Reviewer’s report
Title: 
Evaluation of Role of Hyperbilirubinemia as a New Diagnostic Marker of
Complicated Appendicitis.
Version: 
0 
Date: 
13 Mar 2020
Reviewer's report:
This prospective study focus on the role of hyperbilirubinemia as a biomarker
for identifying patients with complicated appendicitis. If the result is valid, it
would have an impact on the pre-operative assessment of appendicitis patients.
However, there are some aspects that need to be refined.
- Consider repositioning some of the in-text citations that are in the middle of a
sentence.
- The authors frequently cited from secondary sources (i.e., textbook). It would
be better to cite from the original sources or look for an alternative peer-review
article as a reference.
- The introduction is too long. It needs to be re-written to be more concise (i.e.,
the redundant explanation that is not related to the main point of the study should
be omitted, or only briefly described), and better organized. 
--- BACKGROUND -----
1. Many sentences are not supported, in-text citations and reference should be
refined.
for example:
- (1st paragraph). Please provide the reference that acute appendicitis is the most
common cause of emergency laparotomy.
- (3rd paragraph). Please provide the reference that the gangrenous appendicitis
or the perforated appendicitis are associated with higher complications.
- (4th paragraph) Please provide the evidence that MDCT increases the cost of
care, stay time, and delaying the surgery; does this have a negative effect on the
treatment outcome?
- (4th paragraph) Reference [24] seems to be misplaced since its content is
mainly focused on the bacteriology of appendicitis, and not related to the
hyperbilirubinemia, please consider moving it to its corresponding sentence.
- Please add a reference for the pathophysiology as well as the citations for the
cytokines and tumor necrosis factors
2. 3rd paragraph
- The range of incidence in the first and the second sentences are different, and
this can be confusing for the reader. Please consider removing one or the other.
- 2nd sentence - please clarify the term "these cases"; based on the beginning of
the paragraph, it seems like it was referred to cases with appendicular
perforation. However, since the same sentence mentioned that the surgical delay
could lead to perforation, 
the assumption that "these cases" equal to "cases with
perforation" would be illogical (the appendix has already perforated; it shouldn't
lead to perforation). To me, it is more sensible if the term was referred to just the
patients with appendicitis (not with perforation, in particular), in this case, please
clarify the term, and rearrange the order of the sentence to make it less
confusing.
3. The mechanism of appendicitis/perforation
* The "sequences of events" for the mechanism of appendicitis &
hyperbilirubinemia should be made into a figure, instead of an in-text diagram.
* Please re-number the figures (graphs and photos 1, 2, 3 have the same figure
numbers).
4. The last paragraph seems like a conclusion of the present study; this might be
omitted from the background section.
-------- METHODS ------------
* Please elaborate more on the diagnosis of appendicitis. It seems that all the
patients underwent pre-operative ultrasound. The ultrasound of the diameters of
the appendices were available for all of the patients; please explain if the
appendices were really visible in all of the patients, or if the patients whose
appendices were not visible were excluded from the study? In that case, how
may were excluded?
* Consider replacing the "HP" abbreviation with its full term.
-------RESULTS & DISCUSSION --------
Results and Discussion
1. Explanations of the important findings need to be properly written in the form
of paragraphs in the main body of the text. Other details can be referred to tables
and graphs.
⁃
 The majority of the text in the "Discussion" section should instead be placed in
the "Results" section.
2. There are too many figures and tables, for this;
⁃
 For each parameter, please consider using only one graph or table that is the
most representative of the data.
⁃
 Some parameters can be combined together into a single table, so it would be
more organized and easier for comparison.
⁃
 For some parameters, an explanation in the sentence may be sufficient without
the need for a graph or a table.
3. Instead of p<0.05 or p>0.05, the exact p-value should be provided.
4. Regarding serum bilirubin and complicated appendicitis
⁃
 Since this is the main focus of the research; it should be analyzed further.
Which is the best biomarker? Total, direct, or indirect hyperbilirubinemia?
