Publications by authors named "Takayuki Kondo"

139 Publications

Human induced pluripotent stem cells generated from a patient with idiopathic basal ganglia calcification.

Stem Cell Res 2021 Mar 3;53:102274. Epub 2021 Mar 3.

iPSC-based Drug-Discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan. Electronic address:

Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disease, characterized by abnormal calcium deposits in basal ganglia of the brain. The affected individuals exhibit movement disorders, and progressive deterioration of cognitive and psychiatric ability. The genetic cause of the disease is mutation in one of several different genes, SLC20A2, PDGFB, PDGFRB, XPR1 or MYORG, which inheritably or sporadically occurs. Here we generated an induced pluripotent stem cell (iPSC) line from an IBGC patient, which is likely be a powerful tool for revealing the pathomechanisms and exploring potential therapeutic candidates of IBGC.
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http://dx.doi.org/10.1016/j.scr.2021.102274DOI Listing
March 2021

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2021 Apr 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 Mar 5;11(1):5303. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

Propofol midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

JGH Open 2021 Feb 22;5(2):273-279. Epub 2020 Dec 22.

Department of Gastroenterology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single-blind, investigator-initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

Methods: Few- and small-nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100-mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.

Results: Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.

Conclusion: Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.
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http://dx.doi.org/10.1002/jgh3.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857294PMC
February 2021

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity.

Neurol Neuroimmunol Neuroinflamm 2021 03 12;8(2). Epub 2021 Jan 12.

From the Department of Neurology (S.A., C.F., T.M.), Graduate School of Medical Science, Kyoto Prefectural University of Medicine; Department of Geriatric Medicine and Neurology (H.O.), Ehime University Graduate School of Medicine, Toon; Department of Neurology (M.H., R.T.), Kyoto University Graduate School of Medicine; Department of Neurology (M.H., Y.O., Y.H., T.K.), Kansai Medical University Medical Center, Osaka, Japan; Brigham and Women's Hospital (K. Kimura), Harvard Medical School, Boston, MA; Department of Neurology (K. Kawamura), National Hospital Organization Minami Kyoto Hospital; and Department of Immunology (H.U.), Kyoto University Graduate School of Medicine, Japan.

Objective: To clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells.

Methods: A total of 24 immunotherapy-naive patients with anti-acetylcholine receptor (AchR) antibody-positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score.

Results: cTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOScTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOS cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement.

Conclusions: Alternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy.

Classification Of Evidence: This study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.
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http://dx.doi.org/10.1212/NXI.0000000000000945DOI Listing
March 2021

Generation of a human induced pluripotent stem cell line, BRCi009-A, derived from a patient with glycogen storage disease type 1a.

Stem Cell Res 2020 12 23;49:102095. Epub 2020 Nov 23.

iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan. Electronic address:

Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder caused by mutations of the glucose-6-phosphatase (G6PC) gene. Mutations of the G6PC gene lead to excessive accumulation of glycogen in the liver, kidney, and intestinal mucosa due to the deficiency of microsomal glucose-6-phosphatase. Human induced pluripotent stem cells (iPSCs) enable the production of patient-derived hepatocytes in culture and are therefore a promising tool for modeling GSD1a. Here, we report the establishment of human iPSCs from a GSD1a patient carrying a G6PC mutation (c.648G > T; p.Leu216 = ).
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http://dx.doi.org/10.1016/j.scr.2020.102095DOI Listing
December 2020

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

Liver Cancer 2020 Sep 22;9(5):596-612. Epub 2020 Jul 22.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden.

Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs.

Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC.

Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC.

Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.
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http://dx.doi.org/10.1159/000508809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548915PMC
September 2020

Role of Autoimmunity in Patients Transplanted for Acute Liver Failure of Unknown Origin: A Clinical and Graft Biopsy Analysis.

Liver Transpl 2021 02 22;27(2):309-310. Epub 2020 Nov 22.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1002/lt.25917DOI Listing
February 2021

Potential of Lenvatinib for an Expanded Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2020 Aug 5;9(4):382-396. Epub 2020 May 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial.

Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan.

Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores.

Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.
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http://dx.doi.org/10.1159/000507022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506220PMC
August 2020

Effectiveness of active nasal surveillance culture for Methicillin-resistant Staphylococcus aureus in patients undergoing colorectal surgery.

