Publications by authors named "Akihiro Yamada"

118 Publications

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

Muscle Nerve 2021 Oct 12. Epub 2021 Oct 12.

Parexel International, Baltimore, MD, USA.

Introduction/aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates PPARδ to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. Objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo; study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.

Results: A total of 64 (single dose cohort) and 37 (multiple dose cohort) participants were included. Following single doses of 1-120 mg, ASP0367 was rapidly absorbed with median time to maximum plasma concentration (t ) of 1.50-2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, t was delayed 1.7 hours. Following multiple once-daily doses, mean half-life of ASP0367 10-75 mg ranged from 14.1-17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed following repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild-to-moderate in severity; none were deemed drug-related. No clinically significant changes were observed on laboratory or electrocardiography evaluations. Treatment- and dose-dependent upregulation of six PPARδ target genes were observed with single and multiple doses of ASP0367.

Discussion: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.
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http://dx.doi.org/10.1002/mus.27436DOI Listing
October 2021

FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan.

EMBO Rep 2021 Sep 13:e52584. Epub 2021 Sep 13.

Department of Microbiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Xenophagy, also known as antibacterial selective autophagy, degrades invading bacterial pathogens such as group A Streptococcus (GAS) to defend cells. Although invading bacteria are known to be marked with ubiquitin and selectively targeted by xenophagy, how ubiquitin ligases recognize invading bacteria is poorly understood. Here, we show that FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS. FBXO2 targets cytosolic GAS through its sugar-binding motif and GlcNAc expression on the GAS surface. FBXO2 knockout resulted in decreased ubiquitin accumulation on intracellular GAS and xenophagic degradation of bacteria. Furthermore, SCF components such as SKP1, CUL1, and ROC1 are required for ubiquitin-mediated xenophagy against GAS. Thus, SCF recognizes GlcNAc residues of GAS surface carbohydrates and functions in ubiquitination during xenophagy.
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http://dx.doi.org/10.15252/embr.202152584DOI Listing
September 2021

Risk of Colorectal Cancer in Serrated Polyposis Syndrome: A Systematic Review and Meta-analysis.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago Medicine, Chicago, Illinois. Electronic address:

Background & Aims: Serrated polyposis syndrome (SPS) is characterized by development of numerous serrated lesions throughout the colorectum and increased risk of colorectal cancer (CRC). However, SPS has been an underrecognized CRC predisposition syndrome, and the true risk of CRC in SPS, both overall and in surveillance, is not known. The aim of this systematic review and meta-analysis is to describe the risk of CRC in patients with SPS.

Methods: Electronic databases were searched on March 25, 2021, for studies describing CRC risk in SPS. Random-effects meta-analysis was performed to assess pooled risk of CRC among SPS patients. Primary outcomes were risk of CRC at time of SPS diagnosis and during surveillance following diagnosis of SPS. Secondary outcomes included risk of CRC prior to diagnosis of SPS and effect of World Health Organization subtype on CRC risk.

Results: Thirty-six studies including 2788 patients with SPS were included in the analysis. Overall risk of CRC in SPS was 19.9% (95% confidence interval [CI], 15.3%-24.5%). CRC risk at the time of diagnosis was 14.7% (95% CI, 11.4%-18.8%), while risk during surveillance was 2.8% (95% CI, 1.8%-4.4%), or 7 cases per 1000 person-years. SPS patients also had a high incidence of history of CRC prior to SPS diagnosis (7.0%; 95% CI, 4.6%-11.7). Subgroup analysis did not reveal any significant differences based on World Health Organization subtype.

Conclusions: Our meta-analysis demonstrated that patients with SPS have an elevated risk of CRC, which is highest at the time of diagnosis and suggests the importance of early SPS recognition and screening to modify CRC risk. The persistently elevated CRC risk during surveillance supports current guidelines recommending heightened surveillance protocols.
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http://dx.doi.org/10.1016/j.cgh.2021.05.057DOI Listing
June 2021

Electrophysiological properties of maxillary trigeminal Aβ-afferent neurons of rats.

