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Kenta Nakada,1,2 Kazuhiro Shimo,3 Satoshi Ohga,3 Takako Matsubara1,3 1Faculty of Rehabilitation, Kobe Gakuin University Graduate School, Kobe, Japan; 2Department of Rehabilitation, Ikeda Rehabilitation Hospital, Kurobe, Japan; 3Department of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe, JapanCorrespondence: Kazuhiro Shimo, Department of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe, Hyogo, 651-2180, Japan, Tel/Fax +81-78-974-2461, Email shimo@reha.kobegakuin.ac.jpPurpose: This study assessed the pain associated with movement and exercise in older individuals with cognitive decline, using the Abbey Pain Scale (APS) to identify the sub-items that effectively reflect pain during such activities.Patients and Methods: A cross-sectional study was conducted in 225 older patients with musculoskeletal disorders and cognitive decline at the Ikeda Rehabilitation Hospital in Toyama, Japan. Pain during walking or transferring was assessed using the verbal rating scale (VRS) and the APS. Item response theory (IRT) was used to identify the APS sub-items that most accurately reflected the presence and degree of pain.Results: Pain associated with movement scored 1.3 ± 1.1 on the VRS and 2.5 ± 2.6 on the APS. The IRT analysis extracted “vocalization”, “facial expression”, and “change in body language” as the most reliable indicators of pain. These extracted items showed good internal consistency (Cronbach’s α = 0.72), were significantly positively related to changes in the VRS (rs = 0.370, p < 0.001), and showed significant differences between patients with and without subjective pain.Conclusion: Our study suggests that the APS sub-items “vocalization”, “facial expression”, and “change in body language” may be the most effective indicators of pain during movement and exercise in older individuals with cognitive decline. This approach may enhance the reliability of pain assessments and management during exercise therapy.Keywords: behavior observation assessments, pain assessment, pain behavior, item response theory

Yuto Niwa,1 Kazuhiro Shimo,2 Satoshi Ohga,2 Yuji Tokiwa,1 Takafumi Hattori,1 Takako Matsubara1,2 1Faculty of Rehabilitation, Kobe Gakuin University Graduate School, Kobe, Japan; 2Department of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe, JapanCorrespondence: Yuto Niwa, Faculty of Rehabilitation, Kobe Gakuin University Graduate School, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe, Hyogo, 651-2180, Japan, Tel +81-90-6587-2828, Email rm9wol04@s.kobegakuin.ac.jpPurpose: Exercise-induced hypoalgesia (EIH) is a reduction in pain sensitivity that occurs following a single bout of exercise. However, little research has compared the EIH effects of exercise at different intensities, including low intensity, in the same participant. It is unclear as to which exercise intensities demonstrate EIH more effectively. The aim of this study was to examine and compare the effect of different intensities of exercise on pain sensitivity in the same participant.Methods: We included 73 healthy young adult volunteers (35 female and 38 male) in this experimental cross-over study. Each participant completed four experimental sessions of 30 min, consisting of aerobic exercise at 30% heart rate reserve (HRR), aerobic exercise at 50% HRR, aerobic exercise at 70% HRR, and quiet rest. EIH was assessed using the pressure pain threshold (PPT) and temporal summation of pain (TSP) in the quadriceps, biceps, and trapezius.Results: Low- and moderate-intensity exercise increased the multisegmental PPT and reduced TSP (all P < 0.05). High-intensity exercise increased the multisegmental PPT (all P < 0.05), but decreased TSP in only the quadriceps and biceps (P < 0.05), not the trapezius (P = 0.13). We found no difference in relative PPT and TSP changes between exercise intensities (P > 0.05) except for relative PPT change at the quadriceps (P < 0.05).Conclusion: Our results show that not only moderate- and high-intensity exercise, but also low-intensity exercise can produce a hypoalgesic response.Keywords: exercise intensity, exercise-induced hypoalgesia, aerobic exercise, pressure pain threshold, temporal summation of pain

