JerMa88/BMC_Gastroenterology_Peer_Reviews huggingface dataset:
Review for 10.1186/s12876-021-01745-1 (2021)

Title: The emerging epidemic of inflammatory bowel disease in Asia and Iran by 2035: A
modeling study
Version: 2 Date: 22 Feb 2021
Reviewer's report:
Thank you for this work and submission. It was an interesting paper. I appreciate that the authors
are trying to highlight the trends and emerging increase in the prevalence of inflammatory
bowel disease. This is important, yet an extremely complex area of epidemiological research.
I appreciate the goal of the paper. However, I feel that the modeling to generate the predicted
prevalence was too simplified based on current rate of increase. Additionally, I think it is difficult
to model the overall modernization rates, which the authors attribute the increasing incidence
too. Perhaps this complexity can be expanded, detailed and improved. I think the conclusions
drawn from the research are summarized in our need to address the overall worldwide increase
in incidence of IBD is appropriate. Ultimately, I am not sure how novel this concept is to the
readership. Additionally, the methods by which the authors propose to address the increase are
vague. It may be helpful to have more concrete and actionable items on how to reduce the
incidence? Or, if unable to propose a reduction plan, it would be best to move this scope from
the conclusions of the paper. I do appreciate the goal of this paper. However, I think it may
need a bit more depth to inspire the readership - perhaps the authors could consider cost or
financial implications, not only prevalence? or modify their overarching conclusions to include
more concrete and actionable items, like "we would need XX more gastroenterologists, etc".
Review for 10.1186/s12876-021-01745-1 (2021)

Title: The emerging epidemic of inflammatory bowel disease in Asia and Iran by 2035: A
modeling study
Version: 4 Date: 30 Mar 2021
Reviewer's report:
Thank you for addressing all my comments. The current version is clearer. Only a few typos
errors (like in lines 118-119-289) are present in the text.
Review for 10.1186/s12876-021-01798-2 (2021)

Title: Outcomes and limitations of endoscopic ultrasound-guided hepaticogastrostomy in
malignant biliary obstruction
Version: 1 Date: 08 Mar 2021
Reviewer:  Yen-Chih Lin
Reviewer's report:
1. About inclusion criteria, you mentioned you have enrolled the cases of “ malignant infiltration
of duodenal wall in the peripapillary region” ,do you think these cases are accessible or
inaccessible papilla? Is the obstruction level located over anal side of SDA or oral side of SDA?
In your constitution, is ERCP or EUS-CDS  always attemped  before EUS-HGS?
2. In tale 1 ,is the item “Liver metastases” in the table one of the cause of biliary obstruction?
Please make an indent to make it clear.
You may add more tables to demostrate the details of mortality cases and the outcomes/
complications of your study.
Review for 10.1186/s12876-021-01798-2 (2021)

Title: Outcomes and limitations of endoscopic ultrasound-guided hepaticogastrostomy in
malignant biliary obstruction
Version: 1 Date: 13 Mar 2021
Reviewer's report:
The study entitled “Outcomes and limitations of endoscopic ultrasound-guided
hepaticogastrostomy in malignant biliary obstruction“  highlights the use of EUS-guided
endoscopic hepatogastrostomy for failed ERCP drainage for malignant biliary obstruction. This
technique is attractive and has several advantages over surgery.
While the authors study might be of great use for the current literature, several questions
regarding their proposal should be asked:
1. There is a clearly need of extensive English improvement as many of the ideas in the
manuscript are not fully understood due to poor English language.
For example, there irresectable should be replaced with unresectable
written consent to the proposed
etc.
2.  The Methods section
Authors mention this a prospective study and that it was approved by the Ethics Committee
which means that they should have an approval number. They should mention it.
All this section requires to be restructured. All the information provided is scattered with
no actual logic. They should separate this section accordingly, with Patient’s characteristics,
Inclusion criteria, Procedures, Statistics etc…
Line 136 EG38UT is an echoendoscope
Line 135 Endoscopic hepaticogastrostomy procedures (Figures 1A–E) – none of the selected
images focus on EUS characteriscs.
3. The results section
The authors use both endoscopic and endoscopic hepaticogastrostomy – they should decide on
one of them.
Asa mentioned above, this chapter also requires restructuring based on the results obtained either
by procedures, clinical success, complications, groups etc…
Line 232 Detailed clinical characteristics of the patients are presented in Table 1. When checking
the table, the data here is very scarce. Consider providing additional information or restructuring
the table.
Also, surely the authors can provide additional tables regarding their results.
4. Discussions
extrahepatic biliary tract access, via choledochoduodenostomy/cholecystoduodenostomy, to
intrahepatic access, via hepaticogastrostomy, the technical and clinical success rates are similar.
Whereas a higher number of complications are observed in patients with intrahepatic access.
[11,17]
Should be rephrased
Line 327 to 330 perhaps the authors should only use the conclusion that the procedure should
be performed in experienced centers
Line 331 but may also be used first-line treatment. Pulling this conclusion is rather hasty and in
contradiction with the one above, regarding performing it in dedicated centers.
The limitations should also include that cost analysis was not performed and a long follow-up
was not assessed.
Review for 10.1186/s12876-021-01798-2 (2021)