Mol Pain 2021 Jan-Dec;17:17448069211021271

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Aβ-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in orofacial regions. However, electrophysiological properties of these V2 trigeminal Aβ-afferent neurons have not been well characterized so far. Here, we used rat trigeminal nerve preparations and applied patch-clamp recordings to large-sized V2 TG neurons to characterize their electrophysiological properties. All the cells recorded had afferent conduction velocities in the range of Aβ-afferent conduction speeds. However, these V2 trigeminal Aβ-afferent neurons displayed different action potential (AP) properties. APs showed fast kinetics in some cells but slow kinetics with shoulders in repolarization phases in other cells. Based on the derivatives of voltages in AP repolarization with time (dV/dt), we classified V2 trigeminal Aβ-afferent neurons into four types: type I, type II, type IIIa and type IIIb. Type I V2 trigeminal Aβ-afferent neurons had the largest dV/dt of repolarization, the fastest AP conduction velocities, the shortest AP and afterhyperpolarization (AHP) durations, and the highest AP success rates. In contrast, type IIIb V2 trigeminal Aβ-afferent neurons had the smallest dV/dt of AP repolarization, the slowest AP conduction velocities, the longest AP and AHP durations, and the lowest AP success rates. The type IIIb cells also had significantly lower voltage-activated K currents. For type II and type IIIa V2 trigeminal Aβ-afferent neurons, AP parameters were in the range between those of type I and type IIIb V2 trigeminal Aβ-afferent neurons. Our electrophysiological classification of V2 trigeminal Aβ-afferent neurons may be useful in future to study their non-nociceptive and nociceptive functions in orofacial regions.
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http://dx.doi.org/10.1177/17448069211021271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168172PMC
May 2021

Predictability of simple endoscopic score for Crohn's disease for postoperative outcomes in Crohn's disease.

J Gastroenterol Hepatol 2021 Oct 19;36(10):2785-2793. Epub 2021 May 19.

Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA.

Background And Aim: Approximately half of patients with Crohn's disease (CD) who have surgery will experience clinical recurrence within 10 years of their surgery. This study aimed to assess the postoperative outcomes according to disease location and validated the simple endoscopic score for CD (SES-CD) to predict disease-related outcomes.

Methods: We retrospectively assessed medical records of CD patients who underwent ileocolonoscopy within 12 months after surgery at the University of Chicago between 2005 and 2016. We defined patients with postoperative colonic inflammation at the first postoperative ileocolonoscopy or had Montreal classification L2 as colon-dominant disease and patients without colonic involvement or who had L1 as small intestine (SI)-dominant disease. The outcomes included clinical and surgical recurrence.

Results: Among 207 CD patients, 51 (24.6%) and 156 (75.4%) patients had colon-dominant and SI-dominant disease, respectively. Patients with colon-dominant disease had a greater risk of postoperative clinical recurrence compared with those with SI-dominant disease (P = 0.018). Colon-dominant disease was a risk of earlier surgical recurrence compared with SI-dominant disease, although there were no significant differences in the recurrence-free survivals. SES-CD > 2 at the first postoperative ileocolonoscopy was a significant risk of clinical recurrence on log-rank test (P < 0.001) and Cox proportional hazards model (hazard ratio = 2.25; 95% confidence interval = 1.14-4.47; P = 0.020). An SES-CD of 1 was an appropriate cut-off to predict the clinical recurrence of SI-dominant disease, but a higher SES-CD cut-off value of 5 was required for colon-dominant disease.

Conclusions: We demonstrated that SES-CD predicts postoperative clinical recurrence of CD, regardless of disease location.
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http://dx.doi.org/10.1111/jgh.15540DOI Listing
October 2021

Hemolysis and von Willebrand factor degradation in mechanical shuttle shear flow tester.

J Artif Organs 2021 Jun 9;24(2):111-119. Epub 2021 Feb 9.

Department of Preclinical Evaluation, Pre-Clinical Research Center, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Chronic blood trauma caused by the shear stresses generated by mechanical circulatory support (MCS) systems is one of the major concerns to be considered during the development of ventricular assist devices. Large multimers with high-molecular-weight von Willebrand factor (VWF) are extended by the fluid forces in a shear flow and are cleaved by ADAMTS13. Since the mechanical revolving motions in artificial MCSs induce cleavage in large VWF multimers, nonsurgical bleeding associated with the MCS is likely to occur after mechanical hemodynamic support. In this study, the shear stress (~ 600 Pa) and exposure time related to hemolysis and VWF degradation were investigated using a newly designed mechanical shuttle shear flow tester. The device consisted of a pair of cylinders facing the test section of a small-sized pipe; both the cylinders were connected to composite mechanical heads with a sliding-sleeve structure for axial separation during the withdrawing motion. The influence of exposure time, in terms of the number of stress cycles, on hemolysis and VWF degradation was confirmed using fresh goat blood, and the differences in the rates of dissipation of the multimers were established. The plasma-free hemoglobin levels showed a logarithmic increase corresponding to the number of cycles, and the dissipation of large VWF multimers occurred within a few seconds under high shear stress flow conditions.
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http://dx.doi.org/10.1007/s10047-020-01219-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154843PMC
June 2021

The Correlation between Vitamin D Levels and the Risk of Postoperative Recurrence in Crohn's Disease.