Takafumi Hattori,1,2 Satoshi Ohga,3 Kazuhiro Shimo,3 Yuto Niwa,1 Yuji Tokiwa,1 Takako Matsubara1,3 1Faculty of Rehabilitation, Kobe Gakuin University Graduate School, Kobe, Hyogo, Japan; 2Department of Rehabilitation, Maehara Orthopedics Rehabilitation Clinic, Obu, Aichi, Japan; 3Department of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Hyogo, JapanCorrespondence: Takafumi Hattori, Faculty of Rehabilitation, Kobe Gakuin University Graduate School, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe, Hyogo, 651-2180, Japan, Tel/Fax +81-78-974-2461, Email hattor91@gmail.comPurpose: Knee osteoarthritis (KOA) is a degenerative disease with inflammation, becoming persistent as it progresses, resulting in reduced quality of life. Exercise is the recommended treatment for KOA; however, the extent of pain reduction with exercise is heterogeneous and the prognostic implications of baseline factors in patients undergoing exercise are still unknown. This study examined the association between the response to exercise therapy and clinical outcomes, radiologic severity, and pain sensitization, and investigated the optimal predictive value for the effectiveness of exercise.Patients and Methods: Demographics, radiologic severity, pressure pain threshold (PPT), and temporal summation of pain (TSP) at the knee, tibia, and forearm were assessed at baseline. The pain numeric rating scale (NRS) was assessed before and after 12 weeks of exercise. Patients were divided into responder/non-responder groups according to recommended criteria: responder, ≥ 30% reduction in pain; non-responder, < 30% reduction in pain, and each variable was compared between the groups. The area under the curve (AUC) and cutoff points were determined by receiver operating characteristic curve analysis.Results: Sixty-five patients were categorized as responders and 26 as non-responders. In the non-responder group, baseline NRS (P< 0.01), pain duration (P< 0.01), and TSP at the knee (P< 0.001) and tibia (P< 0.05) were significantly higher, and PPT at the knee (P< 0.001), tibia (P< 0.001), and forearm (P< 0.001) were significantly lower, than those in the responder group; however, no significant differences between groups were found in other demographics and radiologic severity. The variables that showed moderate or better predictive ability (AUC≥ 0.7) were PPT at the knee (cutoff points: 241.5 kPa), tibia (307.5 kPa), forearm (318.5 kPa), and TSP at the knee (15.5 mm).Conclusion: Our findings suggest that pain sensitization is associated with the response to exercise therapy. Furthermore, we provide clinically predictive values for PPT and TSP in predicting the outcome to exercise in KOA.Keywords: pressure pain threshold, temporal summation of pain, cutoff point, prognostic prediction

Yuichi Katsura,1,2 Satoshi Ohga,3 Kazuhiro Shimo,3 Takafumi Hattori,2 Tsukasa Yamada,1,2 Takako Matsubara2,3 1Department of Rehabilitation, Kishiwada Rehabilitation Hospital, Kishiwada-shi, Osaka, 596-0827, Japan; 2Faculty of Rehabilitation, Kobe Gakuin University Graduate School, Kobe, Hyogo, 651-2180, Japan; 3Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Hyogo, 651-2180, JapanCorrespondence: Yuichi Katsura, Department of Rehabilitation, Kishiwada Rehabilitation Hospital, 8-10, Kanmatsu-chou, Kishiwada-shi, Osaka, 596-0827, Japan, Tel +81-72-426-7777, Fax +81-72-426-7771, Email rm9xhj04@s.kobegakuin.ac.jpPurpose: The purpose of this study was to investigate the prevalence of post-stroke complex regional pain syndrome (CRPS) and to examine the characteristics of inactivity status of the upper limb in post-stroke CRPS patients. In addition, as a sub-analysis, the association between the upper limb inactivity status and pain intensity was investigated in post-stroke CRPS patients.Patients and Methods: This cross-sectional study included 102 patients with first-ever stroke between April 2019 and February 2020. Each patient was allocated into one of two groups based on the presence or absence of CRPS. Demographic data (age, sex, stroke etiology, lesion side, and number of days since stroke onset) were collected. The following evaluations were performed in all patients: Fugl–Meyer Assessment (FMA), Action Research Arm Test (ARAT), and Motor Activity Log (MAL). The numerical rating scale (NRS) to determine pain intensity was assessed only in patients with post-stroke CRPS.Results: Nineteen and 83 patients were assigned to the post-stroke CRPS and control group, respectively. The prevalence of post-stroke CRPS was 18.6% (19/102). FMA, ARAT, and MAL scores were significantly lower in patients with post-stroke CRPS than those without it. FMA and ARAT scores were significantly correlated with NRS scores, but MAL was almost zero-scored in patients with post-stroke CRPS.Conclusion: The study results indicated that activity status of the affected upper limb was severely deteriorated, and more inactivity of the upper limb was associated with higher pain intensity in patients with post-stroke CRPS. Thus, our results suggest that post-stroke CRPS may be influenced by the degree of upper limb inactivity after stroke.Keywords: complex regional pain syndrome, post-stroke shoulder-hand syndrome, stroke, Fugl–Meyer Assessment, Action Research Arm Test, Motor Activity Log