Title: Outcomes and limitations of endoscopic ultrasound-guided hepaticogastrostomy in
malignant biliary obstruction
Version: 5 Date: 23 Apr 2021
Reviewer:  Yen-Chih Lin
Reviewer's report:
Thanks for your revision. You have made good response to my questions.
Review for 10.1186/s12876-021-01786-6 (2021)

Title: Impact of donor age on liver transplant outcomes in patients with hepatocellular
carcinoma: analysis of the SRTR database
Version: 2 Date: 22 Dec 2020
Reviewer's report:
In the current paper, the authors investigated the impact on donor age on OS and Recurrence
in a cohort of 13,276 patients with HCC who underwent liver transplantation. They found that
older donor age was associated with worse OS but no difference with respect to recurrence was
observed.
Main comments:
The paper lacks some novelty, as it has been previously shown that donor age correlates with
survival (the authors cite respective papers). In the current paper, the differences in OS with
respect to donor age were marginal in groups I-III, only those who received grafts from donors
older that 65 years (group IV) had a relevant drop in 5-year survival rate compared to the very
young donor group (group I). The p-value of <0.001 is highly significant but rather reflects the
large sample size (n=13,276) than clinically relevant differences. These needs to be highlighted
in the discussion. To further elaborate the impact of donor age on survival, it would be critical
to analyze the liver-related mortality in your cohort.
The discussion is way too long and needs to be shortened significantly. It should be sharper to
the point and less repetitive.
Minor:
In Table 1, the authors state Milan status. I assume Milan status was assessed prior to
transplantation (not at the time of listing) and downstaging was allowed. Similarly, I assume
tumor number and size only refer to viable tumor, correct? Where these varibales assessed by
radiology or pathology (explant histology)? Please specify.
Did patients with tumor recurrence have a shorter OS?
Patients who received downstaging before transplant had probably a higher tumor load and thus,
a higher risk of micrometastatic spread and HCC recurrence after transplant. Thus, pre-transplant
tumor therapy should also be included in the univariable analysis of OS.
Some typos should be corrected.
Review for 10.1186/s12876-021-01786-6 (2021)

Title: Impact of donor age on liver transplant outcomes in patients with hepatocellular
carcinoma: analysis of the SRTR database
Version: 2 Date: 26 Dec 2020
Reviewer's report:
The authors report data from the OPTN dataset including almost 13,300 transplant recipients
with HCC. The main aim of the study was to evaluate the impact of donor age on liver transplant
outcomes in patients with hepatocellular carcinoma. Not surprisingly, younger donor age was
associated with an improved survival, while donor age did not impact on HCC recurrence rate.
As attempts to increase the donor pool may lead to transplantation of older organs, the study
subject is interesting, however, the study has some significant drawbacks, which are outlined
below.
Major comments
- The authors did not specify the end of clinical follow-up. This must be added. Additionally,
and as older organs might be increasingly used in the last years, patients with a follow-up of less
than 24 months should be excluded from the primary analyses.
- Studies have indicated that choice of immunosuppressive treatment after liver transplantation
might impact on HCC recurrence. Therefore, HCC recurrence should be analyzed considering
immunosuppressive regimen as co-factor.
- Furthermore, presence or absence of vascular invasion should be considered as co-factor.
- Additionally, tumor biology (as indicated by Edmondson-Steiner grade) should be included
as co-factor.
- It should be stated that even though some differences were statistically significant due to
the large sample size, these differences might not be clinically relevant (e.g. 1-year survival
among the different groups: 91.4% vs. 90.6% vs. 89.5 vs. 89.2%). In line, the authors stated
that “donor age had slight effect on post-transplant tumor recurrence” – this is not supported
by the demonstrated data.
- English needs to be improved throughout the whole manuscript.
- Numbers at risk need to be included in all Kaplan-Meier curves.
Review for 10.1186/s12876-021-01786-6 (2021)

Title: Impact of donor age on liver transplant outcomes in patients with hepatocellular
carcinoma: analysis of the SRTR database
Version: 4 Date: 13 Feb 2021
Reviewer's report:
Dear authors,
You sufficiently answered to my requests and language quality was significantly improved.
However, as important variables are missing (tumor stage, MVI), the comparison of HCC
recurrence has significant limitations which limits the novelty of this manuscript.
Nevertheless, the authors sufficiently declared these limitations and in my opinion, this
manuscript may be accepted for publication after thorough proof reading.
Congratulations and best wishes
Review for 10.1186/s12876-021-01786-6 (2021)

Title: Impact of donor age on liver transplant outcomes in patients with hepatocellular
carcinoma: analysis of the SRTR database
Version: 4 Date: 13 Feb 2021
Reviewer's report:
The authors provide in their revised version the cause of death. However, in my previous review,
I asked for liver-related mortality. Maybe that was a misunderstanding. What I meant was the
liver-specific survival? Can the authors provide that.
I also asked to shorten the discussion. It is still very long (4.5 pages) and somehow hard to read.
Please streamline it. Only discuss what is truly relevant.
The survival differences of the four groups are minimal and only significant because of the
large sample size included. Statistical significance does not mean clinical relevance. Instead of
elaborating on these small differences between the groups in the discussion, you should just state
that differences were small. This is actually good, as it suggests that older donor age may not
implicate long-term outcome in a clinically relevant way.
Review for 10.1186/s12876-021-01791-9 (2021)

