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Aerobic Exercise and Cardiac Function of Murines Exposed to Doxorubicin: a Meta-Analysis

Abstract

Background:

Cardiotoxicity may be a consequence of treatments with doxorubicin (DOX).

Objectives:

To investigate the effect of aerobic exercise on the prevention of cardiac dysfunction in murines exposed to DOX.

Method:

A comprehensive search was conducted in 9 databases in December 2017. Studies that evaluated the cardiac function of murines exposed to DOX were included. The significance level adopted was 5%.

Results:

In a comparison between 230 murines that underwent aerobic exercise plus DOX treatment and 222 control murines (DOX treatment only), fractional shortening showed an improvement of 5.33% in favor of the experimental group (p = 0.00001). Left ventricle developed pressure also showed an increase of 24.84 mm Hg in favor of the group of 153 murines that performed exercise in comparison to the control group of 166 murines (p = 0.00001).

Conclusion:

Preclinical studies included in this meta-analysis indicated that exercise is a good nonpharmacological strategy for preserving post-DOX cardiac function.

Keywords:
Muridae; Exercise; Anti-Bacterial Agents; Doxorubicin; Meta-Analysis

Resumo

Fundamento:

A cardiotoxicidade pode ser uma consequência do tratamento com doxorrubicina (DOX).

Objetivos:

Verificar o efeito do exercício aeróbio na prevenção da disfunção cardíaca de murinos expostos à DOX.

Método:

Uma busca abrangente foi realizada em nove bases de dados, em dezembro de 2017. Estudos que avaliaram a função cardíaca de murinos expostos à DOX foram incluídos. O nível de significância adotado foi de 5%.

Resultados:

Na comparação entre 230 murinos submetidos a exercício aeróbio mais DOX e 222 controles (tratados somente com DOX), a fração de encurtamento mostrou uma melhora de 5,33% a favor do grupo experimental (p = 0,0001). A pressão desenvolvida no ventrículo esquerdo também mostrou um aumento de 24,84 mmHg a favor do grupo de 153 murinos que realizaram exercício em comparação com o grupo controle de 166 murinos (p = 0,00001).

Conclusão:

Estudos pré-clínicos incluídos nesta metanálise indicaram que o exercício é uma boa estratégia não farmacológica para preservar a função cardíaca pós-DOX.

Palavras-chave:
Muridae; Exercício Físico; Antibacterianos; Doxorrubicina; Metanálise

Introduction

Chemotherapy exposes a new panorama in oncology, in which the survival of patients has increased along with their vulnerability to acquired cardiotoxicity in advanced treatments.11. Kalil Filho R, Hajjar LA, Bacal F, Hoff PM, Diz MDP, Galas FRBG, et al. I Diretriz Brasileira de Cardio-Oncologia da Sociedade Brasileira de Cardiologia. Arq Bras Cardiol. 2011;96(2):01-52. The effects of the toxicity generated by the antineoplastic agents used in the treatment may manifest immediately, during their administration, or even years later.22. Yeh ETH, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122-31.,33. Carver JR, Shapiro CL, Andrea Ng, Jacobs L, Schwartz C, Virgo KS, et al. American Society of Clinical Oncology Clinical Evidence Review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. 2007;25(25):3991-4008. Among the organs affected, the heart deserves special attention because heart failure, often acquired after chemical treatment, has an equal or worse prognosis when compared to cancers in the liver, intestine, bladder, prostate, breast, and ovary. Therefore, such complications may interrupt the treatment and compromise the probability of a cure.44. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More ‘malignant'than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3(3):315-22.

Doxorubicin (DOX) is an efficient chemotherapeutic agent in the fight against breast cancer, solid tumors in children, and aggressive lymphomas.55. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56(2):185-229. However, studies suggest that DOX cardiotoxicity promotes a decrease in left ventricular ejection fraction (LVEF). The incidence of cardiomyopathies in patients previously or currently treated with DOX is 3% to 26%, but data on the prevalence are still scarce.66. Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M. Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc. 2014;89(9):1287-306. The decrease in LVEF may begin with the first doses of DOX and is related to the cumulative dose. Doses below 550 mg/m2 may reduce the possibility of cardiomyopathies.22. Yeh ETH, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122-31. Higher doses may cause permanent damage to the myocardium, characterized by apoptosis of the myocytes, resulting in fibrosis and consequent loss of cardiac function.33. Carver JR, Shapiro CL, Andrea Ng, Jacobs L, Schwartz C, Virgo KS, et al. American Society of Clinical Oncology Clinical Evidence Review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. 2007;25(25):3991-4008.

