Combination Therapeutic Effect of Antibacterial and Antiviral Agents on Feline Chronic Gingivostomatitis Nonbounded to Prior Tooth Extraction Confirmed by Physical Signs and Clinical Biomarkers

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

An interesting work, esspecialy for those involved in the feline dentistry.

This study tackles, Feline chronic gingivostomatitis (FCGS) a refractory stomatitis in cats. Antibacterial and antiviral treatment was initiate in 52 cats (tooth-extracted and unextracted), were Moxifloxacin (a broad-spectrum antibacterial agent) and Molnupiravir (an antiviral agent) were evaluated as efficacy.

Abstract:

Well written including the reader in the topic.

Keywords:

Well chosen

Introduction:

Good and circumscrimbed description of FCGS. 

M&M:

Drug administration, Mass Spectrometric Analysis, Animals & Diagnosis well presented. The study also beneficies by statistics (Mann–Whitney nonparametric U test and ANOVA).

What to add  (if possible)

The work would have been even more valuable if the authors, in addition to the semiological, surgical, and paraclinical analysis, could have also presented the cytoarchitecture of the investigated pathologies, (not only the macroscopy of the lessions). Please explain why it was not necessary.

Results:

Analysis of Changes in Physical Signs and Clinical Biomarker Levels is a commendable. A good part well explained, also the Mass Spectrometric Analysis.

Discussion:

Well presented, citing topic's main stream literature.

References:

The list is based in actual titles strongly linked with the research topic. 

Author Response

1. Overview:

An interesting work, especially for those involved in the feline dentistry.

This study tackles, Feline chronic gingivostomatitis (FCGS) a refractory stomatitis in cats. Antibacterial and antiviral treatment was initiate in 52 cats (tooth-extracted and unextracted), were Moxifloxacin (a broad-spectrum antibacterial agent) and Molnupiravir (an antiviral agent) were evaluated as efficacy.

→ I would like to thank you for the high rating our present study.

2. Abstract:

Well written including the reader in the topic.

→ Thank you for your evaluation.

3. Keywords:

Well chosen

→ Thank you for your evaluation.

4. Introduction:

Good and circumscrimbed description of FCGS.

→ Thank you for your evaluation.

5. Materials & Methods:

Drug administration, Mass Spectrometric Analysis, Animals & Diagnosis well presented. The study also beneficies by statistics (Mann–Whitney nonparametric U test and ANOVA).

→ Thank you for your evaluation.

What to add (if possible)

The work would have been even more valuable if the authors, in addition to the semiological, surgical, and paraclinical analysis, could have also presented the cytoarchitecture of the investigated pathologies, (not only the macroscopy of the lesions). Please explain why it was not necessary.

→ We understand that it is extremely valuable to conduct a histopathological examination of the clinical oral lesion for clarifying the cause if any significant differences in the temporal changes in physical signs and various biomarkers are detected between the groups who underwent tooth extraction or not. We did not believe, however, that such an analysis was necessary in this situation, because such a difference has not been identified at all in our present study.

6. Results:

Analysis of Changes in Physical Signs and Clinical Biomarker Levels is a commendable. A good part well explained, also the Mass Spectrometric Analysis.

→ Thank you for your evaluation.

7. Discussion:

Well presented, citing topic's main stream literature.

→ Thank you for your evaluation.

8. References:

The list is based in actual titles strongly linked with the research topic.

→ Thank you for your high valuation.

Reviewer 2 Report

Comments and Suggestions for Authors

In this article, the authors present a study conducted on 52 cats affected by Feline Chronic Gingivostomatitis.In particular, the response of the animals to a combined therapy of antiviral and antibacterial drugs was analyzed in two groups of cats, namely those that underwent tooth extraction and those that did not. The manuscript does not present particular issues and it is believed that the study was conducted correctly. Furthermore, it is considered that the study and its results are of great scientific interest.

Author Response

In this article, the authors present a study conducted on 52 cats affected by Feline Chronic Gingivostomatitis. In particular, the response of the animals to a combined therapy of antiviral and antibacterial drugs was analyzed in two groups of cats, namely those that underwent tooth extraction and those that did not. The manuscript does not present particular issues and it is believed that the study was conducted correctly. Furthermore, it is considered that the study and its results are of great scientific interest.

