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Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."
Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011
Dr. Shankar P.R.
"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."
Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011 Anuradha
Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.
Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020
Original article / research
Full Version
Prediction of Reperfusion Outcome using Platelet Indices in Primary Percutaneous Coronary Intervention- A Prospective Cohort Study
Correspondence Address :
Dr. Thomas Varghese Attumalil,
329, Bapuji Nagar Medical College, Trivandrum-695011, Kerala, India.
E-mail: dr.thomas.attumalil@gmail.com
Introduction: Platelets play a vital role in systemic inflammation and thrombus formation in ST Elevation Myocardial Infarction (STEMI). Understanding its role has diagnostic and prognostic implications in developing therapeutic strategies.
Aim: To estimate the prognostic accuracy of platelet indices- Mean Platelet Volume (MPV), Platelet Distribution Width (PDW) and MPV/Platelet Count (PC) ratio (MPV/PC ratio) on reperfusion outcome in STEMI patients.
Materials and Methods: This prospective cohort study enrolled 262 subjects, who presented with acute chest pain within a window period of 12 hours, and an Electrocardiogram (ECG) suggestive of STEMI. Blood samples collected on admission were measured for MPV and PDW. The major endpoints studied were angiographic thrombus burden and in-hospital Major Adverse Cardiovascular Events (MACE). Data was summarised by mean and Standard Deviation (SD) for continuous variables, frequency and percentage for categorical variables.
Results: This study demonstrated that Acute Coronary Syndrome- STEMI (ACS-STEMI) patients with larger PDW had Larger Thrombus Burden (LTB). PDW of more than 13 fL was the best cut-off for predicting LTB with a sensitivity of 67.01% and a specificity of 53.23%. There was no significant difference between the means of MPV in LTB and small thrombus burden. The total in-hospital MACE at the end of one week was 20.99% (n=55/262 patients). The maximum MACE was contributed by acute heart failure (12.6%), followed by cardiac death (6.1%) and stent thrombosis (1.5%). There was a significant association between increased PDW and in-hospital MACE, mortality and acute heart failure (p-value=0.024, p-value=0.03, p-value=0.02, respectively). The best cut-off PDW value for prediction of the composite MACE endpoint was 14.7 fL with sensitivity of 75.6% and specificity of 51.4% and the area under the Receiver Operating Characteristic (ROC) curve was 0.63 (95% CI, 0.57 to 0.69).
Conclusion: The study emphasised on the use of platelet indices, especially PDW, as a predictor of poorer reperfusion outcomes in primary Percutaneous Coronary Intervention (PCI) as evidenced by higher MACE rates in patients with higher PDW. Hence, PDW can help in predicting the thrombus burden even before doing the angiogram and such high-risk patients could benefit from early initiation of stronger antiplatelets, Glycoprotein (Gp) IIb/IIIa antagonist drugs and thrombus aspiration techniques.
Acute coronary syndrome, Platelet activation, Thrombus burden
Acute Coronary Syndrome (ACS), including unstable angina, Myocardial Infarction (MI), and sudden ischaemic death, are leading causes of morbidity and mortality. Despite immense advancements, prognosticating ACS remains a challenge, with little knowledge on mechanisms of ACS beyond the standard risk factors. Systemic inflammation is considered to be the hallmark of ACS and platelets are the primary source of inflammatory mediators (1).
Platelets play a crucial role at the site of plaque rupture by activating the thrombus formation which a major event in the development of ACS. It remains a significant challenge in the treatment of these patients. Novel antiplatelet strategies that prevent platelet endothelial cell interaction and activation may provide an efficacious intervention to improve the prognosis of patients with coronary atherosclerosis (2).
ACS itself is a proinflammatory state, with increased inflammatory markers like interleukin 3 (IL-3), IL-6, which stimulates megakaryocyte proliferation (3). Larger platelets are released from the bone marrow due to the increase in serum thrombopoietin levels secondary to platelet consumption during acute MI (4). Larger platelets are enzymatically and metabolically more active, and produce more thromboxane A2 (5). The above facts suggest there should be a close association between platelets size, platelet reactivity and events secondary to their activity like ischaemic heart events. To show this association platelets volume indices could be used.
MPV, being a reliable index of the functional status of platelets, is an emerging as a risk marker for atherothrombosis. Elevated MPV may be suggestive of activated platelets, contributing to increased risk of ACS (6). Moreover, evidence suggests that MPV may be a risk factor for recurrent MI independent of other risk factors as hypertension and dyslipidemia (7).