Objectives: To establish the optimal inflammation control of Kawasaki disease (KD), we investigated the clinical and pathophysiological basis of pericardial effusion (PE) during the acute phase of KD. Method: Clinical and laboratory features of Japanese KD children with PE (PE group: n = 9) and without PE (non-PE group: n = 89) were studied retrospectively by using the medical records. Serum levels of soluble tumour necrosis factor receptor 1 (sTNFR1), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assays (ELISAs). Results: PE group patients had coronary artery lesions (CALs) more frequently than non-PE group patients during the acute phase of KD (33% vs. 5.6%, p = 0.024). PE patients also showed lower levels of haemoglobin (p < 0.01) and serum albumin (p < 0.01) and higher platelet counts (p = 0.013) than non-PE patients. The proportion of neurological symptoms, but not other manifestations, in the PE group was higher than in the non-PE group (p = 0.022). All patients survived free from coronary artery aneurisms. Serum levels of sTNFR1, but not the other cytokines, in the PE group were higher than those in the non-PE group (p < 0.001). The sTNFR1 levels correlated positively with C-reactive protein (CRP) (r = 0.30, p = 0.019) or total bilirubin (r = 0.40, p < 0.01) levels. Conclusions: Acute PE in KD patients indicated the severity of TNF-mediated vascular inflammation and concurrent CALs. According to the progression, these patients might need more targeted therapy of anti-inflammation for a better coronary outcome. [ABSTRACT FROM AUTHOR]

Dural arteriovenous fistula (DAVF) represents a pathological group of intracranial shunts arising from the dural artery to venous sinus and veins. Childhood-onset DAVF is generally considered to be poor in prognosis, whereas only limited information is available for the onset and long-term outcomes. We herein report a Japanese girl with trisomy 21, large ventricular septal defects, and pulmonary vein stenosis, for which a transcatheter stent had been placed after birth. At age 6 years, she developed bacterial meningitis due to S. pneumoniae, leading to the diagnosis of venous sinus thrombosis and multiple intracranial shunts. Cerebral angiography identified multiple shunts arising from the middle meningeal arteries to the superior sagittal sinus and a concurrent reflux to cortical vein. Endovascular embolization successfully occluded the shunts without neurovascular complications over 24 months. This report first demonstrates the favorable outcome of DAVF in a pediatric patient with trisomy 21 after the catheter intervention. For children at a risk for intracranial thrombosis, preemptive neurovascular evaluation and transcatheter intervention provide a chance of early diagnosis of DAVF to improve their survival and neurologic outcome., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pregestational diabetes is a risk factor for congenital anomalies, including heterotaxy syndrome, a rare birth defect characterized by the abnormal arrangement of organs relative to the left-right (L-R) body axis. To provide insight into the underlying mechanism by which diabetes induces heterotaxy, we here analyzed the L-R axis of mouse embryos of diabetic dams. Various Pitx2 expression patterns indicative of disruption of L-R axis formation were apparent in such embryos. Expression of Nodal at the node, which triggers a Nodal-Pitx2 expression cascade in lateral plate mesoderm, showed marked regression associated with L-R axis malformation. This regression was similar to that apparent in Wnt3a -/- embryos, and canonical Wnt signalling was indeed found to be downregulated in embryos of diabetic dams. RNA sequencing revealed dysregulation of glycolysis in embryos of diabetic dams, and high glucose lowered intracellular pH in the primitive streak, leading to the suppression of Wnt signalling and the regression of Nodal expression. Of note, maternal vitamin A intake increased the incidence of L-R axis defects in embryos of diabetic dams, with dysregulation of retinoic acid metabolism being apparent in these embryos and in Wnt3a -/- embryos. Our results shed light on the mechanisms underlying embryopathies associated with maternal diabetes and suggest the importance of diet for prevention of