JerMa88/BMC_Gastroenterology_Peer_Reviews huggingface dataset:
Review for 10.1186/s12876-021-01724-6 (2021)

Title: The inverse association between unhealthy eating habit and mucosal healing among
patients with ulcerative colitis
Version: 2 Date: 19 Feb 2021
Reviewer:  Rafael Barreto-zuniga
Reviewer's report:
This is the first study to report the association between eating habits and clinical outcome in
patients with UC. The underlying mechanism linking eating habits and MH among patients with
UC remains unclear. This study has a few limitations. First, this was a cross-sectional study.
The question its to considerate the Japanese food will be similar and comparison to western?
(confounding factors).
Further research is needed to confirm the association between eating habits and MH in the future.
Review for 10.1186/s12876-021-01724-6 (2021)

Title: The inverse association between unhealthy eating habit and mucosal healing among
patients with ulcerative colitis
Version: 2 Date: 02 Mar 2021
Reviewer's report:
The article written by Shinya Furukawa et al. it's really interesting and original. Thanks for
letting me review it.
Overall the manuscript is well structured, English is fluent.
The tables are accurate and easy to understand.
In my opinion, it could benefit from discussing these few articles:
- About BMI: EuroSurg Collaborative. Body mass index and complications following major
gastrointestinal surgery: a prospective, international cohort study and meta-analysis. Colorectal
Dis. 2018 Aug; 20 (8): O215-O225. doi: 10.1111 / code 14292
- Please, consider  also: Gallo G, Kotze PG, Spinelli A. Surgery in ulcerative colitis: When?
How? Best Practice Res Clin Gastroenterol. 2018 Feb-Apr; 32-33: 71-78. doi: 10.1016 /
j.bpg.2018.05.017. Epub 2018 Jun 14. PMID: 30060941.
Congratulations on the good work.
Review for 10.1186/s12876-021-01741-5 (2021)

Title: Evaluation of Circulating Cell-Free DNA in Cholestatic Liver Disease Using Liver-
Specific Methylation Markers
Version: 0 Date: 17 Feb 2021
Reviewer's report:
In this study, Punia et al. seek the potential of circulating free DNAs as a biomarker for PSC
and PBC. Data look solid to support the authors claims and I do not have any major comments
or criticisms for this manuscript. In Discussion, the authors mention that individual variability
is huge in the data, which could be a problem in this technique. Since the authors mention the
potential of cfDNA as a novel biomarker for PBC and PSC, it would be interesting data if the
authors perform ROC curve analysis and show AUC. It may not be beautiful but useful to show
the difficulties of the current study.
Review for 10.1186/s12876-021-01741-5 (2021)

Title: Evaluation of Circulating Cell-Free DNA in Cholestatic Liver Disease Using Liver-
Specific Methylation Markers
Version: 1 Date: 19 Mar 2021
Reviewer:  Roman Liebe
Reviewer's report:
Thank you for addressing all points raised in the last revision succinctly and courteously.
Review for 10.1186/s12876-021-01735-3 (2021)

Title: Influence of a novel classification of the papilla of Vater on the outcome of needle-knife
fistulotomy for biliary cannulation
Version: 1 Date: 11 Jan 2021
Reviewer's report:
This article attempts to built upon pre-existing morphological classifications of the major
ampulla and assess the impact on ampullary morphology on rescue needle knife fistulotomy.
The classification is certainly more expansive but to assist in its usability, a couple of core points
need to be addressed:
1. clarifying the terminology "oral protrusion". This is confusing. Presumably this is referring
to the superior aspect of the intra-duodenal portion of the ampullary complex and its 'protrusion'
into the duodenal lumen. It could also refer to the location and orientation of the orifice. It also
is not mutually exclusive for Type IIIa and IIIb ampullas, of which the classification makes no
mention of their 'oral protrusion'. I suggest revising this key term.
2. reporting on the distribution of each ampullary type in the original classification of 550 still
images, in particular, Type IV. If there are multiple morphologies within Type IV, this would
weaken the exclusivity of 6 other categories.
3. explain why it is important to differentiate between Type IIa and IIb ampullas. This distinction
is difficult for ERCPists to classify with only 59 and 66% (respectively) being able to classify
correctly. The discussion points to an "intuitive(ly) belief" that the two ampullas will behave
differently, but this is not expanded upon.
The article is otherwise comprehensive and provides a good discussion of its merits compared
to prior classification attempts. Whilst my personal belief is that the proposed classification
remains too complicated for everyday clinical use, the article contributes to the growing
discussion and interest in ampullary classification.
Review for 10.1186/s12876-021-01735-3 (2021)