Digestion 2021 8;102(5):767-775. Epub 2021 Feb 8.

Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA,

Background And Aims: Vitamin D deficiency has been associated with disease activity in Crohn's disease (CD). We assessed whether there is a correlation between vitamin D levels and the risk of postoperative recurrence in CD.

Methods: CD patients who underwent surgery were identified from a prospectively maintained database at the University of Chicago. The primary endpoint was the correlation of serum 25-hydroxy vitamin D levels measured at 6-12 months after surgery and the proportion of patients in endoscopic remission, defined as a simple endoscopic score for CD of 0. Clinical, biological (C-reactive protein), and histologic recurrences were also studied.

Results: Among a total of 89 patients, 17, 46, and 26 patients had vitamin D levels of <15, 15-30, and >30 ng/mL, respectively. Patients with higher vitamin D levels were significantly more likely to be in endoscopic remission compared to those with lower levels (23, 42, and 67% in ascending tertile order; p = 0.028). On multivariate analysis, vitamin D >30 ng/mL (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.07-0.66, p = 0.006) and anti-tumor necrosis factor agent treatment (OR 0.25, 95% CI 0.08-0.83, p = 0.01) were associated with reduced risk of endoscopic recurrence. Rates of clinical, biological, and histologic remission trended to be higher in patients with higher vitamin D levels (p = 0.17, 0.55, 0.062, respectively).

Conclusion: In the present study, higher vitamin D level was associated with lower risk of postoperative endoscopic CD recurrence. Further, studies are warranted to assess the role of vitamin D in postoperative CD recurrence.
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http://dx.doi.org/10.1159/000513589DOI Listing
September 2021

Kv4.3 Channel Dysfunction Contributes to Trigeminal Neuropathic Pain Manifested with Orofacial Cold Hypersensitivity in Rats.

J Neurosci 2021 03 20;41(10):2091-2105. Epub 2021 Jan 20.

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294

Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain. Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.
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http://dx.doi.org/10.1523/JNEUROSCI.2036-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018767PMC
March 2021

Rituximab used for simultaneous treatment of PR3-ANCA positive vasculitis associated with rheumatoid arthritis: A case report.

Clin Case Rep 2020 Dec 26;8(12):2716-2720. Epub 2020 Aug 26.

Center for Rheumatic Diseases Dohgo Spa Hospital Matsuyama Japan.

We treated PR3-ANCA positive vasculitis in a patient diagnosed with rheumatoid arthritis using rituximab. Monoclonal antibody therapy can be used to simultaneous treat more than one collagen disease in such patients. This suggests that shared pathogenic pathways exist between different collagen diseases.
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http://dx.doi.org/10.1002/ccr3.3258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752559PMC
December 2020

Correction to: Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex.

Mol Brain 2020 Nov 13;13(1):152. Epub 2020 Nov 13.

Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13041-020-00692-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664103PMC
November 2020

Diagnosis System for Swallowing and Peristalsis Function for Artificial Tongue and Esophagus Development.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5128-5131

With the progress of surgical technology, the survival rate after resection of esophageal and tongue carcinomas has improved. However, the surgical protocol for esophageal and tongue surgery is complex, and surgery for elderly esophageal and tongue carcinoma patients with cardiopulmonary dysfunction is difficult. Using an artificial tongue and esophagus will be helpful for patients. However, peristalsis of foods depends on food size, taste, and viscosity. This study developed and evaluated a new diagnosis machine for drinking and peristalsis motion. Before clinical evaluation, animal experiments were performed on healthy adult goats using a stereo camera. After a feasibility study of the diagnosis system for peristalsis, clinical evaluation was conducted on healthy normal volunteers. We observed no aspiration pneumonia. The foods and drinks tested were safe. There was no mis-swallowing, but the participants' feeling with regard to taste differed. Overall, the results indicated that the quantitative swallowing and peristalsis diagnosis system is safe. Evaluation of the visual imaging and spectral analysis gave us useful information about peristalsis, which will help us design an artificial tongue and esophagus with a good control mechanism in the near future.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176039DOI Listing
July 2020

Evaluation of the Pulse wave in the face for the patients with rotary blood pump (RP) in the Outpatient clinic.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5097-6100

