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Background Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. Methods Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin–producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. Results A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. Conclusion Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan. [ABSTRACT FROM AUTHOR]

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

• More calcium ions were released from the new materials, more calcium bound to carboxyl groups in the matrix. • Biphasic release occurs before Fluoride recharge and monophasic release occurs after recharge. • New materials suppressed S. mutans growth and biofilm formation. • We produced cement by reinforcing the material properties of conventional GIC-based sealant. The aim of this study was to investigate the chemical and biological properties of newly developed bioactive cements, modified such that they are largely composed of calcium, phosphate and fluoride. We investigated whether newly developed bioactive cements have the potential to further protect surrounding hard tissue and enhance remineralization of demineralized tissue by additional ion release. We developed four types of novel GIC based on Fuji VII, modified with phosphate and fluoride and calcium. Compressive strength tests were performed following JIS T6607 methods. Ion release of calcium, phosphate and fluoride after 24 h storage were determined using atomic absorption spectroscopy, colorimetry and an ion-specific electrode. Fluoride releases and recharge were measured at 1, 3, 6, 12, 24 and 168 h. Viability was determined by colony-forming units. Inhibitions of biofilm formation and cell proliferation activity were measured. The GIC groups showed no significant differences in compressive strength after 1 and 7 days. The rates of fluoride ion release from newly developed GICs were significantly greater than those of Fuji VII, Fuji III and BS. All materials except TM can be recharged with fluoride ions. Compared with the control group, which did not release fluoride ions, all materials showed significantly stronger antibacterial effects. The newly developed GICs and BS showed less biofilm formation than Fuji VII and Fuji III. Three of four newly developed GICs modified with calcium, phosphate and fluoride ions were found to be superior to other sealant materials. [ABSTRACT FROM AUTHOR]

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

Background: We sought to quantify the degree of anemia after high-dose intravenous immunoglobulin (IVIG) therapy in patients with Kawasaki disease (KD) by assessing hemoglobin (Hb) dynamics and determining the risk of transfusion.Methods: We analyzed data from a database containing inpatient data collected from 230 hospitals in Japan. In addition to administrative records, this database included laboratory results for some patients. We searched for individuals aged ≤ 18 years with a diagnosis of KD (International Statistical Classification of Diseases and Related Health Problems, 10th revision, code M30.3) who had received high-dose (≥ 1 g/kg) IVIG therapy. The primary outcome measure was post-IVIG therapy Hb dynamics in patients for whom laboratory findings were available. Secondary outcomes included the proportion of patients whose Hb value decreased below a specified threshold (e.g., 1 g/dL) and the number who received red blood cell transfusions, identified by a Japanese administrative code, in the whole cohort.Results: Laboratory data were available for 979 of 8262 patients with KD receiving high-dose IVIG. Hb dynamics assessed on spline curves showed that mild anemia commonly occurred 1-2 days after IVIG infusion and returned to the baseline thereafter. Declines of Hb > 1 g/dL and > 2 g/dL were found in 21.8% and 4.3% of patients, respectively. Two of the 8262 individuals with KD had received transfusions after IVIG therapy (incidence rate 0.024%; 95% confidence interval 0.003-0.087), but the indication for transfusion could not be determined from our records.Conclusions: Although mild anemia commonly occurred post-IVIG therapy in Japanese individuals with KD, severe anemia necessitating transfusion was rare in these patients. [ABSTRACT FROM AUTHOR]

Background: Little is known regarding the epidemiology of idiopathic nephrotic syndrome (INS) in East Asia. Previous studies have suggested higher incidence of INS in Asian children, though decreasing trend of its incidence has also been shown. Methods: We conducted a nationwide study of Japanese children aged 6 months to 15 years with INS. Children who were newly diagnosed with INS between 1 January 2010 and 31 December 2012 were eligible. Children with congenital nephrotic syndrome or nephrotic syndrome secondary to nephritis were excluded. Results: A total of 2099 children were initially diagnosed with INS and were followed for up to 4 years. The estimated incidence of INS was 6.49 cases/100,000 children per year, without clear correlation with geographical region. The male:female ratio was 1.9 and approximately 50 % of children were <5 years old at diagnosis. During the 1-4 years follow-up, 32.7 % developed frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome. Conclusions: Based on our nationwide survey, the incidence of INS in Japanese children is approximately 3-4 times higher than that in Caucasians. However, the male:female ratio and the age at onset were similar to those in previous studies. We are now planning a prospective cohort study to examine the course of INS in Japan. [ABSTRACT FROM AUTHOR]

