Title: Impact of improvement of sleep disturbance on symptoms and quality of life in patients
with functional dyspepsia
Version: 0 Date: 29 Dec 2020
Reviewer's report:
BMC Gastroenterology, Submission ID 759ab808-1a2f-47a2-b3f0-0c93c56f4d70, entitled
“Impact of improvement of sleep disturbance on symptoms and quality of life in patients with
functional dyspepsia” is an open-label nonrandomized pilot trial of pharmacologic sleep aids
for adults with functional dyspepsia.  It aims to determine if gastrointestinal symptoms in
this population are associated with changes in sleep.  Although there are few subjects in this
preliminary and heterogenous cohort, the authors used multiple validated scales to measure
outcomes and acknowledged limitations clearly in the discussion.  The following are comments/
questions for the authors:
1. Introduction, Page 3 – “Irritable Bowel Disease” should be corrected to “Irritable Bowel
Syndrome”.
2. Methods, Questionnaires – I was unfamiliar with several of the scales, and appreciated the
brief explanation and references to validation studies.  When available, validated Japanese
language versions were used---it would be helpful for the authors to comment as well on scales
that were not available in Japanese (mFSSG, GSRS, CSS, and how that was addressed (ie were
they translated?  How might this have affected validity/results)?
3. Methods, Questionnaires, PSQI – This description is a little confusing.  I think it intends to
convey that there are 17 individual items grouped into 7 categories, and each category receives
a score of 0-3 (max total score 21).  However, the sentence “A 4-point scale (scored 0–3) is used
for each item, and the total score is the sum of points from each item” seems to refer back to
the “17 individual items” in the prior sentence---suggesting a max score of 51.  This is a minor
point, but important when considering the total score threshold for sleep disturbance (5.5) and
meaningful change in score (3) chosen by the authors.
a. The authors should clarify how a change in score of 3 points was determined to differentiate
responders versus nonresponders.  It seems the authors could have used 5.5 as the threshold
instead---responders defined as those who had sleep disturbance prior to use of sleep aid (score
>5.5) but then did not have sleep disturbance (score <5.5) while using the sleep aid.
4. Methods, Sleep Aids – Did a single physician care for all of the enrolled patients?  Was that
physician one of the study authors?  This should be mentioned in the methods.
5. Methods, Sleep Aids – It does not appear that ramelteon was used in this study, so the authors
could consider removing the statement “Ramelteon can be used for circadian rhythm sleep
disorders 26 ” here.  The inclusion of ramelteon in the introduction and discussion still seems
warranted.
6. Results, Effect of Sleep Aids on Sleep Disturbance – The authors could further clarify the
scoring used for the PSQI.  Was the frequency of use of sleep aids (3 points) included in the
scoring, but the score still decreased from a median of 10 to 8.5?
7. Results, H. pylori – This is a very helpful paragraph from the authors.  Is presence or absence
of gastric atrophy sufficient to rule out H. pylori infection?  Is there a role of location of gastric
atrophy, presence of H. pylori bacteria (microscopically), or presence of chronic inflammation?
If so, were these assessed histologically?
a. Additionally, the authors indicate in this paragraph for the first time that all subjects underwent
EGD---was this part of the diagnostic pathway prior to FD diagnosis and were results of all EGDs
normal?  Were any other diseases assessed/ruled out in all subjects as part of routine diagnosis?
8. Discussion – In the first paragraph the authors state “It is interesting that less pain may
be associated with administration of sleep aids, which indicates that these drugs caused pain
modulation in FD patients with sleep disturbance.”  I think that “use of the drugs was associated
with both reduced pain in FD patients” is better supported by the evidence in this study
and statements suggesting causation should be avoided.  The authors do an excellent job in
subsequent Discussion paragraphs regarding potential anxiolytic and gaba-ergic effects of some
pharmacologic sleep aids (alternate reasons that GI symptoms may have improved).
9. Discussion – The authors could consider commenting on non-pharmacologic sleep
interventions---if improved sleep is associated with decreased pain/GI symptoms in FD patients,
it would make sense to focus on improving sleep using behavioral techniques/good sleep hygiene
first (and pharmacologic sleep aids later).
10. Figure 1 – Scales for mFSSG and 2 GSRS subscales are included.  Why were these scales
chosen for inclusion in the figure and other scales not?  Did the two non-responders have similar
differences from responders on other measures/scales?
11. Table 2 – I am unfamiliar with the column labelled variability rates (%)---what does this
indicate and how is it calculated?  Does it affect interpretation of results?
12. Table 2 / Results / Discussion– The median score on the PSQI changed from 10 to 8.5.
Although statistically significant (with a small sample size), what clinical meaning/relevance
can be inferred from this magnitude of score change?
13. Table 2 – Current formatting of the table suggests it might be helpful to split into 2 separate
tables to make scanning it easier for the reader---ie. Table 2 including Sleep and QoL, and Table
3 including GI and Psychological (or any combination the authors feel is appropriate).