Title: Clinical and therapeutic features and prognostic factors of metastatic colorectal cancer
over age 80: a retrospective study
Version: 2 Date: 23 Feb 2021
Reviewer:  Taishi Hata
Reviewer's report:
To the author
The authors concluded that carcinoembryonic antigen and prognostic nutritional index were
independent prognostic factors in super-elderly patients with mCRC. The reviewer thinks that
this paper is interested in colorectal surgeons and oncologists. Before the final decision, the
authors should revise several places so that the message of this paper more clearly This reviewer
believes that the process would make the manuscript more attractive.
Comments
Characteristics of the participants
Table1
The reviewer thinks that it is useful for the reader if there is a comparison of the metastatic sites
in the background.
Table1
Tumor located on the right side
Is this percentage calculated including rectal cancer? Also, what is the ratio in the two groups
of rectal cancer? The reviewer believes that the authors should clarify this point.
Chemotherapy
The reviewer was unable to find Table 3.
Survival
Are most of the deaths of super-elderly patients due to current illness? In particular, there were
only 12 patients who received chemotherapy, and if death from other diseases is included, the
data becomes unreliable.The authors should provide details on the cause of death of the super-
elderly patients included this study.
Review for 10.1186/s12876-021-01791-9 (2021)

Title: Clinical and therapeutic features and prognostic factors of metastatic colorectal cancer
over age 80: a retrospective study
Version: 2 Date: 09 Mar 2021
Reviewer's report:
Thanks for the opportunity to review the manuscript about the prognostic analysis of super-
elderly metastatic colorectal cancer. There are some issues needed to be addressed.
1. The study enrolled the patient diagnosed between January 2012 and December 2016 and the
medical records were analyzed until August 2019. If the authors want to analyze the 3-years
survival, the study duration should be extended to Dec 2019 at least.
2. In table 1, and table 5a/b, should the description of "Poorly differentiated cancer and signet-
ring cell carcinoma" be "Poorly differentiated cancer or signet-ring cell carcinoma “?
3. In the result, line 221, the authors mentioned " ...... a similar trend was noted for patients
with PNI > 35 (18.5 vs. 12.9 months; P = 0.64)......." and in the discussion, line 283, the authors
mentioned "As shown in Figure 4b, there is a possibility that chemotherapy may be useful even
in patients with a high level of PNI......" However, there is no statistical difference or even a
trend shown in the figure 4b. The authors should make some modifications.
4. Although in the result, the authors mentioned that " super-elderly patients receiving mono-
chemotherapy (n = 2) did not report any grade 3 or 4 adverse events ", there is no enough
evidence that the authors could conclude that combination chemotherapy based on oxaliplatin
may exceed the treatment limit for super-elderly patients.
5. There are some typos, such as:
table 2, "Resction" of primary tumor -> "Resection"......
page 17, line 210, The 1- and 3-year OS in the in the younger group were...... -> ...... OS in the
younger ......
Review for 10.1186/s12876-021-01791-9 (2021)

Title: Clinical and therapeutic features and prognostic factors of metastatic colorectal cancer
over age 80: a retrospective study
Version: 2 Date: 11 Mar 2021
Reviewer's report:
There are still problems to be solved before this article is published.   Picture quality needs to
be improved.
Please elaborate in detail on the inclusion and exclusion criteria. Furthermore, the flowchart is
supposed to be represented in manuscript. Please provide the flowchart.
Overall the paper is well-written. However, it would benefit the authors to proofread more
carefully.
Review for 10.1186/s12876-021-01791-9 (2021)