PDW is the relative distribution width of platelets in volume index. PDW is an indication of variation in platelet size, which can be a sign of active platelet release (8). The PDW was found to independently predict long-term as well as in-hospital adverse outcomes in patients with ACS (9). An increased PDW is associated with increased severity of Coronary Artery Disease (CAD) in patients with ACS (8). PDW unlike MPV does not get elevated by platelet swelling which occurs during blood storage hence PDW is a more specific indicator of platelet activation (10).
Most studies have shown that platelet indices at the time of hospitalisation are a strong and independent predictor of impaired reperfusion and mortality in STEMI treated with primary PCI (11),(12). High PDW was found to be an independent predictor of adverse prognosis in patients with Heart Failure (HF) (13). However, none of the studies has quantified the thrombus burden in the infarct- related artery or attempted to demonstrate a relationship between the thrombus burden and the platelet indices. Thus, understanding the role of platelets in ACS may lead to new concepts and development of therapeutic strategies (1). In view of its diagnostic importance and prognostic significance, our study in patient’s diagnosed with ACS-STEMI aimed to emphasise the relationship between the platelet indices MPV, PDW and ACS. Hence, a prospective study was planned to evaluate the effectiveness of platelet indices which may determine the outcome of patients admitted with ACS-STEMI, and to estimate the diagnostic accuracy of platelet indices in determining the angiographic thrombus burden.
A prospective cohort study was conducted at the university-level teaching hospital, in Government Medical College, Trivandrum, Kerala, India from April 2017 to May 2018, after obtaining ethical clearance from Institutional Review Board (IEC.No.05/15/2017/MCT). Written informed consent was taken from all the participants prior to the study.
The primary outcome was to determine the association between platelet indices, MACE and thrombus burden. The seven day in-hospital MACE included death, acute heart failure, reinfarction, stent thrombosis, or any repeat revascularisation. Thrombus burden in infarct related artery was graded according to Thrombolysis in Myocardial Infarction (TIMI) grading for thrombus burden (14). The secondary outcome included estimation of the diagnostic accuracy of platelet indices in determining the angiographic thrombus burden.
Sample size calculation: Expecting an incidence of 28.75% of MACE in the study population, the study required a sample size of 240 subjects (p-value <0.05 and 80% power) (15).
Inclusion criteria: All patients above 18 years who were admitted with chest pain within the window period of 12 hours, with Killip class I-IV, an Electrocardiogram (ECG) diagnosis of STEMI according to the 2018 Fourth Universal Definition of MI and agreed to undergo primary PCI were invited to participate in the study (16).
Exclusion criteria: Pregnant women, subjects with history of previous cardiomyopathy, or previous MI or any revascularisation procedures Percutaneous Coronary Intervention (PCI), Coronary Artery Bypass Grafting (CABG), or congenital heart disease, history of intake of any drugs causing thrombocytopenia in the last six months were excluded from the study. Also patients with any platelet or bleeding disorders, or any recent blood transfusions, or any intercurrent fever with thrombocytopenia, Chronic Liver Disease (CLD), Chronic Kidney Disease (CKD) patients, any treatment with a fibrinolytic agent within the previous 24 hours were also excluded from this study.
Study Procedure
A structured questionnaire was used to record clinical and demographic profile of the patient. On admission 4 mL of blood was collected in prefilled Ethylenediaminetetraacetic Acid (EDTA) vials from each patient. Platelet indices were estimated within two hours of collection with automated Sysmex five part haematology analyser. All patients underwent PCI. The principal investigator who was blinded to the platelet indices analysed all the coronary angiograms.
The study population was divided into two groups comprising: 1) low thrombus burden (TIMI thrombus grade 1-3) and 2) high thrombus burden (TIMI thrombus grade 4-5) according to the bi-level thrombolysis in myocardial thrombus grading scale (17). All were followed-up for a week to look for the primary and secondary outcomes.
Statistical Analysis
Data was summarised by Mean and SD for continuous variables and frequency and percentage for categorical variables. The Mann-Whitney U test and the Chi-square test was applied to determine the difference between groups. All tests were two-sided at α=0.05 level of significance. All analyses were done using Statistical Package for Social Sciences (SPSS) version 21.0.
A total of 262 consecutive patients were included in the study. The mean age of the study population was 58.8±11.63 years. The baseline clinical and platelet characteristics of the study population is given in (Table/Fig 1),(Table/Fig 2). There were 121 (46.2%) patients with STEMI Anterior Wall Myocardial Infarction (AWMI), 45 (17.2%) with Inferior Wall (IW) MI, 93 (35.5%) with IWMI+ Right Ventricular (RV) MI and 3 (1.1%) with Lateral Wall (LW) MI.
The total mean ischaemic period was 356.74±156.6 minutes. The mean ST resolution was 55.53±26.8% (Table/Fig 2). The major risk factors for STEMI which were likely to affect the outcome were evenly matched and comparable in all the study groups.