Oxidative stress potentiated by DOX seems to initiate a series of biochemical processes in cardiac muscle fibers, which result in injury to the sarcoplasmic reticulum and mitochondria, structural and functional modification of myofibrils, and modification of the excitation-contraction coupling and calcium flux. These changes lead to apoptosis and, ultimately, loss of the regeneration capacity of the cardiac muscle.77. Scott JM, Khakoo A, Mackey JR, Haykowsky MJ, Douglas PS, Jones LW. Modulation of anthracycline-induced cardiotoxicity by aerobic exercise in breast cancer. Circulation. 2011;124(5):642-50.

Improved immune system function, reduced inflammatory activity, and attenuated metabolic effects of immobility and chemotherapy are some of the benefits of exercise, making it an efficient nonpharmacological tool that can reduce the toxic effects of DOX and help improve the quality of life of patients undergoing treatment.88. Adamsen, L, Quist M, Andersen C, Møller T, Herrstedt J, Kronborg D, et al. Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ. 2009 Oct;339:b3410.,99. Ashrafi J, Roshan VD. Is short-term exercise a therapeutic tool for improvement of cardioprotection against DOX-induced cardiotoxicity? An experimental controlled protocol in rats. Asian Pac J Cancer Prev. 2012;13(8):4025-30. The cardioprotective potential of exercise against cardiotoxicity seems to be linked to several molecular mechanisms, such as increased antioxidant production, regulation of proapoptotic signaling, limitation of myocyte turnover, modulation of cardiac AMP-activated protein kinase (AMPK) activity, negative regulation of cardiac autophagy, reduction in myocardial accumulation of DOX, and others.1010. Lyon AR, Habibian M. Break a sweat to reduce cardiotoxicity-the benefits of exercise training during anthracycline chemotherapy. Eur J Prev Cardiol. 2019;26(3):301-4.1212. Kouzi SA, Uddin MN. Aerobic exercise training as a potential cardioprotective strategy to attenuate doxorubicin-induced cardiotoxicity. J Pharm Pharm Sci. 2016;19(3):399-410.

Studies on exercise and cardiac dysfunction caused by DOX cardiotoxicity in humans are still limited, but there is a reasonable number of preclinical studies in the literature. Therefore, this meta-analysis included preclinical studies and, to the best of our knowledge, is the first on the subject. The aim was to investigate the effects of aerobic exercise on the cardiac function of murines exposed to DOX.

Methods

Inclusion Criteria

Randomized controlled trials (RCTs) of murines that performed aerobic exercise before, during, and after exposure to DOX compared to a control group were included. The cardiac function should have been measured by fractional shortening (FS%) and left ventricular developed pressure (LVDP).

Exclusion Criteria

We excluded studies that used different designs from RCTs, that used concomitant medication in the experimental exercise group, that included humans, or that had no mean and standard deviation for FS% and LVDP results.

Search

The search was conducted in December 2017 using the MEDLINE, LILACS, CENTRAL Cochrane, PEDro, CINAHL, ScienceDirect, SPORTDiscus, Scopus, and Web of Science electronic databases. The descriptors cardiotoxicity, cancer, doxorubicin, exercise, and all synonyms present in the Medical Subject Headings and Descriptors in Health Sciences databases were used in the search.

Data Extracted from the Studies

The types of exercises, training protocols, dosages of DOX infusions, forms of administration, period of exposure to the drug, FS% and LVDP (mm Hg) results, and sample sizes were extracted from the studies selected for review.

For the in vivo analysis of cardiac function, left ventricular FS% measured by echocardiography and Doppler was considered. FS% is one of the main parameters to be monitored in patients exposed to cardiotoxic therapies, as this is an indicative measure of left ventricular systolic function.1313. Costa MP, Castier MB, Salgado CG. Role of echocardiograms for evaluating cardiotoxicity in breast cancer treatment. Rev Bras Cardiol. 2011;24(6):382-6.,1414. Campos Filho O, Zielinsky P, Ortiz J, Maciel BC, Andrade JL, Mathias Jr W, et al. Diretriz para indicações e utilização da ecocardiografia na prática clínica. Arq Bras Cardiol. 2004, 82, 11-34.

