Dear Dr Farley,

Thank you very much for submitting your manuscript "Noma (cancrum oris): a scoping literature review of a neglected disease (1843 to 2021)" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Joseph M. Vinetz

Deputy Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Deputy Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Yes. The review strategy is clear

Reviewer #2: (No Response)

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: In the earlier reports ( lines 161-164) there is a hint that this was seen in adults formerly e.g. in soldiers . Is this correct ?

Line 204 Is it possible to be more precise about the definitions of the earliest signs eg gingivitis and ulceration. How extensive is this before there is oedema of the facial skin or do we know this ?

Activity lines 258-271. In the more recent oral microbiome studies did any analyse the bacterial flora species level, as in other situations, variation in species levels within a single genus can be significant ?

347-350. Can you enlarge on this section of stigma. For instance provide more information on societal attitudes including discrimination against patients.

Reviewer #2: (No Response)

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: For successful intervention it would be important either to devise a preventive strategy or devise a system for recognising children whose oral condition is at risk of progression. Do mother and child services have a role to play?

Is it possible to provide a brief list in table form showing items that could be addressed in order to make a difference?

Reviewer #2: (No Response)

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: NO

Reviewer #2: In the 1st sentence of the abstract, would place a comma after the word ‘disease’ and before ‘afflicting’

Sentence 2 in the abstract states “in these settings” although those settings have yet to be defined – would suggest rewording to “and this care is often difficult to access, as most cases of noma occur in resource-limited settings.”

In the abstract, I would reverse the order and percentages (placing 1900’s before 1800s) – as currently it is 2000s, then 1800s, then 1900s

In abstract would change aetiology to etiology

I would reword this sentence in the abstract, as I would not consider these ‘themes’;

Perhaps:

These manuscripts often focused on a number of characteristics regarding noma, including: the history and epidemiology of the disease, ….

In the last paragraph of the abstract I would remove “many” from “many hundreds of years” and simply state “hundreds of years”. Alternatively, you could also (given this is an encompassing review) be more specific and state when it was first reported in the literature

While mentioning this point – I would suggest removing the word “scoping” from the title of this article

In the article, insert a comma after disfiguring in line 20

Line 22 – in the body, again would comment: “in these settings”; “these settings” have yet to be defined in the manuscript – would suggest rewording to “and this care is often difficult to access, as most cases of noma occur in resource-limited settings.”

Line 22 – would remove the word scoping

Lines 33-35 – again would change this to be chronological order – so 2000s, then 1900s, then 1800s, rather than 2000s, then 1800s, then 1900s as is currently written

Line 39 – again, would remove “many” from hundreds of years in the literature

Line 47 – would add a comma after the word disfiguring

Line 49- I would remove the 2 words “to sequelae”

Line 53 – remove “many”

Line 58 – place a comma after the word rate

Line 65 – place a comma after services

Line 66 – would remove the word microbiology so the sentence clause reads …poorly understood and debated…

Line 68 – would change disfigurements to disfigurement, and would also place a comma after disfigurement

Line 68- 69 currently written as …..multiple physical impairments such as difficulty in eating, drinking, seeing.

Would change to….and other sequelae, including difficulty with eating and drinking, as well as ophthalmologic and other other visual changes, and difficulty with breathing as a result of upper airway sequelae.

Line 69 – would replace disfigurements with sequelae

Lines 70-71

Currently written: This impose great difficulties on both the survivor and their families. Would suggest rewording to:

Therefore, noma is associated with a high degree of morbidity for survivors, and this often has a significant impact on family members given the long-lasting and often permanent sequelae.

Line 73 – would remove the word scoping

Line 107 – suggest replacing themes of interest with areas of interest

Line 114 – would carry through and suggest placing “themes” of interests with areas

Line 115 – aetiology would change to etiology

Line 123, insert a comma after 1843

Lines 121-123 – again would reorder so in chronological order as mentioned above

Line 130

129. The word ‘noma’ is derived from a Greek word which, loosely translated, means ‘to devour’

Suggest rewording to :

The word ‘noma’ is derived from Greek, and loosely translates to ‘to devour.’

