yoshikawa tetsushi

BACKGROUND: Kawasaki disease (KD) onset has been suggested to be associated with infections and various environmental factors. However, research on whether the delivery type plays a role in KD development is limited. This study investigated whether cesarean section (CS) or vaginal delivery (VD) is associated with KD onset using a large administrative claims database in Japan. METHOD: We conducted a case-control study using the JMDC Claims Database from January 2005 to December 2021. Data on children born via CS or VD and their mothers were collected. KD patients were identified from the source population, and controls without KD were randomly selected based on sex, age and registration time, each matched to 4 controls using a risk-set sampling technique. We analyzed the association between delivery type and KD onset using multivariate conditional logistic regression, defining KD as the primary outcome based on specific criteria. RESULTS: Case-control matching created 3363 pairs of cases (n = 3363) and controls (n = 13,363). The proportions of CS, maternal age, Charlson Comorbidity Index, presence of older siblings and low birth weight infants were significantly different between the cases and controls. In the multivariate analysis, KD onset was associated with CS [odds ratio (OR): 1.12; 95% confidence interval (CI): 1.02-1.24], the presence of older siblings (OR: 1.11; 95% CI: 1.02-1.21), lower birth weight (1001-2500 g) (OR: 1.22; 95% CI: 1.04-1.43) and antibiotic use (OR: 1.12; 95% CI: 1.02-1.24). CONCLUSIONS: The risk of developing KD may be influenced by the delivery type (CS or VD), the presence of older siblings, low birth weight and antibiotic use.

Human herpesviruses 6A and 6B (HHV-6A/B) can integrate into the germline, resulting in inherited viral DNA-now proposed to be called "endogenous HHV-6A/B (eHHV-6A/B)." Present in 0.2-3% of humans, this integrated DNA is passed to offspring and may reactivate, posing health risks such as angina or lupus. To reduce confusion caused by varied terminology, researchers advocate using "eHHV-6A/B" for inherited forms and reserving "chromosomally integrated" for somatic integrations only.

The 12th International Conference on Human Herpesvirus (HHV)-6A, HHV-6B, and HHV-7 was held in Himeji, Japan, from March 25 to March 27, 2025. It attracted over 120 basic, translational, and clinical scientists from 17 countries. Important new information was presented regarding: studies of viral genes and proteins; mechanism of chromosomal integration of the viral genome; host cell interactions; inherited chromosomally integrated HHV-6A/B, also called endogenous HHV-6A/B); the role of the viruses in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS); the role of the viruses as opportunistic pathogens in immunocompromised people; the role of the viruses in diseases of the central nervous system, particularly encephalopathy, post-COVID neurological conditions, complex febrile seizures, and synucleinopathies; and the possible role of the viruses in non-Hodgkin lymphoma and autoimmune diseases, including systemic lupus erythematosus. In this review, we summarize many of the oral presentations. The full text of the Conference Abstracts is available at: https://hhv-6foundation.org/wp-content/uploads/2025/06/Abstracts_FINAL-3.10.25.pdf.

BACKGROUND: Pediatric acute hepatitis of unknown etiology (AHUE) has been reported globally since April 2022. The purpose of the present study was to investigate the impact of coronavirus disease 2019 (COVID-19) pandemic on the incidence of AHUE in Japan. METHODS: A nationwide survey of AHUE was conducted in 2510 pediatric hospitals by the Japan Pediatric Society. We retrospectively reviewed AHUE cases, defined by the World Health Organization's working case definition, and compared the incidence, clinical characteristics, and causative pathogens before the COVID-19 pandemic period (pre-pandemic, January 2017 to December 2019) and during the pandemic period (pandemic, January 2020 to June 2022). RESULTS: In total, 707 cases (450 pre-pandemic, 257 pandemic) were reported. The median age was 3 years (interquartile range (IQR): 1-9 years), and 43.8% were female. The number of AHUE cases decreased significantly in the pandemic period (102.8 cases/year) compared with the pre-pandemic period (150.0 cases/year). Investigations of pathogens causing AHUE demonstrated that the most common cause was unknown, accounting for 64% and 75% of cases in the pre-pandemic and pandemic periods, respectively. Among those whose pathogens were identified, the most common pathogens were Epstein-Barr virus (9.6%), cytomegalovirus (6.2%), and influenza (4.0%) in the pre-pandemic, and 7.0%, 3.5%, and 0.4%, respectively, in the pandemic period. SARS-CoV-2 and adenovirus were only 2.7% and 1.9%, respectively, in the pandemic period. CONCLUSIONS: The number of AHUE cases decreased during the COVID-19 pandemic compared with the pre-pandemic period, and no increase in adenovirus-associated disease or severe cases was observed in Japan.

