Cost-effectiveness analysis of adult pneumococcal conjugate vaccines for pneumococcal disease in Japan.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is used in the Japanese National Immunization Program for older adults and adults with increased risk for pneumococcal disease, however, disease incidence and associated burden remain high. We evaluated the cost-effectiveness of pneumococcal conjugate vaccines (PCVs) for adults aged 65 years and high-risk adults aged 60-64 years in Japan. RESEARCH DESIGN AND METHODS: Using a Markov model, we evaluated lifetime costs using societal and healthcare payer perspectives and estimated quality-adjusted life-years (QALYs), and number of prevented cases and deaths caused by invasive pneumococcal disease (IPD) and non-IPD. The base case analysis used a societal perspective. RESULTS: In comparison with PPSV23, the 20-valent PCV (PCV20) prevented 127 IPD cases 10,813 non-IPD cases (inpatients: 2,461, outpatients: 8,352) and 226 deaths, and gained more QALYs (+0.0015 per person) with less cost (-JPY22,513 per person). All sensitivity and scenario analyses including a payer perspective analysis indicated that the incremental cost-effectiveness ratios (ICERs) were below the cost-effectiveness threshold value in Japan (JPY5 million/QALY). CONCLUSIONS: PCV20 is both cost saving and more effective than PPSV23 for adults aged 65 years and high-risk adults aged 60-64 years in Japan.

Preconception underweight impact on postnatal osteoporotic fracture: a retrospective cohort study using Japanese claims data.

BACKGROUND: Undernutrition and underweight are osteoporosis risk factors. Therefore, improving the health of underweight young women in Japan is an important medical issue. However, few studies have evaluated the association between being preconception underweight and postnatal osteoporotic fractures in young women. METHODS: This retrospective cohort study used a Japanese nationwide claims database (JMDC Inc.) to evaluate the effect of preconception underweight on the incidence of osteoporotic fracture within two years after delivery. Data from 16,684 mothers who delivered their first singleton babies between January 2006 and December 2020 were analysed. The combination of disease codes of fractures at sites associated with osteoporosis and medical procedures for fractures was defined as the incidence of osteoporotic fractures, whereas the body mass index (BMI) recorded 12-36 months before delivery was used as the exposure. We estimated the incidence of osteoporotic fractures by BMI category using a Kaplan-Meier curve and examined the fracture risk using Cox hazard regression analyses. RESULTS: Fifty-one women (0.31%) were affected by osteoporotic fractures within two years of delivery. More than 80% of these were rib fractures, and approximately 65% of fractures occurred after the first year postpartum. Preconception underweight (BMI < 18.5 kg/m2) was significantly associated with the incidence of postpartum osteoporotic fractures. There was no significant association between low BMI and postnatal fractures, as analysed via multiple categorical logistic regression analysis. CONCLUSION: Appropriate control of preconception weight might be critical to improving the postpartum quality of life, subsequent bone health, and neonatal care environment.

Assessment of mediastinal shift angles in congenital pulmonary airway malformation: a new fetal magnetic resonance imaging indicator of congenital lung disease.

BACKGROUND: The mediastinal shift angle is a new fetal magnetic resonance imaging (MRI) index that is reportedly correlated with postnatal survival in fetuses with congenital diaphragmatic hernia. However, its correlation in patients with congenital pulmonary airway malformation (CPAM) has not been assessed. OBJECTIVE: This study aimed to establish a normal range for the right/left mediastinal shift angles, to evaluate the mediastinal shift angle in fetuses with CPAM, to compare the mediastinal shift angle with the CPAM volume ratio, and to evaluate the predictive value of the mediastinal shift angle measurements. MATERIALS AND METHODS: To establish the normal range, we measured the mediastinal shift angle bilaterally in 124 fetuses without any lung abnormality (the control group). Subsequently, the mediastinal shift angle was measured in 32 fetuses pathologically diagnosed with CPAM. Moreover, the mediastinal shift angle and CPAM volume ratio were compared using fetal MRI. RESULTS: The mean values for the right/left mediastinal shift angles were 18.6°/26.3° and 39.2°/35.9° for control fetuses and fetuses with CPAM, respectively. The mediastinal shift angle and the CPAM volume ratio showed a positive statistical correlation. The area under the curve demonstrated high discriminatory accuracy for the mediastinal shift angle (0.76). CONCLUSION: The mediastinal shift angle has potential to replace the CPAM volume ratio for evaluating the severity of CPAM in fetal MRI.

