Publications by authors named "Yasunari Sakai"

103 Publications

The up-to-date pathophysiology of Kawasaki disease.

Clin Transl Immunology 2021 10;10(5):e1284. Epub 2021 May 10.

Department of Pediatrics Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Kawasaki disease (KD) is an acute systemic vasculitis of an unknown aetiology. A small proportion of children exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or infected by reproducibly develop principal symptoms of KD in various ethnic areas, but not in all studies. These microbes provoke a rapid cell-damaging process, called 'pyroptosis', which is characterised by a subsequent release of proinflammatory cellular components from damaged endothelial and innate immune cells. In agreement with these molecular events, patients with KD show elevated levels of damage-associated molecular patterns derived from cell death. In addition, an overwhelming amount of oxidative stress-associated molecules, including oxidised phospholipids or low-density lipoproteins, are generated as by-products of inflammation during the acute phase of the disease. These molecules induce abnormalities in the acquired immune system and activate innate immune and vascular cells to produce a range of proinflammatory molecules such as cytokines, chemokines, proteases and reactive oxygen species. These responses further recruit immune cells to the arterial wall, wherein inflammation and oxidative stress closely interact and mutually amplify each other. The inflammasome, a key component of the innate immune system, plays an essential role in the development of vasculitis in KD. Thus, innate immune memory, or 'trained immunity', may promote vasculitis in KD. Hence, this review will be helpful in understanding the pathophysiologic pathways leading to the development of principal KD symptoms and coronary artery lesions in patients with KD, as well as in subsets of patients with SARS-CoV-2 and infections.
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http://dx.doi.org/10.1002/cti2.1284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109476PMC
May 2021

Age-related morphological differences in the spike-and-wave complexes of absence epilepsy.

Epilepsy Res 2021 Apr 22;174:106647. Epub 2021 Apr 22.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objective: Absence epilepsy shows age-related clinical features, as is observed in childhood and juvenile absence epilepsy. Electroencephalogram (EEG) is characterized by bursts of 3 Hz spike-and-wave complex (SWC). We noticed a morphological variation of the slow-wave component of SWCs between patients. This study investigated whether the waveform of SWC might be associated with the child's age of this epilepsy.

Methods: Digitally-recorded EEGs under medication-free conditions were collected from 25 children who received the diagnosis of childhood or juvenile absence epilepsy. The morphology of slow wave in SWC in the frontal midline region was quantitatively compared between younger and older children using a cluster-based permutation test.

Results: At <7 years of age (2.9-6.5 years of age, n = 6), the electrical potential of the descending slope in the slow wave was positively correlated with age whereas this correlation was not observed in patients of ≥7 years of age (7.1-12.9 years, n = 19). A cluster-based permutation test confirmed the results-among the entire slow wave period (0-285 msec), the period of the descending slope (195-260 msec) showed significantly lower potential in patients of <7 years of age in comparison to patients of ≥7 years of age (sum of t-values: 46.57, p-value: 0.011).

Conclusions: The current study demonstrated an age-dependent morphological difference in the slow-wave components of SWCs in EEGs of patients with pediatric absence epilepsy. This finding may provide a clue to understanding the age-related clinical manifestations of this epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106647DOI Listing
April 2021

Periodic discharges with high frequency oscillations recorded from a cerebellar gangliocytoma in an epileptic infant.

Surg Neurol Int 2021 17;12:98. Epub 2021 Mar 17.

Department of Neurosurgery Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Subcortical epilepsies associated with developmental tumors in the cerebellum are rarely experienced. As supportive evidence of the intrinsic epileptogenicity of cerebellar tumors, previous electroencephalogram (EEG) studies with intratumoral depth electrodes demonstrated epileptiform or ictal discharges. Recent studies have demonstrated that high frequency oscillations (HFOs) can be regarded as a new biomarker of epileptogenesis and ictogenesis; however, there are few evidence about HFOs in cases of epilepsy associated with cerebellar tumors.

Case Description: A 6-month-old Japanese male infant presented to our hospital with drug resistant epilepsy. We underwent subtotal resection of a cerebellar gangliocytoma and obtained good seizure outcomes. Intraoperative EEG in the tumor depicted HFOs in the form of ripples, riding on periodic discharges.

Conclusion: Our findings provide further supportive evidence for the intrinsic epileptogenicity of cerebellar tumors.
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http://dx.doi.org/10.25259/SNI_28_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053450PMC
March 2021

The effectiveness of supplemental oxygen during exercise training in patients with chronic obstructive pulmonary disease who show severe exercise-induced desaturation: a protocol for a meta-regression analysis and systematic review.

Syst Rev 2021 Apr 14;10(1):110. Epub 2021 Apr 14.

Department of Clinical Laboratory Sciences, Shinshu University School of Health Sciences, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.

