Publications by authors named "Seung-Hwan Lee"

1,051 Publications

  • Page 1 of 1

Clopidogrel-Induced Interstitial Lung Disease: A Case Report.

Ther Clin Risk Manag 2021 12;17:711-715. Epub 2021 Jul 12.

Department of Pulmonary, Allergy and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.

In patients, with cerebral infarction resulting from intracranial arterial stenosis, the combined administration of clopidogrel and aspirin may be needed for to prevent subsequent ischemic attacks. Clopidogrel has an inevitable adverse effect profile, and the most common complications are related to hemorrhagic propensity. A 79-year-old female patient had used aspirin (100 mg/day) for cerebral infarction and then a dual antiplatelet regimen of aspirin and clopidogrel (75 mg/day) because of severe stenosis in both anterior cerebral arteries. Two weeks later, the patient presented with dyspnea started 3 days ago, which had worsened in the last 24 hours. Chest computed tomography on admission showed symmetric peribronchial ground-glass opacity with reticulation in both lungs. Microorganism tests, including serology and bronchoalveolar lavage for infection, were all negative. Clopidogrel was withdrawn because of suspected clopidogrel-induced interstitial lung disease, and steroid treatment was initiated. Clinical signs and chest radiographs improved after steroid treatment, and she was discharged on day 21 of admission. This case report shows that clopidogrel can induce interstitial lung disease as a rare complication and underscores the importance of recognizing this adverse effect in clinical practice.
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http://dx.doi.org/10.2147/TCRM.S319077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285274PMC
July 2021

Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21.

Cancer Immunol Immunother 2021 Jul 20. Epub 2021 Jul 20.

Research Center for Cancer Immunotherapy, Gwangju, South Korea.

Background: Natural killer (NK) cell-based immunotherapy is a promising treatment approach for multiple myeloma (MM), but obtaining a sufficient number of activated NK cells remains challenging. Here, we report an improved method to generate ex vivo expanded NK (eNK) cells from MM patients based on genetic engineering of K562 cells to express OX40 ligand and membrane-bound (mb) IL-18 and IL-21.

Methods: K562-OX40L-mbIL-18/-21 cells were generated by transducing K562-OX40L cells with a lentiviral vector encoding mbIL-18 and mbIL-21, and these were used as feeder cells to expand NK cells from peripheral blood mononuclear cells of healthy donors (HDs) and MM patients in the presence of IL-2/IL-15. Purity, expansion rate, receptor expression, and functions of eNK cells were determined over four weeks of culture.

Results: NK cell expansion was enhanced by short exposure of soluble IL-18 and IL-21 with K562-OX40L cells. Co-culture of NK cells with K562-OX40L-mbIL-18/-21 cells resulted in remarkable expansion of NK cells from HDs (9,860-fold) and MM patients (4,929-fold) over the 28-day culture period. Moreover, eNK cells showed increased expression of major activation markers and enhanced cytotoxicity towards target K562, U266, and RPMI8226 cells.

Conclusions: Our data suggest that genetically engineered K562 cells expressing OX40L, mbIL-18, and mbIL-21 improve the expansion of NK cells, increase activation signals, and enhance their cytolytic activity towards MM cells.
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http://dx.doi.org/10.1007/s00262-021-02982-9DOI Listing
July 2021

Incidence of peripheral vestibular disorders in individuals with obstructive sleep apnea.

J Vestib Res 2021 Jul 8. Epub 2021 Jul 8.

Departments of Otolaryngology-Head and Neck Surgery, College of Medicine, Hanyang University, Seoul, Republic of Korea.

Background: Obstructive sleep apnea(OSA) could influence peripheral vestibular function adversely via intermittent hypoxia and its consequences.

Objective: This study aimed to evaluate the risk of peripheral vestibular disorders in OSA using a nationwide population-based retrospective cohort study.

Methods: The National Health Insurance Service-National Sample Cohort represents the entire Korean population from 2002 to 2015. OSA was defined as individuals who had used medical services twice or more under a diagnosis of OSA(G47.33 in ICD-10). A comparison cohort consisted of socio-demographically matched non-OSA subjects in a ratio of 1:4. The incidences of benign paroxysmal positional vertigo(BPPV), Meniere's disease, and vestibular neuritis were evaluated in each cohort.

Results: A total of 2,082 individuals with OSA and 8,328 matched non-OSA subjects were identified. The incidence rates(IRs) of peripheral vertigo in OSA and non-OSA were 149.86 and 23.88 per 10,000 persons, respectively (Ratio of IR, IRR = 6.28, 95%CI 4.89 to 8.08). In multivariable analysis, the risk of peripheral vertigo was significantly higher in OSA(adjusted HR = 6.64, 95%CI 5.20 to 8.47), old age(adjusted HR = 1.03, 95%CI 1.02 to 1.04), female sex(adjusted HR = 1.92, 95%CI 1.48 to 2.50), and comorbidities(adjusted HR = 1.09, 95%CI 1.003 to 1.19). The IRRs of each vestibular disorder in the two groups were 7.32(95%CI 4.80 to 11.33) for BPPV, 3.61(95%CI 2.24 to 5.81) for Meniere's disease, and 9.51(95%CI 3.97 to 25.11) for vestibular neuritis.

Conclusions: Subjects diagnosed with OSA had a higher incidence of peripheral vestibular disorders than those without OSA, according to national administrative claims data. It is recommended to take peripheral vertigo into account when counseling OSA.
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http://dx.doi.org/10.3233/VES-210012DOI Listing
July 2021

Esterification of Lignin Isolated by Deep Eutectic Solvent Using Fatty Acid Chloride, and Its Composite Film with Poly(lactic acid).