The angiographic thrombus burden of the study population is given in (Table/Fig 3). Among 262 study participants, 62 (23.7%) of them had only TIMI 0 or 1 thrombus grade, 107 (40.8%) of them had TIMI 2 or 3 thrombus grade and 93 (35.5%) of them had TIMI 4 or 5 thrombus grade. When the study population was divided into two groups comprising small thrombus burden and high thrombus burden according to the bi-level thrombolysis in myocardial thrombus grading scale, it was found that there was a significant difference between the means of PDW in either groups (p-value=0.023). The mean PDW in small thrombus burden was 13.62 fL which was significantly lower when compared to mean PDW of large thrombus burden (14.32 fL) (Table/Fig 4).
The total in-hospital MACE at the end of one week was 20.99% (55/262), out of which the maximum MACE was contributed by acute heart failure 12.6% (33/262 patients) (Table/Fig 5). Other causes were cardiac death 6.1%, stent thrombosis (including probable) 1.5%, reinfarction 0.4%, and repeat revascularistion 0.4%.
There was significant statistical difference between the patients with MACE and without MACE regarding mean PDW (p=0.024). The mean PDW of patients with AHF and mortality was also significantly higher to mean of PDW of patients without AHF or who survived (Table/Fig 5). There was no significant difference in the mean MPV between the patients with MACE and without MACE.
On conducting logistic regression, it was seen that there was a significant positive relation for change in TIMI flow (after PCI) with MPV >9.1 (OR=2.658; 95% CI=1.293-5.467), presence of thrombus burden (OR=1.789; 95% CI=1.235-2.591) and diabetes (OR=2.090; 95% CI=1.039-4.204) (Table/Fig 6). Change in TIMI flow ≥2 was found to have a statistically associated with lower total ischaemic period; with a protective OR=0.997 (95% CI=0.995-0.999). Association with Killip class, lower door to balloon time and ST resolution percentage were not statistically significant.
The diagnostic accuracy of PDW to predict thrombus burden was determined using ROC curve analysis. The area under curve was 0.589 and the best cut-off point for PDW for identifying thrombus burden were found to be >13 fL with a sensitivity and specificity of 67.01% and 53.23%, respectively and Positive Predictive Value (PPV) of 82.5% and Negative Predictive Value (NPV) of 33.7% (Table/Fig 7). The ROC was used to identify cut-off values for predicting the occurrence of MACE endpoints. The best cut-off PDW value for prediction of the composite MACE endpoint was 14.7 fL with sensitivity of 75.6% and specificity of 51.4%. The area under the PDW ROC curve was 0.63 (95% CI 0.57 to 0.69), with PPV as low as 22.6% but NPV of 91.8% (Table/Fig 8).
The present study was designed to find a simple and cost-effective method to evaluate the association between platelets volume indices, and STEMI and to predict the occurrence of thrombus burden and clinical outcomes of STEMI patients undergoing primary PCI.
The mean MPV in this study was obtained as 9.62 fL with SD of 1.03 fL. These values were comparable to the recent Indian study, where the MPV ranged from 6.3 fL to 13.2 fL. (Median 9.1 fL; mean 9.17 (SD 1.0 fL) (15). In this study, the mean PDW was 13.87 fL with SD of 2.44 which was higher than what was observed in another Indian study where the mean PDW in was 10.84±2.2 fL (18).
Significance of PDW in ACS STEMI patients: MPV has been extensively evaluated but novel platelet indices such as PDW have been less well investigated as platelet activation markers. Various morphologic transformations occur during platelet activation such as spherical shape and pseudopodia formation. Thus, platelets with increased number and size of pseudopodia differ in size, which increases PDW. The PDW measures the variability in platelet size (19)
The highlight of this study is the association between PDW and the thrombus burden in the infarct related artery. The mean PDW in small thrombus burden was 13.62 fL which was significantly lower when compared to mean PDW of large thrombus burden. In a study among 13,701 healthy adults in United states, it was observed that PDW and not platelet count or MPV is an independent predictor of cardiovascular and all cause mortality (20).
PDW, being a very economical and automated machine given investigation, can be obtained immediately before the procedure. Hence, the cardiologist can identify those patients who are at high risk for thrombus, and initiate stronger antiplatelets and Gp IIb/IIIa antagonists quite early itself. A higher PDW value can also aid in deciding for thrombus aspiration techniques as well. Currently, thrombus aspiration usage does not have any objective criteria and depends solely on the visual estimation of thrombus by the interventionist. Thus, PDW have a role in the various treatment strategies of primary PCI, especially because it is a powerful predictor of thrombus burden and occurrence of MACE.