Background: Fabry disease is an X-linked lysosomal disorder caused by decreased activity of α-galactosidase A (GLA). Consequent accumulation of globotriaosylceramide (GL-3) in lysosomes results in damage to a variety of organs, including the kidneys. Enzyme replacement therapy (ERT) is an effective treatment, but whether it should be started before organ damage is evident is a matter of debate. Case diagnosis/treatment: A 10-year-old boy who complained of severe sole pain for 3 years had been misdiagnosed with juvenile idiopathic arthritis. Further investigations revealed decreased GLA activity and a M1T mutation in the GLA gene causing protein truncation, suggestive of Fabry disease. Despite normal renal function and urinalysis, renal biopsy showed abnormal structure, with marked accumulation of GL-3 in podocytes, partial effacement of foot processes and irregularly reduced expression of nephrin in the slit diaphragm. After 1 year of ERT with 1 mg/kg agalsidase beta once every 2 weeks, his pain had resolved with ERT combined with carbamazepine and pregabalin. After 3 years of the ERT, repeat biopsy showed little renal GL-3 deposition, resolution of foot process effacement, and a dramatic improvement in nephrin expression. Conclusions: There may be a window of opportunity in which pain and renal injury can be addressed in the early stages of Fabry disease. Early initiation of ERT should therefore be considered for children with Fabry disease. [ABSTRACT FROM AUTHOR]

We examined the associations between natural individual variations in basal oxytocin ( OXT) in postnatal cattle and social behavioral traits. At 1, 2 and 6 weeks of age, the basal OXT exhibited individual variability in 20 Holstein heifer calves. Cluster analysis of mean OXT for these time periods obtained two subgroups: high OXT ( HOXT; n = 9) and low OXT ( LOXT; n = 11). Social behaviors were observed for 2 days at week 6 after introduction into a four-peer group, and at 10-14 months of age (10 months) immediately and 1 week, 1 month and 5 months after introduction into 11-15 heifers. At week 6, the main effect of the OXT groups was not significant for all social behaviors. At 10 months, there tended to be interactions between the OXT groups and time periods with respect to the frequency of escape behaviors. LOXT heifers exhibited more escape behaviors than HOXT heifers on the first day of the second sociality tests. At 10 months, HOXT heifers exhibited both attacking and affiliative behavior for peers more than LOXT heifers during 5 months after the second social introduction. This suggests that postnatal OXT concentrations may have long-lasting effects on individual differences among social behavioral traits in cattle. [ABSTRACT FROM AUTHOR]

The pathogenesis of coronary artery aneurysm (CAA) formation in Kawasaki disease (KD) remains unknown. However, inflammatory cytokines are thought to play an important role in KD. Patients with intravenous immunoglobulin (IVIG)-resistant KD are more likely to develop CAA. For such refractory patients, steroids and emerging infliximab (IFX) are used; however, further verification is required for their efficacy and safety. Plasma exchange (PE), which removes various inflammatory cytokines, has been used in Japan for over 15 years to prevent CAA in IVIG-resistant KD patients. The sequential change in inflammatory cytokines during the time course of PE has yet to be investigated. In this study, we measured plasma levels of 13 cytokines in nine children with IVIG-resistant KD before the start of PE (day 0: D0), as well as at 1 or 2 days (D1/2), and 4 or 5 days (D4/5) after starting PE. The median age of onset was 8 months (range: 3–53 months). Before PE, patients were treated with IVIG (median dose: 4 g/kg, range: 3–4 g/kg). The median starting period of PE was 8 days after the onset of fever (range: 6–21 days), while its duration was 3 days (range: 2–5 days). Among the 13 cytokines, interleukin-6, tumor necrosis factor-α, tumor necrosis factor receptor I (TNFR1), TNFR2, granulocyte colony-stimulating factor, and IL-17 were significantly lower at D4/5 compared with D0 and/or D1/2, reflecting the potential central efficacy of PE. While three patients developed moderate CAA, their condition regressed within 1 year. The removal of inflammatory cytokines could be the central efficacy of PE against refractory KD. [ABSTRACT FROM AUTHOR]

Background: Children with steroid-dependent nephrotic syndrome (SDNS) often suffer from serious adverse events, including growth retardation and obesity. Rituximab (RTX) is a promising therapeutic option to overcome steroid dependency. We have examined the impact of RTX on growth and obesity in children with SDNS. Methods: Thirteen pediatric patients with SDNS who were refractory despite treatment with multiple immunosuppressive agents received RTX infusions. Mean follow-up was 2.3 years from the first administration of RTX. Improvement in the height and obesity indexes from prior to the initial RTX infusion through to the last visit was assessed. Results: After RTX, the number of relapses [2.8 (before RTX) vs. 0.8/year (after RTX); p = 0.0008] and the prednisolone dose (287.9 vs. 70.7 mg/kg/year, respectively; p = 0.0002) were significantly decreased. Marked improvement in the height standard deviation score (SDS) was achieved by ten of the 13 patients (77 %) [ n = 13; −1.6 (before RTX) vs. −0.8 SDS (after RTX); p = 0.03]. Notably, the height SDS of seven of the eight patients whose height was less than average at the first RTX improved from −2.6 to −1.4 SDS with RTX therapy. At the same time, the obesity index of 12 of the 13 patients (92 %) significantly improved ( n = 13; 16.9 vs. 3.1 %; p = 0.004). Conclusion: Therapy with RTX may contribute to an improvement in the growth and obesity indexes in some patients suffering from severe side effects of steroids. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1007/s10157-021-02159-9. Correction to: Clinical and Experimental Nephrology https://doi.org/10.1007/s10157-021-02159-... The article "Safety and efficacy of azilsartan in paediatric patients with hypertension: a phase 3, single-arm, open-label, prospective study", written by Shuichi Ito - Yuya Nishiyama - Kenkichi Sugiura and Kazuaki Enya was originally published Online First without Open Access. [Extracted from the article]