An evaluation of LVDP using a pressure transducer positioned in the left ventricle (LV), based on the Langendorff cardiac isolation model, is common in such studies. Therefore, the ex vivo analysis was also considered to examine the contractile capacity of the LV.1515. Cesaretti MLR, Ginoza M, Ribeiro AB, Kohlmann Jr O. Systemic hemodynamic and left ventricular function of diabetic-induced hypertensive rats. Arq Bras Endocrinol Metab. 2010;54(9):842-51.

Analysis of Methodological Quality

An independent evaluator analyzed the risk of bias in each study included in the meta-analysis using the Cochrane Collaboration tool for assessing risk of bias in randomized trials (2005-2007), available for download at http://www.cochrane-handbook.org. Following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions,1616. Higgins J, Green S. Cochrane handbook for systematic reviews of interventions. New Jersey: John Wiley & Sons; 2008. the GRADE approach via GRADEproGDT, available at https://gradepro.org/, was used to analyze the level of evidence for each outcome (FS% and LVDP).

Statistical analysis

Review Manager v. 5.3, with a continuous outcome, statistical method of inverse variance, random-effects model analysis, measure of effect by mean difference, and 95% confidence interval (CI), was used for the studies and for the meta-analysis and ordering of studies by weight. The significance level adopted was 0.05.

Results

The steps performed in the search of the manuscripts are described in the diagram in Figure 1. Among the 9 studies selected for analysis, 7 had FS% results and 4 had LVDP results. Only 2 studies had both variables analyzed.

Figure 1
Flow diagram of the studies (Prisma, 2009)18. *Studies excluded because they did not fulfill the inclusion criteria; **Studies excluded because of concomitant use of medication in the experimental group, inclusion of humans, and/or absence of mean and standard deviation response for cardiac function. FS%: fractional shortening; LVDP: left ventricular developed pressure.

The study conducted by Hydock et al.1919. Hydock DS, Lien CY, Jensen BT, Parry TL, Schneider CM, Hayward R. Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity. Exp Biol Med. 2012;237(12):1483-92. (2012) tested 2 different DOX injection protocols. Therefore, it was divided into two analyses named “a” and “b”. To assess the influence of the female hormone on DOX-induced cardiotoxicity, the study performed by Calvé et al.2020. Calvé A, Haddad R, Barama SN, Meilleur M, Sebag IA, Chalifour LE. Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training. Am J Physiol Heart Circ Physiol. 2012;302(10):H2048-57. (2012) was divided into “a” with normal rats and “b” with ovariectomized rats. Using 2 different exercise protocols, the study conducted by Jensen et al.2222. Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9. (2013) was divided into “a”, in which the rats underwent a progressive treadmill protocol, and “b”, in which the rats had free access to the running wheel. To better understand the results and their comparisons, Lien et al.2424. Lien CY, Jensen BT, Hydock, DS, Hayward R. Short-term exercise training attenuates acute doxorubicin cardiotoxicity. J Physiol Biochem. 2015;71(4):669-78. (2015) conducted four studies (“a”, “b”, “c”, “d”) according to the number of active groups (Tables 1 and 2).

Table 1
Summary of studies selected for the variable left ventricular fractional shortening (FS%).
Table 2
Summary of studies selected for the variable left ventricular developed pressure (LVDP), mm Hg

The results for FS% and LVDP as well as I22. Yeh ETH, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122-31. in this meta-analysis are shown in Figures 2 and 3.

Figure 2
Forest plot of the studies of murines exposed to doxorubicin that compared fractional shortening in a group that performed aerobic exercise and a sedentary control group. SD: standard deviation; IV: inverse variance; CI: confidence interval.
Figure 3
Forest plot of the studies of murines that compared left ventricular developed pressure in a group that performed aerobic exercise and a sedentary control group. SD: standard deviation; IV: inverse variance; CI: confidence interval.

The risk of bias in the studies and the level of evidence in the meta-analysis are shown in Tables 3 and 4, respectively.

Table 3
Cochrane collaboration tool for evaluation of the risk of bias
Table 4
GRADE tool for analysis of the level of evidence.

Discussion

In the present study, cardiac dysfunction resulting from DOX was evaluated using FS% and LVDP (mm Hg), which are related to left ventricular systolic function. A meta-analysis of the results of 230 murines that underwent aerobic exercise plus DOX treatment and 222 control murines (DOX treatment only) showed a FS% improvement of 5.33 (p = 0.00001) in those that performed aerobic exercise (Figure 2). Similarly, a meta-analysis of the results of 153 murines that underwent aerobic exercise plus DOX treatment and 166 control murines (DOX treatment only) showed a LVDP increase of 24.84 mm Hg (p = 0.00001) in those that performed aerobic exercise (Figure 3). In short, aerobic exercise contributed to improve the systolic function, i.e., to decrease the cardiac dysfunction caused by the use of DOX.