Title: Influence of a novel classification of the papilla of Vater on the outcome of needle-knife
fistulotomy for biliary cannulation
Version: 1 Date: 15 Feb 2021
Reviewer's report:
This seems to be a prospective observational study that objectively verified the novel
classification system of PV devised by the authors.
Major revision
1. The methods for selective biliary cannulation known so far are very diverse, and the
methods may be different depending on the preference of the endoscopist or each endoscopist’s
familiarity with a specific device. In addition, the selection of the 2nd line method may vary
depending on the situation when attempting the first line procedure. In order to evaluate the
clinical usefulness of the proposed PV morphology new classification system, I wonder why the
authors selected the success or failure of NKF and the occurrence of complications as clinical
indicators among several methods of selective biliary cannulation. So, please elaborate this in
the introduction and discussion sections.
2. The content of the method is too long and verbose. Please describe in abbreviated terms
focusing on the core content.
Minor revision
1. In the conclusion, state that this novel classification system would be a guide to selecting
the most optimal biliary cannulation option for each patient though the subsequent clinical
verification process.
2. Please correct any typos pointed out by a reviewer in the manuscript.
Review for 10.1186/s12876-021-01728-2 (2021)

Title: Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse
specialists using the ELF test
Version: 2 Date: 30 Dec 2020
Reviewer's report:
The study by Rhodes et al. aims at investigating prevalence and predictors of advanced fibrosis
assessed by ELF in a cohort of alcoholic patients.
The study is really well conducted and the topic of highly clinical and public relevance. Some
minor points need to be addressed.
- Given the lack of association between fibrosis and both amount of alcohol consumption
and drinking duration, a bias related to the self-reported information about drinking could be
supposed? I suggest that the Authors should make a comment about this possibile bias in the
discussion and also mention the lack of AUDIT about drinking in the limitations. Was data about
desialated transferrin (CDT) available?
- Since type 2 diabetes (T2DM) has been demonstrated as one of the most important fibrogenic
factors, was the information about diabetes status available? If yes please add T2DM in the
analysis, otherwise I suggest that the Authors sould add also this missing information in the
limitations.
- In the outcomes it is stated that "Blood samples were also taken to screen for viral,
immunological and metabolic causes of liver disease if these tests had been omitted during their
hospital admission. ", but it is not clear if bloods were repeated if the information about screening
was not available at the moment of ELF calculation (i.e if referring to 2 years before was valid
because available?). Please clarify.
- How do the Authors explain the lack of association between ELF and FIB4 (predictive both
of advanced fibrosis?).
- Why did the Authors choose to adjust analysis for ALP and not for GGT as the patients are
active drinkers?
- In the discussion it is stated that "Whilst it has previously been reported that ELF scores may
be influenced by inflammation (16, 21), we did not find any correlation between ELF score
and ALT or AST, as markers of hepatic inflammation in this study, suggesting ELF was not
influenced by inflammation in our cohort". Given the fact that transaminases not always reflect
hepatic inflammation possibily underestimating liver damage and that histology is missing, this
sentence should be smoothed.
- Finally, in the follow-up and in the discussion, there is a hint to Fibroscan, however no data
or results referring to fibroscan stiffness could be found anywhere. In particular, it could be
interesting to know how many patients diagnosed with advanced fibrosis by ELF were confirmed
by Fibroscan.
Review for 10.1186/s12876-021-01728-2 (2021)

Title: Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse
specialists using the ELF test
Version: 3 Date: 11 Feb 2021
Reviewer:  Margarita Papatheodoridi
Reviewer's report:
The authors have addressed my main comments, by proving clear explanations and substantial
supplementary data. No further comments from my side.
Review for 10.1186/s12876-021-01728-2 (2021)

Title: Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse
specialists using the ELF test
Version: 3 Date: 02 Mar 2021
Reviewer:  Ian Rowe
Reviewer's report:
Thank you for the thoughtful revisions to the manuscript.  The information regarding
downstream investigation and linkage to care is important.  I am inclined to agree with the
authors that there is a substantial advantage to using a blood-based fibrosis test to identify
patients in secondary care, to maximise the identification of liver disease in this at risk cohort.
However, the data from the elastography examinations suggest that advanced fibrosis (as
assessed by ELF) was not present in 10 of the 17 patients with usable data.  The comment in the
discussion that the elastography data cannot be considered a robust standard due to the impact
of inflammation and alcohol is in part correct but is also likely to lead to false positive rather
than false negative examinations.
This study is important in highlighting a role for direct fibrosis testing in secondary care for this
at risk population.  In my view, the elevated ELF places a patient at high risk of having advanced
fibrosis, requiring further evaluation.
The terminology regarding "1/4 of patients in hospital with AUD had advanced fibrosis (as
assessed by ELF" needs to be reconsidered.  The additional information provided strongly
suggests that the positive predictive value of ELF in this study, in line with the PPV reported by
Thiele et al, is not sufficient to make a diagnosis of advanced fibrosis.
Review for 10.1186/s12876-021-01728-2 (2021)

Title: Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse
specialists using the ELF test
Version: 6 Date: 18 Mar 2021
Reviewer:  Ian Rowe
Reviewer's report:
Thank you.  The changes made better reflect the uncertainty regarding the diagnostic value of
ELF in this context.
Review for 10.1186/s12876-021-01719-3 (2021)