Title: Clinical and therapeutic features and prognostic factors of metastatic colorectal cancer
over age 80: a retrospective study
Version: 3 Date: 10 Apr 2021
Reviewer:  Taishi Hata
Reviewer's report:
To the author
The article has been well revised the reviewers' comments.
I will accept this paper.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 1 Date: 17 Dec 2020
Reviewer's report:
The authors presented an interesting relation between serum chloride concentrations and in
hospital mortality among cirrrhotic patients.  Logistic regression analysis was used to assess this
relation. However, some modifications should be conducted.
Major Comments:
1.More variables should be addeded in Table 1, for example, hemoglobin#platelet#White blood
cells, albumin.
2.Some variables with clinical significance but without  statistical significance in univariate
analysis should also been added in multivariate Logistic regression analysis , like age sex.
3. ROC analysis should be conducted to evaluate the predictive performance of serum chloride;
4. As a study of electrolyte#I suggest  authors eliminate patients with chronic kidney disease(at
least stage 5).
Minor Comments:
Please revise again your grammar and spelling.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 1 Date: 21 Dec 2020
Reviewer's report:
This was retrospective analysis of 1409 cirrhotic patients. I applaud the authors for a large data
set of and a use of novel evaluation of chloride in cirrhotic patients. The demonstrated that
hyponatremia and hypochloremia are significant risk factors for mortality in cirrhotic patients.
I have several significant issues that need to be addressed.
In the Methods: there is no a clear description of the timing of the serum levels. Were all of
these labs taken on admission? During the first 24 hours?
For the definition of hypochloremia, they categorized by hypochloremia and normochloremia.
Did they exclude patients with hyperchloremia? If so it should be stated, otherwise they are
comparing hypochloremia and non-hypochloremia. There is also data in general critically ill
populations that shows that both hypochloremia and hyperchloremia are harmful and that the
mortality vs. level makes a “U”. It would be interesting to see if this remains true in this
population as well.
There are multiple studies also that discuss the change in chloride is predictive of poor outcomes
(AKI, mortality). Was there any consideration for the change of these levels?
For the multivariable logistic regression analysis, was sodium and chloride incorporated into the
same analysis or were they separately run with the same other co-variables? This was unclear
in the methods, it was included in the results, please include in the methods.
Also, it would be nice to see the covariables listed in the methods rather than in the results. Also
how were these variables chosen, a priori? Please state the method.
Given the relationship of AKI and the chloride levels, I would consider adding AKI as covariable
in the regression analyses.
Also in the methods, it would be nice to have the specific sub group analyses spelled out. Please
also include the rationale for why those subgroups were included. If its just for severity of illness
or severity of liver disease then I might consider including those variables in the regression
analyses.
Discussion is appropriate and discusses how this is hypothesis generating. I appreciate the
limitations. One other to consider, was there was no discussion of fluids or diuretics. Since this
is only admission to ICU, fluids/diuretics given prior may have an impact and if they choose to
make edits with multiple time points then this would be a greater consideration.
Minor: multiple grammatical issues. A closer edit is needed. Examples “This result was
remained” and  differences in consistency of spelling of hypchloremia and hypochloraemia.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 2 Date: 26 Jan 2021
Reviewer's report:
The authors have done a nice job of editing the original manuscript. They have addressed the
comments appropriately and the manuscript is much improved.
Discussion: first paragraph 4th sentence. I believe there is a typo. It states that the mortality
rate is lower in patients with hypochloremia when the mortality rate was higher in patients with
hypochloremia.
The paragraph discussing the potential relationship of hypochloremia and mortality does not
discuss that chicken or the egg difficulty with this. Hypochloremia may be the result of the
progressive course of cirrhosis and may be an important biomarker of this progression. It
may also exacerbate this course. An observational study with a single time point is unable to
determine this answer.
Figure 2: I appreciate the combinations of sodium and chloride. I don’t know that A-D are
necessary. E demonstrates the main point. Was there a statistical omnibus test performed
followed by pairwise comparisons with a correction performed? The statistics would be nice to
see in the figure legend.
Figure 5: it would be nice to have the bars be in increasing order of chloride levels. The left bar
would be Cl<99, middle bar would be 99110.
Figure 6 and Figure 5 are a bit repetitive. I personally prefer figure 6.
The figure legends should be bulked up a bit so that each figure is able to stand by itself.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 3 Date: 24 Mar 2021
Reviewer's report:
Some comments are listed as follows.
1. In the Methods section, the description of the exclusion criteria is inconsistent with that in
Figure 1, please modify. In addition, the unit "mEq/dL" of serum chloride seems to be wrong.
2. In the Table 2, when a variable is meaningless in the univariable logistic analysis, it should
not be included in the multivariable logistic regression analysis.
3. In the Results section, there are some questions about the results of Chloride and sodium serum
levels. First, the description of the comparison between groups is very confusing, please modify.
According to your Figure 3, from left to right, there are patients with neither hyponatremia
nor hypochloremia, patients with hyponatremia, patients with hypochloremia, and patients with
hypochloremia combined with hyponatremia. The grouping of patients in the paragraph does
not correspond to the Figure 3. Second, the author said that the difference in mortality between
groups is statistically significant, but the P-value is not mentioned in the Figure 3 and the paper.
Third, the comparison between the two groups should be “vs.” not “vs”.
4. In the Discussion section, the description of “In decompensated cirrhotic patients in the ICU (n
= 389), Sumarsono et al. [18] found that serum chloride levels were independently and inversely
associated with 180-day mortality, but serum sodium levels were not associated with 180-day
mortality after adjustment for other variables.” may be a bit messy.
5. In the Discussion section, the description of the article language needs to be improved, such
as the continuous use of "however", which makes people difficult to understand.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 3 Date: 24 Mar 2021
Reviewer's report:
The authors have addressed all of my concerns. This version is improved from the prior. Only
1 minor comment.
In the results, they discuss the difference in the AUC and claim that there is borderline
significance with a p value of 0.066. This is above the previously stated significance value of
0.05. I would recommend changing the wording to say it was not significant.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 4 Date: 18 Apr 2021
Reviewer's report:
This version is improved from the prior. There is only one minor comment.
The P value added in Figure 2 is not clear. The author should show the P value between the two
groups in detail, rather than simply writing a number in the center of the figure 2.
Review for 10.1186/s12876-021-01797-3 (2021)

Title: Lower serum chloride concentrations are associated with increased risk of mortality in
critically ill cirrhotic patients: an analysis of the MIMIC-III database
Version: 4 Date: 25 Apr 2021
Reviewer's report:
The AUC of MELD score in which admission chloride levels were added can be depicted in
Figure 4.
Review for 10.1186/s12876-021-01789-3 (2021)