5. Since there were many parameters that were associated with complicated
appendicitis, please consider multivariate analysis to look for independent factor,
and to confirm that hyperbilirubinemia is an independent marker of complicated
appendicitis.
6. The discussion section should cover more discussion on the comparison
between the previous and the current studies. The similarities and the differences
should be explained as well as the advantages and the new findings/knowledge
of the current study. Citations should also be provided.
7. The mechanism described in the last paragraph of the discussion (before the
limitation of the study) is not supported by the findings in the current study. 
---- Conclusion -----
While I agree that bilirubin is potentially a helpful biomarker for detecting acute
complicated appendicitis, I would be more careful with some of the suggestions
in the study's conclusion (to be specific, no.3 - no.5)
- It is not known whether the result would be applicable in pregnant or
immunosuppressive patients, because these patients are different from the
population of the current study (i.e., their physiology and their response to sepsis
and inflammation may be different from the normal population).
- Referring to the exclusion criteria, I presumed that patients with appendicular
lump were excluded from the study. Thus, the suggestion on the usefulness of
hyperbilirubinemia in patients with appendicular lump also is not supported by
the result of this study.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
Unable to assess
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. I agree for my report to
be made available under an Open Access Creative Commons CC-BY license
(
http://creativecommons.org/licenses/by/4.0/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title: 
Evaluation of Role of Hyperbilirubinemia as a New Diagnostic Marker of
Complicated Appendicitis.
Version: 
0 
Date: 
13 Mar 2020
Reviewer's report:
This prospective study focus on the role of hyperbilirubinemia as a biomarker
for identifying patients with complicated appendicitis. If the result is valid, it
would have an impact on the pre-operative assessment of appendicitis patients.
However, there are some aspects that need to be refined.
- Consider repositioning some of the in-text citations that are in the middle of a
sentence.
- The authors frequently cited from secondary sources (i.e., textbook). It would
be better to cite from the original sources or look for an alternative peer-review
article as a reference.
- The introduction is too long. It needs to be re-written to be more concise (i.e.,
the redundant explanation that is not related to the main point of the study should
be omitted, or only briefly described), and better organized. 
--- BACKGROUND -----
1. Many sentences are not supported, in-text citations and reference should be
refined.
for example:
- (1st paragraph). Please provide the reference that acute appendicitis is the most
common cause of emergency laparotomy.
- (3rd paragraph). Please provide the reference that the gangrenous appendicitis
or the perforated appendicitis are associated with higher complications.
- (4th paragraph) Please provide the evidence that MDCT increases the cost of
care, stay time, and delaying the surgery; does this have a negative effect on the
treatment outcome?
- (4th paragraph) Reference [24] seems to be misplaced since its content is
mainly focused on the bacteriology of appendicitis, and not related to the
hyperbilirubinemia, please consider moving it to its corresponding sentence.
- Please add a reference for the pathophysiology as well as the citations for the
cytokines and tumor necrosis factors
2. 3rd paragraph
- The range of incidence in the first and the second sentences are different, and
this can be confusing for the reader. Please consider removing one or the other.
- 2nd sentence - please clarify the term "these cases"; based on the beginning of
the paragraph, it seems like it was referred to cases with appendicular
perforation. However, since the same sentence mentioned that the surgical delay
could lead to perforation, 
the assumption that "these cases" equal to "cases with
perforation" would be illogical (the appendix has already perforated; it shouldn't
lead to perforation). To me, it is more sensible if the term was referred to just the
patients with appendicitis (not with perforation, in particular), in this case, please
clarify the term, and rearrange the order of the sentence to make it less
confusing.
3. The mechanism of appendicitis/perforation
* The "sequences of events" for the mechanism of appendicitis &
hyperbilirubinemia should be made into a figure, instead of an in-text diagram.
* Please re-number the figures (graphs and photos 1, 2, 3 have the same figure
numbers).
4. The last paragraph seems like a conclusion of the present study; this might be
omitted from the background section.
