Review Reports - Increasing Disease-Specific Knowledge in Patients with SLE Through a Structured One-Day Seminar: Results of a Randomized, Controlled Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Reviewer Report

Manuscript Title: Increasing Disease-Specific Knowledge in Patients with SLE through a Structured One-Day Seminar

This manuscript presents a randomized controlled study evaluating the effect of a structured one-day educational seminar on disease-specific knowledge in patients with systemic lupus erythematosus (SLE). The topic is clinically relevant, as patient education and empowerment are essential components of chronic disease management.

The study is well organized, and the methodology is generally appropriate. The results show a statistically significant short-term increase in disease-specific knowledge and a reduction in unmet informational needs, although no significant behavioral changes were observed.

However, several methodological limitations—particularly the small sample size, potential selection bias, and the use of a non-validated primary outcome measure—limit the strength of the conclusions.

Major Issues:

Sample size and statistical power
The final analyzed cohort (n = 39) is substantially smaller than the planned sample size. This underpowering likely explains the lack of sustained statistical significance at 3 months and should be more explicitly emphasized as a key limitation.
Primary outcome measure (knowledge test)
The disease-specific knowledge questionnaire is self-designed and not validated. This raises concerns regarding reliability and validity of the primary endpoint. The authors should:
- Provide more detail on its development
- Acknowledge this more prominently as a limitation
Ceiling effect
Baseline knowledge scores were relatively high, limiting the measurable improvement. This potential ceiling effect should be discussed more clearly.
Selection bias and generalizability
Participants were recruited voluntarily and may represent a more motivated and health-literate subgroup of SLE patients. This limits external validity and should be further elaborated.
Interpretation of negative behavioral outcomes
The lack of change in lifestyle behaviors should be interpreted with more nuance. High baseline adherence (e.g., medication, UV protection) may have limited the potential for improvement. This should be emphasized to avoid underestimating the intervention’s value.

Minor Issues:

Language and formatting
- Several hyphenation issues (e.g., “pa-tients”, “in-formation”) should be corrected
- Minor grammatical polishing is recommended
Randomization details
Clarify whether allocation concealment was implemented and provide more detail on the randomization procedure.
Figures and presentation
Some figures could be simplified for clarity and readability.
Discussion
The discussion would benefit from briefly incorporating behavioral science perspectives (e.g., why knowledge alone may not lead to behavioral change).

Recommendation: Major Revision - The manuscript addresses an important topic and provides useful preliminary data. With clearer acknowledgment of methodological limitations, improved discussion, and minor technical revisions, the manuscript could make a valuable contribution to the field.

Author Response

Major Issues:

Sample size and statistical power

The final analyzed cohort (n = 39) is substantially smaller than the planned sample size. This underpowering likely explains the lack of sustained statistical significance at 3 months and should be more explicitly emphasized as a key limitation.

We have attempted to place greater emphasis on the reviewer’s valid point regarding insufficient recruitment and, consequently, the study’s lack of statistical power. The text now reads: “A key limitation was that the intended sample size of 30 participants per group could not be achieved. This underpowering likely explains the lack of sustained statistical significance at three months. The fact that the combined results for the intervention group and the control group (n=39) show a significant increase in knowledge after three months suggests that the sample size was insufficient to demonstrate this effect in a randomized controlled trial design.” (lines 415-422)

Primary outcome measure (knowledge test)

The disease-specific knowledge questionnaire is self-designed and not validated. This raises concerns regarding reliability and validity of the primary endpoint. The authors should:

Provide more detail on its development

We have included additional comments on the development of the multiple-choice test (lines 119-124). For greater clarity, we have provided the test separately in its original German version and in an English translation in the supplement (Document S1).

Acknowledge this more prominently as a limitation

We have incorporated the reviewer’s suggestions and explicitly noted that the validity of the knowledge test has not been tested. The text now reads: “A further major limitation was that the disease-specific knowledge test was self-designed and not validated. To date, there are no validated disease-specific knowledge tests for patients with SLE. An inadequate validation may also have contributed to the higher-than-expected number of correct answers prior to the start of the intervention.“ (lines 423-426).

The reliability of the test was not calculated separately. However, we assume a high level of retest and inter-rater reliability, as repeating the test in the waiting-list control group yielded the same mean score for the group, and the baseline results for the waiting-list control group and the intervention group differed only slightly.

