Purpose:This study aimed to evaluate the efficacy and safety of multi-matrix mesalazine in pediatric patients with ulcerative colitis (UC) in remission. Methods:A multicenter, open-label, uncontrolled study was conducted in Japan, in which multi-matrix mesalazine 40 mg/kg was administered orally once daily for 48 weeks to 23 patients with UC in remission, aged <17 years. The primary endpoint was the nonoccurrence of rectal bleeding based on the Ulcerative Colitis Disease Activity Index (UC-DAI) score. Results:The percentage of patients without rectal bleeding, based on the UC-DAI score in the full analysis set, was 73.9% (two-sided 95% confidence interval [CI]: 51.6%, 89.8%; n=17/23). The lower limit of the two-sided 95% CI exceeded the predetermined threshold of 50%, derived from placebo group data in previous clinical studies involving adult patients with UC. The incidence of adverse events (AEs) and study drug-related AEs was 87.0% (n=20/23) and 13.0% (n=3/23), respectively. No deaths were reported. None of the study drug-related AEs were severe or serious, nor did they lead to discontinuation of the study drug. Conclusion:This study demonstrated the long-term efficacy of multi-matrix mesalazine in pediatric patients with UC in remission in Japan. No noteworthy safety concerns beyond those known to be associated with mesalazine were observed.

Infants require repeated immunizations of injectable-type vaccines against different pathogens because their immune systems are weaker than those of adults. However, these injectable vaccines cause physical and psychological discomfort. Therefore, there is an urgent need to develop pain-free mucosal vaccines that are optimized for immunologically immature infants. Using an infant murine model, we examined the effectiveness of an intranasal norovirus virus-like-particle (VLP) vaccine with zymosan as an adjuvant. The intranasal immunization of infant mice with VLPs alone induced mucosal and systemic VLP-specific immune responses that were substantially weaker than those of adults. In contrast, infant mice administered a minimum dose of intranasal zymosan-adjuvanted VLP vaccine showed increased levels of intestinal and salivary VLP-specific IgA antibodies, as well as plasma VLP-specific IgG antibodies, at levels comparable to those in adults. Importantly, intestinal and salivary antibodies elicited by intranasal immunization with the zymosan-adjuvanted VLP vaccine effectively inhibited norovirus propagation in human-induced pluripotent stem cellderived intestinal epithelial cells. These findings suggest that the intranasal zymosan-adjuvanted norovirus VLP vaccine is an effective mucosal vaccine candidate for infants. It may help reduce the pain associated with injections and the number of immunizations infants required to achieve sufficient protective immunity against norovirus.

Although norovirus can affect people of any age, the majority of deaths and illnesses occur in children under one year old and people over the age of 55. Currently, there is no vaccine or medication available. Previously, we developed a nasal vaccine drug delivery system (DDS) for a small protein antigen by using cationic cholesteryl pullulan (cCHP) nanogels, in which the vaccine antigen was embedded in the nanogel structure through hydrophobic interactions. Here, we developed and tested a virus-like particle (VLP)-based nasal vaccine system that is coated in nanogel. We used VLPs (diameter, approximately 40 nm) of the GII.4 (Sydney_2012) genotype of norovirus, a globally prevalent strain. By using a molar ratio of 1:10 or 1:100 VLPs to nanogel, we successfully covered the VLPs with cationic nanogel by electrostatic force. Following nasal immunization in mice, the nanogel-covered VLPs bound continuously to the nasal epithelium, effectively enabling mucosal dendritic cells to take them up and initiate systemic antigen-specific IgG and IgA antibody responses as well as antigen-specific IgA antibodies in mucosal compartments such as the airways and intestinal tract. The antibodies induced by nasal immunization with the nanogel-covered VLP vaccine neutralized the GII.4 (Sydney_2012) genotype of norovirus. These results provide proof of concept for advancing the development of adjuvant-free cCHP-nanogel-based VLP nasal vaccines.