Title: Quinolone resistant Salmonella species isolated from pediatric patients with diarrhea in
central Iran
Version: 1 Date: 10 Jan 2021
Reviewer:  Yuqing Liu
Reviewer's report:
The present study is the first to report on the frequency of salmonellosis and its associated
resistance patterns for a panel of 16 antibiotics in central Iran. The conclusion is quite regionally
outstanding. High rates of quinolone resistance and low frequency of MDR in Salmonella spp.
were found to be prevalent in central Iran and other parts of Asia#maybe because the traditional
first-line drugs used to treat Salmonella spp. are chloramphenicol, ampicillin, and cotrimoxazole.
Empiric antibiotic therapy should surely be adapted by Uniform rotation of prescribed antibiotics
of AST susceptible to save more children.
Out of 230 samples of infectious diarrhea, 21 (9.1%) cases of Salmonella spp. were identified
using culture methods. Another 28 (12.1%) samples had positive PCR results, with S. serovar
Paratyphi B and C (9/21; 42.8%) and S. Typhi (3/21; 14.3%) being the most recognized. The
expression is not clear
Review for 10.1186/s12876-021-01719-3 (2021)

Title: Quinolone resistant Salmonella species isolated from pediatric patients with diarrhea in
central Iran
Version: 1 Date: 23 Jan 2021
Reviewer's report:
Although resistance was analysed against a wide array of antibiotics , there seems to be a
discrepancy between the high prevalence of class 1 integron and drug resistance among the
isolates. the study is similar in methodology and corroborates the conclusions of other previously
published studies on antibiotic resistance from the region and does not add anything new.
Exclusion of patients who had used antibiotics previously decreased the real life validity of the
results presented.
Review for 10.1186/s12876-021-01719-3 (2021)

Title: Quinolone resistant Salmonella species isolated from pediatric patients with diarrhea in
central Iran
Version: 3 Date: 28 Feb 2021
Reviewer:  Yuqing Liu
Reviewer's report:
The article is revised according to the review comments and conforms to the publication
requirements.
Can be published.
Review for 10.1186/s12876-021-01719-3 (2021)

Title: Quinolone resistant Salmonella species isolated from pediatric patients with diarrhea in
central Iran
Version: 3 Date: 10 Mar 2021
Reviewer's report:
The authors have tested with a large number  of antibiotic resistance assays. Their work will be
helpful in understanding the extent of antibiotic resistance among children in Iran and will help
the doctors practicing there to prescribe antibiotics judiciously
Review for 10.1186/s12876-021-01723-7 (2021)

Title: Expression of tricellular tight junction proteins and the paracellular macromolecule barrier
are recovered in remission of ulcerative colitis
Version: 2 Date: 17 Jan 2021
Reviewer's report:
The manuscript by Hu et al analyzed the expression of tricellulin and angulin along with
intestinal barrier function, aiming to define the role of tricellulin in the relapse of UC. It is well
written, and presented clearly. However, there are several comments that need to be addressed:
Major comments:
1. Does Tricellulin show different distribution pattern in UCact and UCrem patients used in this
study?
2. The claim “point against a primary barrier defect in this barrier component sealing against
macromolecule uptake” is too strong, needs to be toned down. The current study does not
necessarily rule against it.
3. It is quite surprising that angulin-1 of UCact could not be determined, while the same samples
can be used to determine the expression of Tricellulin and claudin-4. These data need to be
shown.
4. The mRNA expression of tricellulin, claudin and angulin in UCact patients should also be
presented (along with data from CTRL and UCrem patients).
5. When normalizing the gene expression, the author should consider epithelial specific gene,
such as hprt1, assuming genes of interests are largely present in epithelial cells.
6. For Figure 1a/b, please clarify if the data is plotted against the total expression of tricellulin
in CTRL (a), or against the ratio of tricellulin/actin in CTRL (b). Please also clarify this for
Figure 1c/d, Figure 1e/f.
Minor comments:
1. In the introduction, the author can briefly mention claudin 2, 4; transepithelial resistance,
epithelial and subepithelial resistance.
Review for 10.1186/s12876-021-01723-7 (2021)

Title: Expression of tricellular tight junction proteins and the paracellular macromolecule barrier
are recovered in remission of ulcerative colitis
Version: 2 Date: 19 Jan 2021
Reviewer's report:
Manuscript is well written clear and concise. The conclusion that levels of tricellulin and
permeability are restored is valid, given a more detailed example of sample distribution (see
below). For other member of the tight junction complex Angulin 2-3, and Cldn 2 there is
evidence that levels somewhat similar although no pvalues are presented. Without UC active
the authors cannot conclude that levels are restored.
Minor:
There is very little information available about the enrolled patients in table 1.
There are very few UC patients in this study. Manuscript would benefit from a second table
listing characteristics for each UC patient. Table2 (UC active patient characteristics) should
include Mayo subscore, gender, medication, disease activity, per patient. For remission patients,
the length of remission should be listed.
Line 101 states that a total of 36 pieces of biopsies were collected from 14 UC patients. Does
this mean that 36 pieces were collected from each of the 14 patient biopsies for a total of 504
pieces? Or did some samples donate more pieces than others?
Authors state that UC active group includes mild, moderate and severe disease activity. This
information should be clearly presented in table 2 (see above). If for example more “pieces”
of biopsies were analyzed from a UC severe patient, this could affect the interpretation of the
results. The comparison would then be between severe UC and normal.
In Figure 1a (tricellulin protein expression of human intestinal tissues) why are there six
observations for UC active when there are 4 patients. Please explain the relationship between
the number of plotted observation in the graphs and patient samples.  If samples are taken from
the same biopsy are they statistically independent observations?
What was the technical reason that angulin-1 of UC active could not be determined?
Have the authors considered different mRNA capture techniques?
It should be possible to get qRT-PCR results for Angulin1-3 as well as Cldn 2 and 4. If nothing
else but to contrast results.
For figure 2 (Combined scatter and bar plots …) there are no pvalues indicated in legend. Even
if the comparisons are non-significant the pvalues should be listed.
Review for 10.1186/s12876-021-01723-7 (2021)

