Publications by authors named "Kenji Hashimoto"

625 Publications

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development.

Authors:
Kenji Hashimoto

Cancers (Basel) 2021 May 11;13(10). Epub 2021 May 11.

Crescendo Biologics, Ltd., Meditrina Building 260, Babraham Research Campus, Cambridge CB22 3AT, UK.

Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8 T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.
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http://dx.doi.org/10.3390/cancers13102288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150789PMC
May 2021

Abnormal composition of microbiota in the gut and skin of imiquimod-treated mice.

Sci Rep 2021 May 28;11(1):11265. Epub 2021 May 28.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.

Psoriasis is a chronic, inflammatory skin disease. Although the precise etiology of psoriasis remains unclear, gut-microbiota axis might play a role in the pathogenesis of the disease. Here we investigated whether the composition of microbiota in the intestine and skin is altered in the imiquimod (IMQ)-treated mouse model of psoriasis. Topical application of IMQ to back skin caused significant changes in the composition of microbiota in the intestine and skin of IMQ-treated mice compared to control mice. The LEfSe algorithm identified the species Staphylococcus lentus as potential skin microbial marker for IMQ group. Furthermore, there were correlations for several microbes between the intestine and skin, suggesting a role of skin-gut-microbiota in IMQ-treated mice. Levels of succinic acid and lactic acid in feces from IMQ-treated mice were significantly higher than control mice. Moreover, the predictive functional analysis of the microbiota in the intestine and skin showed that IMQ caused alterations in several KEGG pathways. In conclusion, the current data indicated that topical application with IMQ to skin alters the composition of the microbiota in the gut and skin of host. It is likely that skin-gut microbiota axis plays a role in pathogenesis of psoriasis.
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http://dx.doi.org/10.1038/s41598-021-90480-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163751PMC
May 2021

Abnormalities in the composition of the gut microbiota in mice after repeated administration of DREADD ligands.

Brain Res Bull 2021 Aug 15;173:66-73. Epub 2021 May 15.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. Electronic address:

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are known as genetically modified G-protein-coupled receptors (GPCRs), which can be activated by synthetic ligands such as clozapine N-oxide (CNO) and DREADD agonist 21 (compound 21: C21). The brain-gut-microbiota axis has a crucial role in bidirectional interactions between the brain and the gastrointestinal microbiota. In this study, we investigated whether repeated administration of CNO or C21 could influence the gut microbiota and short-chain fatty acids (SCFAs) in feces of adult mice. Repeated administration of CNO or C21 as drinking water did not alter the α- and β-diversity of gut microbiota in mice compared with control mice. However, we found significant changes in relative abundance for several bacteria in the CNO (or C21) group at the taxonomic level compared to the control group. The linear discriminant analysis effect size (LEfSe) algorithm distinguished the family Prevotellaceae, the genus Anaerocolumna, the genus Prevotella, and the genus Frisingicoccus, these four specific microbial markers for the CNO group relative to the control group. In addition, the LEfSe algorithm identified the family Clostridiaceae, the genus Faecalicatena and the genus Marinisporobacter, these three bacteria of different taxonomic as potential microbial markers for the C21 group relative to the control group. In contrast, repeated administration of CNO (or C21) did not alter SCFAs in feces samples of adult mice. The data suggest that repeated administration of CNO or C21 contributes to an unusual organization of the gut microbiota in adult mice. Therefore, abnormalities in the composition of gut microbiota by repeated dosing of DREADD ligands should be taken into consideration for behavioral and biological functions in rodents treated with DREADD ligands.
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http://dx.doi.org/10.1016/j.brainresbull.2021.05.012DOI Listing
August 2021

Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder.

J Affect Disord 2021 May 3;290:61-64. Epub 2021 May 3.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address:

Background: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF.

Methods: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls.

Results: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples.

Limitations: Sample sizes are relatively low.

Conclusions: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.
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http://dx.doi.org/10.1016/j.jad.2021.04.042DOI Listing
May 2021

Serum levels of glial cell line-derived neurotrophic factor as a biomarker for mood disorders and lithium response.