Bacillus Calmette-Guérin (BCG) osteomyelitis is a very rare but serious complication of BCG immunization. Although most affected patients experience a good outcome, late orthopedic complications, such as discrepancy in leg length, are a concern. The impact of the extent of surgical intervention on minimizing orthopedic complications remains unclear, especially in patients with BCG osteomyelitis involving the physis. Here, we report the case of a 22-month-old immunocompetent boy who developed BCG osteomyelitis in the proximal metaphysis of the right tibia, which extended to the physis and epiphysis and was accompanied by a large subcutaneous abscess. In the current case, minimal curettage with anti-tuberculosis drugs, which can prevent damage to the physis and epiphysis, was not beneficial. Hence, complete curettage of the lesions was required. No disruption in bone growth was observed at the last follow-up evaluation performed 32 months after the first visit. Based on our experience, timely and sufficient curettage is essential to control the disease and prevent orthopedic complications in patients with BCG osteomyelitis involving the physis and epiphysis.

BACKGROUND:Therapeutic monitoring is recommended for aminoglycoside drugs, which are often used in neonatal care. In this study, we examined whether it is possible to estimate the trough value after administration using serum creatinine (Cr) and serum cystatin C (CysC) values of umbilical cord artery blood in infants, which can be measured without increasing risks due to invasive tests. METHODS:Subjects included infants who were hospitalized between March 2022 and March 2023 and treated with tobramycin (TOB) from 0 days old. In addition to cord blood Cr and CysC, TOB blood concentration (trough value) was measured at 3 days. The correlation coefficient (r) between serum Cr and CysC values and TOB trough value was calculated. RESULTS:Sixteen cases were included in the study. Cord blood Cr and CysC values were divided by gestational week (GW), birth weight (BW), and body surface area (BSA), respectively, and the correlations with TOB trough values were determined. Cord blood CysC/GW/BSA showed a strong correlation with TOB trough value (r = 0.77). The receiver operating characteristic curve for the relationship between cord blood CysC/GW/BSA and TOB trough values ≥1 mg/mL revealed a cut-off value of 0.29 (area under the curve: 0.927, sensitivity: 1.00, specificity: 0.75). CONCLUSION:Umbilical cord blood CysC/GW/BSA values were strongly correlated with TOB trough values. Cord blood samples can be used to estimate trough values before drug administration without increasing the risk to infants associated with invasive tests, enabling determination of the dosage that will not cause nephrotoxicity.

AIM:Part 2 of the DORA study, an international clinical trial evaluating glecaprevir and pibrentasvir (G/P) treatment in children aged 3-11 years with chronic hepatitis C virus (HCV) infection, demonstrated high efficacy and safety. However, there is limited evidence regarding real-world use of G/P in this pediatric population. This prospective multicenter study in Japan evaluated the real-world efficacy and safety of G/P treatment in children aged 3-11 years with chronic HCV. METHODS:Children aged 3-11 years with chronic HCV were prospectively enrolled and received a once-daily dose of G/P for either 8 or 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after treatment completion (SVR12). Safety was assessed through adverse events, laboratory tests, and growth measurements. RESULTS:A total of 18 children (8 girls) from 9 pediatric centers in Japan were enrolled, with a median age of 9 years (range, 3-11). Genotype distribution was as follows: 1b (n = 3), 2a (n = 8), 2b (n = 5), 3a (n = 1), and unknown of Serotype 2 (n = 1). All participants were treatment-naïve and completed G/P treatment (17 for 8 weeks, 1 for 12 weeks). SVR12 was achieved in 17 patients (94%). Most adverse events were mild, with no serious events. Treatment led to significant reductions in serum alanine aminotransferase and Wisteria floribunda agglutinin-positive Mac-2 binding protein levels. No impairments in growth were observed. CONCLUSIONS:In real-world clinical practice, G/P treatment demonstrated high efficacy and good tolerability in children aged 3-11 years with chronic HCV.