Title: Expression of tricellular tight junction proteins and the paracellular macromolecule barrier
are recovered in remission of ulcerative colitis
Version: 4 Date: 12 Mar 2021
Reviewer's report:
The authors have addressed all comments very well, and I believe this work will contribute
significantly to the understandings of UC pathogenesis.
Review for 10.1186/s12876-021-01720-w (2021)

Title: Economic Burden of Non-Alcoholic Steatohepatitis with Significant Fibrosis in Thailand
Version: 1 Date: 21 Jan 2021
Reviewer's report:
Overall this is a well-researched and conducted modeling analysis of the economic burden of
NAFLD and NASH in the Thai population. However, I was confused about how some of the
inputs and data are presented, and would request clarification from the authors.
1. Overall, I am confused about what is reported in the text and the model figure. What is the
population being modeled – the prevalent NAFLD population or the total Thai population?
a. What is the purpose of the ‘normal state’ and what does it represent with respect to NAFLD
– is it the benign NAFL state or is it just the general Thai population without NAFLD?
b. Should the entire cohort enter the model at the normal state? To be more realistic, it would
make more sense for proportions of the population to enter the model with an appropriate
distribution across the health states – for example, 80% in low fibrosis states and 20% with
advanced fibrosis/ cirrhosis - and then varied in the sensitivity analysis.
2. Can you clarify what constitutes incidence of NAFLD – moving from normal to F0? And then
incidence of NASH with significant fibrosis is transition from F1 to F2?
3. Results section: Should the lifetime cost be compared to the 2019 GDP (or is it the $5147
per case value).
4. Are there only two transition probabilities that vary by age: ASMR and Normal to F0 (I assume
this is incidence of NAFLD, but am not sure – se #1 above) the only transition probability It
would be reasonable to assume the probability of receiving a liver transplant also decreases with
age.
5. Costs – as cost data for compensated and decompensated cirrhosis and HCC were derived
from Hep C data, please clarify in the text that cost of anti-viral medication was excluded from
the study. Are costs for viral testing (as part of NAFLD diagnosis) included? Please include that
costs are reported in 2019 US Dollars to Tables 1, 3, 4.
6. Line 166: From the supplementary data, it seems that NAFLD and NASH prevalence were
calculated from other studies, so line 166 in the Results should be changed to reflect this (the
model is not estimating these values as they are inputs).
Review for 10.1186/s12876-021-01720-w (2021)

Title: Economic Burden of Non-Alcoholic Steatohepatitis with Significant Fibrosis in Thailand
Version: 2 Date: 02 Mar 2021
Reviewer's report:
Reviewers have appropriately addressed comments from previous review. Note below:
New HCC cases in Table S6 vs average HCC cases per year in Table S7 is confusing. Can  a
time frame or clarification be added to the title of Table S6?
Review for 10.1186/s12876-021-01727-3 (2021)

Title: Comparison of preoperative two-dimensional shear wave elastography, indocyanine
green clearance test and biomarkers for post hepatectomy liver failure prediction
Version: 2 Date: 04 Feb 2021
Reviewer's report:
This is a retrospective analysis which compares the performance of 2D-SWE, ICG-R15, ALBI,
APRI and FIB-4 to preoperatively predict PHLF for HCC patients undergoing major liver
resection. This comparison is of great clinical value because hepatobiliary surgeons often think
about which one should be trusted in the face of conflicting results.
Major points:
1. The sample size is too small to systematically compare different methods for prediction of
PHLF. Patients between February 2019 and September 2019 were involved in this analysis.
Could you include more patients by extending the time range?
2. The incidence of PHLF is relatively low, which is 10.5% (9/86), 8.6% (5/58) and 9.7%
(14/144) in the development group, validation group and total patients, respectively. And the
grade of PHLF according to ISGLS is not shown. Importantly, patients with grade A PHLF
require no change in the clinical management. If most patients are grade A PHLF patents, the
diagnosis or prediction of PHLF is less meaningful in clinical. Could you show the grade of
PHLF in table 1?
3. Whether the AUC of test A is superior to that of test B needs statistically test, such as Delong
test, rather than directly comparing the exact value of their AUCs.
4. More importantly, for comparison of different diagnostic tests, comparing AUCs between
tests is meaningless. Because AUC involves more than one cutoff value. When we do a
diagnostic test, we just perform diagnosis with a specific cutoff. Therefore, the authors must
compare the sensitivity and specificity with a specific cutoff value between different diagnostic
tests with appropriate statistical methods.
Minor points:
1. The comparison of baseline characteristics between the development group and validation
group should be shown.
2. Language expression of this manuscript needs to be improved.
Review for 10.1186/s12876-021-01727-3 (2021)