Title: Impact of improvement of sleep disturbance on symptoms and quality of life in patients
with functional dyspepsia
Version: 0 Date: 29 Dec 2020
Reviewer's report:
BMC Gastroenterology, Submission ID 759ab808-1a2f-47a2-b3f0-0c93c56f4d70, entitled
“Impact of improvement of sleep disturbance on symptoms and quality of life in patients with
functional dyspepsia” is an open-label nonrandomized pilot trial of pharmacologic sleep aids
for adults with functional dyspepsia.  It aims to determine if gastrointestinal symptoms in
this population are associated with changes in sleep.  Although there are few subjects in this
preliminary and heterogenous cohort, the authors used multiple validated scales to measure
outcomes and acknowledged limitations clearly in the discussion.  The following are comments/
questions for the authors:
1. Introduction, Page 3 – “Irritable Bowel Disease” should be corrected to “Irritable Bowel
Syndrome”.
2. Methods, Questionnaires – I was unfamiliar with several of the scales, and appreciated the
brief explanation and references to validation studies.  When available, validated Japanese
language versions were used---it would be helpful for the authors to comment as well on scales
that were not available in Japanese (mFSSG, GSRS, CSS, and how that was addressed (ie were
they translated?  How might this have affected validity/results)?
3. Methods, Questionnaires, PSQI – This description is a little confusing.  I think it intends to
convey that there are 17 individual items grouped into 7 categories, and each category receives
a score of 0-3 (max total score 21).  However, the sentence “A 4-point scale (scored 0–3) is used
for each item, and the total score is the sum of points from each item” seems to refer back to
the “17 individual items” in the prior sentence---suggesting a max score of 51.  This is a minor
point, but important when considering the total score threshold for sleep disturbance (5.5) and
meaningful change in score (3) chosen by the authors.
a. The authors should clarify how a change in score of 3 points was determined to differentiate
responders versus nonresponders.  It seems the authors could have used 5.5 as the threshold
instead---responders defined as those who had sleep disturbance prior to use of sleep aid (score
>5.5) but then did not have sleep disturbance (score <5.5) while using the sleep aid.
4. Methods, Sleep Aids – Did a single physician care for all of the enrolled patients?  Was that
physician one of the study authors?  This should be mentioned in the methods.
5. Methods, Sleep Aids – It does not appear that ramelteon was used in this study, so the authors
could consider removing the statement “Ramelteon can be used for circadian rhythm sleep
disorders 26 ” here.  The inclusion of ramelteon in the introduction and discussion still seems
warranted.
6. Results, Effect of Sleep Aids on Sleep Disturbance – The authors could further clarify the
scoring used for the PSQI.  Was the frequency of use of sleep aids (3 points) included in the
scoring, but the score still decreased from a median of 10 to 8.5?
7. Results, H. pylori – This is a very helpful paragraph from the authors.  Is presence or absence
of gastric atrophy sufficient to rule out H. pylori infection?  Is there a role of location of gastric
atrophy, presence of H. pylori bacteria (microscopically), or presence of chronic inflammation?
If so, were these assessed histologically?
a. Additionally, the authors indicate in this paragraph for the first time that all subjects underwent
EGD---was this part of the diagnostic pathway prior to FD diagnosis and were results of all EGDs
normal?  Were any other diseases assessed/ruled out in all subjects as part of routine diagnosis?
8. Discussion – In the first paragraph the authors state “It is interesting that less pain may
be associated with administration of sleep aids, which indicates that these drugs caused pain
modulation in FD patients with sleep disturbance.”  I think that “use of the drugs was associated
with both reduced pain in FD patients” is better supported by the evidence in this study
and statements suggesting causation should be avoided.  The authors do an excellent job in
subsequent Discussion paragraphs regarding potential anxiolytic and gaba-ergic effects of some
pharmacologic sleep aids (alternate reasons that GI symptoms may have improved).
9. Discussion – The authors could consider commenting on non-pharmacologic sleep
interventions---if improved sleep is associated with decreased pain/GI symptoms in FD patients,
it would make sense to focus on improving sleep using behavioral techniques/good sleep hygiene
first (and pharmacologic sleep aids later).
10. Figure 1 – Scales for mFSSG and 2 GSRS subscales are included.  Why were these scales
chosen for inclusion in the figure and other scales not?  Did the two non-responders have similar
differences from responders on other measures/scales?
11. Table 2 – I am unfamiliar with the column labelled variability rates (%)---what does this
indicate and how is it calculated?  Does it affect interpretation of results?
12. Table 2 / Results / Discussion– The median score on the PSQI changed from 10 to 8.5.
Although statistically significant (with a small sample size), what clinical meaning/relevance
can be inferred from this magnitude of score change?
13. Table 2 – Current formatting of the table suggests it might be helpful to split into 2 separate
tables to make scanning it easier for the reader---ie. Table 2 including Sleep and QoL, and Table
3 including GI and Psychological (or any combination the authors feel is appropriate).