Psychiatry Res 2021 Apr 27;301:113967. Epub 2021 Apr 27.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.
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http://dx.doi.org/10.1016/j.psychres.2021.113967DOI Listing
April 2021

Intranasal administration of transforming growth factor-β1 elicits rapid-acting antidepressant-like effects in a chronic social defeat stress model: A role of TrkB signaling.

Eur Neuropsychopharmacol 2021 May 7;50:55-63. Epub 2021 May 7.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan. Electronic address:

(R,S)-ketamine causes rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression although the precise molecular mechanisms underlying its antidepressant action remain unclear. We recently reported that transforming growth factor (TGF)-β1 might contribute to the antidepressant-like effects of (R)-ketamine that is a more potent enantiomer in rodents. Although TrkB signaling plays a role in the antidepressant-like actions of (R,S)-ketamine and its enantiomers, the role of TrkB signaling in the antidepressant effects of TGF-β1 remains unclear. Using behavioral tests such as tail-suspension test (TST), forced swimming test (FST), and 1% sucrose preference test (SPT), we investigated whether a single intranasal administration of the recombinant TGF-β1 (1.5 and 3.0 μg/kg) causes rapid and sustained antidepressant-like effects in a chronic social defeat stress (CSDS) model. Both doses of TGF-β1 significantly attenuated the increased immobility time of TST and FST in the CSDS susceptible mice. High dose of TGF-β1, but not low dose, significantly ameliorated the decreased sucrose preference of SPT in the CSDS susceptible mice. Pretreatment with a TrkB antagonist ANA-12 (0.5 mg/kg) blocked the antidepressant-like effects of TGF-β1 in CSDS susceptible mice. The data suggest that intranasal administration of TGF-β1 could elicit rapid-acting antidepressant-like effects via TrkB stimulation in a CSDS model. Therefore, it is likely that intranasal administration of TGF-β1 would be a novel therapeutic approach for depression.
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http://dx.doi.org/10.1016/j.euroneuro.2021.04.010DOI Listing
May 2021

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of (R,S)-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain-gut-microbiota axis and brain-spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
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http://dx.doi.org/10.1038/s41380-021-01121-1DOI Listing
May 2021

Impact of Mammalian Two-Pore Channel Inhibitors on Long-Distance Electrical Signals in the Characean Macroalga and the Early Terrestrial Liverwort .

Plants (Basel) 2021 Mar 29;10(4). Epub 2021 Mar 29.

Department of Plant Physiology and Biophysics, Faculty of Biology and Biotechnology, Institute of Biological Sciences, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin, Poland.

Inhibitors of human two-pore channels (TPC1 and TPC2), i.e., verapamil, tetrandrine, and NED-19, are promising medicines used in treatment of serious diseases. In the present study, the impact of these substances on action potentials (APs) and vacuolar channel activity was examined in the aquatic characean algae and in the terrestrial liverwort . In both plant species, verapamil (20-300 µM) caused reduction of AP amplitudes, indicating impaired Ca transport. In , it depolarized the AP excitation threshold and resting potential and prolonged AP duration. In isolated vacuoles of , verapamil caused a reduction of the open probability of slow vacuolar SV/TPC channels but had almost no effect on K channels in the tonoplast of In both species, tetrandrine (20-100 µM) evoked a pleiotropic effect reduction of resting potential and AP amplitudes and prolongation of AP repolarization phases, especially in but it did not alter vacuolar SV/TPC activity. NED-19 (75 µM) caused both specific and unspecific effects on APs. In , NED-19 increased the duration of repolarization. However, no inhibition of SV/TPC channels was observed in vacuoles, but an increase in open probability and channel flickering. The results indicate an effect on Ca -permeable channels governing plant excitation.
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http://dx.doi.org/10.3390/plants10040647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067100PMC
March 2021

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.

Eur Urol 2021 May 5;79(5):665-673. Epub 2021 Mar 5.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.

Objective: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.

Design, Setting, And Participants: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.

Intervention: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.

Outcome Measurements And Statistical Analysis: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.