Title: Comparison of preoperative two-dimensional shear wave elastography, indocyanine
green clearance test and biomarkers for post hepatectomy liver failure prediction
Version: 2 Date: 17 Feb 2021
Reviewer's report:
Pre-operative prediction of post-operative liver failure in hepatocellular carcinoma is clinically
important to improve patient survival and rational pre-operative clinical decision making by
surgeons, but there is no efficient diagnostic method for pre-operative prediction. The authors
conducted a clinically relevant retrospective study comparing 2D-SWE, ICG-R15, ALBI, APRI
and FIB-4 for preoperative prediction of postoperative hepatic resection in hepatocellular
carcinoma.
Major points:
1. The sample size in this study was too small and could be increased by increasing the time span
to increase the sample size while reducing selection bias. Also, the calculation of the sample
size is not stated in the methods section.
2. The method section of this paper shows that patient cohorts are incorporated into the training
and validation sets chronologically. The patient cohort should be randomised and then included
in the training and validation sets respectively. In small sample machine learning, the ratio of
samples in the training and validation sets is typically 7:3.
3. The calculation of P-values for the different diagnostic methods of AUC is not detailed.
Minor points:
1. The flow chart for the inclusion and exclusion of patients should be added in the figures.
2. The AUC curve for ICG-R15 is not shown in the figure 2, which is inconsistent with the
narrative in the result section of this paper.
3. The results of the AUC curves for different diagnostic methods in the training and validation
sets should be shown separately in the figures.
Review for 10.1186/s12876-021-01734-4 (2021)

Title: Identification of the angiogenesis related genes for predicting prognosis of patients with
gastric cancer
Version: 1 Date: 19 Dec 2020
Reviewer's report:
The study developed a nine gene signature related to the angiogenesis that can predict overall
survival for GC, which could work as potential biomarkers to predict the prognosis and diagnosis
of GC. But my concerns are as the follows.
1. I noticed that in the multivariate COX analysis, stage, T, N and M were all included. But stage
of GC was evaluated using T, N and M, would it be appropriate to include all of them in the
multivariate COX analysis ? And according to the analysis, T, N and M were not independent
prognostic factors for GC patients.
2. In the nomogram, the corresponding score of RS accounted for a great proportion. In the
study, it seems much more important than AJCC TNM staging system.
3. All the data come from network, it would be better if the validation set was experimental data
from your own clinical center.
Review for 10.1186/s12876-021-01734-4 (2021)

Title: Identification of the angiogenesis related genes for predicting prognosis of patients with
gastric cancer
Version: 1 Date: 28 Dec 2020
Reviewer's report:
1#This is an article of pure bioinformatics analysis. A common problem of this type of article
is that different database processing results may be inconsistent and lack of validation of actual
samples.So the best thing to do is, can the author provide clinical validation data for his actual
sample?
2# The results showed that AGT, ANGPT1, SERPINE1, ANGPT2, PROCR, KIT, PLAUR and
CAV1 were strongly positive in GC tissues compared to normal gastric tissues in figure 8.
Whereas the SERPINE1 also see stornge expression in normal tissue. The same problem is that
some other markers expression were found in tumor stromal cells, most of which were poorly
differentiated diffuse tumor tissues, and the expression was not significantly increased in tumor
cells.
3#A positive comparison of other tumor angiogenesis related factors, such as VEGF, is
recommended.
Review for 10.1186/s12876-021-01734-4 (2021)

Title: Identification of the angiogenesis related genes for predicting prognosis of patients with
gastric cancer
Version: 1 Date: 03 Jan 2021
Reviewer's report:
In this manuscript Zheng et al. report several angiogenesis related genes to predict prognosis
of gastric cancer by bioinformatic analysis. Initially, TCGA dataset was mined to discover
angiogenesis related genes (ARGs) differentially expressed between normal and tumor tissues.
Then univariate and multivariate Cox regression analysis was used to identify the associations
between differentially expressed ARSs and prognosis of GC patients. 9 genes (AGT, ANGPT1,
SERPINE1, ANGPT2, PVT1, PROCR, KIT, PLAUR and CAV1) were screened out to construct
a risk scoring mode to predict prognosis of gastric cancer patients; this was followed by
validation in TCGA datasets (training group) and in additional external datasets (validation
group). Next, nomogram was constructed based on age, stage, and risk score to predict survival
of patients with gastric cancer.
Several conceptual weaknesses and issues with data presentation weaken this manuscript in its
current format:
1. The title of Supplementary Table I should be gastric cancer, but not colorectal cancer. The
total number of other characteristics is 378, but the number of Stomach adenocarcinoma is 375,
why these two numbers are inconsistent?
2. Generally, TNM stage is considered to be the most important independent prognostic factor,
however, age is not so significant. In Figure 4d, age but not stage is an independent prognostic
factor for GC patients by multivariate COX regression analysis. Could you give a reasonable
explanation? The Authors need to clarify if age evaluation is a continuous variable or categorical
variable; and stage is based on T1/T2-4 or T1/T2/T3/T4.
3. Though the p-value in Figure 5e is statistically significant, the survival curve doesn’t show
obvious difference between two groups, and the AUC in Figure 5f is only 0.603, which is not
good enough to predict patients’ survival.
4. The results from multivariate COX regression analysis in Figure 4d show that stage is not an
independent prognostic factor, why author put the stage in constructing the nomogram model?
Actually, TNM stage is generally acknowledged as the most important prognostic factor. The
authors should clarify if risk score is superior than TNM stage, or combing age, stage and risk
score (nomogram model) is superior than TNM stage alone.
5. In Figure 8, the authors indicated that AGT, ANGPT1, SERPINE1, ANGPT2, PROCR, KIT,
PLAUR and CAV1 were strongly positive in GC tissues compared to normal gastric tissues.
However, the IHC staining of AGT, CAV1, and KIT do not show strongly positive in tumors.
And the staining of ANGPT2 and SERPINE1 are similar in tumor and normal tissues. I suggest
authors use tissue microarrays to examine the IHC staining of these markers in gastric cancer
tissues.
Review for 10.1186/s12876-021-01684-x (2021)