J Infect Chemother 2020 Dec 26;26(12):1244-1248. Epub 2020 Aug 26.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Objective: The aim of this study was to clarify the role of Methicillin-resistant Staphylococcus aureus (MRSA) carriers in the development of surgical site infection (SSI) after colorectal surgery.

Summary Background Data: MRSA is commonly implicated in hospital-acquired infections. Active surveillance culture (ASC) using the nasal swab test is useful to detect MRSA in surgical patients. We hypothesized that MRSA carriers would be more susceptible to SSI after colorectal surgery METHODS: Patients who underwent ASC between 2010 and 2013 were included in this study. The incidence of SSI was compared between MRSA carriers and non-carriers using the chi-square test. The odds ratio for SSI was computed using logistic regression analyses.

Results: Among 355 patients, 12 (3.4%) were identified as MRSA carriers and 343 as non-carriers. Of all the patients, 65 patients (18.3%) developed an SSI. Of these, 6 cases were in MRSA carriers and 59 cases were in non-carriers (p < 0.01). This meant that half of the 12 MRSA carriers developed an SSI, compared with only 17.2% of non-carriers (59 cases out of 343 patients). Therefore, MRSA carriers had a significantly higher risk of SSI (adjusted odds ratio = 4.77 [1.37 to 16.6], p = 0.01).

Conclusions: Detection of MRSA via ASC is significantly associated with the development of SSI after colorectal surgery. These findings indicate that ASC for MRSA is useful to predict an SSI.
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http://dx.doi.org/10.1016/j.jiac.2020.06.013DOI Listing
December 2020

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

Effect of small coding genes on the circadian rhythms under elevated CO conditions in plants.

Plant Mol Biol 2020 Sep 22;104(1-2):55-65. Epub 2020 Jun 22.

Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka-shi, Fukuoka, 820-8502, Japan.

Increase in atmospheric carbon dioxide (CO) has a significant effect on plant growth and development. To explore the elevated-CO response, we generated transcriptional profiles over a time course (2 h-14 days) of exposure to elevated CO in Arabidopsis thaliana. Genes related to photosynthesis were down-regulated and circadian rhythm-related genes were abnormally regulated in the early to middle phase of elevated CO exposure. To understand the novel mechanism of elevated CO signaling, we focused on 42 unknown small coding genes that showed differential expression patterns under elevated CO conditions. Four transgenic plants overexpressing the small coding gene exhibited a growth-defective phenotype under elevated CO but not under current CO. Transcriptome analysis showed that circadian rhythm-related genes were commonly regulated in four transgenic plants. These circadian rhythm-related genes were transcribed in the dark when CO concentrations in the leaf was high. Taken together, our identified four small coding genes are likely to participate in elevated CO signaling to the circadian rhythm.
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http://dx.doi.org/10.1007/s11103-020-01023-wDOI Listing
September 2020

Aqueous olanexidine versus aqueous povidone-iodine for surgical skin antisepsis on the incidence of surgical site infections after clean-contaminated surgery: a multicentre, prospective, blinded-endpoint, randomised controlled trial.

Lancet Infect Dis 2020 11 15;20(11):1281-1289. Epub 2020 Jun 15.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: Surgical site infection (SSI) is the most common problem after surgery. Although several guidelines have indicated the efficacy of antiseptics, such as chlorhexidine-alcohol and povidone-iodine, in reducing SSI rate, the optimal recommendation is still not established. Olanexidine might have higher bactericidal activity than other antiseptic agents. However, no randomised study has evaluated the efficacy and safety of olanexidine over conventional antiseptics. We compared the effect of aqueous olanexidine and aqueous povidone-iodine on the incidence of SSI following clean-contaminated surgery.

