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Article ; Online: Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic Aging Tenacity ("You are never too old to become younger!") Specialized Center of Research Excellence on Sex Differences Career Enhancement Core: Building the Future.

Pevnick, Joshua M / Diniz, Marcio A / Magoffin, Denis / Ishimori, Mariko / Bairey Merz, C Noel

Journal of women's health (2002)

2023 Volume 32, Issue 8, Page(s) 883–890

Abstract: The objective of the National Institutes of Health Office of Research in Women's Health (NIH/ORWH) Specialized Center of Research and Career Enhancement (SCORE) program is to expedite the development and application of new knowledge that affect women, to ...

Abstract	The objective of the National Institutes of Health Office of Research in Women's Health (NIH/ORWH) Specialized Center of Research and Career Enhancement (SCORE) program is to expedite the development and application of new knowledge that affect women, to learn more about the etiology of these diseases, and to foster improved approaches to treatment and/or prevention. Each SCORE has a Career Enhancement Core (CEC) that serves to meet the career enhancement needs of translational science in the study of sex differences. The Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic aging Tenacity (MAE-WEST) ("You are never too old to become younger!") Specialized Center of Research Excellence (SCORE) on Sex Differences will study pro- and anti-inflammatory responses and small vessel aging traits. As part of our SCORE CEC, we have advanced several initiatives to embed consideration of sex as a biological variable (SABV) into the infrastructure of our two CEC institutions. Unlike other professions, ongoing physician education through continuing medical education (CME) activities is required and embedded in the practice of medicine. The MAE-WEST SCORE in collaboration with the CSMC Clinical Scholars Program, the Center for Research in Women's Health and Sex-differences and the CSMC CME Office requires SABV and as Diversity, Equity, and Inclusion components in all CSMC CME programs. Clinical practice is also increasingly guided by evidence-based guidelines, with Class I recommendations resulting from clinical trials rather than expert consensus. It is essential that women be included in clinical trials proportionate to the prevalence and burden of disease. The MAE-WEST SCORE has developed our own unique CEC for providing novel educational, networking, funding opportunities, and translation to practice support. The developed best practices have found novel ways to enhance studies of women's health and SABV. We welcome visitors on-site and virtual to share with the broader academic and practicing community.
MeSH term(s)	United States ; Female ; Humans ; Male ; Sex Characteristics ; Women's Health ; National Institutes of Health (U.S.)
Language	English
Publishing date	2023-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1139774-3
ISSN	1931-843X ; 1059-7115 ; 1540-9996
ISSN (online)	1931-843X
ISSN	1059-7115 ; 1540-9996
DOI	10.1089/jwh.2022.0505
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Article ; Online: Biological treatment usage in patients with HIV and rheumatic disease, 2003-2021: long-term safety and follow-up.

Naovarat, Benjamin Sornrung / Salazar, Gloria / Ishimori, Mariko / Williams, Francis M / Reveille, John D

RMD open

2022 Volume 8, Issue 2

Abstract: Objective: This study examined the safety and efficacy of biological agents, especially tumour necrosis factor (TNF) inhibitors, for HIV-positive rheumatology patients refractory to standard therapy.: Methods: This study is a retrospective case ... ...

Abstract	Objective: This study examined the safety and efficacy of biological agents, especially tumour necrosis factor (TNF) inhibitors, for HIV-positive rheumatology patients refractory to standard therapy. Methods: This study is a retrospective case series including patients derived from a community HIV clinic as well as from two academic centres. Initial visit data collected included: sociodemographic characteristics, CD4 counts, HIV viral load and medication use. Patients with persistent disease activity despite standard conservative therapy were begun on biological agents.The main outcomes were patient and physician global assessment of treatment response and medication side effects in patients with rheumatological disorders treated with biological medications over time. Results: Seventeen patients were seen from 2003 to 2021, including eight from our previous cohort published in 2008 and nine seen since then, five of whom taking TNF blockers for more than 10 years. Three (17.7%) had rheumatoid arthritis, five (29.4%) psoriatic arthritis, four (23.5%) axial spondyloarthritis and the rest (29.4%) peripheral spondyloarthritis. Antiretroviral therapy had been used in 15. All but one had at least a partial response to biological therapy. There were no major infectious episodes necessitating the discontinuation of medications with only one patient discontinuing treatment due to rising HIV viral load. Patients not on antiretroviral therapy reported no adverse side effects from biological therapy. Four patients were switched to ustekinumab, secukinumab, tocilizumab or upadacitinib from anti-TNF therapy without complications. Conclusions: These data suggest that biological therapy, especially anti-TNF agents are safe and well tolerated in HIV positive individuals even over several years.
MeSH term(s)	Follow-Up Studies ; Humans ; Retrospective Studies ; Rheumatic Diseases/drug therapy ; Tumor Necrosis Factor Inhibitors ; Tumor Necrosis Factor-alpha
Chemical Substances	Tumor Necrosis Factor Inhibitors ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2022-07-19
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2812592-7
ISSN	2056-5933 ; 2056-5933
ISSN (online)	2056-5933
ISSN	2056-5933
DOI	10.1136/rmdopen-2022-002282
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Article: Alterations in genes associated with cytosolic RNA sensing in whole blood are associated with coronary microvascular disease in SLE.