Polymers (Basel) 2021 Jun 29;13(13). Epub 2021 Jun 29.

Institute of Forest Science, Kangwon National University, Chuncheon 24341, Korea.

In this study, the effect of lignin esterification with fatty acid chloride on the properties of lignin and lignin/poly(lactic acid) (PLA) composites was investigated. Lignocellulose ( S. et Z.) was treated using a deep eutectic solvent (DES) with choline chloride (ChCl)/lactic acid (LA). From the DES-soluble fraction, DES-lignin (DL) was isolated by a regeneration process. Lignin esterification was conducted with palmitoyl chloride (PC). As the PC loading increased for DL esterification, the Mw of esterified DL (EDL) was increased, and the glass transition temperature () was decreased. In DL or EDL/PLA composite films, it was observed that EDL/PLA had cleaner and smoother morphological characteristics than DL/PLA. The addition of DL or EDL in a PLA matrix resulted in a deterioration of tensile properties as compared with neat PLA. The EDL/PLA composite film had a higher tensile strength and elastic modulus than the DL/PLA composite film. DL esterification decreased water absorption with lower water diffusion coefficients. The effect of lignin esterification on improving the compatibility of lignin and PLA was demonstrated. These results are expected to contribute to the development of high-strength lignin composites.
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http://dx.doi.org/10.3390/polym13132149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271993PMC
June 2021

Hematological Changes and Reference Intervals in Hanwoo Calves during the First 28 Weeks of Life.

Animals (Basel) 2021 Jun 17;11(6). Epub 2021 Jun 17.

Animal Breeding and Genetics Division, National Institute of Animal Science, Rural Development Administration, 114, Sinbang 1-gil, Seonghwan-eup, Seobuk-gu, Cheonan 31000, Korea.

Hematological reference intervals must consider several parameters, including genotype, age, sex, management, and analytic process. Work is needed to evaluate hematological changes specifically in Hanwoo calves and according to calf sex. Therefore, in this study, we sought to confirm the complete blood cell count (CBC) reference intervals in Hanwoo calves, to monitor changes in hematologic values in Hanwoo calves from birth until 28 weeks of life, and to compare the hematologic values of male and female calves. A total of 35 male calves and 35 female calves was studied. Calf blood was sampled at multiple intervals from the time of birth until 28 weeks of age (including within 6 h of birth and at 2 days, 7 days, and 4 weeks and then at 4-week intervals through 28 weeks). In addition, blood samples were collected from 210 clinically healthy pregnant Hanwoo cows to establish CBC reference intervals for adult cattle. There were significant differences in the results of the cows and calves in all 14 parameters considered. The CBC reference intervals of the calves were wider than those of the cows in all parameters except mean corpuscular volume, mean corpuscular hemoglobin concentration, and mean platelet volume. We also identified differences from birth through 28 weeks between male and female calves at only some ages and some parameters. These results suggest that CBC reference intervals specific to Hanwoo calves are necessary for accurate diagnosis of calf diseases.
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http://dx.doi.org/10.3390/ani11061806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234674PMC
June 2021

Effect of Oxidation Time on the Properties of Cellulose Nanocrystals Prepared from Balsa and Kapok Fibers Using Ammonium Persulfate.

Polymers (Basel) 2021 Jun 7;13(11). Epub 2021 Jun 7.

Department of Forest Biomaterial Engineering, College of Forest and Environmental Sciences, Kangwon National University, Chuncheon 24341, Korea.

This study aimed to evaluate the effect of ammonium persulfate's (APS) oxidation time on the characteristics of the cellulose nanocrystals (CNCs) of balsa and kapok fibers after delignification pretreatment with sodium chlorite/acetic acid. This two-step method is important for increasing the zeta potential value and achieving higher thermal stability. The fibers were partially delignified using acidified sodium chlorite for four cycles, followed by APS oxidation at 60 °C for 8, 12, and 16 h. The isolated CNCs with a rod-like structure showed an average diameter in the range of 5.5-12.6 nm and an aspect ratio of 14.7-28.2. Increasing the reaction time resulted in a gradual reduction in the CNC dimensions. The higher surface charge of the balsa and kapok CNCs was observed at a longer oxidation time. The CNCs prepared from kapok had the highest colloid stability after oxidation for 16 h (-62.27 mV). The CNCs with higher crystallinity had longer oxidation times. Thermogravimetric analysis revealed that the CNCs with a higher thermal stability had longer oxidation times. All of the parameters were influenced by the oxidation time. This study indicates that APS oxidation for 8-16 h can produce CNCs from delignified balsa and kapok with satisfactory zeta potential values and thermal stabilities.
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http://dx.doi.org/10.3390/polym13111894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201228PMC
June 2021

Non-Invasive Diagnosis for Acute Rejection Using Urinary mRNA Signature Reflecting Allograft Status in Kidney Transplantation.

Front Immunol 2021 10;12:656632. Epub 2021 Jun 10.

Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, South Korea.