Methods: This was a multicentre, prospective, randomised, blinded-endpoint superiority trial for surgical skin antisepsis in clean-contaminated gastrointestinal and hepatobiliary pancreatic surgeries in four Japanese hospitals. Patients aged 20 years or older who underwent elective clean-contaminated wound surgery were randomly assigned in a 1:1 replacement ratio using a computer-generated block randomisation. Patients were randomly assigned to surgical skin antisepsis with an aqueous formulation of 1·5% olanexidine or surgical skin antisepsis with an aqueous formulation of 10% povidone-iodine before surgery. We used olanexidine in a ready-to-use applicator, and povidone-iodine was administered by a brush or by compression using pliers. Both antiseptics were applied from the papilla with a cranial limit and to the upper thigh with a caudal limit. The antiseptics were allowed to dry for 3 min, and then surgery started. Participants, some investigators, and data analysts were masked to treatment allocation. Participant enrolment was done by non-masked investigators. The primary outcome was 30-day SSI assessed in the intention-to-treat population. The surgical wound site of each participant was observed daily. After discharge, participants underwent at least one outpatient visit within 30 days after surgery. This trial is registered with University hospital Medical Information Network, 000031560.

Findings: Between June 10, 2018, and April 18, 2019, 883 patients were assessed for eligibility. 587 patients were eligible and 294 received olanexidine and 293 received aqueous povidone-iodine before surgery. 30-day SSI occurred in 19 (7%) patients in the olanexidine group and 39 patients (13%) patients in the povidone-iodine group (adjusted risk difference -0·069; 90% CI -0·109 to -0·029; adjusted risk ratio [RR] 0·48, 90% CI 0·30 to 0·74; p=0·002). Five patients (2%) in the olanexidine group and five (2%) in the povidone-iodine group developed adverse skin reactions (adjusted RR 0·99, 95% CI 0·29 to 3·40; p=1·00).

Interpretation: Olanexidine significantly reduced the occurrence of overall SSI and superficial incisional SSI compared with aqueous povidone-iodine in clean-contaminated surgery. Our results indicate that olanexidine might have a role to prevent SSI in patients who undergo clean-contaminated surgeries.

Funding: Keio University and Ohyama Health Foundation.
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http://dx.doi.org/10.1016/S1473-3099(20)30225-5DOI Listing
November 2020

Generation of a human induced pluripotent stem cell line, BRCi004-A, derived from a patient with age-related macular degeneration.

Stem Cell Res 2020 05 21;45:101787. Epub 2020 Apr 21.

iPSC-based Drug discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan; Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. Electronic address:

Age-related macular degeneration (AMD) is a late-onset progressive blinding disease. We established human induced pluripotent stem cells (iPSCs) from an AMD patient. The generated iPSC line showed pluripotency markers and three-germ layer differentiation ability in vitro. This iPSC line will be useful for elucidating the pathomechanisms of and drug discovery for AMD.
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http://dx.doi.org/10.1016/j.scr.2020.101787DOI Listing
May 2020

Generation of a human induced pluripotent stem cell line, BRCi005-A, derived from a Best disease patient with BEST1 mutations.

Stem Cell Res 2020 05 29;45:101782. Epub 2020 Apr 29.

iPSC-based Drug discovery and Development Team, RIKEN BioResource Research Center, Kyoto, Japan; Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. Electronic address:

Best Disease is an inherited retinal dystrophy that results in progressive and irreversible central vision loss caused by mutations of BESTROPHIN1 (BEST1). We established human induced pluripotent stem cells (iPSCs) from a Best disease patient with mutations R218H and A357V in the BEST1 gene. The generated iPSCs showed pluripotency markers and three-germ layer differentiation ability in vitro. A genetic analysis revealed mutations of R218H and A357V in the iPSCs. This iPSC line will be useful for elucidating the pathomechanisms of and drug discovery for Best disease.
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http://dx.doi.org/10.1016/j.scr.2020.101782DOI Listing
May 2020

Generation of a human induced pluripotent stem cell line derived from a Parkinson's disease patient carrying SNCA duplication.

Stem Cell Res 2020 05 22;45:101828. Epub 2020 Apr 22.

Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address:

Parkinson's disease (PD) is a devastating movement disorder with an unknown etiology. Multiplications of the SNCA gene cause the autosomal dominant form of familial PD as well as missense mutations of the gene. We established and characterized a human induced pluripotent stem cell (iPSC) line from a PD patient carrying SNCA duplication. The iPSC line displayed a capacity to differentiate into midbrain dopaminergic neurons affected in PD. The iPSC line will be useful for disease modeling applications.
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http://dx.doi.org/10.1016/j.scr.2020.101828DOI Listing
May 2020

[New Arrival of Disease Modifying Drugs Initiates New Era in Multiple Sclerosis Treatment in Japan].