Huo, Lihong / Montano, Erica / Tumurkhuu, Gantseg / Bose, Moumita / Berman, Daniel S / Wallace, Daniel / Wei, Janet / Ishimori, Mariko / Merz, C Noel Bairey / Jefferies, Caroline

Research square

2024

Abstract: Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular ... ...

Abstract	Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular disease (CMD), where narrowing of the small blood vessels can lead to ischemia, and frequently reported by SLE patients. Using whole blood RNA samples, we asked whether gene signatures discriminate SLE patients with coronary microvascular dysfunction (CMD) on cardiac MRI (n=4) from those without (n=7) and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD. RNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and healthy control (HC) groups, with virus defense and interferon (IFN) signaling being the key pathways identified as enriched in SLE as expected. We next conducted a comparative analysis of genes differentially expressed in SLE-CMD and SLE-non-CMD relative to HC samples. Our analysis highlighted differences in IFN signaling, RNA sensing and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD. This is the first study to investigate possible gene signatures associating with CMD in SLE, and our data strongly suggests that distinct molecular mechanisms underly vascular changes in CMD and non-CMD involvement in SLE.
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-4171759/v1
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Article ; Online: Low levels of anti-cyclic citrullinated peptide (CCP) 3.1 associated with diseases other than rheumatoid arthritis.

Son, James J / Ishimori, Mariko / Mirocha, James / Weisman, Michael H / Forbess, Lindsy J

Medicine

2021 Volume 100, Issue 16, Page(s) e25558

Abstract: Abstract: Our aim was to investigate the newest generation anti-cyclic citrullinated peptide (CCP) antibody 3.1 assay in diagnosing rheumatoid arthritis (RA) compared with other autoimmune and non-autoimmune diseases. We performed a retrospective ... ...

Abstract	Abstract: Our aim was to investigate the newest generation anti-cyclic citrullinated peptide (CCP) antibody 3.1 assay in diagnosing rheumatoid arthritis (RA) compared with other autoimmune and non-autoimmune diseases. We performed a retrospective observational chart review of patients with a positive CCP level over a one-year period at a single academic institution and assessed the associated diagnoses after at least six-months of follow-up. Of the 281 CCP positive patients during that period, 48% had a diagnosis of RA. The positive predictive value of RA in patients with a high CCP 3.1 assay was 0.619 compared to 0.248 with a low positive CCP 3.1 assay (P < .0001). Overall, there was a lower than expected positive predictive value of CCP 3.1 level with an RA diagnosis, though the likelihood of having an RA diagnosis was higher with a higher CCP level.
MeSH term(s)	Aged ; Arthritis, Rheumatoid/diagnosis ; Autoantibodies/blood ; Autoimmune Diseases/diagnosis ; Female ; Humans ; Male ; Middle Aged ; Peptides, Cyclic/immunology ; Predictive Value of Tests ; Retrospective Studies ; Rheumatic Diseases/diagnosis
Chemical Substances	Autoantibodies ; Peptides, Cyclic ; cyclic citrullinated peptide
Language	English
Publishing date	2021-04-20
Publishing country	United States
Document type	Journal Article ; Observational Study
ZDB-ID	80184-7
ISSN	1536-5964 ; 0025-7974
ISSN (online)	1536-5964
ISSN	0025-7974
DOI	10.1097/MD.0000000000025558
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Article ; Online: Regulation of cGAS-STING Pathway - Implications for Systemic Lupus Erythematosus.

