記述言語：英語   掲載種別：研究論文（学術雑誌）  

Semaphorins were initially identified as axon guidance molecules that were widely expressed and involved in divergent functions in various organs, including neuronal development and immunological processes. Collapsin response mediator proteins (CRMPs) are involved in the intracellular signaling of semaphorin 3A (Sema3a) and are highly expressed in the nervous system. However, the participation of semaphorins or their receptors plexins and CRMPs in the regulation of islet function remains unknown. In this study, we measured the expression of semaphorin, plexin, and CRMP families in mouse islets, and their expression levels were altered by treatment with high glucose or a glucokinase activator (GKA). The expression and phosphorylation of CRMP-2 in islets were upregulated in high-fat diet (HF)-fed obese mice, and the expression of CRMP-2 was downregulated in islets from db/db mice. HF-fed CRMP-2 knockout mice exhibited impaired glucose tolerance. These results indicated that the semaphorin/plexin/CRMP families in mouse islets might be involved in glucose metabolism partly through glucose/glucokinase.

DOI： 10.1038/s41598-025-95300-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Recently, the role of a rapid increase in serum osmolality in the inhibition of postnatal ductal closure has garnered attention. This study evaluated the efficacy of high-humidity care in preventing the onset of patent ductus arteriosus (PDA) in extremely premature infants. METHODS AND RESULTS: The high-humidity group (HHG) comprised 28 infants (240to 276weeks gestational age) recruited prospectively within 6 h after birth between July 2019 and September 2021; these infants were cared for in 90% humidity for the first 72 h of life. The incidence of PDA within the first 7 days of life and the rate of increase in serum sodium concentrations were compared between the HHG and a conventionally managed historical control group (CG; 29 infants born in 2016-2017). Twelve (43%) infants in the HHG and 22 (76%) in the CG developed PDA (P=0.016). Multivariate logistic regression analysis revealed that high-humidity care was effective in reducing the incidence of PDA onset (odds ratio 0.265; 95% confidence interval 0.078-0.907). The rate of increase in serum sodium concentrations was significantly lower in the HHG than CG (median 0.29 [interquartile range 0.21-0.39] vs. 0.46 [interquartile range 0.32-0.62] mEq/L/h, respectively; P<0.001). CONCLUSIONS: High-humidity care for the first 72 h of life may help reduce the onset of PDA in extremely preterm infants by avoiding rapid increases in serum sodium concentrations.

DOI： 10.1253/circj.CJ-24-0705

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The random C-peptide and random C-peptide index (CPI) have been shown to be useful in assessing endogenous insulin secretory capacity in adults with type 2 diabetes. This study aimed to clarify the utility of C-peptide and the CPI in early classification of long-term insulin-dependent status in pediatric diabetes patients. A total of 204 patients aged ≤15 years who received an initial diagnosis of acute-onset type 1 diabetes mellitus (T1DM), slowly progressive insulin-dependent diabetes mellitus (SPIDDM), or type 2 diabetes mellitus (T2DM) at Yokohama City University Medical Center between April 1, 2003 and March 31, 2018 were included. The acute-onset T1DM, SPIDDM, and T2DM groups included 140, 8, and 56 patients, respectively. The median random C-peptide values were 0.67, 3.18, and 4.16 ng/mL and median random CPI values were 0.19, 2.02, and 2.53 for acute-onset T1DM, SPIDDM, and T2DM cases, respectively (acute-onset T1DM vs. T2DM, p < 0.001 (C-peptide), p < 0.001 (CPI), acute-onset T1DM vs. SPIDDM, p < 0.001 (C-peptide), p < 0.001 (CPI), SPIDDM vs. T2DM, p = 0.04 (C-peptide), p = 0.19 (CPI)). Receiver operating characteristic analysis cutoff values of C-peptide levels in differentiating acute-onset T1DM from SPIDDM and acute-onset T1DM from T2DM were 1.60 ng/mL (sensitivity 87.5%, specificity 90.6%) and 1.81 ng/mL (sensitivity 91.1%, specificity 93.5%), while the respective CPI values were 0.46 (100% sensitivity, 77% specificity) and 1.05 (92.1% sensitivity, 87.5% specificity). This study indicates that the random C-peptide and random CPI at diagnosis are helpful in the early classification of childhood diabetes and determining an appropriate time to introduce insulin and predicting the subsequent clinical course.

DOI： 10.1507/endocrj.EJ24-0517

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We encountered two affected male patients born to non-consanguineous parents, who presented with prenatal-onset severe growth impairment, primary microcephaly, developmental delay, adrenal insufficiency, congenital glaucoma, delayed bone aging, craniosynostosis, congenital tracheal stenosis, and primary hypogonadism. By exome sequencing, we identified compound heterozygous TEDC1 variants (NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)] in both affected siblings. We confirmed that the splice site variant, c.104-5C>G, leads to no TEDC1 protein production via nonsense-mediated mRNA decay. The frameshift variant located in the last coding exon, c.787delG, produces a C-terminally truncated protein, which impairs the binding with TEDC2. Thus, both variants are thought to be loss-of-function. TEDC1 and TEDC2 are both required for centriole stability and cell proliferation. Our in vitro experiments using patient-derived cells revealed cell cycle abnormality. Our in vivo study using tedc1-/- zebrafish generated by CRISPR/Cas9 successfully recapitulated the growth impairment and cranial bone dysplasia as seen in our patients. The tedc1-/- mutant zebrafish were sterile and did not have developed gonads. Furthermore, we showed that biallelic TEDC1 deletion causes cilia abnormalities through defective acetylated tubulins.

DOI： 10.1038/s41431-025-01802-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Even though several cases of new-onset nephrotic syndrome following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, none have included the medium- to long-term prognosis of the patients. Here, we report the prognoses of two adolescents, aged 14 and 15 years, who developed nephrotic syndrome soon after receiving the Pfizer-BioNTech SARS-CoV-2 vaccine. Both patients were diagnosed with nephrotic syndrome after developing edema within a few days post-SARS-CoV-2 vaccination. Although they achieved rapid and complete remission with prednisolone therapy, they developed frequently relapsing nephrotic syndrome and were initiated on cyclosporine. In one patient, frequent relapses occurred while taking cyclosporine, requiring rituximab to maintain remission. Measurements of antibody titers against the spike protein of the SARS-CoV-2 vaccine taken over time revealed significantly lower titers in both patients compared with those in healthy individuals. Furthermore, each patient was infected with SARS-CoV-2 about 12 months post vaccination, with mild symptoms. Nephrotic syndrome did not recur in either patient. We also reviewed 49 published cases of patients who developed nephrotic syndrome after SARS-CoV-2 vaccination, compared to our pediatric cases, there are no cases of recurrence with the same frequency in adult cases, and it is desirable to accumulate and compare more pediatric cases in the future.

DOI： 10.1007/s13730-025-00967-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The prognosis of acute myeloid leukemia (AML) with KMT2A::MLLT3 rearrangement and MECOM overexpression and/or KRAS mutation is dismal, and the optimal treatment strategy remains unclear. However, to the best of our knowledge, a suitable model (such as a cell line or its xenograft model) for research on this subtype has not been established. We established a novel AML cell line, YCU-AML2, and its xenograft model harboring KMT2A::MLLT3 rearrangement, MECOM overexpression, and KRAS G12A mutation. YCU-AML2 xenograft mice models developed AML and mimicked the clinical phenotype of the original patient. YCU-AML2 expressed high sensitivity to MEK inhibitors, such as trametinib and selumetinib. Moreover, YCU-AML2 also exhibited high sensitivity to L-asparaginase with glutaminase activity, perhaps because of its reliance on oxidative phosphorylation via glutaminolysis as its main energy source. We believe that the YCU-AML2 cell line and its xenograft model can serve as models to explore the molecular pathogenesis of high-risk AML with KMT2A::MLLT3 rearrangement, MECOM overexpression, and/or KRAS mutation and develop new treatment strategies.

DOI： 10.1007/s12185-025-03929-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Monthly palivizumab prevents severe respiratory syncytial virus infection among high-risk children. Palivizumab is generally initiated early in an epidemic, but the best timing for initiation is unknown. Reducing the number of infected patients prior to palivizumab administration is a public health challenge. METHODS: Kanagawa Prefecture, Japan, has a regionally standardized protocol for the initiation of palivizumab based on epidemic prediction for the following season. We analyzed the efficacy of this prospective intervention during 2019-2022 using a questionnaire completed by regional hospitals. RESULTS: The survey response rate was 53.8%. In 2019, 2021, and 2022, RSV epidemics began in July, May, and June; palivizumab was started in July, May, and April, respectively. In 2020, palivizumab was started in June, but there was no epidemic activity. The median number of palivizumab doses was eight per year. The number of hospitalized patients each year was 1381, 169, 1196, and 1028, with 28, 1, 11, and 13 patients having an indication for palivizumab, respectively. Among them, the number of hospitalized patients before or after the first dose of palivizumab was 16, 1, 10, and 4, respectively. Thirteen of 31 patients (41.9%) infected before or after the first dose needed care in the pediatric intensive care unit and/or nasal high flow therapy; only three of 22 patients (13.6%) received the second of more doses needed (p<0.05). CONCLUSIONS: A standardized regional protocol for palivizumab initiation could be effective in reducing the number of hospitalized and severely ill patients for whom palivizumab is indicated.

DOI： 10.1016/j.jiac.2025.102639

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Interferon regulatory factor 2 binding protein-like (IRF2BPL) is a single-exon gene that is ubiquitously expressed in various tissues, including the brain. IRF2BPL encodes a transcription factor with two zinc-finger domains that potentially downregulate WNT signaling in the nervous system. Pathogenic IRF2BPL variants have been reported to cause developmental delay, seizures, myoclonus epilepsies, autistic spectrum disorder, and other neurodevelopmental disorders. Exome sequencing of 10 patients with developmental delay and/or epilepsy from nine families revealed nine pathogenic IRF2BPL variants, of which eight were novel: five missense, one in-frame indel, and three truncating variants. Using reported pathogenic and benign variants, we highlight here several regions of IRF2BPL that deviate in the frequency of pathogenic and benign variants. This study of detailed clinical and genetic information shows that IRF2BPL missense and in-frame indel variants are often associated with seizures and developmental delay.

DOI： 10.1038/s10038-025-01316-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Data on atrial septal defect (ASD) diagnosis in school heart screenings in Japan are insufficient, and criteria for detecting abnormal waveforms in primary screening are unclear. METHODS: We analyzed 282 elementary school-age (5-10 years) and 90 middle/high school-age (11-18 years) ASD patients, along with 400 age-matched healthy controls. The prevalence of right bundle branch block (RBBB), right axis deviation (RAD), T wave abnormalities, and Crochetage (CR) patterns in inferior leads on electrocardiograms (ECG) was assessed. RBBB was classified as strict definition incomplete RBBB (IRBBB), wide definition IRBBB, or overall RBBB based on the ECG morphology. RESULTS: Strict definition IRBBB was observed in 38.3% and 24.4% of elementary and middle/high school-age ASD patients, respectively, but only in 2.0% of the healthy controls. Wide definition IRBBB was observed in 71.3% and 62.2% of elementary and middle/high school ASD patients, respectively, compared to 3.0% in controls. T wave abnormalities were present in 70.9%, 23.3%, and 0.8% of elementary, middle/high school ASD patients, and healthy controls, respectively. The CR pattern appeared in all inferior leads in 50.7% of elementary school ASD patients, 48.9% of middle/high school ASD patients, and 2.8% of healthy controls. Using a composite of wide definition IRBBB, T wave abnormalities, and CR pattern for screening would capture 89.3% of ASD cases, with a 6.0% false-positive rate in healthy children. CONCLUSION: Combining specific waveforms may improve the detection rate of ASD, though managing false-positives among healthy children remains a challenge.

DOI： 10.1111/ped.70103

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Primary intracranial sarcoma (PIS) is a rare and aggressive pediatric brain tumor, which is partially associated with DICER1 mutant. Although the molecular genetic characteristics of this tumor have previously been investigated, novel therapeutic targets remain unclear. Further, the lack of faithful preclinical models has hampered the development of novel therapeutic strategies. Herein, we describe a pediatric case of PIS with DICER1 mutant and describe the development of the first novel patient-derived xenograft (PDX) model of this rare tumor. Somatic genomic profiling of the tumor revealed mutations in DICER1, TP53, and ATRX. Germline analysis further revealed a pathogenic variant of DICER1, significant for the diagnosis and management of hereditary tumor predisposition syndrome. Overall, we demonstrated that the PDX model faithfully retained the phenotype and genotype of the patient's tumor, as well as the DNA methylation profile. Through high-throughput drug screening using PDX tumor cells, we found that activation of the retinoic acid receptor (RAR) signaling pathway reduced tumor cell viability. These findings indicate that the RAR signaling pathway is a potential therapeutic target for PIS in DICER1 mutant.

DOI： 10.1007/s10014-024-00495-8

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.envpol.2024.124801

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.

DOI： 10.1038/s41375-024-02438-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND HYPOTHESIS: There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS). METHODS: A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined. RESULTS: The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio, 0.28; 95% CI, 0.09-0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children). CONCLUSIONS: A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections.

DOI： 10.1093/ndt/gfae228

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記述言語：日本語   出版者・発行元：日本小児臨床薬理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Urate-lowering efficacy and safety of febuxostat was evaluated in paediatric patients with hyperuricaemia including gout. METHODS: A phase 2 study of febuxostat in paediatric patients aged 6-18 years with hyperuricaemia including gout was conducted. We evaluated the proportion of patients achieving serum uric acid (sUA) level ≤6.0 mg/dL at Week 26, and long-term safety and efficacy at Week 52. We also considered efficacy stratified by renal function. RESULTS: Thirty patients (10 at <40 kg and 20 at ≥40 kg) were enrolled. Twenty-four were male, 29 had asymptomatic hyperuricaemia, and 1 had gout. Age was 8 to 18 years. Of these, 63.3% (95% confidence interval 43.9-80.1%) achieved a sUA level of ≤6.0 mg/dL at Week 26. sUA level (mean ± standard deviation) was 5.55 ± 0.87 mg/dL, reduced from 9.01 ± 1.23 mg/dL at baseline. Febuxostat efficacy appeared similar for mild to moderate renal dysfunction and with normal renal function. There were no major safety issues. CONCLUSIONS: In paediatric patients with hyperuricaemia including gout, febuxostat showed long-term, well-controlled urate-lowering efficacy with no major safety issues. Findings suggest that no dose adjustment is required for paediatric patients with mild to moderate renal dysfunction.

DOI： 10.1093/mr/roae056

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The deletion region of 22q11.2 deletion syndrome (22q11.2DS) contains a gene encoding glycoprotein Ibβ (GPIbβ), which is required to express the GPIb/IX/V complex on the platelet surface. Therefore, patients with 22q11.2DS may have congenital platelet disorders. However, information is limited on platelets and bleeding symptoms. In this study, we investigated clinical information, including bleeding symptoms, platelet counts, and GPIb expression levels in children and adolescents/adults with 22q11.2DS. PROCEDURE: Thirty-two patients with 22q11.2DS were enrolled in a prospective cohort study between 2022 and 2023 at outpatient clinics within our institute. RESULTS: The median platelet counts in adolescents/adults with 22q11.2DS were significantly lower than those in children (p < .0001). A gradual decrease was found along with increasing age (p = .0006). Values of median GPIb expression on platelet surfaces (66% in children and 70% in adolescents/adults) were significantly lower than those in healthy controls (p < .0001 and p = .0002). Bleeding symptoms included surgery-related bleeding (52%), purpura (31%), and epistaxis (22%); most of them were minor. The median International Society on Thrombosis and Hemostasis bleeding assessment tool score was not significantly different between children and adolescents/adults (p = .2311). CONCLUSION: Although there was an age-related decrease in platelet count and a disease-related decrease in GPIb expression, no difference in bleeding symptoms was found between children and adolescents/adults. 22q11.2DS overall had minor bleeding symptoms in daily life, and the disease had little effect on spontaneous bleeding. However, some patients had major bleeding events; further accumulation of data on hemostasis during surgery and trauma is required.

DOI： 10.1002/pbc.31292

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

RATIONALE AND OBJECTIVES: Gadolinium deposition in the dentate nucleus (DN) has been evaluated by T1-weighted imaging (T1WI) and T1 (R1) mapping, but not MR fingerprinting (MRF). This study investigated associations between T1 and T2 values of DN and gadolinium-based contrast agents (GBCAs) using 2-dimensional MRF. MATERIALS AND METHODS: This study included 101 patients. Region of interest analysis was performed for T1 and T2 values of DN on MRF (T1-MRF, T2-MRF) and T1-weighted images (T1WI ratio). T1 and T2 ratios compared to normal cerebellar white matter (T1-MRF ratio, T2-MRF ratio) were calculated. The type of previous GBCA was confirmed in 79 patients, and linear regressions were performed between T1, T2 values and number of GBCAs. RESULTS: Good correlations were observed between T1-MRF and T1WI ratio (ρ = -0.69, P < 0.001) and between T1-MRF ratio and T1WI ratio (ρ = -0.76, P < 0.001). Mild correlations were observed between T2-MRF and T1WI ratio (ρ = -0.32, P < 0.001) and between T2-MRF ratio and T1WI ratio (ρ = -0.44, P < 0.001). The number of linear-type GBCAs was associated with T1-MRF (β = -0.62, P < 0.001) and T1-MRF ratio (β = -0.54, P < 0.001) in univariate linear regression analyses, and with T1-MRF (β = -0.61, P < 0.001) and T1-MRF ratio (β = -0.53, P < 0.001) in multivariate analysis. The number of linear-type GBCAs was associated with T2-MRF (β = -0.30, P < 0.001) and T2-MRF ratio (β = -0.29, P < 0.001) in univariate analyses, and with T2-MRF (β = -0.31, P < 0.001) and T2-MRF ratio (β = -0.32, P < 0.001) in multivariate analyses. No associations were observed between number of macrocyclic GBCAs and T1-MRF (ratio) or T2-MRF (ratio). CONCLUSION: The number of linear-type GBCA administrations was associated with lower T1 and T2 values (ratios) in DN.

DOI： 10.1016/j.acra.2024.08.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: This study aimed to understand the status quo of medical treatments of the primary disease and pregnancy outcomes in patients with Takayasu arteritis (TAK) and children's birth outcomes. METHODS: This study retrospectively enrolled patients with TAK who conceived after the disease onset and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labor, and Welfare for Intractable Vasculitis. RESULTS: This study enrolled 51 cases and 68 pregnancies 2019-2021. Of these, 48 cases and 65 pregnancies (95.6%) resulted in delivery and live-born babies. The median age of diagnosis and delivery was 22 and 31, respectively. Preconception therapy included prednisolone (PSL) in 51 (78.5%, median 7.5 mg/day), immunosuppressants in 18 (27.7%), and biologics in 12 (18.5%) pregnancies. Six cases underwent surgical treatment before pregnancy. Medications during pregnancy included PSL in 48 (73.8%, median: 9 mg/day), immunosuppressants in 13 (20.0%), and biologics in 9 (13.8%) pregnancies. Enlargement of an aneurysm was reported in one pregnancy, which might be associated with increased circulating plasma volume. TAK relapsed in 4 (6.2%) and 8 (12.3%) pregnancies during pregnancy and after delivery, respectively. Additionally, 13/62 (20.9%) preterm infants and 17/59 (28.8%) low birth weight infants were observed, and none had serious postnatal abnormalities. Of the 51 confirmed infants, 42 (82.4%) were exclusively breastfed or mixed with formula. CONCLUSION: Most pregnancies in TAK were manageable with PSL at ≤10 mg/day. Relapse during pregnancy and postpartum occurred in <20% of pregnancies.

DOI： 10.1093/mr/roae068

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記述言語：英語  

DOI： 10.1038/s41372-024-02055-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis. PROCEDURE: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML. RESULTS: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells. CONCLUSIONS: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.

DOI： 10.1002/pbc.31151

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier  

DOI： 10.1016/j.envres.2024.118871

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0305957

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

DOI： 10.1007/s00467-024-06422-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lupus nephritis (LN) is a very severe manifestation of lupus. There is no consensus on which treatment goals should be achieved to protect kidney function in children with LN. METHODS: We retrospectively analyzed trends of commonly used laboratory biomarkers of 428 patients (≤ 18 years old) with biopsy-proven LN class ≥ III. We compared data of patients who developed stable kidney remission from 6 to 24 months with those who did not. RESULTS: Twenty-five percent of patients maintained kidney stable remission while 75% did not. More patients with stable kidney remission showed normal hemoglobin and erythrocyte sedimentation rate from 6 to 24 months compared to the group without stable kidney remission. eGFR ≥ 90 ml/min/1.73m2 at onset predicted the development of stable kidney remission (93.8%) compared to 64.7% in those without stable remission (P < 0.00001). At diagnosis, 5.9% and 20.2% of the patients showed no proteinuria in the group with and without stable kidney remission, respectively (P = 0.0001). dsDNA antibodies decreased from onset of treatment mainly during the first 3 months in all groups, but more than 50% of all patients in both groups never normalized after 6 months. Complement C3 and C4 increased mainly in the first 3 months in all patients without any significant difference. CONCLUSIONS: Normal eGFR and the absence of proteinuria at onset were predictors of stable kidney remission. Significantly more children showed normal levels of Hb and erythrocyte sedimentation rate (ESR) from 6 to 24 months in the group with stable kidney remission.

DOI： 10.1007/s00467-024-06405-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting young children, with an unclear etiology. We investigated the link between maternal heavy metal exposure and KD incidence in children using the Japan Environment and Children's Study, a large-scale nationwide prospective cohort with approximately 100,000 mother-child pairs. Maternal blood samples collected during the second/third trimester were analyzed for heavy metals [mercury (Hg), cadmium (Cd), lead (Pb), selenium (Se), manganese (Mn)], divided into four quartiles based on concentration levels. KD incidence within the first year of life was tracked via questionnaire. Among 85,378 mother-child pairs, 316 children (0.37%) under one year were diagnosed with KD. Compared with the lowest concentration group (Q1), the highest (Q4) showed odds ratios (95% confidence interval) for Hg, 1.29 (0.82-2.03); Cd, 0.99 (0.63-1.58); Pb, 0.84 (0.52-1.34); Se, 1.17 (0.70-1.94); Mn, 0.70 (0.44-1.11), indicating no concentration-dependent increase. Sensitivity analyses with logarithmic transformation and extended outcomes up to age 3 yielded similar results. No significant association was found between maternal heavy metal levels and KD incidence, suggesting that heavy metal exposure does not increase KD risk.

DOI： 10.1038/s41598-024-60830-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Erythropoietin has an angiogenic effect on the retina and might increase the risk of retinopathy of prematurity (ROP). METHODS: This retrospective cohort study included infants born at 22 to 27 weeks' gestation between 2008 and 2018 who were admitted to neonatal intensive care units (NICUs). We compared mortality and morbidities between infants who received erythropoietin and those who did not. RESULTS: Among 18,955 livebirth infants, this study included 16,031 infants, among which 14,373 infants received erythropoietin. The risk of ROP requiring treatment was significantly higher in the erythropoietin group than in the control group (33% vs. 26%; aOR 1.50 [95% CI 1.28-1.76]). On the other hand, the erythropoietin group had lower risks of death and necrotizing enterocolitis. CONCLUSIONS: This study with a large sample size found that erythropoietin use was associated with increased risk of ROP requiring treatment, while being associated with reductions in deaths and NEC.