Ceiling effect

Baseline knowledge scores were relatively high, limiting the measurable improvement. This potential ceiling effect should be discussed more clearly.

We have placed greater emphasis on the ceiling effect and the resulting reduced ability to assess the effect size of our intervention as a limitation. The text now reads: “An inadequate validation may also have contributed to the higher-than-expected number of correct answers prior to the start of the intervention. Therefore, the baseline knowledge scores were relatively high, thus confining the amplitude of measurable improvement. This ceiling effect significantly limited the ability to measure increases in knowledge and, consequently, the statistical power of the study.” (lines 425-429).

Selection bias and generalizability

Participants were recruited voluntarily and may represent a more motivated and health-literate subgroup of SLE patients. This limits external validity and should be further elaborated.

We have provided further clarification of this limitation, which we mentioned earlier, in an additional sentence. (“It can be assumed that participants represent a more motivated and health-literate subgroup of SLE patients.”, lines 435/436).

Interpretation of negative behavioral outcomes

The lack of change in lifestyle behaviors should be interpreted with more nuance. High baseline adherence (e.g., medication, UV protection) may have limited the potential for improvement. This should be emphasized to avoid underestimating the intervention’s value.

We addressed this important issue by incorporating the discussion of behavioral changes into the limitations. In addition, we have emphasized the link between potential sampling bias and the lack of observable behavioral change: “A sampling bias may have influenced the results regarding behavioral changes. Significantly, our educational seminar did not result in behavioral changes three months after the intervention. The greatest changes were expected in areas of behavior that could be improved by the participants with relatively little effort. These were adherence to the medication and the application of UV protection. However, the adherence to treatment reported in the MMSA-4 was already unusually high before the event (92.3 %) and could hardly be improved. This percentage is considerably higher than the 37.9 % [29] and 31.7 % [30] previously reported for other SLE cohorts. This may be partly due to the fact that our cohort of voluntary participants had a particularly high motivation for medication adherence. The same applied to the UV protection recommended for SLE patients, which 97% of patients were already practicing prior to the intervention. There was no further room for improvement in either domain.” (lines 440-451).

Minor Issues:

Language and formatting

Several hyphenation issues (e.g., “pa-tients”, “in-formation”) should be corrected´

We apologize for the errors that apparently occurred during the reformatting. The hyphenation has now been corrected.

Minor grammatical polishing is recommended

Randomization details

Clarify whether allocation concealment was implemented and provide more detail on the randomization procedure.

Participants were allocated in a 1:1 ratio upon receipt of their registration using external randomization lists with randomly defined blocks of 4. We changed the text into: “Participants were allocated in a 1 : 1 ratio using external randomization lists with randomly defined blocks of 4 upon receipt of enrollment.” (lines 95/96) The randomization lists were provided by the Institute of Medical Epidemiology, Biometrics and Informatics of the Medical Faculty of the Martin-Luther-University Halle-Wittenberg. Participant enrollment in the study and subsequent randomization were handled by the secretary of the Department of Internal Medicine II, who was not otherwise part of the study staff. After randomization, the secretary scheduled an appointment for the participants—either for the waiting control group or for the intervention group—depending on their allocation, and sent out the questionnaires. Since no study staff had been involved in the randomization process up to that point, no further measures were taken to ensure allocation concealment.

Figures and presentation

Some figures could be simplified for clarity and readability.

We changed the caption for Figure 1. The text now reads as follows: “Study design. Participants were randomized (R) at baseline. Both groups received the intervention (I) consisting of a one-day seminar. Tests (T) on disease knowledge were conducted in both groups at baseline, directly after the intervention and three months after the intervention. The control group had an additional testing after a 3-month waiting period immediately before the intervention.” (lines 140-146)

The manuscript was sent to MDPI Author Services in order to enhance quality and clarity of the figures.

Discussion

The discussion would benefit from briefly incorporating behavioral science perspectives (e.g., why knowledge alone may not lead to behavioral change).

We have implemented the reviewers' recommendation and emphasized the “knowledge-behavior gap” that could prevent lasting behavioral change: “There is evidence that an increase in knowledge alone may not be sufficient to lead to behavioral changes. Rather, there is often a so-called “knowledge-behavior gap,” in which knowledge is not translated into corresponding action [31,32]. Lifestyle modifications with regard to smoking, exercise and diet are difficult to achieve even with more intensive interventions [33,34]. It is not surprising that a one-day educational event does not lead to a lasting change in eating, nicotine consumption habits or physical activity. Additional motivational strategies are likely to be necessary to bring about lasting behavioral changes.” (lines 452-460). Incorporating the behavioral science perspective led to two additional references [31,32].