Title: Prevalence of chronic hepatitis B phases in Eritrean patients: a laboratory-based cross-
sectional study
Version: 0 Date: 10 Jan 2021
Reviewer's report:
1. Reference 2 indicating a 2018 AASLD hepatitis B ‘guidance’ instead of ‘guideline’, the
authors were recommended to revise the terminology in the context.
2. Because only ALT data were shown in the report, the journal readers might wonder if there
were non-diagnosed cirrhosis or hepatocellular carcinoma among the enrolled subjects.
3. Tables 1-4 might be re-constructed to a big table which described ‘characteristics of all
enrolled subjects of age, gender, ALT level, HBeAg status, and HBV DNA level according to
different HBV phases’ because this is a cross-sectional study only.
4. Figures 1-3 can be deleted in the revised manuscript.
Review for 10.1186/s12876-021-01789-3 (2021)

Title: Prevalence of chronic hepatitis B phases in Eritrean patients: a laboratory-based cross-
sectional study
Version: 0 Date: 14 Jan 2021
Reviewer's report:
Thanks for the opportunity to review this manuscript. The paper provided useful insights
by characterizing clinical stages of CHB patients in Eritrea and the discussed implications
for patient management. The manuscript included comprehensive background, well-defined
objectives and clear methodologies. Results were well presented and thoroughly discussed in
light of international guidelines. I have a couple of minor comments/suggestions for authors to
consider:
• Background:
o Please provide background information on how decision on CHB treatment is currently
made by physicians in Eritrea? Is there a standardized national treatment guidelines for CHB
management in place, or the country adopts AASLD guidelines, or practice varies by facilities/
physicians?
• Methods:
o Line 130-137: Please clarify how patients were recruited. Were ALL patients tested + for both
HBsAg and anti-HBc during the study period included or a sample was selected? If the latter,
please specify sampling methodology.
o Laboratory methods: Provide information on when lab tests (particularly HBeAg, anti-HBe,
viral load and ALT) were conducted? Were all of these tests  performed as part of the standard
management protocol at the study sites or there were tests performed for this study’s purpose?
If the first, which results were used when patients have multiple tests over time?
• Results and Discussion
o Table 1: In addition to mean, median, min/max values for ALT and HBV viral load, it’s useful
to provide % by category groups (normal range/elevated ALT; viral load (<2000 IU/ml, 2000
and 20,000 IU/ml, >20,000 IU/ml)
o Table 2: Is there a specific reason for not including age groups in Demographics while it was
included in other analysis?
o Line 226: typo (relevantduring)
o I think it’s interesting to emphasize and discuss:
# 5 out of 293 patients (equivalent to 1.7%) of the study participants were eligible for antiviral
treatment at the time of study. Given that the participating clinics received patient referrals from
other provinces, would you expect eligibility rate to be lower, higher or similar at other health
facilities in Eritrea?
# 5 out of 15 patients with elevated ALT were eligible for treatment (Figure 4) regardless
of HBeAg and viral load results. Besides, the likelihood that patients with ALT may require
antiviral treatment in patients with positive HBeAg (4 out of 11) is higher than that among
patients with negative HBeAg  (1 out of 4).
# Discussion of the results in the local context of would be beneficial (line 261-271). Were lab
tests  (particularly HBeAg, viral load) widely available in Eritrea? In settings where those tests
are not available, if any, what’s the implications of the study results?
Review for 10.1186/s12876-021-01789-3 (2021)

Title: Prevalence of chronic hepatitis B phases in Eritrean patients: a laboratory-based cross-
sectional study
Version: 1 Date: 06 Mar 2021
Reviewer's report:
The authors investigated the prevalence of chronic hepatitis B virus (HBV)-infected clinical
phases in 293 Eritrean people using a laboratory-based cross-sectional method, they found
that 273 (93.2%) of the enrolled subjects were HBeAg-negative, and 217 (74.1%) were in the
immune-control phase, 71 (24.2%) were in ‘immune-clearance’ or ‘immune-escape’ phases,
while only 5 (1.7%) of them were eligible for antiviral treatment per the 2018 AASLD HBV
guidance. This is the first study to evaluate the natural history of HBV infection in Eritrea where
a national childhood HBV immunization program was started in 2002. Five patients (1.7%) were
in the immune-tolerant phase and two out of them were younger than 20 years old indicating that
the nationwide HBV vaccination program was successful in this country. This report provided
important information for the healthcare policy body in the country but a few issues still needed
some amendment in its revised version.
1. Reference 2 indicating AASLD 2018 hepatitis B ‘guidance’ instead of ‘guideline’, I
recommend the authors revise the terminology in the manuscript.
2. Since the authors choose the AASLD 2018 hepatitis B guidance, I advise the authors to
follow the diagnostic criteria and definition for chronic hepatitis B which shown in Table 6 of
AASLD 2018 hepatitis B guidance and classifying CHB clinical courses into ‘immune-tolerant’,
‘immune-active’, and ‘inactive CHB’ phases because per the Croagh and Lubel classification
(reference 4), it is too heterogeneous and highly-overlap in ‘immune clearance’, ‘immune
control’, and ‘immune escape’ phases according to the definitions.
3. List the 5 patients’ data who eligible for antiviral treatment per the authors’ recommendation
as one single table.
4. The conclusions stated by the authors were assumption only because we did not see any data
on adopting AASLD treatment guidance with ‘adjustments’ to suit ‘the local setting’ represent
a suitable option in the management of Eritrean CHB patients’.
5. Revise legend for table 1 to ‘Summary of patients’ characteristics by gender’.
6. Polish the language.
Review for 10.1186/s12876-021-01788-4 (2021)

