Title: Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential
application dosages and strategies: a network meta-analysis
Version: 1 Date: 19 Oct 2023
Reviewer's report:
Thank you for allowing me to revise this manuscript.  The work is valuable but before
considering it for publication, English language should be thoroughly revised, as well as
considering removal of similar sentences. In my comment I will provide you with examples and
the suggested revised paragraphs.
Introduction:
The introduction provides a general overview of hepatic encephalopathy and the use of rifaximin
for its treatment. However, there are several gaps that could be improved:
1. 1st paragraph had many similar sentences, it is better to avoid redundant phrases and
rephrasing certain parts, I provided you with a revised version : Hepatic encephalopathy (HE) is a
neuropsychiatric syndrome associated with liver disease, leading to impaired cognitive function,
motor activity, and potentially resulting in consciousness and coma [1]. Elevated blood ammonia
and inflammation are the main triggers for HE [2]. It is considered one of the most serious
complications of decompensated cirrhosis, independently predicting hospitalization and death
from liver-related complications [3]. Therefore, the prevention and treatment of HE are crucial
for patients with liver disease.
2. The introduction lacks a clear statement of the research problem or research question. It would
be helpful to explicitly state the objective or purpose of the study, such as investigating the
effectiveness of different doses and application strategies of rifaximin in patients with HE.
3. The introduction briefly mentions that rifaximin has been recommended as an add-on drug
for the prevention of HE recurrence, but it doesn't provide a clear context for the need to explore
different agent doses and application strategies. The rationale for investigating these factors
should be elaborated upon to justify the study's focus.
4. The introduction mentions controversy regarding the effect of rifaximin on mortality, but it
doesn't provide any explanation or context for this controversy. It would be beneficial to briefly
discuss the conflicting findings in the literature and the need for further investigation.
5. The introduction mentions that previous meta-analyses did not consider the influence of drug
dosage and application strategy on the results, but it does not explain why this is important. It
would be helpful to provide a rationale for why considering these factors is crucial for optimizing
the treatment of HE with rifaximin.
6. The introduction could benefit from a clearer structure and flow. It would be helpful to
organize the information in a logical manner, highlighting the gaps in the literature and the
study's objectives more effectively. Moe citations need to be added to allow readers to focus on
the specific study or meta analysis mentioned in the introduction context.
Methods section
1. Lack of search strategy details: The statement does not provide information about how the
search terms were combined or the specific search syntax used. For example, it is unclear
whether the search strategy used Boolean operators (e.g., AND, OR), proximity operators, or
truncation/wildcard symbols to enhance the search results. Including this information would
improve the transparency and reproducibility of the search strategy.
2. Unclear handling of conflicts between reviewers: While the paragraph mentions that
disagreements between reviewers were resolved through discussion, it does not provide details
on the specific methods used to achieve consensus. It is essential to have a robust process for
resolving conflicts to ensure the reliability of the study selection.
3. Inconsistent capitalization and formatting: There are inconsistencies in the capitalization
of certain terms, such as "HE" and "RCT," as well as inconsistencies in the formatting
of the exclusion criteria. Consistency in capitalization and formatting improves the overall
professionalism and readability of the manuscript.
4. Lack of clarity in data extraction process: The paragraph mentions that two authors
independently screened studies and extracted information but does not provide details on how
the data extraction was conducted. It is important to specify the process used for extracting data,
such as whether a standardized form was used and how discrepancies between authors were
resolved.
5. Insufficient explanation of quality assessment parameters: The paragraph mentions that the
Cochrane risk of bias tool was used for quality assessment, but it does not explain the specific
parameters assessed or how they were interpreted. Providing a brief description of the seven
parameters assessed and their relevance to the study outcomes would improve the understanding
of the quality assessment process.
6. Reference no 20 is not suitable in this context: The quality of RCTs was assessed by
seven parameters: randomization sequence generation, allocation concealment, participant and
personnel blinding, assessor blinding, incomplete outcome data, selective reporting, and others.