→ I would like to thank you for the high rating our present study.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript entitled "   Combination Therapeutic Effect of Antibacterial and Antiviral Agents on Feline Chronic Gingivostomatitis Nonbounded to Prior Tooth Extraction Confirmed by Physical Signs and Clinical Biomarkers”was evaluated. This study evaluates the efficacy of a stepwise combination therapy using two commercial formulations in cats diagnosed with feline chronic gingivostomatitis (FCGS), with a specific focus on comparing outcomes between cats with and without prior tooth extraction. The authors report significant improvements in physical signs and multiple clinical laboratory parameters following treatment, with no statistically significant differences between the two groups. The study addresses a clinically relevant and challenging condition, and the use of mass spectrometry to identify the active ingredients is a notable strength. Several issues should be addressed before the manuscript can be considered for publication.

 

Comments:

1. Study Design and Lack of Control Groups

The study lacks a control group (e.g., placebo, standard-of-care comparison, or untreated group), which severely limits the ability to attribute the observed improvements to the intervention. Without a control arm, it is impossible to rule out spontaneous improvement, placebo effects (owner-reported outcomes), or the impact of concurrent treatments. The study is described as retrospective, yet the administration protocol and data collection appear to follow a structured schedule; clarification is needed regarding whether this was truly a retrospective analysis or a prospective observational study.

 

2. Confounding Variables and Prior Treatments

A substantial proportion of cats in both groups received prior or concurrent treatments, including steroids, antibiotics, and immunosuppressants. The potential for confounding is high, yet no statistical adjustment (e.g., multivariate modeling) was performed. The manuscript does not clarify whether these treatments were continued during the study period or how their use was standardized across groups.

 

3. Diagnostic Criteria and Case Definition

While the authors reference established diagnostic methods, the diagnosis of FCGS appears to be based on clinical evaluation alone. No confirmatory testing (e.g., histopathology, viral diagnostics such as PCR for FCV, FHV-1, FIV, FeLV) is reported. Given the heterogeneity of the condition and the proposed infectious etiology, the lack of virological or microbiological characterization of the study population limits the ability to interpret the mechanistic relevance of the antiviral and antibacterial agents used.

 

4. Outcome Assessment Bias

Owner-reported outcomes (appetite, activity, grooming) are subjective and susceptible to bias. Although the authors attempted to standardize scoring, no validation or inter-rater reliability assessment is provided. Similarly, the veterinarian-assessed scores (erythema, ptyalism) were not blinded to treatment status, introducing potential observer bias.

Author Response

The manuscript entitled "Combination Therapeutic Effect of Antibacterial and Antiviral Agents on Feline Chronic Gingivostomatitis Nonbounded to Prior Tooth Extraction Confirmed by Physical Signs and Clinical Biomarkers” was evaluated. This study evaluates the efficacy of a stepwise combination therapy using two commercial formulations in cats diagnosed with feline chronic gingivostomatitis (FCGS), with a specific focus on comparing outcomes between cats with and without prior tooth extraction. The authors report significant improvements in physical signs and multiple clinical laboratory parameters following treatment, with no statistically significant differences between the two groups. The study addresses a clinically relevant and challenging condition, and the use of mass spectrometry to identify the active ingredients is a notable strength. Several issues should be addressed before the manuscript can be considered for publication.

Comments:

1. Study Design and Lack of Control Groups

The study lacks a control group (e.g., placebo, standard-of-care comparison, or untreated group), which severely limits the ability to attribute the observed improvements to the intervention. Without a control arm, it is impossible to rule out spontaneous improvement, placebo effects (owner-reported outcomes), or the impact of concurrent treatments. The study is described as retrospective, yet the administration protocol and data collection appear to follow a structured schedule; clarification is needed regarding whether this was truly a retrospective analysis or a prospective observational study.

→ As explained in detail in the initial submission, our current study is a simple comparative analysis between two groups: one in which tooth extraction was performed prior to the Mutoral treatment (combined administration of antiviral agents and antibiotics), and the other in which tooth extraction was not performed prior to the same therapy. Furthermore, the combined administration of these two drugs has been performed as standard treatment for the cats with FCGS, as explained to the owners in advance and their written informed consents were obtained. Therefore, a placebo-controlled study or set up of untreated cases, where little to no therapeutic effect is expected, would contradict the prior informed consent obtained from these owners. As you know, tooth extraction is now thought to be the standard treatment for FCGS, and our conclusion that no statistically significant difference was detected in the comparative study between two cat groups with and without Mutoral treatments, clearly supports the hypothesis that the effectiveness of tooth extraction on treating FCGS is doubtful. Such criticism has been already launched by many veterinarians, and we believe that most readers of this article will understand our developed rationale is reasonable.   

