Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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On Sep 2018




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Prof. Somashekhar Nimbalkar
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"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



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Lucknow
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On Aug 2018




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"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
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Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
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Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


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.
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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.
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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

Important Notice

Original article / research
Year : 2021 | Month : August | Volume : 15 | Issue : 8 | Page : FC12 - FC15 Full Version

Efficacy and Safety of Linagliptin and Insulin in Patients of Type 2 Diabetes Mellitus with Grade 3-5 Chronic Kidney Disease in a Tertiary Care Hospital


Published: August 1, 2021 | DOI: https://doi.org/10.7860/JCDR/2021/50693.15204
Saajid Hameed, Pankaj Kumar, Ved Prakash, Manish Kumar, Harihar Dikshit

1. Junior Resident, Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. 2. Junior Resident, Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. 3. Associate Professor and Head, Department of Endocrinology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. 4. Associate Professor, Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. 5. Professor and Head, Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India.

Correspondence Address :
Dr. Manish Kumar,
Associate Professor, Department of Pharmacology, Indira Gandhi Institute of
Medical Sciences, Sheikhpura, Patna-800014, Bihar, India.
E-mail: manu072@gmail.com

Abstract

Introduction: Insulin therapy is preferred as safest for glycaemic control in patients with elevated serum urea/creatinine level. Management of diabetes in grade 3-5 Chronic Kidney Disease (CKD) with oral hypoglycaemic is very challenging because most of them cause renal impairment and thus dose adjustment is needed in renal disease. Linagliptin, a DPP-4 (dipeptidyl peptidase-4) inhibitor has only 5% renal excretion; hence its dose adjustment is not needed in patients with CKD.

Aim: To compare the efficacy and safety of linagliptin with insulin in patients of Type 2 Diabetes Mellitus (T2DM) with CKD.

Materials and Methods: The present study was a longitudinal study, in which a total of 101 patients of grade 3-5 CKD with T2DM were divided into two groups, insulin group (n=54) and linagliptin group (n=47), based on their drug therapy. All the cases were tested for HbA1c (Glycated Haemoglobin), Random Blood Sugar (RBS), Creatinine clearance, Urine Protein-Creatinine Ratio (UPCR) and different adverse drug events at their first visit (baseline) and then during follow-up at 1st, 3rd, 6th and 12th month. Statistical analysis was done through GraphPad Instat by unpaired t-test for group comparison and Analysis of Variance (ANOVA) for intragroup comparison.

Results: At the end of study, mean difference of RBS, Creatinine clearance and UPCR in both the groups were not significant. But mean HbA1c level was less in linagliptin group (6.62±0.10) as compared to insulin group (6.82±0.23) on long term therapy and the difference was statistically significant. Hypoglycaemia (33 vs 24), urinary tract infection (6 vs 5) and respiratory tract infection (5 vs 4) were more frequent in insulin group versus linagliptin group.

Conclusion: Linagliptin for glycaemic control provides clinically meaningful improvements in long term glycaemic control without unacceptable side effects in CKD like vulnerable group of patients.

Keywords

Creatinine clearance, Glycaemic control, Glycated haemoglobin, Hypoglycaemia, Urinary tract infection, Urine protein-creatinine ratio

Insulin therapy is preferred as safest for glycaemic control in patient with elevated serum urea/creatinine level. But insulin therapy carries its own drawbacks such as hypoglycaemia, weight gain, lipo-hypertrophy and pain at injection site (1). Diabetes mellitus is identified as the leading cause of renal impairment which can terminate into End Stage Renal Disease (ESRD) and death (2). The prevalence of CKD with T2DM is rising worldwide (3),(4) and the management of blood sugar level of these patients by oral hypoglycaemic has been challenging. As most of antidiabetic drugs either oral or parenteral can cause renal impairment to some extent hence given at reduced dose (5),(6),(7).

Focusing on only managing of CKD and neglecting good glycaemic control can worsen the CKD as standards of diabetes care recommend reducing the risk, or slowing the progression, of CKD by optimising glycaemic control (8). Patient with T2DM need lifelong therapy hence it should be effective and safe. The drugs should be patient compliant especially in developed countries that have adopted luxurious lifestyles with low physical activity and high intake of energy rich foods (9).

Antidiabetic therapy needs frequent monitoring of blood sugar level due to intrinsic risk of hypoglycaemia. Also, it necessitates regular monitoring of organ functions like renal or hepatic function. These laboratory monitoring build additional economic burden on healthcare delivery systems. DPP-4 inhibitors can solve most of these problems because they are non inferior to sulfonylureas regarding efficacy and there is low risk of hypoglycaemia in their use. They are also body weight neutral and can be given as single dose without any titration. In addition to this, DPP-4 inhibitors have a low rate of adverse events and a good compliance (10).