To examine the influence of postnatal oxytocin ( OXT) on behavioral development, we examined individual variations in basal OXT and suckling-induced changes in OXT, and their relationship with emotional traits during development. Blood OXT were measured in 20 Holstein heifer calves at 1 (wk1), 2 (wk2), and 6 weeks of age (wk6). The relationships of OXT variables with principal component scores in the open-field tests at wk2 and 2 months and the number of flinch, step and kick responses during first artificial insemination and machine milking were analyzed. The basal OXT showed individual variability and significantly correlated (wk1 vs. wk2: r = 0.753, P < 0.001; wk1 vs. wk6: r = 0.499, P < 0.05; wk2 vs. wk6: r = 0.476, P < 0.05). The personality traits reflecting a response in the form of escape from novel environments in the open-field test at wk2 were inversely correlated with basal OXT at wk1 ( rs = −0.640, P < 0.01) and wk2 ( rs = −0.447, P < 0.05). However, none of the behavioral variables after 2 months correlated with OXT. These findings suggest that, postnatal OXT might be related to behavioral characteristics in novel environments only during the early stages of life. [ABSTRACT FROM AUTHOR]

Background: Persistent fever after intravenous immunoglobulin (IVIG) is considered to be a major criterion of IVIG resistance in Kawasaki disease (KD), and a risk factor for the development of coronary artery abnormalities (CAA). However, the importance of persistent non-fever symptoms after defervescence has not yet been investigated. We examined the relationship between persistent non-fever symptoms and CAA in KD. Methods: We conducted a retrospective cohort study of patients hospitalized with KD at the National Center for Child Health and Development between 1 April 2008 and 31 March 2009. Patients were divided into two groups; group A included patients who still had non-fever symptoms one month after onset of the illness and group B included patients who did not have persistent non-fever symptoms. Demographic, clinical variables were compared between the groups. Results: Seventy-seven KD patients treated with IVIG were retrospectively analyzed. Patients were divided into two groups; group A included 12 (15.6%) patients and group B 65 (84.4%) patients. Demographic data, baseline laboratory data, and fever duration did not differ between the groups. In group A patients the most common persistent non-fever symptoms were lip erythema (n = 6) and bulbar conjunctivitis (n = 8). One month after onset of the illness CAA developed in seven of 77 patients (9.1%), four (33%) in group A and three (4.6%) in group B (odds ratio 10.3; 95% CI 1.9-54.8). Three patients in group A and one patient in group B developed CAA after the resolution of fever. Conclusions: Persistence of non-fever symptoms after IVIG may suggest persistence of latent inflammation, which may increase the risk of CAA. Therefore, patients with persistent non-fever symptoms may be at risk of developing CAA, even after defervescence. A prospective trial of additional IVIG for such patients should be considered. [ABSTRACT FROM AUTHOR]

Background: Rituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome. Methods: We retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan. Results: Seventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX ( P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete ( n = 6) and partial remission ( n = 6) were achieved. No life-threatening adverse events were experienced. Conclusions: Although this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse. [ABSTRACT FROM AUTHOR]

ABSTRACT This study was conducted to investigate physiological and behavioral effects of the exposure to plant-derived odorants in Holstein steers (8 month of age) under the acute stress of social isolation in a novel environment. Each steer was tethered in a new room alone and exposed to one of three odorants: a mixture of equal amounts of trans-2-hexenal and cis-3-hexenol (green odor, GO; n = 5), essential oil of grapefruits (EOG; n = 5) and solvent (SOL; n = 6). Behaviors were recorded and blood samples were taken at intervals of 10-15 min for 6 h. Compared with SOL, exposure to GO or EOG decreased the frequency of vocalization ( P < 0.05), shortened the latency period before the onset of rumination ( P < 0.05) and increased the duration of rumination ( P < 0.05). Plasma cortisol concentrations in steers exposed to plant-derived odorants (GO and EOG) during 90-130 min from commencement of sampling were significantly lower ( P < 0.05) compared with SOL. These results suggest that appeasing effects of plant-derived odorants on behavioral and physiological stress responses previously reported in laboratory rodents could be also be expected in steers. [ABSTRACT FROM AUTHOR]