Title: Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis
Version: 2 Date: 25 Jan 2021
Reviewer:  Paul Rufo
Reviewer's report:
1.  The manuscript could benefit from English language editing.
2.  There were 162 studies performed in 133 patients.  It may have better to limit the analysis
to one (the first) study for each patient.
3.  A lichtiger score was not obtained universally (125 or 162).  As such, there could be a selection
bias in which only patients with mild or severe disease were provided with scores.
4. The experimental criteria for how the predictability of endoscopic improvement was
determined should be be more fully described.  Which patients and what treatments were
instituted to assess disease response? Were the same patients studies twice?
5.  The cut-off values for FC in Table 5 are higher than those typically reported (either 150 or
250).
Review for 10.1186/s12876-021-01788-4 (2021)

Title: Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis
Version: 2 Date: 26 Jan 2021
Reviewer's report:
The points of minor revision
1. Authors chose MES and LI as clinical evaluations out of many clinical evaluations, such as
Mayo score which includes both clinical and endoscopic evaluation. They should explain the
reason why these two evaluations (LI and MES) were chosen in this study, not Mayo.
2. Basically, MES was obviously not appropriate for the surrogate marker of fecal biomarkers,
because it reflects a part of most severe inflammation, not related to the extent of UC activity. It
was better to select different endoscopic score which evaluates the overall disease state such as
“the sum of MES” which included seven segments of the large intestine (appendicular region,
cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum) as
surrogate marker. (This endoscopic evaluation was used in some studies in UC; ex. Changes
in Intestinal Microbiota Following Combination Therapy with Fecal Microbial Transplantation
and Antibiotics for Ulcerative Colitis. Dai Ishikawa et. al. IBD 2017) In the abstract, the section
of introduction, and the section of discussion, the expression “endoscopic evaluation and/or
activity” was used (ex. Line 54 “assessment of endoscopic and clinical disease activity”). The
exact expression they should convey is “Endoscopic evaluation of the most severe part” or MES,
authors should consider revising these points for giving appropriate expression.
3. Line 51, 54, 70. The blanks between words are not constant. This should be corrected.
Review for 10.1186/s12876-021-01788-4 (2021)

Title: Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis
Version: 2 Date: 27 Jan 2021
Reviewer's report:
As the authors described, there are many studies using fecal biomarkers as a means of monitoring
the activity of ulcerative colitis instead of colonoscopy which is a burden for both patients and
physicians. The authors suggested in this article that the results of fecal biomarker tests needed
to be interpreted differently depending on the disease extent. This point of view was excellent
and very important.
However, there were several concerns as follows.
Major
1. If you intended to conclude that the fecal biomarker test results were unreliable for the proctitis
type, it is a non-negligible problem that the number of cases of proctitis type was extremely low
compared to the other two types. Moreover, the number of MES 2+3 of proctitis type was no
more than five, while the other two types had about thirty cases respectively. And proportion of
severe cases was considerably low as well only in the proctitis type.
2. The comparison between clinical activity index (Lichtger index) and fecal biomarkers was
not necessary, I think. Because it is not clinically useful, unlike using them (fecal biomarkers)
as an alternative to colonoscopy. Rather, how was the correlation between Lichtger index and
Mayo endoscopic subscore?
3. We have often experienced the development of the disease extent, for example developing
from proctitis type to left hemicolitis type. Did you encounter such cases during proceeding
this study? When we would predict the activity from fecal tests, it is interesting issue how
the development affects the results. Similarly, do you think it is necessary to change the
interpretation of fecal test results if the former total colitis type temporarily changes to a mild
proctitis type-like due to remission? It was simple comparison between endoscopic findings and
fecal test results in this study. However, when we would predict the the disease status, proctitis
type is not always proctitis type and vice versa. Please indicate your opinion for this issue.
Minor
1. It is recommended to specify the average value for each graph in Supplemental Figure 1. It is
also better to explain in the text that the reason why it was difficult to distinguish disease activity
by fecal biomarker test in the proctitis type was that the value of the test tended to remain high
regardless of Mayo endoscopic subscore.
Review for 10.1186/s12876-021-01788-4 (2021)