Background: Supplemental oxygen during exercise training is used to increase the training effect of an exercise program in patients with chronic obstructive pulmonary disease (COPD) who show exercise-induced desaturation. Exercise-induced desaturation is not clearly defined in the guidelines; however, it is generally defined in clinical studies as a decrease in SpO of more than 4% from rest or a decrease to less than 88% during exercise. Although some meta-analyses examined the effectiveness of supplemental oxygen during exercise training, these studies concluded that it does not further improve exercise tolerance compared to exercise training alone. However, supplemental oxygen during exercise training may be effective in improving exercise tolerance in COPD patients with severe exercise-induced desaturation. Therefore, this study will be performed to elucidate the effectiveness of supplemental oxygen during exercise training and the relationship between its effectiveness and severity of exercise-induced desaturation at baseline.

Methods: We will first assess the effectiveness of supplemental oxygen during exercise training in COPD. The main outcome is the change in exercise tolerance before and after the intervention, indicated by the 6-min walking distance, the walking distance, or the walking time in incremental shuttle walking test, and analyzed as the standardized mean difference (SMD). The quality and risk of bias in individual studies will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and risk-of-bias tool (RoB ver.2). If statistical heterogeneity in terms of the effectiveness of exercise tolerance is shown, we will conduct meta-regression analyses to examine the association between the effectiveness of exercise training with supplemental oxygen and severity of exercise-induced desaturation at baseline.

Discussion: One strength of this study is that it is a systematic review with meta-regression analysis to elucidate the effectiveness of supplemental oxygen during exercise training in patients with COPD who show severe exercise-induced desaturation. Furthermore, we will assess the severity of exercise-induced desaturation for which exercise training with supplemental oxygen is effective, the influence of acute effects at baseline, and the effect of supplemental oxygen on adverse events.

Systematic Review Registration: Registration number, UMIN000039960.
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http://dx.doi.org/10.1186/s13643-021-01667-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048026PMC
April 2021

Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan.

JAMA Netw Open 2021 04 1;4(4):e214475. Epub 2021 Apr 1.

Kawasaki Disease Center, Fukuoka Children's Hospital, Kashiiteriha, Higashi-ku, Fukuoka, Japan.

Importance: The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD.

Objective: To assess the role of droplet or contact transmission in the etiopathogenesis of KD.

Design, Setting, And Participants: This multicenter, longitudinal, cross-sectional study was conducted from 2015 to 2020 at Fukuoka Children's Hospital and 5 adjacent general hospitals. The number of admissions for KD and infectious diseases were analyzed. Participants were pediatric patients admitted to the participating hospitals for KD or infectious diseases.

Exposures: Quarantine and isolation owing to the COVID-19 state of emergency.

Main Outcomes And Measures: The primary end points were the ratios of patients with KD to patients with respiratory tract or gastrointestinal infections admitted from April to May in 2015 to 2019 and 2020. A Poisson regression model was used to analyze them.

Results: The study participants included 1649 patients with KD (median [interquartile range] age, 25 [13-43] months; 901 boys [54.6%]) and 15 586 patients with infectious disease (data on age and sex were not available for these patients). The number of admissions for KD showed no significant change between April and May in 2015 to 2019 vs the same months in 2020 (mean [SD], 24.8 [5.6] vs 18.0 [4.0] admissions per month; 27.4% decrease; adjusted incidence rate ratio [aIRR], 0.73; 95% CI, 0.48-1.10; P = .12). However, the number of admissions for droplet-transmitted or contact-transmitted respiratory tract infections (mean [SD], 157.6 [14.4] vs 39.0 [15.0] admissions per month; 75.3% decrease; aIRR, 0.25; 95% CI, 0.17-0.35; P < .001) and gastrointestinal infections (mean [SD], 43.8 [12.9] vs 6.0 [2.0] admissions per month; 86.3% decrease; aIRR, 0.14; 95% CI, 0.04-0.43; P < .001) showed significant decreases between April and May in 2015 to 2019 vs the same months in 2020 (total, 12 254 infections). Thus, the ratio of KD to droplet- or contact-transmitted respiratory tract and gastrointestinal infections incidence in April and May 2020 was significantly increased (ratio, 0.40 vs 0.12; χ21 = 22.76; P < .001).

Conclusions And Relevance: In this study, the significantly increased incidence of KD compared with respiratory tract and gastrointestinal infections during the COVID-19 state of emergency suggests that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne infections in most cases.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.4475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025113PMC
April 2021

De novo ATP1A3 variants cause polymicrogyria.

Sci Adv 2021 Mar 24;7(13). Epub 2021 Mar 24.

Department of Pediatrics, Tottori Prefectural Central Hospital, Tottori 680-0901, Japan.