Authors:
Takayuki Kondo

Brain Nerve 2020 May;72(5):517-523

Department of Neurology, Kansai Medical University Medical Center.

Multiple sclerosis disease modifying drugs (MS-DMD) currently used in Japan are interferon β-1a, interferon β-1b and gratiramer acetate, fingolimod, dimethyl furmarate, and natalizumab. Ofatumumab and siponimod will be approved probably in 2021. Ofatumumab is an ant-CD20 human monoclonal antibody. A clinical trial revealed that the efficacy of ofatumumab is clearly superior to teriflunomide that has comparable efficacy to dimethyl fumarate. Siponimod, a selective sphingosine-1-phosphate receptor modulator, exhibited mild, but significant efficacy for secondary progressive form of MS. OCH, a synthetic glycolipid agent, is being tested in phase II clinical trials in Japan. What DMD is to select is challenging since MS prognosis varies and is unexpected. Only very few have truly benign course without treatment. Silent progression should be considered especially in cases with those with interferon β-1a, interferon β-1b and gratiramer acetate. Escalation therapy is more widely accepted than initiation of high efficacy therapy in Japan because emphasizing safety. In such strategy three injectables and dimethyl fumarate are regarded as first line therapies. On the other hand, initiation of high efficacy drugs may be reasonable to prevent from disease progression. Even if either is acceptable, early induction of DMD with sufficient efficacy is mandatory for MS treatment.
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http://dx.doi.org/10.11477/mf.1416201555DOI Listing
May 2020

Altered features of monocytes in adult onset leukoencephalopathy with axonal spheroids and pigmented glia: A clue to the pathomechanism of microglial dyshomeostasis.

Neurobiol Dis 2020 07 7;140:104867. Epub 2020 Apr 7.

Department of Neurology, Kansai Medical University Medical Center, 10-15 Fumizono, Moriguchi 570-8507, Japan. Electronic address:

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal-dominant type of leukoencephalopathy caused by gene mutation of colony stimulating factor 1 receptor, which is expressed mainly on monocyte lineage cells such as monocytes in the peripheral blood and microglia in the brain. Hence, microglial dysfunction is regarded as critical in the pathogenesis of ALSP. However, functional changes in these cells have not been elucidated. In this study, we report the phenotypic and functional alterations of monocytes in four patients with ALSP. Flow cytometric analysis revealed altered expression of antigen presentation- and migration-related molecules, an inflammatory shift in cytokine production and phagocytic impairment in ALSP monocytes. We speculate that the observed altered features of monocytes are mostly shared by microglial cells, leading to the clinical history and pathological characteristics of ALSP. Our analysis of PB monocytes provides novel insights into the pathogenesis of ALSP.
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http://dx.doi.org/10.1016/j.nbd.2020.104867DOI Listing
July 2020

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease.

Mol Brain 2020 03 19;13(1):38. Epub 2020 Mar 19.

Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary cerebral small vessel diseases and is caused by mutations in NOTCH3. Our group has previously reported incorporation of NOTCH3 extracellular domain (N3ECD) in the CADASIL-specific granular osmiophilic materials and increase of PDGFRβ immunoreactivity in CADASIL postmortem brains. Here, we aimed to establish an in vitro model of CADASIL, which can recapitulate those CADASIL phenotypes, using induced pluripotent stem cells (iPSCs). We have refined a differentiation protocol of endothelial cells to obtain mature mural cells (MCs) with their characteristic properties. iPSCs from three CADASIL patients with p.Arg182Cys, p.Arg141Cys and p.Cys106Arg mutations were differentiated into MCs and their functional and molecular profiles were compared. The differentiated CADASIL MCs recapitulated pathogenic changes reported previously: increased PDGFRβ and abnormal structure/distribution of filamentous actin network, as well as N3ECD/LTBP-1/HtrA1-immunopositive deposits. Migration rate of CADASIL MCs was enhanced but suppressed by knockdown of NOTCH3 or PDGFRB. CADASIL MCs showed altered reactivity to PDGF-BB. Patient-derived MCs can recapitulate CADASIL pathology and are therefore useful in understanding the pathogenesis and developing potential treatment strategies.
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http://dx.doi.org/10.1186/s13041-020-00573-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081541PMC
March 2020

Evaluation of Toxic Amyloid 42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator.