Line 135

lesion on the skin or an internal mucous surface of the mouth

would reword phrase to

(lesions on the skin or on the internal mucosal surface of the mouth)

Line 151

Change generalised to generalized

Line 151 – change which to and

Line 152 – replace calls with names

Line 162 – insert a comma after 1900’s

160. Line 164 – change to and in the general population - that is inserting an in in the phrase

Line 168 – insert a comma after the word world

Line 212

Suggest rewording include being aged between two and five years

To being between two and five years of age

Line 213 – suggest adding a hyphen after the word healthcare

Line 215- suggest removing the words of the family from the phrase

Line 215-217, would suggest adding commas, before all the “ands” in these sentences

Line 222, insert comma after variables

Line 231 – changed listed to list

Line 232 change were to are

Line 232 change spelling of anemia

Line 233-234

This formation slows down the circulatory flow to the gums due to compression, leaving the oral cavity more susceptible to infections [54].

Line 245 – you reference the weaning period – the weaning period from breastfeeding – please define if that is the case

Line 248 – diarrheal - spelling

Line 254 – would finish the sentence… potential risk factors in some studies

Line 258 – would change atiology to etiology

line 259 - The pathogenesis of noma is poorly understood and the microbiology is debated

would change to The pathogenesis of noma is poorly understood and debated

line 264 – place a comma after patients

line 265 – place a comma after consistently

line 266-267

currently starts with

Other studies have noted that noma incorporates the characteristics of an opportunistic infection,

Would suggest rewording this clause to

Other have noted that the characteristics of noma are similar to that of an opportunistic infection

Line 269

or immunodeficiency states

rephase to

or occur in immunocompromised individuals

line 269 – what are where are the concurrent infections reference – please comment on this and provide a citation

line 277 change manifestation to manifestations

line 277 change to “are unique”

line 278 starts as an inflammation of the gums

change to starts with inflammation of the gums

line 28 - lasting only a couple of weeks

would define this further

lasting only several weeks or

lasting 1-2 weeks or or lasting 3-4 weeks or other…

line 288 – insert a comma after debridement

line 288 insert a comma after early

line 291 – would replace disfigurements with deformities

line 291 – 292 – this is repetitive (the exact same sentence I believe as above) – see my recommendations on change this sentence, and whether it needs to be repeated again

line 295 – insert a comma after airway

line 295 – 296 suggest rewording sentence to :

The deformities that result from noma can lead to social stigmatization

Line 305 - biomedical

I am not sure what biomedical institutions are – can you define this or further define

Line 307 – insert a comma after leeches

Line 328 defects [102] that need a comprehensive suite of treatments

Suggest rewording to

Defects that often require a number of surgical treatments

Line 329 – suggesting removing the word provision

Line 367 – I see the use of biomedical again – perhaps I would just change all these biomedical to medical all these implies western medicine, rather than herbal treatments as noted

Line 368…..patients, and themselves attending didactic training sessions on noma.

Line 371 – There is limited evidence around the pathogenesis of noma leading to death

Reword to

There is limited and inconclusive data regarding the risk factors that are associated with mortality

Line 373 – suggest changing enumerated to understood

Line 376 – suggesting removing about from the sentence

Line 378

Replace timeously with in a timely manner

Line 382 – insert a comma afte (49-94%)

Line 384

chart reviews, no

change to

chart reviews; no

line 386 – insert a comma after mind

line 402 – replace our ability with the ability

line 413

surgical and non-surgical) insert a comma after this phrase

line 414 – insert a comma after protocols

sentence starting 415

suggesting rewording to :

Healthcare curriculums, both for practicing clinicians as well as trainees, should include noma – with salient information on the pathogenesis, known risk factors, and importance of timely diagnosis and treatment.

Line 418 – insert a comma after messaging

Line 418 -420

Currently

Sincere efforts and political will to eliminate extreme poverty could lead to the elimination of this preventable childhood.

Suggesting rewording to:

Efforts to eliminate extreme poverty may lead to a reduction in the number of cases of noma, and potentially even eliminate this disease.

Line 422 – replace the review with this review

Line 425 – insert a comma after misinterpretation

Line 429 – add In summary, to start off the first sentence

Line 430, insert a comma after disfiguring

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: If there is one message that comes out of this thorough review of noma it is that it has truly been neglected.

Reviewer #2: Thank you for this detailed and throughout review of noma. I have included changes that are mostly syntax in nature.

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Reviewer #1: No

Reviewer #2: No

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References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Dr Farley,

We are pleased to inform you that your manuscript 'Noma (cancrum oris): a scoping literature review of a neglected disease (1843 to 2021)' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Joseph M. Vinetz

Deputy Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Deputy Editor

PLOS Neglected Tropical Diseases

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