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo variants in eight patients. Mutated causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with abnormalities.
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http://dx.doi.org/10.1126/sciadv.abd2368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990330PMC
March 2021

Impaired neurite development and mitochondrial dysfunction associated with calcium accumulation in dopaminergic neurons differentiated from the dental pulp stem cells of a patient with metatropic dysplasia.

Biochem Biophys Rep 2021 Jul 9;26:100968. Epub 2021 Mar 9.

Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.

Transient receptor potential vanilloid member 4 (TRPV4) is a Ca permeable nonselective cation channel, and mutations in the gene cause congenital skeletal dysplasias and peripheral neuropathies. Although TRPV4 is widely expressed in the brain, few studies have assessed the pathogenesis of mutations in the brain. We aimed to elucidate the pathological associations between a specific mutation and neurodevelopmental defects using dopaminergic neurons (DNs) differentiated from dental pulp stem cells (DPSCs). DPSCs were isolated from a patient with metatropic dysplasia and multiple neuropsychiatric symptoms caused by a gain-of-function mutation, c.1855C>T (p.L619F). The mutation was corrected by CRISPR/Cas9 to obtain isogenic control DPSCs. Mutant DPSCs differentiated into DNs without undergoing apoptosis; however, neurite development was significantly impaired in mutant vs. control DNs. Mutant DNs also showed accumulation of mitochondrial Ca and reactive oxygen species, low adenosine triphosphate levels despite a high mitochondrial membrane potential, and lower peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial content. These results suggested that the persistent Ca entry through the constitutively activated TRPV4 might perturb the adaptive coordination of multiple mitochondrial functions, including oxidative phosphorylation, redox control, and biogenesis, required for dopaminergic circuit development in the brain. Thus, certain mutations in that are associated with skeletal dysplasia might have pathogenic effects on brain development, and mitochondria might be a potential therapeutic target to alleviate the neuropsychiatric symptoms of TRPV4-related diseases.
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http://dx.doi.org/10.1016/j.bbrep.2021.100968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960789PMC
July 2021

A nation-wide survey of Japanese pediatric MOG antibody-associated diseases.

Brain Dev 2021 Jun 18;43(6):705-713. Epub 2021 Feb 18.

Department of Pediatrics, Osaka Medical College, Osaka, Japan.

Objective: To elucidate the clinical characteristics of Japanese pediatric patients with acquired demyelinating diseases (ADS), positive for myelin oligodendrocyte glycoprotein antibody (MOG-IgG), we conducted a nation-wide survey.

Methods: Information about pediatric patients under 18 years old with ADS was solicited with surveys sent to 323 facilities. In an initial survey, we asked whether the center had any patients with ADS, and the MOG-IgG serostatus of the patients. In a follow-up survey, we requested more precise information on patients with ADS.

Results: Initial survey: 263 replies providing information on 175 patients were received. MOG-IgG were examined in 78 patients and 54 of those (69%) were positive for MOG-IgG. Follow-up survey: The characteristic involvement was optic neuritis, with visual disturbance and optic pain as characteristic symptoms. The relapse rate was 44% in patients positive for MOG-IgG, which was higher than that in seronegative patients (38%). For acute phase treatments, corticosteroid (CS), plasma exchange, and intravenous immunoglobulin (IVIG) were useful. To prevent relapse, CS, intermittent IVIG, immunosuppressants, and monoclonal antibodies were useful, but the efficacies of disease modifying drugs were uncertain. Sequelae such as visual disturbance, cognitive impairment, motor dysfunction, and epilepsy were observed in 11% of patients with MOG-IgG.

Conclusions: MOG antibody-associated diseases were found to be common among pediatric ADS patients. Since a variety of sequelae were observed in these patients, it is important to identify the appropriate treatment to ensure the best outcome. The presence of the MOG autoantibody should be taken into consideration as part of the diagnostic criteria for pediatric ADS.
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http://dx.doi.org/10.1016/j.braindev.2021.01.008DOI Listing
June 2021

Reply to the 'Comment on "Bi-layering at ionic liquid surfaces: a sum-frequency generation vibrational spectroscopy- and molecular dynamics simulation-based study"' by M. Deutsch, O. M. Magnussen, J. Haddad, D. Pontoni, B. M. Murphy and B. M. Ocko, , 2021, DOI.

Phys Chem Chem Phys 2021 Mar;23(8):5028-5030

Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo, 152-8552, Japan.