Background: Rituximab, an anti-CD20 antibody that targets B cells, is a promising agent against steroid-dependent and steroid-resistant nephrotic syndrome in children. Case-Diagnosis/Treatment: We report a 3-year-old boy who presented with atypical Pneumocystis jiroveci pneumonia (PCP) following administration of rituximab for refractory nephrotic syndrome. He had received cyclosporine and daily prednisolone for over 1 year. Following rituximab therapy, a hazy shadow was observed on his chest X-ray. Chest-computed tomography revealed multiple nodular lesions in bilateral lungs, although his clinical symptoms were subtle. PCR analysis demonstrated the presence of Pneumocystis DNA in his bronchoalveolar lavage. Lung wedge resection of the nodular lesion exhibited granulomas containing a few cysts of P. jiroveci that primarily consisted of T cells and histiocytes and lacked B cells. A deficiency of B cells following rituximab treatment suggests a dramatic effect on the immune response and, therefore, could result in granulomatous PCP. Nodular granulomatous lesions of PCP comprise an emerging concept previously reported in adults with hematological disease, bone marrow transplant, or treatment with rituximab. We report the first pediatric case of nodular PCP. Granulomatous PCP can be life-threatening. Moreover, bronchoalveolar lavage often fails to demonstrate the presence of P. jiroveci DNA. Wedge biopsy is warranted for definitive diagnosis. Our patient fully recovered with sulfamethoxazole/trimethoprim treatment because of early detection. Conclusions: The indication of rituximab for refractory nephrotic syndrome has increased recently. Therefore, recognition of the risk of atypical PCP is important. Our findings suggest that PCP prophylaxis should be considered following rituximab therapy. [ABSTRACT FROM AUTHOR]

Rituximab (RTX) has a significant steroid-sparing effect in children with steroid-dependent nephrotic syndrome (SDNS). However, patients are likely to relapse with the recovery of CD20+ cells. We conducted a small prospective cohort study with a historical control to evaluate the effect of RTX infusion followed by mycophenolate mofetil (MMF) as a maintenance therapy. Nine patients with SDNS who stopped their steroid treatment but were treated with MMF after RTX infusion were prospectively observed (group A). Seven patients with SDNS who discontinued steroid and immunosuppressive agents after RTX administration served as a control (group B). During the first year after the administration of RTX, six patients in group A and one patient in group B did not suffer a relapse ( p < 0.05). The number of patients who relapsed during the 1 year preceding RTX treatment did not differ between the two groups [4.1 (A) vs. 5.7 (B)], but it was significantly lower in the MMF-treated group 1 year after the RTX treatment [0.4 (A) vs. 2.3 (B), p < 0.005]. The daily amount of prednisolone after the RTX treatment was lower in group A than in group B (0.11 vs. 0.46 mg/kg/day, respectively; p < 0.05). Three patients in group A and five patients in group B relapsed to SDNS and needed additional RTX treatment(s) within 1 year (odds ratio 5.0). Based on these results, we conclude that maintenance therapy with MMF after RTX is a good clinical option. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the mineralizing potential of ions released from surface pre-reacted glass-ionomer (S-PRG) fillers on mineral induction by phosphoprotein in vitro.Methods: Phosvitin was used as a model of dentin phosphoprotein in this study. Phosvitin was immobilized on agarose beads with divinyl sulfone. Five aliquots of phosvitin-immobilized agarose beads were incubated in control or experimental mineralizing solution. The experimental mineralizing solutions were made from eluates of resin filled with S-PRG fillers. The beads were incubated at 37°C in a shaking water bath, and aliquots were taken at several time points during the incubation. Then the beads were analyzed for calcium by atomic absorption spectrometry.Results: Phosvitin-immobilized agarose beads induced mineral formation after incubation for 5.3h in the metastable solution without ions eluted from S-PRG fillers. Undiluted eluates significantly reduced mineral induction time. SEM observation and X-ray diffraction revealed larger apatite crystals on the beads incubated with eluates of S-PRG fillers than with the control.Conclusions: S-PRG fillers may play a role in mineral induction. [ABSTRACT FROM AUTHOR]

Background. Childhood-onset systemic lupus erythematosus (SLE) is frequently complicated with lupus nephritis (LN), which is characterized by the deposition of DNA-containing immune complex to the glomerulus. Toll-like receptor 9 (TLR9), capable of recognizing the microbially derived CpG oligonucleotide, plays a crucial role in the innate immunity. TLR9 is also assumed to be related to the aetiology of SLE in the recognition of anti-DNA antibody-containing immune complex, but this remains controversial. We conducted a study to elucidate the association between TLR9 and LN in childhood-onset SLE. [ABSTRACT FROM PUBLISHER]