heterotaxy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Infants born extremely preterm are at high risk for neurodevelopmental problems. However, their neurodevelopment exhibits a variety of trajectories. This study aimed to investigate the association between changes in neurodevelopmental outcomes and clinical characteristics among extremely preterm infants., Methods: This is a retrospective study of surviving children born at gestational age 22-28 weeks in Kyushu University Hospital between 2010 and 2020. We collected perinatal and post-discharge data and investigated the association between clinical characteristics and changes in developmental quotient (DQ) scores between 1.5 and 3 years of corrected age., Results: Out of the 179 eligible extremely preterm infants, 115 (64%) underwent neurological evaluations at 1.5 and 3 years of corrected age. Among them, 33 (29%) showed improvement in their DQ scores (+10 or more), 62 (54%) showed no change (-9 to +9), and 20 (17%) showed a decline (-10 or less). Gestational age, birth weight, and perinatal complications during the NICU stay did not affect individual changes in DQ scores. Multivariable analysis revealed that greater growth in height until age 3 years was a significant predictor of increasing DQ scores, while male sex and having siblings had a negative effect on changes in the DQ scores., Conclusion: We first demonstrate clinical data conceptualizing that growth in height, sex, and sibling status, rather than perinatal complications, are biologically linked with favorable or unfavorable neurodevelopmental changes of extremely preterm infants during the first 3 years of life., (© 2024 S. Karger AG, Basel.)

Objective: Exercise induces a hypoalgesic response and improves affect. However, some individuals are unable to exercise for various reasons. Motor imagery, involving kinesthetic and visual imagery without physical movement, activates brain regions associated with these benefits and could be an alternative for those unable to exercise. Virtual reality also enhances motor imagery performance because of its illusion and embodiment. Therefore, we examined the effects of motor imagery combined with virtual reality on pain sensitivity and affect in healthy individuals., Design: Randomized crossover study., Setting: Laboratory., Subjects: Thirty-six participants (women: 18) were included., Methods: Each participant completed three 10-min experimental sessions, comprising actual exercise, motor imagery only, and motor imagery combined with virtual reality. Hypoalgesic responses and affective improvement were assessed using the pressure-pain threshold and the Positive and Negative Affect Schedule, respectively., Results: All interventions significantly increased the pressure-pain threshold at the thigh (P < .001). Motor imagery combined with virtual reality increased the pressure-pain threshold more than motor imagery alone, but the threshold was similar to that of actual exercise (both P ≥ .05). All interventions significantly decreased the negative affect of the Positive and Negative Affect Schedule (all P < .05)., Conclusions: Motor imagery combined with virtual reality exerted hypoalgesic and affective-improvement effects similar to those of actual exercise., Clinical Trials Registration: The study was enrolled in the UMIN Clinical Trials Registry (registration number: UMIN000046095). The website for registration information is https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000052614., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aim: Even with advancement of medical technologies, liver transplantation still faces several major challenges. Hence, other treatment modalities are urgently needed for patients with end-stage liver disease. Stem cells from human exfoliated deciduous teeth (SHED) was discovered to have highly proliferative and pluripotent properties; including differentiation into hepatocyte-like cells. This study aims to investigate the capability of intrasplenic transplanted SHED and SHED-Hep cells in inducing proliferation of stem cells and native hepatocytes in order to accelerate liver regeneration in liver fibrosis mice models., Methods: Three carbon tetrachloride (CCl 4 )-injured male mice groups were used in this study. Two of those groups were transplanted with either SHED or SHED-Hep, while the other did not undergo transplantation. One age- and sex- matched healthy mice group was used as control. All specimens were immunohistochemically stained with anti-Ki-67 antibodies and anti-proliferating cell nuclear antigen (PCNA) antibodies before counter stained with