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Objectives We elucidate to investigate the prevalence of and factors associated with the use of physical restraints among critically ill or injured children in PICUs. Design This was a multicenter, longitudinal point prevalence study. Setting We included 26 PICUs in Japan. Patients Included children were 1 month to 10 years old. We screened all admitted patients in the PICUs on three study dates (in March, June, and September 2019). Intervention None. Measurements and main results We collected prevalence and demographic characteristics of critically ill or injured children with physical restraints, as well as details of physical restraints, including indications and treatments provided. A total of 398 children were screened in the participating PICUs on the three data collection dates. The prevalence of children with physical restraints was 53% (211/398). Wrist restraint bands were the most frequently used means (55%, 117/211) for potential contingent events. The adjusted odds of using physical restraint in patients 1-2 years old was 2.3 (95% CI, 1.3-4.0) compared with children less than 1 year old. When looking at the individual hospital effect, units without a prespecified practice policy for physical restraints management or those with more than 10 beds were more likely to use physical restraints. Conclusions The prevalence of physical restraints in critically ill or injured children was high, and significant variation was observed among PICUs. Our study findings suggested that patient age, unit size, and practice policy of physical restraint could be associated with more frequent use of physical restraints.

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort. Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing. Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure. Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

A 5-year-old boy presented with nausea, vomiting, and intermittent abdominal pain. Images showed giant cerebriform enlargement of rugal folds in the fundus and the body, which were suggestive of Menetrier’s disease.

There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug.Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration.Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL).We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.

Infection with Streptococcus pyogenes, a Group A beta-hemolytic streptococcus (GAS), is a rare cause of hemolyticuremic syndrome (HUS). Invasive infections with Streptococcus pneumoniae that produce neuraminidase are a well-recognized cause of HUS without diarrhea. The Thomsen- Friedenreich antigen (T antigen) plays a role in the pathophysiology of pneumococcal HUS. We describe the case of a 3-year-old boy with GAS-associated HUS and show how T-antigen exposure was implicated in this case. He had no diarrhea and cultures for blood, urine, and stool were negative. The urinary pneumococcal antigen was negative; his direct Coombs test was positive. Glomerular capillary loops, tubular epithelium on his renal biopsy specimen, and red blood cells in his blood smear showed positive fluorescence with anti-T lectin. Although the pathogenesis of GAS-associated HUS is not well understood, T-antigen exposure may be implicated in some cases with GAS-associated HUS.

Background: Recently we reported that the carotid arteries of Kawasaki disease (KD) appear to develop mild sclerotic changes shortly after onset using the speckle tracking echocardiography. However, it remains to be elucidated what factors hemodynamically may induce these sclerotic changes. Objectives: The aim of this study was to investigate the relationship between KD related-angiopathy and arterial pressure wave reflection using the two-dimensional speckle tracking echocardiography and radial augmentation index (AIx). Subjects & Methods: We studied a cohort of children with history of KD. The subjects were 87 KD patients (age, 9.7±2.9 years) and 93 healthy controls (11.3±3.2 years). As for our methodology, the two regions of interest (ROI) for speckle tracking were manually positioned at near and far carotid arterial walls using a Philips iE33. Continuously, we examined the following strain values: (A) peak strain in expansion phase, (B) peak strain before aortic valve closure, and (C) strain value at aortic valve closure (Figure 1). Also, we examined two ratios, B/A and C/A, for emphasizing recoil function. Concurrently, the radial AIx were obtained. Results: KD patients had significantly the lower A values, the higher B/A, and the higher radial AIx, compared with controls. Furthermore, there was good correlation between B/A and radial AIx in KD. Conclusions: It is well known that a higher AIx results from earlier arrival of reflected pressure waves and an early return of reflected waves is closely correlated with peripheral stiffness. Therefore, these results indicate that peripheral angiopathy may induce sclerotic changes of carotid arteries in KD patients.

Background: Recent epidemiological studies have suggested that some patients with Kawasaki disease (KD) have an atopic tendency. However, it is not clear what the long-term prognosis will be for KD-patient with allergic disease. We aim to investigate the long-term prognosis of KD-patient with allergic disease. Subjects & Methods: We studied a cohort of KD-patient (n=58, follow-up age; 9.95±1.84 years), in whom we examined total serum IgE and specific IgE at KD-onset (onset age; 2.13±1.84 years). Using retrospective patient medical record analysis, we evaluated the prevalence of bronchial asthma at onset and follow-up of KD. In addition, we examined the hospitalization rate, medical history and family history in pediatric bronchial asthma after KD-onset. Results: In our study, KD-patient had markedly higher total serum IgE and prevalence of bronchial asthma at onset of KD than the general children’s population, as reported by Japanese national government (Table 1). The prevalence of bronchial asthma at follow-up was similar to the general children’s population. 9 children had already had a diagnosis of a bronchial asthma at KD-onset. 8 children had subsequently developed bronchial asthma after KD-onset. In these 2 groups, however, 6 and 8 children, respectively, had remitted during follow-up. Nobody was hospitalized for asthmatic exacerbation after KD-onset. Conclusions: These findings demonstrate that KD-patient with atopic bronchial asthma at onset have not developed severe allergic reaction. There results provide that the pathogenic mechanism of KD might weakly or transiently provoke an elevation of total IgE and the developing of allergies.

