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

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.

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

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.

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

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.

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

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.

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.

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

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.

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

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).

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

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.

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

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.

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.

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

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.

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

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 1-4 and 5-11 years of age, 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.

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

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.

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

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.

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

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).

Rhinovirus Infection and Virus-Induced Asthma.

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.