DOI： 10.1038/s41372-024-01929-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Peritonitis is the leading cause of peritoneal dialysis (PD) discontinuation. However, few data concern risk factors of peritonitis development and catheter removal caused by treatment failure in pediatric patients. METHODS: This single-center, retrospective study analyzed data from pediatric patients who underwent chronic PD between March 2002 and June 2022. The incidence rates of peritonitis by the person-year method were calculated, and they were stratified by patient age groups. Risk factors for peritonitis development and catheter removal were also analyzed by multivariate analysis using logistic regression model. RESULTS: Ninety patients were enrolled, and 62 peritonitis episodes were observed in 41 (46%) patients. The incidence rate of peritonitis was 0.21 episodes per patient-year, which was the highest in children aged under 2 years old (0.26 episodes per patient-year). Moreover, 44 (71%) cases were successfully cured by antibiotics alone, although 17 (27%) cases required catheter removal, and 4 (6%) cases transitioned to chronic hemodialysis because of peritoneal dysfunction. One patient died. The risk factor for peritonitis development and catheter removal caused by treatment failure was PD insertion at under 2 years old (odds ratio = 2.5; P = 0.04) and Pseudomonas aeruginosa (odds ratio = 11.0; P = 0.04) in the multivariate analysis. P. aeruginosa was also a risk factor for difficulty in re-initiating PD (P = 0.004). CONCLUSIONS: The incidence rate of peritonitis was the highest in children under 2 years old. P. aeruginosa peritonitis is a risk factor for catheter removal and peritoneal dysfunction.

DOI： 10.1007/s10157-024-02482-x

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.bdcasr.2024.100007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nail-patella syndrome (NPS) is a hereditary disease caused by pathogenic variants in LMX1B and characterized by nail, limb, and renal symptoms. This study revealed a likely pathogenic LMX1B variant, NM_002316.4: c.723_726delinsC (p.Ser242del), in Japanese twins with clubfoot. The patients' mother, who shared this variant, developed proteinuria after delivery. p.Ser242del is located in the homeodomain of the protein, in which variants that cause renal disease tend to cluster. Our findings highlight p.Ser242del as a likely pathogenic variant, expanding our knowledge of NPS.

DOI： 10.1038/s41439-024-00266-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Many developed countries including Japan are experiencing declining birth rates, particularly in urban areas. A gap between the planned number of children and the actual number of children exists, that is attributed to various factors such as: childcare leave and employment policies, childcare services, financial support, husbands' contributions to household chores and childcare, marriage support, community, and couples' well-being. Therefore, we propose HAMA study for having a baby, parenting, and marriage life (HAMA = 'H'aving 'A' baby, parenting, and 'MA'rriage life) in Yokohama (an urban area) to examine these issues. METHODS AND ANALYSIS: In this large-scale cohort study, we will elucidate the actual situation of families and child-rearing in Yokohama, evaluate the current policies and propose future measures to prevent a decline in the birth rate. Overall, 10 000 young married couples (wives aged 20-39 years as of 2022) will be randomly selected, and a survey form will be sent to them annually. They will be followed-up for 5 years to examine the factors associated with the planned number of children, well-being of the couple, childcare support policies, externalisation of housework and childcare, fathers' participation in housework and childcare, wives' free time, loneliness and social connectedness, relationship with the spouse and if they are working, questions regarding their work style and work-life balance will also be included. Ultimately, a conceptual model of the planned number of children and associated factors will be developed. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Yokohama City University (reference number: 2022-10) and will be conducted following appropriate ethical guidelines. Opportunities to withdraw consent to participate in the survey are provided to participants. The results of this survey will be published as research papers in relevant journals and will be reported to the administration of Yokohama city and other agencies.

DOI： 10.1136/bmjopen-2023-076557

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.

DOI： 10.1038/s41525-024-00394-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized arteries. With advances in our understanding of the pathogenesis and classification of vasculitis, PAN and microscopic polyangiitis (MPA), a disease of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), were separated from the group of diseases previously diagnosed as periarteritis nodosa (PN) at the Chapel Hill Consensus Conference (CHCC) in 1994 (1).

DOI： 10.1093/mr/roae010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. METHODS: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. RESULTS: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6-71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. CONCLUSIONS: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. TRIAL REGISTRATION: Not applicable.

DOI： 10.1007/s00467-023-06270-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE-mediated gastrointestinal food allergy. FPIES is considered a rare food allergy disorder and is often under-recognized. Therefore, clinicians should have a better understanding of its manifestations and maintain a high index of suspicion for a correct diagnosis. To this end, information about differences in the characteristics of caregiver-reported and physician-diagnosed FPIES is important. METHODS: The present, national, multicentric, prospective birth cohort study, called the Japan Environment and Children's Study (JECS), enrolled a general population of 104,062 fetal records. The characteristics of FPIES in 1.5-year-old children were categorized as cases reported by caregivers or as those diagnosed by a physician using questionnaire data. RESULTS: The prevalence of caregiver-reported and physician-diagnosed FPIES cases was 0.69% and 0.06%, respectively. Among the former, the most common causative food was hen's egg (HE), and the second most common causative food was cow's milk (CM) (51.0% and 17.1% of patients responded to HE and CM, which accounted for 46% and 15% of all the causative foods, respectively). Conversely, among the physician-diagnosed cases, the most common causative food was CM followed by HE (57.7% and 36.5% of patients responded to CM and HE, which accounted for 46% and 29% of all the causative foods, respectively). CM accounted for a significantly higher proportion of causative foods in physician-diagnosed FPIES while HE accounted for a significantly higher proportion of caregiver-reported FPIES (p &lt; 0.05). CONCLUSION: A discrepancy was found in reports of the most common causative food between caregiver-reported and physician-diagnosed cases of FPIES.

DOI： 10.1159/000535751

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記述言語：英語  

Vitamin K deficiency bleeding (VKDB) in neonates is a significant disorder that causes skin, gastrointestinal, and intracranial hemorrhaging. Early-onset VKDB occurs within 24 hours of birth, and its prognosis is poor due to severe hemorrhage. The causes of early-onset VKDB include maternal intake of warfarin and anticoagulants, and maternal vitamin K deficiency. We report the case of a neonate with early-onset VKDB born to a mother with Crohn's disease. The neonate developed severe cerebellar hemorrhage on the day of birth and subsequent noncommunicating hydrocephalus requiring a ventriculoperitoneal shunt. The mother had a 14-year history of Crohn's disease and short bowel owing to intestinal resection. She was in complete remission during pregnancy according to the Crohn's Disease Activity Index. Endoscopic examination performed shortly before pregnancy revealed inflammatory findings in the residual small intestine. Her blood tests at delivery showed an elevated prothrombin induced by vitamin K deficiency or antagonist II (PIVKA-II) level of 26,900 mAU/mL. A definitive protocol to prevent early-onset VKDB in mothers with Crohn's disease complicated by a short bowel is lacking. Administering vitamin K to mothers with elevated PIVKA-II levels before delivery may help prevent early-onset VKDB.

DOI： 10.1055/a-2219-5024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21-58) and the median doses of eculizumab was three (IQR;2-5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95-555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.

DOI： 10.1038/s41409-023-02161-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IMPORTANCE: Kawasaki disease is an acute systemic vasculitis that primarily affects infants and young children. No reproducible risk factors have yet been identified, but a possible association between maternal folic acid supplementation and Kawasaki disease has been reported previously. OBJECTIVE: To investigate the associations of exposure to maternal serum folic acid levels and maternal folic acid supplementation with onset of Kawasaki disease during infancy among offspring. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Japan Environment and Children's Study, a nationwide birth cohort, which has enrolled children since 2011. This study used the data set released in October 2019, and analysis was performed in January 2023. EXPOSURES: Maternal serum folic acid levels (≥10 ng/mL classified as exposed) during the second and third trimesters and the frequency of maternal folic acid supplementation during the first trimester and during the second and third trimesters of pregnancy (once a week or more was classified as exposed). MAIN OUTCOMES AND MEASURES: The primary outcome was onset of Kawasaki disease in offspring up to age 12 months. Odds ratios (ORs) for each exposure were estimated, and propensity score-adjusted logistic regression was conducted on the basis of the sets of variables. RESULTS: The study population comprised 87 702 children who were followed-up for 12 months. Of these, 336 children developed Kawasaki disease. Mothers who took folic acid supplements (31 275 mothers [35.7%]; mean [SD] age, 32 [5] years) had higher serum folic acid levels than those who did not take supplements. Higher maternal serum folic acid levels were associated with a significantly lower risk of Kawasaki disease in offspring than lower levels (folic acid ≥10 vs <10 ng/mL, 56 of 20 698 children [0.27%] vs 267 of 64 468 children [0.41%]; OR, 0.68; 95% CI, 0.50-0.92). Children whose mothers took folic acid supplementation during the first trimester had a lower prevalence of Kawasaki disease than children whose mothers did not take folic acid (131 of 39 098 children [0.34%] vs 203 of 48 053 children [0.42%]), although the difference was not statistically significant (OR, 0.83; 95% CI, 0.66-1.04). Supplementation during the second and third trimesters was associated with a significantly lower risk of Kawasaki disease compared with no supplementation (94 of 31 275 children [0.30%] vs 242 of 56 427 children [0.43%]; OR, 0.73; 95% CI, 0.57-0.94). CONCLUSIONS AND RELEVANCE: In this cohort study, higher serum folic acid levels (≥10 ng/mL) and maternal folic acid supplementation more than once a week during the second and third trimesters were associated with reduced risk of Kawasaki disease in offspring during infancy.

DOI： 10.1001/jamanetworkopen.2023.49942

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12884-023-05578-6

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12884-023-05810-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.

DOI： 10.1007/s10157-023-02431-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Teenage pregnancy increases the threat of depression because of its many factors. Pregnancy during young adulthood may also have several risk factors for depression compared to older pregnancies. However, data on depression in young adult pregnancies are lacking. This study investigated the association between teenage and young adult pregnancy and depression. Data from the Japan Environment and Children's study was used as a nationwide multicenter prospective cohort study. A multivariate logistic regression was performed to investigate the association between age groups (14-19, 20-24, 25-29, 30-34, ≥ 35 years) and depression, adjusted for behavioral and sociodemographic characteristics. Depression was assessed using the Kessler Psychological Distress Scale. In total, 96,808 pregnant women responded to the questionnaire. Teenage (14-19 years) and young adult (20-24 years) pregnancy were associated with an increased risk of depression compared to older pregnancy (≥ 35 years) (teenage: OR 4.28, 95% confidence interval, CI [3.24-5.64]; young adult: OR 3.00, 95% CI [2.64-3.41]). After adjusting for covariates, the magnitude of the risk of depression was attenuated. However, teenage and young adult pregnancy remained at a significantly increased risk of depression compared to older pregnancy (teenage: OR 2.38, 95% CI [1.77-3.21]; young adult: OR 2.14, 95% CI [1.87-2.46]). Our findings indicate that teenage and young adults' pregnancy are at an increased risk of depression compared to older pregnancy. These findings suggest prioritizing teenage and young pregnant women for prevention and interventions related to depression.

DOI： 10.1007/s00737-023-01400-6

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Medical Association (AMA)  

Importance

It is unclear whether increased television (TV) and DVD viewing in early childhood from age 1 year decreases development or whether poor development increases TV/DVD viewing.

Objective

To investigate the directional association between TV/DVD screen time and performance on developmental screeners in children aged 1 to 3 years.

Design, Setting, and Participants

This longitudinal cohort study analyzed data from 57 980 children and mothers from a national birth cohort, the Japan Environment and Children’s Study. Data were collected in collaboration with 15 regional centers across Japan. The mothers were recruited between January 2011 and March 2014. Analyses using random intercept, cross-lagged panel models were performed for children aged 1, 2, and 3 years. Of 100 303 live births, children with missing developmental screening test scores and screen time data, those with congenital diseases or cerebral palsy, and those diagnosed with an autism spectrum disorder were excluded. Statistical analyses were conducted from October 2022 to July 2023.

Exposures

TV and DVD screen time.

Main Outcomes and Measures

Child development at ages 1, 2, and 3 years was assessed via the mother’s or guardian’s report using the Ages and Stages Questionnaire, third edition.

Results

Of 57 980 included children, 29 418 (50.7%) were male, and the mean (SD) maternal age at delivery was 31.5 (4.9) years. A negative association between screen time and developmental scores was observed. Increased TV/DVD screen times at age 1 and 2 years were associated with lower developmental scores at age 2 and 3 years, respectively (2 years: β = −0.05; 95% CI, −0.06 to −0.04; 3 years: β = −0.08; 95% CI, −0.09 to −0.06). An obverse association was observed from the Ages and Stages Questionnaires, third edition, score in the communication domain at age 1 and 2 years to subsequent screen time (2 years: γ = −0.03; 95% CI, −0.04 to −0.02; 3 years: γ = −0.06; 95% CI, −0.07 to −0.04).

Conclusions and Relevance

In this study, increased TV/DVD screen time from age 1 year negatively affected later development. To reduce the negative consequences of excessive media use, researchers and health care professionals should encourage family media management and recommend social support for parents who tend to rely on the media.

DOI： 10.1001/jamapediatrics.2023.3643

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jacig.2023.100137

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data.

DOI： 10.1038/s41598-023-44313-1

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その他リンク： https://www.nature.com/articles/s41598-023-44313-1

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Mother-to-infant bonding (MIB) is critical for the health and well-being of the mother and child. Furthermore, MIB has been shown to boost the social-emotional development of infants, while also giving mothers a sense of happiness in raising their children. Nausea and vomiting during pregnancy (NVP) is a normal complication of pregnancy, occurring in approximately 50–90% of pregnant women in the early stages of pregnancy. Despite widespread knowledge of MIB and postpartum depression, little research attention has been given to the effects of NVP on MIB. This study aimed to investigate the relationship between NVP and MIB and the mediating effects of postpartum depression.

Methods

We analyzed the data of 88,424 infants and 87,658 mothers from the Japan Environment and Children’s Study (JECS), which is a government-funded nationwide birth prospective cohort study. The Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) was used to assess MIB, and the Edinburgh Postpartum Depression Scale (EPDS) was utilized to assess postpartum depression. We divided participants into four groups according to a self-reported questionnaire assessing NVP (No NVP, Mild NVP, Moderate NVP, and Severe NVP). MIB disorder was defined as a MIBS-J score ≥ 5. Logistic analysis was performed to evaluate the effect of NVP on MIB disorder at one year after delivery. A mediation analysis was conducted to examine whether postpartum depression mediated the association between NVP and MIBS-J scores.

Results

The logistic regression analysis results revealed reduced risks of MIB disorder among mothers with Moderate NVP (adjusted OR 0.93; 95% confidence interval, 0.86–0.99) and Severe NVP (adjusted OR 0.81; 95% confidence interval, 0.74–0.89), compared to those with No NVP. The mediation analysis revealed that NVP positively correlated with MIBS-J score in the indirect effect via postpartum depression, while NVP (Mild NVP, Moderate NVP, and Severe NVP) negatively correlated with MIBS-J score in the direct effect.

Conclusion

The risks of MIB disorder were reduced in the Moderate NVP and Severe NVP mothers, although NVP inhibited the development of MIB via postpartum depression. The development of effective interventions for postpartum depression is important to improve MIB among mothers with NVP.

DOI： 10.1186/s12884-023-06014-5

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その他リンク： https://link.springer.com/article/10.1186/s12884-023-06014-5/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαβ+CD4-CD8- double-negative T cells (αβDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αβDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αβDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αβDNTs. The αβDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αβDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αβDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren's syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αβDNTs in the disease pathogenesis. Examining the characteristics of αβDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases.

DOI： 10.1007/s10875-023-01566-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Many prenatal factors are reported to be associated with congenital heart defects (CHD) in offspring. However, these associations have not been adequately examined using large-scale birth cohorts. Methods and Results We evaluated a data set of the Japan Environmental and Children's Study. The primary outcome was a diagnosis of CHD by age 2 years. We defined the following variables as exposures: maternal baseline characteristics, fertilization treatment, maternal history of diseases, socioeconomic status, maternal alcohol intake, smoking, tea consumption, maternal dietary intake, and maternal medications and supplements up to 12 weeks of gestation. We used multivariable logistic regression analysis to assess the associations between various exposures and CHD in offspring. A total of 91 664 singletons were included, among which 1264 (1.38%) had CHD. In multivariable analysis, vitamin A supplements (adjusted odds ratio [aOR], 5.78 [95% CI, 2.30-14.51]), maternal use of valproic acid (aOR, 4.86 [95% CI, 1.51-15.64]), maternal use of antihypertensive agents (aOR, 3.80 [95% CI, 1.74-8.29]), maternal age ≥40 years (aOR, 1.59 [95% CI, 1.14-2.20]), and high maternal hemoglobin concentration in the second trimester (aOR, 1.10 per g/dL [95% CI, 1.03-1.17]) were associated with CHD in offspring. Conclusions Using a Japanese large-scale birth cohort study, we found 6 maternal factors to be associated with CHD in offspring.

DOI： 10.1161/JAHA.122.029268

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

The primary objective of this study was to examine risk factors for toddler’s hypertension.

Methods

Subjects of this study were children and parents participating in a national birth cohort study in Japan, the Japan Environment and Children’s Study. We measured the children’s blood pressure (BP) at 2 and 4 years old. We obtained children’s and parents’ backgrounds from the questionnaire. We investigated the factors that affect BP elevation.

Results

Within 4988 participants, the mean systolic BP at 2 years old was 91.2 mmHg for boys and 90.0 mmHg for girls. The mean systolic BP at 4 years old was 93.8 mmHg for boys and 93.1 mmHg for girls. Parental smoking was associated with elevated values of BP at 2 and 4 years old. Obesity, gestational hypertension, and parental lower education were associated with elevated values of BP at 4 years old. Hypertensive group had a significantly higher obesity rate. The mother’s lower education and parental smoking were involved in hypertensive groups.

Conclusion

Parental smoking had a significant effect on BP even in early toddlers. We emphasize the importance of avoiding second-hand smoking from early infancy to prevent future lifestyle-related illnesses including hypertension.

Impact

The mean systolic BP at 2 years old was 91.2 mmHg for boys and 90.0 mmHg for girls.

The mean systolic BP at 4 years old was 93.8 mmHg for boys and 93.1 mmHg for girls.

Obesity, parental smoking, and lower education were associated with hypertension at 4 years old.

Parental smoking was associated with hypertension at 2 and 4 years old.

We emphasize the importance of avoiding second-hand smoking from early infancy.

DOI： 10.1038/s41390-023-02796-8

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その他リンク： https://www.nature.com/articles/s41390-023-02796-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND  : Cystinosis is a rare autosomal recessive lysosomal disorder that mainly affects the kidney and eye. Early treatment with cysteamine significantly improves the prognosis. However, early diagnosis of cystinosis, especially the juvenile nephropathic form, remains challenging because typical symptoms only become apparent in adulthood. We herein describe a 13-year-old girl who presented with proteinuria only but was diagnosed with juvenile nephropathic cystinosis based on multinucleated podocytes in her kidney biopsy specimen. We also studied the nephropathology of another case to determine the features of the multinucleated podocytes. CASE DIAGNOSIS: A previously healthy 13-year-old girl presented to our hospital because proteinuria had been detected in her school urine screening. She had been noted to have proteinuria on her school urine screening when she was 11 years of age but there was no consultation with her physician at that time. She was asymptomatic and had no other abnormalities on examination other than a relatively high urinary β-2 microglobulin level. Her kidney biopsy showed 15 multinucleated podocytes in 34 glomeruli, and the mean number of nuclei per multinucleated podocyte was 4.4. Ophthalmological examination showed cystine crystals in her cornea. Her white blood cell cystine level was high, and she was diagnosed with juvenile nephropathic cystinosis. She started oral cysteamine treatment and showed almost no progression of the disease after 2 years. In another patient with juvenile nephropathic cystinosis, there were 25 multinucleated podocytes in 63 glomeruli, and the mean number of nuclei per multinucleated podocyte was 2.9. CONCLUSION: Early diagnosis is crucial to improve the prognosis of patients with cystinosis. This report emphasizes the importance of recognizing the unique pathological feature of multinucleated podocytes as an essential clue to the diagnosis of cystinosis.

DOI： 10.1007/s00467-023-06103-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Despite the fact that rituximab (RTX)-associated adverse events may be relatively frequent in younger patients, recent studies have reported RTX as a suitable first-line steroid-sparing agent for maintaining remission in children with steroid-dependent nephrotic syndrome (SDNS). However, the impact of age at RTX initiation on the long-term outcome remains unknown in this cohort. METHODS: We retrospectively reviewed the clinical course of 61 patients with complicated SDNS who received a single dose of RTX (375 mg/m2) followed by maintenance immunosuppressive agents (IS) from January 2008 to March 2021. In patients who achieved > 12 months of prednisolone-free remission, IS tapering within 6 months was tried to achieve. The primary endpoint was the probability of achieving long-term treatment-free remission at the last follow-up. RESULTS: After RTX initiation, 52 patients (85.2%) relapsed after a median of 665 days, and 44 patients (72.1%) received additional RTX doses (total, 226 infusions). At the last follow-up (median observation period, 8.3 years; median age, 18.3 years), 16 patients (26.2%) achieved long-term remission. Multivariate analysis showed that older age at RTX initiation was the independent predictive factor for achieving long-term remission (odds ratio, 1.25; p < 0.05). The proportion of those who achieved long-term remission was significantly higher in patients aged ≥ 13.5 years than in those aged < 13.5 years at RTX initiation (52.6 vs 14.3%, p < 0.05). Persistent severe hypogammaglobulinemia did not develop in older children (≥ 13.5 years) at RTX initiation. CONCLUSION: For older children with complicated SDNS, RTX appeared to be a suitable disease-modifying therapy without persistent adverse events.

DOI： 10.1007/s10157-023-02374-6

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記述言語：英語  

DOI： 10.1016/j.braindev.2023.07.001

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1038/s41390-023-02723-x

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その他リンク： https://www.nature.com/articles/s41390-023-02723-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Reference blood pressure (BP) values for Japanese children based on a large number of measurements by auscultation have not yet been established. METHODS: This was a cross-sectional analysis of data from a birth-cohort study. The data from the sub-cohort study conducted for children at the age of 2 years in the Japan Environment and Children's Study from April 2015 to January 2017 were analyzed. BP was measured via auscultation using an aneroid sphygmomanometer. Each participant was measured in triplicate, and the average value of two consecutive measurements with a difference of less than 5 mmHg was recorded. The reference BP values were estimated using the lambda-mu-sigma (LMS) method and compared with those obtained via the polynomial regression model. RESULTS: Data from 3361 participants were analyzed. Although the difference between the estimated BP values by the LMS and the polynomial regression model was small, the LMS model was more valid based on the results of the fit curve of the observed values and regression models for each model. For 2-year-old children with heights in the 50th percentile, the 50th, 90th, 95th, and 99th percentile reference values of systolic BP (mmHg) for boys were 91, 102, 106, and 112, and that for girls were 90, 101, 103, and 109, respectively, and those of diastolic BP for boys were 52, 62, 65, and 71, and that for girls were 52, 62, 65, and 71, respectively. CONCLUSION: The reference BP values for 2-year-old Japanese children were determined based on auscultation and were made available.

DOI： 10.1007/s10157-023-02370-w

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

The long-term effects of a Cesarean section (CS) birth on child neurodevelopment are of increasing interest. In this study, we examined the associations between mode of delivery and presence of neurodevelopmental disorders in toddlers. Moreover, given that the prevalence of several neurodevelopmental disorders such as autism spectrum disorder (ASD) is known to differ by sex, we also investigated these associations separately in male and female toddlers.