Dose-Finding and Efficacy Confirmation Trial of the Superselective Intra-arterial Infusion of Cisplatin and Concomitant Radiation Therapy for Locally Advanced Maxillary Sinus Cancer (JCOG1212): Results of the Efficacy Confirmation Phase in Patients with T4aN0M0.

PURPOSE: Locally advanced maxillary sinus cancers require radical surgery as a standard treatment, but this often results in significant disfigurement and impairment of function. JCOG1212 seeks to evaluate the safety and efficacy of the superselective intra-arterial infusion of cisplatin and concomitant radiation therapy (RADPLAT) for T4aN0M0 and T4bN0M0 maxillary sinus squamous cell carcinomas. We herein report the results of the efficacy confirmation phase in the T4a cohort. METHODS AND MATERIALS: Patients received 100 mg/m2 cisplatin intra-arterially weekly for 7 weeks with concomitant radiation therapy (total 70 Gy) as determined by the results of the preceding dose-finding phase. The trial aimed to evaluate the primary endpoint of 3-year overall survival (OS), comparing RADPLAT with the historical control for 3-year OS in surgery (80%). RESULTS: From April 2014 to August 2018, 65 patients were registered in the T4a cohort from 18 institutions, consisting of 54 men and 11 women with a median age of 64 years (range, 40-78 years) and Eastern Cooperative Oncology Group performance status 0/1 (58/7). After excluding 1 ineligible patient, 64 patients were included in the primary analysis of efficacy and safety. The median follow-up was 4.5 years in all eligible patients, and the primary endpoint for 3-year OS was 82.8% (90% CI, 73.4%-89.2%). With regard to acute adverse events, mucositis (grade ≥3), neutropenia (grade ≥3), increased creatinine (grade ≥2), hearing impairment (grade ≥2), and stroke (grade ≥2) were observed in 20.3%, 14.1%, 3.1%, 3.1%, and 1.6% of patients, respectively. One treatment-related death due to a thromboembolic event was reported. CONCLUSIONS: We demonstrated that RADPLAT showed favorable results for patients with T4aN0M0 maxillary sinus squamous cell carcinomas compared with the historical control for 3-year OS in surgery, which was from an earlier period, and showed some specific toxicities. Therefore, RADPLAT, as well as surgery, can be regarded as a possible treatment option for these patients.

Ultrasound measurement of umbilical venous flow volume at the intra-abdominal portion in normal fetuses.

PURPOSE: Umbilical venous flow volume (UVFV) measured using ultrasound can be used to assess placental circulation in a fetus. UVFV measured at the intra-abdominal portion using half the maximum flow velocity of the umbilical vein (UV) has good reproducibility with low variance. However, reference values in previous reports were based on a small number of cases with a wide reference range. In the present study, we evaluated UVFV standard values measured at the intra-abdominal portion in normal Japanese fetuses. METHODS: Measurements were performed on normal pregnant women during routine ultrasound screening at around 20 or 30 weeks of gestation. The diameter and flow velocity of the UV were measured at the fetal abdomen point between the insertion of the UV and branches of the portal vein. UVFV (ml/min) was calculated as follows: (UV diameter [cm]/2)2 × maximum velocity [cm/s] × 0.5 × 3.14 × 60). RESULTS: A total of 278 pregnant women were included in the study. UVFV increased with gestational weeks, and UVFV per estimated fetal weight (EFW) slightly decreased with increasing gestational weeks. The 50th (10th-90th) percentiles of UVFV per EFW at 20, 25, and 30 weeks of gestation were 130 (105-165), 123 (94-147), and 104 (80-131) ml/min/kg, respectively. CONCLUSION: New UVFV reference values measured at the intra-abdominal portion of fetuses using large-scale samples were established. Future studies should assess fetuses under pathologic conditions using UVFV reference values.

Enhanced early skin treatment for atopic dermatitis in infants reduces food allergy.

BACKGROUND: Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization. OBJECTIVES: This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only. METHODS: This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age. RESULTS: This study enrolled 650 infants and analyzed 640 infants (enhanced [n = 318] or conventional [n = 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P = .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age. CONCLUSIONS: This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs.

iPAPP: study protocol for a multicentre randomised controlled trial comparing safety and efficacy of intravenous paracetamol and indomethacin for the treatment of patent ductus arteriosus in preterm infants.