hematoxylin-eosin., Results: Anti-Ki-67 antibodies staining: at both 8 and 12 weeks, proliferating activity was predominantly seen on both SHED- and SHED-Hep-transplanted CCl 4 -injured mice groups, while control and non-transplanted CCl 4 -injured mice group showed little to no sign of proliferation activity. Anti-PCNA staining: at both 8 and 12 weeks, significant proliferating activity was detected by PCNA staining, mainly on stem cells population area on SHED- and SHED-Hep-treated group., Conclusions: In conclusion, this study has provided the evidence that transplantation of SHED or SHED-Hep on liver-injured mice induced proliferation of both transplanted stem cells and native liver cells in order to accelerate liver regeneration., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: This prospective study compared PIVKA-II and PT-INR levels in infants who received two vitamin K (VK) prophylactic regimens., Methods: A single institution administered 119 healthy newborns 2 mg of VK syrup. Infants were assigned to a 3-time regimen (n = 56) with VK at birth, five days (5D), and 1-month-old (1 M), or a 13-time regimen (n = 63) with VK at birth, 5D, and then weekly for 11 weeks., Results: The 13-time regimen significantly lowered PIVKA-II and reduced PT-INR at 1 M in both breastfed (PIVKA-II: 18-16 mAU/mL, p = 0.02; PT-INR: 1.37-1.13, p < 0.01) and formula-fed infants (PIVKA-II: 18-15 mAU/mL, p = 0.01; PT-INR: 1.54-1.24, p < 0.01), compared to baseline measurements taken at 5D. The 3-time regimen did not significantly alter PIVKA-II levels and only improved PT-INR (2.00-1.50, p < 0.01) in formula-fed infants., Conclusion: The 13-time VK regimen significantly enhanced coagulation profiles more effectively than the 3-time regimen., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP)., Study Design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial., Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated., Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group., Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA., (© 2024. Japanese Ophthalmological Society.)

An autism-associated gene Shank3 encodes multiple splicing isoforms, Shank3a-f. We have recently reported that Shank3a/b-knockout mice were more susceptible to kainic acid-induced seizures than wild-type mice at 4 weeks of age. Little is known, however, about how the N-terminal and ankyrin repeat domains (NT-Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry-based proteomic search for proteins interacting with GFP-tagged NT-Ank. In this study, NT-Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA-binding (n = 102), spliceosome (n = 22), and ribosome-associated molecules (n = 9) were significantly enriched. Among them, an X-linked intellectual disability-associated protein, Nono, was identified as a NT-Ank-binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b-knockout mice aberrantly expressed splicing isoforms of autism-associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA-binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism-associated genes after birth., (© 2024 The Author(s). Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2-47 years, 12 males) and 22 controls (age 4-40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, P = 0.00731) and oxidative phosphorylation (hsa00190, P = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Congenital antithrombin (AT) or serpin C1 deficiency, caused by a SERPINC1 abnormality, is a high-risk factor for venous thrombosis. SERPINC1 is prone to genetic rearrangement, because it contains numerous Alu elements. In this study, a Japanese patient who developed deep vein thrombosis during pregnancy and exhibited low AT activity underwent SERPINC1 gene analysis using routine methods: long-range polymerase chain reaction (PCR) and real-time PCR. Sequencing using long-range PCR products revealed no pathological variants in SERPINC1 exons or exon-intron junctions, and all the identified variants were homozygous, suggesting a deletion in one SERPINC1 allele. Copy number quantification for each SERPINC1 exon using real-time PCR revealed half the number of exon 1 and 2 copies compared with controls. Moreover, a deletion region was deduced by quantifying the 5'-upstream region copy number of SERPINC1 for each constant region. Direct long-range PCR sequencing with primers for the 5'-end of each presumed deletion region revealed a large Alu-mediated deletion (∼13 kb) involving SERPINC1 exons 1 and 2. Thus, a large deletion was identified in SERPINC1 using conventional PCR methods., (© 2024. Japanese Society of Hematology.)