We report a 13-year-old girl with epilepsy who experienced syncope after rapid weight loss due to an eating disorder. She developed a lethal (atrioventricular block) arrhythmia, which improved after weight gain. This case suggests that energy depletion might be involved in lethal arrhythmia.

BackgroundRecent studies have revealed that atherosclerosis progresses faster than expected in young adults with a history of Kawasaki disease. However, it is unclear as to when these arterial changes become measurable. In this study, we evaluated subclinical arterial stiffness in young children with a history of Kawasaki disease using two-dimensional ultrasound speckle tracking.MethodsA total of 75 children with a history of Kawasaki disease (mean age, 8.2 ± 2.8 years) and 50 healthy controls (mean age 8.3 ± 3.5 years) were included. The two regions of interest for speckle tracking were manually positioned at the anterior and posterior carotid arterial wall using a Philips iE33 (Philips Medical Systems, Bothell, WA, USA). The peak systolic strain, time to peak systolic strain, early systolic strain rate, and late systolic strain rate were continuously monitored between the two regions of interest. Furthermore, the intimal-medial thickness, stiffness β, and pressure-elastic modulus, as conventional measures of arterial stiffness, were concurrently obtained.ResultsThe peak systolic strain and late systolic strain rate differed significantly between the patients with Kawasaki disease and controls (6.69% versus 8.60%, p < 0.01, and −0.28/second versus −0.51/second, p < 0.0001, respectively). There was no difference in the time to peak systolic strain, early systolic strain rate, and conventional measures.ConclusionsThe arteries of patients with Kawasaki disease appear to develop mild sclerotic changes shortly after the onset of the disease.

Background Several coronary artery Z score models have been developed. However, a Z score model derived by the lambda-mu-sigma (LMS) method has not been established. Methods Echocardiographic measurements of the proximal right coronary artery, left main coronary artery, proximal left anterior descending coronary artery, and proximal left circumflex artery were prospectively collected in 3,851 healthy children ≤18 years of age and divided into developmental and validation data sets. In the developmental data set, smooth curves were fitted for each coronary artery using linear, logarithmic, square-root, and LMS methods for both sexes. The relative goodness of fit of these models was compared using the Bayesian information criterion. The best-fitting model was tested for reproducibility using the validation data set. The goodness of fit of the selected model was visually compared with that of the previously reported regression models using a Q-Q plot. Results Because the internal diameter of each coronary artery was not similar between sexes, sex-specific Z score models were developed. The LMS model with body surface area as the independent variable showed the best goodness of fit; therefore, the internal diameter of each coronary artery was transformed into a sex-specific Z score on the basis of body surface area using the LMS method. In the validation data set, a Q-Q plot of each model indicated that the distribution of Z scores in the LMS models was closer to the normal distribution compared with previously reported regression models. Finally, the final models for each coronary artery in both sexes were developed using the developmental and validation data sets. A Microsoft Excel–based Z score calculator was also created, which is freely available online (http://raise.umin.jp/zsp/calculator/). Conclusions Novel LMS models with which to estimate the sex-specific Z score of each internal coronary artery diameter were generated and validated using a large pediatric population.

Summary: We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance ( CL / F ) and elimination rate constant ( k ). Polymorphisms of CYP3A5 , SLCO1B1 , SLCO1B3 , and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL / F were correlated negatively with age (AGE). The final population mean values of CL / F and k were estimated to be 0.409 · (1 – 0.0377 · (AGE – 3.81)) · WT L/h and 0.175 h - 1 , respectively.

Hemangiolymphangioma (HL) is a congenital anomaly and histologically benign tumor, which was composed of both the lymphatic and the blood vessels. We report an adult case of HL complicated by chronic thromboembolic pulmonary hypertension (CTEPH) in a 20-year-old female. Gastrointestinal bleeding scintigraphy and operative findings elucidate a close relationship between CTEPH and residual HL. This case indicates that HL survivors with remaining left-to-right shunt might lead to CTEPH during the long-term follow-up.

A newborn screening program identified a 23-day-old asymptomatic girl with elevated serum galactose (>18.3 mg/dl) after breast feeding. The enzymes that metabolise galactose showed normal activity, thereby excluding hereditary galactosaemias. Three-dimensional CT venography (Fig. 1) showed direct portocaval communication between the inferior mesenteric vein and the left internal iliac vein. Inferior mesenteric venous portography via the shunt confirmed that the flow was hepatofugal through the communication (Fig. 2). Intrahepatic