INTRODUCTION: Patent ductus arteriosus (PDA) causes severe morbidity in premature infants. Although the use of indomethacin is the standard therapy for PDA, it is sometimes not applicable because of its adverse effects, such as renal and platelet dysfunctions. Paracetamol has emerged as an alternative to indomethacin owing to its excellent safety profile in infants. Of the recently reported case series and clinical trials on the use of paracetamol for PDA, there are few reports in Japan on paracetamol use in preterm infants. Furthermore, indications for the use of paracetamol for PDA have not been approved for use in PDA. While the safety of intravenous paracetamol therapy in case series of preterm infants treated for haemodynamically significant PDA (hsPDA) has been reported, studies which were conducted to compare paracetamol to indomethacin are limited. We, therefore, intend to investigate the hypothesis that intravenous administration of paracetamol has superior safety over indomethacin. METHODS AND ANALYSIS: Multicentre open-label randomised controlled trial for intravenous administration of paracetamol for PDA in preterm infants. The inclusion criteria are (1) hsPDA, (2) gestational age from 24 to 34 weeks and birth weight (BW) from 500 to 2000 g, (3) enrolment between 24 hours and 7 days from birth and (4) obtaining parental consent. The primary outcome is renal dysfunction within 48 hours from the last dose of the study drug. Enrolled patients fulfilling all the inclusion criteria are randomly allocated to either intravenous paracetamol or intravenous indomethacin. This trial requires 110 patients. ETHICS AND DISSEMINATION: The clinical trial would follow Japan's Clinical Trials Act. The trial protocol was approved by the Clinical Research Review Board of Saitama Medical University (approval number: 222001). A written informed consent would be obtained from one of the parents. The results are expected to be published in a scientific journal. TRIAL REGISTRATION NUMBER: jRCTs031220386. PROTOCOL VERSION: 31 March 2022, version 1.0.

Effectiveness of the maternal and child health handbook for improving continuum of care and other maternal and child health indicators: A cluster randomized controlled trial in Angola.

Background: The maternal and child health (MCH) handbook is promoted as a tool for strengthening continuum of care. We assessed the effect of a MCH handbook intervention package on continuum of maternal and child health care and health outcomes for mother and child. Methods: We conducted an open-label, parallel two-arm cluster randomized controlled trial in Angola. We randomly assigned municipalities in Benguela province through block randomization to a group using a package of enhanced maternity care service (which included the MCH handbook distribution and its supplementary intervention) and another using usual care (two stand-alone home-based records). We included women who were pregnant at the beginning of the trial period and attended a public health care facility for maternity care services. Neither health care providers, study participants nor data assessors were masked, but the statistician was. The primary outcome was a measure of service utilization assessed via achievement of maternal behavior-based continuum of care at three months postpartum. We conducted an intention-to-treat analysis in women with available data. Results: We randomized 10 municipalities to either the intervention (five clusters) or control (five clusters) group. Of the 11 530 women approached between June 8, 2019, and September 30, 2020, 11 006 were recruited and 9039 included in the final analysis (82%; 3774 in the intervention group and 5265 in the control group). The odds for achievement of maternal behavior-based continuum of care in the intervention group was not significantly different from that in the control group (adjusted odds ratio (aOR) = 1.18, 95% confidence interval (CI) = 0.46-2.93) at three months postpartum. However, the odds of initiating antenatal care clinic use were significantly higher in the intervention group (odds ratio (OR) = 5.16, 95% CI = 2.50-10.67). No harms associated with the intervention were reported. Conclusions: Distribution of the MCH handbook and its supplementary interventions promoted initiation of antenatal care service use, but did not increase service utilization sufficiently enough for attainment of study defined maternal behavior-based continuum of care. Registration: ISRCTN20510127.

Development of mortality prediction models for infants with isolated, left-sided congenital diaphragmatic hernia before and after birth.