Rotary blood pump (RP) is one of the most important devices in the treatment of profound heart failure and is known to reduce the pulse in the blood pressure waveform, especially when it is used for axial flow. In an outpatient clinic, checking the pulse of a patient implanted with an RP can help diagnose the patient's condition. For that purpose, animal experiments with healthy adult goats implanted with the EVAHEART system were carried out after obtaining ethical committee approval. Visual imaging of the goats' faces was recorded using a video camera. The pulse waves were clearly recorded using the newly developed pulse diagnosis system with video imaging and compared with laser Doppler flowmeter and time series data. Spectral analysis of the time series data showed the usefulness of video imaging from outside the body. Clinical applications are planned, and this newly developed method is expected to be a useful diagnostic method for evaluating the cardiac function in patients implanted with RPs in the future.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175425DOI Listing
July 2020

Modeling Approach for An Aortic Dissection with Endovascular Stenting.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5008-5011

Repair of dissected aorta requires remodeling the structure of the media. Modeling approaches specific to endovascular stenting for aortic dissection have been reported. We created a goat model of descending thoracic aortic dissection and reproduced its morphological characteristics in a mock circulatory system. The purpose of this study was to examine a newly developed aortic stent which was capable of installing to the aortic dissected lesion for biomedical hemodynamics point of view. In this study, we examined the changes in hemodynamics of dissected lesions and the amelioration by endovascular stent intervention. Firstly, we performed animal experiments with the dissected aorta and examined the effects of stenting on volumetric changes in the false lumen. Secondly, we made several types of 3-D stereolithographic dissected aortic models with silicone rubber membrane between the false and the true lumens. Then, the hemodynamic characteristics in each model were evaluated in the pulsatile flow conditions in a mock circulatory system. These modelling approaches enabled the quantitative examination of post-therapeutic effects of stenting followed by elucidating of hemodynamic changes in the vicinity of stents, which may follow the management of clinical amelioration of interventional treatment with aortic stenting.Clinical Relevance- This study represents a modelling approach of the dissected aorta for endovascular intervention using stenting followed by the examination of false lumen volumetric changes resulting in the deterioration of pressure increase in diseased lesions.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176423DOI Listing
July 2020

Safety of nontumor necrosis factor-targeted biologics in the COVID-19 pandemic.

J Med Virol 2021 02 5;93(2):714-716. Epub 2020 Oct 5.

Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/jmv.26528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646662PMC
February 2021

Risk of Cancers in Patients with Pediatric Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.

J Pediatr 2021 02 6;229:102-117.e36. Epub 2020 Sep 6.

Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL. Electronic address:

Objectives: We performed a systematic review and meta-analysis to evaluate the risk of the development of cancers in patients with pediatric-onset inflammatory bowel disease (IBD).

Study Design: A computerized literature search was performed. The primary outcome was the pooled incidence of cancer in studies reporting the risk as a standardized incidence ratio. The secondary outcomes were the pooled incidence rates of all cancers and site-specific cancers including colorectal cancer and hematologic cancers.

Results: Sixty-six studies reporting outcomes in 38 092 patients were included. The pooled standardized incidence ratio for cancer was 2.39 (P < .0001, 95% CI 2.00-2.86) in IBD. The pooled incidence rates for cancer in patients with Crohn's disease (CD) and ulcerative colitis (UC) were 0.014 (95% CI 0.0087-0.021) and 0.031 (95% CI 0.018-0.052), respectively. The pooled incidence rate of colorectal cancer in CD and UC were 0.0075 (95% CI 0.0049-0.011) and 0.020 (95% CI 0.012-0.034), respectively. The pooled rates of hematologic cancers in CD and UC were 0.0061 (95% CI 0.0040-0.0090) and 0.0045 (95% CI 0.0026-0.0079), respectively. Cumulative meta-analyses showed a decreasing trend in the incidence of these cancers in both CD and UC.

Conclusions: Patients with pediatric-onset IBD had an increased risk of cancer development compared with the general population, however, incidence appeared to be decreasing in recent years.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.087DOI Listing
February 2021

Pressure-induced variation of persistent luminescence characteristics in YAlGaO:Ce-M (M = Yb, and Cr) phosphors: opposite trend of trap depth for 4f and 3d metal ions.