Methods

We investigated 65,701 mother–toddler pairs from the Japan Environment and Children’s Study, a nationally representative children’s cohort study. To investigate the associations between mode of delivery (CS or vaginal delivery) and neurodevelopmental disorders (motor delay, intellectual disability, and ASD) in 3-year-old toddlers as a whole and stratified by sex, we used logistic regression models to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs).

Results

The morbidity of ASD at age 3 years was higher for children delivered by CS than those delivered vaginally (aOR 1.38, 95% CI 1.04–1.83). However, no such difference was evident in the case of motor delay or intellectual disability (aOR 1.33, 95% CI 0.94–1.89; aOR 1.18, 95% CI 0.94–1.49, respectively). In the analysis by sex, CS was not associated with increased risk of any of the neurodevelopmental disorders in males, but it was associated with increased risks of motor delay (aOR 1.88, 95% CI 1.02–3.47) and ASD (aOR 1.82, 95% CI 1.04–3.16) in females.

Conclusions

This study provides evidence of significant associations between mode of delivery and neurodevelopmental disorders in early childhood. Females may be more sensitive to the effects of CS than males.

DOI： 10.1186/s12887-023-04128-5

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その他リンク： https://link.springer.com/article/10.1186/s12887-023-04128-5/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Arthritis is one complication of Kawasaki disease (KD); however, the clinical features of arthritis in KD have not been well clarified. We retrospectively investigated the characteristics of persistent arthritis beyond the subacute phase of KD. In this cohort, 49 of 243 patients (20%) developed arthritis, with 33 patients (14%) experiencing persistent arthritis. Among these 33 patients, 31 (94%) had complete KD. Thirty (91%) were resistant to first intravenous immunoglobulin, and 15 (45%) required additional infliximab. Five patients (15%) developed coronary artery lesions, and 24 (73%) had oligoarthritis, mainly in large lower-extremity joints. Twenty-four patients (73%) complained of arthralgia. At arthritis onset, 16 patients (48%) presented with fever, including recurrent fever in 10 patients. Serum C-reactive protein concentration in patients with active arthritis significantly increased compared with after acute KD treatment (2.4 vs. 0.7 mg/dL, p < 0.001). Serum matrix metalloproteinase-3, a biomarker of arthritis, was significantly higher in patients with active arthritis than in remission (93.7 vs. 20.3 ng/mL, p < 0.001). Thirty (91%) and 14 (42%) patients, respectively, were treated with non-steroidal anti-inflammatory drugs and prednisolone, and they completely recovered. To summarize, persistent arthritis is a common complication in refractory KD, and adequate diagnosis and treatment are necessary.

DOI： 10.1038/s41598-023-36308-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes.

DOI： 10.1210/endocr/bqad095

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Dialysate leakage, a major complication in peritoneal dialysis (PD), causes difficulty in continuing PD. However, literature evaluating risk factors for leakage in detail and the appropriate break-in period to avoid leakage in pediatric patients is scarce. METHODS: We conducted a retrospective study on children aged < 20 years who underwent Tenckhoff catheter placement between April 1, 2002, and December 31, 2021, at our institution. We compared clinical factors between patients with and without leakage within 30 days of catheter insertion. RESULTS: Dialysate leakage occurred in 8 of 102 (7.8%) PD catheters placed in 78 patients. All leaks occurred in children with a break-in period of < 14 days. Leaks were significantly more frequent in patients with low body weight at the catheter insertion, single-cuffed catheter insertion, a break-in period ≤ 7 days, and a long PD treatment time per day. Only one patient who had leakage with a break-in period > 7 days was neonate. PD was suspended in four of the eight patients with leakage and continued in the others. Two of the latter had secondary peritonitis, one of whom required catheter removal, and leakage improved in the remaining patients. Three infants had serious complications from bridge hemodialysis. CONCLUSIONS: A break-in period of > 7 days and if possible 14 days is recommended to avoid leakage in pediatric patients. Whereas infants with low body weight are at high risk of leakage, their difficulty in inserting double-cuffed catheter, hemodialysis complications, and possible leakage even under long break-in period make prevention of leakage challenging.

DOI： 10.1007/s10157-023-02365-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Children with lupus have a higher chance of nephritis and worse kidney outcome than adult patients. METHODS: We retrospectively analyzed clinical presentation, treatment and 24-month kidney outcome in a cohort of 382 patients (≤ 18 years old) with lupus nephritis (LN) class ≥ III diagnosed and treated in the last 10 years in 23 international centers. RESULTS: The mean age at onset was 11 years 9 months and 72.8% were females. Fifty-seven percent and 34% achieved complete and partial remission at 24-month follow-up, respectively. Patients with LN class III achieved complete remission more often than those with classes IV or V (mixed and pure). Only 89 of 351 patients maintained stable complete kidney remission from the 6th to 24th months of follow-up. eGFR ≥ 90 ml/min/1.73 m2 at diagnosis and biopsy class III were predictive of stable kidney remission. The youngest and the oldest age quartiles (2y-9y, 5m) (14y, 2m-18y,2m) showed lower rates of stable remission (17% and 20.7%, respectively) compared to the two other age groups (29.9% and 33.7%), while there was no difference in gender. No difference in achieving stable remission was found between children who received mycophenolate or cyclophosphamide as induction treatment. CONCLUSION: Our data show that the rate of complete remission in patients with LN is still not high enough. Severe kidney involvement at diagnosis was the most important risk factor for not achieving stable remission while different induction treatments did not impact outcome. Randomized treatment trials involving children and adolescents with LN are needed to improve outcome for these children. A higher resolution version of the Graphical abstract is available as Supplementary information.

DOI： 10.1007/s00467-023-06018-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Rituximab is a promising option for refractory idiopathic nephrotic syndrome. However, no simple predictive markers for relapse after rituximab have been established. To determine such markers, we investigated the relationship between CD4 + and CD8 + cell counts and relapse after rituximab administration. METHODS: We retrospectively investigated patients with refractory nephrotic syndrome who received rituximab followed by immunosuppressive as maintenance therapy. Patients were divided into no relapse in 2 years after rituximab treatment or relapse group. After rituximab treatment, CD4 + /CD8 + cell counts were measured monthly, at prednisolone discontinuation, and at B-lymphocyte recovery. To predict relapse, these cell counts were analyzed using receiver operating characteristic (ROC). Additionally, relapse-free survival was reevaluated based on the result of ROC analysis for 2 years. RESULTS: Forty-eight patients (18 in the relapse group) were enrolled. At prednisolone discontinuation (52 days after rituximab treatment), the relapse-free group showed significantly lower cell counts than the relapse group (median CD4 + cell count: 686 vs. 942 cells/µL, p = 0.006; CD8 + : 613 vs. 812 cells/µL, p = 0.005). In the ROC analysis, CD4 + cell count > 938 cell/µL and CD8 + cell count > 660 cells/µL could predict relapse in 2 years (sensitivity, 56% and 83%; specificity, 87% and 70%). The patient group with both lower CD4 + and CD8 + cell counts showed significantly longer 50% relapse-free survival (1379 vs. 615 days, p < 0.001 and 1379 vs. 640 days, p < 0.001). CONCLUSIONS: Lower CD4 + and CD8 + cell counts in the early phase after rituximab administration may predict a lower risk of relapse.

DOI： 10.1007/s10157-023-02343-z

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Caesarean section (CS) birth is widely reported to be a risk factor for childhood obesity. Although susceptibility to childhood obesity is influenced by race and ethnicity, it is unclear whether this risk of childhood obesity with CS birth also applies in the Japanese population. We investigated the impact of CS birth on obesity at 3 years of age in Japanese children. We obtained data from 60,769 mother–toddler pairs in the Japan Environment and Children’s Study, a large-scale birth cohort study. Obesity was determined by body mass index measured at 3 years of age. Analysis revealed that 11,241 toddlers (18.5%) had a CS birth and that 4912 toddlers (8.1%) were obese. The adjusted risk ratio for obesity at 3 years of age when born by CS compared with vaginal delivery, estimated using inverse probability of treatment weighting, was 1.16 (95% confidence interval 1.08–1.25). These results suggest that CS birth modestly increases the risk of obesity at 3 years of age in Japanese children.

DOI： 10.1038/s41598-023-33653-7

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その他リンク： https://www.nature.com/articles/s41598-023-33653-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Neurological impairment is not rare in infants with acute liver failure (ALF). This study aimed to investigate the perioperative risk factors for neurological impairment following liver transplantation (LT) in infantile ALF. METHODS: Retrospective analysis was performed in infants who were younger than 1 year with ALF who subsequently underwent LT at our hospital between January 2005 and December 2016. Patients were considered to have neurological impairment if the Pediatric Cerebral Performance Category score was between 2 and 5 at the age of 6 years. A comparison between the groups of infants with and without neurological impairment was performed, and factors with p < .10 in the comparison were analyzed using univariate logistic regression analysis for neurological impairment. RESULTS: Twenty-six infants survived until 6 years of age, and 31% (8/26) of them had neurological impairment. Patients with neurological impairment were significantly younger in age at ALF onset, had significantly higher pre-LT bilirubin and prothrombin time/international normalized ratio, and stayed significantly longer in the intensive care unit than those without neurological impairment. Total bilirubin (odds ratio (OR) = 1.12, 95% confidence interval (CI) 1.02-1.22, p = .012), indirect bilirubin (OR = 1.10, 95% CI 1.01-1.20, p = .025), direct bilirubin (OR = 1.22, 95% CI 1.01-1.47, p = .040), and age in month at ALF (OR = 0.76, 95% CI 0.58-0.999, p = .049) showed significant association with neurological impairment. CONCLUSIONS: High pre-LT peak bilirubin value and younger age at ALF onset can be perioperative risk factors for neurological impairment after LT in infantile ALF.

DOI： 10.1111/petr.14524

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

The association between maternal pre-pregnancy smoking status and asthma risk is unclear. This study aimed to investigate the association between pre- and post-pregnancy maternal smoking status and bronchial asthma at 3 years of age in a large birth cohort. Data of 75,411 mother–child pairs from the Japan Environment and Children's Study (JECS) were analysed using multivariate logistic regression analysis. Overall, 7.2% of the children had bronchial asthma. The maternal smoking status before childbirth was as follows: Never = 60.0%, Quit before recognising current pregnancy = 24.1%, Quit after finding out about current pregnancy = 12.3%, and Still smoking = 3.6%. Children of mothers who sustained smoking during pregnancy had an increased risk of bronchial asthma at 3 years of age even after adjusting for pre- and postnatal covariates (adjusted odds ratio [aOR] 1.34, 95% confidence interval [CI] 1.15–1.56). Children of mothers who quit before (aOR 1.09, 95% CI 1.02–1.18) or after (aOR 1.11, 95% CI 1.01–1.23) recognising the current pregnancy had an increased risk of bronchial asthma at 3 years of age. Maternal smoking throughout pregnancy and smoking exposure pre-pregnancy or in early pregnancy increases the risk of bronchial asthma in children.

DOI： 10.1038/s41598-023-30304-9

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その他リンク： https://www.nature.com/articles/s41598-023-30304-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.15510

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Atopic dermatitis (AD) is reported to be more prevalent in children who were born in autumn than in spring. Here, we investigated how early the association between season of birth and eczema or AD can be observed in the postnatal period. We also examined whether specific prevalence outcomes for infant eczema and AD differed according to sex and maternal history of allergic disease in a large Japanese cohort.

Methods

Using data of 81,615 infants from the Japan Environment and Children’s Study, we examined the associations of birth month or season with four different outcomes—eczema at 1 month, 6 months, and 1 year of age and physician-diagnosed AD up to 1 year of age—using multiple logistic regression analysis. We also analyzed the effect of maternal history of allergic disease on these outcomes stratified by infant sex.

Results

The risk of eczema at 1 month was highest in infants born in July. In contrast, infants born in autumn had higher risks of eczema at 6 months (adjusted odds ratio [aOR], 2.19; 95% confidence interval [CI], 2.10–2.30) and at 1 year (aOR, 1.08; 95% CI, 1.02–1.14) and of physician-diagnosed AD up to 1 year of age (aOR, 1.33; 95% CI, 1.20–1.47) compared with infants born in spring. Eczema and AD were more prevalent in infants with a maternal history of allergic disease, particularly boys.

Conclusions

Our findings suggest that the prevalence of AD is associated with the season of observation. Eczema is prevalent in infants born in autumn, and this phenomenon was observed in infants as young as 6 months old. The risk associated with being born in autumn was particularly clear in boys with a maternal history of allergic disease.

Trial registration

UMIN000030786

DOI： 10.1186/s12887-023-03878-6

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その他リンク： https://link.springer.com/article/10.1186/s12887-023-03878-6/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis (inflammation of the blood vessels) that mainly affects children. Symptoms include fever, chapped lips, strawberry tongue, red eyes (bulbar conjunctival injection), rash, redness, swollen hands and feet or skin peeling; and enlarged cervical lymph nodes. High fevers and systemic inflammation characterise the acute phase. Inflammation of the coronary arteries causes the most serious complication of the disease, coronary artery abnormalities (CAAs). The primary treatment is intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA/aspirin), with doses and regimens differing between institutions. It is important to know which regimens are the safest and most effective in preventing complications. OBJECTIVES: To evaluate the efficacy and safety of IVIG in treating and preventing cardiac consequences of Kawasaki disease. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 26 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating the use of IVIG for the treatment of KD. We included studies involving treatment for initial or refractory KD, or both. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were incidence of CAAs and incidence of any adverse effects after treatment. Our secondary outcomes were acute coronary syndromes, duration of fever, need for additional treatment, length of hospital stay, and mortality. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We identified 31 RCTs involving a total of 4609 participants with KD. Studies compared IVIG with ASA, another dose or regimen of IVIG, prednisolone, or infliximab. The majority of studies reported on primary treatment, so those results are reported below. A limited number of studies investigated secondary or tertiary treatment in IVIG-resistant patients. Doses and regimens of IVIG infusion varied between studies, and all studies had some concerns related to risk of bias. Primary treatment with IVIG compared to ASA for people with KD Compared to ASA treatment, IVIG probably reduces the incidence of CAAs in people with KD up to 30 days (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41 to 0.87; 11 studies, 1437 participants; moderate-certainty evidence). The individual studies reported a range of adverse effects, but there was little to no difference in numbers of adverse effects between treatment groups (OR 0.57, 95% CI 0.17 to 1.89; 10 studies, 1376 participants; very low-certainty evidence). There was limited evidence for the incidence of acute coronary syndromes, so we are uncertain of any effects. Duration of fever days from treatment onset was probably shorter in the IVIG group (mean difference (MD) -4.00 days, 95% CI -5.06 to -2.93; 3 studies, 307 participants; moderate-certainty evidence). There was little or no difference between groups in need for additional treatment (OR 0.27, 95% CI 0.05 to 1.57; 3 studies, 272 participants; low-certainty evidence). No study reported length of hospital stay, and no deaths were reported in either group. Primary treatment with IVIG compared to different infusion regimens of IVIG for people with KD Higher-dose regimens of IVIG probably reduce the incidence of CAAs compared to medium- or lower-dose regimens of IVIG up to 30 days (OR 0.60, 95% CI 0.40 to 0.89; 8 studies, 1824 participants; moderate-certainty evidence). There was little to no difference in the number of adverse effects between groups (OR 1.11, 95% CI 0.52 to 2.37; 6 studies, 1659 participants; low-certainty evidence). No study reported on acute coronary syndromes. Higher-dose IVIG may reduce the duration of fever compared to medium- or lower-dose regimens (MD -0.71 days, 95% CI -1.36 to -0.06; 4 studies, 992 participants; low-certainty evidence). Higher-dose regimens may reduce the need for additional treatment (OR 0.29, 95% CI 0.10 to 0.88; 4 studies, 1125 participants; low-certainty evidence). We did not detect a clear difference in length of hospital stay between infusion regimens (MD -0.24, 95% CI -0.78 to 0.30; 3 studies, 752 participants; low-certainty evidence). One study reported mortality, and there was little to no difference detected between regimens (moderate-certainty evidence). Primary treatment with IVIG compared to prednisolone for people with KD The evidence comparing IVIG with prednisolone on incidence of CAA is very uncertain (OR 0.60, 95% CI 0.24 to 1.48; 2 studies, 140 participants; very low-certainty evidence), and there was little to no difference between groups in adverse effects (OR 4.18, 95% CI 0.19 to 89.48; 1 study; 90 participants; low-certainty evidence). We are very uncertain of the impact on duration of fever, as two studies reported this outcome differently and showed conflicting results. One study reported on acute coronary syndromes and mortality, finding little or no difference between groups (low-certainty evidence). No study reported the need for additional treatment or length of hospital stay. AUTHORS' CONCLUSIONS: The included RCTs investigated a variety of comparisons, and the small number of events observed during the study periods limited detection of effects. The certainty of the evidence ranged from moderate to very low due to concerns related to risk of bias, imprecision, and inconsistency. The available evidence indicated that high-dose IVIG regimens are probably associated with a reduced risk of CAA formation compared to ASA or medium- or low-dose IVIG regimens. There were no clinically significant differences in incidence of adverse effects, which suggests there is little concern about the safety of IVIG. Compared to ASA, high-dose IVIG probably reduced the duration of fever, but there was little or no difference detected in the need for additional treatment. Compared to medium- or low-dose IVIG, there may be reduced duration of fever and reduced need for additional treatment. We were unable to draw any conclusions regarding acute coronary syndromes, mortality, or length of hospital stay, or for the comparison IVIG versus prednisolone. Our findings are in keeping with current guideline recommendations and evidence from long-term epidemiology studies.

DOI： 10.1002/14651858.CD014884.pub2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/cea.14286

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There is a trend towards the adoption of cage-free housing systems in the egg industry across Asia. While cage-free housing systems can hold significant animal welfare advantages over cages, there can also be challenges in managing these systems. This exploratory study aimed to investigate the perspectives of egg producers on the main challenges and proposed solutions associated with cage-free systems in China, Indonesia, Thailand, Japan, Malaysia, and the Philippines. Cage-free producers found disease prevention and maintaining a healthy profit margin more difficult than producers from cage farms, while it was less difficult to provide environmental enrichment in cage-free systems compared to cage farms. The top challenges for cage-free producers were the cost of production, system management, disease, sales, and egg production, and the top proposed solution was to improve on-farm practices and efficiencies. Eighty-one percent of egg producers believed that more support is needed to maintain their farms than is currently available, and support was most needed in helping to improve sales, improve farm operations, lower farm costs, and provide information for producers in the form of education and training. Most responses identified the government as the stakeholder that should offer support. These results may help direct further studies in this field as well as supplying information to develop relevant initiatives with an emphasis on education and training, thereby improving animal welfare on cage-free farms and increasing the uptake of high welfare cage-free farms across the region.

DOI： 10.1017/awf.2023.85

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.15594

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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Japan Epilepsy Society  

DOI： 10.3805/eands.15.42

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Evidence regarding the long-term risk of infections in preterm infants is lacking. In this study, we examined whether preterm infants developed various common childhood infections more frequently than full-term infants by the age of 2 years by analyzing data from a questionnaire completed by 67,282 mother–toddler pairs in a nationwide birth cohort study. Of the target population, 2885 (4.3%) were born prematurely. After covariate adjustment for maternal and children factors, lower respiratory tract infections appeared more frequent in preterm than in full-term infants at both 1 and 2 years (adjusted odds ratio [aOR] 1.21, 95% confidence interval [CI] 1.05–1.41, and aOR 1.27, 95% CI 1.11–1.46, respectively). However, there was no significant difference in the frequencies of lower respiratory tract infection between preterm and full-term infants after Palivizumab administration. The risk of other common infections, such as in the upper respiratory tract infection, otitis media, urinary tract infection, gastroenteritis, herpangina, hand-foot-and-mouth disease, chickenpox, influenza virus, and adenovirus infections, was not higher in preterm than in full-term infants after covariates adjustment for maternal and children factors. These findings suggest Palivizumab prophylaxis could reduce the frequencies of lower respiratory tract infection in preterm to the same level as in full-term infants.

DOI： 10.1038/s41598-022-26748-0

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その他リンク： https://www.nature.com/articles/s41598-022-26748-0

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

The extremes of maternal pre-pregnancy body mass index (BMI) are known to be risk factors associated with obstetric and adverse perinatal outcomes. Among Japanese women aged 20 years or older, the prevalence of underweight (BMI &lt; 18.5 kg/m²) was 11.5% in 2019. Maternal thinness is a health problem caused by the desire to become slim. This study aimed to investigate the association between the severity of maternal low pre-pregnancy BMI and adverse perinatal outcomes, including preterm birth (PTB), low birth weight (LBW), and small-for-gestational age (SGA).

Methods

We conducted a prospective cohort study using data from the Japan Environment and Children’s Study, which recruited pregnant individuals between 2011 and 2014. Pre-pregnancy BMI was categorized as severe-moderate underweight (BMI &lt; 16.9 kg/m²), mild underweight (BMI, 17.0–18.4 kg/m²), low-normal weight (BMI, 18.5–19.9 kg/m²), high-normal weight (BMI, 20.0–22.9 kg/m²), overweight (BMI, 23.0–24.9 kg/m²), and obese (BMI ≥ 25.0 kg/m²). The high-normal weight group was used as the reference for statistical analyses. Adjusted logistic regression was performed to evaluate the association between pre-pregnancy BMI and PTB, LBW, and SGA.

Results

Of 92,260 singleton pregnant individuals, the prevalence was 2.7% for severe-moderate underweight, 12.9% for mild underweight, and 24.5% for low-normal weight. The prevalence of adverse outcomes was 4.6% for PTB, 8.1% for LBW, and 7.6% for SGA. The adjusted odds ratios (aORs) for PTB were 1.72 (95% confidence interval [CI], 1.46–2.03) for severe-moderate underweight and 1.26 (95% CI, 1.14–1.39) for mild underweight. The aORs of LBW were 2.55 (95% CI, 2.27–2.86) for severe-moderate underweight, 1.64 (95% CI, 1.53–1.76) for mild underweight, and 1.23 (95% CI, 1.16–1.31) for low-normal weight. The aORs of SGA were 2.53 (95% CI, 2.25–2.84) for severe-moderate underweight, 1.66 (95% CI, 1.55–1.79) for mild underweight, and 1.29 (95% CI, 1.21–1.38) for low-normal weight.

Conclusions

A dose-response relationship was found between the severity of low pre-pregnancy BMI and PTB, LBW, and SGA. Even low-normal BMI (18.5–19.9 kg/m²) increased the risk of LBW and SGA. This study provides useful information for pre-conception counseling in lean individuals.

DOI： 10.1186/s12884-022-04418-3

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その他リンク： https://link.springer.com/article/10.1186/s12884-022-04418-3/fulltext.html

掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-022-19509-6

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13223-022-00712-z

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記述言語：日本語   出版者・発行元：(一社)日本小児感染症学会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/j.ajkd.2022.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

DOI： 10.1016/j.gim.2022.08.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To identify prognostic factors for severe neurological sequelae and epileptic seizures in children with human herpes virus (HHV) 6/7-associated acute encephalopathy (AE). METHODS: We retrospectively studied pediatric cases of HHV6/7-associated AE between April 2011 and March 2021. Neurological sequelae were assessed using the Pediatric Cerebral Performance Category scale (PCPC) and the presence of epileptic seizures 1 year after onset. We investigated the prognostic factors between the non-severe sequelae group (PCPC scores ≤ 2) and severe sequelae group (PCPC scores ≥ 3) in patients without severe neurological complications before onset. RESULTS: Forty patients, ranging from 4 to 95 months old, were included. AE with biphasic seizures and late reduced diffusion were the most common types of encephalopathy (n = 28). Among the 36 patients evaluated neurological sequelae, 17, nine, eight, and two were categorized as PCPC 1, 2, 3 and 4, respectively. Epileptic seizures were observed in nine patients. In the severe sequelae group, significantly more cases with coma in the acute phase and thalamic lesions on MRI and higher serum aspartate aminotransferase, alanine aminotransferase (ALT), and lactate dehydrogenase levels were observed. Multivariate analysis showed a significant between-group difference in the rate of coma (p = 0.0405). Patients with epileptic seizures had a higher rate of coma and thalamic lesions and higher serum ALT and urinary beta 2-microglobulin levels, but there was no significant difference in the multivariate analysis. CONCLUSIONS: In HHV6/7-associated AE, coma was a significant prognostic factor for severe neurological sequelae.