The findings of the present study, regarding PDW, are consistent with many other studies. Vagdatli E et al., showed that PDW is a more specific marker of platelet activation, since it does not increase like MPV during platelet swelling (10). Bekler A et al., demonstrated increase in severity of coronary artery disease with increased PDW (8). A retrospective study showed that PDW was significantly raised in patients with myocardial infarction and its estimation may help in early detection of myocardial infarction (21). Bae MH et al., also concluded that PDW is a simple haematological marker that can be used as an aid for stratification of patients with MI (22).
Relation of platelet indices within-hospital mortality and MACE rates: There was no significant difference in the mean MPV between the patients with MACE or without MACE. One reason may be attributed to the change in the platelet volumes on adding varied amounts of EDTA reagent in the blood sample and prolonged time taken to process the blood sample.
However, the mean PDW of patients with MACE, acute heart failure and death were significantly higher to the mean of PDW of patients without MACE or acute heart failure or death (Table/Fig 5). Moreover PDW >14.7fL correlated with higher MACE rates (Table/Fig 8). These findings are in line with another similar study (12) which concluded that higher PDW values (≥ 16 fL) correlated with higher mortality rate as compared to PDW <16 fL (17.4% vs. 6.3%, p=0.0012). Interestingly, Celik T et al., demonstrated similar findings, an admission PDW level of 12.95 fL was associated with 60% sensitivity and 64% specificity in identifying in-hospital MACEs (19). Thus, in accordance with the previous reports, the present study confirms that those having higher value of PDW have a poorer prognosis.
Diagnostic accuracy of platelet volume indices: An admission PDW of >13 fL was associated with 67.01% sensitivity and 53.23% specificity in its association with identifying thrombus burden. Thus, the study found that PDW can be used as a diagnostic aid for predicting the thrombus burden even before taking up the patient for Primary PCI. Numerous factors determine the magnitude of thrombus burden, of which platelets play a central role in the thrombotic occlusion of the Infarct-Related Artery (IRA) thus contributing to the pathophysiology of an acute MI (19). Currently, there are no available studies which utilised PDW as a diagnostic parameter for identifying thrombus burden. Now, there is an objective way to predict thrombus burden prior to the primary PCI, which will be essential for deciding the treatment strategies.
Factors determining improvement in TIMI flow (postprocedure) on Logistic regression: This study revealed that the most important factors that influenced the prognosis of patients taken up for primary PCI were total ischaemic period, followed by door to balloon time, ST resolution, MPV, diabetes, and presence of thrombus burden. There was a significant positive correlation for improvement in TIMI flow with MPV >9.1, presence of thrombus burden and diabetes. Another study assessed “spontaneous” reperfusion of the IRA and short-term clinical outcome in 617 patients with STEMI. They demonstrated that an increased MPV is an independent correlate of both a patent IRA and a 30-day mortality among patients with STEMI (23). Therefore, it is of clinical interest that MPV assessed at hospital admission is found to be a marker of IRA patency postprocedure.
Limitation(s)
This study did not measure other known inflammatory markers such as C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR). Also, platelet function tests such as thrombelastograph was not used. Dual antiplatelet therapy does not influence MPV in patients with CAD undergoing PCI. However, whether MPV/PC ratio is changeable by dual antiplatelet therapy is still unknown. Findings of the study necessitate further large-scale prospective studies to establish the relationship of platelet volume indices with thrombus burden and angiographic outcomes of primary PCI. Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) may provide more accurate information on the amount of atherosclerotic plaque and severity of CAD, in the future, a new study should be performed to obtain the conclusion.
The primary objective of this prospective study was to understand the relationship between platelet indices and the reperfusion outcome (MACE) or thrombus burden. This study demonstrated that ACS-STEMI patients with larger PDW had larger thrombus burden and higher MACE rates. PDW is an inexpensive and easily available biomarker may help in risk stratification and management of STEMI patients. It can be used as a diagnostic aid for predicting the thrombus burden even before taking up the patient for primary PCI, and thereby identify high risk patients who could benefit from more potent antiplatelet or Gp IIb/IIIa antagonist drugs. Higher PDW is a predictor of poorer reperfusion outcomes as evidenced by the higher MACE rates and all-cause mortality. Further studies are needed to elucidate the diagnostic and prognostic value of platelet volume indices which might open up newer therapeutic options in the future.
Declaration: This study was presented at the Annual Conference of Cardiological Society of India, at Kolkata, in 2019.
DOI: 10.7860/JCDR/2022/52851.16215
Date of Submission: Oct 13, 2021
Date of Peer Review: Nov 20, 2021
Date of Acceptance: Jan 10, 2022
Date of Publishing: Apr 01, 2022
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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