Phys Chem Chem Phys 2020 Sep;22(35):19502-19511

Graduate School of Human and Environmental Studies, Kyoto University, Yoshida-nihonmatsu-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Changing the electronic structure of materials by pressure and the accompanying changes in optical properties have attracted scientific interest. We have reported that the energy position of the conduction band (CB) bottom and the crystal field splitting of the Ce3+:5d excited level in Y3Al5-xGaxO12:Ce3+ are changed by applying pressure, which results in the red shifting of the Ce3+:5d → 4f luminescence and the increase of the quenching temperature. We also reported dramatic improvement of the persistent luminescence performance by either Cr3+ or Yb3+ codoping into the Y3Al5-xGaxO12:Ce3+ phosphors. The different trap depths formed by Cr3+ and Yb3+ affect the initial persistent luminescence intensity and the persistent luminescence duration. In this study, the effect of pressure on the persistent luminescence performance was investigated. For the Y3AlGa4O12:Ce3+-Yb3+ phosphor, the slope of persistent luminescence decay curve becomes more gentle with increasing pressure, while for the Y3AlGa4O12:Ce3+-Cr3+ phosphor the slope becomes steeper. These results indicate that the trap depth of Yb3+ becomes deeper and that of Cr3+ becomes shallower with increasing pressure. Based on the pressure-dependence of the luminescence quenching and the trap depth change estimated from the decay slopes, the relative electronic energies of the CB bottom and the Yb2+ (4f14) or Cr2+ (3d4) levels are discussed. The CB bottom energy is increased relative to the ground 1S0 state of Yb2+ with increasing pressure, which results in deepening of the electron trap depth of the Yb2+ state. The opposite tendency of the Cr3+ codoped sample was described by a decreasing tendency of the energy gap between the CB bottom and the Cr2+:eg level, the relative energy level of which is increased by the increase of the crystal field with increasing pressure in the garnet host material, where the electron-trapping Cr2+ ions take the high spin state (t32ge1g) rather than the low-spin state (t42g).
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http://dx.doi.org/10.1039/d0cp03520cDOI Listing
September 2020

The risk of respiratory tract infections and interstitial lung disease with interleukin 12/23 and interleukin 23 antagonists in patients with autoimmune diseases: A systematic review and meta-analysis.

J Am Acad Dermatol 2021 Mar 11;84(3):676-690. Epub 2020 Aug 11.

Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois. Electronic address:

Background: Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL) 12/23 or IL-23 antagonists have been reported in autoimmune diseases.

Objective: To assess the risk of RTIs and noninfectious ILD with these drugs.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials. Risk of RTIs and noninfectious ILD was compared to placebo by Mantel-Haenszel risk difference. We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Noninfectious ILD included ILD, eosinophilic pneumonia, and pneumonitis.

Results: We identified 54 randomized controlled trials including 10,907 patients with 6 IL-12/23 or IL-23 antagonists and 5175 patients with placebo. These drugs significantly increased the risk of RTIs (Mantel-Haenszel risk difference, 0.019; 95% confidence interval, 0.005-0.033; P = .007), which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and noninfectious ILD between 2 groups.

Limitations: Because of the rarity of infectious pneumonia and ILD, sensitivity analysis was required.

Conclusions: The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and noninfectious ILD.
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http://dx.doi.org/10.1016/j.jaad.2020.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417275PMC
March 2021

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Clin Pharmacol Ther 2021 03 14;109(3):605-618. Epub 2020 Aug 14.

Servier, Suresnes, France.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.
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http://dx.doi.org/10.1002/cpt.1987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983940PMC
March 2021

Systemic review and network meta-analysis: Prophylactic antibiotic therapy for spontaneous bacterial peritonitis.

World J Hepatol 2020 May;12(5):239-252

Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, The University of Chicago Medicine, Chicago, IL 60637, United States.

Background: Spontaneous bacterial peritonitis (SBP) is an important prognostic factor for outcomes in patients with cirrhosis. Antibiotic prophylaxis is recommended in patients at high risk for developing SBP, but the choice of antibiotics remains unclear.

Aim: To evaluate the efficacy of various antibiotics for prophylaxis of SBP based on randomized control trials (RCTs).

Methods: Electronic databases were searched through November 2018 for RCTs evaluating the efficacy of therapies for primary or secondary prophylaxis of SBP. The primary outcome was the development of SBP. Sensitivity analyses limited to studies of primary or secondary prophylaxis and studies reported after 2010 were performed. The secondary outcome was the risk of all-cause mortality or transplant. The outcomes were assessed by rank of therapies based on network meta-analyses. Individual meta-analyses were also performed.