Title: Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis
Version: 3 Date: 18 Mar 2021
Reviewer's report:
As the authors described, there are many studies using fecal biomarkers as a means of monitoring
the activity of ulcerative colitis instead of colonoscopy which is a burden for both patients and
physicians. The authors suggested in this article that the results of fecal biomarker tests needed
to be interpreted differently depending on the disease extent. This point of view was excellent
and very important.
However, there were several concerns as follows.
Major
1. If you intended to conclude that the fecal biomarker test results were unreliable for the proctitis
type, it is a non-negligible problem that the number of cases of proctitis type was extremely low
compared to the other two types. Moreover, the number of MES 2+3 of proctitis type was no
more than five, while the other two types had about thirty cases respectively. And proportion of
clinically severe cases was considerably low as well only in the proctitis type.
2. The comparison between clinical activity index (Lichtger index) and fecal biomarkers was
not necessary, I think. Because it is not clinically useful, unlike using them (fecal biomarkers)
as an alternative to colonoscopy. Rather, how was the correlation between Lichtger index and
Mayo endoscopic subscore?
3. We have often experienced the development of the disease extent, for example developing
from proctitis type to left hemicolitis type. Did you encounter such cases during proceeding
this study? When we would predict the activity from fecal tests, it is interesting issue how
the development affects the results. Similarly, do you think it is necessary to change the
interpretation of fecal test results if the former total colitis type temporarily changes to a mild
proctitis type-like due to remission? It was simple comparison between endoscopic findings and
fecal test results in this study. However, when we would predict the the disease status, proctitis
type is not always proctitis type and vice versa. Please indicate your opinion for this problem. I
do not think the results of this research alone could refer the issue of prediction.
Minor
1. It is recommended to specify the average value for each graph in Supplemental Figure 1.
2. According to the Supplemental Figure 1, the value of fecal biomarker tests in the proctitis
type seemed to remain high tendency regardless of Mayo endoscopic subscore. Regarding the
proctitis type, in addition to the small sample size, this tendency was somehow related to the
result of difficulty of distinguishing disease activity by fecal biomarker test, I think. If you agree
with my opinion, it is better to explain this in the text. If you disagree with my opinion, please
mention your opinion in the response letter.
Review for 10.1186/s12876-021-01769-7 (2021)

Title: Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric
neuroendocrine neoplasms
Version: 1 Date: 03 Jan 2021
Reviewer's report:
The present manus by Dou et al. presents miRNA202-3p as a novel possible marker for GNENs
type 1.
I suggest a major revision.
Minor comments:
Background: Well differentiated GNENs are divided in ECL-cell carcinoids (type 1-3) and non
ECL-cell carcinoids according to WHO 2010. The classification that the authors present is not
valid.
Results: “To investigate the characteristics of patients in more detail, gastroscopy and pathology
were performed after collecting blood samples.” The above phrase should be moved to material
and methods.
Results: “The ultrasonic gastroscopy” should be altered to “endoscopic ultrasound
investigation”.
At figure 2 it is shown that 5 patients did not have polyps but at Grading it is shown that 26
cases were of G1 and 1 of G2. At the cases without polyps from which areas were the biopsies
taken? What was the pathology? Furthermore, under the title abnormal proliferation of gastric
NE cells how the authors define tumor?
Discussion: “This leads to achlorhydria and corresponding symptoms such as bloating,
indigestion, and constipation”. These symptoms are not relevant to GNENs, the authors do not
present a reference either.
Major comments:
Discussion: “However, there was no significant stratified diagnostic value between serum
miRNA-202-3p levels in patients with different pathologies and different gastroscopic findings.”
I suggest that the authors will present at the results correlation between mi-RNA-202-3p and
size of largest polyp, number of polyps and grade OLGIM classification. Is mi-RNA-202-3p
more increased in patients with more advanced disease?
Gastrin levels should be also presented as hypergastrinemia is a cornerstone for the diagnosis
of type 1 ECLomas.
Review for 10.1186/s12876-021-01769-7 (2021)

Title: Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric
neuroendocrine neoplasms
Version: 1 Date: 06 Jan 2021
Reviewer:  Roberta Modica
Reviewer's report:
In this paper miRNA-202-3p is a proposed as a potential novel biomarker for type 1 gastric
neuroendocrine neoplasms (g-NENs). The need of reliable diagnostic biomarkers is of utmost
importance in the field of NEN.
This is an interesting study, with a relatively novel concept, which would likely add new insights.
There are however some weaknesses, that should be addressed or revised.
Inclusion criteria are based on 2016 NCCN guidelines, which are updated yearly; authors should
explain this choice. Diagnostic and inclusion criteria have to be clarified, as it is stated that
“to investigate the characteristics of patients in more detail, gastroscopy and pathology were
performed after collecting blood samples” but patients needed a pathological diagnosis of g-
NEN to be enrolled. Furthermore, if the blood sample was taken in all patients, why CgA is not
available in 9 subjects?
Do control participants underwent gastroscopy for other purposes?
If patients were enrolled with pathological diagnosis of g-NEN, in the 5 subjects without polyps
authors should describe the kind of lesion detected or if it was an incidental finding.
Pharmacological treatment with somatostatin analog or other drugs should be specified.
CgA is expressed in pg/l in the text and ng/ml in the tab, please standardize.
It is stated that the serum expression of miRNA-202-3p was quantified to confirm the expression
of miRNA-202-3p in the tumor tissue, but was the tissue expression evaluated in the same
subjects? Consequently, the serum expression was performed before or after tumor removal?
The expression of miRNA in subjects and controls could be easier to understand if expressed
with the same exponent (tab 3).
The dense vascular network and high blood tumor flow are suggested to explain the serum
miRNA elevation, but other hypothesis should be proposed due to the small tumor dimensions
in the majority of patients.
In summary, although interesting, the power of this miRNA as a diagnostic biomarker in g-
NEN is moderate and this limit should be highlighted in the conclusions, as well as the limited
number of samples.
Review for 10.1186/s12876-021-01769-7 (2021)