Tooth extraction procedures, including the prior diagnosis of the periodontal disease severity and the inflammatory grades of the gingiva and associated mucosa surrounding the teeth, as well as the decision of whether to perform partial or complete extraction, are highly dependent on the veterinarian's pathological knowledge and surgical skills, and it has been suggested that they do not always lead to improvement of FCGS disease, especially in the cases of surgery performed by an inexperienced veterinarian, etc. Furthermore, since a significant risk associated with long duration of anesthesia required cannot be ignored, the possibility of avoiding tooth extraction procedures is a major step forward in FCGS treatment. These latter points have already been explained in detail in the Discussion section of the initially submitted manuscript (page 12, lines 467-470), but the earlier points are also considered important, so I will add them to the same section (page 12, lines 471-474, in our revised manuscript).

Furthermore, while our study seemed to be structurally classified into a retrospective study, the fact that both groups with and without tooth extraction each of which reached more than 20 cases, led to our conclusion that difference between the two groups could be statistically determined using repeated measures ANOVA. This analytic approach is investigated during this study, which can therefore be considered to have characteristics of prospective study. Considering the possibility of conflicting opinions on this point, a clear definition has been avoided in our manuscript. Your understanding is much appreciated.

 

2. Confounding Variables and Prior Treatments

A substantial proportion of cats in both groups received prior or concurrent treatments, including steroids, antibiotics, and immunosuppressants. The potential for confounding is high, yet no statistical adjustment (e.g., multivariate modeling) was performed. The manuscript does not clarify whether these treatments were continued during the study period or how their use was standardized across groups.

→ In this study, we have obtained prior informed consent from the cat’s owners to conduct standard therapy, including the combined administration of two drugs (antiviral and antimicrobial), to all the cases of FCGS. Since the administration of steroids, antibiotics, and immunosuppressants can be understood as a common therapeutic option for FCGS in usual veterinary medicine, it is generally difficult to avoid their concurrent utilization. We suspect, in addition, it is also difficult to conduct sufficient statistical analysis using only the cases without such administration.

If our present study can reveal a certain usefulness of the combined antiviral and antibiotic therapy in the FCGS treatment, we prospectively understand that our future study should involve verifying the statistical significance of Mutoral therapeutic effect on the FCGS cases with and without prior treatments using the other antibiotics, steroids, or immunosuppressants, similarly to the tooth extraction used as a comparison factor addressed in this study.

 

3. Diagnostic Criteria and Case Definition

While the authors reference established diagnostic methods, the diagnosis of FCGS appears to be based on clinical evaluation alone. No confirmatory testing (e.g., histopathology, viral diagnostics such as PCR for FCV, FHV-1, FIV, FeLV) is reported. Given the heterogeneity of the condition and the proposed infectious etiology, the lack of virological or microbiological characterization of the study population limits the ability to interpret the mechanistic relevance of the antiviral and antibacterial agents used.

→ We understand that it is extremely valuable to conduct a histopathological examination of the clinical oral lesion for clarifying the cause if any significant differences in the temporal changes in physical signs and various biomarkers are detected between the groups who underwent tooth extraction or not. We did not believe, however, that such an analysis was necessary in this situation, because such a difference has not been identified at all in our present study.

Furthermore, we fully recognize importance of the tests to detect multiple viruses, including FCV considered risk factors for FCGS, and the confirmatory tests to identify the infectious bacteria, in this study. PCR tests to detect each virus, however, cannot be performed in-house at a small clinic like ours and therefore must be outsourced to external testing laboratories. Rapid treatment is basically required for FCGS, so it is necessary to start medication without waiting for their results, making it extremely difficult to obtain the consent of cat’s owners for performing these tests within the scope of standard treatment. Also, as explained in the discussion of our initial submission, identifying the virus species in which the antiviral agent (Molnupiravir) shows antiviral activity and confirming the antibacterial spectrum of the antibiotic (Moxifloxacin) can be considered as the highest priorities. It must be difficult, however, to include them in our current study, since both require large-scale in vitro and in vivo testing. Our current study can strongly suggest that combination therapy with both drugs may not necessarily require tooth extraction, recognized as the standard FCGS treatment in the present situation. We have confidence that our observation has paved the way for gradually conducting the various confirmation tests mentioned above, and we intend to conduct them soon through collaborative research with the institutions both domestically and internationally.