To examine whether patterns, such as the timings of onset or recovery from sleep disturbance, are associated with later developmental problems, including autism spectrum disorder (ASD). Mothers participating in the Japan Environment and Children's Study with a child aged 3 years were included in the analyses. Children were assessed for short sleep and frequent awakenings at 1 month, 6 months, and 1 year of age. Developmental problems were evaluated at 3 years of age based on ASD diagnosis and developmental delay, using the Japanese translation of the Ages and Stages Questionnaire (ASQ) 3rd edition. Sleep disturbance patterns were classified by onset age, and developmental problem risks were examined based on onset/recovery ages. Among 63,418 mother-infant dyads, 0.4% of infants were later diagnosed with ASD, and 14.4% had abnormal scores on any ASQ domains. The later the onset of short sleep, the lower the risk of abnormal ASQ scores (RR of short sleep onset at 1 year: 1.41; 6 months: 1.52; 1 month: 1.57). The earlier the infants recovered from short sleep persistence, the lower the risk of developmental delay (RR of remittance of sleep problems identified at 1 month by 6 months: 1.07; 1 year: 1.31; not before 1 year: 1.57). Although not all patterns were significant, later short sleep onset and earlier recovery were associated with lower ASD risk. These findings may have significant implications for future interventions in infant development., (© 2024. The Author(s).)

To cultivate specialists in pediatric infectious diseases (ID) in Japan, the Japanese Society for Pediatric Infectious Diseases initiated board certification for pediatric ID in 2017. Previously, in 2014, we had formed a committee for board certification in pediatric ID and discussed the fundamentals of the board certification system, including the goals, requirements for designated training institutions, provisional certification of pediatric ID specialists and eligibility for and content of the board certification examination. After approval from 31 programs, the pediatric ID programs started in 2017 with 8 fellows in 7 programs. The first 6 graduates received board certification in 2020. To date, 61 pediatricians have been board certified as pediatric ID specialists. In parallel, we introduced board certification for pediatricians who work mainly in primary care settings and have a special interest in pediatric ID. This system has certified 338 pediatricians. During and after the development of the programs, we achieved substantial progress in highlighting the pivotal role of pediatric ID specialists, including the establishment and maintenance of antimicrobial stewardship programs, pediatric ID consultations and introduction of viral diagnosis by polymerase chain reaction at institutions. However, several issues need to be addressed, including the establishment of independent pediatric ID departments in institutions, payment of consultation fees, program site visits, maintenance of certification and cultivation of physician-scientists. These challenges will be the focus of future efforts., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient's iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy., (© 2024. The Author(s).)