Int J Mol Sci 2020 Feb 11;21(4). Epub 2020 Feb 11.

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.

Amyloid 42 (Aβ42), a causative agent of Alzheimer's disease (AD), is derived extracellularly from A precursor protein (APP) following the latter's cleavage by -secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing A production. Since Aβ42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKC-dependent A-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known -secretase stabilizer, was reduced by treatment with . Notably, prevented the formation of intracellular toxic oligomers. Furthermore, suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that was not neurotoxic toward either cell line, these findings suggest that is a potential drug lead for AD therapy.
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http://dx.doi.org/10.3390/ijms21041179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072833PMC
February 2020

Clinical significance of the long-loop reflex and giant evoked potentials in genetically proven benign adult familial myoclonic epilepsy.

Clin Neurophysiol 2020 04 27;131(4):978-980. Epub 2020 Jan 27.

Department of Neurology, National Hospital Organization Utano National Hospital, Kyoto, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2020.01.005DOI Listing
April 2020

Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure.

J Hepatol 2020 07 24;73(1):102-112. Epub 2020 Jan 24.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom. Electronic address:

Background & Aims: Toll-like receptor 4 (TLR4) plays an essential role in mediating organ injury in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Herein, we assess whether inhibiting TLR4 signaling can ameliorate liver failure and serve as a potential treatment.

Methods: Circulating TLR4 ligands and hepatic TLR4 expression were measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo (10 mg/kg intraperitoneally) in rodent models of ACLF (bile duct ligation + lipopolysaccharide [LPS]; carbon tetrachloride + LPS) and ALF (galactosamine + LPS) and in vitro on immortalized human monocytes (THP-1) and hepatocytes (HHL5). The in vivo therapeutic effect was assessed by coma-free survival, organ injury and cytokine release and in vitro by measuring IL-6, IL-1β or cell injury (TUNEL), respectively.

Results: In patients with cirrhosis, hepatic TLR4 expression was upregulated and circulating TLR4 ligands were increased (p <0.001). ACLF in rodents was associated with a switch from apoptotic cell death in ALF to non-apoptotic forms of cell death. TAK-242 reduced LPS-induced cytokine secretion and cell death (p = 0.002) in hepatocytes and monocytes in vitro. In rodent models of ACLF, TAK-242 administration improved coma-free survival, reduced the degree of hepatocyte cell death in the liver (p <0.001) and kidneys (p = 0.048) and reduced circulating cytokine levels (IL-1β, p <0.001). In a rodent model of ALF, TAK-242 prevented organ injury (p <0.001) and systemic inflammation (IL-1β, p <0.001).

Conclusion: This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF; its inhibition reduces the severity of organ injury and improves outcome. TAK-242 may be of therapeutic relevance in patients with liver failure.

Lay Summary: Toll-like receptor 4 (or TLR4) mediates endotoxin-induced tissue injury in liver failure and cirrhosis. This receptor sensitizes cells to endotoxins, which are produced by gram-negative bacteria. Thus, inhibiting TLR4 signaling with an inhibitor (TAK-242) ameliorates organ injury and systemic inflammation in rodent models of acute and acute-on-chronic liver failure.
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http://dx.doi.org/10.1016/j.jhep.2020.01.011DOI Listing
July 2020

Switching to systemic therapy after locoregional treatment failure: Definition and best timing.

Clin Mol Hepatol 2020 04 15;26(2):155-162. Epub 2020 Jan 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients' survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.
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http://dx.doi.org/10.3350/cmh.2019.0021nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160341PMC
April 2020

Effect of High Blood Glucose Level on the Antimicrobial Activity of Daptomycin against Staphylococcus aureus in Streptozotocin-Induced Diabetic Mice.

Jpn J Infect Dis 2020 May 25;73(3):205-209. Epub 2019 Dec 25.

Department of Clinical Infectious Diseases, Aichi edical University Graduate School of Medicine.