Reviewer 2 Report

Comments and Suggestions for Authors

The topic is relevant and clinically meaningful. Patient education is an important component of SLE management. The randomized design is a strength. However, the manuscript does not clearly define the specific knowledge gap addressed by a one-day educational intervention. The introduction should more explicitly explain why a short seminar format is preferable to existing educational strategies and what new contribution this model provides.

• The study design raises concerns regarding statistical power and sample size. The initial power calculation assumed 30 participants per group. In reality, only 39 participants completed the study. This substantially reduces statistical power and limits the reliability of the findings. The authors acknowledge this limitation, but its impact on the interpretation of results should be discussed more critically.

• Measurement of the primary outcome requires further clarification. The disease-specific knowledge test was self-designed and its psychometric properties were not reported. Information about validation, reliability testing, or pilot evaluation is missing. Without such evidence, it is difficult to assess whether the questionnaire accurately measures knowledge change. The authors should provide more methodological detail or discuss this limitation explicitly.

• The interpretation of results should be more balanced. The seminar clearly increased knowledge immediately after the intervention, but this effect weakened at three months. Moreover, no measurable changes were observed in lifestyle behaviors or adherence outcomes. The discussion should emphasize that knowledge gain alone may not translate into behavioral change and that additional or repeated educational strategies may be required.

• The presentation of results could be improved. Some tables contain many descriptive variables that are not directly related to the primary outcome. The manuscript would benefit from clearer prioritization of key results. Figures summarizing knowledge change are useful but their interpretation could be explained more clearly in the text. A more concise presentation would improve readability.

The manuscript addresses an important aspect of patient education in systemic lupus erythematosus and uses a randomized design, which strengthens its methodological basis. However, several issues require revision, including clarification of the study rationale, improved description of measurement tools, and a more cautious interpretation of results in light of the small sample size and limited long-term effects. With these revisions, the manuscript could provide a useful contribution to the literature on patient education in rheumatic diseases.

Author Response

Comments and Suggestions for Authors

We have taken the reviewer’s important comment into account and included a sentence explicitly noting the lack of structured treatment options for SLE patients to date: “Currently, there are no structured patient information programs for patients with SLE in Germany.” (lines 63/64). In addition, in the introduction we explained in more detail the benefits we expect from a one-day seminar. “Therefore, it was our intention to address the need for reliable information from medical professionals. We believe that a one-day seminar is more likely to be accepted and attended by SLE-patients than more extensive educational programs involving multiple sessions.” (lines 75-78)

The study design raises concerns regarding statistical power and sample size. The initial power calculation assumed 30 participants per group. In reality, only 39 participants completed the study. This substantially reduces statistical power and limits the reliability of the findings. The authors acknowledge this limitation, but its impact on the interpretation of results should be discussed more critically.

We have attempted to place greater emphasis on the reviewer’s valid point regarding insufficient recruitment and, consequently, the study’s lack of statistical power (lines 415-422). “A key limitation was that the intended sample size of 30 participants per group could not be achieved. This underpowering likely explains the lack of sustained statistical significance at three months. The fact that the combined results for the intervention group and the control group (n=39) show a significant increase in knowledge after three months suggests that the sample size was insufficient to demonstrate this effect in a randomized controlled trial design.”

Measurement of the primary outcome requires further clarification. The disease-specific knowledge test was self-designed and its psychometric properties were not reported. Information about validation, reliability testing, or pilot evaluation is missing. Without such evidence, it is difficult to assess whether the questionnaire accurately measures knowledge change. The authors should provide more methodological detail or discuss this limitation explicitly.

We have incorporated the reviewer’s suggestions and explicitly noted that the validity of the knowledge test has not been tested (lines 423-425).

The interpretation of results should be more balanced. The seminar clearly increased knowledge immediately after the intervention, but this effect weakened at three months. Moreover, no measurable changes were observed in lifestyle behaviors or adherence outcomes. The discussion should emphasize that knowledge gain alone may not translate into behavioral change and that additional or repeated educational strategies may be required.

In the discussion section, we have described the limitations in greater detail in the revised version. Specifically, we highlight three key factors that may have influenced the study results:

1. Insufficient recruitment.
2. An inadequately validated measurement tool with a higher percentage of correct answers at baseline than calculated.
3. Suspected selection bias involving a motivated group of attendants who may have had an unusually high level of health literacy at baseline.

