<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04450576</url>
  </required_header>
  <id_info>
    <org_study_id>PIRB74</org_study_id>
    <nct_id>NCT04450576</nct_id>
  </id_info>
  <brief_title>HbA1c as an Early Serologic Marker for the Hemodynamic Progression of Stage A Heart Failure</brief_title>
  <official_title>HbA1c as an Early Serologic Marker for the Hemodynamic Progression of Stage A Heart</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Parkview Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Parkview Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In a retrospective community based cohort study from Pueblo County Colorado which has a&#xD;
      higher population proportion of metabolic syndrome and diabetes mellitus, we hope to clarify&#xD;
      and quantify an association of the AGE HBa1c elevation with the early subclinical hemodynamic&#xD;
      changes of diabetic cardiomyopathy as measured by LAV, LVM, E/A ratio, E/e' ratio and BNP in&#xD;
      patients with stage A heart failure.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The classic association of glycemic control, as represented by HBa1c, with progression or&#xD;
      improvement of microvascular and macrovascular clinical complications has been well&#xD;
      documented. Additionally, while the association of HBa1c elevation with a syndrome described&#xD;
      as diabetic cardiomyopathy has also been well documented, the use of the advanced glycation&#xD;
      end product axis (AGE/sRAGE/esRAGE which includes HBa1c) as markers for the early subclinical&#xD;
      hemodynamic changes of diabetic cardiomyopathy has been suggested but less well characterized&#xD;
      or utilized. Stage A heart failure is defined as persons with normal cardiac structure and&#xD;
      function who have predisposing subclinical risks for cardiovascular disease. Estimates&#xD;
      suggest that Stage A heart failure may comprise up to 56% of any community's patient&#xD;
      population and are patients most commonly seen in non-specialty primary care clinics. In&#xD;
      light of newer cardiometabolic agents which show promise in cardiovascular disease primary&#xD;
      prevention, these patients may be an important target for preventative cardiometabolic care.&#xD;
      In a retrospective community based cohort study from Pueblo County Colorado which has a&#xD;
      higher population proportion of metabolic syndrome and diabetes mellitus, we hope to clarify&#xD;
      and quantify an association of the AGE HBa1c elevation with the early subclinical hemodynamic&#xD;
      changes of diabetic cardiomyopathy as measured by LAV, LVM, E/A ratio, E/e' ratio and BNP in&#xD;
      patients with stage A heart failure.&#xD;
&#xD;
      Methods: Retrospective cohort analysis by chart review of patients presenting to Parkview&#xD;
      Medical Center's inpatient service and outpatient clinics who obtained a full resting echo&#xD;
      characterized by normal cardiac structure and function in conjunction with HBa1c and BNP&#xD;
      levels within a 3 month time window. Using multiple regression analysis of the dependent&#xD;
      variables LAV, LVM, E/A ratio, E/e' ratio and BNP, powered to detect a 5% change in LAV in&#xD;
      conjunction with rising HBa1c levels characterized as normal (&lt;5.7), metabolic syndrome&#xD;
      (5.7-6.4) or diabetic (&gt;6.4) after controlling for the presence of hypertension and coronary&#xD;
      artery disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">December 20, 2019</start_date>
  <completion_date type="Anticipated">December 30, 2020</completion_date>
  <primary_completion_date type="Actual">October 30, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Left Atrial volume</measure>
    <time_frame>3 months</time_frame>
    <description>Echocardiogram</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>BNP</measure>
    <time_frame>3 months</time_frame>
    <description>Serum total values in pg/ml</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>E/e'</measure>
    <time_frame>3 months</time_frame>
    <description>Echocardiogram measure of the ratio of early LA to LV diastolic inflow velocity (E) to tissue doppler measure of mitral annular early diastolic velocity (e') in m/sec. This is a marker of left atrial pressure.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Heart Failure, Diastolic</condition>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Glycosylated hemoglobin</intervention_name>
    <description>Glycosylated hemoglobin levels associated with correlative measures of diastolic cardiac function</description>
    <other_name>Echocardiogram</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Stage A heart failure patients who have had a Glycosylated hemoglobin, BNP and&#xD;
        Echocardiogram with any 3 month contiguous time period during the lookback period&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stage A heart failure on basis of metabolic criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  LV dysfunction, valvular heart disease, hypertension and CAD&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Doug Duffee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Parkview Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Parkview Medical Center</name>
      <address>
        <city>Pueblo</city>
        <state>Colorado</state>