Daptomycin is active against Staphylococcus aureus including methicillin-resistant S. aureus (MRSA), demonstrating efficacy in the treatment of infections in diabetic patients. However, daptomycin degrades in 5% glucose solution, and data on the efficacy of daptomycin in hyperglycemic patients are limited. Therefore, we investigated the effect of high levels of blood glucose on the efficacy and concentration of daptomycin. The efficacy of simulated human exposure to daptomycin against S. aureus was compared in a neutropenic murine thigh model, with and without hyperglycemia. A clinically isolated MRSA strain and S. aureus ATCC25923 standard strain were used. Daptomycin concentrations, in the serum and at the infected site, were preliminarily analyzed using the high-performance liquid chromatography assay. Even in hyperglycemic mice, the mean concentration of daptomycin in hyperglycemic mice was equivalent to that in untreated mice within the physiological blood glucose levels. Additionally, the efficacy of daptomycin against MRSA was equal to that observed in the untreated and hyperglycemic mice. Based on similar studies using S. aureus ATCC25923, the efficacy in hyperglycemic mice was equal to or greater than that observed in untreated mice. In conclusion, daptomycin is an alternative therapeutic option in diabetic mice with serious staphylococcal infections, regardless of blood glucose control in this animal model.
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http://dx.doi.org/10.7883/yoken.JJID.2019.457DOI Listing
May 2020

Incidence of and risk factors for recurrent Clostridioidesdifficile infection in Japan using a claims database: A retrospective cohort study.

Anaerobe 2020 Feb 10;61:102139. Epub 2019 Dec 10.

Medical Affairs, MSD K.K, Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo, 102-8667, Japan. Electronic address:

This retrospective cohort study aimed to determine the incidence rates of and risk factors for recurrent Clostridioides difficile infection (rCDI) in Japan using a claims database. Inpatients of any age with ≥1 record of C. difficile infection (CDI) during the study period (January 2012-September 2016) were analyzed. We estimated the incidence rate of health care onset, health care facility associated (HO-HCFA) primary CDI and HO-HCFA rCDI for each of the first to fifth recurrences. Risk factors for the first recurrence were investigated using a univariate, and subsequently, a multivariable Cox regression model. The incidence rates (95% confidence interval [CI]) of CDI and HO-HCFA CDI were 2.43 (2.40-2.46) and 1.26 (1.24-1.28) cases per 10,000 inpatient-days, respectively. Among the 11,287 inpatients with ≥1 HO-HCFA CDI, 1424 patients had ≥1 recurrent episode (12.6% [95% CI 12.0-13.2]). The rCDI incidence rates consistently increased, with the number of recurrences ranging from 29.2 to 181.8 cases per 10,000 inpatient-days. The multivariable analysis revealed five risk factors (hazard ratio [95% CI]): age ≥65 years (vs. <65 years; 65-74 years, 1.275 [1.048-1.551]; 75-79 years, 1.612 [1.315-1.975]; ≥80 years, 2.110 [1.776-2.507]); cephalosporin use both before (vs. without cephalosporin; 1.241 [1.098-1.402]) and during the primary CDI (vs. without cephalosporin; 1.137 [1.011-1.279]); higher number of comorbidities (vs. ≤10 comorbidities; 11-14 comorbidities: 1.336 [1.131-1.580]; 15-20 comorbidities: 1.433 [1.219-1.685]; ≥21 comorbidities: 1.310 [1.099-1.561]); and gastrointestinal surgery (vs. without surgery; 0.823 [0.701-0.965]). In conclusion, CDI recurred in some Japanese patients, and the incidence rates increased with the number of recurrences. Special care is needed in patients aged ≥65 years, those with a higher number (>10) of comorbidities, and those who have received cephalosporin before or during the primary CDI.
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http://dx.doi.org/10.1016/j.anaerobe.2019.102139DOI Listing
February 2020

Modeling Neurological Disorders with Human Pluripotent Stem Cell-Derived Astrocytes.

Int J Mol Sci 2019 Aug 8;20(16). Epub 2019 Aug 8.

iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto 619-0237, Japan.

Astrocytes play vital roles in neurological disorders. The use of human induced pluripotent stem cell (iPSC)-derived astrocytes provides a chance to explore the contributions of astrocytes in human diseases. Here we review human iPSC-based models for neurological disorders associated with human astrocytes and discuss the points of each model.
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http://dx.doi.org/10.3390/ijms20163862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720891PMC
August 2019

Clinical characteristics of autoimmune disorders in the central nervous system associated with myasthenia gravis.

J Neurol 2019 Nov 24;266(11):2743-2751. Epub 2019 Jul 24.

Department of Neurology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ogimachi, Kita-ku, Osaka, 530-8480, Japan.