Urine has been regarded as a good resource based on the assumption that urine can directly reflect the state of the allograft or ongoing injury in kidney transplantation. Previous studies, suggesting the usefulness of urinary mRNA as a biomarker of acute rejection, imply that urinary mRNA mirrors the transcriptional activity of the kidneys. We selected 14 data-driven candidate genes through a meta-analysis and measured the candidate genes using quantitative PCR without pre-amplification in the cross-sectional specimens from Korean kidney transplant patients. Expression of 9/14 genes (CXCL9, CD3ϵ, IP-10, LCK, C1QB, PSMB9, Tim-3, Foxp3, and FAM26F) was significantly different between acute rejection and stable graft function with normal pathology and long-term graft survival in 103 training samples. CXCL9 was also distinctly expressed in allografts with acute rejection in hybridization analysis. This result, consistent with the qPCR result, implies that urinary mRNA could reflect the magnitude of allograft injury. We developed an AR prediction model with the urinary mRNAs by a binary logistic regression and the AUC of the model was 0.89 in the training set. The model was validated in 391 independent samples, and the AUC value yielded 0.84 with a fixed manner. In addition, the decision curve analysis indicated a range of reasonable threshold probabilities for biopsy. Therefore, we suggest the urine mRNA signature could be used as a non-invasive monitoring tool of acute rejection for clinical application and could help determine whether to perform a biopsy in a recipient with increased creatinine.
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http://dx.doi.org/10.3389/fimmu.2021.656632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222723PMC
June 2021

Influence of Variants and Childhood Trauma on Brain Volume in Non-clinical Individuals.

Front Behav Neurosci 2021 3;15:663052. Epub 2021 Jun 3.

Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, South Korea.

The present study aimed to investigate the possible influence of childhood trauma and its interaction effect with 10 single-nucleotide polymorphisms (SNPs) of the FK506-binding protein 51 () gene on brain volume in non-clinical individuals. One hundred forty-four non-clinical volunteers (44 men and 100 women) were genotyped with respect to 10 variants (rs9296158, rs3800373, rs1360780, rs9470080, rs4713916, rs4713919, rs6902321, rs56311918, rs3798345, and rs9380528) of . Participants underwent magnetic resonance imaging (MRI) scan and psychological assessments such as the childhood Trauma Questionnaire (CTQ), Hospital Anxiety and Depression Scale, rumination response scale, and quality of life assessment instrument. Individuals with the high CTQ score showed enlarged volume of the left orbitofrontal cortex (OFC) if they have childhood trauma-susceptible genotype of rs3800373, rs1360780, rs4713916, rs4713919, rs6902321, and rs3798345 and enlarged volume of the left middle temporal gyrus (MTG) if they have childhood trauma-susceptible genotype of rs3800373, rs1360780, rs4713916, and rs3798345. Among those with the childhood trauma-susceptible genotype, the left OFC and left MTG showed significant negative correlations with positive feelings about life, and the left OFC showed significant positive correlations with negative cognition. This is one of the few studies to identify the volume alteration of the left OFC and the left MTG for the gene-childhood trauma interaction in non-clinical individuals.
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http://dx.doi.org/10.3389/fnbeh.2021.663052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209293PMC
June 2021

Effect of Coronary CTA on Chronic Total Occlusion Percutaneous Coronary Intervention: A Randomized Trial.

JACC Cardiovasc Imaging 2021 Jun 9. Epub 2021 Jun 9.

Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea. Electronic address:

Objectives: The purpose of this study was to test whether the success rate of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) increased with pre-procedural coronary computed tomography angiography (CTA).

Background: Coronary CTA provides valuable information before and during CTO-PCI. However, there are no randomized data that explore whether coronary CTA increases its success rate.

Methods: In this multicenter, randomized trial, a total of 400 patients with CTO were randomized to receive PCI with pre-procedural coronary CTA (coronary CTA-guided group; n = 200) or without coronary CTA (angiography-guided group; n = 200) between January 2014 and September 2019. The primary endpoint was the successful recanalization rate, a final TIMI (Thrombolysis In Myocardial Infarction) grade ≥2, and ≤30% residual stenosis on the final angiogram.

Results: A total of 10 operators performed PCI. Successful recanalization was achieved in 187 patients (93.5%) in the coronary CTA-guided group and in 168 patients (84.0%) in the angiography-guided group (absolute difference, 9.5% [95% confidence interval: 3.4% to 15.6%]; p = 0.003). When comparing the success rates according to the Multicenter CTO Registry of Japan score (J-CTO), the coronary CTA guidance was favored over the angiography-guidance in the subset of J-CTO ≥2 versus in the subset of J-CTO <2 (p interaction = 0.035). Coronary perforations occurred in 2 (1%) and 8 patients (4%) in the coronary CTA- and angiography-guided groups, respectively (p = 0.055). Periprocedural myocardial infarction was not observed in the coronary CTA-guided group, whereas it occurred in 4 patients (2%) in the angiography-guided group (p = 0.123). Total procedure and fluoroscopic times were not different. There were no differences between the groups in the occurrences of cardiac death, target vessel-related myocardial infarction, or target-vessel revascularization at 1 year.

Conclusions: Pre-procedural coronary CTA-guidance for CTO resulted in higher success rates with numerically fewer immediate periprocedural complications such as coronary perforations or periprocedural myocardial infarction than angiography guidance. Higher success rates were more prominently observed in patients with CTO who had a high J-CTO score than those who did not. (Role of CT Scan for the Successful Recanalization of Chronic Total Occlusion; a Randomized Comparison Between 3D CT-guided PCI vs. Conventional Treatment [CT-CTO Trial]; NCT02037698).
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http://dx.doi.org/10.1016/j.jcmg.2021.04.013DOI Listing
June 2021

Heart Rate Variability in Postoperative Patients with Nonfunctioning Pituitary Adenoma.