DOI： 10.1016/j.braindev.2022.10.005

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記述言語：日本語   出版者・発行元：(一社)日本小児リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児リウマチ学会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.placenta.2022.08.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.15366

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/cga.12496

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Urinary cotinine concentration (UCC) reflects smoking status. However, in pregnant women, its association with adverse birth outcomes related to fetal growth is not widely known. Thus, we aimed to explore this relationship by focusing on dose-response relationships. We investigated 86,638 pregnant women enrolled between 2011 and 2014 in a prospective cohort study in Japan and observed three birth outcomes (preterm birth, low birth weight, and small-for-gestational age). We measured UCC in the second or third trimester, and categorized the participants using cut-off values (negative cotinine concentration, passive cotinine concentration, and active cotinine concentration corresponding to non-smokers, passive smokers, and active smokers, respectively). Logistic regression analyses were conducted to evaluate the risks, and dose-response relationships were visualized using restricted cubic spline curves. Analyses based on self-reported smoking status were also performed. We found that in low active and highly active cotinine concentrations, the adjusted odds ratios (aORs) of birth outcomes were significantly increased (preterm birth, 1.24 [95% CI 1.06-1.46], 1.39 [95% CI 1.19-1.62]; low birth weight, 1.40 [95% CI 1.24-1.58], 2.27 [95% CI 2.05-2.53]; small-for-gestational age, 1.35 [95% CI 1.19-1.52], 2.39 [95% CI 2.16-2.65]). Restricted cubic spline curves demonstrated risk elevations in the active cotinine concentration range. Our research revealed dose-response relationships between UCC during pregnancy and the risks of preterm birth, low birth weight, and small-for-gestational age. Measurement of UCC to ascertain smoking status during pregnancy may be a useful approach for predicting the risks of these birth outcomes.

DOI： 10.1016/j.envres.2022.114302

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Using cohort data from the Japan Environment and Children’s Study (JECS), we previously reported that the risk of sleep deprivation in 1-year-old children was reduced with a higher maternal intake of fermented foods, particularly miso. The present study, which evaluates children from the same cohort at 3 years of age, is a continuation of that work.

Methods

After applying exclusion criteria to 104,062 records in the JECS dataset, we evaluated 64,200 mother-child pairs in which the child was 3 years old. We examined the association of the dietary intake of fermented foods during pregnancy with child sleep duration &lt; 10 h at the age of 3 years.

Results

Multivariable logistic regression analysis with the lowest quartile used as a reference revealed adjusted odds ratios (95% confidence intervals) for the second through fourth quartiles of 0.98 (0.90–1.06), 0.93 (0.85–1.01), and 0.85 (0.78–0.94) for cheese intake.

Conclusions

The consumption of fermented foods during pregnancy is associated with reduced risk of sleep deprivation in 3-year-old children, albeit in a limited way.

DOI： 10.1186/s12889-022-13805-6

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その他リンク： https://link.springer.com/article/10.1186/s12889-022-13805-6/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Rapidly progressive (RP) interstitial lung disease (ILD) is a life-threatening complication of juvenile dermatomyositis (JDM); however, it is generally refractory to treatment; to the best of our knowledge, no evidence-based treatment has been established for RP-ILD yet. We present the case of a 2-year-old girl with RP-ILD who showed resistance to treatment with methylprednisolone, cyclosporine A, cyclophosphamide, immunoglobulin, and plasma exchange (PE) and was finally treated with extracorporeal membrane oxygenation. We further present a literature review of 18 cases of JDM with RP-ILD. CASE PRESENTATION: A 2-year-old girl presented with malar rash, mild muscle weakness, and weight loss for a few months before admission. She had a history of dry cough and dyspnea for a few days, followed by rapid respiratory failure. The patient was diagnosed with JDM with RP-ILD through physical examination (malar rashes and Gottron's sign) and based on the finding of myositis on femoral magnetic resonance imaging, elevated levels of serum muscle enzymes, positive anti-melanoma differentiation-association gene 5 (MDA5) antibody (> 7,500 index), elevated level of Krebs von den Lungen-6 glycoprotein (KL-6; 3,420 U/mL), and extensive ground-glass opacities with consolidation in the bilateral lungs on chest high-resolution computed tomography. She received combination therapy, including methylprednisolone pulse therapy, followed by oral prednisolone and intravenous cyclosporine A, cyclophosphamide, and immunoglobulin. On day 11 of hospitalization, she was placed on ventilation support and PE was initiated. However, her respiratory condition continued to deteriorate and veno-venous extracorporeal membrane oxygenation was started on day 24 of hospitalization. Rituximab was administered on day 28. After 2 weeks of rituximab therapy initiation, her respiratory condition showed gradual improvements. Eventually, on day 52 of hospitalization, the patient could be weaned off extracorporeal membrane oxygenation. Finally, she was discharged with minimal ventilation support and no neurological complications 11 months after admission. CONCLUSIONS: Our literature review suggest that JDM with RP-ILD has a high mortality rate. In JDM, rituximab may be a promising treatment option for RP-ILD. In the future, the efficacy of rituximab in the early phases of ILD should be investigated.

DOI： 10.1186/s12969-022-00723-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The aim of this study was to investigate the association between maternal prepregnancy physical activity (PA) and overweight/obesity in 3-year-old children. METHODS: Using data from the Japan Environment and Children's Study (a birth cohort study), maternal prepregnancy PA was categorized into low, moderate, and high with the International Physical Activity Questionnaire (IPAQ). The reference group was defined as children born to mothers with moderate PA. The association between prepregnancy PA and overweight/obesity or obesity in children was investigated using univariable and multivariable logistic regression analyses. RESULTS: Of the 65,245 participants, 48.7%, 32.7%, and 18.6% were born to mothers in the low, moderate, and high PA groups, respectively. Furthermore, 24.9%, 24.6%, and 25.9% of children with overweight/obesity and 9.4%, 9.2%, and 10.4% of children with obesity were born to mothers in the low, moderate, and high PA groups, respectively. The adjusted odds ratios for overweight/obesity in the low and high PA groups were 1.02 (95% CI: 0.98-1.06) and 1.04 (95% CI: 0.98-1.09), and those for obesity were 1.03 (95% CI: 0.97-1.09) and 1.08 (95% CI: 0.99-1.16), respectively. CONCLUSIONS: Maternal prepregnancy PA was not associated with overweight/obesity or obesity in 3-year-old children.

DOI： 10.1002/oby.23516

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: As there are no large-scale reports of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with nephrotic syndrome using immunosuppressive agents, we conducted the prospective study. METHODS: SARS-CoV-2 mRNA vaccines were administered to patients with nephrotic syndrome receiving immunosuppressive agents. The titers of SARS-CoV-2 spike protein receptor-binding domain antibodies were measured before and after vaccination. We evaluated factors associated with antibody titers after vaccination and analyzed adverse events. RESULTS: We enrolled 40 patients and evaluated vaccine immunogenicity in 35 of them. Seroconversion (> 0.8 U/mL) was achieved in all patients, and the median antibody titer was 598 U/mL (interquartile range, 89-1380 U/mL). Patients using mycophenolate mofetil (MMF) showed lower antibody titers than those who were not (median: 272 U/mL vs. 2660 U/mL, p = 0.0002), and serum immunoglobulin G (IgG) levels showed a weak linear relationship with antibody titers (R2 = 0.16). No breakthrough infections were noted. Three patients (7.5%) suffered from a relapse of nephrotic syndrome (2 and 3 days, respectively, after the first dose and 8 days after the second dose), two of whom had a history of relapse within 6 months before the vaccination. CONCLUSIONS: The SARS-CoV-2 mRNA vaccine was immunogenic in patients with nephrotic syndrome using immunosuppressive agents, although the use of MMF and low levels of serum IgG were associated with lower antibody titers after vaccination. Patients with high disease activity may experience a relapse of nephrotic syndrome after vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

DOI： 10.1007/s00467-022-05633-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pompe disease (PD) is a lysosomal glycogen storage disorder caused by a deficiency in acid α-glucosidase (GAA) activity. Various organs, including the skeletal muscle, cardiac muscle, and liver, are commonly involved. Early initiation of enzyme replacement therapy (ERT) with recombinant human α-glucosidase (rhGAA) can improve the outcome. However, some patients experience a poor clinical course despite ERT because of the emergence of anti-rhGAA antibodies that neutralize rhGAA. Treatment against anti-rhGAA antibodies is challenging. CASE-DIAGNOSIS/TREATMENT: A 14-year-old boy with late-onset PD was referred to our hospital with proteinuria detected by school urinalysis screening. He was diagnosed with PD at the age of 4 years based on muscle biopsy and decreased GAA activity. Treatment with rhGAA was initiated, but anaphylaxis occurred frequently. Anti-rhGAA antibodies were detected and immune tolerance therapy was therefore given, but his antibody titer remained high. Kidney biopsy revealed stage II membranous nephropathy. Immunohistochemistry staining revealed anti-rhGAA antibody/rhGAA immune complexes along the glomerular capillary loop. Aggressive immunotherapy combined with bortezomib and rituximab was then initiated. Serum levels of anti-rhGAA antibodies decreased significantly and his proteinuria finally resolved. CONCLUSIONS: There have been few reports of membranous nephropathy associated with ERT for PD. We clarified the cause in the current patient. Bortezomib and rituximab effectively suppressed anti-rhGAA antibody production resulting in the resolution of proteinuria and maintenance of ERT efficacy.

DOI： 10.1007/s00467-022-05672-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Nephrology ({ASN})  

<jats:p>Background: Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histological variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. Methods: This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathological findings were obtained from referring clinicians. We analyzed the associations of histological variants with clinical characteristics, kidney survival, and gene variant detection rates. Results: The distribution of histological variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end-stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), andACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; p&lt;0.001). Conclusions: We revealed the distributions of histological variants of genetic FSGS and non-genetic FSGS in a large patient population. Detailed data concerning gene variants and pathological findings are important for understanding the etiology of FSGS.</jats:p>

DOI： 10.34067/kid.0000812022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Short stature is a common clinical condition in pediatric outpatient clinics and is associated with various clinical conditions, ranging from normal variants to severe diseases. Short stature is known to be caused by chronic inflammatory conditions, in which over-produced inflammatory cytokines are reported to be involved in growth suppression. Castleman disease is a rare lymphoproliferative disorder known as a chronic inflammatory disease with overproduction of interleukin 6 (IL-6), which often causes systemic symptoms such as fever, fatigue, weight loss, and night sweats. Here, we report the case of a ten-year-old female diagnosed with unicentric Castleman disease, who presented with short stature as the sole clinical sign but lacked typical systemic symptoms of Castleman disease. An elevated serum C-reactive protein level led us to suspect a chronic inflammatory condition, and we found an intra-abdominal tumor that was histopathologically confirmed as Castleman disease. The tumor removal resulted in a steady catch-up in her height in the six years following the surgery. We also present a brief review of relevant literature on pediatric cases of Castleman disease associated with growth impairment. Clinicians should be aware that chronic inflammatory conditions can cause growth impairment, which may be a key clinical manifestation of such conditions.

DOI： 10.1093/mrcr/rxac034

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jacig.2022.02.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Eculizumab was approved for atypical haemolytic-uremic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in the real-world setting. METHODS: Paediatric patients in the PMS cohort who were < 18 years old at first administration of eculizumab and diagnosed with aHUS (excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopenic purpura, and secondary thrombotic microangiopathy [TMA]) were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness (complete TMA response, TMA event-free status, platelet count [PLT] and lactate dehydrogenase [LDH] normalization, serum creatinine [sCr] decrease, and estimated glomerular filtration rate [eGFR] improvement) were analysed in patients treated with ≥ 1 dose of eculizumab. Serious adverse events (SAEs) were also evaluated. RESULTS: Forty paediatric patients (median age 5 years) were included. Median eculizumab treatment duration was 66 weeks. PLT, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement, and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3%, and 77.5%, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation; and 5 patients, including one patient with aHUS relapse, continued the treatment but extended treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. CONCLUSION: Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

DOI： 10.1093/ndt/gfac150

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Medical Association (AMA)  

DOI： 10.1001/jamapediatrics.2021.5778

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.envres.2021.112470

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記述言語：日本語   出版者・発行元：(一社)日本小児腎臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児腎臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypertrophic pachymeningitis (HP) is a rare inflammatory disorder characterized by local or diffuse thickening of the cranial and spinal dura mater. HP occurs owing to idiopathic or secondary causes, including autoimmune disease, infection, and trauma. HP has mainly been reported in adults, with few reported cases in children. We encountered an 11-year-old boy with idiopathic HP who presented with chronic inflammation and daily occipital headache. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) helped us to diagnose him with HP. He was successfully treated with corticosteroids and azathioprine with no recurrence. We also conducted a literature review of childhood-onset HP and found only 16 cases including our patient. Seven patients had idiopathic HP and the remaining nine had secondary HP, including two with rheumatic disease. The most common clinical symptoms were headache (68.8%) and cranial nerve-related symptoms (68.8%). Inflammatory laboratory markers were elevated in 60% of patients with available data. Fifteen cases were diagnosed using Gd-enhanced MRI. The main initial treatment was steroids and/or immunosuppressants, to which 87.5% of patients responded. However, two patients with HP associated with trauma and neuroblastoma (12.5%) died, and seven patients (43.8%) had left cranial nerve-related sequelae. As the prognosis for childhood HP is poor, early diagnosis and treatment are essential. Children with headache, cranial nerve symptoms, and elevated inflammatory marker levels should be suspected of having HP and Gd-enhanced MRI should be considered.

DOI： 10.1093/mrcr/rxac026

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

This study aimed to evaluate the association of neonatal transfer with the risk of neurodevelopmental outcomes at 3 years of age. Data were obtained from the Japan Environment and Children’s Study. A general population of 103,060 pregnancies with 104,062 fetuses was enrolled in the study in 15 Regional Centers between January 2011 and March 2014. Live-born singletons at various gestational ages, including term infants, without congenital anomalies who were followed up until 3 years were included. Neurodevelopmental impairment was assessed using the Ages and Stages Questionnaire, third edition (ASQ-3) at 3 years of age. Logistic regression was used to estimate the adjusted risk and 95% confidence interval (CI) for newborns with neonatal transfer. Socioeconomic and perinatal factors were included as potential confounders in the analysis. Among 83,855 live-born singletons without congenital anomalies, 65,710 children were studied. Among them, 2780 (4.2%) were transferred in the neonatal period. After adjustment for potential confounders, the incidence of neurodevelopmental impairment (scores below the cut-off value of all 5 domains in the ASQ-3) was higher in children with neonatal transfer compared with those without neonatal transfer (communication: 6.5% vs 3.5%, OR 1.42, 95% CI 1.19–1.70; gross motor: 7.6% vs 4.0%, OR 1.26, 95% CI 1.07–1.49; fine motor: 11.3% vs 7.1%, OR 1.19, 95% CI 1.03–1.36; problem solving: 10.8% vs 6.8%, OR 1.29, 95% CI 1.12–1.48; and personal-social: 6.2% vs 2.9%, OR 1.52, 95% CI 1.26–1.83).

   Conclusion: Neonatal transfer was associated with a higher risk of neurodevelopmental impairment at 3 years of age.<table><tbody><tr><td colspan="2">What is Known:• Neonatal transfer after birth in preterm infants is associated with adverse short-term outcomes.• Long-term outcomes of outborn infants with neonatal transfer in the general population remain unclear.</td> </tr><tr><td colspan="2">What is New:• This study suggests that neonatal transfer at birth is associated with an increased risk of neurodevelopmental impairment.• Efforts for referring high-risk pregnant women to higher level centers may reduce the incidence of neonatal transfer, leading to improved neurological outcomes in the general population.</td> </tr></tbody></table>

DOI： 10.1007/s00431-022-04450-7

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その他リンク： https://link.springer.com/article/10.1007/s00431-022-04450-7/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, rash, hepatosplenomegaly, and macrophage activation syndrome; however, its pathogenesis is still unclear. Elevated serum interleukin (IL)-18 concentrations and decreased natural killer (NK) cell activity are characteristic of active disease; thus, we examined IL-18 signaling in NK cells from sJIA. METHODS: We analyzed mitogen-activated protein kinase (MAPK) p38 and nuclear factor κ light chain enhancer of activated B cells (NFκB) p65 phosphorylation in NK cells after in vitro recombinant IL-18 (rIL-18) stimulation in 31 patients with sJIA. Associations between clinical features, serum IL-18, and phosphorylation intensity were analyzed. Furthermore, we investigated the effects of high IL-18 concentrations on phosphorylation in NK cells. RESULTS: Patients were divided according to their disease activity: systemic features (n = 8), chronic arthritis (n = 7), remission on medication (n = 10), and remission off medication (n = 6). MAPK p38 and NFκB p65 phosphorylation intensity were the highest in healthy controls, followed by remission off medication, remission on medication (vs. control; MAPK p38, P < 0.01; NFκB p65, P < 0.05), chronic arthritis (P < 0.001, P < 0.001), and systemic features (P < 0.001, P < 0.001). The systemic features group showed a complete defect in phosphorylation. Serum IL-18 was the highest in the systemic features group followed by chronic arthritis, remission on medication (P < 0.01), remission off medication (P < 0.01), and healthy controls (P < 0.01). Phosphorylation intensity was negatively correlated with serum IL-18 (MAPK p38, r2  = 0.42; NFκB p65, r2  = 0.54). Furthermore, healthy control NK cells were cultured with rIL-18; impaired phosphorylation was reproduced in vitro. CONCLUSION: Impaired IL-18 signaling in NK cells correlated with disease activity in sJIA. High serum IL-18 exposure induces impaired MAPK and NFκB phosphorylation in NK cells.

DOI： 10.1002/acr2.11426

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Risks and renal outcomes of severe acute kidney injury (AKI) in children with steroid-resistant nephrotic syndrome (SRNS), particularly those who require dialysis, have not been fully explored. METHODS: This retrospective cohort study enrolled children who had been diagnosed with idiopathic nephrotic syndrome at the National Center for Child Health and Development between March 2002 and December 2018. Children with steroid-sensitive nephrotic syndrome or SRNS-related gene mutations were excluded. RESULTS: Sixty-two children with SRNS (37 boys; median age, 3.6 years [interquartile range (IQR) 2.0-10.3]) were enrolled. Sixteen patients (25.8%) had severe AKI, including nine patients (14.5%) who received dialysis. The period from nephrotic syndrome (NS) onset to partial remission (median [IQR]) was not significantly influenced by dialysis status, but tended to be longer in the dialysis group (125 days [74-225] vs. 40 days [28-113]; p = 0.09); notably, no patient developed chronic kidney disease during the follow-up period. Infection and posterior reversible encephalopathy (PRES) were significantly associated with AKI. Patients with AKI tended to require dialysis in the presence of infection, undergo treatment with cyclosporine A, and have PRES. The period from onset of NS to AKI was significantly longer in the dialysis group (26 days [15.5-46.0] vs. 4 days [0.0-14.0]; p = 0.01). CONCLUSION: Dialysis was commonly required among children with SRNS who exhibited severe AKI. The period from onset of NS to partial remission tended to be longer in patients receiving dialysis, whereas renal prognosis was satisfactory during subsequent follow-up.

DOI： 10.1007/s10157-022-02198-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although overall survival of ALF has improved, neurological restoration after recovery from ALF may not always be satisfactory. The purpose of this study was to investigate the occurrence and possible causes of NI in children with ALF following LT. METHODS: We retrospectively examined all children younger than 16 years old with ALF who subsequently underwent LT at our center between January 2005 and December 2016. NI was assessed in December 2016 using the six-point Pediatric Cerebral Performance Category score and was defined as any increase in the score. RESULTS: There were 62 children with median age 10 months (quartile range 5-34). The etiology of ALF was indeterminate in 47 children (75.8%). The median duration from admission to LT was 5.5 days (quartile range 4-7), and 96.8% (60/62) received living donor LT. The overall survival was 83.9% (52/62) in a median follow-up period of 4.2 years. Mild-to-moderate NI was observed in 23.1% (12/52) of the survivors. Possible causes of NI were underlying systemic disease (n = 3), perioperative brain lesion (n = 2), and unclassified (n = 7). All seven patients with unclassified NI were less than 12 months old. The unclassified NI causes were presumed to be ALF, its perioperative care, and the vulnerable infant brain. CONCLUSIONS: NI in children with ALF following LT was not rare and should be prevented. Further investigations are required to clarify the characteristics of the patients with unclassified NI.

DOI： 10.1111/petr.14240

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits varying degrees of protective immunity conferred by neutralizing antibodies (nAbs). In this study, we report the persistence of nAb responses over 12 months after infection despite their decreasing trend noticed from 6 months. Methods: The study included sera from 497 individuals who had been infected with SARS-CoV-2 between January and August 2020. Samples were collected at 6 and 12 months after onset. The titers of immunoglobulin (Ig)G to the viral nucleocapsid protein (NP) and receptor-binding domain (RBD) of the spike protein were measured by chemiluminescence enzyme immunoassay. The nAb titer was determined using lentivirus-based pseudovirus or authentic virus. Results: Antibody titers of NP-IgG, RBD-IgG, and nAbs were higher in severe and moderate cases than in mild cases at 12 months after onset. Although the nAb levels were likely to confer adequate protection against wild-type viral infection, the neutralization activity to recently circulating variants in some of the mild cases (~30%) was undermined, implying the susceptibility to reinfection with the variants of concerns (VOCs). Conclusions: Coronavirus disease 2019 convalescent individuals have robust humoral immunity even at 12 months after infection albeit that the medical history and background of patients could affect the function and dynamics of antibody response to the VOCs.

DOI： 10.1093/ofid/ofab626

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Glucocorticoid discontinuation, a challenge in systemic lupus erythematosus (SLE), might be achievable with the advent of new therapeutic options. METHODS: This single-center study included 31 children with newly diagnosed pediatric SLE between 2002 and 2021, after the exclusion of patients who were followed for less than 1 year after treatment initiation and those lost to follow-up. Patient characteristics, clinical course including flares, treatment, glucocorticoid discontinuation, and outcomes were retrospectively analyzed. RESULTS: Glucocorticoids could be discontinued in 19 (61%) patients during a median observation period of 105.5 (range, 17-221) months. Of these, 5 (26%), 12 (63%), and 18 (95%) patients could discontinue glucocorticoids in 3, 5, and 10 years from treatment initiation, respectively. Additionally, 18 of the 19 patients did not experience flares after glucocorticoid discontinuation during a median duration of 37.2 (7.2-106.8) months. Three of the nineteen patients achieved drug-free remission. At last follow-up, all patients achieved low disease activity with or without glucocorticoids and 19, 8, and 1 patient were receiving mycophenolate mofetil (MMF), MMF plus tacrolimus, and MMF plus ciclosporin A, respectively. Flares were observed in 15 patients during the observation period. MMF as initial immunosuppressant (P = 0.01) and shorter interval between therapy initiation and achieving maintenance prednisolone dose of 0.1-0.15 mg/kg/day (P = 0.001) were associated with significantly reduced flare risk. Femoral head necrosis was observed in two patients. CONCLUSION: Despite the small sample size, these results support glucocorticoid discontinuation as a therapeutic target in pediatric SLE.