 

4. Outcome Assessment Bias

Owner-reported outcomes (appetite, activity, grooming) are subjective and susceptible to bias. Although the authors attempted to standardize scoring, no validation or inter-rater reliability assessment is provided. Similarly, the veterinarian-assessed scores (erythema, ptyalism) were not blinded to treatment status, introducing potential observer bias.

→ Observational assessments by the cat's owners may be considered as subjective evaluation methods (Ref. No. 3; Soltero-Rivera, M., et al. JFMS, 2023). It is also true, however, the SDAI score, a key factor of the FCGS severity assessment method proposed by Dr. Anderson, has been followed in several academic reports by many veterinarians to date, making it a historically established diagnostic method. While we do not deny the need to verify its validity and evaluate inter-rater reliability, we have decided to adopt this observation method currently to maintain compatibility with previous FCGS treatment outcomes. Additionally, while we do not deny the possibility of observer bias in veterinary assessments, visual examination of oral lesions in the cats with FCGS is not something that every veterinarian can perform. Such observation requires expertise, and only veterinarians with experience in examining many FCGS cases can perform accurate performance. Since such a subjective bias cannot be ruled out when relying solely on observational findings from pet owners and veterinarians, this study also evaluated the time-dependent changes of other physical and clinical biomarkers (hematological and biochemical laboratory test indicators) and reports that almost all of them showed similar behavior.

Reviewer 4 Report

Comments and Suggestions for Authors

• The study lacks a proper control group (e.g., placebo or standard-of-care only). How do the authors exclude the possibility that observed improvements are due to natural disease fluctuation, prior treatments, or regression to the mean rather than the combination therapy itself?
• Given that this is a non-randomized, observational study with heterogeneous prior treatments (e.g., steroids, antibiotics, immunosuppressants), how were confounding variables controlled or adjusted for in the statistical analysis to ensure the internal validity of the conclusions?
• The identification of active ingredients (moxifloxacin and molnupiravir) is based on mass spectrometry; however, no quantitative analysis is provided. How do the authors justify dosing accuracy and reproducibility without determining the exact concentrations of active compounds in the formulations?
• The antiviral rationale is largely hypothetical, particularly regarding feline calicivirus (FCV). Can the authors provide direct in vitro or in vivo evidence supporting the efficacy of molnupiravir against FCV or other FCGS-associated viruses?
• The conclusion suggests that this therapy may be preferable to tooth extraction, yet no direct comparative clinical trial was conducted. How do the authors justify this strong claim without a randomized controlled comparison against surgical intervention outcomes?
• Owner-reported clinical scores (e.g., appetite, activity, grooming) introduce subjective bias. What measures were taken to validate or standardize these assessments, and how do the authors address potential reporting bias?
• The exclusion of 20 cases due to incomplete follow-up may introduce selection bias. Can the authors clarify how these exclusions might have influenced the overall efficacy results and whether an intention-to-treat analysis was considered?
• Methods: “pixcel”  - “pixel”. Several instances of awkward phrasing (e.g., “Resultantly”) should be revised to standard scientific English

Author Response

1. The study lacks a proper control group (e.g., placebo or standard-of-care only). How do the authors exclude the possibility that observed improvements are due to natural disease fluctuation, prior treatments, or regression to the mean rather than the combination therapy itself?

→ As explained in detail in the initial submission, our current study is a simple comparative analysis between two groups: one in which tooth extraction was performed prior to the Mutoral treatment (combined administration of antiviral agents and antibiotics), and the other in which tooth extraction was not performed prior to the same therapy.  Furthermore, the combined administration of these two drugs has been performed as standard treatment for the cats with FCGS, as explained to the owners in advance and their written informed consents were obtained. Therefore, a placebo-controlled study or set up of untreated cases, where little to no therapeutic effect is expected, would contradict the prior informed consent obtained from these owners.  As you know, tooth extraction is now thought to be the standard treatment for FCGS, and our conclusion that no statistically significant difference was detected in the comparative study between two cat groups with and without Mutoral treatments, clearly supports the hypothesis that the effectiveness of tooth extraction in the treatment of FCGS is questionable. Such criticism has been already launched by many veterinarians, and we believe that most readers of this article will understand our developed rationale well.