BACKGROUND: Recent studies have reported the possible link between adeno-associated virus 2 (AAV2) and severe pediatric acute hepatitis. It has been suggested that aberrant AAV2 replication initiated by coinfection with "helper viruses" such as human adenovirus and human herpesvirus-6B (HHV-6B) may induce abnormal immune responses. Encephalitis/encephalopathy is a severe complication of primary HHV-6B infection, but the underlying mechanisms remain unclear. This study analyzed the association between AAV2 coinfection and neurologic complications of primary HHV-6B infection in children. METHODS: Preserved serum samples obtained from 36 patients with HHV-6B-associated encephalitis/encephalopathy, 39 with febrile seizure, and 83 without neurologic complications were retrospectively analyzed. Primary HHV-6B infection was confirmed if HHV-6B DNA was detected and the HHV-6B antibody was negative in serum. AAV2 and HHV-6 DNA loads were quantitated using real-time PCR. RESULTS: AAV2 was detected in 4 (11%) and 3 (8%) patients in the encephalitis/encephalopathy and febrile seizure groups, respectively. In contrast, AAV2 was undetectable in 83 patients without neurologic complications. AAV2 detection frequency was significantly higher in the encephalitis/encephalopathy and febrile seizure groups compared with the no neurologic complications group (P = 0.01 and P = 0.03, respectively). Among 4 patients with HHV-6B-associated encephalitis/encephalopathy, AAV2 DNA was detected in the cerebrospinal fluid of 2 patients. Serum HHV-6B DNA load was not significantly different among patients who were AAV2 positive or AAV negative and with or without neurologic complications. CONCLUSIONS: These findings suggest that coinfection of AAV2 and HHV-6B is associated with neurologic complications such as encephalitis/encephalopathy and febrile seizure in children.

OBJECTIVE: To elucidate the trends and clinical features of virologically diagnosed breakthrough varicella (BV) 9 years after implementation of the universal vaccination program in Japan. PATIENTS AND METHODS: Study participants were patients with suspected varicella less than 15 years of age who visited 1 of 15 pediatric clinics in the Nagoya VZV Study Group between September 2015 and August 2023. Practitioners collected patient samples and information such as background characteristics, clinical symptoms, and immunization status. All patients had varicella confirmed by real-time polymerase chain reaction assays. RESULTS: Of 719 patients with suspected varicella, 512 had laboratory-diagnosed varicella and available information on vaccination status. They were divided into 3 groups: 167 with natural varicella, 250 with BV and 1 dose of vaccine, and 95 with BV and 2 doses. The monthly number of patients with varicella decreased gradually during the observation period. Typical seasonal peaks were observed until the 2019-2020 season. The proportion of patients with BV, particularly BV after 2 doses of vaccine, gradually increased. Patients with BV and 2 doses had a significantly lower median age (5 years) than those with 1 dose (6 years) (p < 0.001). The transmission route for BV was unknown in approximately 30-50 % of patients. Duration of fever was significantly longer (p = 0.0138) and the number of skin eruptions was also significantly higher (p = 0.0013) in the 1-dose group than in the 2-dose group. CONCLUSIONS: Although the number of pediatric patients with varicella declined after implementation of national immunization with 2 doses of varicella vaccine, the proportion of patients with BV, especially those who received 2 doses, gradually increased. Clinical symptoms were significantly milder in patients with BV and 2 doses. Laboratory diagnosis of varicella is becoming increasingly important due to an increase in the proportion of patients with BV who have mild symptoms.