In our recent paper titled "Bi-layering at ionic liquid surfaces: a sum-frequency generation vibrational spectroscopy- and molecular dynamics simulation-based study" co-authored by T. Iwahashi, T. Ishiyama, Y. Sakai, A. Morita, D. Kim, and Y. Ouchi, Phys. Chem. Chem. Phys., 2020, 22, 12565 (hereafter referred to as IW), the sum-frequency (SF) spectra for a homologous series of 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([Cnmim][TFSA] n = 4, 6, 8, 10, and 12) were reported. In particular, a clear decrease in the SF signals from the [TFSA]- anions with increasing chain length of the [Cnmim]+ cation (Fig. 5 of IW) was explained in terms of "head-to-head" bi-layer formation at the air/ionic liquid (IL) interface. A comment by M. Deutsch et al. (hereafter referred to as DE) questioned this report, claiming that our proposed structure is not consistent with a multilayered electron density (ED) profile obtained by X-ray reflectivity (XR).
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http://dx.doi.org/10.1039/d1cp00171jDOI Listing
March 2021

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

Brain Dev 2021 Apr 9;43(4):505-514. Epub 2021 Jan 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objective: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.

Methods: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.

Results: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.

Conclusion: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
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http://dx.doi.org/10.1016/j.braindev.2020.12.006DOI Listing
April 2021

GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.

FASEB J 2020 12 27;34(12):16601-16621. Epub 2020 Oct 27.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (Gα ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of Gα . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that Gα and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain.
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http://dx.doi.org/10.1096/fj.202001113RDOI Listing
December 2020

Forskolin rapidly enhances neuron-like morphological change of directly induced-neuronal cells from neurofibromatosis type 1 patients.

Neuropsychopharmacol Rep 2020 12 10;40(4):396-400. Epub 2020 Oct 10.

Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aim: Neurofibromatosis type 1 (NF1) is a multifaceted disease, and frequently comorbid with neurodevelopmental disorders such as autism spectrum disorder (ASD) and learning disorder. Dysfunction of adenylyl cyclase (AC) is one of the candidate pathways in abnormal development of neuronal cells in the brain of NF1 patients, while its dynamic abnormalities have not been observed. Direct conversion technology can generate induced-neuronal (iN) cells directly from human fibroblasts within 2 weeks. Just recently, we have revealed that forskolin, an AC activator, rescues the gene expression pattern of iN cells derived from NF1 patients (NF1-iN cells). In this microreport, we show the dynamic effect of forskolin on NF1-iN cells.

Methods: iN cells derived from healthy control (HC-iN cells) and NF1-iN cells were treated with forskolin (final concentration 10 μM), respectively. Morphological changes of iN cells were captured by inverted microscope with CCD camera every 2 minutes for 90 minutes.

Results: Prior to forskolin treatment, neuron-like spherical-form cells were observed in HC-iN cells, but most NF1-iN cells were not spherical-form but flatform. Only 20 minutes after forskolin treatment, the morphology of the iN cells were dramatically changed from flatform to spherical form, especially in NF1-iN cells.

Conclusion: The present pilot data indicate that forskolin or AC activators may have therapeutic effects on the growth of neuronal cells in NF1 patients. Further translational research should be conducted to validate our pilot findings for future drug development of ASD.
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http://dx.doi.org/10.1002/npr2.12144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722681PMC
December 2020

Parvovirus B19-Infected Tubulointerstitial Nephritis in Hereditary Spherocytosis.

Open Forum Infect Dis 2020 Aug 6;7(8):ofaa288. Epub 2020 Jul 6.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Human parvovirus B19 (B19V) causes glomerulopathy or microangiopathy, but not tubulopathy. We experienced an 11-year-old girl with spherocytosis who developed acute kidney injury on a primary infection of B19V. She presented with anuria, encephalopathy, thrombocytopenia, and coagulopathy, along with no apparent aplastic crisis.

Methods: Continuous hemodiafiltration, immunoglobulin, and intensive therapies led to a cure.

Results: A kidney biopsy resulted in a histopathological diagnosis of tubulointerstitial nephritis without immune deposits. The virus capsid protein was limitedly expressed in the tubular epithelial cells with infiltrating CD8-positive cells.

Conclusions: Viral and histopathological analyses first demonstrated B19-infected tubulointerstitial nephritis due to the aberrant viremia with hereditary spherocytosis.
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http://dx.doi.org/10.1093/ofid/ofaa288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395673PMC
August 2020

De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies.

J Neurol Sci 2020 Sep 17;416:117047. Epub 2020 Jul 17.

Department of Neurology and Stroke Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address:

Introduction: Variants of CACNA1G, which encodes Ca3.1, have been reported to be associated with various neurological disorders.

Methods: Whole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels.

Results: Two patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.Ala961Thr and c.4591A > G, p.Met1531Val, respectively. One patient with Lennox-Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.Ile1273Phe. Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca currents by p.Ala961Thr and p.Met1531Val SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.Ile1273Phe showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined.

