Manuscript ID: ODI-07-20-RA-8730
Title: Melatonin levels in periodontal disease vs health: A systematic review and meta-analysis

This is an interesting topic.
Authors evaluated differences in melatonin levels between periodontal health and disease, and concluded that there is a reduction in salivary melatonin levels in individuals with periodontitis when compared to healthy ones.

General comments
Overall, authors should use the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework to evaluate the quality (or certainty) of evidence and strength of recommendations.
Manuscript should be reformulated and discussed accordingly.

Specific comments
Please consider revising the manuscript in relation to English grammar and structure.

Introduction
There are more recent references from the World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions (2018) or other papers to support the description / characterization of periodontal diseases and its pathogenesis than the one from the 1999 International Workshop for a Classification of Periodontal Diseases and Condition (Caton & Armitage, 1999).
Please update references of the Introduction.

Untreated gingivitis not always progresses to periodontitis.
Moreover, untreated periodontitis not always lead to edentulism.
There are some misconceptions in the clinical course / pathogenesis of periodontal diseases. Please rephrase and clarify.

The sentence “In the pathogenesis of periodontitis … immune modulator” needs a supporting reference.
The sentence “Melatonin levels … pathobiology of the disease” needs a supporting reference.

Since the search strategy used the key-word “periodontitis”, should the focus question be “Does melatonin levels vary between healthy individuals and patients with periodontitis?
As authors stated in the first paragraphs of the Introduction section, periodontal disease comprises gingivitis and periodontitis.
Why not using a search strategy comprising the terms “periodontal disease OR periodontal diseases OR periodontitis OR gingivitis”?

Authors should consistently use the term “periodontitis” instead of “periodontal disease”, when referring to the destructive disease.
Moreover, the term “chronic periodontitis” should be used only when referring to studies that used this terminology.
Based on the new classification scheme for periodontal and peri-implant diseases and conditions, this terminology is not applicable anymore.

Authors should briefly discuss the impact of language restriction on the results of the review.

Manuscript ID: ODI-07-20-RA-8730.R1
Manuscript Title: Melatonin levels in periodontitis versus the healthy state: A systematic review and meta-analysis
Comments
I would like to congratulate the authors for all the effort in modifying the manuscript, that has greatly improved.
Some minor comments are still applicable.
Abstract
Results, lines 8 and 9 – please change “periodontal disease” to “periodontitis”.
Introduction
Reference supporting the sentence “According to the currently available classification of periodontal diseases, periodontitis refers … and exfoliation of teeth (Armitage & Cullinan, 2010)” needs to be changed or this sentence modified. It is impossible that a reference from 2010 can support the new classification systems of periodontal diseases and conditions from 2018.
Results, Meta-analysis
Would you mind checking the p-value from the sentence “The meta-analysis revealed a significantly lower (p<0.0001) salivary melatonin level …”? Is it (p<0.0001) or (p<0.001)?
Discussion
Authors stated that “In addition, the GRADE methodology was adopted to ascertain the quality of evidence derived from the included studies ... Hence, representativeness of the general population was lacking. This could be considered a limitation of the results obtained in the present review.”
In my point of view, this is not a limitation of the results from the present systematic review, but a limitation of the results from the primary studies. Indeed, this systematic review retrieved robust findings: the available evidence regarding differences on melatonin levels from periodontitis and healthy individuals is from low to very low overall quality as evaluated by GRADE methodology.

No further comments.