Results: Thirteen RCTs (1742 patients) including norfloxacin, ciprofloxacin, rifaximin, trimethoprim-sulfamethoxazole (TMP-SMX), or placebo/no comparator were identified. Individual meta-analyses showed superiority of rifaximin over norfloxacin as well as norfloxacin and TMP-SMX over placebo. Network meta-analysis demonstrated the rank of efficacy in reducing the risk of SBP as: Rifaximin, ciprofloxacin, TMP-SMX, norfloxacin, and placebo/no comparator. Rifaximin ranked highest in sensitivity analyses limited to studies of primary or secondary prophylaxis and studies reported after 2010. Similarly, rifaximin ranked highest in reducing the risk of death/transplant.

Conclusion: The present comprehensive network meta-analysis provides RCT based evidence for superior efficacy of rifaximin compared to other antibiotics for the prophylaxis of SBP and reducing risk of death/transplant. Further RCTs are warranted to confirm our findings.
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http://dx.doi.org/10.4254/wjh.v12.i5.239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280858PMC
May 2020

Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex.

Mol Brain 2020 03 26;13(1):49. Epub 2020 Mar 26.

Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

Anterior cingulate cortex (ACC) plays important roles in sensory perception including pain and itch. Neurons in the ACC receive various neuromodulatory inputs from subcortical structures, including locus coeruleus noradrenaline (LC-NA) neurons. Few studies have been reported about synaptic and behavioral functions of LC-NA projections to the ACC. Using viral-genetic method (AAV-DIO-eYFP) on DBH-cre mice, we found that LC-NA formed synaptic connections to ACC pyramidal cells but not interneurons. This is further supported by the electron microscopic study showing NAergic fibers contact the presynaptic inputs and post-synaptic areas of the pyramidal cells. NA application produced both pre- and post-synaptic potentiation effects in ACC excitatory transmission in vivo and in vitro. Activation of LC-NA projection to the ACC by optogenetic method produced enhancement of excitatory transmission in vitro and induced scratching and behavioral sensitization for mechanical stimulation. Our results demonstrate that LC-NA projections enhance or facilitate brain responses to pain and itch by potentiating glutamatergic synaptic transmissions in the ACC.
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http://dx.doi.org/10.1186/s13041-020-00586-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098117PMC
March 2020

[Effectiveness and limitations of thiopurines as remission maintenance therapy after calcineurin inhibitor treatment in ulcerative colitis].

Nihon Shokakibyo Gakkai Zasshi 2020;117(3):224-229

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center.

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http://dx.doi.org/10.11405/nisshoshi.117.224DOI Listing
May 2020

Efficacy and Safety of Monoclonal Antibodies Against Clostridioides difficile Toxins for Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis.

J Clin Gastroenterol 2021 01;55(1):43-51

Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL.

Background: Clostridioides difficile infection is one of the most common health care-associated infections. To reduce the recurrent Clostridioides difficile infection (rCDI), monoclonal antibodies against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab) were developed. In the present study, we performed a systematic review and meta-analysis to assess their efficacy and safety.

Materials And Methods: An electronic database was searched for relevant randomized controlled trials assessing bezlotoxumab and/or actoxumab. Outcomes included rate of rCDI and adverse events including cardiovascular and gastrointestinal events.

Results: Four randomized controlled trials comparing antitoxin antibodies (n=1916) versus placebo (n=889) were identified. rCDI was significantly reduced by bezlotoxumab plus actoxumab (risk ratio=0.54, 95% confidence interval=0.41-0.70, P<0.001) and bezlotoxumab monotherapy (risk ratio=0.62, 95% confidence interval=0.51-0.76, P<0.001) compared with placebo. Subgroup analysis showed that bezlotoxumab plus actoxumab was remarkably preventive for patients with the following high-risk features: inpatients, vancomycin treatment, and BI/NAP/027 strain. Regarding safety, there was no difference in cardiovascular and gastrointestinal events as well as all-cause mortality between bezlotoxumab-treated patients and placebo.

Conclusions: The results of our meta-analysis demonstrated the effectiveness and safety of bezlotoxumab for the prevention of rCDI. Bezlotoxumab may be a good therapeutic option for severe C. difficile infection rather than mild cases.
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http://dx.doi.org/10.1097/MCG.0000000000001330DOI Listing
January 2021

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn's disease.

J Gastroenterol 2020 Jun 27;55(6):615-626. Epub 2020 Jan 27.

Department of Gastroenterology, Kure Kyosai Hospital, Kure, Japan.

Background: Small bowel stricture is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD.

Methods: Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available.

Results: A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation.