BACKGROUND: Mortality prediction of congenital diaphragmatic hernia (CDH) is essential for developing treatment strategies, including fetal therapy. Several researchers have reported prognostic factors for this rare but life-threatening condition; however, the optimal combination of prognostic factors remains to be elucidated. OBJECTIVES: This study aimed to develop the most discriminative prenatal and postnatal models to predict the mortality of infants with an isolated left-sided CDH. METHODS: This multi-institutional retrospective cohort study included infants with CDH born at 15 tertiary hospitals of the Japanese CDH Study Group between 2011 and 2016. We developed multivariable logistic models with every possible combination of predictors and identified models with the highest cross-validated area under the receiver operating characteristic curve (AUC) for prenatal and postnatal predictions. RESULTS: Among 302 eligible infants, 44 died before discharge. The prenatal mortality prediction model was based on the observed/expected lung area to head circumference ratio (O/E LHR), liver herniation, and stomach herniation (AUC, 0.830). The postnatal mortality prediction model was based on O/E LHR, liver herniation, and the lowest oxygenation index (AUC, 0.944). CONCLUSION: Our models can facilitate the prenatal and postnatal mortality prediction of infants with isolated left-sided CDH.

Safety of and antibody response to the BNT162b2 COVID-19 vaccine in adolescents and young adults with underlying disease.

BACKGROUND: Data are limited regarding the safety of and antibody response to the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid vaccine in adolescents and young adults with underlying disease. METHODS: This prospective observational study enrolled patients age 12-25 years with chronic underlying disease who received 2 doses of BNT162b2. A 18-item questionnaire was used to assess adverse events within 7 days post-vaccination, and data regarding severe adverse events were collected from electronic medical records. An antibody titer for the receptor-binding domain of the spike protein in SARS-CoV-2 was used to assess antibody response after the second vaccine dose. RESULTS: Study participants were 429 patients (241 [56.2%] age 12-15 years; 188 [43.8%] age 16-25 years). The most common underlying diseases were genetic or chromosomal abnormalities and/or congenital anomalies, followed by endocrine or metabolic diseases; 32% of participants were immunocompromised. Severe adverse events were observed after the second dose in 1 (0.4%) patient age 12-15 years and in 2 (1.1%) patients age 16-25 years; all patients recovered. Seropositivity after the second vaccine dose was 99.0%. The geometric mean antibody titer was higher in patients age 12-15 years versus 16-25 years (1603.3 [1321.8-1944.7] U/mL vs. 949.4 [744.2-1211.0] U/mL). Compared with immunocompetent patients, immunocompromised patients had a lower antibody titer (2106.8 [1917.5-2314.7] U/mL vs. 467.9 [324.4-674.8] U/mL). CONCLUSIONS: Vaccination with BNT162b2 was acceptably safe and immunogenic for adolescents and young adults with underlying disease.

Comparison of mortality and survival without major morbidities of very preterm infants with very low birth weight from Japan and Brazil / Comparação entre mortalidade e sobrevida sem morbidades importantes dos recém-nascidos prematuros de muito baixo peso entre o Japão e o Brasil

Abstract Objective: This study was carried out to understand the disparities in mortality and survival without major morbidities among very premature and very low birth weight infants between participating Neonatal Intensive Care Units (NICUs) from the Brazilian Network on Neonatal Research (RBPN) and the Neonatal Research Network of Japan (NRNJ). Methods: Secondary data analysis of surveys by the RBPN and NRNJ was performed. The surveys were conducted in 2014 and 2015 and included 187 NICUs. Primary outcome was mortality or survival without any major morbidity. Logistic regression analysis adjustment for confounding factors was used. Results: The study population consisted of 6,406 infants from the NRNJ and 2,319 from the RBPN. Controlling for various confounders, infants from RBPN had 9.06 times higher adjusted odds of mortality (95%CI 7.30-11.29), and lower odds of survival without major morbidities (AOR 0.36; 95%CI 0.32-0.41) compared with those from the NRNJ. Factors associated with higher odds of mortality among Brazilian NICUs included: Air Leak Syndrome (AOR 4.73; 95%CI 1.26-15.27), Necrotizing Enterocolitis (AOR 3.25; 95%CI 1.38-7.26), and Late Onset Sepsis (LOS) (AOR 4.86; 95%CI 2.25-10.97). Conclusions: Very premature and very low birth weight infants from Brazil had significantly higher odds for mortality and lower odds for survival without major morbidities in comparison to those from Japan. Additionally, we identified the factors that increased the odds of in-hospital neonatal death in Brazil, most of which was related to LOS.