You need to properly cite Cochrane risk of bias tool.
Results section:
1. Should be corrected to " tablet" in the following paragraph: Regarding the rifaximin dose, one
study designed the rifaximin table and increased the water solubility
Discussion:
1. This paragraph need more than one references, Rifaximin was approved by the FDA for HE
treatment. The current recommended dose of rifaximin in the treatment of HE is 1200 mg or
1100 mg/day. However, there is still a lack of uniformity regarding the dose and frequency of
application
2. The following paragraph is of poor English: One study reported that reducing the applied
dose of rifaximin can still achieve endotoxin reduction similar to the conventional dose [19],
but whether dose reduction still has a good therapeutic effect on HE or less risk of adverse
effects still needs further study. It should be re phrased as such: A single study indicated that
reducing the administered dose of rifaximin can yield comparable reductions in endotoxin levels
to the standard dose [19]. However, additional research is required to determine whether dose
reduction maintains therapeutic efficacy for HE and reduces the risk of adverse effects.
3. The following 2 paragraphs are related to Introduction rather than discussion section:
The overgrowth and alterations of intestinal bacteria could contribute to hyperammonemia,
hyperendotoxemia, and systemic inflammation, leading to the development of HE [42].
Rifaximin is a gastrointestinal selective broad-spectrum antibiotic that is rarely absorbed
systemically [43]. It significantly inhibits the proliferation of urease-producing bacteria in the
intestine and reduces the production of ammonia and other toxins [21], but it has a low impact on
the normal intestinal flora [44]. Plasma ammonia is also considered a predictor of hospitalization
and mortality due to liver-related complications in stable cirrhosis outpatients [3].
Additionally, rifaximin is a small intestine-specific pregnane X receptor agonist that inhibits
the inflammatory response and reduces the release of proinflammatory factors [45]. Systemic
inflammation is very common in decompensated cirrhotic patients and correlates with the
severity of HE [46][26557005]. This inflammation affects the gut-liver-brain axis, including
microglial activation and brain aggregation of proinflammatory factors [47]. Thus, rifaximin
may also have a therapeutic effect through systemic anti-inflammatory effects to slow down HE
processes.
4. Insufficient reporting of study limitations: The paragraph mentions that the majority of
included RCTs were unable to confirm the reduction of mortality with rifaximin, but it does not
discuss the limitations of these studies or potential reasons for the lack of significant findings.
Addressing the limitations of the included studies would provide a more comprehensive
understanding of the evidence.
5. The term study is not the suitable term to be used over the article, because in some paragraphs
it is little bit confusing, It should be replaced with the term "review".
Title: Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential
application dosages and strategies: a network meta-analysis
Version: 1 Date: 19 Oct 2023
Reviewer's report:
Thank you for allowing me to revise this manuscript.  The work is valuable but before
considering it for publication, English language should be thoroughly revised, as well as
considering removal of similar sentences. In my comment I will provide you with examples and
the suggested revised paragraphs.
Introduction:
The introduction provides a general overview of hepatic encephalopathy and the use of rifaximin
for its treatment. However, there are several gaps that could be improved:
1. 1st paragraph had many similar sentences, it is better to avoid redundant phrases and
rephrasing certain parts, I provided you with a revised version : Hepatic encephalopathy (HE) is a
neuropsychiatric syndrome associated with liver disease, leading to impaired cognitive function,
motor activity, and potentially resulting in consciousness and coma [1]. Elevated blood ammonia
and inflammation are the main triggers for HE [2]. It is considered one of the most serious
complications of decompensated cirrhosis, independently predicting hospitalization and death
from liver-related complications [3]. Therefore, the prevention and treatment of HE are crucial
for patients with liver disease.
2. The introduction lacks a clear statement of the research problem or research question. It would
be helpful to explicitly state the objective or purpose of the study, such as investigating the
effectiveness of different doses and application strategies of rifaximin in patients with HE.