Conclusions: In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD.
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http://dx.doi.org/10.1007/s00535-020-01670-2DOI Listing
June 2020

Cloud Database Construction for the Expressway Design by the use of the Medical Information.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:1448-1451

Your heart rate and blood pressure are respond to the curve, slope, lane width, and road surface friction coefficient of the expressway design. However, no report was reported concerning about the Expressway design from the viewpoint of medical information of the driver until now. To prevent the traffic accident, human factor is of course one of the most important factors. In this study, the Cloud Database Construction for the Expressway Design by the use of the Medical Information had been tried to carry out. HR response and PWV responses had been tried to be analyzed by the sensors in the car during driving. LF, HF and LF/HF of Heart rate variability had been calculated and tagged with expressway information including left and right curve, slope, lane width, and road surface friction coefficient. Furthermore, pulse of the descending aorta had been tried to be recorded from the sensor in a driver seat, so, the pulse wave velocity and blood pressure could be evaluated. Recording system of an Eye movement, pupil diameter, cerebral blood flow, and EEG are now under construction. So, all human driver's data will be combined in the Cloud of the Central office. this method will be useful for the development of the designing method the Expressway in near future.
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http://dx.doi.org/10.1109/EMBC.2019.8856546DOI Listing
July 2019

Roles of the noradrenergic nucleus locus coeruleus and dopaminergic nucleus A11 region as supraspinal defecation centers in rats.

Am J Physiol Gastrointest Liver Physiol 2019 10 28;317(4):G545-G555. Epub 2019 Aug 28.

Department of Basic Veterinary Science, Laboratory of Physiology, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.

We previously demonstrated that administration of norepinephrine, dopamine, and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are released mainly from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles of the noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex. Colorectal motility was measured with a balloon in anesthetized rats. Electrical stimulation of the LC and A11 region increased colorectal pressure only when a GABA receptor antagonist was injected into the lumbosacral spinal cord. The effects of the LC stimulation and A11 region stimulation on colorectal motility were inhibited by antagonists of α1-adrenoceptors and D2-like dopamine receptors injected into the lumbosacral spinal cord, respectively. Spinal injection of a norepinephrine-dopamine reuptake inhibitor augmented the colokinetic effect of LC stimulation. The effect of stimulation of each nucleus was abolished by surgical severing of the parasympathetic pelvic nerves. Our findings demonstrate that activation of descending noradrenergic neurons from the LC and descending dopaminergic neurons from the A11 region causes enhancement of colorectal motility via the lumbosacral defecation center. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers. The present study demonstrates that electrical and chemical stimulations of the locus coeruleus or A11 region augment contractions of the colorectum. The effects of locus coeruleus and A11 stimulations on colorectal motility are due to activation of α1-adrenoceptors and D2-like dopamine receptors in the lumbosacral defecation center, respectively. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.
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http://dx.doi.org/10.1152/ajpgi.00062.2019DOI Listing
October 2019

Systematic review with meta-analysis: risk of new onset IBD with the use of anti-interleukin-17 agents.

Aliment Pharmacol Ther 2019 08 15;50(4):373-385. Epub 2019 Jul 15.

Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, The University of Chicago Medicine, Chicago, Illinois.

Background: New onset IBD has been reported with the use of anti-IL-17 agents, but it remains unclear to what extent this is attributed to treatment or to underlying disease.

Aim: To evaluate the risk of new onset IBD with the use of anti-IL-17 agents METHODS: Electronic databases were searched for randomised controlled trials (RCT) of anti-IL-17 agents (brodalumab, ixekizumab and secukinumab). Risk of new onset IBD was compared to placebo by Mantel-Haenszel (MH) risk difference (RD). Sensitivity analyses including meta-analysis using fixed-effect model, MH and Peto odds ratio and MH risk ratio were performed due to incidence of rare adverse events. The risk of diarrhoea was also assessed due to the possibility of underdiagnosis of IBD.

Results: Thirty-eight RCTs including 16 690 patients treated with anti-IL-17 agents were included. Twelve cases of new onset IBD were reported with anti-IL-17 agents in five studies, whereas no cases were reported with placebo. There was no difference in the risk of developing new onset IBD with anti-IL-17 agents compared to placebo (MH RD 0.00062, 95% CI -0.00072-0.0021, P = 0.35). Sensitivity analyses demonstrated no consistent risk with any method. There was no difference in the risk of diarrhoea (MH RD 0.0013, 95% CI -0.0014-0.0041, P = 0.34).

Conclusions: New onset IBD with the use of anti-IL-17 agents was rare. Interpretation of the results needs caution due to the presence of many zero-event studies.
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http://dx.doi.org/10.1111/apt.15397DOI Listing
August 2019

Risk Factors for Mortality in Pneumonia in Patients with Inflammatory Bowel Disease.