AIM:Excessive fructose ingestion causes fat accumulation and can lead to fatty liver, obesity, and related diseases. Eucalyptus leaf extract (ELE) contains oenothein B, which inhibits fructose absorption in the intestine. In this study, we evaluated the effects of ELE on fat accumulation caused by sugar-sweetened beverage intake in adult Japanese men with a body mass index of ≥ 23 and < 30 kg/m2. METHODS:In this randomized, placebo-controlled, double-blind, and parallel-group pilot study, participants consumed test capsules containing oenothein B (3.38 mg/day), along with a beverage containing free sugars (22.5 g/day), as a loading diet for 12 weeks. The abdominal visceral fat area (VFA) and controlled attenuation parameter (CAP), which is an indicator of hepatic fat levels, were measured and compared to those in the placebo group. RESULTS:Twenty participants were included in the analysis of the placebo and intervention groups. After 12 weeks, VFA and CAP increased significantly from baseline (p = 9.81 × 10-3 and 1.59 × 10-2) in the placebo group, whereas no significant increase was observed in the intervention group. Sensitivity analysis after unblinding revealed that the CAP was significantly lower in the intervention group (p = 4.84 × 10-2) than that in the placebo group after 12 weeks. CONCLUSION:ELE ingestion suppressed visceral and hepatic fat accumulation. Thus, oenothein B-containing ELE may be a useful antiobesity agent. This is the first report showing that the consecutive ingestion of dietary free sugars results in hepatic and visceral fat accumulation in adult Japanese men. TRIAL REGISTRATION:UMIN000037428; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000042668.

To identify patients with infantile hemangioma (IH) in need of early-stage treatment in this multicenter, prospective, observational study, we investigated the potential of plasma cytokines as a clinically useful marker. Plasma samples were collected at three time points from 41 patients with infantile hemangioma: baseline (days 14-60 after delivery), visit 1 (days 61-150, the proliferative phase), and visit 2 (days 151-395, the involuting phase). With a twofold or more increase in tumor volume during the baseline-visit 1 period regarded as progression, progression was seen in 15 cases (36.6%). In the first step, cytokine arrays were performed using plasma samples in five progressive and five non-progressive cases. Plasma levels of six cytokines at baseline were selected for a prediction marker of change in tumor volume during baseline-visit 1. Validation enzyme-linked immunosorbent assay indicated that the baseline growth differentiation factor 1 (GDF1) concentration tended to correlate with the proliferation ratio of total lesions or target lesion during baseline-visit 1, although without statistical significance. However, the plasma GDF1 concentrations were significantly lower in patients with a fourfold or more increase in total volume (p = 0.013). Furthermore, changes in plasma interleukin (IL)-7Rα levels showed a statistically significant inverse correlation between volume change of the target lesion during baseline-visit 1 (p = 0.0069). Our results suggest that plasma GDF1 measurement after birth is a useful marker for progression of IH. Additionally, the downregulation of IL-7Rα that begins several months after birth may also contribute to tumor growth. (UMIN-CTR: UMIN000038574).

Fontaine progeroid syndrome (FPS) is a rare condition characterized by abnormalities in SLC25A24. Some instances of FPS have been reported to be fatal early in life. Here we present the first case of mitochondrial disease diagnosed with FPS in Japan. The diagnosis was based on the presence of the heterozygous known pathogenic variant of SLC25A24, NM_013386.5: c.649C>T and decreased activity of mitochondrial respiratory chain enzyme activity.

Infantile hemangiomas (IHs) are the most common benign tumors of infancy, occurring in approximately 5-10% of the population. Among what appear to be typical IHs with proliferative and involuting phases, we noticed that there are also IHs that are already present at birth and regress without proliferating. We therefore aimed to determine the frequency and clinical characteristics of this type of IH. A retrospective study was conducted on 176 lesions of 137 Japanese patients with IH. As a result, six lesions (3.4%) in three patients with IH (2.1%) were already present at birth and lacked subsequent proliferation. Analysis of the clinical characteristics of IHs without proliferation revealed that they are significantly less common in the head and neck region, which is the preferred site of the tumor, than typical IHs with proliferation (0% vs. 42.9%, p < 0.05 by Fisher's exact test). This suggests that when the clinical course of IH is uncommon, their distribution can also be atypical. Furthermore, all of the IHs without proliferation were superficial types, and there were no deep types in this cohort. This study demonstrates that the clinical course of IH can be diverse, and that very rarely there can be a type of IH that does not grow after birth. It may be necessary to consider conducting a detailed interview for the growth history at the first visit for the possibility of such a type of IH without proliferation, as it is likely that they can be followed up without the need for treatment.