-------- METHODS ------------
* Please elaborate more on the diagnosis of appendicitis. It seems that all the
patients underwent pre-operative ultrasound. The ultrasound of the diameters of
the appendices were available for all of the patients; please explain if the
appendices were really visible in all of the patients, or if the patients whose
appendices were not visible were excluded from the study? In that case, how
may were excluded?
* Consider replacing the "HP" abbreviation with its full term.
-------RESULTS & DISCUSSION --------
Results and Discussion
1. Explanations of the important findings need to be properly written in the form
of paragraphs in the main body of the text. Other details can be referred to tables
and graphs.
⁃
 The majority of the text in the "Discussion" section should instead be placed in
the "Results" section.
2. There are too many figures and tables, for this;
⁃
 For each parameter, please consider using only one graph or table that is the
most representative of the data.
⁃
 Some parameters can be combined together into a single table, so it would be
more organized and easier for comparison.
⁃
 For some parameters, an explanation in the sentence may be sufficient without
the need for a graph or a table.
3. Instead of p<0.05 or p>0.05, the exact p-value should be provided.
4. Regarding serum bilirubin and complicated appendicitis
⁃
 Since this is the main focus of the research; it should be analyzed further.
Which is the best biomarker? Total, direct, or indirect hyperbilirubinemia?
5. Since there were many parameters that were associated with complicated
appendicitis, please consider multivariate analysis to look for independent factor,
and to confirm that hyperbilirubinemia is an independent marker of complicated
appendicitis.
6. The discussion section should cover more discussion on the comparison
between the previous and the current studies. The similarities and the differences
should be explained as well as the advantages and the new findings/knowledge
of the current study. Citations should also be provided.
7. The mechanism described in the last paragraph of the discussion (before the
limitation of the study) is not supported by the findings in the current study. 
---- Conclusion -----
While I agree that bilirubin is potentially a helpful biomarker for detecting acute
complicated appendicitis, I would be more careful with some of the suggestions
in the study's conclusion (to be specific, no.3 - no.5)
- It is not known whether the result would be applicable in pregnant or
immunosuppressive patients, because these patients are different from the
population of the current study (i.e., their physiology and their response to sepsis
and inflammation may be different from the normal population).
- Referring to the exclusion criteria, I presumed that patients with appendicular
lump were excluded from the study. Thus, the suggestion on the usefulness of
hyperbilirubinemia in patients with appendicular lump also is not supported by
the result of this study.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
Unable to assess
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. I agree for my report to
be made available under an Open Access Creative Commons CC-BY license
(
http://creativecommons.org/licenses/by/4.0/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title: 
Evaluation of Role of Hyperbilirubinemia as a New Diagnostic Marker of
Complicated Appendicitis.
Version: 
0 
Date: 
13 Mar 2020
Reviewer's report:
This prospective study focus on the role of hyperbilirubinemia as a biomarker
for identifying patients with complicated appendicitis. If the result is valid, it
would have an impact on the pre-operative assessment of appendicitis patients.
However, there are some aspects that need to be refined.
- Consider repositioning some of the in-text citations that are in the middle of a
sentence.
- The authors frequently cited from secondary sources (i.e., textbook). It would
be better to cite from the original sources or look for an alternative peer-review
article as a reference.
- The introduction is too long. It needs to be re-written to be more concise (i.e.,
the redundant explanation that is not related to the main point of the study should
be omitted, or only briefly described), and better organized. 
--- BACKGROUND -----
1. Many sentences are not supported, in-text citations and reference should be
refined.
for example:
- (1st paragraph). Please provide the reference that acute appendicitis is the most
common cause of emergency laparotomy.
- (3rd paragraph). Please provide the reference that the gangrenous appendicitis
or the perforated appendicitis are associated with higher complications.
- (4th paragraph) Please provide the evidence that MDCT increases the cost of
care, stay time, and delaying the surgery; does this have a negative effect on the
treatment outcome?