Endocrinol Metab (Seoul) 2021 Jun 10;36(3):678-687. Epub 2021 Jun 10.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Decreased heart rate variability (HRV) has been reported to be associated with cardiac autonomic dysfunction. Hypopituitarism in nonfunctioning pituitary adenoma (NFPA) is often linked to increased cardiovascular mortality. We therefore hypothesized that postoperative NFPA patients with hormone deficiency have an elevated risk of HRV alterations indicating cardiac autonomic dysfunction.

Methods: A total of 22 patients with NFPA were enrolled in the study. Between 3 and 6 months after surgery, a combined pituitary function test (CPFT) was performed, and HRV was measured. The period of sleep before the CPFT was deemed the most stable period, and the hypoglycemic period that occurred during the CPFT was defined as the most unstable period. Changes in HRV parameters in stable and unstable periods were observed and compared depending on the status of hormone deficiencies.

Results: In patients with adrenocorticotropic hormone (ACTH) deficiency with other pituitary hormone deficiencies, the low frequency to high frequency ratio, which represents overall autonomic function and is increased in the disease state, was higher (P=0.005). Additionally, the standard deviation of the normal-to-normal interval, which decreases in the autonomic dysfunction state, was lower (P=0.030) during the hypoglycemic period. In panhypopituitarism, the low frequency to high frequency ratio during the hypoglycemic period was increased (P=0.007).

Conclusion: HRV analysis during CPFT enables estimation of cardiac autonomic dysfunction in patients with NFPA who develop ACTH deficiency with other pituitary hormone deficiencies or panhypopituitarism after surgery. These patients may require a preemptive assessment of cardiovascular risk.
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http://dx.doi.org/10.3803/EnM.2021.978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258319PMC
June 2021

Five-year clinical outcomes of the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.

Medicine (Baltimore) 2021 May;100(19):e25765

Department of Cardiology, Ajou University School of Medicine, Suwon.

Abstract: This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years.We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years.The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.
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http://dx.doi.org/10.1097/MD.0000000000025765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133141PMC
May 2021

Expression of Nutrient Transporters on NK Cells During Murine Cytomegalovirus Infection Is MyD88-Dependent.

Front Immunol 2021 3;12:654225. Epub 2021 May 3.

Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.

Natural killer (NK) cells are the predominant innate lymphocytes that provide early defense against infections. In the inflammatory milieu, NK cells modify their metabolism to support high energy demands required for their proliferation, activation, and functional plasticity. This metabolic reprogramming is usually accompanied by the upregulation of nutrient transporter expression on the cell surface, leading to increased nutrient uptake required for intense proliferation. The interleukin-1 family members of inflammatory cytokines are critical in activating NK cells during infection; however, their underlying mechanism in NK cell metabolism is not fully elucidated. Previously, we have shown that IL-18 upregulates the expression of solute carrier transmembrane proteins and thereby induces a robust metabolic boost in NK cells. Unexpectedly, we found that IL-18 signaling is dispensable during viral infection , while the upregulation of nutrient transporters is primarily MyD88-dependent. NK cells from mice displayed significantly reduced surface expression of nutrient receptors and mTOR activity during MCMV infection. We also identified that IL-33, another cytokine employing MyD88 signaling, induces the expression of nutrient transporters but requires a pre-exposure to IL-12. Moreover, signaling through the NK cell activating receptor, Ly49H, can also promote the expression of nutrient transporters. Collectively, our findings revealed multiple pathways that can induce the expression of nutrient transporters on NK cells while highlighting the imperative role of MyD88 in NK cell metabolism during infection.
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http://dx.doi.org/10.3389/fimmu.2021.654225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177011PMC
May 2021

Prefrontal Functional Connectivity During the Verbal Fluency Task in Patients With Major Depressive Disorder: A Functional Near-Infrared Spectroscopy Study.

Front Psychiatry 2021 21;12:659814. Epub 2021 May 21.

Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, South Korea.

Deviations in activation patterns and functional connectivity have been observed in patients with major depressive disorder (MDD) with prefrontal hemodynamics of patients compared with healthy individuals. The graph-theoretical approach provides useful network metrics for evaluating functional connectivity. The evaluation of functional connectivity during a cognitive task can be used to explain the neurocognitive mechanism underlying the cognitive impairments caused by depression. Overall, 31 patients with MDD and 43 healthy individuals completed a verbal fluency task (VFT) while wearing a head-mounted functional near-infrared spectroscopy (fNIRS) devices. Hemodynamics and functional connectivity across eight prefrontal subregions in the two groups were analyzed and compared. We observed a reduction in prefrontal activation and weaker overall and interhemispheric subregion-wise correlations in the patient group compared with corresponding values in the control group. Moreover, efficiency, the network measure related to the effectiveness of information transfer, showed a significant between-group difference [t (71.64) = 3.66, corrected p < 0.001] along with a strong negative correlation with depression severity (rho = -0.30, = 0.009). The patterns of prefrontal functional connectivity differed significantly between the patient and control groups during the VFT. Network measures can quantitatively characterize the reduction in functional connectivity caused by depression. The efficiency of the functional network may play an important role in the understanding of depressive symptoms.
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http://dx.doi.org/10.3389/fpsyt.2021.659814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175962PMC
May 2021

The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity.

Cancers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea.

Genes associated with the DEAD-box helicase are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with -specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. -deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, could determine PARP inhibitor sensitivity in RCC. could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.
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http://dx.doi.org/10.3390/cancers13112574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197413PMC
May 2021

Preparation and Properties of Wet-Spun Microcomposite Filaments from Various CNFs and Alginate.