Title: Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric
neuroendocrine neoplasms
Version: 1 Date: 15 Jan 2021
Reviewer's report:
In this article, Dou Dou et al. studied the diagnostic potential of circulating levels of
miRNA-202-3p in patients with gastric neuroendocrine neoplasms (gNEN). They evaluated 27
serum samples of patients with gNEN and compared them to 27 sex- and age-matched healthy
controls. As a result, they found a significant increase in miRNA-202-3p levels.
Unfortunately, the manuscript is not well written and therefore needs significant language
revision. Moreover, doubts remain on the methodology and therefore on the analysis of the
results presented.
1. The authors performed standard curve quantification to measure miRNA expression without
using an exogenous or endogenous control/normalization. Unfortunately, this is technically not
correct and not enough for exact and validated measurements. When using the standard curve
quantification, cycle thresholds are converted to copy numbers by drawing a standard curve
using a synthetic chemical standard. For accurate quantification, copy numbers are normalized
according to recovery rations of e.g. spiked-in-cel-miR-39 or cel-miR-238.
(Kook HY, Jin SH, Park PR, Lee SJ, Shin HJ, Kim TJ. Serum miR-214 as a novel
biomarker for ankylosing spondylitis. Int J Rheum Dis. 2019 Jul;22(7):1196-1201. doi:
10.1111/1756-185X.13475. Epub 2019 Feb 6. PMID: 30729703;
Iguchi, T., Niino, N., Tamai, S., Sakurai, K., Mori, K. Absolute Quantification of
Plasma MicroRNA Levels in Cynomolgus Monkeys, Using Quantitative Real-time Reverse
Transcription PCR. J. Vis. Exp. (132), e56850, doi:10.3791/56850 (2018))
2. The authors should explain why they have preferred to use standard curve quantification
since relative qRT-PCR is a reliable and more common method for measuring expression of
circulating miRNA.
3.Given the low number of patients in this study (n=27), the authors should reduce their
conclusions since the lack of statistical value is limited due to their sample size. The authors
should also point out more clearly that further investigations are necessary to investigate the
diagnostic potential of this biomarker.
4. The clinical relevance of miR-222 should be worked out more clearly, e. g by correlating the
biomarker to clinical characteristics such as grading, number of lesions, gender, age, secondary
illnesses (arterial hypertension or diabetes). Moreover, survival data should be included to
investigate the prognostic potential of miRNA 202-3p (e.g.by using Kaplan Meyer analysis).
5. The first two paragraphs of the discussion section should be shortened and included into the
introduction. Moreover, results in the discussion are not confronted enough to previous study
results of circulating miRNA in neuroendocrine neoplasms (also in respect of sample size or
normalization).
Review for 10.1186/s12876-021-01769-7 (2021)

Title: Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric
neuroendocrine neoplasms
Version: 2 Date: 04 Mar 2021
Reviewer:  Roberta Modica
Reviewer's report:
All the issues proposed in the first manuscript revision have been clarified.
Review for 10.1186/s12876-021-01769-7 (2021)

Title: Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric
neuroendocrine neoplasms
Version: 2 Date: 09 Mar 2021
Reviewer's report:
Thank you for the revisions provided including the shrotcomings of the manuscript.
Review for 10.1186/s12876-021-01769-7 (2021)

Title: Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric
neuroendocrine neoplasms
Version: 2 Date: 09 Mar 2021
Reviewer's report:
Language editing is recommended. The authors should add at the results and the discussion
that the miRNA-202-3p could be a marker of neuroendocrine cell hyperplasia as 5 patients
without polyps had elevated levels. I suggest that that it will be addressed at the reults and the
discussion that there is no significant statistical relationship between miRNA-202-3p and polyp
size/number, OLGIM state etc.
Review for 10.1186/s12876-021-01764-y (2021)

Title: Correlation between the geographical origin of Helicobacter pylori homB-positive strains
and their clinical outcomes: a systematic review and meta-analysis
Version: 1 Date: 26 Jan 2021
Reviewer's report:
I could not find out what the abbreviations were in the article, for example it is not clear whether
GC and CG are the same or different.
The evidence level of the articles taken in meta-analysis is low. Conditions that are considered
as serious complications are not clearly understood.
Figures can be more beautiful and understandable
Review for 10.1186/s12876-021-01764-y (2021)

Title: Correlation between the geographical origin of Helicobacter pylori homB-positive strains
and their clinical outcomes: a systematic review and meta-analysis
Version: 1 Date: 27 Jan 2021
Reviewer:  Yavuz Beyazit
Reviewer's report:
Dear Editor,
The present review clearly summarize the Correlation between the geographical origin of
Helicobacter pylori homB-positive strains and their clinical outcomes. The paper seems to be
well written and presented. It can be published in its current form.