Abstract: Objectives: The purpose of this study was to compare the water sorption/solubility, percent conversion and microtensile bond strength of three single-step self-etching adhesives with those of a two-step self-etching primer adhesive system. Methods: Solvent evaporation from the adhesives was determined gravimetrically. After removal of volatile solvents, the resins were cast into disks and polymerized. One-half of the disks were incubated in water while the other half were incubated in hexadecane. Repeated measurements of water sorption were made for 10 days followed by drying for 2.5 days to a constant weight. Percent conversion was done using FTIR spectroscopy. Microtensile bond strengths were measured 24h after bonding. Results: All of the adhesives lost 20–30% of their weight after 4min of forced air except for Fluorobond II which lost no weight. All resins stored in water exhibited a time-dependent increase in water sorption and solubility. The resins stored in hexadecane showed very low sorption and solubility. Water sorption was highest for Absolute 2 (20.7%), intermediate for Fluorobond Shake One (10.2%) and lowest for Clearfil 3S (8.9%) and Fluorobond II (7.5%). Percent conversions ranged from a low of 68.3% for Absolute 2 to a high of 87.4% for Clearfil 3S. The two-step self-etching primer adhesive (Fluorobond II) gave the lowest water sorption and lowest solubility of any of the tested adhesives. SEM observations of resin disks incubated in hexadecane looked similar to unincubated controls. Incubating resin disks in artificial saliva covered the surfaces of the resins with mineral crystallites. Significance: Single bottle self-etching adhesives show higher water sorption/solubilities than two-step self-etching adhesives. The former products would not be expected to function as well as the latter products. [Copyright &y& Elsevier]

Abstract: Oxytocin and prolactin are potential candidates for the regulation of behavioral and physiological stress responses in the brain. To investigate the neurobiological basis of individual differences in stress responses in cattle, we examined the association of behavioral and hypothalamo-pituitary-adrenal axis reactivity to acute stressors and basal and stimulated levels of oxytocin and prolactin. Twenty Holstein heifer calves aged 2weeks were subjected to a 10min open-field test (OFT) followed by presentation of a feeding bucket for 15min in the OF. If the calf contacted the bucket, a blast of air was applied to its muzzle (surprise test). Jugular blood samples collected before and after both tests were analyzed for oxytocin, prolactin, and cortisol. Relationships of basal and percent change in oxytocin or prolactin with behavioral responses in each test and percent change in cortisol were analyzed using principal components analysis and Spearman rank correlations. Plasma cortisol and prolactin concentrations were significantly elevated by the tests (p <0.005), but plasma oxytocin concentration did not significantly change (p >0.1). Four principal components explained 56.1% of the total variation: curiosity, general activity, fearfulness, and dependence on humans. Curiosity was inversely correlated with basal oxytocin level (rS=−0.683, p <0.05). General activity was positively correlated with prolactin reactivity (rS=0.448, p <0.05) and inversely with oxytocin reactivity to the novel environment (rS=−0.717, p <0.05). Fearfulness tended to correlate positively with basal oxytocin level (rS=0.583, p <0.1). Dependence on humans correlated with none of the hormonal parameters. The relationships of basal oxytocin level with curiosity and fearfulness for novel environments are of particular interest for future study. [Copyright &y& Elsevier]

The article presents two case studies related to diseases caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria. The first case centers on the case of a baby boy with grade II vesicoureteral reflux (VUR) where the catheter urinary culture showed ESBL-producing Klebsiella oxytoca. The second study focuses on the case of a 7-month-old baby boy admitted due to urinary track infecstion (UTI) where ESBL-producing E. coli was found in the catheter urine culture.