Conclusion: De novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype-phenotype correlations of patients with CACNA1G mutations.
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http://dx.doi.org/10.1016/j.jns.2020.117047DOI Listing
September 2020

Bi-layering at ionic liquid surfaces: a sum-frequency generation vibrational spectroscopy- and molecular dynamics simulation-based study.

Phys Chem Chem Phys 2020 Jun 26;22(22):12565-12576. Epub 2020 May 26.

Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo, 152-8552, Japan.

Room-temperature ionic liquids (RTILs) are being increasingly employed as novel solvents in several fields, including chemical engineering, electrochemistry, and synthetic chemistry. To further increase their usage potential, a better understanding of the structure of their surface layer is essential. Bi-layering at the surfaces of RTILs consisting of 1-alkyl-3-methylimidazolium ([Cmim]; n = 4, 6, 8, 10, and 12) cations and bis(trifluoromethanesulfonyl)amide ([TFSA]) anions was demonstrated via infrared-visible sum-frequency generation (IV-SFG) vibrational spectroscopy and molecular dynamics (MD) simulations. It was found that the sum-frequency (SF) signal from the [TFSA] anions decreases as the alkyl chain length increases, whereas the SF signal from the r mode (the terminal CH group) of the [Cmim] cations is almost the same regardless of chain length. MD simulations show the formation of a bi-layered structure consisting of the outermost first layer and a submerged second layer in a "head-to-head" molecular arrangement. The decrease in the SF signals of the normal modes of the [TFSA] anions is caused by destructive and out-of-phase interference of vibrations of corresponding molecular moieties oriented toward each other in the first and second layers. In contrast, the r mode of [Cmim] does not experience destructive interference because the peak position of the r mode differs marginally at the surface and in the bulk. Our conclusions are not limited to the system presented here. Similar bi-layered structures can be expected for the surfaces of conventional RTILs, which necessitates the consideration of bi-layering in the design and application.
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http://dx.doi.org/10.1039/d0cp01219jDOI Listing
June 2020

Gastrointestinal symptoms as an extended clinical feature of Pierson syndrome: a case report and review of the literature.

BMC Med Genet 2020 04 15;21(1):80. Epub 2020 Apr 15.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive.

Case Presentation: We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: p.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems.

Conclusions: This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life.
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http://dx.doi.org/10.1186/s12881-020-01019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160948PMC
April 2020

Impact of physical performance on prognosis among patients with heart failure: Systematic review and meta-analysis.

J Cardiol 2020 08 12;76(2):139-146. Epub 2020 Apr 12.

Department of Rehabilitation, Shinshu University Hospital, Nagano, Japan.

Background: This study aimed to clarify the relationship between physical performance and prognosis of patients with heart failure using a meta-analysis given the inconsistencies in published studies regarding the same.

Methods: A total of 22 studies with 10,368 patients were included in this review. Hazard ratios were used for analysis, while meta-analysis was performed using the inverse-variance method. Among all physical performance tests reported in the literature, the six-minute walk distance (6MD) test was most frequently used. However, short physical performance battery (SPPB) and walking speed were more frequently used as outcomes among studies investigating patients with a higher mean age.

Results: The results of our meta-analysis showed that 6MD cut-off values were significantly associated with mortality [hazard ratio (HR), 2.04; 95% confidence interval (CI), 1.48-2.83; p<0.001] and cardiovascular disease (HR, 2.18; 95% CI, 1.68-2.83; p<0.001). Although a number of studies have also reported on the relationship between other physical performance tests and prognosis, meta-analysis could not be performed. Our results revealed that physical performance was strongly correlated with prognosis among patients with heart failure.

Conclusions: Our meta-analysis showed a strong relationship between 6MD and prognosis. However, studies investigating more elderly patients have tended to more frequently utilize walking speed and SPPB as outcomes.
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http://dx.doi.org/10.1016/j.jjcc.2020.02.022DOI Listing
August 2020

The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S.

Mol Genet Genomic Med 2020 04 27;8(4):e1175. Epub 2020 Feb 27.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP.

Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets.

Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S.

Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP.
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http://dx.doi.org/10.1002/mgg3.1175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196457PMC
April 2020

Survival and ocular preservation in a long-term cohort of Japanese patients with retinoblastoma.

BMC Pediatr 2020 01 28;20(1):37. Epub 2020 Jan 28.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Retinoblastoma is an ocular tumor in infants with cancer predisposition. Treatment of the rare tumor needs to be optimized for ocular preserved survival without second primary malignancy (SPM).

Methods: We studied the outcomes of all patients with retinoblastoma at a tertiary center in 1984-2016, when preservation method changed from radiotherapy (1984-2001) to systemic chemotherapy (2002-2016).