3. The introduction briefly mentions that rifaximin has been recommended as an add-on drug
for the prevention of HE recurrence, but it doesn't provide a clear context for the need to explore
different agent doses and application strategies. The rationale for investigating these factors
should be elaborated upon to justify the study's focus.
4. The introduction mentions controversy regarding the effect of rifaximin on mortality, but it
doesn't provide any explanation or context for this controversy. It would be beneficial to briefly
discuss the conflicting findings in the literature and the need for further investigation.
5. The introduction mentions that previous meta-analyses did not consider the influence of drug
dosage and application strategy on the results, but it does not explain why this is important. It
would be helpful to provide a rationale for why considering these factors is crucial for optimizing
the treatment of HE with rifaximin.
6. The introduction could benefit from a clearer structure and flow. It would be helpful to
organize the information in a logical manner, highlighting the gaps in the literature and the
study's objectives more effectively. Moe citations need to be added to allow readers to focus on
the specific study or meta analysis mentioned in the introduction context.
Methods section
1. Lack of search strategy details: The statement does not provide information about how the
search terms were combined or the specific search syntax used. For example, it is unclear
whether the search strategy used Boolean operators (e.g., AND, OR), proximity operators, or
truncation/wildcard symbols to enhance the search results. Including this information would
improve the transparency and reproducibility of the search strategy.
2. Unclear handling of conflicts between reviewers: While the paragraph mentions that
disagreements between reviewers were resolved through discussion, it does not provide details
on the specific methods used to achieve consensus. It is essential to have a robust process for
resolving conflicts to ensure the reliability of the study selection.
3. Inconsistent capitalization and formatting: There are inconsistencies in the capitalization
of certain terms, such as "HE" and "RCT," as well as inconsistencies in the formatting
of the exclusion criteria. Consistency in capitalization and formatting improves the overall
professionalism and readability of the manuscript.
4. Lack of clarity in data extraction process: The paragraph mentions that two authors
independently screened studies and extracted information but does not provide details on how
the data extraction was conducted. It is important to specify the process used for extracting data,
such as whether a standardized form was used and how discrepancies between authors were
resolved.
5. Insufficient explanation of quality assessment parameters: The paragraph mentions that the
Cochrane risk of bias tool was used for quality assessment, but it does not explain the specific
parameters assessed or how they were interpreted. Providing a brief description of the seven
parameters assessed and their relevance to the study outcomes would improve the understanding
of the quality assessment process.
6. Reference no 20 is not suitable in this context: The quality of RCTs was assessed by
seven parameters: randomization sequence generation, allocation concealment, participant and
personnel blinding, assessor blinding, incomplete outcome data, selective reporting, and others.
You need to properly cite Cochrane risk of bias tool.
Results section:
1. Should be corrected to " tablet" in the following paragraph: Regarding the rifaximin dose, one
study designed the rifaximin table and increased the water solubility
Discussion:
1. This paragraph need more than one references, Rifaximin was approved by the FDA for HE
treatment. The current recommended dose of rifaximin in the treatment of HE is 1200 mg or
1100 mg/day. However, there is still a lack of uniformity regarding the dose and frequency of
application
2. The following paragraph is of poor English: One study reported that reducing the applied
dose of rifaximin can still achieve endotoxin reduction similar to the conventional dose [19],
but whether dose reduction still has a good therapeutic effect on HE or less risk of adverse
effects still needs further study. It should be re phrased as such: A single study indicated that
reducing the administered dose of rifaximin can yield comparable reductions in endotoxin levels
to the standard dose [19]. However, additional research is required to determine whether dose
reduction maintains therapeutic efficacy for HE and reduces the risk of adverse effects.
3. The following 2 paragraphs are related to Introduction rather than discussion section:
The overgrowth and alterations of intestinal bacteria could contribute to hyperammonemia,
hyperendotoxemia, and systemic inflammation, leading to the development of HE [42].