- (4th paragraph) Reference [24] seems to be misplaced since its content is
mainly focused on the bacteriology of appendicitis, and not related to the
hyperbilirubinemia, please consider moving it to its corresponding sentence.
- Please add a reference for the pathophysiology as well as the citations for the
cytokines and tumor necrosis factors
2. 3rd paragraph
- The range of incidence in the first and the second sentences are different, and
this can be confusing for the reader. Please consider removing one or the other.
- 2nd sentence - please clarify the term "these cases"; based on the beginning of
the paragraph, it seems like it was referred to cases with appendicular
perforation. However, since the same sentence mentioned that the surgical delay
could lead to perforation, 
the assumption that "these cases" equal to "cases with
perforation" would be illogical (the appendix has already perforated; it shouldn't
lead to perforation). To me, it is more sensible if the term was referred to just the
patients with appendicitis (not with perforation, in particular), in this case, please
clarify the term, and rearrange the order of the sentence to make it less
confusing.
3. The mechanism of appendicitis/perforation
* The "sequences of events" for the mechanism of appendicitis &
hyperbilirubinemia should be made into a figure, instead of an in-text diagram.
* Please re-number the figures (graphs and photos 1, 2, 3 have the same figure
numbers).
4. The last paragraph seems like a conclusion of the present study; this might be
omitted from the background section.
-------- METHODS ------------
* Please elaborate more on the diagnosis of appendicitis. It seems that all the
patients underwent pre-operative ultrasound. The ultrasound of the diameters of
the appendices were available for all of the patients; please explain if the
appendices were really visible in all of the patients, or if the patients whose
appendices were not visible were excluded from the study? In that case, how
may were excluded?
* Consider replacing the "HP" abbreviation with its full term.
-------RESULTS & DISCUSSION --------
Results and Discussion
1. Explanations of the important findings need to be properly written in the form
of paragraphs in the main body of the text. Other details can be referred to tables
and graphs.
⁃
 The majority of the text in the "Discussion" section should instead be placed in
the "Results" section.
2. There are too many figures and tables, for this;
⁃
 For each parameter, please consider using only one graph or table that is the
most representative of the data.
⁃
 Some parameters can be combined together into a single table, so it would be
more organized and easier for comparison.
⁃
 For some parameters, an explanation in the sentence may be sufficient without
the need for a graph or a table.
3. Instead of p<0.05 or p>0.05, the exact p-value should be provided.
4. Regarding serum bilirubin and complicated appendicitis
⁃
 Since this is the main focus of the research; it should be analyzed further.
Which is the best biomarker? Total, direct, or indirect hyperbilirubinemia?
5. Since there were many parameters that were associated with complicated
appendicitis, please consider multivariate analysis to look for independent factor,
and to confirm that hyperbilirubinemia is an independent marker of complicated
appendicitis.
6. The discussion section should cover more discussion on the comparison
between the previous and the current studies. The similarities and the differences
should be explained as well as the advantages and the new findings/knowledge
of the current study. Citations should also be provided.
7. The mechanism described in the last paragraph of the discussion (before the
limitation of the study) is not supported by the findings in the current study. 
---- Conclusion -----
While I agree that bilirubin is potentially a helpful biomarker for detecting acute
complicated appendicitis, I would be more careful with some of the suggestions
in the study's conclusion (to be specific, no.3 - no.5)
- It is not known whether the result would be applicable in pregnant or
immunosuppressive patients, because these patients are different from the
population of the current study (i.e., their physiology and their response to sepsis
and inflammation may be different from the normal population).
- Referring to the exclusion criteria, I presumed that patients with appendicular
lump were excluded from the study. Thus, the suggestion on the usefulness of
hyperbilirubinemia in patients with appendicular lump also is not supported by
the result of this study.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
Unable to assess
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. I agree for my report to
be made available under an Open Access Creative Commons CC-BY license
(
http://creativecommons.org/licenses/by/4.0/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
assistant