All three factors likely contributed to the weakening of the effect (lines 414-443). Furthermore, the high percentage of participants who reported regular use of sunscreen and high medication adherence at baseline made it impossible to achieve further improvement in these easily implementable areas (lines 444-451).

The presentation of results could be improved. Some tables contain many descriptive variables that are not directly related to the primary outcome. The manuscript would benefit from clearer prioritization of key results. Figures summarizing knowledge change are useful but their interpretation could be explained more clearly in the text. A more concise presentation would improve readability.

The manuscript was sent to MDPI Author Services in order to enhance quality and clarity of the figures.

In fact, the descriptive variables in Table 1 have no direct relationship to the primary outcome measures. However, these are measures that clinically characterize the group of SLE patients under study and are of interest to rheumatologists, which is why we would like to include them here.

We have made an effort to improve the clarity of the caption for Figure 1. The text now reads as follows: “Study design. Participants were randomized (R) at baseline. Both groups received the intervention (I) consisting of a one-day seminar. Tests (T) on disease knowledge were conducted in both groups at baseline, directly after the intervention and three months after the intervention. The control group had an additional testing after a 3-month waiting period immediately before the intervention.” (lines 140-146)

Reviewer 3 Report

Comments and Suggestions for Authors

This are some points to improve this manuscript.

Address the Underpowered Nature of the Study and Small Sample Size: The manuscript explicitly states that the intended sample size of 30 participants per group could not be reached, leading to an underpowered study, particularly for detecting long-term differences. The final analysis included only 39 participants (19 in the intervention group, 20 in the control group), which is a significant limitation for a randomized controlled trial and impacts the generalizability and statistical robustness of the findings, especially for the three-month follow-up.

Enhance Strategies for Sustained Knowledge Retention and Lifestyle Modification: While immediate knowledge gain was significant, it notably declined after three months. More critically, the one-day seminar failed to induce sustainable lifestyle modifications. The discussion acknowledges this, suggesting a need for follow-up interventions, reinforcement, or a more extended educational program to solidify knowledge and translate it into lasting behavioral changes.

Refine Assessment to Account for Potential Ceiling Effects: The baseline knowledge score of participants was higher than initially assumed, which the authors identify as a potential "ceiling effect" for the multiple-choice test. This means the assessment might not have been able to fully capture the potential for improvement in a group that already had a relatively good understanding of their disease. Future studies could consider more nuanced or advanced knowledge assessments or target populations with lower baseline knowledge.

Acknowledge and Discuss Sampling Bias More Broadly: The voluntary nature of participation and the exclusion criteria (e.g., high disease activity, severe concomitant disease, mental/cognitive impairment) likely resulted in a highly motivated and relatively healthier patient cohort. This limits the generalizability of the findings to the broader, more diverse SLE patient population, particularly those with more complex needs or lower adherence. Explicitly discussing how this might influence the observed high baseline medication adherence (92.3%) would also be beneficial.

Improve Clarity in Control Group Methodology: The description of the control group's testing schedule (lines 116-119) can be confusing. While a wait-list control design is clear from Figure 1, the text's phrasing "The control group completed the questionnaire four times: three months before and immediately before the seminar, immediately after the seminar, and three months later" could be rephrased for absolute clarity. It should explicitly state that "the seminar" in this context refers to their later-scheduled intervention, or use consistent time points (e.g., baseline, 3 months, 6 months) relative to the study's start for both groups, specifying when each group received the intervention.

Incorporate or Justify Lack of Tools for Emotional, Motivational, and Direct Behavioral Responses: The "Highlights" section itself notes that "Assessment tools are needed to record emotional, motivational, behavioral responses to education." While the BIPQ touches on illness perception, the manuscript indicates a gap in directly assessing emotional and motivational changes specifically resulting from the education. Including such tools, or clearly justifying their absence, would strengthen the understanding of why behavioral changes were not observed, beyond just high baseline adherence.

Author Response

Address the Underpowered Nature of the Study and Small Sample Size: The manuscript explicitly states that the intended sample size of 30 participants per group could not be reached, leading to an underpowered study, particularly for detecting long-term differences. The final analysis included only 39 participants (19 in the intervention group, 20 in the control group), which is a significant limitation for a randomized controlled trial and impacts the generalizability and statistical robustness of the findings, especially for the three-month follow-up.