Please review this paper.
user
Title: Impact of improvement of sleep disturbance on symptoms and quality of life in patients
with functional dyspepsia
Version: 0 Date: 29 Dec 2020
Reviewer's report:
BMC Gastroenterology, Submission ID 759ab808-1a2f-47a2-b3f0-0c93c56f4d70, entitled
“Impact of improvement of sleep disturbance on symptoms and quality of life in patients with
functional dyspepsia” is an open-label nonrandomized pilot trial of pharmacologic sleep aids
for adults with functional dyspepsia.  It aims to determine if gastrointestinal symptoms in
this population are associated with changes in sleep.  Although there are few subjects in this
preliminary and heterogenous cohort, the authors used multiple validated scales to measure
outcomes and acknowledged limitations clearly in the discussion.  The following are comments/
questions for the authors:
1. Introduction, Page 3 – “Irritable Bowel Disease” should be corrected to “Irritable Bowel
Syndrome”.
2. Methods, Questionnaires – I was unfamiliar with several of the scales, and appreciated the
brief explanation and references to validation studies.  When available, validated Japanese
language versions were used---it would be helpful for the authors to comment as well on scales
that were not available in Japanese (mFSSG, GSRS, CSS, and how that was addressed (ie were
they translated?  How might this have affected validity/results)?
3. Methods, Questionnaires, PSQI – This description is a little confusing.  I think it intends to
convey that there are 17 individual items grouped into 7 categories, and each category receives
a score of 0-3 (max total score 21).  However, the sentence “A 4-point scale (scored 0–3) is used
for each item, and the total score is the sum of points from each item” seems to refer back to
the “17 individual items” in the prior sentence---suggesting a max score of 51.  This is a minor
point, but important when considering the total score threshold for sleep disturbance (5.5) and
meaningful change in score (3) chosen by the authors.
a. The authors should clarify how a change in score of 3 points was determined to differentiate
responders versus nonresponders.  It seems the authors could have used 5.5 as the threshold
instead---responders defined as those who had sleep disturbance prior to use of sleep aid (score
>5.5) but then did not have sleep disturbance (score <5.5) while using the sleep aid.
4. Methods, Sleep Aids – Did a single physician care for all of the enrolled patients?  Was that
physician one of the study authors?  This should be mentioned in the methods.
5. Methods, Sleep Aids – It does not appear that ramelteon was used in this study, so the authors
could consider removing the statement “Ramelteon can be used for circadian rhythm sleep
disorders 26 ” here.  The inclusion of ramelteon in the introduction and discussion still seems
warranted.
6. Results, Effect of Sleep Aids on Sleep Disturbance – The authors could further clarify the
scoring used for the PSQI.  Was the frequency of use of sleep aids (3 points) included in the
scoring, but the score still decreased from a median of 10 to 8.5?
7. Results, H. pylori – This is a very helpful paragraph from the authors.  Is presence or absence
of gastric atrophy sufficient to rule out H. pylori infection?  Is there a role of location of gastric
atrophy, presence of H. pylori bacteria (microscopically), or presence of chronic inflammation?
If so, were these assessed histologically?
a. Additionally, the authors indicate in this paragraph for the first time that all subjects underwent
EGD---was this part of the diagnostic pathway prior to FD diagnosis and were results of all EGDs
normal?  Were any other diseases assessed/ruled out in all subjects as part of routine diagnosis?
8. Discussion – In the first paragraph the authors state “It is interesting that less pain may
be associated with administration of sleep aids, which indicates that these drugs caused pain
modulation in FD patients with sleep disturbance.”  I think that “use of the drugs was associated
with both reduced pain in FD patients” is better supported by the evidence in this study
and statements suggesting causation should be avoided.  The authors do an excellent job in
subsequent Discussion paragraphs regarding potential anxiolytic and gaba-ergic effects of some
pharmacologic sleep aids (alternate reasons that GI symptoms may have improved).
9. Discussion – The authors could consider commenting on non-pharmacologic sleep
interventions---if improved sleep is associated with decreased pain/GI symptoms in FD patients,
it would make sense to focus on improving sleep using behavioral techniques/good sleep hygiene
first (and pharmacologic sleep aids later).
10. Figure 1 – Scales for mFSSG and 2 GSRS subscales are included.  Why were these scales
chosen for inclusion in the figure and other scales not?  Did the two non-responders have similar
differences from responders on other measures/scales?
11. Table 2 – I am unfamiliar with the column labelled variability rates (%)---what does this
indicate and how is it calculated?  Does it affect interpretation of results?
12. Table 2 / Results / Discussion– The median score on the PSQI changed from 10 to 8.5.
Although statistically significant (with a small sample size), what clinical meaning/relevance
can be inferred from this magnitude of score change?
13. Table 2 – Current formatting of the table suggests it might be helpful to split into 2 separate
tables to make scanning it easier for the reader---ie. Table 2 including Sleep and QoL, and Table
3 including GI and Psychological (or any combination the authors feel is appropriate).
assistant