Results And Limitations: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.

Conclusions: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.

Patient Summary: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.
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http://dx.doi.org/10.1016/j.eururo.2021.01.003DOI Listing
May 2021

Less Social Support for Patients With COVID-19: Comparison With the Experience of Nurses.

Front Psychiatry 2021 1;12:554435. Epub 2021 Feb 1.

Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Since December 2019, more than 80,000 patients have been diagnosed with coronavirus disease 2019 (COVID-19) in China. Social support status of COVID-19 patients, especially the impact of social support on their psychological status and quality of life, needs to be addressed with increasing concern. In this study, we used social support rating scale (SSRS) to investigate the social support in COVID-19 patients and nurses. The present study included 186 COVID-19 patients at a Wuhan mobile cabin hospital and 234 nurses at a Wuhan COVID-19 control center. Responses to a mobile phone app-based questionnaire about social support, anxiety, depression, and quality of life were recorded and evaluated. COVID-19 patients scored significantly lower than nurses did on the Social Support Rating Scale (SSRS). Among these patients, 33.9% had anxiety symptoms, while 23.7% had depression symptoms. Overall SSRS, subjective social support scores and objective support scores of patients with anxiety were lower than those of patients without anxiety. This result was also found in depression. In addition, all dimensions of social support were positively correlated with quality of life. Interestingly, in all dimensions of social support, subjective support was found to be an independent predictive factor for anxiety, depression, and quality of life, whereas objective support was a predictive factor for quality of life, but not for anxiety and depression via regression analysis. Medical staffs should pay attention to the subjective feelings of patients and make COVID-19 patients feel respected, supported, and understood from the perspective of subjective support, which may greatly benefit patients, alleviate their anxiety and depression, and improve their quality of life.
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http://dx.doi.org/10.3389/fpsyt.2021.554435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901979PMC
February 2021

Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents.

Transl Psychiatry 2021 Feb 24;11(1):140. Epub 2021 Feb 24.

Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China.

The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.
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http://dx.doi.org/10.1038/s41398-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904924PMC
February 2021

Dextran sulfate sodium-induced inflammation and colitis in mice are ameliorated by (R)-ketamine, but not (S)-ketamine: A role of TrkB signaling.

Eur J Pharmacol 2021 Apr 19;897:173954. Epub 2021 Feb 19.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. Electronic address:

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that causes long-lasting inflammation and colitis in the gastrointestinal tract. Depression is a common symptom in patients with UC. (R)-ketamine is a new safer antidepressant than (R,S)-ketamine and (S)-ketamine. Here, we examined the effects of two ketamine enantiomers on the dextran sulfate sodium (DSS)-induced colitis model of UC. Ingestion of 3% DSS in drinking water for 14 days increased the scores of Disease Activity Index (DAI) in mice. Repeated administration of (R)-ketamine (10 mg/kg/day, 14 days or last 7 days), but not (S)-ketamine (10 mg/kg/day, 14 days or last 7 days), significantly ameliorated the increased DAI score and increased blood levels of interleukin-6 (IL-6) in DSS-treated mice. In addition, (R)-ketamine, but not (S)-ketamine, attenuated the reduced colonic length in DSS-treated mice. Furthermore, DSS-induced increased DAI score and blood IL-6 levels were significantly ameliorated after subsequent repeated administration of (R)-ketamine (10 mg/kg/day for last 7 days), but not 5-aminosalicyclic acid (50 mg/kg/day for last 7 days). Moreover, the pretreatment with a tropomyosin-receptor-kinase B (TrkB) antagonist ANA-12 (0.5 mg/kg) significantly blocked the beneficial effects of (R)-ketamine in DSS-induced UC model. The study shows that (R)-ketamine can produce beneficial effects in DSS-induced colitis model through TrkB stimulation. Therefore, (R)-ketamine may be a novel therapeutic drug for inflammatory bowel diseases such as UC.
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http://dx.doi.org/10.1016/j.ejphar.2021.173954DOI Listing
April 2021

Perception of and anxiety about COVID-19 infection and risk behaviors for spreading infection: an international comparison.