Rifaximin is a gastrointestinal selective broad-spectrum antibiotic that is rarely absorbed
systemically [43]. It significantly inhibits the proliferation of urease-producing bacteria in the
intestine and reduces the production of ammonia and other toxins [21], but it has a low impact on
the normal intestinal flora [44]. Plasma ammonia is also considered a predictor of hospitalization
and mortality due to liver-related complications in stable cirrhosis outpatients [3].
Additionally, rifaximin is a small intestine-specific pregnane X receptor agonist that inhibits
the inflammatory response and reduces the release of proinflammatory factors [45]. Systemic
inflammation is very common in decompensated cirrhotic patients and correlates with the
severity of HE [46][26557005]. This inflammation affects the gut-liver-brain axis, including
microglial activation and brain aggregation of proinflammatory factors [47]. Thus, rifaximin
may also have a therapeutic effect through systemic anti-inflammatory effects to slow down HE
processes.
4. Insufficient reporting of study limitations: The paragraph mentions that the majority of
included RCTs were unable to confirm the reduction of mortality with rifaximin, but it does not
discuss the limitations of these studies or potential reasons for the lack of significant findings.
Addressing the limitations of the included studies would provide a more comprehensive
understanding of the evidence.
5. The term study is not the suitable term to be used over the article, because in some paragraphs
it is little bit confusing, It should be replaced with the term "review".
Please review this paper.
user
Title: Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential
application dosages and strategies: a network meta-analysis
Version: 1 Date: 19 Oct 2023
Reviewer's report:
Thank you for allowing me to revise this manuscript.  The work is valuable but before
considering it for publication, English language should be thoroughly revised, as well as
considering removal of similar sentences. In my comment I will provide you with examples and
the suggested revised paragraphs.
Introduction:
The introduction provides a general overview of hepatic encephalopathy and the use of rifaximin
for its treatment. However, there are several gaps that could be improved:
1. 1st paragraph had many similar sentences, it is better to avoid redundant phrases and
rephrasing certain parts, I provided you with a revised version : Hepatic encephalopathy (HE) is a
neuropsychiatric syndrome associated with liver disease, leading to impaired cognitive function,
motor activity, and potentially resulting in consciousness and coma [1]. Elevated blood ammonia
and inflammation are the main triggers for HE [2]. It is considered one of the most serious
complications of decompensated cirrhosis, independently predicting hospitalization and death
from liver-related complications [3]. Therefore, the prevention and treatment of HE are crucial
for patients with liver disease.
2. The introduction lacks a clear statement of the research problem or research question. It would
be helpful to explicitly state the objective or purpose of the study, such as investigating the
effectiveness of different doses and application strategies of rifaximin in patients with HE.
3. The introduction briefly mentions that rifaximin has been recommended as an add-on drug
for the prevention of HE recurrence, but it doesn't provide a clear context for the need to explore
different agent doses and application strategies. The rationale for investigating these factors
should be elaborated upon to justify the study's focus.
4. The introduction mentions controversy regarding the effect of rifaximin on mortality, but it
doesn't provide any explanation or context for this controversy. It would be beneficial to briefly
discuss the conflicting findings in the literature and the need for further investigation.
5. The introduction mentions that previous meta-analyses did not consider the influence of drug
dosage and application strategy on the results, but it does not explain why this is important. It
would be helpful to provide a rationale for why considering these factors is crucial for optimizing
the treatment of HE with rifaximin.
6. The introduction could benefit from a clearer structure and flow. It would be helpful to
organize the information in a logical manner, highlighting the gaps in the literature and the
study's objectives more effectively. Moe citations need to be added to allow readers to focus on
the specific study or meta analysis mentioned in the introduction context.
Methods section
1. Lack of search strategy details: The statement does not provide information about how the
search terms were combined or the specific search syntax used. For example, it is unclear
whether the search strategy used Boolean operators (e.g., AND, OR), proximity operators, or
truncation/wildcard symbols to enhance the search results. Including this information would
improve the transparency and reproducibility of the search strategy.