Enhance Strategies for Sustained Knowledge Retention and Lifestyle Modification: While immediate knowledge gain was significant, it notably declined after three months. More critically, the one-day seminar failed to induce sustainable lifestyle modifications. The discussion acknowledges this, suggesting a need for follow-up interventions, reinforcement, or a more extended educational program to solidify knowledge and translate it into lasting behavioral changes.

We have expanded the discussion of the limitations of this study and critically address the points raised by the reviewer. “A sampling bias may have influenced the results regarding behavioral changes. Significantly, our educational seminar did not result in behavioral changes three months after the intervention. The greatest changes were expected in areas of behavior that could be improved by the participants with relatively little effort. These were adherence to the medication and the application of UV protection. However, the adherence to treatment reported in the MMSA-4 was already unusually high before the event (92.3 %) and could hardly be improved. This percentage is considerably higher than the 37.9 % [29] and 31.7 % [30] previously reported for other SLE cohorts. This may be partly due to the fact that our cohort of voluntary participants had a particularly high motivation for medication adherence. The same applied to the UV protection recommended for SLE patients, which 97% of patients were already practicing prior to the intervention. There was no further room for improvement in either domain.

There is evidence that an increase in knowledge alone may not be sufficient to lead to behavioral changes. Rather, there is often a so-called “knowledge-behavior gap,” in which knowledge is not translated into corresponding action [31,32]. Lifestyle modifications with regard to smoking, exercise and diet are difficult to achieve even with more intensive interventions [33,34]. It is not surprising that a one-day educational event does not lead to a lasting change in eating, nicotine consumption habits or physical activity. Since this study focused primarily on knowledge acquisition, motivation and emotion were not measured using separate psychometric instruments. Additional motivational strategies are likely to be necessary to bring about lasting behavioral changes.” (lines 440-460)

Refine Assessment to Account for Potential Ceiling Effects: The baseline knowledge score of participants was higher than initially assumed, which the authors identify as a potential "ceiling effect" for the multiple-choice test. This means the assessment might not have been able to fully capture the potential for improvement in a group that already had a relatively good understanding of their disease. Future studies could consider more nuanced or advanced knowledge assessments or target populations with lower baseline knowledge.

We have addressed the reviewer's recommendation in the discussion as follows: “A further major limitation was that the disease-specific knowledge test was self-designed and not validated. To date, there are no validated disease-specific knowledge tests for patients with SLE. An inadequate validation may also have contributed to the higher-than-expected number of correct answers prior to the start of the intervention. Therefore, the baseline knowledge scores were relatively high, thus confining the amplitude of measurable improvement. This ceiling effect significantly limited the ability to measure increases in knowledge and, consequently, the statistical power of the study. In addition, the mean score after completing the questionnaire before the intervention was higher than the assumed 10 points, so that a ceiling effect may have compromised the achievable improvement after the intervention. Future studies could consider more nuanced or advanced knowledge assessments.” (lines 423-433)

Acknowledge and Discuss Sampling Bias More Broadly: The voluntary nature of participation and the exclusion criteria (e.g., high disease activity, severe concomitant disease, mental/cognitive impairment) likely resulted in a highly motivated and relatively healthier patient cohort. This limits the generalizability of the findings to the broader, more diverse SLE patient population, particularly those with more complex needs or lower adherence. Explicitly discussing how this might influence the observed high baseline medication adherence (92.3%) would also be beneficial.

These comments from the reviewer are now addressed in greater detail in the discussion: “A sampling bias may have influenced the results regarding behavioral changes. Significantly, our educational seminar did not result in behavioral changes three months after the intervention. The greatest changes were expected in areas of behavior that could be improved by the participants with relatively little effort. These were adherence to the medication and the application of UV protection. However, the adherence to treatment reported in the MMSA-4 was already unusually high before the event (92.3 %) and could hardly be improved. This percentage is considerably higher than the 37.9 % [29] and 31.7 % [30] previously reported for other SLE cohorts. This may be partly due to the fact that our cohort of voluntary participants had a particularly high motivation for medication adherence. The same applied to the UV protection recommended for SLE patients, which 97% of patients were already practicing prior to the intervention. There was no further room for improvement in either domain.” (lines 440-451)

Improve Clarity in Control Group Methodology: The description of the control group's testing schedule (lines 116-119) can be confusing. While a wait-list control design is clear from Figure 1, the text's phrasing "The control group completed the questionnaire four times: three months before and immediately before the seminar, immediately after the seminar, and three months later" could be rephrased for absolute clarity. It should explicitly state that "the seminar" in this context refers to their later-scheduled intervention, or use consistent time points (e.g., baseline, 3 months, 6 months) relative to the study's start for both groups, specifying when each group received the intervention.