        <zip>81003</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Fowler MJ. Microvascular and macrovascular complications of diabetes. Clinical Diabetes. 2011;29(3):116-122.</citation>
  </reference>
  <reference>
    <citation>Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum In: Lancet 1999 Aug 14;354(9178):602.</citation>
    <PMID>9742976</PMID>
  </reference>
  <reference>
    <citation>Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.</citation>
    <PMID>8366922</PMID>
  </reference>
  <reference>
    <citation>Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002 May 15;287(19):2570-81. doi: 10.1001/jama.287.19.2570.</citation>
    <PMID>12020339</PMID>
  </reference>
  <reference>
    <citation>Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D'Agostino RB Sr, Wilson PW, Savage PJ. Trends in cardiovascular complications of diabetes. JAMA. 2004 Nov 24;292(20):2495-9. doi: 10.1001/jama.292.20.2495.</citation>
    <PMID>15562129</PMID>
  </reference>
  <reference>
    <citation>van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbely A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008 Jan 1;117(1):43-51. doi: 10.1161/CIRCULATIONAHA.107.728550. Epub 2007 Dec 10.</citation>
    <PMID>18071071</PMID>
  </reference>
  <reference>
    <citation>Levelt E, Gulsin G, Neubauer S, McCann GP. MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review. Eur J Endocrinol. 2018 Apr;178(4):R127-R139. doi: 10.1530/EJE-17-0724. Epub 2018 Feb 12.</citation>
    <PMID>29440374</PMID>
  </reference>
  <reference>
    <citation>Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014 Feb;18(1):1-14. doi: 10.4196/kjpp.2014.18.1.1. Epub 2014 Feb 13.</citation>
    <PMID>24634591</PMID>
  </reference>
  <reference>
    <citation>Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016 Mar;12(3):144-53. doi: 10.1038/nrendo.2015.216. Epub 2015 Dec 18.</citation>
    <PMID>26678809</PMID>
  </reference>
  <reference>
    <citation>Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20;112(12):e154-235. doi: 10.1161/CIRCULATIONAHA.105.167586. Epub 2005 Sep 13. No abstract available.</citation>
    <PMID>16160202</PMID>
  </reference>
  <reference>
    <citation>Ammar KA, Jacobsen SJ, Mahoney DW, Kors JA, Redfield MM, Burnett JC Jr, Rodeheffer RJ. Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community. Circulation. 2007 Mar 27;115(12):1563-70. doi: 10.1161/CIRCULATIONAHA.106.666818. Epub 2007 Mar 12.</citation>
    <PMID>17353436</PMID>
  </reference>
  <reference>
    <citation>Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkovic V. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019 Aug 27;140(9):739-750. doi: 10.1161/CIRCULATIONAHA.119.042007. Epub 2019 Jul 11.</citation>
    <PMID>31291786</PMID>
  </reference>
  <reference>
    <citation>From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol. 2010 Jan 26;55(4):300-5. doi: 10.1016/j.jacc.2009.12.003. Erratum In: J Am Coll Cardiol. 2010 Nov 2;56(19):1612.</citation>
    <PMID>20117433</PMID>
  </reference>
  <reference>
    <citation>Pueblo County 2016 Community Health Status report.</citation>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 29, 2020</study_first_posted>
  <last_update_submitted>November 12, 2020</last_update_submitted>
  <last_update_submitted_qc>November 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Heart Failure, Diastolic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chrysarobin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>no plan to make IPD available outside our facility</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>January 28, 2021</submitted>
    <returned>February 16, 2021</returned>
    <submitted>September 21, 2021</submitted>
    <returned>October 19, 2021</returned>
    <submitted>September 30, 2022</submitted>
    <returned>August 14, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04450576
org study id: PIRB74
nct id: NCT04450576
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In a retrospective community based cohort study from Pueblo County Colorado which has a
      higher population proportion of metabolic syndrome and diabetes mellitus, we hope to clarify
      and quantify an association of the AGE HBa1c elevation with the early subclinical hemodynamic
      changes of diabetic cardiomyopathy as measured by LAV, LVM, E/A ratio, E/e' ratio and BNP in
      patients with stage A heart failure.
The classic association of glycemic control, as represented by HBa1c, with progression or
      improvement of microvascular and macrovascular clinical complications has been well
      documented. Additionally, while the association of HBa1c elevation with a syndrome described
      as diabetic cardiomyopathy has also been well documented, the use of the advanced glycation
      end product axis (AGE/sRAGE/esRAGE which includes HBa1c) as markers for the early subclinical
      hemodynamic changes of diabetic cardiomyopathy has been suggested but less well characterized
      or utilized. Stage A heart failure is defined as persons with normal cardiac structure and
      function who have predisposing subclinical risks for cardiovascular disease. Estimates
      suggest that Stage A heart failure may comprise up to 56% of any community's patient
      population and are patients most commonly seen in non-specialty primary care clinics. In
      light of newer cardiometabolic agents which show promise in cardiovascular disease primary
      prevention, these patients may be an important target for preventative cardiometabolic care.