We conducted a multicenter prospective trial to evaluate the efficacy, safety and pharmacokinetics of a single dose of rituximab (375 mg/m2 body surface area) for the treatment of children with refractory steroid-dependent nephrotic syndrome (SDNS). All patients ( n = 12) were able to discontinue steroids at a median of 74 days after treatment. The frequency of relapses per 6 months was significantly reduced and the steroid-free period per 6 months was significantly increased after treatment compared with those before treatment. The condition in nine of the patients (75%) relapsed at a median of 129 days after treatment, and seven patients were given additional rituximab due to steroid dependency. Most of the relapses developed simultaneously with recovery of B-cells. However, three patients (25%) did not have a relapse with B-cell recovery and the disease was kept in remission for more than 1 year. None of the patients developed life-threatening adverse events. This is the first report of a prospective study of a single dose of rituximab for refractory SDNS. Treatment with a single dose of rituximab may be effective for refractory SDNS, but its efficacy to prevent relapses was transient in most of the patients. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic disease of unknown etiology that is characterized by chronic non-caseating granulomatous inflammation with tissue destruction. It is an uncommon disease in children, and renal sarcoidosis in particular is very rare in adults and children. A 17-year-old boy with renal sarcoidosis was referred to our hospital with an initial diagnosis of pyelonephritis. Prior treatment with various antibiotics had not been effective, but tentative oral daily prednisolone (PSL) had partially ameliorated his symptoms, although the symptoms recurred during steroid tapering. We detected non-caseating granulomatous interstitial nephritis and numerous sclerotic glomeruli in a second biopsy specimen, compatible with the diagnosis of renal sarcoidosis. The patient was treated with pulsed methyl-prednisolone and oral daily doses of PSL and mizoribine (MZR). During the treatment with MZR, the PSL was successfully tapered, and the patient has since presented no signs of recurrence. Our treatment of this patient shows that treatment with MZR can allow steroid sparing and prevent recurrence in a patient with sarcoidosis. [ABSTRACT FROM AUTHOR]

We report the case of a girl with steroids and cyclosporine (CsA) resistant focal segmental glomerulosclerosis (FSGS) whose proteinuria and hypoproteinaemia were dramatically resolved by pravastatin. She had been in a nephrotic condition for 6 years. Prednisolone, pulse methylprednisolone therapy, low-density lipoprotein (LDL) apheresis, CsA, cyclophosphamide and mizoribine (MZR) had proved to be ineffective. She was started on pravastatin for her hyperlipidaemia 6 and a half years from onset, in addition to the baseline therapy, which included CsA; remission of the nephrotic syndrome was unexpectedly attained after 10 months of treatment. The baseline therapy has not been changed since the inclusion of pravastatin. This case suggests that, in patients with hyperlipidaemia, the response to CsA could be restored by lowering cholesterol levels with statins. The decrease of cholesterol levels might have improved the pharmacokinetics of CsA in this patient. Furthermore, the anti-inflammatory and immuno-modulatory effects, recently attributed to statins, may also have been involved in the improvement experienced by our patient. [ABSTRACT FROM AUTHOR]

We encountered the case of a 4-year-old boy with thrombotic microangiopathy (TMA) of unknown etiology. Verotoxin-induced hemolytic uremic syndrome (HUS), Streptococcus-pneumoniae-related HUS, factor H deficiency, drug-induced thrombotic thrombocytopenic purpura (TTP), and ADAMTS13 (von Willebrand factor-cleaving protease; a disintegrin-like and metalloprotease with thrombospondin type 1 repeats)-related TTP were excluded. His condition was refractory to anticoagulants and plasma exchange, and his clinical course was catastrophic, with central nervous system symptoms and progressive renal failure. However, factual treatment of intravenous gamma globulin (IVIG) ended the hemolysis and resulted in a rise in platelet count. He fully recovered except for end-stage renal failure, but he underwent a successful renal transplant after peritoneal dialysis. He has not suffered a relapse of TMA or an allograft rejection for 4 years. IVIG might be an option for some patients with TMA of unknown etiology refractory to conventional treatment. [ABSTRACT FROM AUTHOR]

Abstract: Electrical impedance spectroscopy (EIS) offers a quantitative method of measuring the stability of resin films in aqueous solution over time. Purpose: The purpose of this study was to measure the EIS of five experimental dental adhesive films (ca. 17μm thick) of increasing hydrophilicity (ranked by their Hoy''s solubility parameters), and how much these values change over 3 weeks in aqueous buffer. Methods: The resin films were placed in a U-shaped chamber and a pair of Ag–AgCl electrodes was used for EIS. The EIS results were confirmed by immersing the films in 50% AgNO3 for 24h to trace the distribution of any water absorption into the resins by TEM observations. Results: The resistance (R r) of the resins 1–4 films increased most during the first day, and varied from 1×1011 ohm for resin 1, to 40Ω for resin 5 at day 1. The day 1 R r values of resins 1–4 were inversely proportional to their Hoy''s solubility parameter for hydrogen bonding forces. Electrical impedance values of resins 1–3 and 5 varied widely but were relatively constant over time, while those of resin 4 decreased more than 99% from day 1 to 21 (). Capacitance (C r) of films of resins 1–4 all increased over the first day and then were relatively unchanged over the 20 days (except for resin 4 that continued to increase) and were between 0.01 and 1nF. Silver uptake by TEM revealed the development of water-filled branching structures that formed in resins 4 and 5 over time. [Copyright &y& Elsevier]