Ann Gen Psychiatry 2021 Feb 18;20(1):13. Epub 2021 Feb 18.

Center for Forensic Mental Health, Chiba University, 260-8670 Inohana 1-8-1, Chuo-ku, Chiba, Japan.

Background: To control the spread of the new SARS-CoV-2 infection's disease (COVID-19), appropriate precautionary behaviors by the public should be promoted. There are international differences in public cognitive and behavioral pattern, attitudes toward information sources, and anxiety about COVID-19. Information about these differences could increase understanding of the patterns of epidemic-related anxiety and behavior, and would help optimize future policies for preventing the next wave of the epidemic.

Methods: To examine between-country differences in perception, attitude, and precautionary behaviors toward COVID-19, we conducted a cross-sectional study using an online questionnaire survey. Participants were adults who had been registered in Cross Marketing Group Inc. and living in the UK, Spain, or Japan. A total of 8,000 people stratified by age were recruited on a first-come, first-serve basis. Knowledge of and anxiety about COVID-19, the frequency of access and perceived credibility of several information sources, and the frequency of each precautionary behavior were examined on March 27-28, 2020, in Japan and April 17-21, 2020, in the UK and Spain.

Results: Knowledge, anxiety, and the frequency of precautionary behaviors were higher in the UK and Spain than in Japan. Participants with infected acquaintances were more concerned about COVID-19. However, participants in the UK rarely wore a medical mask. Participants in the UK and Spain were more eager to obtain information about COVID-19 than those in Japan. Participants in Spain tended not to trust official information and to believe specialists' comments instead.

Conclusion: The rapidity of the spread of COVID-19, cultural background, and recent political situations seemed to contribute to the international differences here.
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http://dx.doi.org/10.1186/s12991-021-00334-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890773PMC
February 2021

Reduction of dopamine and glycogen synthase kinase-3 signaling in rat striatum after continuous administration of haloperidol.

Pharmacol Biochem Behav 2021 Mar 22;202:173114. Epub 2021 Jan 22.

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

Background: Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats.

Methods: Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions.

Results: In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/β and an increase in the pGSK-3β/GSK-3β ratio, whereas AKT was not changed.

Conclusions: Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS.
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http://dx.doi.org/10.1016/j.pbb.2021.173114DOI Listing
March 2021

Reply to Reeves and Dunn: Risk for autism in offspring after maternal glyphosate exposure.

Proc Natl Acad Sci U S A 2021 01;118(2)

Department of Entomology and Nematology, University of California, Davis, CA 95616.

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http://dx.doi.org/10.1073/pnas.2016496118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812790PMC
January 2021

Neural rhythm in the retrosplenial cortex during ketamine-induced dissociation.

Authors:
Kenji Hashimoto

Eur Arch Psychiatry Clin Neurosci 2021 Apr 12;271(3):583-585. Epub 2021 Jan 12.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan.

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http://dx.doi.org/10.1007/s00406-020-01226-8DOI Listing
April 2021

Effects of repeated electroconvulsive shocks on dopamine supersensitivity psychosis model rats.

Schizophr Res 2021 02 8;228:1-6. Epub 2021 Jan 8.

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

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.
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http://dx.doi.org/10.1016/j.schres.2020.11.062DOI Listing
February 2021

A role of the subdiaphragmatic vagus nerve in depression-like phenotypes in mice after fecal microbiota transplantation from Chrna7 knock-out mice with depression-like phenotypes.

Brain Behav Immun 2021 05 8;94:318-326. Epub 2021 Jan 8.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan. Electronic address:

The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR: coded by Chrna7) regulates the cholinergic ascending anti-inflammatory pathway involved in depression. We previously reported that Chrna7 knock-out (KO) mice show depression-like phenotypes through systemic inflammation. In this study, we investigated whether fecal microbiota transplantation (FMT) from Chrna7 KO mice causes depression-like phenotypes in mice treated with an antibiotic cocktail (ABX). Chrna7 KO mice with depression-like phenotypes show an abnormal gut microbiota composition, although the alpha diversity and beta diversity were not altered. FMT from Chrna7 KO mice caused depression-like phenotypes, systemic inflammation, and downregulation of synaptic proteins in the prefrontal cortex (PFC) in the ABX-treated mice compared to FMT from the control mice. The Principal component analysis based on the OTU level showed that the FMT group from the KO mice were different from the FMT group from the control mice. We found differences in abundance for several bacteria in the FMT group from the KO mice at the taxonomic level when compared with the other group. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of depression-like phenotypes in the ABX-treated mice after FMT from Chrna7 KO mice. These data suggest that FMT from Chrna7 KO mice produce depression-like phenotypes in ABX-treated mice via the subdiaphragmatic vagus nerve. The brain-gut-microbiota axis association with the subdiaphragmatic vagus nerve plays an important role in the development of depression.
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http://dx.doi.org/10.1016/j.bbi.2020.12.032DOI Listing
May 2021

Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor.

Authors:
Kenji Hashimoto

Eur Arch Psychiatry Clin Neurosci 2021 Mar 5;271(2):249-258. Epub 2021 Jan 5.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan.

The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein-protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication. Interestingly, a recent clinical trial demonstrated that treatment with the antidepressant fluvoxamine, which has a high affinity at the sigma-1 receptor, could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In this review, we discuss the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells. Here, we propose repurposing of traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients. Finally, we discussed the potential of other CNS candidates such as cutamesine and arketamine.
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http://dx.doi.org/10.1007/s00406-020-01231-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785036PMC
March 2021

Association between serum levels of glial cell line-derived neurotrophic factor and inattention in adult patients with attention deficits/hyperactivity disorder.

Psychiatry Res 2021 Feb 29;296:113674. Epub 2020 Dec 29.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Child Psychiatry, Chiba University Hospital, Chiba, Japan; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Glial cell line-derived neurotrophic factor (GDNF) may play an important role in attention. We investigated the association between serum GDNF levels and clinical status in unmedicated adults with attention deficit/hyperactivity disorder (ADHD) (n = 16) and healthy controls (n = 33); the levels were comparable between the ADHD and control groups (107.2 ± 31.7 vs. 110.5 ± 40.0 pg/mL, respectively; p = 0.77). In the ADHD group, higher GDNF serum levels were associated with severe subjective inattention (r = 0.528, p = 0.035). These preliminary results suggest that the serum GDNF level may not be a suitable biomarker for adult ADHD, although it may be associated with the pathophysiology of persistent inattention in adult ADHD.
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http://dx.doi.org/10.1016/j.psychres.2020.113674DOI Listing
February 2021

Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder.

J Psychiatr Res 2021 02 21;134:48-56. Epub 2020 Dec 21.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address:

Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.051DOI Listing
February 2021

Symptom Under-Recognition of Atrial Fibrillation Patients in Consideration for Catheter Ablation: A Report From the KiCS-AF Registry.

JACC Clin Electrophysiol 2021 05 24;7(5):565-574. Epub 2020 Dec 24.

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

Objectives: This study sought to investigate whether symptom under-recognition is associated with the application of catheter ablation.

Background: Atrial fibrillation (AF) symptom burden is frequently under-recognized and may affect the choice of treatment strategies.

Methods: A total of 3,276 patients with AF consecutively registered in a Japanese multicenter database from 2012 to 2017 were analyzed. All patients underwent AF symptom burden assessment via the symptom and daily activities domain within the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. For the present analysis, 1,173 symptomatic patients (AFEQT score ≤80) with a clinical indication for catheter ablation were included. Under-recognition of symptom burden was defined as no subjective complaints checked by physicians despite self-reported AFEQT scores ≤80. Logistic regression analysis identified the predictors associated with receiving catheter ablation.

Results: Of the 1,173 patients (age: 68 ± 12 years, men: 61%) analyzed, 459 underwent catheter ablation (ablation group); they had lower overall AFEQT scores (p < 0.01 for all domains) compared with the nonablation group. At the 1-year follow-up, greater improvement in the AFEQT scores was noted in the ablation group, even after adjusting for clinically relevant factors (+20.0 ± 1.2, +14.2 ± 0.9, respectively; p < 0.001). Notably, 306 (28%) patients met the criteria for symptom under-recognition, which was associated with the nonuse of catheter ablation during follow-up (odds ratio: 0.41; 95% confidence interval: 0.28 to 0.60; p < 0.001).