AIM:Fontan-associated liver disease (FALD) is a complication after Fontan surgery, and a common cause of liver tumors and cirrhosis. However, no diagnostic criteria for FALD have been established, leading to an underestimation of its prevalence. METHODS:We conducted a national survey to elucidate the characteristics of FALD by collecting data from high-volume centers managing patients who had undergone the Fontan surgery in Japan. In total, 1168 patients were enrolled in the study. First, we examined typical liver findings on ultrasonography after the Fontan surgery. Next, we proposed diagnostic criteria for FALD and advanced FALD based on blood tests, imaging, liver tumors, and pathological examinations. We investigated the sensitivity of histologically diagnosed FALD and advanced FALD based on criteria for blood or imaging tests. RESULTS:Hepatomegaly, hepatic venous dilatation, caudate lobe enlargement, splenomegaly, liver atrophy, ascites, hepatocellular carcinoma, and hepatic tumors other than hepatocellular carcinoma were observed in 37.7%, 29.9%, 18.4%, 33.2%, 3.2%, 6.0%, 0.85%, and 10.0% of patients, respectively. Typical ultrasound findings of FALD included hepatomegaly, hepatic vein dilatation, and splenomegaly, reflecting liver congestion. With the progression of fibrosis, caudate lobe enlargement and splenomegaly became more prominent. Based on these findings, we proposed diagnostic criteria for FALD. Using these criteria, FALD was diagnosed in 1014 (86.8%) of the patients, and all patients with a pathological diagnosis of FALD were successfully identified. Eight patients were found to have pathological cirrhosis, and all were diagnosed with advanced FALD using our criteria based on blood tests or imaging. CONCLUSION:Our diagnostic criteria facilitate detection of FALD or advanced FALD after the Fontan surgery. The accuracy of these criteria should be further evaluated.

BackgroundThe long-term impact of Kawasaki disease on coronary arteries in vivo is unclear.ObjectivesThe purpose of this study was to investigate coronary arteries in the late convalescent phase, we followed patients with Kawasaki disease who developed coronary artery aneurysms (CAAs).MethodsWe followed 24 patients and used optical coherence tomography at a median of 16.6 years after the onset of Kawasaki disease.ResultsOf 72 coronary arteries, optical coherence tomography was performed on 61 arteries: 17 with a persistent CAA, 29 with a regressed CAA, and 15 without a CAA. Between-group comparison was performed by chi-square or Fisher’s exact test, and intimal thickening (17 vs 29 vs 15, all 100%, P = NA) and medial disruption (17 [100%] vs 29 [100%] vs 14 [93%], P = 0.25) were commonly observed in the investigated arteries. Advanced features of atherosclerosis were more frequently seen in arteries with persistent CAAs than in those with regressed CAAs and in those without CAAs: calcification (12 [71%] vs 5 [17%] vs 1 [7%], P < 0.001), microvessels (12 [71%] vs 10 [35%] vs 4 [27%], P = 0.020), cholesterol crystals (6 [35%] vs 2 [7%] vs 0 [0%], P = 0.009), macrophage accumulation (11 [65%] vs 4 [14%] vs 4 [27%], P = 0.002), and layered plaque (8 [47%] vs 11 [38%] vs 0 [0%], P = 0.004).ConclusionsLong after onset of Kawasaki disease, all arteries showed pathological changes. Arteries with persistent CAAs had more advanced features of atherosclerosis than those with regressed CAAs and those without CAAs.

The Fontan operation, which directly connects the superior and inferior vena cava to the pulmonary artery, is a palliative surgery for children with a functional or anatomic single ventricle. This procedure leads to hemodynamic changes (Fontan circulation) in patients, who tend to develop congestive hepatic fibrosis characterized by sinusoidal fibrosis and dilatation beginning approximately 10 years after the procedure. In addition, in the context of severe fibrosis and cirrhosis, hepato-gastrointestinal complications including hepatocellular carcinoma, focal nodular hyperplasia, and portal hypertension can arise. Fontan-associated liver disease (FALD) encompasses the broad spectrum of liver alterations secondary to postoperative hemodynamic changes, and the effective management of FALD requires contributions from specialists in hepatology, gastroenterology, surgery, radiology, histopathology, and pediatric and adult cardiology. In this article, we outline the pathogenesis of FALD and discuss the importance of a multidisciplinary collaborative approach to its management.