Title: Higher Frailty Burden in Older Adults with Chronic Constipation
Version: 1 Date: 15 Dec 2020
Reviewer's report:
Thank you for this interesting work. The manuscript is well written and focuses on an important
and understudied area of frailty research.  I have a couple suggestions regarding reporting the
characteristics in the results and in Table 1 in order to strengthen the findings and possibly to
better elucidate the association between frailty and CC. First, it would be helpful to include
categorical frailty: robust, N (%); pre-frail, N (%); and frail, N (%).  Second, it would also be
helpful to include the same information for each of the five frailty components: slowness, N
(%), etc.  This would provide a better understanding of what frailty items are most common,
and perhaps, may be contributing most to this association.
I have added specific comments below.
On page 2, in the abstract results, the word "both" seems unnecessary.
On page 4, can you please clarify what is meant by "systematic aging per se"?
One page 6, it should be noted that the criteria used in this study follow the five main CHS frailty
phenotype criteria but with modifications. For example, use of a a different physical activity
scale; no stratification for walking speed by sex or height.  This is not a major concern but it
should noted that it is not identical to the CHS assessment.
On page 7, does the depressive mood assessment include the 2 exhaustion questions in the frailty
assessment?  Seeing that you did not adjust for depression in the logistic regression analysis,
this should be fine.
On page 10, the word "fall" should be "falls".
On pages 11, a minor suggestion is to change the word "researches" to "research".
In Table 1, please consider adding frailty by category (robust, pre-frail, frail) as well.  I do see
this is captured in Figure 1B. Also, per above, please consider adding frailty components.
In Table 2, please consider including all odds ratios and CIs, even if not statistically significant,
unless it is the journal policy to report NS.
Thank you.
Review for 10.1186/s12876-021-01684-x (2021)

Title: Higher Frailty Burden in Older Adults with Chronic Constipation
Version: 1 Date: 11 Jan 2021
Reviewer's report:
Thank you for giving me the opportunity to review this manuscript. All research that furthers
our understanding of frailty is important in our ageing world. Here, using a community
dwelling population representative cross sectional cohort study, the authors evaluate chronic
constipation's relationship (prevalence/severity) with frailty. They conclude that they are
associated. Please see below for additional comments.
1. Even though the the frailty phenotype is a 5 point score, usually the focus of the scoring is
on characterizing patients into robust/pre-frail/frail and not as a 5 point scale. From what I am
able to gather some analysis was done with frailty as a continuous score. It might be worthwhile
to acknowledge this in the manuscript.
2. Study design: I would likely take out "Through annual evaluations...." sentence as I am not
sure if this is relevant to the manuscript.
3. With the FC definition of CC, two of three items had to be present. One was insufficient
symptoms to diagnose the condition as IBS that lasted for at least 3 months. Presumably they
still had to have constipation symptoms outlined in IBS-C and not other representations of IBS.
4. The methods stated that evaluated was 'general bowel habits including self-reported
constipation...' but I did not see where or how this was presented elsewhere in the manuscript
other than the prevalence of self reported constipation in the participants.
5. How would you comment on the differences between self reported constipation and CC
definition used (IBS-C / FC). Did self report constipation have similar results? Is this a normal
difference in prevalence found elsewhere in the literature?
6. What was the purpose of model 2 considering model 1 and 3 are reported.
7. The results would be more transparent if instead of 'NS' in Table 2, the OR and CI were present.
8. I would recommend simplifying some of the results lines that you repeat the full methods/
analysis methods descriptions. Your full methods were reported elsewhere. I understand if you
would like to leave this comment as is.
9. Crude model means univariable?
10. I am based toward frailty but would the discussion create the opportunity to comments
on targeting chronic constipation as a potential reversible component of frailty rather than just
using multicomponent interventions for chronic constipation? Treating constipation is a major
component of acute illness management, evaluating all elimination, including constipation is
part of comprehensive geriatric assessments and frailty interventions are highly investigated.
Thank you.
Review for 10.1186/s12876-021-01684-x (2021)

