive ascending muscle weakness, urinary retention and disturbed consciousness. Initially his cerebrospinal fluid showed pleocytosis, and protein-cellular dissociation developed later. Campylobacter jejuni was isolated from his stool and serum anti-ganglioside antibodies were positive. Our case suggests that coexistence of meningoencephalitis at an early stage of illness does not necessarily exclude the diagnosis of Guillain-Barre syndrome.

急速に脳ヘルニアに陥り,死亡した劇症型急性散在性脳脊髄炎の1例

二階堂弘輝, 津川毅, 土井俊明, 堤裕幸, 菊地成佳, 関公平, 平木雅久

小児科臨床 ( (株)総合医学社 ) 57 ( 6 ) 1194 - 1198 2004.06 [Refereed]

4歳4ヵ月男児.発熱を主訴に近医を受診,急性気道炎の診断で加療されたが,発症から3日目に頭痛が出現して再診時に1分間の顔色不良・意識減損,項部硬直を認めたため髄膜炎を疑われ紹介入院となった.入院時,髄液蛋白の異常高値を認め,頭部MRIのT2強調像で両側小脳皮質と大脳白質部に多発性の高信号域を認めたことから,急性散在性脳脊髄炎と診断してメチルプレドニゾロンのパルス療法を開始した.しかし,薬剤抵抗性のけいれん重積状態が続き,脳ヘルニアと考えられる呼吸不全に陥り,免疫グロブリン大量療法や脳低温療法を施行したが効果なく,発症1週間後に死亡した.剖検は得られなかったが,MRI所見やCT像の経時的変化から一番症状の激しかった小脳病変または大脳白質部病変の増悪,あるいはその両方によって生じた脳ヘルニアが脳血流低下を引き起こして大脳組織の壊死が起こったものと推測された

Intracranial hypertension in a boy with Mycoplasma pneumoniae infection: the first report.

Sari Masutani, Rumiko Takayama, Takeshi Tsugawa, Koki Nikaido, Toshiaki Doi, Hiroyuki Tsutsumi

Scandinavian journal of infectious diseases ( TAYLOR & FRANCIS AS ) 36 ( 9 ) 700 - 1 2004 [Refereed] [International journal]

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