Polymers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Department of Forest Biomaterials Engineering, College of Forest and Environmental Sciences, Kangwon National University, Chuncheon 24341, Korea.

We aimed to improve the mechanical properties of alginate fibers by reinforcing with various cellulose nanofibrils (CNFs). Pure cellulose nanofibril (PCNF), lignocellulose nanofibril (LCNF) obtained via deep eutectic solvent (DES) pretreatment, and TEMPO-oxidized lignocellulose nanofibril (TOLCNF) were employed. Sodium alginate (AL) was mixed with PCNF, LCNF, and TOLCNF with a CNF content of 5-30%. To fabricate microcomposite filaments, the suspensions were wet-spun in calcium chloride (CaCl) solution through a microfluidic channel. Average diameters of the microcomposite filaments were in the range of 40.2-73.7 μm, which increased with increasing CNF content and spinning rate. The tensile strength and elastic modulus improved as the CNF content increased to 10%, but the addition of 30% CNF deteriorated the tensile properties. The tensile strength and elastic modulus were in the order of LCNF/AL > PCNF/AL > TOLCNF/AL > AL. An increase in the spinning rate improved the tensile properties.
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http://dx.doi.org/10.3390/polym13111709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197178PMC
May 2021

Comparison of Selection Signatures between Korean Native and Commercial Chickens Using 600K SNP Array Data.

Genes (Basel) 2021 May 27;12(6). Epub 2021 May 27.

Division of Animal and Dairy Science, Chungnam National University, Daejeon 34134, Korea.

Korean native chickens (KNCs) comprise an indigenous chicken breed of South Korea that was restored through a government project in the 1990s. The KNC population has not been developed well and has mostly been used to maintain purebred populations in the government research institution. We investigated the genetic features of the KNC population in a selection signal study for the efficient improvement of this breed. We used 600K single nucleotide polymorphism data sampled from 191 KNCs (NG, 38; NL, 29; NR, 52; NW, 39; and NY, 33) and 54 commercial chickens (Hy-line Brown, 10; Lohmann Brown, 10; Arbor Acres, 10; Cobb, 12; and Ross, 12). Haplotype phasing was performed using EAGLE software as the initial step for the primary data analysis. Pre-processed data were analyzed to detect selection signals using the 'rehh' package in R software. A few common signatures of selection were identified in KNCs. Most quantitative trait locus regions identified as candidate regions were associated with traits related to reproductive organs, eggshell characteristics, immunity, and organ development. Block patterns with high linkage disequilibrium values were observed for LPP, IGF11, LMNB2, ERBB4, GABRB2, NTM, APOO, PLOA1, CNTN1, NTSR1, DEF3, CELF1, and MEF2D genes, among regions with confirmed selection signals. NL and NW lines contained a considerable number of selective sweep regions related to broilers and layers, respectively. We recommend focusing on improving the egg and meat traits of KNC NL and NW lines, respectively, while improving multiple traits for the other lines.
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http://dx.doi.org/10.3390/genes12060824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230197PMC
May 2021

Diabetic Retinopathy and Hearing Loss: Results from the Fifth Korean National Health and Nutrition Survey.

J Clin Med 2021 May 28;10(11). Epub 2021 May 28.

Department of Ophthalmology, Hanyang University College of Medicine, Seoul 04763, Korea.

We investigated the association between the severity of diabetic retinopathy (DR) and hearing loss based on vascular etiology. We used data from the Korean National Health and Nutrition Survey 2010-2012. Adults aged >40 years with diabetes were enrolled. Demographic, socioeconomic, general medical, noise exposure and biochemical data were used. Participants were classified into three groups: diabetes without DR, non-proliferative DR (NPDR), and proliferative DR (PDR); participants were also divided into two groups (middle age (40 ≤ age < 65 years) vs. old age (age ≥ 65 years)). The association between hearing loss and DR was determined using logistic regression analysis. A total of 1045 participants ( = 411, middle-aged group; = 634, old-age group) were enrolled. Overall, the prevalence of hearing loss was 58.1%, 61.4%, and 85.0% in the no DR, NPDR, and PDR groups, respectively. After adjusting for confounding factors, the logistic regression model showed that there was no significant association between the prevalence of DR and hearing loss in the overall sample. However, the presence of PDR (OR 7.74, 95% CI 2.08-28.82) was significantly associated with hearing loss in the middle-aged group. Middle-aged people with diabetes may have an association between DR severity and hearing loss. The potential role of microvascular diseases in the development of hearing loss, especially in middle-aged patients, could be considered.
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http://dx.doi.org/10.3390/jcm10112398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199348PMC
May 2021

Glycolysis on F-18 FDG PET/CT Is Superior to Amino Acid Metabolism on C-11 Methionine PET/CT in Identifying Advanced Renal Cell Carcinoma at Staging.

Cancers (Basel) 2021 May 14;13(10). Epub 2021 May 14.

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03772, Korea.

