PONE-D-24-29059Incidence of macular hole in patients undergoing pars plana vitrectomy for submacular hemorrhagePLOS ONE Dear Dr. Matsumoto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript raises interesting concern about the development of MH in patients who underwent PPV for SMH. The authors described the differences in features between individuals with RAM and AMD who had been selected for the surgery. However, there are certain points should be clarified in order to maximize the manuscript's usefulness.

Methods:

Nowadays, treatment options for SMH vary, including intravitreal gas injections with and without TPA, and with and without anti-VEGF factor injections. It would be interesting to know about the indications and ocular features of the individuals that led the physician to recommend PPV for this group of patients, such as the size or duration of SMH (if available). Without this information, reporting on the incidence of MH-associated SMH among these operated patients may be biased.

Results:

1. Differences in pre and intra-operative interventions, such as timing of TPA injection (pre vs intra-operative injection), route of TPA injection (intravitreal vs subretinal injection), and intra-operative ILM peeling (done vs not done), are all potential risk factors for MH development. As a result, I recommend to add more details of these methods (either in text or in table form), as seen below.

• In patients who received a pre-operative intravitreal TPA injection, how many cases developed MH?

• In patients with ILM peeling and experienced MH, how many cases received subretinal gas/TPA injections?

• In patients that developed post-operative MH, how many days after surgery did it develop?

2. Regarding MH, it is interesting to know the difference in baseline features between RAM patients who acquired and did not develop MH. The information provided may be beneficial to the readers. I recommend that authors incorporate this information.

Discussion:

1. The authors should clarify that the incidence of MH in PPV patients may not accurately reflect the true incidence in all SMH patients which including those who did not schedule the operation.

2. The authors should add and emphasize that patients with pre-operative MH may not have the same mechanism as those who developed MH during or after vitrectomy, which could be due to disease pathology or surgical maneuvers.

3. 3. In the discussion of subretinal gas/TPA injection and MH, please further note that the volume and pressure might vary between patients due to retrospective studies. As a result, the relationship between subretinal TPA injection and MH should be investigated further in a prospective design.

Table 1:

Correct row for "preoperative VH"

Reviewer #2: I had the pleasure to review the manuscript by Matsumoto et al investigating the incidence of macular hole (MH) during pars plana vitrectomy for submacular hemorrhage due to either retinal arterial microaneurysm rupture or age-related macular degeneration. The manuscript is well formatted and fluent. The study design is clear and the introduction is well focused. The methods are widely explained and the results are clearly analyzed. The discussion is fluent , updated and solid.

Reviewer #3: Dear authors there appears to be a conflict trying to understand if the manuscript is focused on MH as a complication of SMH surgery or MH occuring after SMH in which case surgery (PPV) is not to be consider. You need to resolve this conflict or modify your title . Please se my comments below to provide some more information on your manuscript

Title : The title raises questions. First it gives the impression that the MH developed as a result of the surgery. But this is not the case as some eyes had MH even before the surgery, while other eyes developed the MH during or after the surgery. So this is a mixed group of MHs all related to the SMH and not necessarily to the surgery. The author needs to decide on if the surgery for SMH or the SMH is the focus of research.

Question: Were all the macular holes formed or noticed during vitreoretinal surgery? What of MHs that occurred post vitrectomy? How long after the primary surgery did the post operative MH occur? Were there extrafoveal MHs too?

The abstract’s purpose states that the MHs was during PPV for SMH. This does not appear to be correct and reflective of the work done as pre operative and post operative OCTs reflects timing of the MH as not only during surgery.

What does the author mean by” initial surgical treatment”?

What was the indication for the surgery and was present vitreous hemorrhage an indication for surgery in some cases? What technique was used for the surgery? Was it submacular surgery with subretinal tPA? Then a detailed description of the surgical procedure is required including the site of subretinal tPA injection.

Please include the mechanism of MH formation in the eyes with SMH?

Since this was a retrospective study, was there a standardized surgical procedure for all the cases.

Introduction section:

Again in line 47, “patients who underwent PPV” appears to mean that the focus is on the PPV for SMH.

Methods section:

Line 53: Why were patients who underwent pneumatic displacement before PPV excluded? This has a direct effect on the incidence. How many were excluded?

Line 63: Incidence of MH would not be one of the data extracted from the patients’ records. Rather MH and its dimensions on OCT would be a more likely data extracted.

Line 80: Which data was expressed as means and standard deviation?

Results section:

In table 1, the proportion of eyes with VH in the RAM group is missing.

I would have liked to see the OCT based size of the MHs including the minimum or basal diameter. I appreciate that this may not be available for all eyes since some eyes had a media opacity including VH.

It appears that subretinal t-PA carried a risk for the formation of intraoperative MH? Can the authors perform an analysis to examine the risk element comparing t-PA with the other grous.