Results: One-hundred sixteen infants developed unilateral- (n = 77), bilateral- (n = 38), or trilateral-onset (n = 1) tumor. Ten (8.6%) had a positive family history, despite a few studies on RB1 gene. Contralateral disease occurred in one unilateral-onset case. One-hundred eight of 155 eyes (70%) were enucleated. Nine binocular survivors were from 5 bilateral- and 4 unilateral-onset cases. Two survivors received bilateral enucleation. Six deaths occurred; brain involvement (including 3 trilateral diseases) in 4 bilateral-onset, systemic invasion in a unilateral-onset, and SPM (osteosarcoma) in a bilateral-onset case(s). Two others survived SPM of osteosarcoma or lymphoma. The 10-year overall survival (OS: 98.5% vs. 91.3%, p = 0.068) and binocular survivors (13.2% vs. 5.2%, p = 0.154) between bilateral- and unilateral-onsets did not differ statistically. The 10-year OS and cancer (retinoblastoma/SPM)-free survival (CFS) rates of all patients were 94.9 and 88.5%, respectively. The proportion of preserved eyes did not differ between radiotherapy and chemotherapy eras. The CFS rate of bilateral-onset cases in systemic chemotherapy era was higher than that in radiotherapy era (p = 0.042). The CFS rates of bilateral-onset patients with neoadjuvant chemotherapy (upfront systemic therapy for preservation) was higher than those without it (p = 0.030).

Conclusions: Systemic chemotherapy and local therapy raised OS and binocular survival rates of bilateral-onset patients similarly to those of unilateral-onset patients. All but one death was associated with a probable germline defect of the RB1 gene. Neoadjuvant stratified chemotherapy may support the long-term binocular life with minimized risk of SPM.
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http://dx.doi.org/10.1186/s12887-020-1923-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986142PMC
January 2020

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature.

Eur J Med Genet 2020 Apr 16;63(4):103825. Epub 2019 Dec 16.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations.

Case Report: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge.

Results: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy.

Conclusions: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.
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http://dx.doi.org/10.1016/j.ejmg.2019.103825DOI Listing
April 2020

Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease.

Cardiovasc Res 2021 Jan;117(1):96-108

Kawasaki Disease Center, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka 813-0017, Japan.

Aims: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD.

Methods And Results: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls.

Conclusion: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.
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http://dx.doi.org/10.1093/cvr/cvz305DOI Listing
January 2021

Management of apnea in infants with trisomy 18.

Dev Med Child Neurol 2020 07 25;62(7):874-878. Epub 2019 Nov 25.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

This case series aimed to characterize the clinical features, management, and outcomes of apnea in infants with trisomy 18. Participants in this study were infants with trisomy 18 who were born alive and admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2018. Retrospective analysis was performed on clinical data recorded in our department. Twenty-seven infants with trisomy 18 were admitted to our hospital during the study period, of which 25 (nine males, 16 females) were enrolled as eligible participants in this study. Among them, 14 started presenting with apnea from median 3.5 days of age (range 0-47d). In these infants with apnea, eight received respiratory support of positive pressure ventilation (PPV). The 1-year survival rate of infants in the PPV group was higher than that of non-PPV-supported infants (5 out of 8 vs 0 out of 6 infants). Five PPV-supported infants received a diagnosis of epilepsy, which was controlled by antiepileptic drugs. Postnatal respiratory intervention provides better prognosis in infants with trisomy 18. Improved survival leads to accurate diagnosis and treatment of apneic events in association with epilepsy. WHAT THIS PAPER ADDS: Respiratory support is effective against apnea in infants with trisomy 18. Intervention with ventilation provides a higher chance of prolonged survival. Improved survival leads to the accurate diagnosis and treatment of epilepsy-associated apnea.
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http://dx.doi.org/10.1111/dmcn.14403DOI Listing
July 2020

Using SpO Recovery Index after a 6-Minute Walk Test to Predict Respiratory-Related Events in Hospitalized Patients with Interstitial Pneumonia.

Sci Rep 2019 10 23;9(1):15226. Epub 2019 Oct 23.

Respiratory Center, Shinshu University Hospital, Matsumoto, Japan.

Although the prognostic factors of interstitial pneumonia (IP) patients have been reported, IP has poor prognosis. Hospitalized patients with IP have severely impaired pulmonary diffusion capacity and prominent desaturation. We hypothesized that determining oxygen saturation recovery (SpO recovery index) after the 6-minute walk test (6MWT) can provide additional prognostic information regarding rehospitalization for respiratory-related events. We evaluated 73 IP patients at our hospital for demographic characteristics, pulmonary function tests and 6MWT. The Kaplan-Meier method was used to estimate rehospitalisation for respiratory-related events using SpO recovery index. Cox regression analysis revealed a relationship between SpO recovery index and rehospitalisation. The optimum cutoff value of SpO recovery index was 4% (sensitivity, 71.4%; specificity, 79.2%). SpO recovery index was most closely related to pulmonary diffusion capacity (r = 0.684, P < 0.001). In a multivariable model, it was the strongest independent predictor of rehospitalisation for respiratory-related events (hazard ratio, 0.3; 95% confidence interval, 0.10-0.90; P = 0.032). In this study, we estimated pulmonary diffusion capacity using SpO recovery index values obtained from 6MWT. A SpO recovery index of <4% can be useful in predicting rehospitalisation for respiratory-related events.
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http://dx.doi.org/10.1038/s41598-019-51818-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811585PMC
October 2019

Cough Strength Is an Indicator of Aspiration Risk When Restarting Food Intake in Elderly Subjects With Community-Acquired Pneumonia.