Title: Higher Frailty Burden in Older Adults with Chronic Constipation
Version: 4 Date: 26 Jan 2021
Reviewer's report:
The authors have done a great job incorporating feedback from reviewers. My only
recommendation to the text would be to include in the results that slowness and low activity
were the frailty components that had statistically significant differences between the CC and
non-CC groups.  Please see minor suggested edits as follows. Thank you.
Minor notes:
Page 4, 2nd paragraph, last sentence: please add "and" before chronic diseases.
Page 9, 1st paragraph, 1st sentence: please add a space between the words frailty and phenotype.
Page 9, 1st paragraph, 3rd sentence: this newly added sentence appears to be incomplete (perhaps
"there was a" trend?).
Page 10, 2nd paragraph, last sentence: please change "is" to "are" known as factors.
Page 11, 1st paragraph, 2nd-to-last sentence: I think the word "is" is missing:  Conversely, as
CC "is" a possible reversible clinical condition.
Review for 10.1186/s12876-021-01684-x (2021)

Title: Higher Frailty Burden in Older Adults with Chronic Constipation
Version: 4 Date: 04 Feb 2021
Reviewer's report:
Thank you for your thoughtful revisions and responses. I hope you continue to produce useful
findings in this area of health research.
-Sam Searle MD, FRCPC
Review for 10.1186/s12876-021-01721-9 (2021)

Title: Association of Circulating Adipsin with Nonalcoholic Fatty Liver Disease in Obese
Adults: A Cross-Sectional Study
Version: 1 Date: 08 Jan 2021
Reviewer's report:
Here, the authors mainly concluded that circulating adipsin concentrations were inversely
associated with NAFLD in their study group, which may be interpreted as a protective factor for
NAFLD development. In my opinion, this is a well written study and contributes to the current
knowledge about this issue greatly. The authors can improve their work taking my suggestions
into account.
1. The authors referred to the 18. reference for further information about the study design.
However, in this reference another reference was cited for further information. In my opinion,
this confuses the reader. I recommend explaining the study design separately for this research.
2. This study was conducted with obese Chines individuals. Therefore, the results could not be
generalized to the world population. Please mention this in limitations.
3. Here, ultrasonography was chosen as diagnostic method for the diagnosis of NAFLD.
However, it is well known that hepatic steatosis defined by ultrasonography is not as accurate
as other diagnostic methods such as controlled attenuation parameter by Fibroscan, MRI-PDFF
or liver biopsy. A significant amount of patients with hepatic steatosis less than 20% may
be underdiagnosed as non-NAFLD in their study group. Please discuss and mention this in
limitation in the light of the references I recommend here (World J Gastroenterol. 2019 Mar
21; 25(11): 1307–1326.; Eur J Gastroenterol Hepatol. 2013 Nov;25(11):1330-4.; J Pediatr
Endocrinol Metab. 2020 Apr 28;33(4):473-479).
4. Could the authors also analyse the association between liver fibrosis grade and adipsin levels?
The authors did not perform liver biopsy. However, I recommend calculation of FIB-4 or NFS for
the estimation of advanced fibrosis as recommended in the major guidelines (Hepatol Int. 2020
Oct 1. doi: 10.1007/s12072-020-10094-2. Online ahead of print.; Hepatology. 2018;67:328–
357.; J Hepatol. 2016;64:1388–1402.). Those tests have been shown to be clinically useful for
ruling out advanced fibrosis owing to their negative predictive values (Gut Liver. 2020 Jul 15;
14(4): 486–491.) and can also be used the patients with normal transaminases (Hepatology
Forum 2020; 1(1): 8-13 DOI: 10.14744/hf.2020.0006). However, recently it has been shown
that those tests could not perform adequately among lean and morbidly obese individuals (Eur
J Gastroenterol Hepatol. 2020 Sep 23. doi: 10.1097/MEG.0000000000001946. Online ahead of
print.). How many patients are categorized as morbidly obese in your population? Please also
add this information. All in all, in my opinion calculating those scores for estimation of liver
fibrosis would enrich their analysis greatly. Please also discuss the use of those scores citing the
references I recommended here.
Review for 10.1186/s12876-021-01721-9 (2021)

Title: Association of Circulating Adipsin with Nonalcoholic Fatty Liver Disease in Obese
Adults: A Cross-Sectional Study
Version: 1 Date: 21 Jan 2021
Reviewer:  Norberto Chavez-tapia
Reviewer's report:
To the authors:
Jinhua Zhang, Kangli Li, Lingling Pan, Fei Teng, Bingquan Lin, Youwen Yuan, Xueyun Wei,
Peizhen Zhang, Wenyuan Li, Huijie Zhang.
I read the paper “Zhang J, Li K, Pan L, et al. Association of Circulating Adipsin with
Nonalcoholic Fatty Liver Disease in Obese Adults: A Cross-Sectional Study”, were the central
issue is the association of adipsin with NAFLD in obese adults. The key points that I find in
the paper is that the populations differ in the expected anthropometric parameters (like waist
circumference, BMI, triglycerides, total cholesterol, etc.). In the characteristics by quartiles of
serum adipsin, it seems that in fact, NAFLD is more prevalent in the upper quartile compare
with the others; and is demonstrated by performing the multivariate analysis.
The next points I consider can work and improve the paper.
- In the diagnosis of fatty liver disease by ultrasonography, please consider to analyze the intra-
observer variability.
- Please consider to use a semi-quantitative sonographic scoring, to perform sensitivity analysis.
Also include non-invasive markers of fibrosis and steatosis.
- At the results, consider create categories according the diagnostic criteria in clinical practice,
instead of quartiles.
- In the characteristics by quartiles, showed in the table 2, explain how the increase in adipsin
levels is associated with more waist circumference and body fat, but not with biochemical
markers of MtS, and less prevalence of NAFLD.
- Tables 3 and 4, are not enough clear to explain the concept.
- Table 3 does not provide clinical information to test the hypothesis.
- Why carotid intima-media thickness is included in table 5?
Review for 10.1186/s12876-021-01717-5 (2021)