The toxicity of anthracyclines causes severe dysfunction in all muscle tissues. However, the cells in the cardiac muscle appear to accumulate higher amounts of DOX than the cells in the smooth and skeletal muscles.2727. Hayward R, Hydock D, Gibson N, Greufe S, Bredahl E, Parry T. Tissue retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle function. J Physiol Biochem. 2013;69(2):177-87. Thus, early detection of cardiovascular risk factors, careful monitoring of parameters of left ventricular systolic and diastolic function, and measurement of LVEF and left ventricular filling pressure should be performed periodically in patients undergoing chemotherapy in order to avoid permanent loss of cardiac muscle function due to cardiotoxicity.2828. Margarida C, Duarte-Rodrigues J, Campelo M. Cardiotoxicity in anthracycline therapy: prevention strategies. Rev Port Cardiol. 2016;35(6):359-71.

Aerobic exercise appears to promote the release of antioxidants, thus protecting the cardiac fiber from damage caused by excessive release of reactive oxygen species after exposure to DOX.2929. Ascensão A, Magalhães J, Soraes J, Ferreira R, Neuparth M, Marques F, et al. Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol. 2005;100(3):451-60.3232. Ashrafi J, Roshan VD, Mahjoub S. Cardioprotective effects of aerobic regular exercise against doxorubicin-induced oxidative stress in rat. Afr J Pharm Pharmacol. 2012;6(31):2380-8. This oxidative anti-stress effect is noticed when exercise is performed systematically, before or after exposure to the drug.3333. Marques-Aleixo I, Santos-Alves E, Mariani D, Rizo-Roca D, Padrão AI, Rocha-Rodrigues S, et al. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion. 2015 Jan;20:22-33. Although the cells are endowed with an endogenous anti-oxidant system, cardiomyocytes have a very low capacity for activation of this system when compared with cells from other tissues.3434. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57(7):727-41.,3535. Kirkham AA, Margot KD. Exercise prevention of cardiovascular disease in breast cancer survivors. J Oncol. 2015;2015:917606. Thus, aerobic exercise has proved to be a good nonpharmacological strategy to fight cardiotoxicity.3636. Ashrafi J, Roshan VD. Pretreatment effect of running exercise on HSP70 and DOX-induced cardiotoxicity. Asian Pac J Cancer Prev. 2012;13(11):5849-55.

In humans, regular aerobic exercise 3 to 4 times a week for 40 minutes using moderate-to-extreme intensity activities seems to have a direct effect on the prevention of cardiovascular diseases, regardless of other risk factors, and contributes to lower the rates of cardiac mortality among those who practice it.3737. Eckel RH, Jakicic JM, Ard JD, Jesus JM, Miller NH, Hubbard VS, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl):S76-99.,3838. Perk J, De Backer G, Gohlke H, Graham I, Reiner Ž, Verschuren WM, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Int J Behav Med. 2012;19(4):403-88. This frequency of exercise also affects the production of free radicals, protecting trained patients from the chronic effects generated by the oxidative stress of daily physical activities.3939. Leaf DA, Kleinman MT, Hamilton M, Deitrick RW. The exercise-induced oxidative stress paradox: the effects of physical exercise training. Am J Med Sci. 1999;317(5):295-300.

A metaepidemiological study showed that an aerobic exercise intervention had a similar effect to drugs such as beta-blockers and angiotensin-converting enzyme inhibitors on mortality rates and secondary prevention in patients with coronary diseases, stroke rehabilitation, and treatment of heart failure.4040. Naci H, Ioannidis JP. Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. BMJ. 2013 Oct 01;347:f5577. Thus, it is important to consider the nonpharmacological treatment with exercise for patients exposed to interventions that accentuate the risk of cardiovascular diseases, such as chemotherapy.