Respir Care 2020 Feb 15;65(2):169-176. Epub 2019 Oct 15.

Department of Physical Therapy, Shinshu University, School of Health Sciences, Matusmoto, Japan.

Background: The incidence of community-acquired pneumonia (CAP) is relatively high in elderly subjects. Cough peak flow (CPF) is an objective indicator of cough strength, and CPF evaluation might be useful to assess whether food intake can be restarted. We aimed to examine whether cough strength assessed with CPF can be used as an indicator of the aspiration risk when restarting food intake in elderly subjects with CAP.

Methods: This cross-sectional study included 82 elderly subjects with CAP between August 2016 and March 2018. CPF was measured using a peak flow meter, and we performed the repetitive saliva-swallowing test (RSST), which is a videoendoscopic evaluation of swallowing and is used to assess dysphagia and aspiration. Receiver operating characteristic (ROC) curve analysis was performed. The cutoff value was determined, and the area under the ROC was calculated.

Results: The areas under the RSST and CPF curves were 0.87 and 0.83, respectively. The RSST value for identifying the aspiration risk was 2.5 swallows. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 70.0%, 71.7%, 2.5, and 0.42, respectively. The CPF for identifying the aspiration risk was 190 L/min. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 82.6%, 69.4%, 2.7, and 0.25, respectively.

Conclusions: Our findings suggest that cough strength assessed with CPF can be used as an indicator of the aspiration risk when restarting food intake in elderly subjects with CAP and that CPF evaluation is not inferior to the RSST. However, CPF evaluation should be performed together with swallowing screening tests to determine the aspiration risk.
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http://dx.doi.org/10.4187/respcare.07067DOI Listing
February 2020

Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis.

Int J Hematol 2020 Jan 23;111(1):131-136. Epub 2019 Sep 23.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Hemophagocytic lymphohistiocytosis (HLH) occurs in neonates with disseminated infection of herpes simplex virus (HSV). Little has been reported on the control of rapid HLH progression. We studied the cytokine profile and genetic basis of two index cases with divergent outcomes after early treatment of type 2 HSV infection. One survivor had fever and elevated serum levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ at diagnosis. The other neonate had no fever or TNF-α production, but significant IL-6 or IFN responses during the treatment course, and died 19 days after birth. Among 16 reported cases of neonatal HSV-HLH including index cases, eight deceased neonates experienced significantly less fever at presentation (p = 0.028), lower platelet counts (p = 0.019), and lower ratios of soluble IL-2 receptor (sIL-2R) to ferritin levels (p = 0.044) than eight survivors. The 100-day overall survival rates were significantly higher in patients with fever (p = 0.004), > 100 × 10/L of platelet counts (p = 0.035) or > 20 of sIL-2R/ferritin ratio at diagnosis (p = 0.004). The first febrile and cytokine responses to HSV infection predict the early outcome of neonatal HSV-HLH.
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http://dx.doi.org/10.1007/s12185-019-02738-3DOI Listing
January 2020

Association of perinatal factors of epilepsy in very low birth weight infants, using a nationwide database in Japan.

J Perinatol 2019 11 16;39(11):1472-1479. Epub 2019 Sep 16.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: To determine clinical features of very low birth weight infants (VLBWIs) who had developed epilepsy by age 3 years.

Study Design: Multicenter cohort study using the Neonatal Research Network of Japan database. We analyzed clinical variables of 8431 VLBWIs who had recorded data of neurological sequelae at age 3 years. Logistic regression identified the association between variables and development of epilepsy.

Result: One hundred and forty-three (1.7%) infants developed epilepsy, 683 (8.1%) showed cerebral palsy (CP), and 1114 (13.2%) had psychomotor delay. Epilepsy was associated with history of sepsis [adjusted odds ratio (AOR) 3.23], severe intraventricular hemorrhage (IVH; AOR 5.13), and cystic periventricular leukomalacia (PVL; AOR 12.7). Severe IVH and cystic PVL were also frequently associated with CP and psychomotor delay.