DOI： 10.1007/s00467-021-05350-y

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Otitis media (OM) is common among young children and is related to hearing loss. We investigated the association between maternal insecticide use, from conception to the first and second/third trimesters, and OM events in children in the first year of age. Data from Japan Environment and Children's Study were used in this prospective cohort study. Characteristics of patients with and without history of OM during the first year of age were compared. The association between history of OM in the first year and insecticide use was evaluated using logistic regression analysis. The study enrolled 98,255 infants. There was no significant difference in the frequency of insecticide use between groups. Insecticide use of more than once a week from conception to the first trimester significantly increased the occurrence of OM in children in the first year (odds ratio [OR] = 1.30, 95% confidence interval [CI] 1.01–1.67). The association between OM in the first year and insecticide use from conception to the first trimester was only significant in the group without daycare attendance (OR 1.76, 95% CI 1.30–2.38). Maternal insecticide use more than once a week from conception to the first trimester significantly increased OM risk in offspring without daycare attendance.

DOI： 10.1038/s41598-022-05433-2

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その他リンク： https://www.nature.com/articles/s41598-022-05433-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41390-021-01925-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although childhood undervaccination among single mother families is a concern for child healthcare, their association is still under debate. This study aimed to investigate the association between maternal marital status and the risk of childhood undervaccination and determine the mediating effect of household income. METHODS: We utilised prospective birth cohort from the Japan Environment and Children's Study (JECS). Of 104,062 foetal records (children) from 97,413 mothers, 82,462 that included mothers recruited between 2011 and 2014, were analysed. Childhood undervaccination was defined as not having been vaccinated with at least one routine vaccine. A log-binomial regression analysis was used to estimate the risk ratio (RR) for the association between maternal marital status and the risk of childhood undervaccination. A causal mediation analysis was further performed to investigate the proportion of the association mediated by household income. RESULTS: Among 82,462 children, 3188 and 79,274 had unmarried and married mothers, respectively. Childhood undervaccination was observed in 1053 (33.0%) and 16,901 (21.3%) children of unmarried and married mothers, respectively. Maternal marital status was associated with a higher risk of childhood undervaccination (adjusted risk ratio [aRR], 1.34; 95% confidence interval [CI], 1.27 to 1.41). Compared with married and older mothers, both unmarried and older (aRR, 1.54; 95% CI, 1.35 to 1.77) and unmarried and younger (aRR, 1.66; 95% CI, 1.54 to 1.79) mothers were associated with a higher risk of childhood undervaccination. The causal mediation analysis showed that the proportion mediated by household income was 10.5% (95% CI, 9.9 to 11.0%). CONCLUSIONS: This nationwide, prospective, large-scale birth cohort study found that a household with a single mother was associated with an increased risk of childhood undervaccination, and 10% of this association was explained by household income. These findings underscore the importance of improving the social environment among single mother families, including not only poverty but also working conditions.

DOI： 10.1186/s12889-022-12511-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A decline in the proportion of male births (secondary sex ratio, SSR) has been seen in several countries including Japan in recent years. Although previous studies have reported that the SSR is affected by exposure to chemical substances such as dioxins and polychlorinated biphenyls, as well as heavy metals such as methylmercury, the effects of lead exposure on the SSR have been little studied. The aim of this study was to determine the association between maternal lead exposure and SSR. In a large-scale nationwide birth cohort study, maternal blood lead level (BLL) was determined using whole blood from the second or third trimester of pregnancy. The association between SSR and maternal BLL was estimated using multivariable logistic models. Binomial distribution was applied to examine the differences in SSR by dividing the participants into five groups based on BLL. The primary outcome was SSR, and the child sex was obtained from the medical record transcripts. Of 104,062 fetal records, 85,171 were examined for analysis. The median maternal BLL was 5.85 ng/g (5th-95th percentile 3.45-10.6 ng/g). The overall proportion of males among participating infants was 0.512. In logistic regression models adjusted for covariates, the analysis revealed an increased odds ratio for SSR with higher blood lead concentrations [Group 2: adjusted OR 1.082, 95% confidence interval 1.037 to 1.129, Group 3: 1.122, 1.074 to 1.171, Group 4: 1.214, 1.163 to 1.268, Group 5: 1.279, 1.224 to 1.336]. Compared to the general birth probability in Japan, the group with low BLL had a lower SSR and the group with high BLL had a higher SSR. Higher maternal lead exposures during pregnancy were associated with increased SSR. Further investigations including assessment of paternal lead exposure are necessary to understand the association between lead exposure and SSR.

DOI： 10.1016/j.scitotenv.2021.152726

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ipd.12791

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We conducted a prospective study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccination in children and adolescents who were taking immunosuppressive agents. METHODS: Two doses of SARS-CoV-2 mRNA vaccine were administered to patients taking immunosuppressive agents. Titers of SARS-CoV-2 spike protein receptor-binding domain antibodies were measured before and after vaccination. Vaccine failure was defined as a postvaccination antibody titer of <0.8 U/mL. Seroconversion rates, factors associated with antibody titers after vaccination, clinical effectiveness against breakthrough infection, and adverse events were evaluated. RESULTS: A total of 42 patients (median age, 18.1 years) were enrolled. Immunogenicity was measured in 34 patients. The median SARS-CoV-2 spike antibody titer was 329 U/mL (interquartile range [IQR] 50-812 U/mL). Seroconversion (≥0.8 U/mL) was achieved in 29 patients (85%), whereas vaccine failure was diagnosed in five (15%). All patients with vaccine failure were recipients of solid organ transplants (SOTs) and were taking two immunosuppressants. The median antibody titer in SOT recipients (57 U/mL) was significantly lower than that in non-recipients (653 U/mL, P = 0.0002); that of patients taking two immunosuppressive agents (93 U/mL) was lower than that of patients taking one (506 U/mL, P = 0.003). Breakthrough infection occurred in three patients (7%). Adverse events were non-specific, and no flares of primary disease or acute rejection in SOT recipients occurred. CONCLUSIONS: SARS-CoV-2 mRNA vaccine was immunogenic in children and adolescents taking immunosuppressive agents, although SOT recipients and patients taking two immunosuppressive agents tended to show lower postvaccination antibody titers.

DOI： 10.1111/ped.15331

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.15022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Little is known about the epidemiology of Henoch-Schönlein purpura nephritis (HSPN). METHODS: We conducted a nationwide epidemiological survey of Japanese children aged 1 to 15 years with HSPN. Children who were newly diagnosed with HSPN by biopsy between January 2013 and December 2015 were eligible for the survey to clarify the incidence of HSPN. We also conducted an institutional survey on kidney biopsy criteria and treatment protocols. RESULTS: A total of 353 of 412 institutions (85.7%) responded to the questionnaire. Of the 353 institutions, 174 reported to perform kidney biopsies at their institutions, and 563 children were diagnosed with HSPN. Considering the collection rate, the estimated incidence of biopsy-proven HSPN was 1.32 cases/100,000 children per year. The median age at biopsy was 7.0 years, and the male-to-female ratio was 1.2:1. The kidney biopsy criteria and treatment protocols for HSPN were as follows. Patients with acute kidney injury underwent biopsy at least one month after onset. For patients without kidney dysfunction, the timing for biopsy was determined by the amount of proteinuria. Regarding the treatment of HSPN, there were certain commonalities among the treatment protocols, they eventually differed depending on the institutions involved. CONCLUSIONS: The incidence of biopsy-proven HSPN was 1.32 cases/100,000 children per year in Japan. The male-to-female ratio and date of diagnosis of HSPN were similar to those in previous studies. The kidney biopsy criteria and treatment protocols for HSPN varied among institutions. Further studies are warranted to establish an optimal treatment policy based on the prognosis.

DOI： 10.1371/journal.pone.0270796

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The aim of this study was to examine the relationship between breastfeeding and postpartum maternal weight change. METHOD: This study used data from the Japan Environment and Children's Study (JECS), an ongoing nationwide birth cohort study. Participants were categorized into two groups: full breastfeeding (FB) and non-full breastfeeding (NFB) groups. Postpartum weight changes between the FB (n = 26,340) and NFB (n = 38,129) groups were compared. RESULTS: At 6 months postpartum, mean weight retention was significantly lower in the FB group than in the NFB group (0.2 vs 0.8 kg, respectively, p<0.001). Weight retention differed by pre-pregnancy body mass index (BMI), with postpartum weights of overweight (pre-pregnancy BMI 25.0-29.9) and obese (pre-pregnancy BMI ≥30.0) participants being lower than pre-pregnancy weight; this trend was more pronounced in the FB group than in the NFB group (overweight: -2.2 vs -0.7 kg, respectively; obese: -4.8 vs -3.4 kg, respectively). Factors affecting weight retention at 6 months postpartum were weight gain during pregnancy (β = 0.43; p<0.001), pre-pregnancy BMI (β = -0.147; p<0.001) and feeding method. FB resulted in lower weight retention than NFB (β = -0.107; p<0.001). CONCLUSION: Breastfeeding reduced maternal weight retention, which was greater in mothers who were obese before pregnancy. For obese women, active breastfeeding may improve their health.

DOI： 10.1371/journal.pone.0268046

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cleft lip and palate (cleft L/P) is one of the most common congenital anomalies and its etiology is assumed to be multifactorial. Recent epidemiological data involving a small number of participants suggested an association between perinatal exposure to heavy metals and cleft L/P in affected children. However, this association requires further investigation in a large cohort. METHODS: This nested case-control study used a dataset of The Japan Environment and Children's Study, which is an ongoing research project to investigate the association between environmental factors and mother-child health. Participants were enrolled between 2011 and 2014. From the records of fetuses/children, we extracted data of isolated cleft L/P cases and matched children without cleft L/P at a ratio of 1:10. The exposures of interest were in utero exposure to four metals (mercury [Hg], lead [Pb], cadmium [Cd], and manganese [Mn]), which were sampled from mothers in the second/third trimester. Conditional logistic regression was used to assess the association between heavy metal exposure and isolated cleft L/P. Three sensitivity analyses were conducted to test the robustness of the findings, including the change in case definition and statistical methods. RESULTS: Of 104,062 fetal records involving both live-birth and stillbirth, we identified 192 children with isolated cleft L/P and 1,920 matched controls. Overall, the blood metal levels were low (for example, median Pb level was 5.85, 6.22, and 5.75 μg/L in the total cohort, cases, and controls, respectively). Univariate and multivariate analyses showed that levels of none of the four heavy metals in the mother's blood during pregnancy were associated with the risk of cleft L/P in offspring; the adjusted odds ratios (per 1 μg/L increase) with 95% intervals were 0.96 (0.91-1.03), 1.01 (0.94-1.08), 1.00 (0.61-1.63) and 1.00 (0.97-1.03) for Hg, Pb, Cd and Mn, respectively. The results were consistent in all sensitivity analyses. CONCLUSIONS: Exposure to these four metals during pregnancy was not associated with isolated cleft L/P at the low exposure level in our cohort.

DOI： 10.1371/journal.pone.0265648

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Our previous research showed that uric acid lowering therapy (ULT) for gout and hyperuricemia is being prescribed for pediatric patients even though these drugs have not been approved for use in children. However, the actual clinical situation has not been clearly elucidated. In this paper, we provide an in-depth look at the details of actual clinical practice. METHODS: This retrospective cross-sectional study accessed health insurance data for 696,277 children from April 2016 through March 2017 to identify pediatric patients with gout or asymptomatic hyperuricemia, calculate the proportion of patients prescribed ULTs, and analyze population characteristics. Adherence and mean dose for febuxostat and allopurinol, the most commonly prescribed drugs, were also analyzed. RESULTS: Among children with gout or asymptomatic hyperuricemia, we found that 35.1% (97/276) were prescribed ULT. This proportion increased with age, especially among males. By comorbidity, ULT was prescribed to 47.9% (46/96) of patients with kidney disease, 41.3% (26/63) for cardiovascular disease, 40.0% (6/15) for Down syndrome, and 27.1% (32/118) for metabolic syndrome. In patients with kidney disease, febuxostat was prescribed more than twice as frequently as allopurinol (28 vs. 12). Median values for the medication possession ratio (MPR) of febuxostat and allopurinol were 70.1 and 76.7%, respectively, and prescriptions were continued for a relatively long period for both drugs. Both drugs were prescribed at about half the adult dose for patients 6-11 years old and about the same as the adult dose for patients 12-18 years old. CONCLUSIONS: This study showed that the continuous management of serum uric acid is being explored using off-label use of ULT in pediatric patients with gout or asymptomatic hyperuricemia in Japan. Drug selection is based on patient characteristics such as sex, age, and comorbidities, and pediatric dosage is based on usage experience in adults. To develop appropriate pediatric ULT, clinical trials are needed on the efficacy and safety of ULT in the pediatric population. TRIAL REGISTRATION: UMIN000036029 .

DOI： 10.1186/s12887-021-03051-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu). Although the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions. In vitro subcellular localization assays revealed that the p.Arg99Leu mutant localized to Golgi apparatus, similar to the wild-type, whereas the p.Asp67Val mutant tended to show a disperse cytosolic pattern together with abnormally dispersed Golgi localization, similar to that observed in a known dominant negative variant (p.Thr31Asn). Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function. Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu. These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system. Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu).

DOI： 10.1093/hmg/ddab224

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic heart failure caused by aortic valve regurgitation is a common complication of Takayasu arteritis (TA). However, fewer patients develop acute heart failure (AHF), and no specific treatment for AHF in TA has been established. We encountered a 12-year-old girl with TA who developed AHF at onset. We successfully treated her with intravenous methylprednisolone and tocilizumab. She developed palpitations and shortness of breath three weeks before admission. Her symptoms exacerbated rapidly and she finally entered the intensive care unit due to respiratory distress and tachycardia. Blood pressure measurements on the left arm and bilateral legs were paradoxically lower than that on the right arm. Chest X-ray revealed a severely enlarged heart. Contrast computed tomography showed an expanded aorta, aortic aneurysm, meandering, and irregular diameter of the aorta. The left ventricular ejection fraction (LVEF) was 20% on cardiac ultrasound. Her medical condition was finally diagnosed as TA with AHF. Along with inotropes and diuretics, methylprednisolone pulse therapy was administered on hospital days 2-4 and hospital days 12-14, followed by oral prednisolone. However, cardiac function was not notably improved. As intravenous cyclophosphamide therapy requires hydration and may exacerbate AHF, we initiated weekly subcutaneous tocilizumab treatment (162 mg/week) from hospital day 20. Inotropes were discontinued on hospital day 51 and her LVEF had gradually improved to 37.5% at discharge (day 63). As AHF in TA is presumed to be due to inflammation of the myocardium, tocilizumab could be a treatment option for TA with AHF.

DOI： 10.1093/mrcr/rxab036

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background. Rituximab is the standard therapy for childhood-onset complicated frequently-relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS following peripheral B cell recovery. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). Thirty-nine patients (per group) were treated with rituximab, followed by either MMF or placebo until Day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until Day 505 for the last enrolled patient). Results. TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median: 784.0 vs. 472.5 days, hazard ratio (HR): 0.593, 95% confidence interval (CI): 0.336-1.049, log-rank test: P=0.0694). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR: 0.202, 95% CI: 0.081-0.503). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. Conclusions. Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

DOI： 10.1681/ASN.2021050643

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although vaccination may precipitate relapses of nephrotic syndrome (NS) in children with idiopathic NS, no data are available regarding NS activity regarding influenza (flu) virus infections and NS relapses after receiving inactivated flu vaccines. We conducted a nationwide study of children aged 6 months to 15 years with idiopathic NS to assess the relationship between NS relapse, flu vaccination, and flu infections. We used a multivariate Poisson regression model (MPRM) to calculate the risk ratio (RR) for flu infection and for NS relapse in children with and without flu vaccination. Data of 306 children were assessed. The MPRM in all 306 children showed a significantly lower RR for flu infection (RR: 0.21, 95% confidence interval CI 0.11-0.38) and for NS relapse (RR: 0.22, 95% CI 0.14-0.35) in children receiving flu vaccination compared with unvaccinated children. In an additional MPRM only among 102 children receiving flu vaccination, they had a significantly lower risk for NS relapse during the post-vaccination period (RR: 0.31. 95% CI 017-0.56) compared with the pre-vaccination period. Although our study was observational, based on the favorable results of flu vaccinations regarding flu infections and NS relapse, the vaccine may be recommended for children with NS.

DOI： 10.1038/s41598-021-02644-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd  

DOI： 10.1186/s12884-021-03827-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Research  

DOI： 10.1038/s41598-021-85900-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd  

DOI： 10.1186/s12884-021-04001-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring’s HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children’s Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring’s body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387–1.969) for the impact of maternal smoking during pregnancy on their offspring’s smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring’s HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring’s neurological impairment even after pregnancy.

DOI： 10.1038/s41598-021-98311-2

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その他リンク： https://www.nature.com/articles/s41598-021-98311-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12887-021-03005-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>We examined the association between maternal air purifier use during pregnancy and neurodevelopmental delay in toddlers by analysing data from 82,457 mother-toddler pairs. Air purifier use was measured using a simple yes/no question. Developmental delays at 1.5, 2.0, 2.5, and 3.0 years were assessed using the Ages and Stages Questionnaire, Third Edition. Generalized additive mixed model analysis with 21 covariates revealed that air purifier use was associated with lower prevalence of developmental delay in all five areas—communication, gross motor, fine motor, problem solving, and personal-social—at all four time points (adjusted risk ratios ranged from 0.827 to 0.927, and only one 95% confidence interval crossed the reference). These findings suggest a negative association between air purifier use during pregnancy and neurodevelopmental delay in toddlers.

Trial registration: UMIN000030786 (15/01/2018).

DOI： 10.1038/s41598-021-98482-y

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その他リンク： https://www.nature.com/articles/s41598-021-98482-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). METHODS: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 pediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over 4 reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with 3 patients. RESULTS: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0-5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including PET-CT, and two on treatment intensification. CONCLUSIONS: We developed a T2T algorithm and proposals for standardized remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

DOI： 10.1093/mr/roab081

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Azilsartan is an angiotensin II receptor blocker indicated for the treatment of adult hypertension. A previous single-dose study suggested that azilsartan may also be a promising agent for paediatric hypertension. However, the long-term safety and efficacy of azilsartan in children have not been established. METHODS: We conducted a phase 3, single-arm, open-label, prospective study to evaluate the safety and efficacy of azilsartan in pediatric patients with hypertension. Twenty-seven patients aged 6-15 years were treated with once-daily azilsartan for 52 weeks. The starting dose was 2.5 mg for patients weighing < 50 kg (N = 22) and 5 mg for patients weighing ≥ 50 kg (N = 5), with doses titrated up to a maximum of 20 and 40 mg, respectively. RESULTS: Azilsartan showed acceptable tolerability at doses up to 20 mg in patients weighing < 50 kg and 40 mg in those weighing ≥ 50 kg. Most drug-related adverse events (AEs) were mild, with one patient (3.7%) experiencing a severe and serious drug-related AE (acute kidney injury). One patient (3.7%) had a mild increase in serum creatinine level, which resolved after treatment discontinuation. The blood pressure-lowering effect of azilsartan was observed as early as Week 2. Overall, approximately half of the patients achieved their target blood pressure at the end of azilsartan treatment. CONCLUSIONS: Our study suggests that azilsartan has an acceptable safety profile in hypertensive patients aged 6-15 years. Azilsartan may be a promising agent for treating paediatric hypertension.

DOI： 10.1007/s10157-021-02159-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Various new vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been rapidly developed. The new onset and recurrence of nephrotic syndrome triggered by some vaccines have been documented and several adult cases of minimal change nephrotic syndrome newly developing after SARS-CoV-2 vaccination have been reported. However, no reports of pediatric cases have been published. Indications for SARS-CoV-2 vaccines have been expanded to those as young as 12 years old and vaccination of children has just started in Japan. We encountered a 15-year-old boy without underlying disease who newly developed nephrotic syndrome after SARS-CoV-2 vaccination with BNT162b2 (Pfizer-BioNTech). He developed eyelid edema 4 days after vaccination and peripheral edema of the lower extremities a further 4 days later. Twenty-one days after vaccination, 60 mg of oral daily prednisolone was started. He achieved complete remission in 12 days without complications such as hypertension or acute kidney injury. We clinicians should be aware of the possibility of nephrotic syndrome developing after SARS-CoV-2 vaccination, not only in adults, but also in children.

DOI： 10.1007/s13730-021-00656-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This prospective cohort study aimed to examine the associations between mold growth, type of stoves, and fragrance materials and early childhood wheezing and asthma, using data from the Japan Environment and Children's Study. Mold growth at home, usage of kerosene/gas stove, wood stove/fireplace, and air freshener/deodorizer were surveyed using a questionnaire at 1.5-year-old, and childhood wheezing and doctor-diagnosed asthma during the previous year were obtained using a 3-year-old questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between exposure to childhood wheezing and asthma. A total of 60 529 children were included in the analysis. In multivariate analyses, mold growth and wood stove/fireplace had significantly higher odds ratios (ORs) for wheezing (mold growth: 1.13; 95% CI, 1.06-1.22; wood stove/fireplace: 1.23; 95% CI, 1.03-1.46). All four exposures had no significant ORs for childhood doctor-diagnosed asthma; however, in the supplemental analysis of northern regions, wood stove/fireplace had a significantly higher OR for asthma. Mold growth and wood stove/fireplace had significant associations with childhood wheezing in the northern regions. Mold elimination in the dwellings and use of clean heating (no air pollution emissions) should be taken into consideration to prevent and improve childhood wheezing and asthma.

DOI： 10.1111/ina.12931

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media Deutschland GmbH  

DOI： 10.1007/s00467-021-05198-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jid.2021.05.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Electronic health (eHealth) for infants and mothers is a current focus of attention, but its effectiveness has rarely been examined in Japan. For infants, skin problems, including atopic dermatitis (AD), which is known to lead to other allergic diseases, is one of the most common conditions. Mothers of infants are prone to experience parenting stress, which adversely affects mothers' and children's well-being. Additionally, studies have reported that AD among offspring enhances parenting stress, and postnatal maternal psychological problems can increase the risk of AD in children. OBJECTIVE: To evaluate the effectiveness of pediatric teleconsultation for preventing atopic dermatitis in infants and reducing parenting stress in mothers in Japan. METHODS: The study was an open-label, randomized, parallel-armed controlled trial. In total, 318 pairs of infants and mothers in Yokohama City Sakae Ward in Japan were recruited when they submitted birth cards to the ward, received the explanation, and completed online informed consent on the website for this trial. Eligible pairs of infants and mothers were randomly assigned to the intervention group (n=140) or the control group (n=138). Participants in both the intervention and control groups received routine postnatal care from local government services. In addition, participants in the intervention group had the option to combine routine pediatric services with teleconsultation and email newsletters without charge from the date of registration until the infant was 4 months of age. Primary outcomes were (i) the prevalence of AD in infants diagnosed based on the United Kingdom Working Party's criteria; and (ii) parenting stress and mental status in mothers, assessed using the Parenting Stress Index-Short Form (PSI-SF) and General Health Questionnaire-12 (GHQ-12). Data were collected via the ward office staff and researcher at the 4-month checkup. RESULTS: The prevalence of AD in infants was significantly lower in the intervention group than in the control group at the 4-month checkup (20% vs. 33%, P=.03; relative risk ratio, 0.614 [95% confidence interval, 0.406 to 0.927]). No significant differences were observed in the PSI-SF and GHQ-12 scores between the two groups. There was a significant difference in the prevalence of AD between participants who used teleconsultation services and email newsletters, participants who did not use teleconsultation services but received email newsletters, and participants who neither received nor used either service (18% vs 22% vs 33%, P=.048). CONCLUSIONS: This is the first randomized controlled trial demonstrating that routine pediatric care combined with teleconsultation and email newsletters was effective in reducing the prevalence of AD in infants. The findings highlight the potential for pediatric eHealth to become a useful new strategy for preventing AD. CLINICALTRIAL: UMIN000029774; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034022.