Hagiwara, Audrey M / Moore, Richard E / Wallace, Daniel J / Ishimori, Mariko / Jefferies, Caroline A

Rheumatology and immunology research

2021 Volume 2, Issue 3, Page(s) 173–184

Abstract: Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the "interferonopathies." Recently, the cytosolic DNA sensor cyclic guanosine ... ...

Abstract	Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the "interferonopathies." Recently, the cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have been identified as having important, if not central, roles in driving IFN-I expression in response to self-DNA. This review highlights the many ways in which this pathway is regulated in order to prevent self-DNA recognition and underlines the importance of maintaining tight control in order to prevent autoimmune disease. We will discuss the murine and human studies that have implicated the cGAS-STING pathway as being an important contributor to breakdown in tolerance in SLE and highlight the potential therapeutic application of this knowledge for the treatment of SLE.
Language	English
Publishing date	2021-12-15
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	2719-4523
ISSN (online)	2719-4523
DOI	10.2478/rir-2021-0023
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Article ; Online: High-throughput mRNA sequencing of human placenta shows sex differences across gestation.

Flowers, Amy E / Gonzalez, Tania L / Wang, Yizhou / Santiskulvong, Chintda / Clark, Ekaterina L / Novoa, Allynson / Jefferies, Caroline A / Lawrenson, Kate / Chan, Jessica L / Joshi, Nikhil V / Zhu, Yazhen / Tseng, Hsian-Rong / Wang, Erica T / Ishimori, Mariko / Karumanchi, S Ananth / Williams, John / Pisarska, Margareta D

Placenta

2024 Volume 150, Page(s) 8–21

Abstract: Introduction: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex ... ...

Abstract	Introduction: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. Objectives: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. Study design: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. Results: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. Discussion: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.
MeSH term(s)	Humans ; Female ; Pregnancy ; Male ; Placenta/metabolism ; Sex Characteristics ; High-Throughput Nucleotide Sequencing ; RNA, Messenger/metabolism ; RNA, Messenger/genetics ; Adult ; Transcriptome ; Pregnancy Trimester, Third/genetics ; Sequence Analysis, RNA ; Pregnancy Trimester, First/genetics ; Pregnancy Trimester, First/metabolism
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2024-03-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	603951-0
ISSN	1532-3102 ; 0143-4004
ISSN (online)	1532-3102
ISSN	0143-4004
DOI	10.1016/j.placenta.2024.03.005
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Article: Socioeconomic Status, Reserve Capacity, and Depressive Symptoms Predict Pain in Rheumatoid Arthritis: An Examination of the Reserve Capacity Model.

Azizoddin, Desiree / Olmstead, Richard / Anderson, Kris-Ann / Hirz, Alanna E / Irwin, Michael R / Gholizadeh, Shadi / Weisman, Michael / Ishimori, Mariko / Wallace, Daniel / Nicassio, Perry

Research square

2023

Abstract: Background: Guided by the reserve capacity model, we examined the roles of socioeconomic status (SES), reserve capacity, and negative emotions as determinants of pain in patients with Rheumatoid Arthritis (RA).: Methods: The study used cross- ... ...

Abstract	Background: Guided by the reserve capacity model, we examined the roles of socioeconomic status (SES), reserve capacity, and negative emotions as determinants of pain in patients with Rheumatoid Arthritis (RA). Methods: The study used cross-sectional baseline data from 106 adults in a clinical trial comparing behavioral treatments for RA. Structural equation modeling evaluated the direct effects of SES, reserve capacity (helplessness, self-efficacy, social support) and negative emotions (stress and depressive symptoms) on pain, and the indirect effects of SES as mediated by reserve capacity and negative emotions. Results: Results showed that low SES contributed to greater pain, through lower reserve capacity and higher negative emotions. Mediational analyses showed that reserve capacity and negative emotions partially mediated the effect of SES on pain. Conclusions: The findings indicate that interventions that target negative emotions in patients with low SES may facilitate better pain control with RA. Trial registration: clinicaltrials.gov NCT00072657; 02/2004.
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2758092/v1
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Article ; Online: Interaction effects of significant risk factors on low bone mineral density in ankylosing spondylitis.

