PONE-D-22-09854Characteristics of medication-induced xerostomia and factors associated with treatment responsePLOS ONE

Dear Dr. Ito,

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There are some minor concerns on the details of the methodology and results. However, a reviewer also raised a concern about conflict of interest. Please review the comments and address them accordingly.

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Sompop Bencharit, DDS, MS, PhD, FACP

Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Competing Interests:

“This study was funded by Pfizer Japan, Inc..

Naoko Izumi was involved in research and preparation of the manuscript as an employee of Pfizer Japan Inc.”

We note that one or more of the authors have an affiliation to the commercial funders of this research study : Pfizer Japan, Inc.

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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?

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: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: 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: General comments

The data are interesting, but the authors need to do a better job of presenting and describing their findings, and of making the case for conducting the study (Introduction section).

They have used something like triple spacing – which is not reader-friendly at all. I suggest that they use 1.5 spacing, which is much easier to read.

I am somewhat concerned by one of the authors being an employee of the private-sector funder (Pfizer). There needs to be a very careful explanation of how any associated conflicts of interest were managed in respect of this research.

The authors should be very clear about when they are referring to “xerostomia” (the symptoms of dry mouth) and when they are referring to low salivary flow (or salivary gland hypofunction, SGH). The subjective and objective aspects of dry mouth do not necessarily coincide, and the authors’ choice of terms should reflect that dichotomy. People with an unstimulated flow rate of <0.1 mL/min do not necessarily have xerostomia, but they definitely have SGH.

The study design is not clear, but I think I have worked it out – it could be described as a retrospective cohort study of a large clinical convenience sample, but there is an actual intervention, so it’s not strictly observational (and therefor enot a cohort study as such). I think it is a case series analysis a large clinical convenience sample for which there was an intervention (or interventions). The authors need to be very clear about their design, because the reader’s understanding of the findings is very much dependent on the design being explicit.

Always hyphenate “side-effect”. It is a compound word.

Headings and subheadings are huge – do we really need them that big?

Section comments

Title

This needs to better reflect the study design and the research question, and the term “xerostomia” should be replaced by “dry mouth”.

Abstract

Will need rewriting anyway, but some comments follow.

The logic of the first two sentences escapes me.

Use the past tense in describing findings. Do not rely on P vlues – put some actual data in the Results paragraph. Your study should not be a P value hunt – see Amrhein et al, Nature 2019; 567: 305-307.

Conclusion – that phrase “…can prevent decreased drug compliance for the primary disease” is also a mystery – what are you saying? By what logic?

Introduction

Overall, this should make a more compelling case for conducting the study.

Paragraph 1

Sentence 1 – change “decreased” to “low”. For a better and more recent estimation of prevalence rates, see Agostini BA et al. How common is dry mouth? Systematic review and meta-regression analysis of prevalence estimates. Brazilian Dental Journal 29: 606-618 (2018).

Last sentence – that is an unsupported sweeping statement – where is the evidence for that assertion?

Paragraph 2

Sentence 2 – medication-induced dry mouth accounts for well over 95% of cases of dry mouth – see the recent US Surgeon General’s Report on Oral Health.

Sentence 3 – That Sreebny list is far too inclusive, and you should avoid using those specific numbers.

Paragraph 3

See the Surgeon General report for a good overview of the therapeutic approaches for treating dry mouth – there is a very useful Table there. Last sentence of para 3 – change the awful “regarding” to “on”.

Paragraph 4

Sentence 1 – “…and eventual imrpovement of the primary disease” – really? That’s drawing a very long bow. How might that work? Next sentence – change “Therefore” to “Accordingly”. And specify the research question. The way the last sentence is worded is far too loose and woolly, and the reader has no idea of what the study is about.

Methods

Lines 93-94 – patients were not identified; the drugs were. Rewrite that sentence accordingly.

Lines 105-107 – express those as mL/min, not per 15 min.