Objectives: Drug-induced hypersensitivity syndrome (HS) is a rare but life-threatening disease. We experienced carbamazepine-induced HS in a 14-year-old boy, who had cefaclor-induced cutaneous eruptions 15 months later. To clarify the mechanisms of HS and the differences between two diseases we studied this case in detail. Methods: We investigated the associated viral agents by polymerase chain reaction and the specific antibodies. We also studied the mechanism of diseases by measuring chemical mediators including cytokines, ECP and immunoglobulins. Results: The patient was diagnosed as having carbamazepine-induced HS associated with reactivation of human herpesvirus 6 based on the clinical course and laboratory data including drug-induced lymphocyte stimulation tests. Similarly, the diagnosis of cefaclor-induced eruption without any viral reactivation was made. Serum levels of IFN-γ, IL-6, TNF-α, IL-5 and ECP were increased significantly at HS but mildly at cefaclor-induced eruptions. Furthermore, we detected transient hypogammaglobulinemia only at HS. Conclusions: This is the first report of anticonvulsant-induced HS followed by antibiotic-induced eruptions in a patient. In addition, we demonstrated difference in serum levels of inflammatory cytokines, immunoglobulins, activated eosinophils and viral reactivation between these diseases. This case would contribute to the understanding of the pathophysiology of adverse drug reactions including HS. [ABSTRACT FROM AUTHOR]

Abstract: As acidic monomers of self-etching adhesives are incorporated into dental adhesives at high concentrations, the adhesive becomes more hydrophilic. Water sorption by polymers causes plasticization and lowers mechanical properties. The purpose of this study was to compare the water sorption and modulus of elasticity (E) of five experimental neat resins (EX) of increasing hydrophilicity, as ranked by their Hoy''s solubility parameters and five commercial resins. Methods: After measuring the initial modulus of all resin disks by biaxial flexure, half the specimens were stored in hexadecane and the rest were stored in water. Repeated measurements of stiffness were made for 3 days. Water sorption and solubility measurements were made in a parallel experiment. Results: None of the specimens stored in oil showed any significant decrease in modulus. All resins stored in water exhibited a time-dependent decrease in modulus that was proportional to their degree of water sorption. Water sorption of EX was proportional to Hoy''s solubility parameter for polar forces () with increasing polarity resulting in higher sorption. The least hydrophilic resin absorbed 0.55wt% water and showed a 15% decrease in modulus after 3 days. The most hydrophilic experimental resin absorbed 12.8wt% water and showed a 73% modulus decrease during the same period. The commercial resins absorbed between 5% and 12% water that was associated with a 19–42% reduction in modulus over 3 days. [Copyright &y& Elsevier]

Induction of experimental hemolytic uremic syndrome (HUS) by simply administering Shiga-like toxin (Stx) to rodents has not yet been successful. Attention has been paid to the role of lipopolysaccharide (LPS) in the pathogenesis of HUS. In this study, we showed successful induction of an experimental HUS in LPS responder mice by administering Stx together with LPS. Intraperitoneal administration of 200 ng of Stx 2 for 2 days, followed by 250 μg of LPS on the 2nd day of Stx administration, caused a significant decrease of thrombocytes and deterioration of renal function, with proteinuria and hematuria. Electron microscopy revealed alterations of glomerular endothelial cells. Administration of Stx alone or LPS alone caused neither hematological nor histopathological changes, as were observed with Stx and LPS co-administration. Interestingly, when LPS was administered before Stx, no hematological and histological changes were observed. The results showed that LPS was essential for the induction of HUS, but LPS pretreatment might protect against Stx toxicity. The order of LPS and Stx administration is important for the induction of experimental HUS. [ABSTRACT FROM AUTHOR]

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

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

Etanercept is a tumor necrosis factor (TNF)-α inhibitor that has been applied beneficially for juvenile idiopathic arthritis (JIA). We experienced long-term remission of nephrotic syndrome (NS) in a boy treated with etanercept, which was initially used for concomitant JIA. He developed NS at age 3 years 7 months and had mostly been treated with cyclosporine because of steroid dependency and frequent relapses. Cyclosporine was halted at 10 years 7 months because of nephrotoxicity, and he was subsequently treated with mizoribine. However, he had three relapses in the first year and developed JIA at 11 years 7 months. He was treated with sulfasalazine, methotrexate, and prednisolone, but his arthritis persisted. Etanercept was started at 12 years 3 months. Thereafter, his arthritis went into complete remission. Surprisingly, he has remained relapse-free for both NS and JIA for more than 3 years with etanercept and mizoribine. It is difficult to know whether the NS remission after initiating etanercept was coincidental. However, there are many reports of increased TNF-α or soluble TNF-α receptor in NS relapse. To date, there are two reports of the efficacy of TNF-α inhibitors against NS. It is possible that TNF-α inhibitors may have potential as therapeutic agents for NS. [ABSTRACT FROM AUTHOR]

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

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

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. [ABSTRACT FROM AUTHOR]