DOI： 10.2196/27615

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Childhood Takayasu arteritis (c-TA) often shows nonspecific symptoms, such as fever of unknown origin (FUO). Delay of diagnosis may result in organ dysfunction by arterial occlusion; therefore, early diagnosis is very important. Although ultrasonography is the first-line screening tool for children with FUO, its diagnostic efficacy of evaluation of systemic arteries in c-TA that presents as FUO remains unclear. We evaluated the suitability of ultrasonography evaluation that included systemic vessels for the early diagnosis of c-TA initially presenting as FUO. Methods: We review five patients who received a diagnosis of c-TA in our institution and also performed a literature review regarding TA cases with FUO and diagnosed on the basis of initial ultrasonography. Results: As in our cases, the median period from onset to diagnosis was 25 days (interquartile range [IQR], 21-35). Comparing the initial ultrasonography findings with later contrast-enhanced computed tomography (CECT) findings in the abdominal aorta, celiac artery, superior mesenteric artery, bilateral renal arteries, and bilateral common carotid arteries, the concordance rate between ultrasonography and CECT was moderate (Kappa coefficient was 0.50). All the patients were successfully treated without severe vascular damage. The literature review revealed 12 articles; although 9 of the 13 patients did not show the characteristic features (such as blood pressure discrepancy, bruit, or pulse deficiency), the median time to diagnosis was still 5 months (IQR, 3-12). Conclusions: During initial screening for patients with FUO, ultrasonography including evaluation of systemic vessels could contribute to earlier diagnosis of c-TA.

DOI： 10.31662/jmaj.2020-0115

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We studied the rate of remission of lupus nephritis (LN) in an international cohort of 248 children and adolescents with biopsy proven LN. Five different definitions from scientific studies and the definitions recommended by the American College of Rheumatology and Kidney Disease Improving Global Outcomes (KDIGO) were used. METHODS: Anonymized clinical data in patients with biopsy proven LN class ≥ III (International Society of nephrology/Royal Pathology Society-ISN/RPS) diagnosed and treated in the last 10 years in 23 international centers from 10 countries were collected. We compared the rate of patients in complete and partial remission applying the different definitions. RESULTS: The mean age at diagnosis was 11 years and 4 month and 177 were females.The number of patients in complete and partial remission varied a lot between the different definitions. At 24 months, between 50% and 78.8% of the patients were in full remission as defined by the different criteria. The number of patients in partial remission was low, between 2.3% and 25%. No difference in achieved remission was found between boys and girls or between children and adolescents (P > 0.05). Patients with East Asian ethnicity reached remission more often than other ethnicities (P = 0.03-0.0008). Patients treated in high income countries showed a higher percentage of complete remission at 12 and 24 months (P = 0.002-0.000001). CONCLUSION: The rate of children and adolescents with LN achieving remission varied hugely with the definition used. Our results give important information for long awaited treatment studies in children and young people.

DOI： 10.1093/rheumatology/keab746

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Allergology  

DOI： 10.1016/j.alit.2021.04.008

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

The association between delivery mode and subsequent development of diseases is a growing area of research. Cesarean delivery affects the diversity of the microbiota in the infant gut, which may be associated with gastrointestinal disorders, including functional constipation, in infants. In this study, we investigated the association between delivery mode and prevalence of functional constipation in 3-year-old Japanese toddlers.

Methods

This study used data from the Japan Environment and Children’s Study, an ongoing nationwide birth cohort study. We analyzed 71,878 toddler–mother pairs. The presence of functional constipation was determined according to the Rome III diagnostic criteria. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis.

Results

The prevalence of functional constipation in 3-year-old Japanese toddlers was estimated to be 12.3%. Logistic regression analysis revealed that the prevalence of functional constipation was higher in toddlers born by cesarean delivery (13.1%) compared with those born by vaginal delivery (12.1%), independent of 22 confounders (adjusted odds ratios = 1.064, 95% confidence interval = 1.004–1.128).

Conclusions

We determined the prevalence of functional constipation in 3-year-old Japanese toddlers and found that delivery mode was associated with the prevalence of functional constipation in Japanese toddlers.

DOI： 10.1186/s12887-021-02885-9

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その他リンク： https://link.springer.com/article/10.1186/s12887-021-02885-9/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Apgar score (AS) is a well-established tool for assessing viability of newborns, and its association with subsequent child development has been suggested. We aimed to assess whether Apgar scores (ASs) ≥ 7 (generally considered normal) are associated with the developmental status at 3 years of age while adjusting for perinatal and socioeconomic confounders. We extracted the data of ASs at 1 and 5 min among participants of the Japan Environment and Children's Study datasets, which were used in this nationwide cohort study. The outcomes comprised developmental status that was less than each cutoff value for the following five domains of the Ages & Stages Questionnaire (Japanese version, 3rd edition): communication, gross and fine motor, problem-solving, and personal-social domains. For this objective, we conducted multivariable logistic regression analyses on the data of 54,716 children. Compared with ASs ≥ 9 at 5 min, the adjusted odds ratios (aOR) for delayed development in children with ASs ≤ 8 were 1.31 (95% confidence interval, 1.11-1.56), 1.20 (1.04-1.38), and 1.16 (1.01-1.34), respectively, for gross and fine motor, and problem-solving domains. Among neonates with ASs ≤ 8 at 1 min, when those with ASs ≤ 8 at 5 min were compared with those with ASs ≥ 9 at 5 min, the aOR for gross motor domain was 1.34 (1.11-1.61).Conclusion: ASs ≤ 8 compared with those ≥ 9 at 5 min, even considering the change of AS from 1 to 5 min, were associated with increased ORs for developmental delay in 3-year-olds. Even ASs that are considered normal might affect the subsequent development. What is Known: • Apgar score is a general tool for evaluating the vitality of newborns. It is also basically measured at 1 minute and 5 minutes after birth and the scores of ≥7 are considered normal. • The Apgar scores at each minute affect clinical findings of neonates after birth and the subsequent long-term development. What is New: • Neonates with Apgar scores of ≤8 at 5 minutes compared with those of ≥9, including the change in Apgar score from 1 minute to 5 minutes, are associated with increased odds ratios for developmental status at 3 years of age adjusting for perinatal and socioeconomic confounders.

DOI： 10.1007/s00431-021-04249-y

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Purpose

N-3 polyunsaturated fatty acids (n-3 PUFAs), which are an important nutrient for humans, are particularly essential to the growth and development of the central nervous system (CNS) in fetuses and infants. Consequently, sufficient n-3 PUFA intake by mothers during pregnancy is considered to contribute to CNS development in their infants. CNS development is known to be associated with sleep, but no large epidemiological studies have yet confirmed that n-3 PUFA intake during pregnancy is associated with infants’ sleep.

Methods

After exclusion and multiple imputation from a dataset comprising 104 065 records from the Japan Environment and Children’s Study (JECS), we examined 87 337 mother–child pairs for the association between mothers’ fish and n-3 PUFA intakes and risk of their infants sleeping less than 11 h at 1 year of age.

Results

Multiple logistic regression analysis with the lowest quintile used as a reference revealed odds ratios for the second through fifth quintiles of 0.81 (95% confidence interval [95% CI] 0.76–0.87), 0.81 (95% CI 0.76–0.87), 0.78 (95% CI 0.72–0.84), and 0.82 (95% CI 0.76–0.88) for fish intake (p for trend &lt; 0.001) and 0.90 (95% CI 0.84–0.97), 0.88 (95% CI 0.81–0.94), 0.88 (95% CI 0.82–0.95), and 0.93 (95% CI 0.86–0.998) for n-3 PUFA intake (p for trend = 0.04).

Conclusions

Low fish intake during pregnancy may increase the risk of infants sleeping less than 11 h at 1 year of age. This relationship may have been mediated by maternal n-3 PUFA intake and infant neurodevelopment, but further evidence from interventional and other studies is needed to determine the appropriate level of fish intake during pregnancy.

Trial registration

The Japan Environment and Children’s Study, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035091 (Registration no. UMIN000030786).

DOI： 10.1007/s00394-021-02671-4

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その他リンク： https://link.springer.com/article/10.1007/s00394-021-02671-4/fulltext.html

記述言語：英語  

BACKGROUND: An atypical form of Burkitt leukemia/lymphoma (BL), BL with a phenotype of precursor B-cells (preBLL), is listed in the WHO Classification. Recent reports suggested that preBLL and classical BL could be distinguished by the differences in IG-MYC translocation architecture and an additional mutated genes profile. The characteristics of classical BL are IG-MYC by aberrant somatic hypermutation or class switch recombination, and BL-specific gene mutations such as MYC, ID3, and CCND3. Meanwhile, preBLL is characterized by IG-MYC due to aberrant VDJ recombination and mutations in NRAS and KRAS. However, it is not clear whether all preBLL cases can be differentiated. This report investigated the molecular characteristics of an infant preBLL case, with a more advanced stage of maturity than typical preBLL. CASE: The patient showed BL-like morphology with IGH-MYC rearrangement. In the immunophenotyping, CD20 and surface immunoglobulin were negative, whereas other markers were consistent with BL. To evaluate the genetic contribution, we performed whole-exome sequencing. The breakpoint analysis revealed the IG-MYC occurred due to an aberrant VDJ recombination. Meanwhile, additional somatic mutations were detected in FBXO11, one of the mutant genes specific to BL. In the analysis of the specimen in complete remission, mutation in KRAS, frequently mutated in preBLL, was detected with low frequency, suggesting somatic mosaicism. CONCLUSION: The present case showed the characteristics of both typical preBLL and classical BL. Because preBLL includes atypical cases such as the present case, further studies are required to elucidate preBLL features.

DOI： 10.1002/cnr2.1545

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.waojou.2021.100581

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CONTEXT: Maternal cholesterol is important for fetal development. Whether maternal serum total cholesterol (maternal TC) levels in mid-pregnancy are associated with small- (SGA) or large- (LGA) for-gestational-age independent of pre-pregnancy body mass index (BMI) and weight gain during pregnancy is inconclusive. OBJECTIVE: To prospectively investigate the association between maternal TC in mid-pregnancy and SGA or LGA. DESIGN AND SETTING: The Japan Environment and Children's Study is a nationwide prospective birth cohort study in Japan. PARTICIPANTS: A total of 37,449 non-diabetic, non-hypertensive mothers with singleton birth at term without congenital abnormalities. OUTCOME MEASURES: Birth weight for the gestational age <10 percentile and ≥90 percentile were respectively defined as SGA and LGA by the Japanese neonatal anthropometric charts. RESULTS: The mean gestational age at blood sampling was 22.7±4.0 weeks. After adjustment for maternal age, sex of child, parity, weight gain during pregnancy, pre-pregnancy BMI, smoking, alcohol drinking, blood glucose levels, household income, and Study Areas, one standard deviation decrement of maternal TC was linearly associated with SGA [odds ratio (OR): 95% confidence intervals (CI) = 1.20: 1.15-1.25]. In contrast, one standard deviation increment of maternal TC was linearly associated with LGA [OR: 95% CI = 1.13: 1.09-1.16]. Associations did not differ according to pre-pregnancy BMI and gestational weight gain (p for interaction>0.20). CONCLUSION: Maternal TC levels in mid-pregnancy were associated with SGA or LGA in Japanese. Maternal TC in mid-pregnancy may help to predict SGA and LGA. Favorable maternal lipid profiles for fetal development must be explored.

DOI： 10.1210/clinem/dgab618

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Postpartum depression is one of the most commonly experienced psychological disorders for women after childbirth, usually occurring within one year. This study aimed to clarify whether women with delivery with anesthesia, including epidural analgesia, spinal-epidural analgesia, and paracervical block, had a decreased risk of postpartum depression after giving birth in Japan.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>The Japan Environment and Children’s Study (JECS) was a prospective cohort study that enrolled registered fetal records (n = 104,065) in 15 regions nationwide in Japan. Binomial logistic regression analyses were performed to calculate the adjusted odd ratios (aORs) for the association between mode of delivery with or without anesthesia and postpartum depression at one-, six- and twelve-months after childbirth.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>At six months after childbirth, vaginal delivery with anesthesia was associated with a higher risk of postpartum depression (aOR: 1.233, 95% confidence interval: 1.079–1.409), compared with vaginal delivery without analgesia. Nevertheless, the risk dropped off one year after delivery. Among the pregnant women who requested delivery with anesthesia, 5.1% had a positive Kessler-6 scale (K6) score for depression before the first trimester (<jats:italic>p</jats:italic> &lt; 0.001), which was significantly higher than the proportions in the vaginal delivery without analgesia (3.5%).</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>Our data suggested that the risk of postpartum depression at six months after childbirth tended to be increased after vaginal delivery with anesthesia, compared with vaginal delivery without analgesia. Requests for delivery with anesthesia continue to be relatively uncommon in Japan, and women who make such requests might be more likely to experience postpartum depressive symptoms because of underlying maternal environmental statuses.</jats:p>
</jats:sec>

DOI： 10.1186/s12884-021-03996-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

DOI： 10.1038/s41467-021-24609-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Kawasaki disease (KD) is an acute systemic vasculitis that mainly affects infants and young children. The etiology of KD has been discussed for several decades; however, no reproducible risk factors have yet been proven. We used the Japan Environment and Children's Study data to explore the association between the causal effects of exposure during the fetal and neonatal periods and KD onset. The Japan Environment and Children's Study, a nationwide birth cohort study, has followed approximately 100,000 children since 2011. We obtained data on exposures and outcomes from the first trimester to 12 months after birth. Finally, we included 90,486 children who were followed for 12 months. Among them, 343 children developed KD. Multivariate logistic regression revealed that insufficient intake of folic acid during pregnancy (odds ratio [OR], 1.37; 95% CI 1.08-1.74), maternal thyroid disease during pregnancy (OR, 2.03; 95% CI 1.04-3.94), and presence of siblings (OR, 1.33; 95% CI 1.06-1.67) were associated with KD onset in infancy. In this study, we identified three exposures as risk factors for KD. Further well-designed studies are needed to confirm a causal relationship between these exposures and KD onset.

DOI： 10.1038/s41598-021-92669-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In recent years, there has been an increase in the number of problems associated with neurodevelopmental disorders in children, and there has been a growing interest in the relationship between environmental chemicals and children's health. The objective of this study was to examine whether an association exists between occupational or environmental prenatal maternal exposure to volatile organic compounds and the risk of neurodevelopmental disorders in children using Japanese translations of the Ages & Stages Questionnaires, Third Edition (J-ASQ-3). An increase in the risk of neurodevelopmental delay in 12-month-old children associated with maternal exposure to formalin or formaldehyde was identified in terms of problem-solving (odds ratio (OR): 1.76, 95% confidence interval (CI): 0.99-3.12) and personal-social skills (OR: 3.32, 95% CI: 1.46-7.55). It is not clear whether or not this tendency is reversible, and whether it is observed past 12 months of age. Further research and a preventive approach are needed.

DOI： 10.1016/j.scitotenv.2021.148643

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1-RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)-AML patients. The 5 year event-free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%-69.4%] vs. 74.7% [95% CI, 63.0%-83.2%] P-value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%-NA vs. 89.7% [95% CI, 69.6%-96.8%] P-value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF-AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1-RUNX1T1-positive AML.

DOI： 10.1111/bjh.17569

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although hypotension is a life-threatening complication of nephrectomy in children, risk factors for its development remain unknown. We evaluated the incidence, clinical course, and associated risk factors of pediatric post-nephrectomy hypotension in an observational study. METHODS: This retrospective observational study included the clinical data of children who underwent nephrectomy in our center between 2002 and 2020. Patients undergoing nephrectomy at kidney transplantation and those who developed hypotension before nephrectomy were excluded. RESULTS: The study included 55 nephrectomies in 51 patients, including 42 unilateral, 4 two-stage bilateral, and 5 simultaneous bilateral nephrectomies. The diagnoses were isolated Wilms tumor, neuroblastoma, congenital nephrotic syndrome, Denys-Drash syndrome, WAGR (Wilms tumor, aniridia, genitourinary malformations, and mental retardation) syndrome, and autosomal recessive polycystic kidney disease in 24, 10, 9, 6, 1, and 1 patient, respectively. Post-nephrectomy hypotension developed in 11 (20%) patients. Two patients (3.6%) had persistent hypotension; both had their kidneys resected, and one patient (1.8%) died. Male sex, kidney disease, resection of both kidneys, low estimated glomerular filtration rate, increased left ventricular posterior wall thickness in diastole, hypertension before nephrectomy, antihypertensive use, hyperreninemia, and hyperaldosteronism were significantly associated with post-nephrectomy hypotension. Multivariate logistic regression analysis revealed that hypertension before nephrectomy was the only significant risk factor for post-nephrectomy hypotension (P = 0.04). CONCLUSIONS: Hypertension before nephrectomy is a significant risk factor for pediatric post-nephrectomy hypotension. Life-threatening hypotension, which might occur after bilateral nephrectomy in infants, should be considered, especially in children with higher risks.

DOI： 10.1007/s00467-021-05115-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.alit.2021.05.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The new disease concept of multisystem inflammatory syndrome in children (MIS-C), which is a systemic inflammatory syndrome with multiple organ involvement after SARS-CoV2 infection, was established in 2020. MIS-C is common in Hispanic and black children in Europe and North America, with few reports in East Asians. A significant portion of patients with MIS-C develop Kawasaki disease (KD)-like symptoms. Therefore, differential diagnosis is challenging, especially in East Asia, where KD is most prevalent. No Japanese cases have been reported in the literatures so far. We report a case of MIS-C in Japan with KD-like symptoms. A 9-year-old Japanese boy, who was infected with SARS-CoV2 1 month previously along with his family, was admitted to our hospital owing to fever for 6 days and erythema mainly in the groyne and pubic area. He also had conjunctivitis, strawberry tongue, and diarrhoea. His laboratory findings were as follows: WBC, 12,840/µL (lymphocytes, 4%); CRP, 22.6 mg/dL, pro-calcitonin, 1.8 ng/mL (normal, <0.50 ng/mL); NT pro-BNP, 7627 pg/mL (<125 pg/mL); and troponin T, 0.14 ng/mL (<0.01 ng/mL). His cardiac function was normal. We initially diagnosed him with KD. His fever rapidly resolved with intravenous immunoglobulin and there were no coronary artery lesions. Desquamation of the fingers was observed later. Finally, a history of SARS-COV2 infection, his age, atypical skin rash, elevation of markers of inflammation and heart failure, and lymphopenia suggested the diagnosis of MIS-C rather than KD. Differentiation between KD and MIS-C is necessary even in Japan, especially in patients with atypical features of KD.

DOI： 10.1080/24725625.2021.1920140

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications Ltd  

DOI： 10.1177/1055665620951399

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s00394-020-02294-1

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その他リンク： https://link.springer.com/article/10.1007/s00394-020-02294-1/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Rituximab is effective for maintaining remission in patients with complicated nephrotic syndrome, although a history of steroid-resistant nephrotic syndrome (SRNS) is a risk factor for early relapse. We investigated the efficacy of prophylactic rituximab treatment for maintaining remission after B cell recovery. METHODS: Patients with complicated steroid-dependent or frequently relapsing nephrotic syndrome with history of SRNS who received a single dose of rituximab (375 mg/m2) and continued immunosuppressive agents were enrolled in this retrospective study. Patients were divided into two groups: a prophylaxis group, which received additional rituximab treatment at B cell recovery and a non-prophylaxis group. The relapse-free period from the last rituximab infusion (the second treatment in prophylaxis group and the first treatment in non-prophylaxis group) was compared between two groups using the Kaplan-Meier method, and risk factors for early relapse were calculated using multivariate analysis by Cox proportional hazards model. RESULTS: Sixteen patients in the prophylaxis group and 45 in the non-prophylaxis group were enrolled. Fifty-percent relapse-free survival after the last rituximab treatment was 667 days in the former and 335 days in the latter (p = 0.001). Multivariate analysis showed that additional rituximab treatment was the only significant negative factor for early relapse, with a hazard ratio of 0.40 (p = 0.02). Fifty-percent relapse-free survival after B cell recovery was much longer in the prophylaxis group (954 vs. 205.5 days, p = 0.003). CONCLUSIONS: Additional rituximab treatment at B cell recovery can maintain prolonged remission even after B cell recovery in patients with complicated nephrotic syndrome with history of SRNS.

DOI： 10.1007/s00467-020-04771-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neonatal jaundice occurs in >80% of newborns in the first week of life owing to physiological hyperbilirubinemia. Severe hyperbilirubinemia could cause brain damage owing to its neurotoxicity, a state commonly known as kernicterus. Therefore, periodic bilirubin monitoring is essential to identify infants at-risk and to initiate treatment including phototherapy. However, devices for continuous measurements of bilirubin have not been developed yet. Here, we established a wearable transcutaneous bilirubinometer that also has oxygen saturation (SpO2) and heart rate (HR) sensing functionalities. Clinical experiments with neonates demonstrated the possibility of simultaneous detection of bilirubin, SpO2, and HR. Moreover, our device could consistently measure bilirubin during phototherapy. These results demonstrate the potential for development of a combined treatment approach with an automatic link via the wearable bilirubinometer and phototherapy device for optimization of the treatment of neonatal jaundice.

DOI： 10.1126/sciadv.abe3793

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.braindev.2020.11.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Research  

DOI： 10.1038/s41598-020-67321-x

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjh.17006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press  

DOI： 10.1093/ajcn/nqaa190

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W.B. Saunders Ltd  

DOI： 10.1016/j.placenta.2020.09.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.14410

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.waojou.2020.100479

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/ped.14316

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ped.14316

掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.kint.2020.05.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (NS) because of their high risk of severe infections. Vaccinations may precipitate relapses of NS, but there is no available data regarding inactivated influenza (flu) virus vaccines. METHODS: We retrospectively reviewed the medical records of children with NS who had received flu vaccines between 2002 and 2015. The day of flu vaccination was defined as day 0, and the period between the pre-vaccination and the post-vaccination days was defined as - X to + Y. The risk ratios and their 95% confidence intervals for NS relapse rate were estimated by generalized estimating equation (GEE) Poisson regression. RESULTS: A total of 104 pediatric patients received 208 flu vaccines. The mean age at onset of NS was at 4.85 ± 3.87 years old. There were 261 NS relapses between days - 180 and + 180. Compared with the relapse rate in the - 180 to 0 interval (1.19 times/person-year), those in 0 to + 30 (1.23), + 31 to + 60 (1.58), + 61 to + 90 (1.41), + 91 to + 120 (1.41), and + 121 to + 180 (1.32) days groups were slightly increased, but without significance. Multivariate analysis using GEE Poisson regression also showed no significant increase in relapse rate in each day group compared with days - 180 to 0. Risk ratios for NS relapse were significantly higher in children who were treated with steroids at the first vaccination. CONCLUSIONS: Our results suggest that flu vaccines should not be avoided in children with NS based on the potential for NS relapses.