Title: Study on the relationship of depression, anxiety, lifestyle and eating habits with the
severity of reflux esophagitis
Version: 4 Date: 20 Dec 2020
Reviewer's report:
This is a case-control study with a sizable number of participants to evaluate the risk factors
of RE and its severity, including anxiety/depression, life style including dietary habits. They
found that low education level, drinking strong tea, preference for sweets and acidic foods,
overeating, short interval between dinner and sleep, anxiety, depression, sleeping on low pillow
and constipation were independent risk factors of RE. Sleeping on low pillow was associated
severity of RE. Depression but not anxiety is positively associated with scores of symptoms and
impaired quality of life. The manuscript is generally well written.
Major concerns:
1. The RE cases were recruited from the department of gastroenterology, but were not well
defined , because the indications for endoscopy, socioeconomic status and other clinical features
including comorbidities and medication of participants were not mentioned and could be
potential confounders.
2. The authors found that sleeping on low pillow was associated the RE severity, however, the
data of RE severity and the prevalence of sleeping on low pillow in patients with different RE
severity were not presented. Besides, sleeping on low pillow was not defined. Was it the same
as “no head-of-the-bed elevation”?
3. The authors found that there were more RE patients having low pillows compared to
asymptomatic controls (44% vs. 14%). Since sleeping on high pillow is a therapeutic strategy
for reflux, why 86% of asymptomatic controls need to take the action?
Minor concerns:
1. Smoking cessation has been recognized to reduce reflux previously. However, the authors
found that smoking was a risk in univariate analysis but was not in multivariate analysis. Was
this finding due to different logistic regression models?
2. Was the questionnaire in the supplementary material self-administered or face-to-face
interviewing?  If it was self-administered, how did the participants know the definition of each
item? What was the response rate of filling out questionnaire?
3. Would the authors explain why depression but not anxiety is associated with symptom severity
and quality of life?
4. Typo: Table 1 alcohol drinking 75 (20.8) in RE group
5. Terminology: The experimental group…..; should it be the “case group”
6. Reference 22 has nothing to do with reflux disease.
Thank you for the opportunity to review your paper.
Review for 10.1186/s12876-021-01717-5 (2021)

Title: Study on the relationship of depression, anxiety, lifestyle and eating habits with the
severity of reflux esophagitis
Version: 4 Date: 03 Jan 2021
Reviewer's report:
This is a retrospective case-controlled study attempting to identify the risk factors or associated
factors of reflux esophagitis, including demographic data, lifestyle habits, eating habits,
depression, and anxiety. The study also tried to correlate the severity of reflux esophagitis and
the severity of anxiety and depression, as well as the severity of anxiety and depression with
patients’ quality of life.
Major comments:
1. Given the retrospective nature of this study, risk factors or causation cannot be determined.
May consider using the word “correlation or association or relationship” instead.
2. The timeline of when patients getting the diagnosis of reflux esophagitis and completing the
questionnaires should be mentioned in the study design.
3. Authors provided clear definitions of multiple measures. Please also clarify “sleeping on low
pillow.”
Minor comments:
1. There are multiple spacing, punctuation errors that should be corrected
2. Please correct “There were also significant differences in the relationship between smoking,
drinking alcohol, coffee and other lifestyles and RE similar to previous some of the previous
studies.”
3. Please expand h. (in 2.4 definitions section)
4. Please format citations and references per journal specifications.
Review for 10.1186/s12876-021-01712-w (2021)

Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 1 Date: 08 Jan 2021
Reviewer:  Saul Rugeles
Reviewer's report:
Congratulations to the authors for this very original and innovative study. I think results are
valuable but is very important to make precisions about EFI diagnosis criteria, bias of not
blindness  and sample size calculations.
Review for 10.1186/s12876-021-01712-w (2021)

Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 2 Date: 02 Feb 2021
Reviewer:  Saul Rugeles
Reviewer's report:
Blinding procedure is not described. I suggest the blinding procedure be described in detail.
On the other hand the study is described as "pilot study". I suggest this expression must be
eliminated as a "pilot study" is used mainly as a preliminar study before design a big trail with
objectives such as knowing the population, calculate the recruitment frequency, etc
Review for 10.1186/s12876-021-01712-w (2021)

Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 2 Date: 06 Feb 2021
Reviewer's report:
Thank you for addressing all my concerns i raised in my first review. I have no further edits
to suggest
Review for 10.1186/s12876-021-01712-w (2021)

Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 5 Date: 02 Mar 2021
Reviewer:  Saul Rugeles
Reviewer's report:
Thank you for accept my suggestions and correct your manuscript.