The exposure of family caregivers to anticancer drugs for pediatric patients with malignancy is a potential health risk that needs to be minimized. We monitored the amount of cyclophosphamide (CPM) that had adhered to the undershirts of patients and the personal protective equipment (PPE) of family caregivers as well as the caregivers' urine levels of CPM within the first three days after the first and second courses of high-dose CPM therapy. Liquid chromatography/mass spectrometry (LC/MS/MS) detected >0.03 ng/ml of CPM in 26% (23/88) of urine samples from 8 of 11 (72.7%) patients' family caregivers, with a peak of 0.7 ng/ml from 24 to 48 h after administration. Since urine CPM concentrations in family caregivers varied after the first and second courses, the exposure risk factors were analyzed by scoring the PPE-wearing time index (caring minutes × PPE points from wearing masks, gloves, and/or gowns) and CPM adhesion of PPE items with the caring patterns of diaper change, washing body care, oral care, eating assistance, emotional support, and co-sleeping. The closest association was observed for CPM adhesion between oral care gloves and undershirts (correlation coefficient 0.67, p = 0.001). The mixed-effect model analysis indicated only a significant correlation between the PPE-wearing time index and emotional care (playing, cuddling, and physical contact) (p = 0.016). These results suggest that prolonged emotional support results in poor PPE protection, which increases the risk of exposure in family caregivers. Strict PPE care within 48 h after high-dose CPM controls the exposure to high-risk anticancer drugs in caregivers of pediatric patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. This work was supported in part by the Grants-in-Aid for Young Scientific Research (B) (2019–2022, Yuko Noda). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: The impact of parent-childbearing age on child development at 36 months of age is controversial., Aims: We used data from a large cohort study with multiple imputation and mediation analyses of variables., Methods and Procedures: A total of 72,606 parent-child pairs from the Japan Environment and Children's Study were included in the study. Parents' ages were categorized into five groups. We used five domains of the Japanese translation of the Ages and Stages Questionnaire, Third Edition (J-ASQ-3). Scores below the cutoff value at 36 months were defined as developmental delays in each domain. We used three logistic analysis models. In Model 3, we analyzed maternal and paternal age using other variables and covariates., Outcomes and Results: The outcome was a developmental delay in the five domains of J-ASQ-3. In Model 3, ORs for the developmental delay scores regarding parental age were significantly associated with all five domains of J-ASQ-3. The mediation analysis showed a significant mediation interaction effect for mothers but localized for fathers., Conclusion: Advanced paternal and maternal ages were associated with developmental delay in children. Awareness of the risks of childbearing at an advanced age is crucial., What's the Paper Adds: This manuscript used data from a large cohort study with multiple imputation and mediation analyses. With these analyses, we identified the pure effect of advanced parental age on their children's development at 36 months., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest, except the association with the Ministry of Environment, Japan., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To develop an equation for defining a low skeletal muscle mass (SMM) in children and to investigate risk factors and outcomes associated with low SMM in critically ill pediatric patients., Design: Single-center retrospective pediatric cohorts, 2011-2018., Setting: Tertiary Emergency and Critical Care Center of Kyushu University Hospital in Japan., Patients: We studied two cohorts of pediatric patients 1-15 years old who underwent abdominal CT at the level of the third lumbar vertebra (L3). First a cohort of trauma patients presented to the emergency department in whom we developed an SMM regression equation. Second, a cohort of patients who had undergone abdominal CT within 3 days of PICU admission., Interventions: None., Measurements and Main Results: The equation for estimating normal SMM used sex, age, and weight. Low SMM was defined as less than 80% of normal. In the 112 patients in the PICU cohort, median (range) age was 68 (13-191) months, and 83 (74.1%) had underlying disease. There was low SMM in 54 patients (48.2%). Regarding associations, using odds ratio (OR) and 95% CI, we found that low dietary intake (OR 4.33 [95% CI, 1.37-13.70]; p = 0.013) and the presence of underlying disease (OR 7.44 [95% CI, 2.10-26.30]; p = 0.002) were independently associated with greater odds of low SMM. Low SMM, compared with normal SMM, was also associated with longer hospital stays (42.5 d vs. 20.5 d; p = 0.007; β, 1.59; 95% CI, 1.09-2.33; p = 0.016)., Conclusions: In this retrospective PICU cohort from a single center in Japan, we found that low SMM at PICU admission was present in almost half the cases. Low SMM, as defined by being less than 80% of the normal, was associated with greater odds of low dietary intake and underlying chronic disease. Furthermore, low SMM was associated with longer hospital stays., Competing Interests: Drs. Matsuoka, Mizuguchi, and Kaku’s institution received funding from the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP21K11215). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients., Methods: Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70 Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8 months was mandatory for patients with intermediate or high-risk prostate cancer., Results: From 20 institutions, 134 patients enrolled. The median follow-up was 5.16 years (range, 1.43-6.47 years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5 years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5 years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958)., Conclusion: The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Pathogenic variants in ATP1A3, the gene encoding the α3 subunit of the Na+/K+-ATPase, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerated symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as Eif4g (encoded by Eif4g1), Pabpc1 and Fmrp (encoded by Fmr1), in mouse Neuro2a cells. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C variant of human ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 (encoded by Rps6) and increased susceptibility to heat stress. In agreement with these findings, induced pluripotent stem cells (iPSCs) from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient-derived iPSCs showed lower calcium influxes in responses to stimulation with ATP than those in control iPSCs. These data indicate that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes in patients with the p.R756C variant among a variety of ATP1A3-related disorders., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Lifelong health is dependent on prenatal growth and development, influenced by the placental intrauterine environment. Charged with dual functions--exchange of oxygen and nutrients as well as a barrier against toxins--the placenta itself is susceptible to environmental exposure to heavy metals., Objective: To examine the use of placenta weight as a biomarker for heavy metal exposure using a large Japanese cohort of pregnant women., Methods: The placenta weight, as a biomarker of exposure to heavy metals (cadmium, lead, and mercury), was investigated using data from the Japan Environment and Children's Study (2011-2014). Selenium and manganese were included as factors directly affecting fetal growth or heavy metal toxicity. Maternal blood samples collected in the second or third trimester were used to measure heavy metal concentrations. The association between maternal blood metal concentrations and placenta weight was explored by applying Z scores and multivariable logistic regression analysis and classifying participants into quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations., Results: This study included a total of 73,005 singleton pregnant women who delivered via live births and met the inclusion criteria. The median heavy metal concentrations in the maternal whole blood were 0.662 ng/g cadmium, 5.85 ng/g lead, 3.61 ng/g mercury, 168 ng/g selenium, and 15.3 ng/g manganese. Regression analysis revealed a significant correlation between placenta weight Z scores and maternal blood metal concentrations: cadmium, 0.0660 (standard error = 0.0074, p < 0.001); selenium, -0.3137 (standard error = 0.0276, p < 0.001); and manganese, 0.1483 (standard error = 0.0110, p < 0.001)., Conclusion: This study provides a robust examination of the association between heavy metal exposure and placenta weight. Cadmium and manganese showed a positive correlation with significant differences, whereas selenium showed a negative correlation. Essential elements notably affect placenta weight differently. No significant association was noted between lead or mercury and placenta weight., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To assess the performance of pediatric extracorporeal membrane oxygenation (ECMO) centers, outcomes were compared between metropolitan and other areas., Methods: A retrospective cohort study was conducted at three regional centers on Kyushu Island and the largest center in the Tokyo metropolitan area of Japan. The clinical outcomes of patients of ≤15 years of age who received ECMO during 2010-2019 were investigated, targeting the survival and performance at discharge from intensive care units (ICUs), using medical charts., Results: One hundred and fifty-five patients were analyzed (regional, n = 70; metropolitan, n = 85). Survival rates at ICU discharge were similar between the two areas (64%). In regional centers, deterioration of Pediatric Cerebral Performance Category (PCPC) scores were more frequent (65.7% vs. 49.4%; p = 0.042), but survival rates and ΔPCPC scores (PCPC at ICU discharge-PCPC before admission) improved in the second half of the study period (p = 0.005 and p = 0.046, respectively). Veno-arterial ECMO (odds ratio [OR], 3.00; p < 0.03), extracorporeal cardiopulmonary resuscitation (OR, 8.98; p < 0.01), and absence of myocarditis (OR, 5.47; p < 0.01) were independent risk factors for deterioration of the PCPC score. A sub-analysis of patients with acute myocarditis (n = 51), the main indicator for ECMO, revealed a significantly higher proportion of cases with deteriorated PCPC scores in regional centers (51.9% vs. 25.0%; p = 0.049)., Conclusions: The survival rates of pediatric patients supported by ECMO in regional centers were similar to those in a metropolitan center. However, neurological outcomes must be improved, particularly in patients with acute myocarditis., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)