DPP-4 inhibitors have been perceived as crucial addition to the treatment algorithm in T2DM patients and have been suggested as second-and third-line therapy among other agents within the recent joint position statement of the American Diabetes Association (ADA) and also the European Association for the Study of Diabetes (EASD) (10). Linagliptin is the first DPP-4 inhibitor available that is mainly eliminated via a hepatobiliary route and only approximately 5% of linagliptin are excreted with the urine in unmetabolised form (11),(12),(13). Therefore, there is no need for a dose adjustment of linagliptin in patients with CKD (14),(15).

Various studies have shown significant clinical improvement with linagliptin in T2DM as monotherapy (16),(17),(18), in combination with metformin (19), with metformin/sulfonylurea (20), and with thiazolidinedione (21). Keeping these findings of previous researches in mind and to further strengthen the evidence for the use of linagliptin in higher grades of CKD, this study was planned to compare the efficacy and safety of linagliptin and insulin in patients of T2DM and CKD.

Material and Methods

This was a longitudinal study, conducted at Outpatient Department (OPD) of Endocrinology and Department of Pharmacology at Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, Bihar, India. This study was approved by Institutional Ethics Committee of IGIMS, Patna (vide Letter No-637/IEC/IGIMS/2018/Dated 18/12/2018). Informed consent was taken from each study participant.

The study duration was from February 2019 to July 2020. In the first six months, 118 study participants were selected (approx. 500 cases of T2DM with 3-5 grade CKD in the hospital (22). In next months during follow-up, the participant’s laboratory parameters were analysed and compared.

Sampling was done keeping 8% margin of error, 95% confidence level and 62% response distribution of diabetes induced CKD.

Inclusion criteria

• Diagnosed cases of T2DM of age above 18 years and of all gender.
• Diagnosed cases of CKD (grade 3-5) (22).

Exclusion criteria

• Patient having previous hypersensitivity reaction to other DPP-4 inhibitors.
• Immunocompromised patients
• Patients having urinary tract or other systemic infections, haematuria, decompensated heart failure, liver failure, debilitating illness that may adversely affect renal function.

Study Procedure

Total of 118 consecutive patients of grade 3-5 CKD with T2DM were selected from OPD of Endocrinology. They were prescribed either insulin or linagliptin as drug therapy. Out of 118 cases, 67 were given insulin therapy and 51 were given linagliptin therapy. In insulin group and linagliptin group data collection of 54 and 47 cases was done because 13 cases from insulin and four cases form linagliptin group didn’t turn up during follow-up period.

All the patients were screened for demography and baseline clinical characteristics; and tested for following laboratory tests at their first visit (at baseline) and during follow-up period at 1st month, 3rd months, 6th month and 12th month. The tests were:

• HbA1c (Glycated Haemoglobin)
• RBS (Random Blood Sugar)
• Creatinine Clearance (estimated by the Cockcroft-Gault formula)
• Urine Protein-Creatinine ratio (UPCR)
• Hypoglycaemia and other adverse events

Doses of study drugs were given according to the level of blood sugar of individual patients:

• Insulin-6 units of regular insulin were given before breakfast, before lunch and before dinner in most of the patients with RBS level between 200-300 mg/dL. Single dose of 10 units of insulin glargine was given at bedtime.
• Linagliptin- 5 mg once a day in controlled diabetes. Dose had been increased upto 10 mg when required.

Statistical Analysis

Intergroup comparison was done by unpaired t-test and comparison of parameters in the same group was done by repeated measure ANOVA. Data with p-value <0.05 was considered as statistically significant. GraphPad and MS excel 365 was used for statistical analysis.

Results

The study groups were demographically similar (Table/Fig 1). Both the groups showed significant improvement in mean RBS and HbA1c. However, decline in mean RBS and HbA1c in linagliptin group was much better than insulin group (Table/Fig 2), (Table/Fig 3). There was no significant improvement or decline of mean creatinine clearance seen in either group (Table/Fig 4).

Reduction in mean UPCR was extremely significant in both the groups. At the end of the study, the reduction of mean UPCR in linagliptin group was better than insulin group but the difference was not significant (Table/Fig 5).

The most common adverse event was hypoglycaemia followed by hyperglycaemia in both the groups (Table/Fig 6).

Discussion

In this study, the efficacy and safety of linagliptin and insulin was compared in 118 patients of T2DM with grade 3-5 CKD. Linagliptin showed better glycaemic control over insulin on long term therapy. Any deuteriation or reduction of kidney function tests were not evident in either of the groups.

