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PURPOSE: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). STUDY DESIGN: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. METHODS: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. RESULTS: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. CONCLUSION: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.
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The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2-47 years, 12 males) and 22 controls (age 4-40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, Pâ =â 0.00731) and oxidative phosphorylation (hsa00190, Pâ =â 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.
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Citocinas , Células Dendríticas , Síndrome de Down , Lipopolissacarídeos , Monócitos , Humanos , Síndrome de Down/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Masculino , Feminino , Adolescente , Adulto , Criança , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Monócitos/metabolismo , Pré-Escolar , Pessoa de Meia-Idade , Citocinas/metabolismo , Adulto Jovem , Células CultivadasRESUMO
We report a pediatric case developing hypoglycemic encephalopathy during the acute phase of coxsackievirus (CV)-A4 infection. A part of the sequence of the virus detected from our patient was completely identical to that in other CV-A4 strain reported as a recombinant strain with lethal CV-A2, suggesting that the properties of CV-A4 might be associated with the severe hypoglycemic encephalopathy.
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BACKGROUND: The impact of parent-childbearing age on child development at 36 months of age is controversial. AIMS: We used data from a large cohort study with multiple imputation and mediation analyses of variables. METHODS AND PROCEDURES: A total of 72,606 parent-child pairs from the Japan Environment and Children's Study were included in the study. Parents' ages were categorized into five groups. We used five domains of the Japanese translation of the Ages and Stages Questionnaire, Third Edition (J-ASQ-3). Scores below the cutoff value at 36 months were defined as developmental delays in each domain. We used three logistic analysis models. In Model 3, we analyzed maternal and paternal age using other variables and covariates. OUTCOMES AND RESULTS: The outcome was a developmental delay in the five domains of J-ASQ-3. In Model 3, ORs for the developmental delay scores regarding parental age were significantly associated with all five domains of J-ASQ-3. The mediation analysis showed a significant mediation interaction effect for mothers but localized for fathers. CONCLUSION: Advanced paternal and maternal ages were associated with developmental delay in children. Awareness of the risks of childbearing at an advanced age is crucial. WHAT'S THE PAPER ADDS: This manuscript used data from a large cohort study with multiple imputation and mediation analyses. With these analyses, we identified the pure effect of advanced parental age on their children's development at 36 months.
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Desenvolvimento Infantil , Deficiências do Desenvolvimento , Idade Materna , Idade Paterna , Humanos , Japão , Feminino , Masculino , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Adulto , Estudos de Coortes , Pais , Inquéritos e Questionários , Modelos LogísticosRESUMO
BACKGROUND: Lifelong health is dependent on prenatal growth and development, influenced by the placental intrauterine environment. Charged with dual functions--exchange of oxygen and nutrients as well as a barrier against toxins--the placenta itself is susceptible to environmental exposure to heavy metals. OBJECTIVE: To examine the use of placenta weight as a biomarker for heavy metal exposure using a large Japanese cohort of pregnant women. METHODS: The placenta weight, as a biomarker of exposure to heavy metals (cadmium, lead, and mercury), was investigated using data from the Japan Environment and Children's Study (2011-2014). Selenium and manganese were included as factors directly affecting fetal growth or heavy metal toxicity. Maternal blood samples collected in the second or third trimester were used to measure heavy metal concentrations. The association between maternal blood metal concentrations and placenta weight was explored by applying Z scores and multivariable logistic regression analysis and classifying participants into quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. RESULTS: This study included a total of 73,005 singleton pregnant women who delivered via live births and met the inclusion criteria. The median heavy metal concentrations in the maternal whole blood were 0.662 ng/g cadmium, 5.85 ng/g lead, 3.61 ng/g mercury, 168 ng/g selenium, and 15.3 ng/g manganese. Regression analysis revealed a significant correlation between placenta weight Z scores and maternal blood metal concentrations: cadmium, 0.0660 (standard error = 0.0074, p < 0.001); selenium, -0.3137 (standard error = 0.0276, p < 0.001); and manganese, 0.1483 (standard error = 0.0110, p < 0.001). CONCLUSION: This study provides a robust examination of the association between heavy metal exposure and placenta weight. Cadmium and manganese showed a positive correlation with significant differences, whereas selenium showed a negative correlation. Essential elements notably affect placenta weight differently. No significant association was noted between lead or mercury and placenta weight.