Also, I would imagine that the height of the SMH would contribute to the mechanical stretching of the macular and cause considerable tangential and posterior anterior traction that could predispose to the development of the MH. Therefore can the author give an idea of the OCT based height of the SMH between the RAM and AMD eyes. More SMH and more height of elevated retina would be associated with more MH.

How many MHs occurred after vitrectomy? What was the time from vitrectomy to the occurrence of the MHs?

What was the rate of follow in the two groups?

A major drawback of this study is that multiple surgical techniques by multiple surgeons is likely to have been employed as this is a retrospective study. So it is truly difficult to compare and draw a reasonable conclusion since the surgical techniques are not controlled for. This general is a difficult study like any other surgical research in which the surgical techniques and steps are not controlled.

Discussion:

Because of the excluded eyes, the incidence is likely to be under estimated. Please provided the number of eyes excluded

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes:  OGUGUA NDUBUISI OKONKWO

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PONE-D-24-29059R1Incidence of macular hole in patients undergoing pars plana vitrectomy for submacular hemorrhagePLOS ONE

Dear Dr. Matsumoto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jan 13 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Jiro Kogo

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to express my gratitude to the authors for their substantial contribution to the scientific knowledge conveyed in this study. Additionally, the limitations related to the retrospective data analysis have been emphasized more clearly. I have a few minor recommendations for the authors.

Introduction and abstract and Table:

- It is advisable to use the genera term "rupture arterial macroaneurysm" in place of " rupture arterial microaneurysm."

Results:

� Line: 105-107

“Intravitreal t-PA injection was performed in three eyes (10.7%, day before surgery: 2, in surgery: 1) in the RAM group and two eyes (10.5%, 107 before surgery: 2) in the AMD group (p=1).”

� This statement presents challenges in interpretation. It is advisable to eliminate either surgery 1 or surgery 2 from this statement and describe using an alternative sentence.

� Line 155:

“None of the patients who received intravitreal t-PA injection developed MH.”

� It would be more accurate to state the time point of injection, (preoperative, correct?).

Table 1 and Table 2:

� Considering use:

“Preoperative intravitreal t-PA” instead of “intravitreal t-PA”.

“Intraoperative subretinal t-PA injection” instead of “subretinal t-PA injection”

It is advisable to include the Mean ± SD within parentheses for continuous variables.

Reviewer #3: Dear Authors, it is my impression that you have put in a lot of work to revise this manuscript. However, I still have difficulties getting a clear understanding of the reporting of your research.

For example, you have stated that all the macular holes were discovered intraoperatively, this is not clearly reflected in the abstract.

Please state clearly that in all cases the MH was “discovered” during PPV after removal of the vitreous hemorrhage. This helps explain why the MH was identified only during PPV.

Secondly, following your explanation in the revised letter, the incidence can not include those cases in which MH was induced by the surgical procedure or subretinal TPA injection. To give the true incidence, the sample MUST be representative of only those cases that was as a result of RAP or nAMD only and not iatrogenic. Therefore those MHs that developed following surgery have to be excluded all through the manuscript.

“Purpose: To investigate the incidence of macular hole (MH) during pars plana vitrectomy (PPV) for submacular hemorrhage (SMH) due to either retinal arterial microaneurysm (RAM) rupture or age-related macular degeneration (AMD). Methods: We retrospectively evaluated 47 eyes of 47 patients with SMH due to RAM rupture or AMD who underwent PPV. The presence or development of MHs was confirmed intraoperatively by the surgeon. We compared the incidence of MH between the RAM and AMD groups

This understanding is also lacking in the later segment below

“The MH was closed by initial surgical treatment in all eight cases. In the RAM group, subretinal tissue plasminogen activator (t-PA) injection was performed in 12 eyes. Of the 12 eyes, two developed an MH before t-PA subretinal injection. Of the remaining 10 eyes, four (40%) developed an MH intraoperatively or postoperatively”

First, please make it clear that the MH was closed during the same procedure to remove the vitreous hemorrhage. Initial surgical treatment gives the impression that a planned MH surgery was done.

Secondly, those eyes that developed MH after t-PA injection should be excluded for the simple reason that the intervention could be the reason for MH and not entirely the disease. So, if the injection was not done, the MH may not have occurred. This point has to be reflected in the manuscript.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #3: Yes:  OGUGUA NDUBUISI OKONKWO

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Incidence of macular hole in patients undergoing pars plana vitrectomy for submacular hemorrhage

PONE-D-24-29059R2

Dear Dr. Matsumoto

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Jiro Kogo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript explores the incidence of MH found during the operation for SMH which is one point that should be considered. Several points have been responded and the revised manuscript has been improved.

Reviewer #3: The authors have addressed the issues raised in previous rounds of review satisfactorily.

This paper can now be accepted for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #3: Yes:  OGUGUA NDUBUISI OKONKWO

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