BACKGROUND: Human herpesvirus 6 (HHV-6) can integrate its genome into host chromosomes, including germline cells, resulting in inherited chromosomally integrated HHV-6 (iciHHV-6). Affecting approximately 0.4%-2.9% of the population, individuals with iciHHV-6 carry the viral genome in every nucleated cell, often leading to diagnostic confusion. METHODS: This review summarizes current findings on the epidemiology, integration mechanisms, clinical features, diagnostic strategies, and potential reactivation of iciHHV-6, based on recent clinical and molecular research. RESULTS: HHV-6 integrates into telomeric regions through homologous recombination, involving both viral and host telomeric repeats. iciHHV-6 is frequently identified incidentally via polymerase chain reaction-based testing during the evaluation of central nervous system infections or transplant monitoring. High HHV-6 DNA loads in blood or cerebrospinal fluid may mimic active infection, potentially leading to unnecessary antiviral therapy. Although iciHHV-6 is often asymptomatic, emerging evidence indicates possible viral gene expression and rare reactivation, especially in immunocompromised individuals. Additionally, iciHHV-6 may be associated with clinical conditions such as angina, preeclampsia and reproductive disorders. CONCLUSIONS: Distinguishing iciHHV-6 from active infection is essential to avoid misdiagnosis and inappropriate treatment. Awareness of its clinical implications, integration patterns and diagnostic markers is crucial. Further research is needed to clarify the pathogenic potential of iciHHV-6 and guide clinical management.

The recent clinical features of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections in young children in developed countries remain unclear. This study investigated the clinical features of EBV and CMV infections and the latest seroepidemiology in Japan. Seroprevalence was analyzed 303 stored serum samples using commercial Enzyme Immunosorbent Assay kits, and viral infections were investigated in a cohort of febrile children under 5 years of age. After maternal antibody levels declined, the seroprevalences of EBV and CMV gradually increased by adolescence to 42.9% and 57.1%, respectively. Among 2,732 febrile children, serum EBV and CMV DNAs were detected in 1.76% and 1.24%, respectively. Of 25 primary EBV-infected patients, 15 (60.0%) had infectious mononucleosis (IM) with significantly higher IM frequency, WBC, atypical lymphocyte ratios, AST, ALT, LDH, and EBV DNA load compared to EBV-reactivated patients. No CMV DNA-positive patients had IM. Among primary EBV-infected patients, those with IM were older and had more atypical lymphocytes and higher EBV DNA load than those without IM. The age of primary EBV infection appears to have decreased compared to reports from Western countries in the 1990s. Even among children under 5 years of age, 60.0% of those with primary EBV infection developed IM.

ABSTRACT Human herpesvirus 6B (HHV‐6B) encephalitis is a rare but severe complication of hematopoietic cell transplantation. This study investigated the pathogenesis of HHV‐6B encephalitis by comparing plasma proteomic profiles of four pediatric patients with HHV‐6B encephalitis to three with asymptomatic HHV‐6B reactivation following umbilical cord blood transplantation (UCBT). Plasma proteomic profiling was conducted using liquid chromatography‐mass spectrometry. Overall, 260 proteins were identified and quantified in plasma samples. At the onset of HHV‐6B encephalitis and asymptomatic reactivation, 20 and 24 proteins, respectively, were significantly upregulated compared to their respective pre‐onset levels. Of these, 11 proteins were uniquely upregulated in HHV‐6B encephalitis. S100‐A9 and S100‐A8 were the most and second‐most upregulated proteins in HHV‐6B encephalitis, respectively. Elevated plasma S100A8/A9 heterodimer levels were confirmed via enzyme‐linked immunosorbent assay in three of the four patients with HHV‐6B encephalitis. Pathway analysis identified neutrophil degranulation as the most enriched category among upregulated proteins in HHV‐6B encephalitis. Additionally, proteins related to the protein‐lipid complex remodeling pathway were more prominently upregulated in HHV‐6B encephalitis than in asymptomatic reactivation. Proteomic analysis revealed distinct plasma protein profiles between HHV‐6B encephalitis and asymptomatic HHV‐6B reactivation in pediatric UCBT recipients. The inflammatory response mediated by S100A8/A9 proteins may play a critical role in the pathogenesis of HHV‐6B encephalitis. These findings indicate that proteomic analysis may provide novel insights into the host response to HHV‐6B reactivation and the subsequent development of HHV‐6B encephalitis.