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Poluentes Ambientais , Mercúrio , Metais Pesados , Placenta , Selênio , Humanos , Feminino , Gravidez , Metais Pesados/sangue , Japão , Adulto , Selênio/sangue , Poluentes Ambientais/sangue , Mercúrio/sangue , Exposição Materna/estatística & dados numéricos , Cádmio/sangue , Chumbo/sangue , Manganês/sangue , Tamanho do Órgão/efeitos dos fármacos , Estudos de Coortes , Adulto Jovem , Recém-Nascido , Biomarcadores/sangueRESUMO
The quality of indoor environment is a risk factor for early childhood eczema and atopic dermatitis; however, its influence during pregnancy on childhood eczema in Japan has not been investigated. In this study, we aimed to determine the indoor environmental factors that are associated with eczema in children up to 3 years of age, using national birth cohort data from the Japan Environment and Children's Study (JECS). Information on indoor environments and eczema symptoms until 3 years of age was collected using self-administered questionnaires to the mothers. A total of 71,883 and 58,639 mother-child pairs at 1.5- and 3-years-old, respectively, were included in the former analyses. To account for prenatal indoor risk factors, 17,568 (1.5-years-old) and 7063 (3-years-old) children without indoor mold and/or ETS exposure were included in the final analysis. A higher mold index, gas heater use, parquet flooring use, and frequent insecticide use showed significantly increased risks for childhood eczema up to 3 years of age. These associations were consistent after stratification analysis among children whose parents did not have a history of allergies. The updated WHO guidelines on indoor air quality should be implemented based on recent findings regarding the effects of prenatal exposure to indoor dampness on health effects of children further in life, including asthma, respiratory effects, eczema, and other immunological effects.
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Poluição do Ar em Ambientes Fechados , Eczema , Efeitos Tardios da Exposição Pré-Natal , Humanos , Japão/epidemiologia , Feminino , Pré-Escolar , Gravidez , Eczema/epidemiologia , Eczema/etiologia , Fatores de Risco , Lactente , Poluição do Ar em Ambientes Fechados/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Incidência , Masculino , Adulto , Inquéritos e QuestionáriosRESUMO
ABSTRACT: Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.
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Antineoplásicos , Neoplasias Encefálicas , Exposição Ocupacional , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Gravidez , Feminino , Humanos , Criança , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Estudos de Coortes , Japão/epidemiologia , Fatores de Risco , Mães , Exposição Ocupacional/efeitos adversos , Antineoplásicos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Estudos de Casos e ControlesRESUMO
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.
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Depressão , Gravidez na Adolescência , Criança , Adolescente , Gravidez , Feminino , Adulto Jovem , Humanos , Adulto , Depressão/epidemiologia , Japão/epidemiologia , Estudos Prospectivos , Gestantes/psicologiaRESUMO
We report a pediatric case of disseminated Bartonella henselae infection accompanied by multiple intracranial lesions. The patient developed multiple intracranial lesions despite treatment with azithromycin and gentamicin. After switching to rifampicin, the clinical symptoms of the patient improved. Given its good penetration into the central nervous system, rifampicin may be recommended for the treatment of B. henselae infection accompanied by intracranial lesions.
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BACKGROUND: Neonatal disseminated intravascular coagulation (DIC) is a rare disease with a poor outcome. However, data on the incidence, treatment, and outcome of neonatal DIC are scarce. Thus, this study investigated the status of neonatal DIC in Japan. METHODS: We sent a retrospective questionnaire-based survey regarding the status of diagnosis and treatment of neonatal DIC from January 1, 2016, to December 31, 2018, to 30 hospitals in Kyushu with a neonatal-perinatal medicine division. The data collected by the questionnaire survey included information about the patients diagnosed with neonatal DIC. RESULTS: Among the 13,582 neonates surveyed, 120 (0.9 %) were diagnosed with DIC. Of them, clinical data were available for 105 cases. There were 11 deaths (mortality rate: 10.4 %), with the most common underlying condition being infection (n = 9), followed by neonatal asphyxia and hematologic disease (both, n = 1). Compared with the survival group, the death group had more infections, as well as a higher rate of bleeding symptoms and organ dysfunction. CONCLUSIONS: Neonatal DIC associated with infectious diseases has a poor outcome. Therefore, it is necessary to formulate diagnostic and treatment guidelines for early intervention in such cases.