RESUMO Objetivo: Este estudo foi realizado para compreender as disparidades na mortalidade e sobrevivência sem as principais morbidades entre recém-nascidos muito prematuros e de muito baixo peso entre Unidades de Terapia Intensiva Neonatal (UTINs) participantes da Rede Brasileira de Pesquisas Neonatais (RBPN) e Rede de Pesquisa Neonatal do Japão (NRNJ). Métodos: Foi realizada uma análise dos dados secundários dos bancos de dados da RBPN e da NRNJ. As pesquisas foram realizadas em 2014 e 2015 e incluíram 187 UTINs. O desfecho primário foi mortalidade ou sobrevida sem qualquer morbidade importante. Utilizou-se a análise de regressão logística com ajuste para os fatores de confusão. Resultados: A população do estudo foi composta por 6.406 recém-nascidos do NRNJ e 2.319 do RBPN. Ajustando para diversos fatores de confusão, os prematuros da RBPN tiveram 9,06 vezes maiores chances de mortalidade (IC95% 7,30-11,29) e menores chances de sobrevivência sem morbidades importantes (AOR 0,36; IC95% 0,32-0,41) em comparação com os da NRNJ. Fatores associados a maiores chances de mortalidade entre as UTINs brasileiras incluíram: síndrome de escape de ar (AOR 4,73; IC95% 1,26-15,27), enterocolite necrosante (AOR 3,25; IC95% 1,38-7,26) e sepse de início tardio (AOR 4,86; IC95% 2,25-10,97). Conclusões: Os recém-nascidos muito prematuros e de muito baixo peso do Brasil apresentaram chances significativamente maiores de mortalidade e menores chances de sobrevivência sem as principais morbidades em comparação aos do Japão. Além disso, identificamos os fatores que aumentam as chances da morte neonatal no Brasil, sendo a maioria relacionada à sepse tardia.

Comparison of mortality and survival without major morbidities of very preterm infants with very low birth weight from Japan and Brazil.

OBJECTIVE: This study was carried out to understand the disparities in mortality and survival without major morbidities among very premature and very low birth weight infants between participating Neonatal Intensive Care Units (NICUs) from the Brazilian Network on Neonatal Research (RBPN) and the Neonatal Research Network of Japan (NRNJ). METHODS: Secondary data analysis of surveys by the RBPN and NRNJ was performed. The surveys were conducted in 2014 and 2015 and included 187 NICUs. Primary outcome was mortality or survival without any major morbidity. Logistic regression analysis adjustment for confounding factors was used. RESULTS: The study population consisted of 6,406 infants from the NRNJ and 2,319 from the RBPN. Controlling for various confounders, infants from RBPN had 9.06 times higher adjusted odds of mortality (95%CI 7.30-11.29), and lower odds of survival without major morbidities (AOR 0.36; 95%CI 0.32-0.41) compared with those from the NRNJ. Factors associated with higher odds of mortality among Brazilian NICUs included: Air Leak Syndrome (AOR 4.73; 95%CI 1.26-15.27), Necrotizing Enterocolitis (AOR 3.25; 95%CI 1.38-7.26), and Late Onset Sepsis (LOS) (AOR 4.86; 95%CI 2.25-10.97). CONCLUSIONS: Very premature and very low birth weight infants from Brazil had significantly higher odds for mortality and lower odds for survival without major morbidities in comparison to those from Japan. Additionally, we identified the factors that increased the odds of in-hospital neonatal death in Brazil, most of which was related to LOS.

Ba1/3CoO2: A Thermoelectric Oxide Showing a Reliable ZT of ∼0.55 at 600 °C in Air.

Thermoelectric energy conversion technology has attracted attention as an energy harvesting technology that converts waste heat into electricity by means of the Seebeck effect. Oxide-based thermoelectric materials that show a high figure of merit are promising because of their good chemical and thermal stability as well as their harmless nature compared to chalcogenide-based state-of-the-art thermoelectric materials. Although several high-ZT thermoelectric oxides (ZT > 1) have been reported thus far, the reliability is low due to a lack of careful observation of their stability at elevated temperatures. Here, we show a reliable high-ZT thermoelectric oxide, Ba1/3CoO2. We fabricated Ba1/3CoO2 epitaxial films by the reactive solid-phase epitaxy method (Na3/4CoO2) followed by ion exchange (Na+ → Ba2+) treatment and performed thermal annealing of the film at high temperatures and structural and electrical measurements. The crystal structure and electrical resistivity of the Ba1/3CoO2 epitaxial films were found to be maintained up to 600 °C. The power factor gradually increased to ∼1.2 mW m-1 K-2 and the thermal conductivity gradually decreased to ∼1.9 W m-1 K-1 with increasing temperature up to 600 °C. Consequently, the ZT reached ∼0.55 at 600 °C in air.