We evaluated the value of F-18 fluorodeoxyglucose (FDG) and C-11 methionine positron emission tomography/computed tomography (PET/CT) to predict high-Fuhrman grade and advanced-stage tumours in patients with renal cell carcinoma (RCC). Forty patients with RCC underwent F-18 FDG and C-11 methionine PET/CT between September 2016 and September 2018. They were classified into limited (stages I and II, = 15) or advanced stages (stages III and IV, = 25) according to pathological staging. Logistic regressions were used to predict the advanced stage using various parameters, including maximum standardised uptake value (SUV) and metabolic tumour volume (MTV). Receiver operating characteristic analyses were performed to predict high-grade tumours (Fuhrman 3 and 4). On univariate analysis, tumour size, SUV and MTV of F-18 FDG and C-11 methionine, and Fuhrman grades were significant predictors for the advanced stage. On multivariate analysis, F-18 FDG MTV > 21.3 cm was the most significant predictor ( < 0.001). The area under the curve for predicting high-grade tumours was 0.830 for F-18 FDG ( < 0.001) and 0.726 for C-11 methionine PET/CT ( = 0.014). In conclusion, glycolysis on F-18 FDG PET/CT and amino acid metabolism on C-11 methionine PET/CT were variable but increased in high-grade RCCs. Increased MTV on F-18 FDG PET/CT is a powerful predictor of advanced-stage tumours.
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http://dx.doi.org/10.3390/cancers13102381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155930PMC
May 2021

Effects of an Audiovisual Emotion Perception Training for Schizophrenia: A Preliminary Study.

Front Psychiatry 2021 5;12:522094. Epub 2021 May 5.

Department of Psychology, Chonnam National University, Gwangju, South Korea.

Individuals with schizophrenia show a reduced ability to integrate facial and vocal information in emotion perception. Although emotion perception has been a target for treatment, no study has yet examined the effect of multimodal training on emotion perception in schizophrenia. In the present study, we developed an audiovisual emotion perception training and test in which a voice and a face were simultaneously presented, and subjects were asked to judge whether the emotions of the voice and the face matched. The voices were either angry or happy, and the faces were morphed on a continuum ranging from angry to happy. Sixteen patients with schizophrenia participated in six training sessions and three test sessions (i.e., pre-training, post-training, and generalization). Eighteen healthy controls participated only in pre-training test session. Prior to training, the patients with schizophrenia performed significantly worse than did the controls in the recognition of anger; however, following the training, the patients showed a significant improvement in recognizing anger, which was maintained and generalized to a new set of stimuli. The patients also improved the recognition of happiness following the training, but this effect was not maintained or generalized. These results provide preliminary evidence that a multimodal, audiovisual training may yield improvements in anger perception for patients with schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2021.522094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131526PMC
May 2021

Virtual tourism for older adults living in residential care: A mixed-methods study.

PLoS One 2021 20;16(5):e0250761. Epub 2021 May 20.

RTA School of Media, Ryerson University, Toronto, Ontario, Canada.

Due to financial and mobility barriers, a majority of older adults living in collective dwellings are no longer able to engage in tourism, a leisure activity that contributes to quality of life and wellbeing. Immersive Virtual Reality (VR) may serve as a programmatic tool to facilitate tourism. This pilot study examined the effects of VR tourism exposure on indices of psychosocial wellbeing among older adults living in residential care. Using a mixed-methods study design, 18 older adults were exposed to VR tourism three times a week, over six weeks. Participants reported decreased anxiety and fatigue immediately following exposure, and increased social engagement and quality of life following six weeks of VR tourism. Qualitative data offered additional insight on the process by which VR tourism may enhance wellbeing. Findings suggest that immersive VR tourism may be a viable program for older adults in residential care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250761PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136674PMC
May 2021

Nontraditional Risk Factors for Obesity in Modern Society.

J Obes Metab Syndr 2021 Jun;30(2):93-103

Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Overweight and obesity, which have rapidly increased around the world in recent years, are significant health problems. They can lead to various morbidities, including cardiovascular diseases, cerebrovascular diseases, type 2 diabetes, some types of cancer, and even death. Obesity is caused by an energy imbalance due to excessive calorie intake and insufficient energy consumption, and genetic factors and individual behavioral problems are also known to be major contributing factors. However, these are insufficient to explain the surge in obesity that has occurred in recent decades. Recent studies have suggested that environmental factors arising from the process of socioeconomic development and modernization contribute to this phenomenon. These environmental factors include light pollution due to artificial lighting, air pollution, endocrine-disrupting chemicals, and reduced exposure to green spaces due to urbanization of residential areas. In this manuscript, the findings and mechanisms of these novel risk factors causing overweight and obesity are reviewed.
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http://dx.doi.org/10.7570/jomes21004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277595PMC
June 2021

Incorporation of a Novel CD16-Specific Single-Domain Antibody into Multispecific Natural Killer Cell Engagers With Potent ADCC.

Mol Pharm 2021 06 17;18(6):2375-2384. Epub 2021 May 17.

Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.

Multispecific antibodies that bridge immune effector and tumor cells have shown promising preclinical and clinical efficacies. Here, we isolated and characterized novel llama single-domain antibodies (sdAbs) against CD16. One sdAb, NRC-sdAb048, bound recombinant human and cynomolgus monkey CD16 ectodomains with equivalent affinity (: 1 nM) but did not recognize murine CD16. Binding was similar for human CD16a expressed on NK cells and CD16b (NA2) expressed on neutrophils but dramatically weaker (: ∼6 μM) for the CD16b (NA1) allotype. The sdAb stained primary human peripheral blood NK cells. Irrespective of fusion orientation and linker length, bispecific sdAb-sdAb and sdAb-scFv dimers (anti-CD16/EGFR, anti-CD16/HER2, and anti-CD16/CD19) retained full binding affinity for each target, coengaged both antigens simultaneously, elicited ADCC against target antigen-expressing tumor cells in a reporter bioassay, and triggered target-specific activation and degranulation of primary NK cells as measured via interferon-γ and CD107a expression. These molecules may have applications in cancer immunotherapy.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00208DOI Listing
June 2021

Erratum to: Comparison of prediction accuracy for genomic estimated breeding value using the reference pig population of single-breed and admixed-breed.