Sun, Wenting / Mu, Wenjun / Jefferies, Caroline / Learch, Thomas / Ishimori, Mariko / Wu, Juan / Yan, Zeran / Zhang, Nan / Tao, Qingwen / Kong, Weiping / Yan, Xiaoping / Weisman, Michael H

PeerJ

2023 Volume 11, Page(s) e16448

Abstract: Background: To analyze individually and interactively critical risk factors, which are closely related to low bone mineral density (BMD) in patient with ankylosing spondylitis (AS).: Methods: A total of 249 AS patients who visited China-Japan ... ...

Abstract	Background: To analyze individually and interactively critical risk factors, which are closely related to low bone mineral density (BMD) in patient with ankylosing spondylitis (AS). Methods: A total of 249 AS patients who visited China-Japan Friendship Hospital were included in this training set. Patients with questionnaire data, blood samples, X-rays, and BMD were collected. Logistic regression analysis was employed to identify key risk factors for low BMD in different sites, and predictive accuracy was improved by incorporating the selected significant risk factors into the baseline model, which was then validated using a validation set. The interaction between risk factors was analyzed, and predictive nomograms for low BMD in different sites were established. Results: There were 113 patients with normal BMD, and 136 patients with low BMD. AS patients with hip involvement are more likely to have low BMD in the total hip, whereas those without hip involvement are more prone to low BMD in the lumbar spine. Chest expansion, mSASSS, radiographic average grade of the sacroiliac joint, and hip involvement were significantly associated with low BMD of the femoral neck and total hip. Syndesmophytes, hip involvement and higher radiographic average grade of the sacroiliac joint increases the risk of low BMD of the femoral neck and total hip in an additive manner. Finally, a prediction model was constructed to predict the risk of low BMD in total hip and femoral neck. Conclusions: This study identified hip involvement was strongly associated with low BMD of the total hip in AS patients. Furthermore, the risk of low BMD of the femoral neck and total hip was found to increase in an additive manner with the presence of syndesmophytes, hip involvement, and severe sacroiliitis. This finding may help rheumatologists to identify AS patients who are at a high risk of developing low BMD and prompt early intervention to prevent fractures.
MeSH term(s)	Humans ; Spondylitis, Ankylosing/complications ; Bone Density ; Osteoporosis/etiology ; Bone Diseases, Metabolic/complications ; Risk Factors
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2703241-3
ISSN	2167-8359 ; 2167-8359
ISSN (online)	2167-8359
ISSN	2167-8359
DOI	10.7717/peerj.16448
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Article: Reduced left ventricular function on cardiac MRI of SLE patients correlates with measures of disease activity and inflammation.

Hagiwara, Audrey M / Montano, Erica / Tumurkhuu, Gantseg / Bose, Moumita / Bernardo, Marianne / Berman, Daniel S / Wiens, Galen Cook / Nelson, Michael D / Wallace, Daniel / Wei, Janet / Ishimori, Mariko / Merz, C Noel Bairey / Jefferies, Caroline

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Women with SLE have an elevated risk of cardiovascular disease. Many women with SLE frequently report chest pain in the absence of obstructive coronary artery disease (CAD) due to coronary microvascular dysfunction (CMD), a form of ischemia ... ...