2. Unclear handling of conflicts between reviewers: While the paragraph mentions that
disagreements between reviewers were resolved through discussion, it does not provide details
on the specific methods used to achieve consensus. It is essential to have a robust process for
resolving conflicts to ensure the reliability of the study selection.
3. Inconsistent capitalization and formatting: There are inconsistencies in the capitalization
of certain terms, such as "HE" and "RCT," as well as inconsistencies in the formatting
of the exclusion criteria. Consistency in capitalization and formatting improves the overall
professionalism and readability of the manuscript.
4. Lack of clarity in data extraction process: The paragraph mentions that two authors
independently screened studies and extracted information but does not provide details on how
the data extraction was conducted. It is important to specify the process used for extracting data,
such as whether a standardized form was used and how discrepancies between authors were
resolved.
5. Insufficient explanation of quality assessment parameters: The paragraph mentions that the
Cochrane risk of bias tool was used for quality assessment, but it does not explain the specific
parameters assessed or how they were interpreted. Providing a brief description of the seven
parameters assessed and their relevance to the study outcomes would improve the understanding
of the quality assessment process.
6. Reference no 20 is not suitable in this context: The quality of RCTs was assessed by
seven parameters: randomization sequence generation, allocation concealment, participant and
personnel blinding, assessor blinding, incomplete outcome data, selective reporting, and others.
You need to properly cite Cochrane risk of bias tool.
Results section:
1. Should be corrected to " tablet" in the following paragraph: Regarding the rifaximin dose, one
study designed the rifaximin table and increased the water solubility
Discussion:
1. This paragraph need more than one references, Rifaximin was approved by the FDA for HE
treatment. The current recommended dose of rifaximin in the treatment of HE is 1200 mg or
1100 mg/day. However, there is still a lack of uniformity regarding the dose and frequency of
application
2. The following paragraph is of poor English: One study reported that reducing the applied
dose of rifaximin can still achieve endotoxin reduction similar to the conventional dose [19],
but whether dose reduction still has a good therapeutic effect on HE or less risk of adverse
effects still needs further study. It should be re phrased as such: A single study indicated that
reducing the administered dose of rifaximin can yield comparable reductions in endotoxin levels
to the standard dose [19]. However, additional research is required to determine whether dose
reduction maintains therapeutic efficacy for HE and reduces the risk of adverse effects.
3. The following 2 paragraphs are related to Introduction rather than discussion section:
The overgrowth and alterations of intestinal bacteria could contribute to hyperammonemia,
hyperendotoxemia, and systemic inflammation, leading to the development of HE [42].
Rifaximin is a gastrointestinal selective broad-spectrum antibiotic that is rarely absorbed
systemically [43]. It significantly inhibits the proliferation of urease-producing bacteria in the
intestine and reduces the production of ammonia and other toxins [21], but it has a low impact on
the normal intestinal flora [44]. Plasma ammonia is also considered a predictor of hospitalization
and mortality due to liver-related complications in stable cirrhosis outpatients [3].
Additionally, rifaximin is a small intestine-specific pregnane X receptor agonist that inhibits
the inflammatory response and reduces the release of proinflammatory factors [45]. Systemic
inflammation is very common in decompensated cirrhotic patients and correlates with the
severity of HE [46][26557005]. This inflammation affects the gut-liver-brain axis, including
microglial activation and brain aggregation of proinflammatory factors [47]. Thus, rifaximin
may also have a therapeutic effect through systemic anti-inflammatory effects to slow down HE
processes.
4. Insufficient reporting of study limitations: The paragraph mentions that the majority of
included RCTs were unable to confirm the reduction of mortality with rifaximin, but it does not
discuss the limitations of these studies or potential reasons for the lack of significant findings.
Addressing the limitations of the included studies would provide a more comprehensive
understanding of the evidence.
5. The term study is not the suitable term to be used over the article, because in some paragraphs
it is little bit confusing, It should be replaced with the term "review".
assistant