Furthermore, it is a well-known fact that there is no possibility of spontaneous healing in FCGS, and therapeutic effectiveness of various treatments other than tooth extraction, including steroids and immunosuppressants, on FCGS was observed to be limited in the previous studies (Ref. No. 3; Soltero-Rivera, M., et al. JFMS, 2023).

 

2. Given that this is a non-randomized, observational study with heterogeneous prior treatments (e.g., steroids, antibiotics, immunosuppressants), how were confounding variables controlled or adjusted for in the statistical analysis to ensure the internal validity of the conclusions?

→ In this study, we have obtained prior informed consent from the cat’s owners to conduct standard therapy, including the combined administration of two drugs (antiviral and antimicrobial), to all the cases of FCGS. Since the administration of steroids, antibiotics, and immunosuppressants can be understood as a common therapeutic option for FCGS in usual veterinary medicine, it is generally difficult to avoid their concurrent utilization. We suspect, in addition, it is also difficult to conduct sufficient statistical analysis using only the cases without such administration.

If our present study can reveal a certain usefulness of the combined antiviral and antibiotic therapy in the FCGS treatment, we prospectively understand that our future study should involve verifying the statistical significance of Mutoral therapeutic effect on the FCGS cases with and without prior treatments using the other antibiotics, steroids, or immunosuppressants, similarly to the tooth extraction used as a comparison factor addressed in this study.

 

3. The identification of active ingredients (moxifloxacin and molnupiravir) is based on mass spectrometry; however, no quantitative analysis is provided. How do the authors justify dosing accuracy and reproducibility without determining the exact concentrations of active compounds in the formulations?

→ The manufacturer's instructions is describing that Mutoral-I tablets contain a total of 50 mg of antiviral and antibiotic ingredients, while Mutoral-II tablets contain only 100 mg of antiviral agent. The instructions also explains that Mutoral-I should be administered at half a tablet per kg of body weight twice a day, and Mutoal-II should be administered at 1/4 tablet per kg of body weight once a day. Assuming the information in the manufacturer's instructions is correct, and that Mutoral-I contains equal amounts of antiviral and antibiotic (25 mg each), it is estimated that during the period of administration of both tablets, a total of 25 mg/kg of antibiotic and 25 mg/kg of antiviral agent will be administered per day. All of this information is provided just by the manufacturers, and currently, we have no choice but to rely on this information. The disclosure policy regarding information on the formulations, including the active ingredients, is determined based on this companies' intellectual property strategies, and therefore, the specific measures that users can take are extremely limited. We hope you to understand we meet such a particular situation.

In our current study, we focused on identifying the active ingredients of the two formulations (Mutoral-I and -II) and publishing that information in the academic article as soon as possible. For veterinarians and the cat’s owners who are considering using them in their daily practice when facing severe FCGS cases, the lack of clarity regarding the active ingredients is the biggest source of anxiety and is likely the reason they hesitate to actually use them. After publishing this article, we plan to begin precise measurements of the active ingredient content of these two formulations and will publish that information sequentially. Since it will take a long time to perform such an experiment, however, we have initially decided it was desirable to report only our current results at this stage. We have explained the above description at the end of the "Second limitation of our study" section in the revised manuscript (page 13, lines 488-492, in our revised manuscript).

 

4. The antiviral rationale is largely hypothetical, particularly regarding feline calicivirus (FCV). Can the authors provide direct in vitro or in vivo evidence supporting the efficacy of molnupiravir against FCV or other FCGS-associated viruses?

→ As explained in the discussion of our initial submission, identifying the virus species in which the antiviral agent (Molnupiravir) shows antiviral activity and confirming the antibacterial spectrum of the antibiotic (Moxifloxacin) can be considered as the highest priorities. It must be difficult, however, to include them in our current study, since both require large-scale in vitro and in vivo testing. Our current study can strongly suggest that combination therapy with both drugs may not necessarily require tooth extraction, recognized as the standard FCGS treatment in the present situation. We have confidence that our observation has paved the way for gradually conducting the various confirmation tests mentioned above, and we intend to conduct them soon through collaborative research with the institutions both domestically and internationally.

 

5. The conclusion suggests that this therapy may be preferable to tooth extraction, yet no direct comparative clinical trial was conducted. How do the authors justify this strong claim without a randomized controlled comparison against surgical intervention outcomes?