J Anim Sci Technol 2020 Nov 30;62(6):960. Epub 2020 Nov 30.

Division of Animal and Dairy Science, Chungnam National University, Daejeon 34134, Korea.

[This corrects the article DOI: 10.5187/jast.2020.62.4.438.].
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http://dx.doi.org/10.5187/jast.2020.62.6.960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721567PMC
November 2020

Population structure analysis of Yeonsan Ogye using microsatellite markers.

J Anim Sci Technol 2020 Nov 30;62(6):790-800. Epub 2020 Nov 30.

Division of Animal and Dairy Science, Chungnam National University, Daejeon 34134, Korea.

The Yeonsan Ogye (YO) chicken is a natural heritage of Korea, characterized by black feathers, skin, bones, eyes, and comb. The purebred of YO population has been reared under the natural mating system with no systematic selection and breeding plan. The purpose of this study was to identify the genetic diversity and find the optimal number of population sub-division using 12 polymorphic microsatellite (MS) markers to construct a pedigree-based breeding plan for the YO population. A total of 509 YO birds were used for this study. Genetic diversity and population structure analysis were conducted based on the MS marker genotype information. The overall average polymorphic information content value and expected heterozygosity of the population were 0.586, and 0.642, respectively. The K-mean cluster analysis based on the genetic distance result confirmed that the current YO population can be divided into three ancestry groups. Individuals in each group were evaluated based on their genetic distance to identify the potential candidates for a future breeding plan. This study concludes that a future breeding plan with known pedigree information of selected founder animals, which holds high genetic diversity, could be the best strategy to ensure the conservation of the Korean YO chicken population.
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http://dx.doi.org/10.5187/jast.2020.62.6.790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721577PMC
November 2020

The Protective Effects of Statins Towards Vessel Wall Injury Caused by a Stent Retrieving Mechanical Thrombectomy Device : A Histological Analysis of the Rabbit Carotid Artery Model.

J Korean Neurosurg Soc 2021 May 14. Epub 2021 May 14.

Department of Neurosurgery, Veterans Health Service Medical Center, Seoul, Korea.

Objective: Endovascular mechanical thrombectomy (MT) has been regarded as one of the standard treatments for acute ischemic stroke caused by large vessel occlusion. Despite the wide use of stent retrievers for MT, arterial intimal damage caused when deployed stent is pulled has been a certain disadvantage. We hypothesized that statin could protect and stabilize vessel damage after endovascular MT using a stent retriever. In this animal study, we observed the protective effects of the statins towards MT-induced vessel wall injury.

Methods: Twenty-eight carotid arteries of fourteen rabbits were used in the experiments with MT using stent retriever. We divided the rabbits into four groups as follows : group 1, negative control; group 2, positive control; group 3, statin before MT; and group 4, statin after MT. After MT procedures, we harvested the carotid arteries and performed histomorphological and immunohistochemical analyses.

Results: In histomorphological analysis with hematoxylin and eosin and Masson's trichrome stain, significant intimal thickening (p<0.05) was observed in the positive control (group 2), compared to in the negative control (group 1). Intimal thickening was improved in the statin-administered groups (groups 3 and 4 vs. group 2, p<0.05). We also observed that statin administration after MT (group 4) resulted in a more effective decrease in intimal thickness than statin administration before MT (group 3) (p<0.05). We performed immunohistochemical analysis with the antibodies for tumor necrosis factor-alpha (TNF-α), cluster of differentiation (CD)11b, and CD163. In contrast to the negative control (group 1), the stained percentage areas of all immunological markers were markedly increased in the positive control (group 2) (p<0.05). Based on statin administration, the percentage area of TNF-α staining was significantly reduced (p<0.05) in group 3, compared to the positive control group (group 2). However, significant differences were not observed for CD11b and CD163 staining. In group 4, no significant differences were observed for TNF-α, CD11b, and CD163 staining (p≥0.05). The differences in the percentage areas of the different markers between the statin-administered groups (groups 3 and 4) were also not revealed.

Conclusion: We presented that statin administration before and after MT exerted protective effects towards vessel wall injury. The efficacy of statins was greater post-administration than pre-administration. Thus, statin administration in routine prescriptions in the peri-procedural period is strongly advised.
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http://dx.doi.org/10.3340/jkns.2020.0303DOI Listing
May 2021

Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment.

Front Immunol 2021 19;12:624324. Epub 2021 Apr 19.

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.

Cancer cells are metabolically vigorous and are superior in the uptake of nutrients and in the release of the tumor microenvironment (TME)-specific metabolites. They create an acidic, hypoxic, and nutrient-depleted TME that makes it difficult for the cytotoxic immune cells to adapt to the metabolically hostile environment. Since a robust metabolism in immune cells is required for optimal anti-tumor effector functions, the challenges caused by the TME result in severe defects in the invasion and destruction of the established tumors. There have been many recent developments in NK and T cell-mediated immunotherapy, such as engineering them to express chimeric antigen receptors (CARs) to enhance tumor-recognition and infiltration. However, to defeat the tumor and overcome the limitations of the TME, it is essential to fortify these novel therapies by improving the metabolism of the immune cells. One potential strategy to enhance the metabolic fitness of immune cells is to upregulate the expression of nutrient transporters, specifically glucose and amino acid transporters. In particular, the amino acid transporters SLC1A5 and SLC7A5 as well as the ancillary subunit SLC3A2, which are required for efficient uptake of glutamine and leucine respectively, could strengthen the metabolic capabilities and effector functions of tumor-directed CAR-NK and T cells. In addition to enabling the influx and efflux of essential amino acids through the plasma membrane and within subcellular compartments such as the lysosome and the mitochondria, accumulating evidence has demonstrated that the amino acid transporters participate in sensing amino acid levels and thereby activate mTORC1, a master metabolic regulator that promotes cell metabolism, and induce the expression of c-Myc, a transcription factor essential for cell growth and proliferation. In this review, we discuss the regulatory pathways of these amino acid transporters and how we can take advantage of these processes to strengthen immunotherapy against cancer.
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http://dx.doi.org/10.3389/fimmu.2021.624324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089370PMC
April 2021

Does the Loudness Dependence of Auditory Evoked Potential Predict Response to Selective Serotonin Reuptake Inhibitors?: A Meta-analysis.