Another positive aspect of exercise is related to fatigue, which, in addition to being a primary symptom of many cardiac events, is common in patients exposed to chemotherapy. Puetz, Beasman, and O'Connor4141. Puetz TW, Beasman KM, O'Connor PJ. The effect of cardiac rehabilitation exercise programs on feelings of energy and fatigue: a meta-analysis of research from 1945 to 2005. Eur J Cardiovasc Prev Rehabil. 2006;13(6):886-93. concluded in a meta-analysis that exercise programs for cardiac rehabilitation are associated with the perception of increased energy and decreased fatigue.4141. Puetz TW, Beasman KM, O'Connor PJ. The effect of cardiac rehabilitation exercise programs on feelings of energy and fatigue: a meta-analysis of research from 1945 to 2005. Eur J Cardiovasc Prev Rehabil. 2006;13(6):886-93.

The results found in this meta-analysis in favor of the group that underwent aerobic exercise plus DOX are strengthened by the findings of previous systematic reviews on the subject, which showed that the ability of aerobic exercise to prevent and fight cardiotoxicity generated by DOX exposure appears to be well established in animal studies.4242. Hahn VS, Lenihan DJ, Ky B. Cancer therapy–induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. J Am Heart Assoc. 2014;3(2):e000665.,4343. Wonders KY, Reigle BS. Trastuzumab and doxorubicin-related cardiotoxicity and the cardioprotective role of exercise. Integr Cancer Ther. 2009;8(1):17-21. However, the mechanisms of this effect have not yet been fully clarified.4444. Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB. Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):114-21.,4545. Maia TN, Araujo GBRD, Teixeira JAC, Alves Jr ED, Dias KP. Cardiotoxicity of doxorubicin treatment and physical activity: a systematic review. Int J Cardiovasc Sci. 2017;30(1):70-80.

In a review of the effects of physical exercise on cardiovascular response in patients with breast cancer, Sturgeon et al.4646. Sturgeon KM, Ky B, Libonati JR, Schmitz KH. The effects of exercise on cardiovascular outcomes before, during, and after treatment for breast cancer. Breast Cancer Res Treat. 2014;143(2):219-26. revealed a lack of studies focused on cardiotoxicity in humans. They showed that although a few preclinical studies indicate a decrease in resting heart rate and blood pressure in patients who practiced aerobic exercise during and after chemotherapy, these parameters are not sufficient to indicate good cardiac function. Kirkham et al.4747. Kirkham AA, Shave RE, Bland KA, Bovard JM, Eves ND, Gelmon KA, et al. Protective effects of acute exercise prior to doxorubicin on cardiac function of breast cancer patients: a proof-of-concept RCT. Int J Cardiol. 2017;245:263-70. however, in a recent proof-of-concept study of patients with breast cancer, found favorable results when assessing the systolic function of the group that practiced only 1 aerobic exercise session of vigorous-intensity treadmill running up to 24 hours prior to DOX treatment.

Limitations

For both outcomes, the inconsistency between the studies was very high, with I22. Yeh ETH, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122-31. = 87% (p = 0.00001) for FS% and I22. Yeh ETH, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122-31. = 94% (p = 0.00001) for LVDP (Figures 2 and 3). Such inconsistency may be related to the wide variation in types of exercises, intervention protocols, and DOX dosage used (Tables 1 and 2). Thus, a random-effects analysis of the results was chosen. However, the final result does not seem to have been affected by this great heterogeneity. For example, of the 4 studies with the highest weight for FS%, 2 performed exercise before DOX and 2 after DOX, protocols ranged from 4 weeks to 10 weeks, and total DOX dose ranged from 3 mg/kg to 32 mg/kg. Therefore, it was not possible to conclude which protocols were the best.

These findings from preclinical studies provide only indirect evidence regarding clinical practice. Therefore, the GRADE tool had 2 levels lowered in the indirectness item, which resulted in a low level of evidence for the study variables.

Conclusion

This meta-analysis showed that, in studies of murines exposed to DOX, aerobic exercise before, during, or after exposure, performed in a single session or for up to 3 months, is a good strategy for maintenance of left ventricular function. Preclinical studies showed that, at this stage of research, exercise was a good nonpharmacological strategy to preserve cardiac function against damage caused by DOX cardiotoxicity.

  • Sources of Funding
    There were no external funding sources for this study.
  • Study Association
    This study is not associated with any thesis or dissertation work.
  • Ethics Approval and Consent to Participate
    This article does not contain any studies with human participants or animals performed by any of the authors.

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Publication Dates

  • Publication in this collection
    07 Dec 2020
  • Date of issue
    Nov 2020

History

  • Received
    31 May 2019
  • Reviewed
    04 Aug 2019
  • Accepted
    10 Sept 2019
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