DOI： 10.1007/s10157-020-01930-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

DOI： 10.1136/annrheumdis-2020-217320

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although gout is rare in children, chronic sustained hyperuricemia can lead to monosodium urate deposits progressing to gout, just as in adults. This study assessed prevalence and characteristics of gout and asymptomatic hyperuricemia, and incidence of gouty arthritis in the pediatric population, using data from Japanese health insurance claims. The diagnosis and treatment of pediatric gout and hyperuricemia were analyzed, and specific characteristics of those patients were assessed. Since Japanese guidelines recommend treatment with uric acid lowering drugs for asymptomatic hyperuricemia as well as for gout, these data were also used to investigate the real-world use of uric acid lowering drugs in a pediatric population. METHODS: This cross-sectional study was based on a 2016-2017 Japanese health insurance claims database, one of the largest epidemiology claims databases available in Japan, which included 356,790 males and 339,487 females 0-18 years of age. Outcomes were measured for prevalence, patient characteristics, treatment with uric acid lowering drugs for gout and asymptomatic hyperuricemia, and prevalence and incidence of gouty arthritis. Because uric acid can be elevated by some forms of chemotherapy, data from patients under treatment for malignancies were excluded from consideration. RESULTS: Total prevalence of gout and asymptomatic hyperuricemia in 0-18 year-olds was 0.040% (276/696,277 patients), with gout prevalence at 0.007% (48/696,277) and asymptomatic hyperuricemia at 0.033% (228/696,277). Prevalence of gout and asymptomatic hyperuricemia was highest in adolescent males, at 0.135% (176/130,823). The most common comorbidities for gout and asymptomatic hyperuricemia were metabolic syndrome at 42.8% (118/276) and kidney disease at 34.8% (96/276). Of the patients diagnosed with gout or asymptomatic hyperuricemia, 35.1% (97/276) were treated with uric acid lowering drugs. Gouty arthritis developed in 43.8% (21/48) of gout patients during the study, at an incidence of 0.65 flares/person-year. CONCLUSIONS: Even the pediatric population could be affected by asymptomatic hyperuricemia, gout, and gouty arthritis, and uric acid lowering drugs are being used in this population even though those drugs have not been approved for pediatric indications. Such off-label use may indicate a potential need for therapeutic agents in this population. TRIAL REGISTRATION: UMIN000036029 .

DOI： 10.1186/s12887-020-02379-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/01443615.2019.1673709

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.14326

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記述言語：英語  

DOI： 10.1002/pbc.28618

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The parameters of lung sounds have been suggested as biomarkers of airway changes. Using a commercially available lung sound analyzer, we investigated the characteristics of the lung sounds in infants with acute respiratory infection (ARI). Methods: Infants with ARI who were 6 to 18 months of age were included in this study. The lung sound parameters, the ratio of the third area and fourth areas to the total area under the curve of the sound spectrum (A3/AT and B4/AT), and the ratio of power and frequency at 75% and 50% of the highest frequency of the power spectrum (RPF75 and RPF50) were evaluated. With an original Japanese questionnaire based on American Thoracic Society-Division of Lung Disease, the risk factors of asthma development in infants were examined. Results: One hundred ten infants with ARI and 248 infants in good health for comparison were included. All infants were completely analyzed, and then divided into 2 age groups for a stratification analysis (6-12 and 13-18 months). In the overall analysis, among infants with a history of wheezing, recurrent wheezing, allergy, and atopic dermatitis, the values of RPF50 of infants with ARI were significantly lower compared with those without ARI. In the 6- to 12-month-old group, the RPF50 values of atopy-positive infants with ARI were lower compared with those without ARI (P = 0.003). Conclusions: The lung sounds of the infants with asthma-developing risk factors were more affected by ARI than those of infants without risk factors. Analyzing the changes in the lung sounds induced by ARI may be useful for evaluating the characteristics of the airways in infants.

DOI： 10.1089/ped.2019.1131

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Denys-Drash syndrome is characterized by progressive nephropathy, gonadal dysgenesis, and Wilms tumor caused by a WT1 gene mutation. Infants with Denys-Drash syndrome frequently experience severe hypertension, but detailed clinical manifestations have yet to be clarified. Cases of infantile-onset Denys-Drash syndrome with severe hypertension at our hospital were retrospectively analyzed and the pathogenesis of hypertension was investigated. Six infants who received the diagnosis of Denys-Drash syndrome at the median age of 10 days (range: 2-182 days) were enrolled. Five infants had the complication of severe hypertension within a few days of diagnosis. All the patients showed rapid progression to end-stage renal disease and urgently required dialysis due to anuria/oliguria and hypervolemia with a median duration of 7.5 days (range: 0-17 days) on the day after diagnosis. Even under dialysis, all the patients continued to need antihypertensive treatment. Five patients underwent a preventive nephrectomy for Wilms tumor, and one patient underwent a nephrectomy due to progression to Wilms tumor. Two patients developed hypotension after a nephrectomy. The main causes of hypertension were hypervolemia in the predialysis stage, renin-associated hypertension in the dialysis stage, and multiple factors, including increased plasma catecholamine-associated hypertension in the postnephrectomy dialysis stage. At last the follow-up after bilateral nephrectomy, four of the five patients required antihypertensive treatment. Not all the patients showed target organ complications caused by hypertension. Severe hypertension is a common complication of infantile-onset Denys-Drash syndrome. The possibility of hypotension after nephrectomy should be considered in patients with Denys-Drash syndrome.

DOI： 10.1620/tjem.252.45

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/jdi.13238

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jdi.13238

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd  

DOI： 10.1186/s12884-020-03131-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer  

DOI： 10.1007/s10803-020-04380-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Despite advances in non-invasive vascular imaging, detection of renal artery stenosis via catheter angiography is the criterion standard for the diagnosis of renovascular hypertension (RVH). However, because of lack of evidence, the utility of various blood tests and imaging modalities remains unclear. METHODS: We retrospectively analyzed the utility of blood tests (plasma renin activity [PRA], aldosterone, and renal vein renin [RVR] values) and imaging studies (computed tomography angiography [CTA], kidney ultrasonography [US]) by comparing them with catheter angiography. Ten pediatric patients with RVH at two institutions from January 2008 to December 2017 were recruited. The sensitivities for diagnosing RVH via imaging and blood tests (kidney [US], PRA, and aldosterone) were derived by examining patient records. Furthermore, the sensitivity and specificity of CT angiography were calculated by considering both the affected and non-affected renal arteries of the patients. RESULTS: A high sensitivity for diagnosing RVH via kidney US (89%) and PRA (80%) was observed. The sensitivity and specificity of CTA were 100%, each. RVR sampling did not aid in the diagnosis of RVH; only two of six patients with unilateral RVH showed significant laterality of RVR boundary ratios. Renal scintigraphy facilitated detection of a non-functional kidney (split renal function <5%). CONCLUSIONS: RVH in children could be diagnosed utilizing non-invasive blood and imaging tests, without catheter angiography. We recommend kidney length measurement along with measurement of PRA level, as a simple and highly useful screening test, followed by CTA as a diagnostic test.

DOI： 10.1111/ped.14224

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

X-linked inhibitor of apoptosis protein (XIAP) deficiency results in monogenic inflammatory bowel disease. To date, no vasculitis associated with XIAP deficiency has been reported. A 10-year-old boy was diagnosed with Crohn's disease and he responded poorly to conventional treatment for Crohn's disease. He was dependent on corticosteroids and parenteral nutrition. To manage severe colitis, he underwent ileostomy followed by ileocolectomy for an ileo-sigmoid fistula. At the age of 15 years, he developed IgA vasculitis and at the age of 17 years, he developed refractory Takayasu arteritis (TAK), which was resistant to corticosteroid and immunosuppressive therapy. Whole-exome sequencing revealed a novel mutation of the splice acceptor site in XIAP (c.1057-1G > A) at the age of 19 years. Allogeneic hematopoietic stem cell transplantation was successful with subsequent withdrawal of intensive immunosuppressive therapy and clinical remission of both enterocolitis and TAK. This case suggests that patients with XIAP deficiency could develop intractable inflammatory disease involving the intestinal tract and blood vessels.

DOI： 10.1016/j.clim.2020.108495

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記述言語：英語  

Intensive analysis of the SMARCB1 gene in malignant rhabdoid tumors (MRT) revealed eight of 16 patients with constitutional genetic variants. Three patients had mosaicism of deletion/variant of the SMARCB1 gene, which conventional methods might overlook. The prevalence of cancer predisposition in MRT may thus be higher than previously reported.

DOI： 10.1038/s41431-020-0614-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central  

DOI： 10.1186/s12199-020-00873-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central  

DOI： 10.1186/s12199-020-00864-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.clim.2020.108441

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.waojou.2020.100128

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pathogenic variants of paired box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes renal coloboma syndrome (RCS). Patients with PAX2-related disorder present with renal and ophthalmological pathologies, as well as with other abnormalities, including developmental problems and hearing loss. We sequenced PAX2 in 457 patients with congenital anomalies of the kidney and urinary tract or with renal dysfunction of unknown cause and identified 19 different pathogenic variants in 38 patients from 30 families (6.5%). Thirty-four patients had renal hypodysplasia or chronic kidney disease of unknown cause, and three had focal segmental glomerulosclerosis. Although no obvious genotype-phenotype correlation was observed, six of the seven patients who developed end-stage renal disease in childhood had truncating variants. Twenty-three patients had ocular disabilities, mostly optic disc coloboma. Non-renal and non-ophthalmological manifestations included developmental disorder, electrolyte abnormality, and gonadal abnormalities. Two unrelated patients had congenital cystic adenomatoid malformations in their lungs. Six of ten probands with PAX2 mutation identified by next-generation sequencing did not show typical RCS manifestations. We conclude that PAX2-related disorder has a variable clinical presentation and can be diagnosed by next-generation sequencing even in the absence of typical RCS manifestations.

DOI： 10.1038/s10038-020-0741-y

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.placenta.2020.04.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-63268-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Orofacial clefts are common birth defects with a lack of strong evidence regarding their association with maternal nutrition. We aimed to determine whether a relationship exists between maternal nutrient or multivitamin intake and orofacial clefts. DESIGN: This is a prospective, population-based nationwide cohort study. SETTING: The study was conducted in 15 regional centres, consisting of local administrative units and study areas. PARTICIPANTS: A total of 98 787 eligible mother-child pairs of the Japan Environment and Children's Study were included. INTERVENTION: Exposures were maternal nutrition and the use of supplemental multivitamins in mothers. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes were the occurrence of any orofacial cleft at birth. Multinomial logistic regression analyses were used to evaluate the association between maternal multivitamin intake and the incidence of orofacial clefts. RESULTS: Of the 98 787 children, 69 (0.07%) were diagnosed with cleft lip alone, 113 (0.11%) were diagnosed with cleft lip and palate, and 52 (0.05%) were diagnosed with cleft palate within 1 month after birth. Regarding the total orofacial cleft outcome, statistically significant point estimates of relative risk ratios (RR) were determined for multivitamin intake before pregnancy (RR=1.71; 95% CI 1.06 to 2.77) and during the first trimester (RR=2.00; 95% CI 1.18 to 3.37), but the association was not significant for multivitamin intake after the first trimester (RR=1.34; 95% CI 0.59 to 3.01). Maternal micronutrient intake via food was not associated with the incidence of orofacial clefts in offspring. CONCLUSIONS: Intake of multivitamin supplements shortly before conception or during the first trimester of pregnancy was found to be associated with an increased incidence of orofacial clefts at birth. Pregnant women and those intending to become pregnant should be advised of the potential risks of multivitamin supplementation.

DOI： 10.1136/bmjopen-2019-035817

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10995-019-02835-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

We describe the case of a 7-year-old girl with repeated vaginal Enterobius vermicularis infection, never detected as a digestive tract infection. Two-dose pyrantel pamoate or 2-dose albendazole could not suppress recurrence. Finally, 3-dose albendazole after 2-week intervals was successful in preventing relapse.

DOI： 10.1097/INF.0000000000002546

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jog.14189

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00737-018-0938-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Renal coloboma syndrome (RCS, MIM#120330), also known as papillorenal syndrome, is an inherited autosomal dominant disease characterized by ocular and/or renal involvement due to PAX2 mutation. The renal involvement typically consists of a hypo/dysplatic kidney and/or vesicoureteral reflux. Recent studies reported that missense PAX2 mutations cause familial focal segmental glomerular sclerosis (FSGS) without renal morphological malformations. To date, the reports of genotype-phenotype correlation including pathological findings regarding PAX2 mutations are scarce. We report a case of RCS with a novel PAX2 mutation that was pathologically diagnosed as FSGS and rapidly progressed to end-stage kidney failure (ESKD) with a review of past literature. A 6-year-old boy, who had bilateral coloboma and loss of vision in the left eye, was noted non-nephrotic proteinuria and renal dysfunction via school urine screening. Abdominal ultrasound showed no renal and urinary tract malformations and kidney biopsy showed FSGS. Genetic analysis revealed a novel insertion-deletion mutation in PAX2 (NM003987.4: c.70_72delinsA; p.Gly24Argfs*29). His kidney function deteriorated gradually during the following 2 years and kidney transplantation was performed at 9 years of age. In previous reports describing PAX2 mutations with FSGS, affected individuals with missense PAX2 mutations developed ESKD in adulthood, whereas one case with truncating PAX2 mutations developed ESKD in childhood similar to the current case. Our case highlighted the association of truncating PAX2 mutations with the risk of rapid progression to ESKD. Thus, PAX2 mutations should be included in genetic screening for such cases even in the absence of renal and urinary tract malformations.

DOI： 10.1007/s13730-019-00419-y

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/pai.13156

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pai.13156

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jad.2019.11.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10995-019-02840-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-19-0773

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Singapore  

DOI： 10.1007/978-981-15-1185-1_38

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：Institute of Electrical and Electronics Engineers Inc.  

DOI： 10.1109/MEMS46641.2020.9056167

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with steroid-resistant nephrotic syndrome (SRNS) who develop resistance to immunosuppressive agents, defined as refractory SRNS, have poor renal outcomes. Although the chimeric anti-CD20 monoclonal antibody rituximab has shown efficacy for frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome, its efficacy for refractory SRNS remains uncertain due to limited data. According to previous case reports, 50.4% of patients with refractory SRNS showed clinical improvements after rituximab treatment. Remission rates in patients with initial steroid resistance and late steroid resistance were 43.9 and 57.7%, respectively, and 41.5 and 63.6% in patients with focal segmental glomerulosclerosis and minor glomerular abnormalities, respectively. However, various factors (race, disease severity, number of rituximab doses, concomitant treatments, and observation period) differed among these observational studies and their consensus may also have been affected by potential publication bias. Rituximab monotherapy may have some degree of efficacy and lead to satisfactory outcomes in a subset of patients with refractory SRNS. However, administration of concomitant treatments during rituximab-mediated B cell depletion, such as methylprednisolone pulse therapy, daily oral prednisolone therapy, and immunosuppressive agents, may lead to better outcomes in these patients. Large-scale, multi-center prospective studies are needed to evaluate the efficacy and safety of such regimens.

DOI： 10.1007/s00467-018-4166-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13104-020-4915-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijerph17010205

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peripheral blood stem cell transplantation (PBSCT) is being increasingly performed as an alternative to bone marrow transplantation (BMT); however, PBSCT has not been proven to have equivalent outcome to BMT. We conducted a meta-analysis to compare survival rates and treatment-related complications between PBSCT and BMT for pediatric hematologic malignancies. We searched Medline, Embase plus Embase classics, and the Cochrane Central Register of Controlled Trials for the terms "hematopoietic stem cell transplantation" AND "allogeneic transplantation" AND "children", including randomized controlled studies and cohort studies without language limitations. We identified 7 of 5368 studies for inclusion in our meta-analysis. The cohorts of these studies included a total of 4328 patients, 3185 who underwent BMT and 1143 who underwent PBSCT. Five-year overall survival was similar in the 2 groups (PBSCT, 56.2%; BMT, 63.5%; relative risk [RR], 1.17; 95% confidence interval [CI], .91 to 1.52), as was the 5-year event-free survival (PBSCT, 49.9%; BMT, 57.2%; RR, 1.14; 95% CI, .93 to 1.39). The incidences of nonrelapse mortality and chronic graft-versus-host disease were higher in the PBSCT group compared with the BMT group (RR, 1.73; 95% CI, 1.50 to 1.99 versus RR, 1.55; 95% CI, 1.18 to 2.03). This meta-analysis found insufficient evidence to conclude that peripheral blood stem cells are equivalent to bone marrow. The results indicate that bone marrow can still be a preferred donor source for pediatric hematologic malignancies.

DOI： 10.1016/j.bbmt.2019.07.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：John Wiley and Sons Inc  

DOI： 10.1002/ejp.1717

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記述言語：英語  

Background: Thromboembolic events are rare but critical complications in childhood nephrotic syndrome. The veins are more commonly affected, while arterial thrombosis is extremely rare but often life-threatening. Herein, we describe the clinical course of a 10-years-old girl with catastrophic multiple arterial thrombosis at the primary onset of nephrotic syndrome who underwent bilateral above-knee amputation. Case diagnosis/treatment: A previous healthy 10-years-old girl contracted the influenza B virus. Five days later, she suddenly developed severe ischemia in both legs. Physical examination showed eyelid and leg edema, and laboratory tests revealed hypoalbuminemia and acute kidney injury. After undergoing contrast-enhanced computed tomography, the patient was diagnosed with multiple arterial thrombosis (including the bilateral iliac arteries) due to nephrotic syndrome. Despite the performance of surgical thrombectomies, fasciotomy, and systematic heparinization, she required bilateral above-knee amputation. The patient achieved spontaneous remission of nephrotic syndrome, and her renal function fully recovered. There were no findings suggestive of secondary nephrotic syndrome and antiphospholipid syndrome. Her protein C and protein S concentrations were slightly decreased at admission. However, whole-exome sequencing revealed a thrombotic risk variant (T630I) in the PROS1 gene encoding protein S. This missense variant is often reported in patients with thrombosis or protein S deficiency, and may result in a thrombotic predisposition in some situations, such as nephrotic syndrome. Conclusions: Arterial thrombosis is a rare complication; however, it must be considered, especially in patients with new-onset nephrotic syndrome. Early recognition is important for early intervention and prevention of serious sequelae.

DOI： 10.3389/fped.2020.00107

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vaccine adjuvants are traditionally used to augment and modulate the immunogenicity of vaccines, although in many cases it is unclear which specific molecules contribute to their stimulatory activity. We previously reported that both subcutaneous and intranasal administration of hydroxypropyl-β-cyclodextrin (HP-β-CD), a pharmaceutical excipient widely used to improve solubility, can act as an effective adjuvant for an influenza vaccine. However, the mechanisms by which mucosal immune pathway is critical for the intranasal adjuvant activity of HP-β-CD have not been fully delineated. Here, we show that intranasally administered HP-β-CD elicits a temporary release of IL-33 from alveolar epithelial type 2 cells in the lung; notably, IL-33 expression in these cells is not stimulated following the use of other vaccine adjuvants. The experiments using gene deficient mice suggested that IL-33/ST2 signaling is solely responsible for the adjuvant effect of HP-β-CD when it is administered intranasally. In contrast, the subcutaneous injection of HP-β-CD and the intranasal administration of alum, as a damage-associated molecular patterns (DAMPs)-inducing adjuvant, or cholera toxin, as a mucosal adjuvant, enhanced humoral immunity in an IL-33-independent manner, suggesting that the IL-33/ST2 pathway is unique to the adjuvanticity of intranasally administered HP-β-CD. Furthermore, the release of IL-33 was involved in the protective immunity against influenza virus infection which is induced by the intranasal administration of HP-β-CD-adjuvanted influenza split vaccine. In conclusion, our results suggest that an understanding of administration route- and tissue-specific immune responses is crucial for the design of unique vaccine adjuvants.

DOI： 10.3389/fimmu.2020.00360

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients receiving immunosuppressive agents are at risk of life-threatening infections. However, live vaccines are generally contraindicated in them. We conducted a prospective study regarding live attenuated vaccines for them. Patients elder than one year of age with immunosuppressive agents who showed negative or borderline antibody titers (virus-specific IgG levels < 4.0) against one or more of measles, rubella, varicella, and mumps and fulfilled the criteria (CD4 cell counts ≥ 500/mm3, stimulation index of lymphocyte blast transformation by PHA ≥ 101.6, serum IgG level ≥ 300 mg/dl, no steroid use or prednisolone < 1 mg/kg/day or < 2 mg/kg/2 days, trough levels of tacrolimus or cyclosporine were < 10 ng/ml or < 100 ng/ml and under good control of primary disease) were enrolled. Sixty-four vaccinations were administered to 32 patients. The seroconversion rates for measles, rubella, varicella, and mumps were 80.0%, 100.0%, 59.1%, and 69.2%, respectively. No life-threatening adverse events were observed, although one patient suffered from vaccine-strain varicella who showed cellular and humoral immunodeficiency (CD4 cell counts = 511/mm3, stimulation index of lymphocyte blast transformation by PHA = 91.1, serum IgG level = 208 mg/dl). This girl was immunized before we established the criteria for vaccination. Immunization with live attenuated vaccines for patients receiving immunosuppressive agents might be effective and safe if their cellular and humoral immunological parameters are within normal levels. However, determining the criteria for vaccination by immunological parameters should be established to guarantee the safety of live vaccines in the future. Clinical Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000007710. The date of registration: 2012/4/13.

DOI： 10.1371/journal.pone.0240217

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12887-019-1877-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12884-019-2632-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S0007114519002204

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12888-019-2401-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

DOI： 10.1186/s12884-019-2608-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.braindev.2019.07.001

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/1471-0528.15899

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1471-0528.15899

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.13986

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0886260519881517

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of extranodal non-Hodgkin lymphoma that carries an unsatisfactory prognosis. Treating refractory PCNSL is challenging because of resistance to conventional cytotoxic and intrathecal chemotherapies. Therefore, novel therapeutic approaches are needed. Here, we report a 12-year-old boy with CD20-positive PCNSL, which was refractory to combination chemotherapy and intravenous rituximab. However, the patient achieved complete remission after repeated intraventricular rituximab administration. The results of this case indicate that intraventricular rituximab is an effective option to treat refractory PCNSL in children.

DOI： 10.1097/MPH.0000000000001291

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Information on the epidemiology of idiopathic nephrotic syndrome (INS) in children, complications of INS and the side effects of steroid therapy is scarce. METHODS: The Japanese Pediatric Survey Holding Information of Nephrotic Syndrome, a nationwide cohort study, was conducted by the Japanese Study Group of Renal Disease in Children and enrolled 2099 children with newly diagnosed INS between 1 January 2010 and 31 December 2012. We conducted a follow-up study of the complications during the first onset and the patients' prognosis in this cohort. RESULTS: We obtained follow-up data on 999 children (672 males) with a median age at onset of 4.5 years [interquartile range (IQR) 2.8-9.4] and a median follow-up period of 4.1 years (IQR 2.5-5.1). At the first onset, 24% of patients experienced severe acute kidney injury (AKI), defined as a serum creatinine increase to a level two or more times the baseline. On logistic regression analysis, age, hematuria, severe hypoalbuminemia (serum albumin <1.0 g/dL) and severe bacterial infection were not independent factors, but female sex {hazard ratio [HR] 1.5 [95% confidence interval (CI) 1.1-1.7]} and hypertension [HR 4.0 (95% CI 2.6-6.0)] were significantly related to AKI. During the observation period, ocular hypertension requiring treatment occurred in 17.4% of patients, among which 0.4% received surgical treatment. Progression to frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome in 3 years was seen in 44.2% of the patients and was shown by the Cox regression analysis to be significantly related to younger age and days until remission at the first episode, but not to sex, hematuria, the minimum serum albumin level or AKI. Two patients died during the observation period. One patient showed progression to end-stage kidney disease. CONCLUSION: Based on the results of a multicenter questionnaire survey, the overall survival and renal survival rates were found to be excellent. However, proper management of complications, particularly in AKI and ocular hypertension, is mandatory.