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BACKGROUND: Fish are a rich source of essential nutrients that protect against preterm birth. However, as fish can absorb environmental pollutants, their consumption can also increase the risk of preterm birth. This study aimed to assess whether maternal fish consumption during pregnancy is associated with preterm birth in a nationwide large Japanese cohort that consumed relatively high amounts and many types of fish. METHODS: This study included 81,428 mother-child pairs enrolled in a nationwide prospective Japanese birth cohort study. Fish consumption was assessed using a validated food frequency questionnaire. Multivariate logistic regression was used to investigate the association of total consumption of fish, fatty fish and lean fish, fish paste, and seafood and clams with preterm birth, adjusted for potential confounders. RESULTS: There was no association between overall fish consumption and preterm births. However, the highest quintile of fish paste consumption was significantly associated with an increased risk of preterm birth (odds ratio [OR]: 1.11; 95% confidence interval [CI: 1.04, 1.17]). The consumption of baked fish paste at least three times per week was significantly associated with preterm birth (OR: 1.20; 95% CI: 1.03, 1.40). Consumption of other types of fish, except fish paste, was not significantly associated with preterm birth risk. CONCLUSIONS: Fish paste consumption may increase the risk of preterm birth. Further studies are required to confirm this association.
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Poluentes Ambientais , Nascimento Prematuro , Recém-Nascido , Animais , Feminino , Gravidez , Humanos , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Estudos de Coortes , Japão/epidemiologia , Estudos ProspectivosRESUMO
BACKGROUND: The usefulness of an induced sputum in the identification of causative bacteria of community-acquired pneumonia (CAP) in young children is controversial. This study aimed to investigate the significance of the implementation of an induced sputum culture among children with CAP and the impact of prior use of antimicrobial agents on the quality of the sample and result of the culture. METHODS: This prospective study included 96 children hospitalized for acute bacterial CAP whose sputum samples were collected by suctioning from the hypopharynx through the nose. The samples were evaluated for their quality using Geckler classification, and the result of this conventional culture method was compared to that of a clone library analysis of the bacterial 16S rRNA gene sequence for each sample. RESULTS: The concordance between bacteria isolated by sputum culture and the most predominant bacteria identified by a clonal library analysis was significantly higher in the samples judged as a good quality (Geckler 5, 90%) than in others (70%). The rate of good-quality sputum sample was significantly higher in samples collected from patients without prior antimicrobial therapy (70%) than in those from patients with it (41%). The concordance between the two methods was significantly higher in the former (88%) than in the latter population (71%). CONCLUSION: Bacteria isolated by the culture using good-quality sputum samples collected from children with CAP were more likely to be causative pathogens. Sputum samples collected before starting antimicrobial therapy showed better quality and higher probability of the identification of causative pathogens.
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Anti-Infecciosos , Infecções Comunitárias Adquiridas , Pneumonia , Pré-Escolar , Humanos , Bactérias , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Estudos Prospectivos , RNA Ribossômico 16S/genética , Escarro/microbiologiaRESUMO
Cyclic vomiting syndrome (CVS) is characterized by recurrent episodes of severe vomiting with a completely asymptomatic interictal interval. Relatively few patients develop CVS in the neonatal period, and an early diagnosis is difficult. We experienced an infant who was diagnosed with neonatal-onset CVS in early infancy. An 8-day-old girl was admitted to our neonatal intensive care unit because of frequent vomiting beginning 12 h after birth and weight loss reaching 84.2% of her birth weight. Despite extensive examinations, no abnormalities to explain the vomiting were found. She continued to vomit, and a cyclical pattern with a vomiting phase lasting for three days followed by a non-vomiting phase lasting for about one to two weeks became obvious. Based on her clinical course, the family history of migraine and the effectiveness of Phenobarbital, she was diagnosed with CVS at three months old. Although CVS is a diagnosis of exclusion, a family history of migraine can aid its early diagnosis. If the illness is suspected in the neonatal period, diagnostic treatment with Phenobarbital may be considered. The case suggests the need to include CVS in the differential diagnosis of neonates with unexplained repetitive vomiting.