We have made an effort to clarify the methodology. The text now reads as follows: “Both groups filled in the multiple-choice test at baseline after randomization. The intervention group repeated the test immediately after intervention and three months later. The control group repeated the questionnaire after a waiting period of three months immediately before the intervention and immediately after the intervention, and three months later (Figure 1).” (lines 125-131)

In addition, the caption for Figure 1 has been changed. The text now reads as follows: “Study design. Participants were randomized (R) at baseline. Both groups received the intervention (I) consisting of a one-day seminar. Tests (T) on disease knowledge were conducted in both groups at baseline, directly after the intervention and three months after the intervention. The control group had an additional testing after a 3-month waiting period immediately before the intervention.” (lines 140-146)

Incorporate or Justify Lack of Tools for Emotional, Motivational, and Direct Behavioral Responses: The "Highlights" section itself notes that "Assessment tools are needed to record emotional, motivational, behavioral responses to education." While the BIPQ touches on illness perception, the manuscript indicates a gap in directly assessing emotional and motivational changes specifically resulting from the education. Including such tools, or clearly justifying their absence, would strengthen the understanding of why behavioral changes were not observed, beyond just high baseline adherence.

We would agree with the reviewer's suggestion and revise the third sentence of the “Highlights” section. In fact, only the BIPQ was used to measure, at least in part, emotional responses to the intervention. No other instruments were used to assess the participants’ emotions or motivations. We changed the last sentence of the “Highlights” to: “Additional motivational elements might be needed to bring about lasting behavioral changes.” (lines21/22).

Furthermore, we addressed the reviewer's suggestion and added one sentence to the discussion: “Since this study focused primarily on knowledge acquisition, motivation and emotion were not measured using separate psychometric instruments.” (lines 458/459).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

This revision shows strong responsiveness to critique, good scientific maturity, improved discussion framing. The study itself remains limited (small, underpowered, self-designed tool), but it is now appropriately presented and not overstated.

Strength of revision:

Methodology: improved clarity.
Limitations: appropriately strengthened.
Interpretation: more cautious and balanced.
Behavioral science integration: improved.

Remaining issue: Allocation concealment not implemented; This is transparent, but still a methodological weakness.

The manuscript is suitable for publication after minor revision.

Author Response

Comments 1:

Remaining issue: Allocation concealment not implemented; This is transparent, but still a methodological weakness.

The manuscript is suitable for publication after minor revision.

Answer 1:

We thank the reviewer for raising this important point.

We agree that formal allocation concealment procedures (such as central randomization or sequentially numbered, sealed opaque envelopes) were not implemented. Randomization was conducted using externally generated allocation lists by a secretary not involved in patient recruitment, ensuring separation between sequence generation and enrollment. While this approach does not strictly fulfill all criteria for allocation concealment, it substantially reduces the likelihood of selection bias.

This aspect has been clarified in the revised manuscript and acknowledged as a limitation.

Importantly, patient recruitment was conducted consecutively, and baseline characteristics were well balanced between the groups, indicating that any potential impact on group comparability is likely negligible.

We have added the following sentence to the methods section:

“Randomization was performed by an independent secretary not involved in patient recruitment, ensuring separation between sequence generation and enrollment.”

The limitations in the discussion section were supplemented as follows:

“A further methodological consideration relates to allocation concealment. While randomization was conducted using externally generated allocation lists by a secretary not involved in patient recruitment, formal allocation concealment procedures (e.g., central randomization or sequentially numbered, sealed opaque envelopes) were not implemented. Nevertheless, the separation between sequence generation and enrollment, together with consecutive patient recruitment, reduces the likelihood of selection bias. In addition, baseline characteristics were well balanced between the groups, suggesting that any potential impact on group comparability is minimal.”

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript have improved with the revision.

Author Response

Comment:

The manuscript has improved with the revision.

Answer:

We sincerely thank you for your positive assessment of our revised manuscript. We greatly appreciate your time and thoughtful evaluation, and we are pleased that the revisions have improved the work.