Clin Psychopharmacol Neurosci 2021 May;19(2):254-261

Clinical Emotion and Cognition Research Laboratory, Goyang, Korea.

Objective: Loudness of dependence of the auditory evoked potential (LDAEP) is an electroencephalogram-based measure that represents amplitude changes of auditory evoked potentials in primary auditory cortex. Several narrative reviews argued that pre-treatment LDAEP values predict responses to selective serotonin reuptake inhibitors (SSRIs). This study aims to quantify the overall relationship between baseline LDAEP values and treatment response to SSRIs in patients with depression and generalized anxiety disorders, evidenced by clinical symptoms reductions, across multiple studies.

Methods: In our meta-analysis, seven articles with a total sample of 241 patients were included.

Results: Our results showed that stronger baseline LDAEP values predicted favorable response to SSRIs for depression and anxiety, with a moderate effect size.

Conclusion: The current results support the idea that LDAEP is a promising biomarker for SSRIs treatment prediction in patients with depression and generalized anxiety disorder.
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http://dx.doi.org/10.9758/cpn.2021.19.2.254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077049PMC
May 2021

Role of mTORC2 in biphasic regulation of brown fat metabolism in response to mild and severe cold.

J Biol Chem 2021 Jan-Jun;296:100632. Epub 2021 Apr 15.

Department of Medicine, Division of Nephrology, University of California at San Francisco, San Francisco, California, USA; Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, USA. Electronic address:

Nonshivering thermogenesis is essential for mammals to maintain body temperature. According to the canonical view, temperature is sensed by cutaneous thermoreceptors and nerve impulses transmitted to the hypothalamus, which generates sympathetic signals to ß-adrenergic receptors in brown adipocytes. The energy for heat generation is primarily provided by the oxidation of fatty acids derived from triglyceride hydrolysis and cellular uptake. Fatty acids also activate the uncoupling protein, UCP1, which creates a proton leak that uncouples mitochondrial oxidative phosphorylation from ATP production, resulting in energy dissipation as heat. Recent evidence supports the idea that in response to mild cold, ß-adrenergic signals stimulate not only lipolysis and fatty acid oxidation, but also act through the mTORC2-Akt signaling module to stimulate de novo lipogenesis. This opposing anabolic effect is thought to maintain lipid fuel stores during increased catabolism. We show here, using brown fat-specific Gs-alpha knockout mice and cultured adipocytes that, unlike mild cold, severe cold directly cools brown fat and bypasses ß-adrenergic signaling to inhibit mTORC2. This cell-autonomous effect both inhibits lipogenesis and augments UCP1 expression to enhance thermogenesis. These findings suggest a novel mechanism for overriding ß-adrenergic-stimulated anabolic activities while augmenting catabolic activities to resolve the homeostatic crisis presented by severe cold.
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http://dx.doi.org/10.1016/j.jbc.2021.100632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121962PMC
April 2021

Cumulative Exposure to Metabolic Syndrome Components and the Risk of Dementia: A Nationwide Population-Based Study.

Endocrinol Metab (Seoul) 2021 Apr 14;36(2):424-435. Epub 2021 Apr 14.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Metabolic disturbances are modifiable risk factors for dementia. Because the status of metabolic syndrome (MetS) and its components changes over time, we aimed to investigate the association of the cumulative exposure to MetS and its components with the risk of dementia.

Methods: Adults (n=1,492,776; ≥45-years-old) who received health examinations for 4 consecutive years were identified from a nationwide population-based cohort in Korea. Two exposure-weighted scores were calculated: cumulative number of MetS diagnoses (MetS exposure score, range of 0 to 4) and the composite of its five components (MetS component exposure score, range of 0 to 20). Hazard ratio (HR) and 95% confidence interval (CI) values for dementia were analyzed using the multivariable Cox proportional-hazards model.

Results: Overall, 47.1% of subjects were diagnosed with MetS at least once, and 11.5% had persistent MetS. During the mean 5.2 years of follow-up, there were 7,341 cases (0.5%) of incident dementia. There was a stepwise increase in the risk of all-cause dementia, Alzheimer's disease, and vascular dementia with increasing MetS exposure score and MetS component exposure score (each P for trend <0.0001). The HR of all-cause dementia was 2.62 (95% CI, 1.87 to 3.68) in subjects with a MetS component exposure score of 20 compared with those with a score of 0. People fulfilling only one MetS component out of 20 already had an approximately 40% increased risk of all-cause dementia and Alzheimer's disease.

Conclusion: More cumulative exposure to metabolic disturbances was associated with a higher risk of dementia. Of note, even minimal exposure to MetS components had a significant effect on the risk of dementia.
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http://dx.doi.org/10.3803/EnM.2020.935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090478PMC
April 2021