Inflamm Intest Dis 2019 Apr 6;3(4):167-172. Epub 2019 Feb 6.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Background: pneumonia (PJP) is highly fatal once infection is established. In this study, we investigated the risk of PJP mortality in patients with inflammatory bowel disease (IBD).

Methods: We conducted a retrospective observational study of case data from IBD patients who developed PJP, compiled from 17 collaborating institutions. Parameters such as age, sex, medications used, and blood test results were analyzed to identify risk factors for mortality.

Results: The mortality rate among the 28 IBD patients who developed PJP was 17.9%. A low serum albumin level at the start of IBD treatment was identified as a risk factor for mortality and showed the following association with probability of death (): = 1/[1 + exp(-5.5 + 2.4 × Alb). The probability of death exceeded 0.5 when serum albumin was 2.2 g/dL or lower.

Conclusion: Patients with IBD who develop PJP have a high mortality rate and often cannot continue treatment with medication alone. Therefore, it is necessary to pay attention to albumin levels at the start of immunosuppressive therapy when creating a treatment plan.
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http://dx.doi.org/10.1159/000495035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501549PMC
April 2019

Sound velocity of CaSiO perovskite suggests the presence of basaltic crust in the Earth's lower mantle.

Nature 2019 01 9;565(7738):218-221. Epub 2019 Jan 9.

Geodynamics Research Center, Ehime University, Matsuyama, Japan.

Laboratory measurements of sound velocities of high-pressure minerals provide crucial information on the composition and constitution of the deep mantle via comparisons with observed seismic velocities. Calcium silicate (CaSiO) perovskite (CaPv) is a high-pressure phase that occurs at depths greater than about 560 kilometres in the mantle and in the subducting oceanic crust. However, measurements of the sound velocity of CaPv under the pressure and temperature conditions that are present at such depths have not previously been performed, because this phase is unquenchable (that is, it cannot be physically recovered to room conditions) at atmospheric pressure and adequate samples for such measurements are unavailable. Here we report in situ X-ray diffraction and ultrasonic-interferometry sound-velocity measurements at pressures of up to 23 gigapascals and temperatures of up to 1,700 kelvin (similar to the conditions at the bottom of the mantle transition region) using sintered polycrystalline samples of cubic CaPv converted from bulk glass and a multianvil apparatus. We find that cubic CaPv has a shear modulus of 126 ± 1 gigapascals (uncertainty of one standard deviation), which is about 26 per cent lower than theoretical predictions (about 171 gigapascals). This value leads to substantially lower sound velocities of basaltic compositions than those predicted for the pressure and temperature conditions at depths between 660 and 770 kilometres. This suggests accumulation of basaltic crust in the uppermost lower mantle, which is consistent with the observation of low-seismic-velocity signatures below 660 kilometres and the discovery of CaPv in natural diamond of super-deep origin. These results could contribute to our understanding of the existence and behaviour of subducted crust materials in the deep mantle.
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http://dx.doi.org/10.1038/s41586-018-0816-5DOI Listing
January 2019

Ethanol-induced enhancement of inhibitory synaptic transmission in the rat spinal substantia gelatinosa.

Mol Pain 2018 Jan-Dec;14:1744806918817969. Epub 2018 Nov 19.

1 Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan.

Recent studies have shown that ethanol produces a widespread modulation of neuronal activity in the central nervous system. It is not fully understood, however, how ethanol changes nociceptive transmission. We investigated acute effects of ethanol on synaptic transmission in the substantia gelatinosa (lamina II of the spinal dorsal horn) and mechanical responses in the spinal dorsal horn. In substantia gelatinosa neurons, bath application of ethanol at low concentration (10 mM) did not change the frequency and amplitude of spontaneous inhibitory postsynaptic currents. At medium to high concentrations (20-100 mM), however, ethanol elicited a barrage of large amplitude spontaneous inhibitory postsynaptic currents. In the presence of tetrodotoxin, such enhancement of spontaneous inhibitory postsynaptic currents was not detected. In addition, ethanol (20-100 mM) increased the frequency of spontaneous discharge of vesicular GABA transporter-Venus-labeled neurons and suppressed the mechanical nociceptive response in wide-dynamic range neurons in the spinal dorsal horn. The present results suggest that ethanol may reduce nociceptive information transfer in the spinal dorsal horn by enhancement of inhibitory GABAergic and glycinergic synaptic transmission.
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http://dx.doi.org/10.1177/1744806918817969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293375PMC
April 2019
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