Myasthenia gravis (MG) is occasionally associated with autoimmune diseases in the central nervous system (CNS), such as neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), Morvan syndrome, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Here, we report five original cases associated with autoimmune disorders in the CNS among 42 patients with MG in a single tertiary hospital in Japan (11.9%). In four of these five cases, the second disease developed when the preceding disease was unstable. Accurate diagnosis of the newly developing disease may be difficult in such cases, because some neurological symptoms can be seen in both disorders. This implies the great importance of recognizing the possible co-occurrence of MG and disorders in the CNS. In addition, a comprehensive review of the literature revealed distinct clinical characteristics depending on the associated disease in the CNS, including thymic pathology and temporal relationship between MG and associated CNS disorders. Notably, NMOSD usually develops after the onset of MG and thymectomy, in clear contrast to MS. Thymoma is highly prevalent among patients with Morvan syndrome, in contract to cases with NMOSD and MS. The analysis of clinical characteristics, representing the first such investigation to the best of our knowledge, suggests different pathogeneses of these autoimmune diseases in the CNS, and provides significant implications for clinical practice.
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http://dx.doi.org/10.1007/s00415-019-09461-3DOI Listing
November 2019

Adenocarcinoma arising in adenomyoma of small intestine.

Pathol Int 2019 Sep 23;69(9):556-558. Epub 2019 Jul 23.

Department of Surgery, National Tokyo Medical Center.

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http://dx.doi.org/10.1111/pin.12839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703863PMC
September 2019

Hormone-like peptides and small coding genes in plant stress signaling and development.

Curr Opin Plant Biol 2019 10 29;51:88-95. Epub 2019 Jun 29.

Gene Discovery Research Group, RIKEN Center for Sustainable Resource Science, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.

Recent works have shed light on the long-distance interorgan signaling by which hormone-like peptides precisely regulate physiological effects in a manner similar to phytohormones. Many such peptides have already been identified in the primary model plant, Arabidopsis thaliana. In addition, Arabidopsis genome reanalysis revealed over 7000 novel candidate small coding genes, some of which are likely to be associated with hormone-like peptides. Hormone-like peptides have also been reported to play critical roles in interorgan communications during morphogenesis and stress responses. In this review, we focus on the functional roles of hormone-like peptides and small coding genes in cell-to-cell and/or long-distance communications during plant stress signaling and development and discuss the evolutionary conservation of these peptides among plants.
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http://dx.doi.org/10.1016/j.pbi.2019.05.011DOI Listing
October 2019

Comparison of olanexidine versus povidone-iodine for preventing surgical site infection in gastrointestinal surgery: study protocol for a multicentre, single-blind, randomised controlled clinical trial.

BMJ Open 2019 05 28;9(5):e028269. Epub 2019 May 28.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Introduction: The prevalence of surgical site infection (SSI) remains higher in gastrointestinal surgery than in other surgeries. Although several guidelines have indicated the efficacy of chlorhexidine and povidone-iodine in reducing the SSI rate, the optimal recommendation has still not been established. Therefore, it is necessary to determine the more effective antiseptic for surgical site preparation. Olanexidine (1.5% olanedine, Otsuka Pharmaceutical Factory, Tokushima, Japan), which is a new antiseptic in Japan, has antimicrobial activity against a wide range of bacteria, including Gram-positive and Gram-negative bacteria. Our study will contribute to determining a new antiseptic for use in gastrointestinal and other surgeries.

Methods And Analysis: We propose a multicentre, randomised controlled clinical trial for comparing two treatments, that is, 1.5% olanexidine or 10% povidone-iodine, for surgical skin preparation to prevent SSI in clean-contaminated gastrointestinal surgeries with surgical wounds. Patients aged ≥20 years at the time of consent will be included. The primary outcome measure is the 30-day postoperative SSI rate. For the primary analysis, which is aimed at comparing the treatment effects, the adjusted risk ratio and its 95% CI will be estimated using the Mantel-Haenszel method.

Ethics And Dissemination: The protocol was first approved by the Institutional Review Board of Keio University School of Medicine, followed by the institutional review board of each participating site. Participant recruitment began in June 2018. The final results will be published in international peer-reviewed medical journals.

Trial Registration Number: UMIN 000031560; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-028269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549615PMC
May 2019