→ As explained in detail in the initial submission, our current study is a simple comparative analysis between two groups: one in which tooth extraction was performed prior to the Mutoral treatment (combined administration of antiviral agents and antibiotics), and the other in which tooth extraction was not performed prior to the same therapy.  Furthermore, the combined administration of these two drugs has been performed as standard treatment for the cats with FCGS, as explained to the owners in advance and their written informed consents were obtained. Therefore, a placebo-controlled study or set up of untreated cases, where little to no therapeutic effect is expected, would contradict the prior informed consent obtained from these owners.  As you know, tooth extraction is now thought to be the standard treatment for FCGS, and our conclusion that no statistically significant difference was detected in the comparative study between two cat groups with and without Mutoral treatments, clearly supports the hypothesis that the effectiveness of tooth extraction on treating FCGS is doubtful. Such criticism has been already launched by many veterinarians, and we believe that most readers of this article will understand our developed rationale is reasonable.

 

6. Owner-reported clinical scores (e.g., appetite, activity, grooming) introduce subjective bias. What measures were taken to validate or standardize these assessments, and how do the authors address potential reporting bias?

→ Observational assessments by the cat's owners may be considered as subjective evaluation methods (Ref. No. 3; Soltero-Rivera, M., et al. JFMS, 2023). It is also true, however, the SDAI score, a key factor of the FCGS severity assessment method proposed by Dr. Anderson, has been followed in several academic reports by many veterinarians to date, making it a historically established diagnostic method. While we do not deny the need to verify its validity and evaluate inter-rater reliability, we have decided to adopt this observation method currently to maintain compatibility with previous FCGS treatment outcomes. Additionally, while we do not deny the possibility of observer bias in veterinary assessments, visual examination of oral lesions in the cats with FCGS is not something that every veterinarian can perform. Such observation requires expertise, and only veterinarians with experience in examining many FCGS cases can perform accurate performance. Since such a subjective bias cannot be ruled out when relying solely on observational findings from pet owners and veterinarians, this study also evaluated the time-dependent changes of other physical and clinical biomarkers (hematological and biochemical laboratory test indicators) and reports that almost all of them showed similar behavior.

 

7. The exclusion of 20 cases due to incomplete follow-up may introduce selection bias. Can the authors clarify how these exclusions might have influenced the overall efficacy results and whether an intention-to-treat analysis was considered?

→ As explained in the initially-submitted manuscript, we used repeated measures ANOVA to analyze whether there was a statistically significant difference in the changes in physical and clinical laboratory indicators at four time points (before administration of Mutoral tablets, 1-2 weeks after administration, 1-2 months after administration, and just prior to the end of administration) between two groups: one group of patients who underwent prior tooth extraction and the other group who did not. In this statistical method (repeated measures ANOVA), the absence of data at just one time point automatically excludes all data from the other three time points for that patient from the analysis. Therefore, there is no room for observer intent in the exclusion of these 20 patients; it was simply a matter of following the exclusion criteria for conducting statistical analysis, and we can confidently say that no bias occurred. We felt that a more detailed explanation should be added on this point, so we have added the explanation to the revised manuscript (page 3, line 124-127, in our revised manuscript).

In addition, it is extremely difficult to force the cat’s owners to visit our hospital, since we are collecting their data within the scope of routine clinical practice. Therefore, unfortunately, there is no other way than to exclude the cases with missing data from this analysis. Among the 20 excluded cases, some cases were difficult to follow up on because other diseases developed, making medication difficult. It is also presumed, however, any of the owners discontinued medication just for their economic reasons even if some therapeutic effects could be achieved. Since none of these cases were examined by our veterinarians, we decided not to describe our speculation and have limited the explanation to a general one in our manuscript.

 

8. Methods: “pixcel” - “pixel”. Several instances of awkward phrasing (e.g., “Resultantly”) should be revised to standard scientific English.

→ I have corrected all of the specific errors and unnatural expressions that you have indicated in our revised manuscript (page 3, line 108, or page 12, line 465 of the revised manuscript). We have asked our friend fluent in English to proofread the manuscript, and they were unable to find any other expressions in the manuscript that were not fluent in English just within 7 days. If there are any descriptions inappropriate in English, I would appreciate it if you could point them out specifically.

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

No comment.

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Author,

I appreciate your efforts in revising the manuscript. I would recommend this article for further processing.

Thank you.