OBJECTIVE: To clarify the difference in clinical-radiological features between neonatal-onset arterial ischemic stroke (AIS) and presumed neonatal AIS with a normal neonatal neurological history. METHODS: Twenty-one neonatal AIS patients and seven with presumed neonatal AIS were identified in Aichi Prefecture, Japan, between 2010 and 2014. MRI and clinical characteristics were determined. RESULTS: Nine patients (43 %) with neonatal AIS and only one patient (13 %) with presumed neonatal AIS underwent emergency cesarean sections (ECS). Pyramidal tract involvement was more common in patients with presumed neonatal AIS (71 %) than in those with neonatal AIS (24 %). The most common sequela, hemiplegia, was present in 33 % of patients with neonatal AIS and 71 % with presumed neonatal AIS. CONCLUSIONS: The small number of ECS in presumed neonatal AIS suggests different causal factors from those of neonatal AIS. Given the different distributions of lesions and sequelae, there can be undiagnosed patients with presumed neonatal AIS and no sequelae.

OBJECTIVE: To evaluate the long-term hearing outcomes of infants with symptomatic congenital cytomegalovirus (CMV) disease who received 16 mg/kg of oral valganciclovir (VGCV) twice daily for six months. STUDY DESIGN: We have currently performed a long-term extension study of an investigator-initiated, single-arm, prospective, multicenter clinical trial, in which 24 infants were treated with VGCV. Hearing outcomes up to three years after treatment initiation were described and the longitudinal changes in the proportion of "Improved hearing" were analyzed using logistic regression. The factors associated with these outcomes were explored. Adverse events that occurred after the completion of the administration period were assessed. RESULTS: At 3 years, among 48 ears from 24 infants, the number of "improved hearing," which was 19 (40.0 %) ears at 6 months, increased to 27 (56.3 %) ears (p = 0.032). When including "maintaining normal hearing" or "maintaining normal hearing or the same degree of hearing impairment", the corresponding numbers were observed in 35 (72.9 %) and 45 (93.7 %) ears at 3 years, which were 25 (52.5 %) and 45 (93.7 %) ears at 6 months, respectively. Infants with milder hearing impairment at baseline showed high likelihood of hearing improvement (p for trend = 0.018 by the regression analysis). No adverse events were observed after completion of the administration period. CONCLUSION: Oral administration of VGCV demonstrated efficacy in improving hearing in infants with symptomatic congenital CMV disease at 3 years of age. These results suggest that the treatment response may be particularly favorable in patients with a lower initial degree of hearing impairment.

This report describes the case of a previously healthy nine-year-old girl who developed a left temporal lobe brain abscess following spontaneous exfoliation of a healthy deciduous tooth. She presented in convulsive status epilepticus without fever or focal neurological symptoms, and the initial MRI revealed a ring-enhancing lesion with adjacent dural inflammation. Surgical drainage and intravenous antibiotic therapy led to a full recovery with no neurological sequelae after six weeks of treatment. Pus culture revealed Streptococcus intermedius and Aggregatibacter aphrophilus, both of which are part of the normal oral flora. The route of infection in this case is suggested to be hematogenous spread from the site of tooth exfoliation, as evidenced by the ipsilateral location of the abscess. This highlights the potential for serious intracranial infections to originate from the exfoliation of a deciduous tooth in healthy children, particularly those with orthodontic appliances.