Conclusions: Under-recognition of AF symptom burden was frequently noted and was associated with less use of catheter ablation. Standardized recognition of symptoms using the application of validated questionnaires may facilitate outcome improvement.
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http://dx.doi.org/10.1016/j.jacep.2020.10.016DOI Listing
May 2021

Multicolour chemical imaging of plant tissues with hyperspectral stimulated Raman scattering microscopy.

Analyst 2021 Feb;146(4):1234-1238

Department of Electrical Engineering and Information Systems, The University of Tokyo, Tokyo 113-8656, Japan.

Recent development of stimulated Raman scattering (SRS) microscopy allows for label-free biological imaging with chemical specificity based on molecular-vibrational signatures. In particular, hyperspectral SRS imaging can acquire a molecular-vibrational spectrum at each pixel, allowing us not only to investigate the spectral difference of various biological molecules but also to discriminate different constituents based on their spectral difference. However, the number of constituents discriminated in previous label-free SRS imaging was limited to four because of the subtleness of spectral difference. Here, we report hyperspectral SRS imaging of plant tissues including leaves of Camellia japonica, roots of Arabidopsis thaliana, and thalli of a liverwort Marchantia polymorpha L. We show that SRS can discriminate as many as six components in Marchantia polymorpha L. without labeling. Our results demonstrate the effectiveness of hyperspectral SRS imaging as a tool for label-free multicolour imaging analysis of various biomolecules in plant tissues.
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http://dx.doi.org/10.1039/d0an02181dDOI Listing
February 2021

Corrigendum to "Prophylactic Effects of Sulforaphane on Depression-Like Behavior and Dendritic Changes in Mice After Inflammation" [Journal of Nutritional Biochemistry; 39(2017); 134-144].

J Nutr Biochem 2021 Mar 18;89:108562. Epub 2020 Dec 18.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jnutbio.2020.108562DOI Listing
March 2021

Corrigendum to "Prophylactic Effects of Sulforaphane on Depression-Like Behavior and Dendritic Changes in Mice After Inflammation" Journal of Nutritional Biochemistry 39 (2017) 134-144.

J Nutr Biochem 2021 Feb 23;88:108550. Epub 2020 Nov 23.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jnutbio.2020.108550DOI Listing
February 2021

Rapid-acting and long-lasting antidepressant-like action of (R)-ketamine in Nrf2 knock-out mice: a role of TrkB signaling.

Eur Arch Psychiatry Clin Neurosci 2021 Apr 12;271(3):439-446. Epub 2020 Nov 12.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.

The transcription nuclear factor-erythroid factor 2-related factor 2 (Nrf2) plays a key role in inflammation that is involved in depression. We previously reported that Nrf2 knock-out (KO) mice exhibit depression-like phenotypes through systemic inflammation. (R)-ketamine, an enantiomer of ketamine, has rapid-acting and long-lasting antidepressant-like effects in rodents. We investigated whether (R)-ketamine can produce antidepressant-like effects in Nrf2 KO mice. Effects of (R)-ketamine on the depression-like phenotypes in Nrf2 KO mice were examined. Furthermore, the role of TrkB in the antidepressant-like actions of (R)-ketamine was also examined. In the tail-suspension test (TST) and forced swimming test (FST), (R)-ketamine (10 mg/kg) significantly attenuated the increased immobility times of TST and FST in the Nrf2 KO mice. In the sucrose preference test (SPT), (R)-ketamine significantly ameliorated the reduced preference of SPT in Nrf2 KO mice. Decreased expression of synaptic proteins (i.e., GluA1 and PSD-95) in the medial prefrontal cortex (mPFC) of Nrf2 KO mice was significantly ameliorated after a single injection of (R)-ketamine. Furthermore, the pre-treatment with the TrkB antagonist ANA-12 (0.5 mg/kg) significantly blocked the rapid and long-lasting antidepressant-like effects of (R)-ketamine in Nrf2 KO mice. Furthermore, ANA-12 significantly antagonized the beneficial effects of (R)-ketamine on decreased expression of synaptic proteins in the mPFC of Nrf2 KO mice. These findings suggest that (R)-ketamine can produce rapid and long-lasting antidepressant-like actions in Nrf2 KO mice via TrkB signaling.
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http://dx.doi.org/10.1007/s00406-020-01208-wDOI Listing
April 2021

Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.

Cancer Cell 2020 12 5;38(6):803-817.e4. Epub 2020 Nov 5.

Vanderbilt University Medical Center, Nashville, TN, USA.

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.
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http://dx.doi.org/10.1016/j.ccell.2020.10.011DOI Listing
December 2020

Anatomical changes in the pulmonary veins and left atrium after cryoballoon ablation.

Pacing Clin Electrophysiol 2020 11 21;43(11):1289-1294. Epub 2020 Oct 21.

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

Background: The anatomical changes in pulmonary veins (PVs) after cryoballoon ablation (CBA) are unclear. We aimed to determine the morphological changes in the PVs and left atrium (LA) along with the predictive factors for clinical PV stenosis.

Methods: We analyzed data of 320 PVs from 80 patients who underwent CBA for atrial fibrillation (age: 62 ± 10 years, 59 males). All patients underwent pre- and post-procedural cardiac computed tomography. We defined clinical PV stenosis when the cross-sectional area decreased by more than 50%.

Results: The average ostial PV area and LA volume decreased significantly after CBA (pre- vs post-CBA; 2.4 ± 1.0 cm vs 2.3±1.1 cm , P < .001, 75.0 ± 23.2 cm vs 70.7 ± 21.9 cm , P < .001, respectively). There was a significant correlation between the reduction rates of the PV area and those of LA volume (R = 0.411, P < .001). The larger preoperative PV area and greater reduction in LA volume were associated with advanced PV narrowing. Clinical PV stenosis was observed in six PVs, was more common in females (male vs female; 0.8% vs 4.8%, P = .043), and tended to be more frequent in left PVs (left PVs vs right PVs; 3.1% vs 0.6%: P = .107), irrespective of the LA volume reduction.

Conclusions: The significant reduction of the ostial PV area occurred after CBA, which correlated with the reduction rate of LA volume. The narrowing of the PV was partly produced by the LA volume reduction. Clinical PV stenosis was more common in females and tended to be more frequent in left PVs.
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http://dx.doi.org/10.1111/pace.14092DOI Listing
November 2020

Lack of rewarding effects of a soluble epoxide hydrolase inhibitor TPPU in mice: Comparison with morphine.

Neuropsychopharmacol Rep 2020 12 7;40(4):412-416. Epub 2020 Sep 7.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Aim: Although opioids have been used as treatment of neuropathic pain, opioids have abuse potential in humans. Since soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids plays a key role in the pain, sEH inhibitors would be promising new therapeutic drugs for neuropathic pain. In this study, we examined the effect of the sEH inhibitor TPPU on rewarding effects in mice using the conditioned place preference (CPP) paradigm.

Methods: The rewarding effects of morphine (10 mg/kg) and TPPU (3, 10, or 30 mg/kg) in mice were examined using CPP paradigm. Furthermore, the effect of TPPU (30 mg/kg) on morphine-induced rewarding effects was examined.

Results: TPPU (3, 10, or 30 mg/kg) did not increase CPP scores in the mice whereas morphine significantly increased CPP scores in the mice. Furthermore, pretreatment with TPPU did not block the rewarding effects of morphine in the mice, suggesting that sEH does not play a role in the rewarding effect of morphine.

Conclusion: This study suggests that TPPU did not have rewarding effects in rodents. This would make sEH inhibitors potential therapeutic drugs without abuse potential for neuropathic pain.
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http://dx.doi.org/10.1002/npr2.12136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722641PMC
December 2020