The long-term impact of Kawasaki disease on coronary arteries in vivo is unclear. The purpose of this study was to investigate coronary arteries in the late convalescent phase, we followed patients with Kawasaki disease who developed coronary artery aneurysms (CAAs). We followed 24 patients and used optical coherence tomography at a median of 16.6 years after the onset of Kawasaki disease. Of 72 coronary arteries, optical coherence tomography was performed on 61 arteries: 17 with a persistent CAA, 29 with a regressed CAA, and 15 without a CAA. Between-group comparison was performed by chi-square or Fisher's exact test, and intimal thickening (17 vs 29 vs 15, all 100%, P = NA) and medial disruption (17 [100%] vs 29 [100%] vs 14 [93%], P = 0.25) were commonly observed in the investigated arteries. Advanced features of atherosclerosis were more frequently seen in arteries with persistent CAAs than in those with regressed CAAs and in those without CAAs: calcification (12 [71%] vs 5 [17%] vs 1 [7%], P < 0.001), microvessels (12 [71%] vs 10 [35%] vs 4 [27%], P = 0.020), cholesterol crystals (6 [35%] vs 2 [7%] vs 0 [0%], P = 0.009), macrophage accumulation (11 [65%] vs 4 [14%] vs 4 [27%], P = 0.002), and layered plaque (8 [47%] vs 11 [38%] vs 0 [0%], P = 0.004). Long after onset of Kawasaki disease, all arteries showed pathological changes. Arteries with persistent CAAs had more advanced features of atherosclerosis than those with regressed CAAs and those without CAAs.

We report successful percutaneous retrieval of a foreign body located in an infant's right pulmonary artery using the new boomerang loop–snare technique. The case was an 18-month-old girl. A central venous catheter for chemotherapy was inserted from the right subclavian vein during treatment for myelodysplastic syndrome at another hospital. A postprocedural chest X-ray showed a foreign body in her right lung, and contrast-enhanced computed tomography confirmed the linear foreign body was located in the right pulmonary artery. The patient was transferred to our hospital to retrieve the foreign body. Under cooperation with pediatric cardiologists, a 6 Fr sheath was inserted via the right femoral vein, and a guiding catheter was advanced into the right pulmonary artery. Owing to the risk of vascular injury when using endoscopic forceps, we decided to use the loop–snare technique. We successfully crossed over the foreign body using a steerable microcatheter and a long microguidewire. The microguidewire was reinserted into the guiding catheter, and a loop was created by grasping the end of the wire using a microsnare catheter, which was inserted coaxially within the guiding catheter. By pulling the microsnare catheter, we were able to pull the foreign body into the guiding catheter and successfully retrieved it. There were no complications, such as pulmonary artery injuries or thrombi. The recovered foreign body was a piece of a guidewire. The boomerang loop–snare technique using a small-diameter system is useful for the retrieval of a foreign body in infants.

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients’ IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

Respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection, especially in children and the elderly. Various vaccines containing the major transmembrane surface proteins of RSV (proteins F and G) have been tested; however, they have either afforded inadequate protection or are associated with the risk of vaccine-enhanced disease (VED). Recently, F protein-based maternal immunization and vaccines for elderly patients have shown promising results in phase III clinical trials, however, these vaccines have been administered by injection. Here, we examined the potential of using the ectodomain of small hydrophobic protein (SHe), also an RSV transmembrane surface protein, as a nasal vaccine antigen. A vaccine was formulated using our previously developed cationic cholesteryl-group-bearing pullulan nanogel as the delivery system, and SHe was linked in triplicate to pneumococcal surface protein A as a carrier protein. Nasal immunization of mice and cotton rats induced both SHe-specific serum IgG and mucosal IgA antibodies, preventing viral invasion in both the upper and lower respiratory tracts without inducing VED. Moreover, nasal immunization induced greater protective immunity against RSV in the upper respiratory tract than did systemic immunization, suggesting a critical role for mucosal RSV-specific IgA responses in viral elimination at the airway epithelium. Thus, our nasal vaccine induced effective protection against RSV infection in the airway mucosa and is therefore a promising vaccine candidate for further development.