UNLABELLED: Most cases of pulmonary arteriovenous malformation (PAVM) are associated with hereditary hemorrhagic telangiectasia (HHT). HHT is typically caused by loss-of-function gene mutations in the genes ENG, ACVRL1, or SMAD4, all participating in transforming growth factor β (TGF-β) family signaling pathways. We describe the case of an 11-year-old Japanese girl with PAVM, with no known family history of HHT or similar disease. She was found to carry a novel nonsense variant in SMAD9 (SMAD9-p. T267*), which we speculate contributed to her disease, because SMAD9 also participates in TGF-β family signaling pathways. SMAD9 mutations have been linked with pulmonary arterial hypertension (PAH), and, hence, mutations in SMAD9-as for ENG, ACVRL1, and SMAD4-may predispose to both PAH and HHT(-characteristic) disease features. The PAVM in our patient spread diffusely inside the lower lobe of the left lung, and coil embolization was considered difficult. Therefore, after feasibility assessment by performing a balloon occlusion test during cardiac catheterization, left lower lobectomy was performed. The patient's dyspnea recovered well postoperatively, and two years later an increase in left lung volume was observed and disease symptoms had not recurred. Thus, if PAVM spreads diffusely in a certain lung area, surgical treatment can be a viable option. LEARNING OBJECTIVE: SMAD9 gene mutations have been linked to pulmonary arterial hypertension (PAH). However, their associations with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arteriovenous malformation (PAVM), which usually is HHT-associated, have not been reported previously. Our PAVM patient carrying a SMAD9 variant suggests that mutations in this gene, like in others participating in TGF-β family signaling pathways (like ENG, ACVRL1, and SMAD4), predispose to both PAH and HHT(-characteristic) disease features. Diffuse PAVM confined to a lung area may be treated by lobectomy.

OBJECTIVES: In developing countries, acute gastroenteritis (AGE) is a leading cause of death in children younger than 5 years. In Myanmar, no comprehensive study has been done to investigate the microorganisms responsible for AGE among hospitalized children. Multiplex polymerase chain reaction (PCR) was used to identify the microorganisms responsible for AGE in children hospitalized in Myanmar before the introduction of the rotavirus vaccine. METHODS: This prospective study enrolled children younger than 12 years with AGE who were hospitalized at the Yankin Children's Hospital in Yangon, Myanmar, between September 2019 and February 2020. Multiplex PCR (FilmArrayTM GI panel, BioFire Diagnostics, Salt Lake City, USA) and genotyping with Sanger sequencing of rotavirus were performed. Clinical data, including disease severity, were collected from the medical records. RESULTS: We collected stool samples from 92 patients. Multiple microorganisms (median 3; interquartile range 2-4) were detected in 81 patients (88%). Rotavirus and norovirus were detected in 77 (84%) and 33 patients (36%), respectively. The most frequent bacterial pathogen detected was Enteroaggregative E. coli (n = 62/92, 67%). The most common rotavirus genotypes were G1P [8] (19/73; 26%) and G2P [4] (19/73; 26%). CONCLUSIONS: Rotavirus is the predominant pathogen associated with AGE in hospitalized children in Myanmar. The introduction of a rotavirus vaccine will reduce the morbidity and mortality of children with rotavirus-associated AGE in Myanmar.

UBA1 is an E1 ubiquitin-activating enzyme that initiates the ubiquitylation of target proteins and is thus a key component of the ubiquitin signaling pathway. Three disorders are associated with pathogenic variants of the UBA1 gene: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, lung cancer in never smokers (LCINS), and X-linked spinal muscular atrophy (XL-SMA, SMAX2). We here report a case of infantile respiratory distress syndrome followed by continuing neuromuscular symptoms. We identified a de novo hemizygous mutation, c.1660 C > T (p.Pro554Ser), in exon 15 of the UBA1 gene in this baby. This missense mutation was located with the AAD (active adenylation domain) of the protein, a known hotspot of SMAX2 mutations. This case lends support to the genotype-phenotype correlation regarding the UBA1 mutation and its related diseases.