      In a retrospective community based cohort study from Pueblo County Colorado which has a
      higher population proportion of metabolic syndrome and diabetes mellitus, we hope to clarify
      and quantify an association of the AGE HBa1c elevation with the early subclinical hemodynamic
      changes of diabetic cardiomyopathy as measured by LAV, LVM, E/A ratio, E/e' ratio and BNP in
      patients with stage A heart failure.

      Methods: Retrospective cohort analysis by chart review of patients presenting to Parkview
      Medical Center's inpatient service and outpatient clinics who obtained a full resting echo
      characterized by normal cardiac structure and function in conjunction with HBa1c and BNP
      levels within a 3 month time window. Using multiple regression analysis of the dependent
      variables LAV, LVM, E/A ratio, E/e' ratio and BNP, powered to detect a 5% change in LAV in
      conjunction with rising HBa1c levels characterized as normal (<5.7), metabolic syndrome
      (5.7-6.4) or diabetic (>6.4) after controlling for the presence of hypertension and coronary
      artery disease.
observational model: Cohort
time perspective: Retrospective
measure: Left Atrial volume
time frame: 3 months
description: Echocardiogram
measure: BNP
time frame: 3 months
description: Serum total values in pg/ml
measure: E/e'
time frame: 3 months
description: Echocardiogram measure of the ratio of early LA to LV diastolic inflow velocity (E) to tissue doppler measure of mitral annular early diastolic velocity (e') in m/sec. This is a marker of left atrial pressure.
intervention type: Diagnostic Test
intervention name: Glycosylated hemoglobin
description: Glycosylated hemoglobin levels associated with correlative measures of diastolic cardiac function
other name: Echocardiogram
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
last name: Doug Duffee, MD
role: Principal Investigator
affiliation: Parkview Medical Center
facility: 
country: United States
citation: Fowler MJ. Microvascular and macrovascular complications of diabetes. Clinical Diabetes. 2011;29(3):116-122.
citation: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum In: Lancet 1999 Aug 14;354(9178):602.
PMID: 9742976
citation: Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
PMID: 8366922
citation: Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002 May 15;287(19):2570-81. doi: 10.1001/jama.287.19.2570.
PMID: 12020339
citation: Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D'Agostino RB Sr, Wilson PW, Savage PJ. Trends in cardiovascular complications of diabetes. JAMA. 2004 Nov 24;292(20):2495-9. doi: 10.1001/jama.292.20.2495.
PMID: 15562129
citation: van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbely A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008 Jan 1;117(1):43-51. doi: 10.1161/CIRCULATIONAHA.107.728550. Epub 2007 Dec 10.
PMID: 18071071
citation: Levelt E, Gulsin G, Neubauer S, McCann GP. MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review. Eur J Endocrinol. 2018 Apr;178(4):R127-R139. doi: 10.1530/EJE-17-0724. Epub 2018 Feb 12.
PMID: 29440374
citation: Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014 Feb;18(1):1-14. doi: 10.4196/kjpp.2014.18.1.1. Epub 2014 Feb 13.
PMID: 24634591
citation: Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016 Mar;12(3):144-53. doi: 10.1038/nrendo.2015.216. Epub 2015 Dec 18.
PMID: 26678809
citation: Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20;112(12):e154-235. doi: 10.1161/CIRCULATIONAHA.105.167586. Epub 2005 Sep 13. No abstract available.
PMID: 16160202
citation: Ammar KA, Jacobsen SJ, Mahoney DW, Kors JA, Redfield MM, Burnett JC Jr, Rodeheffer RJ. Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community. Circulation. 2007 Mar 27;115(12):1563-70. doi: 10.1161/CIRCULATIONAHA.106.666818. Epub 2007 Mar 12.
PMID: 17353436
citation: Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkovic V. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019 Aug 27;140(9):739-750. doi: 10.1161/CIRCULATIONAHA.119.042007. Epub 2019 Jul 11.
PMID: 31291786
citation: From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol. 2010 Jan 26;55(4):300-5. doi: 10.1016/j.jacc.2009.12.003. Erratum In: J Am Coll Cardiol. 2010 Nov 2;56(19):1612.
PMID: 20117433
citation: Pueblo County 2016 Community Health Status report.
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Heart Failure, Diastolic
mesh term: Chrysarobin
sharing ipd: No
ipd description: no plan to make IPD available outside our facility
submitted: January 28, 2021
returned: February 16, 2021
submitted: September 21, 2021
returned: October 19, 2021
submitted: September 30, 2022
returned: August 14, 2023