Establishment of an objective index for the diagnosis of attention deficit/hyperactivity disorder by the continuous performance test "MOGRAZ".

OBJECTIVE: The diagnosis of attention deficit/hyperactivity disorder (AD/HD) in Japan is mainly based on information obtained from caregivers. There is therefore a need to establish an objectivity index that can be easily used in clinical practice. The purpose of the study was to create a predictive model for the diagnosis of AD/HD using the MOGRAZ, a visual continuous performance test developed in Japan. METHODS: We collected data from an AD/HD group and a non-AD/HD group. The AD/HD group included 75 children with predominantly inattentive type AD/HD and 48 with combined type AD/HD who were aged 6 to 12 years and diagnosed at our department. The non-AD/HD group included 153 Japanese children aged 6 to 11 years enrolled in regular classes at a public elementary school. In both groups, multiple logistic regression analysis was performed using the results of MOGRAZ, age, and sex as parameters, and algorithms for a predictive diagnostic model of AD/HD were created. RESULTS: The area under the receiver operating characteristic curve (ROC-AUC) between the predominantly inattentive type AD/HD subgroup and non-AD/HD group was 0.884 (95% confidence interval: 0.837-0.932), and the ROC-AUC between the combined type AD/HD subgroup and non-AD/HD group was 0.914 (95% CI: 0.869-0.959). CONCLUSION: The prediction model using the MOGRAZ score allowed us to create an objectivity index to determine the diagnosis of AD/HD that can be easily used in clinical practice. We plan additional verification of this prediction model with additional participants.

A phase I/IIa trial of atorvastatin in Japanese patients with acute Kawasaki disease with coronary artery aneurysm: Study protocol of a multicenter, single-arm, open-label trial.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis complicated with coronary artery abnormalities (CAAs). Intravenous immunoglobulin reduces the occurrence of CAAs, but significant number of KD patients with CAAs still exists. Thus, new approaches to prevent and attenuate CAAs are warranted. Atorvastatin has been shown to promote endothelial cell homeostasis and suppress vascular inflammation and has received enthusiasm as a potentially new candidate treatment for KD. In the United States, a phase I/IIa dose-escalation study of atorvastatin in KD patients with CAAs demonstrated the safety and pharmacokinetic data of atorvastatin. However, due to the uncertainty in the application of these results to other populations, we aim to examine the tolerability and generate pharmacokinetics data in Japanese KD patients. METHODS: This is a multicenter, single-arm, open-label, phase I/IIa study of atorvastatin in acute KD patients with CAAs in Japan. A minimum of 9 and a maximum of 18 KD patients (2 years-17 years old) will be recruited for a 3 + 3 dose-escalation study of a 6-week course of atorvastatin (0.125-0.5 mg/kg/day). The primary outcome will be safety of atorvastatin. The secondary outcomes will be pharmacokinetics of atorvastatin, activity of atorvastatin and echocardiographic assessment of CAAs. The activity of atorvastatin will include assessment of C-reactive protein or high sensitivity C-reactive protein and white blood cell levels. DISCUSSION: This study will provide evidence of the safety, tolerability, and pharmacokinetics of atorvastatin in Japanese KD patients and may lead new standard therapy for acute-phase KD associated with CAA complications. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs031180057). Registered December 19, 2018, https://jrct.niph.go.jp/en-latest-detail/jRCTs031180057.

Two ovarian candidate enhancers, identified by time series enhancer RNA analyses, harbor rare genetic variations identified in ovarian insufficiency.

The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development-such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)-the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics.