Conclusion: Severe IVH and cystic PVL are strongly associated with development of epilepsy, as well as other neurological sequelae, and are potential critical therapeutic targets.
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http://dx.doi.org/10.1038/s41372-019-0494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892414PMC
November 2019

Decision-making dilemmas of paediatricians: a qualitative study in Japan.

BMJ Open 2019 08 19;9(8):e026579. Epub 2019 Aug 19.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: To delineate the critical decision-making processes that paediatricians apply when treating children with life-threatening conditions and the psychosocial experience of paediatricians involved in such care.

Design: We conducted semistructured, individual face-to-face interviews for each participant from 2014 to 2015. The content of each interview was subjected to a comprehensive qualitative analysis. The categories of dilemma were extracted from a second-round content analysis.

Participants: Participants were board-certified paediatricians with sufficient experience in making decisions in relation to children with severe illnesses or disabilities. We repeated purposive sampling and analyses until we reached saturation of the category data.

Results: We performed interviews with 15 paediatricians. They each reported both unique and overlapping categories of dilemmas that they encountered when making critical decisions. The dilemmas included five types of causal elements: (1) paediatricians' convictions; (2) the quest for the best interests of patients; (3) the quest for medically appropriate plans; (4) confronting parents and families and (5) socioenvironmental issues. Dilemmas occurred and developed as conflicting interactions among these five elements. We further categorised these five elements into three principal domains: the decision-maker (decider); consensus making among families, colleagues and society (process) and the consequential output of the decision (consequence).

Conclusions: This is the first qualitative study to demonstrate the framework of paediatricians' decision-making processes and the complex structures of dilemmas they face. Our data indicate the necessity of establishing and implementing an effective support system for paediatricians, such as structured professional education and arguments for creating social consensus that assist them to reach the best plan for the management of severely ill children.
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http://dx.doi.org/10.1136/bmjopen-2018-026579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707677PMC
August 2019

Late-Onset Circulatory Collapse and Risk of Cerebral Palsy in Extremely Preterm Infants.

J Pediatr 2019 09 20;212:117-123.e4. Epub 2019 Jun 20.

Department of Pediatrics, Graduate School of Medical Sciences, Fukuoka, Japan; Comprehensive Maternity and Perinatal Care Center, Kyushu University, Fukuoka, Japan.

Objective: To investigate whether the development of postnatal, late-onset refractory hypotension, referred to as late-onset circulatory collapse, was associated with an increased risk of developing cerebral palsy (CP) at 3 years of age in extremely preterm infants.

Methods: In this historical cohort study, infants who were born at 22-27 weeks of gestation from 2008 to 2012 in the Neonatal Research Network of Japan were eligible. The study sample consisted of 3474 infants (45.6% of 7613 potentially eligible infants) who were evaluated at 36-42 months of age. Late-onset circulatory collapse was defined as a clinical diagnosis of late-onset circulatory collapse requiring treatment with corticosteroids. We compared the neurodevelopmental outcomes between infants with and without late-onset circulatory collapse.

Results: Late-onset circulatory collapse was diagnosed in 666 of the infants studied. Infants with late-onset circulatory collapse had a higher incidence of CP than those without late-onset circulatory collapse (18.0% vs 9.8%; P < .01). In multivariable logistic analysis, late-onset circulatory collapse was independently associated with CP (aOR, 1.52; 95% CI, 1.13-2.04) and developmental quotient score of <50 (OR, 1.83; 95% CI, 1.23-2.72).

Conclusions: Late-onset circulatory collapse may be a relatively common event occurring in extremely preterm infants and an independent risk factor for CP at 3 years of age.
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http://dx.doi.org/10.1016/j.jpeds.2019.05.033DOI Listing
September 2019

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Late-onset sepsis and encephalopathy after bicycle-spoke injury: a case report.

BMC Infect Dis 2019 May 28;19(1):472. Epub 2019 May 28.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Bicycle-spoke injuries rarely cause late complications of infection, including sepsis and sepsis-associated encephalopathy, with appropriate treatments.

Case Presentation: We experienced a 2-year-old girl who developed the signs of encephalopathy with fever 6 months after a spoke-injury. On admission, the injured skin was inflamed with cellulitis. The blood culture was positive for methicillin-sensitive Staphylococcus aureus. Electroencephalogram showed diffuse slow-wave activity. Diffusion-weighted magnetic resonance imaging detected a high-intensity lesion with decreased diffusivity at the right frontal cortex. She received immunoglobulin and combined antibiotics treatments in the intensive care unit, and successfully overcame the sepsis-associated encephalopathy without neurological impairments.

Conclusion: This is the first report demonstrating that sepsis and its associated encephalopathy occurs in a remote period after the bicycle-spoke injury.
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http://dx.doi.org/10.1186/s12879-019-4082-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537365PMC
May 2019