Lines 111 to 113 – how do you know they “developed xerostomia”? Or did they “have” the condition?

Line 121 – “educated regarding” is poor wording – they were “made aware of” it, or taught how to do it – something like that is better.

Lines 126-7 – what herbal medicines? How given? When? Why? No reference – just a throwaway comment is given.

Line 135 – how exactly was xerostomia assessed? What was asked, and what were the response options?

Line 137 should be reworded.

Statistical analysis section – concentrate less onf the test stistics (such as chi-square tests) and more on the procedures – such as “cross-tabulations”, etc etc.

Results

Line 159 makes no sense at all. Line 166 also has problems – “all types” – really? Do you mean “any type”?

Table 1 is just a list. What not make it more informative for readers by cross-tabulating by sex or age group? And no Table should continue onto a second page. Think about reducing your use of gridlines – they actually distract the eye from the data.

In the Results text, do not repeat Table data – the reader can see the data in the Tables; your job is to draw his/her attention to the important parts and features. Have one paragraph of Results text per Table – this helps the reader to navigate your paper – and introduce each Table at the beginning of its paragraph, not at the end. Concentrate on what the data show, NOT on the P values – they are far less important.

Avoid using the term "compared to" when making comparisons - use 'than' – for example, in Line 227, replace “increased compared to baseline” with “was higher than at baseline’.

Table 3 would be enhanced by presenting effect sizes (the difference in mean score divided by the SD of the baseline score, and prsented to 1 decimal place. For example, that for those <65 years is 1.0, which is a large effect. And you will be able to demonstrate that the ES for the Sjogren’s patients was lower (0.4) than for those with medication-induced xerostomia (1.0) – that is important information, and much more useful and informative than the P values – which you could indicate with a footnote anyway.

Discussion

This will need rewriting anyway – in its current form, it is too long and discursive. In the Discussion and conclusion, use the term 'findings' rather than 'results'. See Docherty and Smith, BMJ 1999; 318: 1224-5 for how to structure a Discussion section. It is a useful structure. As a general rule, the first paragraph of the Discussion should briefly reiterate what the study did and what it showed. The second paragraph should address the weaknesses of the study design and measures, etc. The paragraphs which follow should then discuss how the findings support or refute the current literature. The final paragraph should tie it all together – so what? Where next? What are the implications for practice?

The current conclusion is not useful – what’s the take-home message from this study?

Reference 23 – is that legit?

Reviewer #2: Dear authors,

Congratulations for the study. It will definitely contribute to the scientific field of Pharmacology. Though I would suggest small changes to improve the quality of the reported results.

Line 63 - You better explain what OAB stands for. Does it refer to overreactive bladder?

Line 72 - You better explain what QOL stands for. Does it refer to quality of life?

In the results section I would suggest you to diplay the results in tables only as the majority of them were explained in the text and repeated on the tables. You could have a small paragraph describing a little about what will be displayed without mentioning the figures. I would also suggest you to re-organize table 1 as data are not clear. For instance , I took some time to understand that data presented as 70 on line 2, stands for the median age, and on the next line the figure stands for the size of the sample >= 65 years old. Its seems confuse!

On the headline of the columns write to what the figure stands for and in brackets you could write frequency in %. You better verify the total percentage for medical history.

Line 183 - What kind of Japanese Herbal medicine was used? Do they all have the same mechanism of action?

Did the use of anticholinergic drugs present any type of pharmacological interaction with the other drugs in use by patients? Did you have this data on patient´s record? Nothing was mentioned on the text about it.

Best regards.

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Reviewer #1: No

Reviewer #2: No

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Characteristics of medication-induced xerostomia and effect of treatment

PONE-D-22-09854R1

Dear Dr. Ito,

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.

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Kind regards,

Sompop Bencharit, DDS, MS, PhD, FACP

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for the revision.

Reviewers' comments:

The authors have sufficiently addressed all comments.