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Transtornos de Enxaqueca , Vômito , Humanos , Lactente , Feminino , Recém-Nascido , Vômito/etiologia , Vômito/terapia , Transtornos de Enxaqueca/complicações , Diagnóstico Precoce , Fenobarbital/uso terapêuticoRESUMO
BACKGROUND: Sleep problems and irritable temperaments are common among infants with autism spectrum disorder (ASD). The prospective association between such sleep problems and irritable temperaments and ASDs needs to be determined for elucidating the mechanism and exploring the future intervention study. Thus, in this study, we investigated whether sleep quality and temperament in 1-month-old infants are associated with the onset of ASD in 3-year-old children. We also assessed its sex-stratified associations. METHODS: We conducted a longitudinal study using data from 69,751 mothers and infants from a large-cohort study, the Japan Environment and Children's Study. We examined the prospective association between infant sleep quality and temperament at 1 month of age and ASD diagnosis by 3 years of age. RESULTS: Here we show infants with longer daytime sleep have a higher risk of later ASD than those with shorter daytime sleep (risk ratio [RR]: 1.33, 95% confidence interval [CI]: 1.01-1.75). Infants who experienced intense crying have a higher risk of ASD than those who did not (RR: 1.31, 95% CI: 1.00-1.72). There is a difference in sex in the association between a bad mood and later ASD. In particular, female infants experiencing bad moods have a higher risk of ASD than others (RR: 3.59, 95% CI: 1.91-6.75). CONCLUSIONS: The study findings provide important information for future intervention to reduce the risk of future ASD.
Sleep problems and irritable temperaments are common among infants with autism. This study looked at the sleep and temperament of nearly 70,000 1-month-old infants in Japan and whether they were subsequently diagnosed with autism spectrum disorder during the first three years of life. Children who had slept for longer during the day and were more prone to frequent, prolonged, or intense crying were more likely to have been diagnosed with Autism Spectrum Disorder by age 3. The findings of this study might be useful for those monitoring the development of autism spectrum disorder or developing support for those with autism spectrum disorders.
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BACKGROUND: Prenatal exposure to metal elements has been reported as a potential risk factor for congenital malformation. However, studies on the relationship with congenital anomalies of the kidney and urinary tract (CAKUT) are very scarce. METHODS: Participants of a prospective cohort from the Japan Environment and Children's Study, conducted at 15 research centers, were recruited between January 2011 and March 2014. The exposure factors were concentrations of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) measured from maternal whole blood in the second or third trimester. The primary outcome was CAKUT diagnosed during the first three years of life, which was classified into isolated cases and complicated cases accompanied by extrarenal congenital defects. To conduct a nested case-control design within the cohort, we selected 351 isolated cases with 1404 matched controls, and 79 complicated cases with 316 matched controls. RESULTS: A logistic regression model was used to examine the associations between individual metal concentrations and each subtype of CAKUT. A higher level of Se was associated with an increased risk of isolated CAKUT (adjusted odds ratio [95 % confidence interval]: 3.22 [1.33-7.77]). Meanwhile, higher levels of Pb and Mn were associated with a reduced risk of the complicated subtype (0.46 [0.24-0.90] and 0.33 [0.15-0.73], respectively). A Bayesian kernel machine regression model accounting for mixed effects of multiple metals further demonstrated that a higher level of Mn alone was significantly associated with a reduced occurrence of the complicated subtype. CONCLUSIONS: Using a stringent statistical approach, the present study demonstrated that a higher Mn concentration in the maternal blood was associated with a lower risk of complicated CAKUT in offspring. Further cohort and experimental studies are needed to verify the clinical impact of this finding.
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Mercúrio , Selênio , Sistema Urinário , Gravidez , Feminino , Humanos , Criança , Estudos Prospectivos , Japão/epidemiologia , Teorema de Bayes , Chumbo , RimRESUMO
We report a case with Clavispora lusitaniae-induced purulent thrombophlebitis. The patient had multiple risk factors for the development of fungal thrombophlebitis including surgical procedure, mechanical ventilation, admission to intensive care unit, total parenteral nutrition and long-term antimicrobial therapy in addition to the insertion of central venous catheter. The symptoms finally improved by a combination therapy of micafungin and flucytosine, but the therapy did not rapidly resolve candidemia. The appropriate antifungal therapy for C. lusitaniae-induced purulent thrombophlebitis is uncertain. Further study is desired to seek the appropriate therapy for the disease.