BACKGROUND: Walnut (Juglans regia) frequently triggers nut allergies in the United Kingdom and in the United States, with increasing cases in Japan. While oral food challenges (OFCs) are the definitive method for diagnosing these allergies, they pose the risk of symptom provocation, necessitating safer alternative tests. Our aim here was to evaluate the diagnostic utility of IgE (immunoglobulin E) crosslinking-induced luciferase expression (EXiLE) for walnut allergy compared with the walnut-specific IgE (sIgE) test, Jug r 1-sIgE test, and skin prick test (SPT). METHODS: This retrospective study analyzed 55 patients tested for walnut allergy (WA) at Fujita Health University Bantane Hospital from January 2021 to December 2023. Among them, 38 had allergic reactions to walnuts based on history or OFCs and 17 did not. We evaluated the sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: The EXiLE method (AUC = 0.938) exhibited superior diagnostic accuracy compared to the walnut-sIgE and comparable performance to Jug r 1-sIgE and SPT. The optimal cutoff value of 1.26-fold change demonstrated high sensitivity (0.92), specificity (0.88), positive predictive value (0.92), and negative predictive value (0.82). The EXiLE method yielded positive results in all three cases with negative Jug r 1-sIgE (< 0.35 UA/mL). CONCLUSION: The EXiLE method showed high sensitivity and specificity for diagnosing WA, indicating its potential clinical utility. Furthermore, the combination of Jug r 1-sIgE and EXiLE may enhance diagnostic accuracy. Future large-scale studies are warranted to confirm these findings and establish comprehensive diagnostic protocols.

Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.

To elucidate the seroprevalence and rate of asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Japanese children, serological analysis was performed using serum samples collected from March 2020 to February 2023. A total of 1493 serum samples were collected during the first study period (March 2020 to February 2021). None of the serum samples was positive for SARS-CoV-2 antibody. In the second period (March 2021 to February 2022), seven of the 1055 patients (0.7%) experienced SARS-CoV-2 infection. The third period (March 2022 to February 2023) was divided into three terms: from March to June 30, 2022; from July to October 2022; and from November 2022 to February 2023. The seroprevalence gradually increased throughout this period, with rates of 6.0%, 18.6%, and 30.4% in the three terms, respectively. Pediatric cases of asymptomatic SARS-CoV-2 infection occurred after the surge of Omicron variants. Since none of the SARS-CoV-2 antibody-positive patients had a previous history of coronavirus disease 2019, the seroprevalence rate in this study may represent the rate of asymptomatic infection.

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection in developed countries. Although a standard therapy has not yet been established, evidence for the management of cCMV infection has been accumulating. The first edition of the "Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection" was published in Japan in 2023. This summary outlines the clinical questions (CQs) in the guidelines, with reference to the Japanese Medical Information Distribution Service Manual. Overall, 20 CQs with statements regarding prenatal risk assessment, prevention and management at diagnosis (CQs 1-1-1-3), diagnosis (CQs 2-1-2-6), treatment (CQs 3-1-3-7) and follow-up requirements (CQs 4-1-4-4) have been discussed. For each statement, the levels of recommendation, evidence and consensus rates were determined. These guidelines will assist in the management of patients with cCMV infection.

The live attenuated human rotavirus vaccine strain RIX4414 (Rotarix®) is used worldwide to prevent severe rotavirus-induced diarrhea in infants. This strain was attenuated through the cell culture passaging of its predecessor, human strain 89-12, which resulted in multiple genomic mutations. However, the specific molecular reasons underlying its attenuation have remained elusive, primarily due to the absence of a suitable reverse genetics system enabling precise genetic manipulations. Therefore, we first completed the sequencing of its genome and then developed a reverse genetics system for the authentic RIX4414 virus. Our experimental results demonstrate that the rescued recombinant RIX4414 virus exhibits biological characteristics similar to those of the parental RIX4414 virus, both in vitro and in vivo. This novel reverse genetics system provides a powerful tool for investigating the molecular basis of RIX4414 attenuation and may facilitate the rational design of safer and more effective human rotavirus vaccines.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

We encountered a previously healthy 3-year-old girl with interstitial pneumonitis that initially developed due to human adenovirus type 2 infection and exacerbated by primary human herpesvirus 7 infection. A comprehensive serum biomarker analysis showed patterns that differed by viral infection, suggesting that respiratory and lymphotropic viral infections might have different pathophysiology in interstitial pneumonitis.