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

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

Background: The role of prenatal diet on childhood wheezing and subsequent risk of asthma is inconclusive, which may be partly due to the heterogeneity in wheezing phenotypes. We aimed to identify wheeze trajectories in early childhood and to examine their associations with periconceptional maternal diet quality. Methods: Data from 70,530 mother–child pairs of liveborn singletons from the Japan Environment and Children's Study were analysed. Wheezing was reported by caregivers using a modified International Study of Asthma and Allergies in Childhood questionnaire yearly from 1 to 4 years of age, from which trajectories were derived using group‐based trajectory modelling. Maternal diet in the year preceding the first trimester of pregnancy was assessed using a validated food frequency questionnaire; overall diet quality was determined using the balanced diet score based on the Japanese Food Guide Spinning Top. Bayesian inference of multinomial logistic regression models was performed to examine the association between maternal diet quality and wheeze trajectory in early childhood. Results: We identified four wheeze trajectories: 'never/infrequent' (69.1%; reference group), 'early‐childhood onset' (6.2%), 'transient early' (16.5%) and 'persistent' (8.2%). After adjustment for confounders, a higher quartile of maternal balanced diet score was associated with a lower risk of belonging to the 'transient early' and 'persistent' wheeze trajectories compared with the 'never/infrequent' wheeze trajectory by 10% of both. Maternal balanced diet score was not associated with belonging to the 'early‐childhood onset' wheeze trajectory. Conclusion: Improving maternal diet quality prior to conception may reduce certain wheeze phenotypes in early childhood. [ABSTRACT FROM AUTHOR]

Aim: While associations between vitamin D deficiency and neurodevelopmental disorders have been found, large studies on child vitamin D, neurodevelopment, and sex differences among the general population are lacking. This study aimed to investigate the association between child serum 25‐hydroxyvitamin D (25(OH)D)) levels and neurodevelopmental problems (NDPs). Methods: Serum 25(OH)D and NDPs were measured at age two among the subcohort study of the Japan Environment and Children's Study. NDPs were assessed with the Kyoto Scale of Psychological Development 2001 (Kyoto scale). Adjusted odds ratios (aORs) for the Kyoto‐scale developmental quotient scores <70 were calculated, for postural–motor, cognitive–adaptive, and language–social domains and overall scores, adjusted for test month, latitude, small for gestational age, maternal age, and daycare attendance. Results: Among 2363 boys and 2290 girls, boys had higher 25(OH)D levels, but scored lower in the Kyoto scale. For boys in the vitamin D deficiency (<20 ng/mL) group, aORs of scoring the Kyoto‐scale DQs <70 were 2.33 (p = 0.006) for overall DQs, 1.91 (p = 0.037) for cognitive–adaptive, and 1.69 (p = 0.024) for language–social domains. For girls, results were inconclusive. Conclusion: Only boys showed a clear and cross‐modal association between vitamin D deficiency and NDPs. [ABSTRACT FROM AUTHOR]

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

Background: There is a lack of large, nationwide, birth cohort studies in Japan that examine the relationships of initial feeding habits and breastfeeding period duration with offspring functional constipation at 3 years of age. This study assessed the impact of breastfeeding during infancy on early childhood functional constipation. Methods: The fixed data of 70,078 singleton births from the ongoing Japan Environment and Children's Study cohort study that commenced in 2011 were used to identify functional constipation as estimated by Rome III at 3 years of age. The exposure variables were breastfeeding period duration until 12 months of age (never, up to 6 months, or ≥ 7 months) as well as breastfeeding status at 1 month and 6 months of age (breastfeeding exclusively, partial breastfeeding, or infant formula feeding only). Multiple logistic regression analysis was employed to search for correlations for functional constipation development with breastfeeding period duration until 12 months of age and breastfeeding status during infancy. Results: We identified 8,118 toddlers (11.6%) who met the Rome III criteria at 3 years of age. After controlling for potential covariates, a breastfeeding period duration of 7 months or more was inversely related to functional constipation development (≥ 7 months: adjusted odds ratio [OR] [95% confidence interval (CI)] 0.76 [0.65, 0.88] versus never breastfed, P for trend < 0.001). Other initial feeding methods were significantly related to an increased risk of functional constipation as compared with breastfeeding exclusively at 1 month of age (partial breastfeeding: adjusted OR [95% CI] 1.17 [1.11, 1.23], formula feeding only: 1.23 [1.07, 1.40]) and 6 months of age (partial breastfeeding: adjusted OR [95% CI] 1.18 [1.12, 1.24], formula feeding only: adjusted OR [95% CI] 1.42 [1.20, 1.68]). Conclusion: This large nationwide survey revealed a possible protective effect of a prolonged breastfeeding period duration and early exclusive breastfeeding in infancy on functional constipation at 3 years. [ABSTRACT FROM AUTHOR]

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

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

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

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

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