Abstract	Background: Women with SLE have an elevated risk of cardiovascular disease. Many women with SLE frequently report chest pain in the absence of obstructive coronary artery disease (CAD) due to coronary microvascular dysfunction (CMD), a form of ischemia with no obstructive CAD. Echocardiographic studies have shown that SLE patients have reduced left ventricular (LV) function, which may also correlate with higher SLE disease activity scores. As such, we used cardiac magnetic resonance imaging (cMRI) to investigate the relationship between SLE, related inflammatory biomarkers, and cardiac function in female SLE patients. Methods: We performed stress cMRI in women with SLE and chest pain with no obstructive CAD (n=13, all met ACR 1997 criteria,) and reference controls (n=22) using our published protocol. We evaluated LV function, tissue characterization (T1 mapping, ECV), and delayed enhancement, using CV142 software (Circle Cardiovascular Imaging Inc, Calgary, AB, Canada). Myocardial perfusion reserve index (MPRI) was calculated using our published protocol. SLEDAI and SLICC Damage Index (DI) were calculated per validated criteria. Serum samples were analyzed for inflammatory markers and autoantibodies. Wilcoxon rank-sum test was performed on clinical values with CMD and no CMD SLE subjects, and on cMRI values with all SLE subjects and controls. Correlation analysis was done on clinical values, and cMRI values on all SLE subjects. Results: Overall, 40% of SLE subjects had MPRI values < 1.84, consistent with CMD. Compared to controls, SLE subjects had significantly lower LVEF, and higher LVESVi and LVMi. Corresponding to this, radial, longitudinal, and circumferential strain were significantly lower in the SLE subjects. In correlation analysis of serum inflammatory biomarkers to cMRI values in the SLE subjects, SLICC DI was related to worse cardiac function (lower radial, circumferential and longitudinal strain) and higher T1 time. Additionally, fasting insulin and ESR were negatively correlated with LVMi. Fasting insulin also negatively correlated with ECV. CRP had a positive association with LVESV index and CI and a negative association with longitudinal strain. Conclusions: Among women with SLE with chest pain and no obstructive CAD, 40% have CMD. While evaluations of known inflammatory markers (such as CRP and ESR) predictably correlated with decreased cardiac function, our study found that decreased fasting insulin levels as a novel marker of diminished LV function. In addition, low insulin levels were observed to correlate with increased LVMi and ECV, suggesting a cardioprotective effect of insulin in SLE patients. We also noted that SLICC DI, an assessment of SLE damage, correlates with cardiac dysfunction in SLE. Our findings underline the potential of non-invasive cMRI as a tool for monitoring cardiovascular function in SLE, particularly in patients with high SLICC DI, ESR and CRP and low fasting insulin levels.
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.24.23294127
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Article ; Online: Reduced Left Ventricular Function on Cardiac MRI in SLE Patients Correlates with Measures of SLE Disease Activity and Inflammation.

Hagiwara, Audrey M / Montano, Erica / Tumurkhuu, Gantseg / Bose, Moumita / Bernardo, Marianne / Berman, Daniel S / Wiens, Galen Cook / Nelson, Michael D / Wallace, Daniel J / Wei, Janet / Ishimori, Mariko / Bairey Merz, C Noel / Jefferies, Caroline

Journal of radiology and clinical imaging

2023 Volume 6, Issue 4, Page(s) 197–207

Abstract: Background: Women with SLE have an elevated risk of CVD morbidity and mortality and frequently report chest pain in the absence of obstructive CAD. Echocardiographic studies often demonstrate reduced LV function, correlating with higher disease activity. ...

Abstract	Background: Women with SLE have an elevated risk of CVD morbidity and mortality and frequently report chest pain in the absence of obstructive CAD. Echocardiographic studies often demonstrate reduced LV function, correlating with higher disease activity. We used cardiac MRI (cMRI) to investigate the relationship between SLE, related inflammatory biomarkers and cardiac function in female SLE patients. Methods: Women with SLE reporting chest pain with no obstructive CAD (n=13) and reference controls (n=22) were evaluated using stress-rest cMRI to measure LV structure, function, tissue characteristics, and myocardial perfusion reserve index (MPRI). Coronary microvascular dysfunction (CMD) was defined as MPRI <1.84. Serum samples were analyzed for inflammatory markers. Relationships between clinical and cMRI values of SLE subjects were assessed, and groups were compared. Results: 40% of SLE subjects had MPRI < 1.84 on cMRI. Compared to controls, SLE subjects had higher LV volumes and mass and lower LV systolic function. SLICC DI was related to worse cardiac function and higher T1. CRP was related to higher cardiac output and a trend to better systolic function, while ESR and fasting insulin were related to lower LV mass. Lower fasting insulin levels correlated with increased ECV. Conclusions: Among our female SLE cohort, 40% had CMD, and SLICC DI correlated with worse cardiac function and diffuse fibrosis. Higher inflammatory markers and low insulin levels may associate with LV dysfunction. Our findings underline the potential of non-invasive cMRI as a tool for monitoring cardiovascular function in SLE patients.
Language	English
Publishing date	2023-12-29
Publishing country	United States
Document type	Journal Article
ISSN	2644-2809
ISSN (online)	2644-2809
DOI	10.26502/jrci.2809088
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