Vaccine development for herpes simplex virus 2 (HSV-2) has been attempted, but no vaccines are yet available. A plasmid-based reverse genetics system for Rotavirus (RV), which can cause gastroenteritis, allows the generation of recombinant RV containing foreign genes. In this study, we sought to develop simian RV (SA11) as a vector to express HSV-2 glycoprotein D (gD2) and evaluated its immunogenicity in mice. We generated the recombinant SA11-gD2 virus (rSA11-gD2) and confirmed its ability to express gD2 in vitro. The virus was orally inoculated into suckling BALB/c mice and into 8-week-old mice. Serum IgG and IgA titers against RV and gD2 were measured by ELISA. In the 8-week-old mice inoculated with rSA11-gD2, significant increases in not only antibodies against RV but also IgG against gD2 were demonstrated. In the suckling mice, antibodies against RV were induced, but gD2 antibody was not detected. Diarrhea observed after the first inoculation of rSA11-gD2 in suckling mice was similar to that induced by the parent virus. A gD2 expressing simian RV recombinant, which was orally inoculated, induced IgG against gD2. This strategy holds possibility for genital herpes vaccine development.

UNLABELLED: This study aimed to identify the appropriate dose of aspirin to be prescribed to patients with acute Kawasaki disease (KD). Using a Japanese national inpatient database, we identified patients with KD treated with intravenous immunoglobulin between 2010 and 2021.The outcomes included the occurrence of coronary artery abnormalities and intravenous immunoglobulin resistance, length of hospital stay, and medical costs. Restricted cubic spline functions were performed to examine the association between aspirin dose and the outcomes. Data of 82,109 patients were extracted from the database. Non-linear associations were observed between aspirin dose and the outcomes. In comparison with an aspirin dose of 30 mg/kg/day, the odds ratio (95% confidence interval) for coronary artery abnormalities was 1.40 (1.13-1.75) at 5 mg/kg/day. An aspirin dose of ≥ 30 mg/kg/day did not significantly change the odds ratio for coronary artery abnormalities. Intravenous immunoglobulin resistance was significantly lower at a dose of 60 mg/kg/day or higher. CONCLUSION:  The results showed no significant association between aspirin escalation over standard-dose and coronary artery abnormalities in patients with acute KD. High-dose aspirin showed the potential to reduce hospital stay and medical costs without increasing complications. WHAT IS KNOWN: • Aspirin is used as a standard treatment together with intravenous immunoglobulin for acute Kawasaki disease (KD). However, few studies have shown the most effective dosage of aspirin to prevent coronary artery abnormalities (CAAs). WHAT IS NEW: • There was no significant association between aspirin dose escalation and CAAs in patients with acute KD.

OBJECTIVES: The Gunma score is used to predict the severity of Kawasaki disease (KD), including coronary artery aneurysm (CAA) as a cardiac complication, in Japan. Additionally, the characteristic ratio of ventricular repolarization (T-peak to T-end interval to QT interval [Tp-e/QT]) on a surface electrocardiogram reflects myocardial inflammation. This study aimed to determine whether the Tp-e/QT can be used to predict CAA in children with KD. METHODS: We analyzed chest surface electrocardiograms of 112 children with KD before receiving intravenous immunoglobulin therapy using available software (QTD; Fukuda Denshi, Tokyo, Japan). RESULTS: The Tp-e/QT (lead V5) was positively correlated with the Gunma score (r=0.352, p<0.001). The Tp-e/QT was larger in patients with CAA (residual CAA at 1 month after onset) than in those without CAA (0.314±0.026 versus 0.253±0.044, p=0.003). A receiver operating characteristic curve analysis was performed to assess whether the Gunma score and Tp-e/QT could predict subsequent CAA. The area under the curve of the Gunma score was 0.719 with the cutoff set at 5 points. The area under the curve of the Tp-e/QT was 0.892 with a cutoff value of 0.299. The fit of the prediction models to the observed probability was tested by the Hosmer-Lemeshow test with calibration plots using Locally weighted scatterplot smoothing (LOESS) fit. The Gunma score (p=0.95) and Tp-e/QT (p=0.95) showed a good fit. CONCLUSIONS: The Tp-e/QT is a useful biomarker in predicting coronary aneurysm complications in KD.