Morton JI et al., found in their study that the cases of ESKD in T2DM patients increases with increasing duration of diabetes and age, suggesting a complex relationship of ESKD risk with age of onset of diabetes (23). McGill JB et al., conducted a 1-year randomised, double-blind, placebo-controlled study for investigation of the long-term safety, tolerability, and efficacy of an oral hypoglycaemic agent exclusively in patients with T2DM and severe renal impairment, and found that the addition of linagliptin (5 mg once daily) to background insulin therapy provided a clinically significant HbA1c reduction after 12 weeks and this reduction was sustained over 52 weeks (24).

Glycaemic control is most important part of management of diabetic patient (25). Significant relationship between hyperglycaemia and the development of microvascular complications, such as CKD was demonstrated by several large clinical trials in patients with T2DM (26),(27),(28).

However, glucose lowering treatment options are limited in patients with T2DM and CKD because most of the oral anti-diabetic agents are cleared by the kidney. Therefore, in patients with higher grade of CKD, most of these drugs are either not recommended or contraindicated (29).

No significant differences in renal safety parameters between two groups were found in the present study. However, many factors can affect progression of renal disease and longer-term clinical studies are needed to highlight the potential effects of linagliptin on renal function. Along with a previous finding that linagliptin therapy hadn’t have any variable effects in patients with normal, mild, or moderate renal impairment (30), the pharmacokinetic data from previous studies also suggest that linagliptin has no potential to accumulate at any degree of renal impairment (24).

In this study, there was a significant decrease in mean UPCR in both the groups. In linagliptin group, mean UPCR decreased from 1.18 at baseline to 0.71 at the end of the study while mean UPCR decrease from 1.19 at baseline to 0.75 at the end of the study. The reduction was more in UPCR in linagliptin group as compared to insulin group. While this difference in UPCR between two group at the end of the study was not statistically significant but this result does highlight need for some more long-term studies.

Some other studies also found that linagliptin therapy can reduce albuminuria which is most important risk factor for progression of CKD and Cardiovascular Disease, therefore producing newer evidences for nephrologists about the therapeutic options for this category of patients (31),(32). Ku E et al., found in their study that there was 8 years lesser time spent in stage 3a, 5.6 years lesser time in stage 3b, but only 6 months lesser time in stage 5 in patients with proteinuria ≥1 g/g as compared to those with proteinuria <1 g/g (33).

Hypoglycaemia was found more frequently in insulin group (61.11 per 100 patients) than linagliptin group (51.06 per 100 patients). Linagliptin is a safe and effective alternative to multi-dose insulin therapy, resulting in similar glucose control with lower hypoglycaemia (34),(35).

Limitation(s)

Patients were selected from outdoor unit hence compliance of the patients was not pursued uniformly. The study did not include different drug interactions which might be possible with other medications for CKD. For gathering more refined data about efficacy and safety of linagliptin, studies must be performed on larger populations.

Conclusion

This study showed that addition of linagliptin for glycaemic control provides clinically meaningful improvements in glycaemic control without unacceptable side effects in this vulnerable group of patients. This supports the use of linagliptin as an effective, convenient and safe once daily treatment option in patients with T2DM and CKD.

References

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Powers AC, Alessio DD. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycaemia. Brunton LL, Dandan RH, Knollmann BC. Goodman & Gilman’s The Pharmacological Basics of Therapeutics. 13th ed. McGraw Hill Education, New York; 2018: Pp. 873.
2.
Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, et al. Nephropathy in diabetes. Diabetes Care. 2004;27(Suppl. 1):S79-83. [crossref] [PubMed]
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Grassmann A, Gioberge S, Moeller S, Brown G. ESRD patients in 2004: Global overview of patient numbers, treatment modalities and associated trends. Nephrol Dial Transplant. 2005;20:2587-93. [crossref] [PubMed]
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Atkins RC. The epidemiology of chronic kidney disease. Kidney Int Suppl. 2005;94:S14-18. [crossref] [PubMed]
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Powers AC, Alessio DD. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycaemia. Brunton LL, Dandan RH, Knollmann BC. Goodman & Gilman’s The Pharmacological Basics of Therapeutics. 13th ed. McGraw Hill Education, New York; 2018: Pp. 882.
6.
Bakris GL. Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc. 2011;86:444-56. [crossref] [PubMed]
7.
Shrishrimal K, Hart P, Michota F. Managing diabetes in hemodialysis patients: Observations and recommendations. Cleve Clin J Med. 2009;76:649-55. [crossref] [PubMed]
8.
American Diabetes Association. Standards of medical care in diabetes 2011. Diabetes Care. 2011;34(Suppl. 1):S11-61 [crossref] [PubMed]
9.
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DOI and Others

10.7860/JCDR/2021/50693.15204

Date of Submission: Jun 07, 2021
Date of Peer Review: Jun 29, 2021
Date of Acceptance: Jun 30, 2021
Date of Publishing: Aug 01, 2021

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

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Jun 08, 2021
• Manual Googling: Jun 28, 2021
• iThenticate Software: Jul 09, 2021 (10%)

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