DOI： 10.1093/ndt/gfz185

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Exposure Science and Environmental Epidemiology  

DOI： 10.1038/s41370-019-0139-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2188/jea.JE20180059

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

DOI： 10.1007/s10157-019-01747-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Infant acute lymphoblastic leukemia with lysine (K)-specific methyltransferase 2A (KMT2A) rearrangements usually has a poor prognosis regardless of the fusion partners of KMT2A. However, the prognosis of pediatric acute myeloid leukemia (AML) with KMT2A rearrangements depends on its translocation partners. We herein report the case of a 9-month-old boy with a KMT2A-USP2 fusion, which required diagnosis by whole transcriptome sequencing after the failure of detection of known translocation partners by conventional screening approaches. As this first report of a patient with AML with a KMT2A-USP2 fusion illustrates, identification of the partners in all patients with KMT2A-rearranged AML is critical to elucidate the outcomes associated with specific rearrangements and to develop appropriate treatment strategies. Moreover, development of additional methods to detect specific translocation partners of KMT2A and leukemia-specific targeting drugs is important to improve further the outcomes of KMT2A-rearranged AML.

DOI： 10.1002/gcc.22751

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: Subcutaneous involvement, including calcinosis and panniculitis, is a more common complication in juvenile dermatomyositis (JDM) than in adult dermatomyositis. Magnetic resonance imaging (MRI) is useful for evaluating disease distribution. We investigated the clinical significance of subcutaneous involvement in JDM. Methods: Thighs and hips in 18 newly diagnosed JDM patients were evaluated with fat-suppression MRI. Bilateral muscle, fascial and subcutaneous fat involvement were scored from 0 to 8 points according to the severity of distribution on MRI. Associations between clinical manifestations, serum muscle enzymes, and MRI scores were also evaluated. Results: Abnormal MRI findings in muscle, fascia and subcutaneous fat were observed in 18, 18, and 10 patients, respectively. Subcutaneous fat scores were significantly higher in early-diagnosed JDM patients (diagnosed less than 2 months from onset) than in late-diagnosed JDM patients (diagnosed later) (p = .025). Serum aldolase was elevated in all patients, although only eight demonstrated elevated serum creatine phosphokinase. Serum aldolase was significantly correlated with MRI scores for subcutaneous fat (p < .0001, ρ = .787) and fascia (p = .013 ρ = 0.574), but not muscle. Additionally, serum aldolase was significantly correlated with serum triglycerides (p = .009, ρ = 0.629). Conclusion: Subcutaneous fat involvement is a characteristic finding in early-diagnosed JDM and correlates with elevated serum aldolase.

DOI： 10.1080/14397595.2018.1511026

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Neonatal-onset Denys-Drash syndrome (NODDS) is a distinctive clinical entity and has a poor renal and life outcome. Early diagnosis of NODDS is important for managing disorders of sexual development and determining assigned gender. Although patients with NODDS and congenital nephrotic syndrome of the Finnish type (CNF) present with nephrotic syndrome in neonatal life or infancy, the clinical course of NODDS and factors distinguishing these diseases at onset is unknown. METHODS: We performed a retrospective cohort study of patients with NODDS and CNF between 1997 and 2017. Patients with nephrotic syndrome and WT1 or NPHS1 mutations with neonatal onset (within 30 days) were eligible. RESULTS: We studied eight patients with NODDS and 15 with CNF. The median serum creatinine level at onset in the NODDS group was significantly higher (1.85 mg/dL) than that in the CNF group (0.15 mg/dL; P = 0.002). The median placental/fetal weight ratio in the NODDS and CNF group was 41.8% and 21.0%, respectively (P = 0.001). Kaplan-Meier analysis showed that the median number of days for progression to ESRD from onset in the NODDS and CNF groups was 6 and 910 days, respectively (P < 0.001). All patients in the NODDS group were alive at follow-up. Only one patient in the CNF group died of cardiac complications during follow-up. CONCLUSION: CNS, renal dysfunction at onset, and a relatively large placenta are prominent signs of NODDS. Prognosis for patients with NODDS is satisfactory if appropriate and active management is performed.

DOI： 10.1007/s10157-019-01732-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although chronic kidney disease (CKD) is still a common complication, the prognosis of kidney function after liver transplantation (LT) is not well known. Moreover, kidney function after LT in children with renal involvement is unknown. METHODS: We retrospectively analyzed patients aged <20 years who underwent LT between November 2005 and March 2015 at our institute. RESULTS: The cohort included 313 pediatric LT recipients (135 males). The median age at LT was 1.1 years (interquartile range, 0.6 to 4.8 y), and the median duration of follow-up was 3.8 years (interquartile range, 1.7 to 6.2 y). We divided the patients by their primary disease into BA (biliary atresia), non-BA (other liver disease without primary renal involvement), or KD (patients with a pre-existing kidney disease) group, which comprised 141, 141, and 31 patients, respectively. Eight-year renal survival with stage 3 CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m) as the event was 99.2%, 92.4%, and 47.7% for the BA, non-BA, and KD group, respectively. Multivariate analysis disclosed primary kidney disease and multiple acute rejections as independent predictors of renal survival. The KD group showed no increase in the rate of kidney function deterioration after LT. CONCLUSIONS: Eight-year renal survival with stage 3 CKD, particularly in patients with non-pre-existing KD, exceeded 92.0%, and end-stage kidney disease developed in only one patient. Kidney function can be highly preserved following LT even in patients with KD, provided that LT is not contraindicated in patients with renal involvement receiving optimal immunosuppressive management.

DOI： 10.1097/TP.0000000000002548

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study was performed to determine the clinical features and outcomes of childhood-onset anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). METHODS: A retrospective Japanese multicenter study was performed in patients diagnosed with AAV before 16 years of age. RESULTS: Of 49 patients with AAV, 36 were female. The diagnoses were as follows: MPA (n = 38, 78%), granulomatosis with polyangiitis (GPA; n = 9, 18%), eosinophilic granulomatosis with polyangiitis (EGPA; n = 1, 2%), and other (n = 1, 2%). The median age at onset was 10.7 years, and median time to diagnosis was 2.0 months. Twenty-seven (55%) patients were identified through a school urinary screening program. Initial symptoms included fever and fatigue (45%), and renal (71%), pulmonary (29%), ocular (20%), and mucocutaneous involvement (22%). Although 27 (55%) patients achieved remission and none had died at the last follow-up, at least one recurrence occurred in 13 (48%) patients after a median of 48 months and was more common in patients with GPA (P < 0.01). After a median follow-up of 43 months, seven (14%) patients (all with MPA) progressed to end-stage renal disease (ESRD). CONCLUSIONS: Childhood-onset AAV has an estimated prevalence of 3.41-4.28 per million children and is characterized by female predominance and high frequency of detection in school urinary screening programs. More than 10% of patients with childhood-onset AAV still progress to ESRD without achieving remission. Histological chronicity is a factor associated with ESRD.

DOI： 10.1007/s00467-019-04228-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The association between the clinical presentation of congenital anomalies of the kidney and urinary tract (CAKUT) and gene mutations has yet to be fully explored. METHODS: In this retrospective cohort study, we examined patients with CAKUT who underwent gene analysis. The analysis was performed in patients with bilateral renal lesions, extrarenal complications, or a family history of renal disease. The data from the diagnosis, gene mutations, and other complications were analyzed. RESULTS: In total, 66 patients with CAKUT were included. Of these, gene mutations were detected in 14 patients. Bilateral renal lesions were significantly related to the identification of gene mutations (p = 0.02), and no gene mutations were observed in patients with lower urinary tract obstruction (six patients). There was no significant difference in the rate of gene mutations between those with or without extrarenal complications (p = 0.76). The HNF1β gene mutation was identified in most of the patients with hypodysplastic kidney with multicystic dysplastic kidney (six of seven patients). There was no significant difference in the presence or absence of gene mutations with respect to the renal survival rate (log-rank test p = 0.53). The renal prognosis varied, but the differences were not statistically significant for any of the gene mutations. CONCLUSIONS: CAKUT with bilateral renal lesions were significantly related to gene mutations. We recommend that CAKUT-related gene analysis be considered in cases of bilateral renal lesions. No gene mutations were observed in patients with lower urinary tract obstruction. The renal prognosis varied for each gene mutation.

DOI： 10.1007/s00467-019-04230-w

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/cga.12293

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cga.12293

掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12199-019-0795-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Varicella zoster virus (VZV) disease is a common complication after hematopoietic cell transplantation (HCT). The mortality rate for disseminated VZV infection is 34%. Acyclovir has been used for the prophylaxis of VZV disease after HCT, but the effectiveness of prophylaxis is controversial. We conducted a meta-analysis of the incidence of VZV disease within the first 1 year after acyclovir prophylaxis had been discontinued and assessed the risk of VZV disease during acyclovir prophylaxis. METHODS: Medline, EMBASE plus EMBASE classics, and the Cochrane Central Register of Controlled Trials were used for a systematic search. The inclusion criteria were both randomized controlled trials and cohort studies that described the effectiveness of acyclovir as prophylaxis against VZV disease after allogeneic HCT. RESULTS: We included seven studies involving a total of 2265 patients. No mortality by VZV was identified. Acyclovir prophylaxis significantly reduced the rate of VZV infection within the first 1 year after discontinuation (risk ratio: 0.38, 95% confidence interval (CI): 0.29-0.51). The risk of VZV disease during acyclovir prophylaxis was also reduced (risk ratio: 0.17, 95% CI: 0.12-0.24). Both short-term and long-term prophylaxis reduced the incidence of VZV infection (RR: 0.51, 95% CI: 0.30-0.86 vs RR: 0.34, 95% CI: 0.22-0.54). Low-dose acyclovir (<400 mg/d) is sufficient to reduce the risk of VZV disease. CONCLUSION: This study showed that acyclovir prophylaxis reduced VZV infection after HCT with no fatal cases and acyclovir prophylaxis is beneficial. No significant adverse effects occurred and no delayed VZV disease was identified.

DOI： 10.1111/tid.13061

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

DOI： 10.1136/jmedgenet-2018-105775

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/ppe.12551

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ppe.12551

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report the clinical course and outcome of primary varicella infection in six children with systemic juvenile idiopathic arthritis (sJIA) receiving tocilizumab. None had disseminated or fatal varicella infection, but one patient developed macrophage activation syndrome (MAS) and another had an arthritis relapse. All patients had a significant elevation of serum IL-6 levels, and the two children who developed MAS or arthritis relapse showed high serum IL-18 levels, which could cause a sJIA flare-up.

DOI： 10.1080/14397595.2016.1254314

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Persistent proteinuria seems to be a risk factor for progression of renal disease. Its reduction by angiotensin-converting inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is renoprotective. Our previous pilot study showed that 2-year lisinopril therapy is effective and safe for children with mild IgA nephropathy. When combined with ACEI and ARB, reported results are of greater decrease in proteinuria than monotherapy in chronic glomerulonephritis, including IgA nephropathy. To date, however, there have been no randomized controlled trials in children. METHODS: This is an open-label, multicenter, prospective, and randomized phase II controlled trial of 63 children with biopsy-proven proteinuric mild IgA nephropathy. We compared efficacy and safety between patients undergoing lisinopril monotherapy and patients undergoing combination therapy of lisinopril and losartan to determine better treatment for childhood proteinuric mild IgA nephropathy. RESULTS: There was no difference in proteinuria disappearance rate (primary endpoint) between the two groups (cumulative disappearance rate of proteinuria at 24 months: 89.3% vs 89% [combination vs monotherapy]). Moreover, there were no significant differences in side effects between the two groups. CONCLUSIONS: We propose lisinopril monotherapy as treatment for childhood proteinuric mild IgA nephropathy as there are no advantages of combination therapy. CLINICAL TRIAL REGISTRATION: Clinical trial registry, UMIN ID C000000006, https://www.umin.ac.jp .

DOI： 10.1007/s00467-018-4099-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.envres.2019.02.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0039-1677733

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jpag.2018.10.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.envint.2019.01.051

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s41105-018-0195-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41440-019-0206-x

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpsychires.2018.11.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Antenatal betamethasone (BMZ) is a standard therapy for reducing respiratory distress syndrome in preterm infants. Recently, some reports have indicated that BMZ promotes ductus arteriosus (DA) closure. DA closure requires morphological remodeling; that is, intimal thickening (IT) formation; however, the role of BMZ in IT formation has not yet been reported. Methods and Results: First, DNA microarray analysis using smooth muscle cells (SMCs) of rat preterm DA on gestational day 20 (pDASMCs) stimulated with BMZ was performed. Among 58,717 probe sets, ADP-ribosyltransferase 3 (Art3) was markedly increased by BMZ stimulation. Quantitative reverse transcription polymerase chain reaction (RT-PCR) confirmed the BMZ-induced increase of Art3 in pDASMCs, but not in aortic SMCs. Immunocytochemistry showed that BMZ stimulation increased lamellipodia formation. BMZ significantly increased total paxillin protein expression and the ratio of phosphorylated to total paxillin. A scratch assay demonstrated that BMZ stimulation promoted pDASMC migration, which was attenuated byArt3-targeted siRNAs transfection. pDASMC proliferation was not promoted by BMZ, which was analyzed by a 5'-bromo-2'-deoxyuridine (BrdU) assay. Whether BMZ increased IT formation in vivo was examined. BMZ or saline was administered intravenously to maternal rats on gestational days 18 and 19, and DA tissues were obtained on gestational day 20. The ratio of IT to tunica media was significantly higher in the BMZ-treated group. CONCLUSIONS: These data suggest that antenatal BMZ administration promotes DA IT through Art3-mediated DASMC migration.

DOI： 10.1253/circj.CJ-18-1033

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00420-018-1367-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jad.2018.11.061

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12884-019-2213-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.13756

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The purpose of this study was to resolve the clinical question as to whether all patients with unilateral multicystic dysplastic kidney (MCDK) should receive voiding cystourethrography (VCUG). METHODS: This is a retrospective study using cross-sectional analysis. Seventy-five children with unilateral MCDK were enrolled, excluding patients with other genetic or chromosome abnormalities, spinal cord diseases, or anal atresia. We reviewed their records from medical charts and calculated risk factors for abnormal VCUG using multivariate logistic regression analysis. RESULTS: Abnormal VCUG findings were present in 24 of 75 patients (32.0%), specifically, vesicoureteral reflux (VUR) in 8 (10.6%), including high-grade VUR in 2 (2.7%), and only lower urinary tract or bladder disease in 16 (21.3%). In multivariate analysis, only abnormal findings by ultrasonography was an independent risk factor for abnormal VCUG findings with statistical significance in multivariate analysis (OR 6.57; 95% CI 1.99-26.26; P = 0.002). When we excluded five patients who showed similar findings by ultrasonography and VCUG, abnormal findings by ultrasonography were again calculated as an independent risk factor (OR 4.44; 95% CI 1.26-28.42; P = 0.02). Sensitivity, specificity, positive predictive value, and negative predictive value of abnormal findings by ultrasonography to predict urologic anomalies by VCUG in these children were 83%, 59%, 49%, and 88%, respectively. Two children required a third ultrasonography to detect abnormal findings. CONCLUSIONS: We can select, using only abnormal findings by ultrasonography, children with unilateral MCDK who should undergo VCUG. We would also like to emphasize that ultrasonography should be performed repeatedly to detect congenital anomalies of the urinary tract.

DOI： 10.1007/s00467-018-4079-z

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：Institute of Electrical and Electronics Engineers Inc.  

DOI： 10.1109/MEMSYS.2019.8870677

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Eculizumab has been available for the treatment of atypical hemolytic-uremic syndrome (aHUS) in Japan since 2013. To assess safety and effectiveness of eculizumab in adult aHUS patients in the real-life setting, we performed interim analysis of a post-marketing surveillance mandated by Japanese regulations. METHODS: This study enrolled any patient who was diagnosed with TMA excluding Shiga toxin-producing Escherichia coli-HUS or thrombotic thrombocytopenic purpura based on Japanese clinical guide published in 2013 as inclusion criteria and treated with eculizumab. Although the term aHUS was redefined to denote only complement-mediated HUS in the guide revised in 2016, the patients with TMA caused by other causes (secondary TMA) were included. Patient outcomes and safety were evaluated at 6 months, 12 months, and annually thereafter. RESULTS: Thirty-three patients with aHUS and 27 patients with secondary TMA were enrolled. Median treatment duration of aHUS was 24weeks. Complement genes variants were detected in 11 of 18 patients with aHUS (61.1%). Among the 29 aHUS patients with available baseline data, platelet count (PLT), lactic dehydrogenase and serum creatinine (SCr) improved within 1-month after eculizumab initiation. TMA event-free status, complete TMA response, PLT normalization, and SCr decrease were achieved in 67.9% (19/28), 27.8% (5/18), 56.5% (13/23), and 57.1% (16/28) of patients, respectively. Thirty-three and 11 adverse reactions were observed in patients with aHUS (13/33 patients) and secondary TMA (6/27 patients), respectively. CONCLUSIONS: This interim analysis confirmed the acceptable safety profile and effectiveness of eculizumab for Japanese adult aHUS patients in real-world settings.

DOI： 10.1007/s10157-018-1609-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Breath sound parameters have been suggested as biomarkers of the airway narrowing in children. Using a commercially available breath sound analyzer, the characteristics of the airway condition were investigated in infants with the risk factors for asthma development. METHODS: A total of 443 infants (mean age, 9.9 months; range, 3-24 months) were included in the present study. The breath sound parameters of the frequency limiting 99% of the power spectrum (F99), the roll-off from 600 to 1200 Hz (Slope) and spectrum curve indices, the total area under the curve of the dBm data (A3/AT) and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF75 and RPF50), were evaluated. Using an ATS-DLD based original Japanese questionnaire, we examined the characteristics of airway condition of infants. RESULTS: Finally, 283 infants in good health were included in the present study. The RPF75, RPF50, Slope and F99 in infants with positive results of allergy and atopic dermatitis were significantly increased more than those in the infants with negative result. CONCLUSIONS: Our data highlight the characteristics of breath sounds in infants with risk factors for asthma. The breath sound analysis may be useful for assessing the airways of infants for asthma development.

DOI： 10.1016/j.alit.2018.07.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S0007114518002842

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In 2013, eculizumab was approved for treatment of the atypical hemolytic-uremic syndrome (aHUS) in Japan, which was defined as a thrombotic microangiopathy (TMA) excluding Shiga toxin-producing Escherichia coli-HUS and thrombotic thrombocytopenic purpura. Simultaneously, post-marketing surveillance was started to assess its safety and effectiveness. In 2016, Japanese clinical guide redefined terms to limit the use of "aHUS" to complement-mediated HUS only. Accordingly, TMA with other causes was defined as secondary TMA. Here we report the interim analysis of post-marketing surveillance of pediatric patients with aHUS and secondary TMA. METHODS: Pediatric patients treated with eculizumab from approval to 15 March 2017 were included in this observational real-world study. Clinical endpoints of effectiveness were TMA event-free status, complete TMA response, platelet count normalization, and improvement of estimated glomerular filtration rate (eGFR). Adverse reactions to eculizumab were also analyzed. RESULTS: In 27 pediatric patients with aHUS, median age at diagnosis was 4 years. Complement genes' variants were detected in 14 of 21 patients (66.7%). Median time from diagnosis to eculizumab initiation was 2.0 days. TMA event-free status, complete TMA response, platelet normalization, and improvement in eGFR were achieved in 85.2, 36.4, 78.3, and 75.0% of patients, respectively. Three patients with aHUS died. Twenty-four and 10 adverse reactions were reported in 31 aHUS patients and 17 secondary TMA patients, respectively; however, no eculizumab-related death or meningococcal infection was reported. CONCLUSIONS: This interim analysis confirmed that eculizumab is well-tolerated and effective for Japanese pediatric patients with aHUS in a real-world setting.

DOI： 10.1007/s10157-018-1610-2

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記述言語：英語  

Background: Eculizumab has dramatically changed poor outcomes of complement-mediated atypical hemolytic uremic syndrome (aHUS) as first-line treatment. Discontinuation of eculizumab remains challenging, and doctor's visits every 2 weeks for intravenous injection because of standard dosing protocols is a huge burden. The Ultra-high cost of eculizumab is also an issue. We attempted to establish a personalized dosing regimen of eculizumab based on pharmacokinetics and pharmacodynamics in a 2-year-old girl with aHUS with a C3 mutation. Case presentation: She developed aHUS at 5 months of age and was successfully treated with eculizumab. At 2 years of age, we measured eculizumab concentrations and performed pharmacokinetics and pharmacodynamics analysis to optimize her dosing protocol. Her blood concentrations at every 2-, 3-, and 4-week intervals were simulated. Pharmacokinetics analysis showed that her eculizumab clearance was 40% lower than the population mean reported for aHUS. Pharmacokinetic simulation suggested that the 2- and 3-week interval regimen could be sufficient to achieve an efficient trough concentration (>100 μg/mL). We simulated her individual pharmacokinetics profile at 4 years of age with consideration of her growth, which still showed complete inhibition of the alternative complement pathway with the 3-week interval regimen. We continued the 300-mg eculizumab infusion every 3 weeks while CH50 levels were constantly maintained at undetectably low concentrations with no recurrence until 6 years of age. Conclusions: Pharmacokinetics and pharmacodynamics estimation was useful for establishing a personalized dosing regimen for eculizumab and reducing the patient's burden and high medical costs.

DOI： 10.3389/fped.2019.00519

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extracellular host-derived DNA, as one of damage associated molecular patterns (DAMPs), is associated with allergic type 2 immune responses. Immune recognition of such DNA generates the second messenger cyclic GMP-AMP (cGAMP) and induces type-2 immune responses; however, its role in allergic diseases, such as asthma, has not been fully elucidated. This study aimed to determine whether cGAMP could induce asthma when used as an adjuvant. We intranasally sensitized mice with cGAMP together with house dust mite antigen (HDM), followed by airway challenge with HDM. We then assessed the levels of eosinophils in the broncho-alveolar lavage fluid (BALF) and serum HDM-specific antibodies. cGAMP promoted HDM specific allergic asthma, characterized by significantly increased HDM specific IgG1 and total IgE in the serum and infiltration of eosinophils in the BALF. cGAMP stimulated lung fibroblast cells to produce IL-33 in vitro, and mice deficient for IL-33 or IL-33 receptor (ST2) failed to develop asthma enhancement by cGAMP. Not only Il-33-/- mice, but also Sting-/-, Tbk1-/-, and Irf3-/-Irf7-/- mice which lack the cGAMP-mediated innate immune activation failed to increase eosinophils in the BALF than that from wild type mice. Consistently, intranasal and oral administration of amlexanox, a TBK1 inhibitor, decreased cGAMP-induced lung allergic inflammation. Thus, cGAMP functions as a type 2 adjuvant in the lung and can promote allergic asthma in manners that dependent on the intracellular STING/TBK1/IRF3/7 signaling pathway and the resultant intercellular signaling pathway via IL-33 and ST2 might be a novel therapeutic target for allergic asthma.

DOI： 10.3389/fimmu.2019.02212

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