The protective effect of Centella asiatica and its constituent, araliadiol on neuronal cell damage and cognitive impairment.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, and the number of affected individuals has increased worldwide. However, there are no effective treatments for AD. Therefore, it is important to prevent the onset of dementia. Oxidative stress and endoplasmic reticulum (ER) stress are increased in the brains of AD patients, and are postulated to induce neuronal cell death and cognitive dysfunction. In this study, Centella asiatica, a traditional Indian medicinal herb, were fractionated and compared for their protective effects against glutamate and tunicamycin damage. Araliadiol was identified as a component from the fraction with the highest activity. Further, murine hippocampal cells (HT22) were damaged by glutamate, an oxidative stress inducer. C. asiatica and araliadiol suppressed cell death and reactive oxygen species production. HT22 cells were also injured by tunicamycin, an ER stress inducer. C. asiatica and araliadiol prevented cell death by mainly inhibiting PERK phosphorylation; additionally, C. asiatica also suppressed the expression levels of GRP94 and BiP. In Y-maze test, oral administration of araliadiol (10 mg/kg/day) for 7 days ameliorated the arm alternation ratio in mice with scopolamine-induced cognitive impairment. These results suggest that C. asiatica and its active component, araliadiol, have neuroprotective effects, which may prevent cognitive dysfunction.

Erratum: Correction of the received and accepted dates: Exposure to paraben and triclosan and allergic diseases in Tokyo: A pilot cross-sectional study.

[This corrects the article e5 in vol. 9, PMID: 30740353.].

Exercise Intervention for Academic Achievement Among Children: A Randomized Controlled Trial.

OBJECTIVES: Physical inactivity is an important health concern worldwide. In this study, we examined the effects of an exercise intervention on children's academic achievement, cognitive function, physical fitness, and other health-related outcomes. METHODS: We conducted a population-based cluster randomized controlled trial among 2301 fourth-grade students from 10 of 11 public primary schools in 1 district of Ulaanbaatar between February and December 2018. Schools were allocated to an intervention or control group with 5 schools each by using urban and mixed residential area stratified block randomization. The intervention group received a 3-minute high-intensity interval exercise program that included jumps, squats, and various steps implemented twice weekly over 10 weeks for 10 to 25 minutes per session. The control group received the usual physical education class. The primary outcome was academic achievement assessed by scores on the national examination. A linear mixed-effects model was applied. The difference between preintervention and post intervention was compared by least-squares means, estimated on the basis of the interaction of group, measurement time point, and school location. Only 1 statistician, responsible for the analysis, was blinded. RESULTS: Of 2301 students, 2101 (1069 intervention; 1032 control) were included in the analysis. Intervention group members in an urban area showed an 8.36-point improvement (95% confidence interval: 6.06 to 10.66) in academic scores when compared with the control group, whereas those in a mixed residential area showed a 9.55-point improvement (95% confidence interval: 6.58 to 12.51). No intervention-associated injuries were observed. CONCLUSIONS: The exercise program significantly improved children's academic achievement.

Ductus diameter and left pulmonary artery end-diastolic velocity at 3 days of age predict the future need for surgical closure of patent ductus arteriosus in preterm infants: A post-hoc analysis of a prospective multicenter study.

BACKGROUND: There is inconsistent evidence suggesting the clinical relevance of the early detection of future needs of preterm patent ductus arteriosus (PDA) surgery. We tested the hypothesis that echocardiographic indices at 3 days of age predict the future need for PDA surgery. METHODS: We analyzed a database including the clinical and echocardiographic data of 710 preterm infants with gestational ages between 23 and 29 weeks in 34 Japanese neonatal intensive care units, and prospectively collected data over 14 months. The predictive or discriminative ability of each echocardiographic index at 3 days of age for future PDA surgical closure was evaluated using multivariable logistic regression analyses with adjustment for gestational age, sex, and small-for-gestational-age status, according to the areas under the receiver-operating characteristic curves (AUCs) of the models. RESULTS: A total of 688 eligible patients (median gestational age: 26 weeks, body weight at birth: 843 g) were analyzed, of whom 77 (11%) underwent PDA surgery (median age: 21 days) after full consideration of clinical conditions. The AUC of PDA diameter (PDAd) was the largest, followed by that of the left pulmonary artery end-diastolic velocity (LPAedv). Compared with the ratio of left atrial-to-aorta diameter (AUC 0.76), PDAd (AUC 0.84, p < 0.001) and LPAedv (AUC 0.82, p = 0.003) were significantly better predictors of future PDA surgery. CONCLUSION: Echocardiographic indices at 3 days of age, especially PDAd and LPAedv, may predict the future need for surgical closure of PDA in preterm infants.